DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed July 14, 2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 July 14, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1 – 3, 5 – 9, 11, 12, 15, 18, and 27 – 34 are examined here-in.
Claim Rejections - 35 USC § 103 (Maintained)
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 non-obviousness.
Claims 1 – 3, 5 – 9, 11, 12, 15, 18, and 27 – 34 are rejected under 35 U.S.C. 103 as being unpatentable over Afsharzadeh (Afsharzadeh, M. et al. “PEG-PLA nanoparticles decorated with small-molecule PSMA ligand for targeted delivery of galbanic acid and docetaxel to prostate cancer cells” Journal for Cellular Physiology 2020; 235: p. 4618 – 4630, of record) and Bhat (Bhat, M. et al. “Opportunities and challenges of fatty acid conjugated therapeutics” Chemistry and Physics of Lipids 2021; 236; 105053, of record).
Afsharzadeh teaches an ACUPA-PEG-PLA conjugate as PSMA targeting ligand (abstract, Scheme 1).
Afsharzadeh teaches ACUPA, ((S)-2-3((S)-5-amino-1-carboxypentyl)ureido) pentanedioic acid is a small molecule inhibitor that targets prostate-specific membrane antigen in prostate cancer cells (abstract). Afsharzadeh teaches the conjugation of ACUPA to PEG-PLA leads to self-assembled polymeric nanoparticles that are targeted to prostate cancer cells (abstract).
Afsharzadeh teaches that targeting PSMA is an attractive approach for detection and therapies for primary and metastatic prostate cancer, and may also contribute to minimize drug resistance of cancer to chemotherapeutic drugs because the targeting ligand improves tumor localization and uptake (p. 4619 column 2).
Afsharzadeh teaches the ACUPA-PEG-PLA conjugate nanoparticles contain anticancer drugs galbanic acid and docetaxel (p. 4619 column 2). Afsharzadeh teaches nanoparticles encapsulate, protect, and selectively deliver chemotherapeutic drugs (p. 4619 column 1).
Afsharzadeh teaches that nanoparticles with diameters less than 200 nm tend to be taken up and accumulated within tumor tissue more than in normal tissue: this is known as the EPR effect (p. 4623 column 2). In Afsharzadeh’s work, each ACUPA conjugated nanoparticle had negative zeta potential (p. 4623 Table 1).
Afsharzadeh does not teach conjugation to a fatty acid.
Bhat teaches the missing element of Afsharzadeh.
Bhat teaches that the conjugation of therapeutics to fatty acids leads to enhanced lipophilicity and stability (abstract). Bhat teaches that conjugation of fatty acids to therapeutics is also useful for targeted tumor delivery (abstract).
Bhat teaches that stearic acid, palmitic acid, linoleic acid, squalenoic acid, lauric acid, myristic acid, and docosahexaenoic acid have previously been conjugated to drugs and shown to improve lipophilicity (page 1 column 2 to page 2 column 1). Furthermore, each of the aforementioned fatty acids is naturally occurring and has 4 to 28 carbon atoms (page 2 column 1).
Bhat teaches one method of non-reversible lipidization is via formation of a stable amide bond with fatty acids at the Ɛ-lysyl amino group (page 4 column 1).
Bhat teaches fatty acid-drug conjugates can be delivered via nano-carrier systems including liposomes, micelles, nanoparticles, nano-emulsions, etc (page 14 column 1, page 15 Figure 5).
The combination of Afsharzadeh and Bhat renders claims 1 – 3, 5 – 9, 11, 12, 15, 18, and 27 – 34 prima facie obvious according to MPEP 2143(i)(g) because a person of ordinary skill in the art would be motivated to modify Afsharzadeh’s teaching for an ACUPA-PEG-PLA conjugate to include fatty acid as taught by Bhat because Bhat teaches that the conjugation of therapeutics to fatty acids leads to enhanced lipophilicity and stability, and that these conjugates are compatible with well-known nano-carrier systems (abstract, page 14 column 1, page 15 Figure 5). In other words, a person of ordinary skill in the art would be motivated to modify the teachings of Afsharzadeh with the teachings of Bhat, because Bhat teaches conjugation of therapeutics to fatty acids has several benefits for drug delivery. The modification of a prior art reference motivated by the teachings or suggestions of another is prima facie obvious according to MPEP 2143(i)(g).
The combination of Afsharzadeh’s teaching for ACUPA (which is a PSMA-targeting ligand) conjugation to PEG-PLA (abstract, Scheme 1), with Bhat’s teaching for the conjugation of therapeutics to fatty acids (abstract), such as stearic acid, palmitic acid, linoleic acid, squalenoic acid, lauric acid, myristic acid, and docosahexaenoic acid (page 1 column 2 to page 2 column 1) reads on instant claim 1.
PEG-PLA reads on the linker and/or spacer recited in claim 1. Neither “linker” or “spacer” is explicitly defined in the instant specification, although some examples are described (paragraphs 0005 – 0009, 0067, 0070 – 0073). The instant specification does recite the linker is covalently bound to the PSMA-targeting ligand (paragraph 0061). Since PEG-PLA is covalently bound to ACUPA in Afsharzadeh’s teachings, PEG-PLA reads on the limitation “wherein said linker is PEG”.
Bhat’s teaching for fatty acids such as stearic acid, palmitic acid, linoleic acid, squalenoic acid, lauric acid, myristic acid, and docosahexaenoic acid (page 1 column 2 to page 2 column 1) reads on the recitation of claim 1 “wherein R represents a C5 – C30 alkyl, a C5 – C30 alkenyl, or a C5 – C30 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is optionally substituted” because Bhat’s fatty acids have carbon chains within the range of C5 – C30. Claimed ranges that overlap teachings of the prior art are prima facie obvious according to MPEP 2144.05(i).
The combination of Afsharzadeh and Bhat’s teachings read on the recitation of instant claim 2 “wherein a first portion of said linker is covalently bound to a carbonyl group of the fatty acid derivative, and a second portion of said linker is covalently bound to an Ɛ-amine of the lysine of said PSMA ligand” because Afsharzadeh teaches the PEG-PLA group is bound to the Ɛ-amine of the PSMA ligand (scheme 1) and Bhat teaches a preferred lipidization technique includes a bound between the Ɛ-lysyl amino group (page 4 column 1). Furthermore, Bhat teaches that fatty acid conjugation to a therapeutic molecule is often done on the free carboxylic acid group (page 2 column 1), i.e. the carbonyl group of the fatty acid.
Bhat’s teaching for fatty acids such as stearic acid, palmitic acid, linoleic acid, squalenoic acid, lauric acid, myristic acid, and docosahexaenoic acid (page 1 column 2 to page 2 column 1) reads on the recitation of claim 3 “wherein said fatty acid derivative is a C10 – C30 fatty acid derivative”.
Afsharzadeh teaches the PEG-PLA polymer conjugated with ACUPA has a MW of about 5,000 to about 16,000 Da (page 4619 column 2), overlapping on the instant recitation of between 1,000 and 5,000 Da in claim 5.
Afsharzadeh’s teaching the PEG-PLA group is bound the Ɛ-amine of the PSMA ligand (scheme 1) reads on instant claim 6.
With regards to claim 7, Afsharzadeh teaches that PLA is a commonly used polymer for drug delivery, explaining that it's hydrophobicity is preferably attenuated via conjugation to PEG, which masks the particle’s hydrophobic core and prolongs blood circulation (page 4619 column 1, page 4622 column 2). Afsharzadeh also teaches that PEG-PLA is amphiphilic, with hydrophilic PEG forming a stable, biocompatible shell that can associate with aqueous media and hydrophobic PLA in the core providing stability for organics (page 4622 column 1, page 4628 column 2). Afsharzadeh’s teachings would lead a person of ordinary skill in the art to understand that the hydrophobic nature of PLA allows it to provide stability for organic cargoes. Further, a person of ordinary skill in the art would have the necessary expertise to recognize that fatty acids are also hydrophobic, and thus may be a suitable substitute for PLA in the ACUPA-PEG-PLA conjugate. Although there are many possible reasons to substitute PLA for a fatty acid, one may be that the fatty acids taught by Bhat are naturally occurring and naturally found in the human body, therefore, and ACUPA-PEG-fatty acid conjugate may be more biocompatible than an ACUPA-PEG-PLA conjugate. From a consumer perspective, compounds that are naturally found in the body are also more attractive than synthetic compounds for use in the human body (i.e. consumers prefer “natural” over “synthetic”). Therefore, a person of ordinary skill in the art would be motivated to modify Afsharzadeh’s ACUPA-PEG-PLA conjugate to exclude PLA and instead include a fatty acid as taught by Bhat for an ACUPA-PEG-fatty acid conjugate. The simple substitution of one known element (in this case PLA) for another (in this case a fatty acid) to obtain a predictable result is prima facie obvious according to MPEP 2143(i)(b). As discussed above, a person of ordinary skill in the art would expect an ACUPA-PEG-fatty acid conjugate to self-assemble to form a nanoparticle with a hydrophobic core and hydrophilic shell. The combination of Afsharzadeh and Bhat’s teachings for an ACUPA-PEG-fatty acid conjugate reads on the structure of claim 7 where n is 0.
Bhat’s teaching that fatty acid-drug conjugates can be delivered via nano-carrier systems including liposomes, micelles, nanoparticles, and nano-emulsions (page 14 column 1, page 15 Figure 5) reads on the core/shell nanoparticles of claim 8. Afsharzadeh’s teaching that for an ACUPA-PEG-PLA conjugate, hydrophilic PEG forms a stable, biocompatible shell that can associate with aqueous media and hydrophobic PLA is in the core providing stability for organics (page 4622 column 1, page 4628 column 2) reads on “core comprises a liquid oil” as recited in claim 8. Afsharzadeh’s teaching that the core is hydrophobic would lead a person of ordinary skill in the art to pick a hydrophobic medium for the core, such as a liquid oil.
As written, claim 9’s recitation of “further comprising a PEG-ylated fatty acid” seems to require a PEG-ylated fatty acid in addition to the conjugate of claim 1 and in addition to the liquid oil recited in claim 8. Bhat’s teaching that inclusion of fatty acids in nano-carrier systems such as liposomes, micelles, nanoparticles, and nano-emulsions (page 14 column 1, page 15 Figure 5) contributes to enhanced properties for drug delivery (abstract) would lead a person of ordinary skill in the art to include an additional PEG-ylated fatty acid as required by claim 9. The weight ratio of PEG-ylated fatty acid and liquid oil would be reasonably identified via routine experimentation, which is prima facie obvious according to MPEP 2144.05(ii). A person of ordinary skill in the art would be motivated to experiment with PEG-ylated fatty acid and liquid oil ratios starting with a simple ratio such as 1:1, because a 1:1 ratio is an appropriate starting point to determine if the compounds in question perform most favorably when in equal amounts or if there is an indication that one compound should be in an amount greater than the other.
Afsharzadeh’s teaching for ACUPA-PEG-PLA conjugate nanoparticles containing anticancer drugs galbanic acid and docetaxel (p. 4619 column 2) reads on instant claim 11.
Afsharzadeh’s teaching for nanoparticles with diameters less than 200 nm diameter (p. 4623 column 2) and approximately negative 15 mV zeta potential (p. 4623 Table 1) reads on instant claim 12, which recites a particle size range of 30 to 300 nm and a negative zeta potential between 0.5 and 50 mV. Claimed ranges that overlap teachings of the prior art are prima facie obvious according to MPEP 2144.05(i).
Afsharzadeh’s table 1 also shows ACUPA-PEG-PLA to drug ratios as weight by weight ratios. ACUPA-PEG-PLA-DOC is reported to have a 25:1.25 w/w ratio (p. 4623 Table 1). By the Examiner’s calculations, with PEG-PLA MW of 5,000 g/mol, ACUPA MW of 319.31 g/mol, and Docetaxel MW 807.88 g/mol, a 25:1.25 w/w ratio is approximately a 1:0.32 molar ratio of ACUPA-PEG-PLA to DOC. 0.32 moles of drug per 1 mole ACUPA-PEG-PLA falls within the range of 0.1:1 to 1:1 pharmaceutically active agent to PEGylated-fatty acid as recited in claim 15. As noted above, Afsharzadeh’s teaching for nanoparticles with diameters less than 200 nm diameter (p. 4623 column 2) also overlaps the claimed range of 50 to 200 nm as recited in claim 15. The optional claim limitations “wherein said liquid oil is a fatty acid” and “wherein said composition further comprises an aqueous solution, wherein said plurality of nanoparticles is dispersed within said aqueous solution” are not explicitly taught by Afsharzadeh or Bhat, however, Afsharzadeh’s teaching that hydrophilic PEG forms a stable, biocompatible shell that can associate with aqueous media and hydrophobic PLA is in the core providing stability for organics (page 4622 column 1, page 4628 column 2) would lead a person of ordinary skill in the art to recognize that the particles with PEG in the shell would easily disperse in aqueous solution. Further, as discussed above with regards to claims 7 and 8, Afsharzadeh’s teaching that for an ACUPA-PEG-PLA conjugate, hydrophobic PLA is in the core providing stability for organics (page 4622 column 1, page 4628 column 2) would lead a person of ordinary skill in the art to consider substituting PLA for a fatty acid, and the hydrophobic compound in the core reads on “wherein said liquid oil is a fatty acid” as recited in claim 15.
Afsharzadeh and Bhat’s teachings are each directed to drug delivery, therefore it would be obvious to include a pharmaceutically acceptable carrier as recited in claim 18.
Afsharzadeh teaches the PSMA-conjugate is administered to treat prostate cancer (abstract) and administration of a PSMA-conjugate with anti-cancer drug resulted in cancer cell death (page 4627, Figure 6) reading on instant claims 27 – 30 and 34.
Afsharzadeh teaches PSMA is overexpressed on the surface of cells in prostate cancer as compared to a non-cancerous control (page 4619 column 2), reading on instant claims 31 - 33.
Examiner’s Reply to Attorney Arguments Dated July 14, 2026
Applicant argues that a person of ordinary skill in the art would not be motivated to combine the cited references (Remarks page 7). The Examiner disagrees, because as discussed in the body of the rejection above, a person of ordinary skill in the art would be motivated to modify Afsharzadeh’s teaching for an ACUPA-PEG-PLA conjugate to include fatty acid as taught by Bhat because Bhat teaches that the conjugation of therapeutics to fatty acids leads to enhanced lipophilicity and stability, and that these conjugates are compatible with well-known nano-carrier systems (abstract, page 14 column 1, page 15 Figure 5). In other words, a person of ordinary skill in the art would be motivated to modify the teachings of Afsharzadeh with the teachings of Bhat, because Bhat teaches conjugation of therapeutics to fatty acids has several benefits for drug delivery. The modification of a prior art reference motivated by the teachings or suggestions of another is prima facie obvious according to MPEP 2143(i)(g).
Applicant argues that “starting from Afsharzadeh, a skilled artisan would be solely motivated using polymers… in no way it is reasonable to assume that based on Afsharzadeh, a skilled artisan would consider the instantly claimed fatty acid as the self-assembled moiety responsible for nanoparticle formation (Remarks page 8). The Examiner disagrees, because the rejection is over Afsharzadeh and Bhat. As discussed in the body of the rejection above, a person of ordinary skill in the art would be motivated to modify Afsharzadeh’s teaching for an ACUPA-PEG-PLA conjugate to include fatty acid as taught by Bhat because Bhat teaches that the conjugation of therapeutics to fatty acids leads to enhanced lipophilicity and stability, and that these conjugates are compatible with well-known nano-carrier systems (abstract, page 14 column 1, page 15 Figure 5). Applicants are reminded that a skilled artisan is not an automaton, but a person having ordinary skill in the art of formulating pharmaceutical compositions, i.e. a synthetic chemist of M.D., and is capable of fitting teachings of multiple prior art documents together like pieces of a puzzle. See MPEP 2141.03. Therefore, a skilled artisan would be highly capable of combining the teachings of Afsharzadeh and Bhat to modify Afsharzadeh’s ACUPA-PEG-PLA conjugate to include a fatty acid in order to enhance lipophilicity and stability. Since the cited prior art teaches each of the instantly recited limitations, a prima facie case of obviousness is established.
Applicant argues that “Bhat is solely teaching conjugation of fatty acids to drugs and not targeting ligands” (Remarks page 8) and that Bhat teaches fatty acids as the targeting moiety rather than the PSMA targeting moiety (Remarks page 9). While Bhat may teach the conjugation to small molecule drugs rather than small molecule targeting ligands, the conjugation itself and the conferred properties of enhanced lipophilicity and stability would be the same. Furthermore, although Bhat does not teach fatty acid to the targeting moiety (i.e., the rationale of Applicant), Bhat does give motivation to conjugate small molecules with fatty acids. Therefore, although Applicant’s rationale (conjugation of fatty acid to targeting moiety) is not the same as Bhat’s (conjugation of drug to fatty acid to small molecule drug) according to MPEP 2144(iv) rationale different from Applicant’s is permissible “it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by Applicant”. Therefore, it is the Examiner’s position that a person of ordinary skill in the art would have been motivated to modify Afsharzadeh’s teaching for an ACUPA-PEG-PLA conjugate to include fatty acid as taught by Bhat because Bhat teaches that the conjugation of therapeutics to fatty acids leads to enhanced lipophilicity and stability, and that these conjugates are compatible with well-known nano-carrier systems (abstract, page 14 column 1, page 15 Figure 5). In other words, a person of ordinary skill in the art would be motivated to modify the teachings of Afsharzadeh with the teachings of Bhat, because Bhat teaches conjugation of therapeutics to fatty acids has several benefits for drug delivery. The modification of a prior art reference motivated by the teachings or suggestions of another is prima facie obvious according to MPEP 2143(i)(g).
Applicant argues that Bhat provides no motivation to use fatty acid conjugates as nanoparticle forming building blocks (Remarks page 9). As written, instant claim 8 recites “a composition comprising a plurality of nanoparticles, wherein each of said plurality of nanoparticles comprises a core and a shell, wherein: said shell comprises the conjugate of claim 1; and said core comprises a liquid oil”. As an initial matter, instant claim 8 does not require “fatty acid conjugates as nanoparticle forming building blocks”. Instant claim 8 does not require fatty acid conjugates to be involved in the forming, building, or assembly of the nanoparticle composition, as written instant claim 8 requires the conjugate of claim 1 to be a component of nanoparticle shell. As discussed in the body of the rejection above, the combination of Afsharzadeh and Bhat’s teachings, specifically Afsharzadeh’s teaching that for an ACUPA-PEG-PLA conjugate, hydrophilic PEG forms a stable, biocompatible shell (page 4622 column 1, page 4628 column 2) and Bhat’s teachings that conjugation to fatty acids leads to enhanced lipophilicity and stability, and that conjugation as such is compatible with well-known nano-carrier systems (abstract, page 14 column 1, page 15 Figure 5) reads on the recitation of claim 8 that the conjugate of claim 1 (which includes ACUPA, PEG, and fatty acid) makes up the shell of core/shell nanoparticle. In addition, claim 8 includes “comprising” language, which means additional, unrecited ingredients may be included in the shell or core. According to MPEP 2111.03(i), the transitional term “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements.
Applicant argues that Afsharzadeh’s particles are entirely solid, which is distinct from the claimed nanoparticles of claim 8 which have a liquid core and solid shell (Remarks page 9). As discussed in the body of the rejection above, Afsharzadeh’s teaching that for an ACUPA-PEG-PLA conjugate, hydrophilic PEG forms a stable, biocompatible shell that can associate with aqueous media and hydrophobic PLA is in the core providing stability for organics (page 4622 column 1, page 4628 column 2) reads on “core comprises a liquid oil” as recited in claim 8. Afsharzadeh’s teaching that the core is hydrophobic would lead a person of ordinary skill in the art to pick a hydrophobic medium for the core, such as a liquid oil. For these reasons, the claimed nanoparticles with a liquid core and solid shell recited in claim 8 are prima facie obvious.
Conclusion
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Toriana N. Vigil whose telephone number is (571)270-7549. The examiner can normally be reached Monday - Friday 9:00 a.m. - 5:00 p.m. EST.
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/TORIANA N. VIGIL/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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