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 .
Status of the Claims
In the reply filed 6/17/25, Applicants amended claims 1-3, 10, 11, 15-17 and 65.
Claims 1-8, 10-17, 19-22 and 65 are pending.
Claims 1-8, 10-17, 19-22 and 65 are under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/28/23 was considered by the examiner.
Claim Objections-Withdrawn
The objection to claims 1-3, 16, 17 and 65 is withdrawn due to amendment of the claims.
Claim Rejections - Withdrawn
The rejection of claims 10-17 and 19-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn due to amendment of the claims.
Claim Rejections - 35 USC § 103-NEW
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Kotha et al. (WO2015/042585) in view of Alferiev et al. (US2013/0296285) and Qi et al. (“Multishelled hollow micro-/nanostructures” Chemical Society Reviews Issue 19, 2015) as evidenced by Eftekhari et al. (Phys. Chem. Chem. Phys, 2020, 22, 2238-2248).
Kotha et al. teach multilayered nanoparticles for transfecting cells. Kotha et al. teach the nanoparticles are designed for improved serum stability, targeted delivery to specific cell types, greater nuclear specificity and compartment specific unpackaging, improved ability to retain specificity, improved ability to retain significant payload levels during initial stages of internalization and ability to maintain release of payload for a various durations following internalization [0025]. Kotha et al. also states that it should be understood that the specific examples, while indicating embodiments of the invention are given by way of illustration only and are not by way of limitation and various substitutions, modifications, additions and/or arrangement within the spirit and/or scope of the inventive concept will be apparent to those with ordinary skill in the art [0024]. With respect to claim 1, Kotha et al. teach a nanoparticle comprising a core polyplex and a silica coating thereon; wherein said core polyplex comprises an anionic polymer, a cationic polymer, a cationic polypeptide and a nucleotide (claim 1), meeting the limitation of “a core comprising a first payload, wherein the first payload comprises a a nucleic acid and/or protein”. With respect to a “first sheddable layer encapsulating the core”, Kotha et al. teach silica coatings of polyplexes may seal their payloads before and during initial cellular uptake and commonly used polyplexes consisting of poly(ethylenimine) and DNA have a tendency to shed the majority of their payloads during cellular internalization, with the remaining payload often remaining bound to its cationic nanocarrier’s polymeric remains. Kotha et al. teach with transiently stabilizing interlayers of silica, greater intracellular delivery efficiency may be observed [0028]. Kotha et al. teach the nanoparticle may comprises a reversible coating that provides stability to the polyplex core prior to cellular or compartmental internalization, preventing premature degradation or destabilization. For example, the silica coating may be applied to the polyplex core [0035].
With respect to an intermediate layer comprising a second payload, wherein the second payload comprises a nucleic acid and/or a protein wherein the intermediate layers surrounds the first sheddable layer”, Kotha et al. teach a polymer comprising a layer attached to the external surface of the coated core polyplex may comprise a polymer, a polypeptide or polynucleotide sequence that exhibits base pair complementarity or binding affinity for an amino acid sequence binding motif to bind additional layers that may be added thereupon [0037]
With respect to “a second sheddable layer surrounding the intermediate layer”, Kotha et al. teach stabilizing interlayers of silica results in greater intracellular delivery efficiently may be observed despite decreased probability of cellular uptake [0028]. Kotha et al. teach further coating of silica coated nanoparticles with poly(arginine) causes nanoparticles to be stable in serum and causes extended residence of nanoparticles payload within cells [0051]. Kotha et al. teach that no aggregation of nanoparticles containing an additional layer on the outside of the silica coating indicating that such nanoparticles remain stable in serum [0051].
With respect to (i) an anionic polymer composition, (ii)a cationic polymer composition and (iii) a cationic polypeptide composition, Kotha et al. teach a core polyplex comprises an anionic polymer, a cationic polymer, a cationic polypeptide and a nucleotide (claim 1). With respect to the limitation “wherein (a) the anionic polymer composition comprises polymers of D-isomers and an anionic amino acid and polymers of L-isomers of an anionic amino acid; and/or (b) the cationic polymer composition comprises polymers of D-isomers of a cationic amino acid and polymers of L-isomers of a cationic amino acid. Kotha et al. teach in one example, a cationic polymer may comprise a poly(arginine), such as poly(L-arginine), in another example, a cationic polymer may comprise a D-isomer of poly(arginine) or of any of the foregoing polymers such as polypeptide which may be particularly advantageous because polymers containing D-isomers may be less susceptible to degradation within a cell and therefore have prolonged effect on influencing payload release and the rate thereof over time [0032]. Kotha et al. teach in another example, an anionic polymer may comprise a D-isomer of any of the foregoing polymers or polypeptides, which may be particularly advantageous because polymers such as polypeptides containing a D-isomer may be less susceptible to degradation within a cell and therefore have a prolonged effect on influencing payload release and the rate thereof over time [0033].
Kotha et al. does not teach (a) the anionic polymer composition comprises polymers of D-isomers and an anionic amino acid and polymers of L-isomers of an anionic amino acid; and/or (b) the cationic polymer composition comprises polymers of D-isomers of a cationic amino acid and polymers of L-isomers of a cationic amino acid. However, the teachings of Alferiev et al. cure this deficiency.
Alferiev et al. teach nanoparticles (abstract) comprising poly(L-glutamic acid)[00381].
It would have been obvious to a person before the effective filing date of the invention to modify the nanoparticle of Kotha et al. to include poly(L-glutamic acid) as taught by Alferiev et al. One of ordinary skill in the tart would have been motivated to do so in order to provide a superior method to retain the payload within the nanoparticle for extended periods of time [0022]. There is a reasonable expectation of success given that Kotha et al. teach multiple polymers as the payload.
Kotha et al. also does not teach an example of a second sheddable layer. However, the teachings of Qi et al. cure this deficiency.
Qi et al. teach multi-shelled nanostructured materials are advantageous (para. 4.6). Qi et al. teaches successful fabricated multi-shelled hollow silica nanospheres by shell-by-shell assembly which could be used in dual-modality for imaging as well as drug co-delivery vectors. Qi et al. also teach the synthesis of multi-shelled hollow silica spheres with mesoporous shells and further investigated their applications in drug loading and releasing, in which triple- and double-shelled hollow silica exhibit a higher capacity of loading ibuprofen (IBU) than their single-shelled counterparts (para. 4.6).
It would have been obvious to a person of ordinary skill in the art to provide a second silica layer to the nanoparticle of Kotha et al. because Qi et al. teach that the silica multishelled nanoparticles exhibited a higher payload capacity compared to the single shelled counterparts. There is a reasonable expectation of success given that the multilayered silica nanoparticles comprising were successfully fabricated and could be used in dual modality for imagining and drug co-delivery vectors.
With respect to claims 2 and 3, Kotha et al. teach Fig. 1A, wherein an anionic polymer maybe be a polypeptide containing anionic amino acids, for example poly-glutamic acid or poly-aspartic acid or a polypeptide that comprises any combination of the foregoing. Kotha et al. teach polymers consisting of or including a D-isomer of glutamic acid may be particularly advantageous because they may be less susceptible to degradation within the cell and therefore have a prolonged effect on influencing payload release and the rate over time (p. 8). Kotha et al. teach the cationic polymer may be a poly(arginine), poly(lysine), poly(histidine), poly(ornithine), poly(citriline) or a polypeptide that comprises any combination of the more than one of the foregoing [0031]. Kotha et al. also teach the cationic polymer may comprising poly(arginine) such as poly(L-arginine). The cationic polymer may comprise a D-isomer of poly(arginine) or of any of the foregoing polymers which are advantageous because polymers such as polypeptide containing D-isomers may be less susceptible to degradation within a cell and will therefore have a prolonged effect on influencing payload release and the rate thereof over time [0032].
With respect to claims 4 and 5, Kotha et al. does not explicitly teach the ratio of D-isomers to L-isomers, however Kotha et al. is suggestive of the limitation. The ratio of D to L-isomers in the polymer is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). In the instant case, Kotha et al. teach the amount of L and D-isomers is a result driven variable because polymers comprising D-isomers are less susceptible to degradation and. Therefore, a person of ordinary skill in the art would be motivated the ratio in order to prepare a nanoparticle with the least susceptibility to degradation. It would have been obvious and routine experimentation to a person of ordinary skill in the art to look to the teachings of Kotha et al. with a reasonable expectation of success to optimize the ratio of D and L-isomers in the cationic and anionic polymer, to arrive at the ratios of claims 4-5.
With respect to claims 6-8, Kotha et al. teach the sheddable coat is silica [0005,0028] and claim 1. As evidenced by the instant specification, silica is acid labile, meeting the limitation of pH sensitive [PGPUB0383]. As evidenced by Eftekhari et al., silica nanoparticles are negatively charged in a pH range between 2 and 14 (top of p. 2240).. Please note that MPEP 2131.01 states: that an extra reference or evidence can be used to show an inherent characteristic of the thing taught by the primary reference. In the instant case, the reference is relied upon only to establish that silica meets the limitation of anionic coat.
With respect to claims 10-13, Kotha et al. teach the nanoparticle may comprise a layer of polymers attached to or electrostatically bound with the external surface of coated polyplex, such as to or with the external surface of a silica coating [0036]. Kotha et al. teach examples of polymer comprising a polymer layer attached to the external surface of the coated core polyplex include those represented by SEQ ID NO: 4, which is an approximately 10 kDa poly(arginine) polymer, and SEQ ID NO: 5, which is human vasoactive endothelial growth factor protein [0037]. A polyarginine polymer meets the limitation of “cationic component”. Kotha et al. teach the external polymers may serve to prevent cellular repulsion of the coated polyplex so as to promote contact with and uptake by a cell and may serve to promote internalization by specific cell types [0036]. It would have been obvious to a person of ordinary kill in the art to optimize the surface coat in order to create a nanoparticle that is taken up and internalized by the desired cell type and meeting the limitations of claim 13. There is a reasonable expectation of success given that Kotha et al. teach many different polymers for attachment to the silica coat.
With respect to claims 14-16, Kotha et al. teach the polymers comprising a layer attached to the external surface of the silica may comprise an anchor substrate from 1 to 25 repeating anionic or cationic moieties at the N-terminus, C-terminus, 5', or 3' end of a polymer, polypeptide, or polynucleotide to provide electrostatic conjugation of a targeting motif contained in the polymer, polypeptide, or polynucleotide to the coated polyplex core [0037]. Kotha et al. teach examples of polymer comprising a polymer layer attached to the external surface of the coated core polyplex include those represented by SEQ ID NO: 4, which is an approximately 10 kDa poly(arginine) polymer [0037]. Kotha et al. teach layering silica-coated polyplex cores with polymers specifically directed to bind to particular cell types can further enhance uptake. Associating ligands for cellular receptors with the surface of a nanoparticle can enhance affinity of the nanoparticle for cells that express such receptors and increase transfection of such cells. Kotha et al. teach silica-coated polyplexes were coated with VEGF (SEQ ID NO: 5), a high-affinity ligand for VEGF receptors, which are expressed at high levels by human umbilical vein endothelial cells (HUVECs). VEGF would meet the limitation of targeting ligand [0053]. It would have been obvious to a person of ordinary skill in the art to optimize the anchoring domain and targeting domain in order to target the desired cell type. A person of ordinary skill in the art would have a motivation optimize the polyarginine domain resulting in a domain comprising SEQ ID NO: 15 because Kotha et al. teach from 1 to 25 repeating anionic or cationic moieties and teaches an example of poly(arginine). There is a reasonable expectation of success given that polyarginine of different lengths are known linkers.
Claims 1-17 and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Kotha et al. (WO2015/042585) in view of Alferiev et al. (US2013/0296285) and Qi et al. (“Multishelled hollow micro-/nanostructures” Chemical Society Reviews Issue 19, 2015) and Friedman et al. (“The Smart targeting of Nanoparticles” Curr Pharm Des. PMC 2014 May 10) as evidenced by Eftekhari et al. (Phys. Chem. Chem. Phys, 2020, 22, 2238-2248).
The teachings of the references are presented in detail above. The references do not teach cationic anchoring domain is conjugated to the targeting ligands via a linker. However, the teachings of Friendman et al. cure this deficiency.
Friendman et al. teach the challenges of nanomedicine is how to selectively deliver nanoparticles to diseased tissues (Abstract). Friendman et al. teach that functionalizing nanoparticles is a widely used technique that allows for conjugation with targeting ligand which posses inherent ability to direct selective binding to cell types and therefore confer “smartness” to the nanoparticles (Abstract). Friedman et al. teach many conjugation techniques, such as those exploiting lysine side chain amines and cysteine sulfhydryl groups yield heterogeneous mixtures of targeting nanoparticles (p. 5, 4th para.). Friedman et al. teach ligands can be engineered further to contain a primary amine for conjugation through a flexible linker, such as PEG for targeted delivery (p. 4, 1st para.).
It would have been obvious to conjugate the targeting ligands via a linker, such as a peptide because Friendman et al. teach smart nanoparticles with targeting ligands conjugated via a linker. A person of ordinary skill in the art would have a motivation to use a peptide linker comprising a cysteine and conjugation via a sulfhydryl because Freidman et al. teach many conjugation techniques, such as those exploiting lysine side chain amines and cysteine sulfhydryl groups yield heterogeneous mixtures of targeting nanoparticles. There is a reasonable expectation of success given that conjugation techniques including sulfhydryl are well known and routine in the art.
Claims 1-16 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Kotha et al. (WO2015/042585) in view of Alferiev et al. (US2013/0296285) and Qi et al. (“Multishelled hollow micro-/nanostructures” Chemical Society Reviews Issue 19, 2015) and Duskey et al. (“Nanoparticle Ligand Presentation for Targeting Solid Tumors” AAPS PharmSciTech. 2014; 15(5):1345-1354) as evidenced by Eftekhari et al. (Phys. Chem. Chem. Phys, 2020, 22, 2238-2248).
The teachings of the references are presented above in detail. The references do not teach the targeting ligands provides for targeted binding to a family B G-protein coupled receptor (GPCR). However, the teachings of Duskey et al. cure this deficiency.
Duskey et al. teach nanoparticles for delivery of drugs or gene cargos to tumor cells (Introduction). Duskey et al. teach that targeted nanoparticles for cancer treatment have many hurdles, including overcoming unwanted biodistribution to the liver while maximizing delivery to the tumor. Duskey et al. examines ligands that have been most used to target nanoparticles to solid tumors (Abstract). Duskey et al. teach bombesin is a 14 amino acid peptide that targets GPCR family neuromedin B and GRPR. Bombesin receptors are upregulated in tumor cell membranes including breast, prostate, small cell lung and pancreatic cancer (p. 1349, bottom of 2nd col.).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention to optimize the targeting sequence to target a GPCR such as neuromedin B in order to target cancers such as breast, prostate and pancreatic cancer cells. There is a reasonable expectation of success given that Duskey et al. teach the bombesin 14 amino acid sequence specifically targets the neuromedin B.
Claims 1-16 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Kotha et al. (WO2015/042585) in view of Alferiev et al. (US2013/0296285) and Qi et al. (“Multishelled hollow micro-/nanostructures” Chemical Society Reviews Issue 19, 2015) and Mali et al. (“RNA guided human genome engineering via Cas9” Science, 2013 ;339(6121):823-826) as evidenced by Eftekhari et al. (Phys. Chem. Chem. Phys, 2020, 22, 2238-2248).
In addition to the teachings above, Kotha et al. teach nanoparticle may comprise other types of polynucleotides or analogs thereof, such as species of RNA or DNA including mRNA, siRNA, miRNA, aptamers, shRNA, AAV-derived nucleic acids, morpholino RNA, peptoid and peptide nucleic acids, cDNA, DNA origami, DNA and RNA with synthetic nucleotides, DNA and RNA with predefined secondary structures and CRISPR sequences [0057]. However, Kotha et al. does not disclose the RNA encodes a programmable gene editing protein (i.e. Cas9).
Mali et al. discloses CRISPR-Cas9 gene editing in mammalian cells using DNA encoding Cas9 and a guide RNA (Abstract). It would have been obvious to a person of ordinary skill in the art to before the effective filing date of the invention to use the mRNA encoding Cas9 as taught by Mali et al. in order to achieve genome editing in the target cell. There is a reasonable expectation of success given the routine use of both plasmid and mRNA formats for Cas9 delivery.
Conclusion
No claims are allowed.
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/TARA L MARTINEZ/Examiner, Art Unit 1654