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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 23, 2024 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 Objections
Claims 1 and 2 are objected to because of the following informalities:
In claim 1 on line 2, “wherein said covalently bound is via a linker” should be re-written as “wherein said covalent bond is via a linker” or “wherein said covalently bound fatty acid is via a linker”.
In claim 1, lines 5 - 6 and 9 – 10 each contain the phrase “wherein the wavy bond represents and attachment point to the linker”. At present, the repetition of this phrase does not appear necessary and may confuse the reader, so the Examiner recommends that one of these repeated phrases should be deleted.
In claim 1, line 7 “Formula” should be named. For example “Formula A” or “Formula 3” to avoid confusion with “Formula I” as recited in claim 1 and “Formula 2” as recited in claim 7.
In claim 1 on line 10 “liker” should be “linker”.
In line 2 of claim 2, there appears to be a space before and after the comma. The space before the comma should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 11, 15, 33, and 34 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 11 recites the limitation "the pharmaceutically active agent". Claim 11 depends on claim 9, which does not recite a pharmaceutically active agent - claim 9 recites an active agent (not a pharmaceutically active agent). There is insufficient antecedent basis for the limitations "the pharmaceutically active agent" in claim 11.
Claim 15 recites the limitation "the pharmaceutically active agent" and “the PEG-ylated fatty acid”. Claim 15 depends on claim 12, which does not recite a pharmaceutically active agent or a PEG-ylated fatty acid. Claim 12 depends on claim 8, which does not recite a pharmaceutically active agent or a PEG-ylated fatty acid. Claim 9, which is not in the chain of dependency of claims 12 and 15, recites an active agent (not a pharmaceutically active agent) and a PEG-ylated fatty acid. There is insufficient antecedent basis for the limitations "the pharmaceutically active agent" and “the PEG-ylated fatty acid” in claim 15.
Claim 33 recites the limitation "said prostate cancer". Claim 33 depends on claim 32, which does not recite prostate cancer. Claim 32 depends on claim 27, which does not recite prostate cancer. Claim 30, which is not in the chain of dependency of claims 32 and 33, recites prostate cancer. There is insufficient antecedent basis for the limitation "said prostate cancer" in claim 33.
Claim 34 recites the limitation "said cancer". Claim 34 depends on claim 27, which does not recite cancer. There is insufficient antecedent basis for the limitation "said cancer" in claim 34.
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 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) and Bhat (Bhat, M. et al. “Opportunities and challenges of fatty acid conjugated therapeutics” Chemistry and Physics of Lipids 2021; 236; 105053).
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 instantly claimed linker.
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’s teachings for PSMA bound to PEG reads on the recitation “wherein said linker comprises PEG” of instant claim 3.
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.
Conclusion
All claims are rejected. No claims are allowed.
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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