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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/9/2025 has been entered.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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 21, 22 and 33-38, 40-41 are rejected under 35 U.S.C. 103(a) as being unpatentable over Liu et al, (Chem. Commun., 2012) in view of Lu et al, (WO 2016/141185), Mook et al (Cancer Gene Ther., 2009), Shah et al (Nature, 2012) as evidenced by Clark et al, (Nat. Genet. 2016), Ding et al, (Materials Sci. and Eng., 2018), Lin et al, (Biomaterials, 2017) and Ngwuluka et al, (AAPS PharmSciTech, 2017). This rejection is maintained for reasons made of record in the Office Actions dated 9/25/2024 and 3/14/2025.
Liu et al teaches a pH activated nanoparticle (Abstract, pg 4869, Scheme 1 and its legend,), comprising a shell comprising a phospholipid bilayer (pg 4869, cols 1-2), and a core comprising carbon dioxide bound to a substrate by a pH sensitive interaction (pg 4869, col 2). Liu teaches treatment of cancer where the drug loaded liposomes significantly circumvented the breast cancer cells resistant to doxorubicin due to enhanced cellular uptake and endosomal escape (pg. 4871; col 2). The teachings of Liu et al are considered to provide sufficient CO2 to disrupt endosomes because such is explicitly taught by Liu on page 4871, second column in the release of doxorubicin from endosomes. Also see page 4869, Scheme 1 and the teaching of doxorubicin release at pH 5.0 by production of CO2 gas.
Liu et al does not teach a TP53 deficient cancer, triple negative breast cancer, wherein the core comprises a POLR2A-targeting siRNA (siPol2), or a calcium carbonate core.
Lu et al teaches methods of treating a patient having a cancer that exhibits a hemizygous loss of the TP53 gene and a hemizygous loss of the POLR2A gene. The methods comprise administering a therapeutically effective amount of a POLR2A inhibitor comprising a nucleic acid that inhibits the expression of a POLR2A protein (¶’s [0005]-[0006]). Moreover, Lu et al teaches the anti-tumor effect of POLR2A inhibition in vivo by Dox-inducible POLR2A shRNA (paragraph [0124]). To test the efficacy of POLR2A silencing in vivo, Lu et al teaches that a nanoliposomal delivery platform was used for systemic delivery of POLR2A siRNAs. Lu et discloses other therapeutic agents for the treatment of breast cancer including paclitaxel and docetaxel gemcitabine, doxorubicin (including morpholino-doxorubicin, (paragraph [0063]). Lu et al discloses liposomal nanoparticles for encapsulation of siRNAs comprising DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine, ¶ [0107]).
Mook et al teaches methods of treating cancer by administration of allele-specific siRNA that can selectively inhibit POLR2A expression in cases of hemizygosity (pg. 533. Col.1). Mook et al teaches that the POLR2A gene is located in close proximity to the tumor suppressor gene p53, which frequently shows loss of heterozygosity (LOH) in cancer cells (abstract). Furthermore, Mook et al discloses SNP-specific siRNAs so as to target selectively the only POLR2A allele remaining in the cancer cells and not the other allele still present in normal cells (introduction, p. 533; col. 1).
Lin et al discloses that the acidic environment of the extracellular pH of tumors can be chosen as a target for treatment and in this acidic milieu, inorganic mineral calcium carbonate (CaCO3) can react with protons and dissolve to form CO2 gas and trigger the release of the encapsulated molecule (page 162, col. 1, para. 1). Lin et al discloses their drug delivery systems comprise Poloxamer 407 (page 155, col.2, para 2).
The claimed methods are essentially disclosed by Liu et al et al with the exception of the TP53 deficient cancer, POLR2A siRNA therapeutic, poloxamer and calcium carbonate substrate limitations. The ordinary skilled artisan, seeking a method to treat cancer, specifically breast cancer, would have been motivated to use the POLR2A siRNA with the liposomal methods of Liu et al because Lu and Mook et al teach such siRNAs to be a well-known type of breast cancer therapeutic that have utility in liposomal-based TP53 deficient breast cancer therapeutics. It would have been obvious for one of ordinary skill in the art to substitute Liu’s pH-sensitive liposome NH4HCO3 substrate with the CaCO3 of Lin et al based on the design of both substrates to produce carbon dioxide from the carbonate group in an acidic environment with a reasonable expectation of success.
It would have been obvious for the skilled artisan to do this because of the known benefit of generating liposomal cancer therapeutics for administration as taught by Liu, Lu, Lin and Mook et al. Given the teachings of the cited references and the level of skill of the ordinary skilled artisan at the time of applicants’ invention, it must be considered, absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Shah et al discloses that primary triple-negative breast cancers (TNBCs), a tumor type defined by lack of estrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers, and is characterized by the accumulation of somatic genetic alterations including inactivation of tumor suppressor genes p53 (also known as TP53), PIK3CA and PTEN (abstract). The POLR2A gene encodes the catalytic subunit of RNA polymerase II which mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life, as evidenced by Clark et al (abstract).
It would therefore have been obvious for one of ordinary skill in the art to select TNBCs as the type of cancer cell to be treated by a pH activated nanoparticle and selectively targeting he POLR2A gene product by delivery of POLR2A siRNAs in cases of hemizygous TNBCs (i.e. partial loss of POLR2A) to increase the efficacy of therapeutics for these types of cancers, as taught by Lu, Liu, Mook and Shah et al. Furthermore, because the POLR2A gene is located in close proximity to the tumor suppressor gene p53, which frequently shows loss of heterozygosity (LOH) in cancer cells according Mook et al, the close proximity of the p53 gene and POLR2A gene should predictably result in mutation or deletion of both p53 and POLR2A genes and loss of heterozygosity in TNBCs with a reasonable expectation of success.
The combined teachings of Liu, Lu, Lin and Mook et al do not teach a substrate comprising chitosan-guanidine (CG), chitosan-arginine (CA) or metformin, or a shell comprising PLGA.
Ding et al teaches that besides proteins, “DNA could also be incorporated into pH-switchable PLGA NPs for controlled release. For example, positively-charged glycol chitosan (GC) was employed to coat hydrophobic PLGA NPs where fluorescent quantum dots (QDs) were encapsulated” (page 1047; col. 1). Ding et al discloses the advantage of using PLGA’s due to their excellent biocompatibility and controllable biodegradability (abstract).
Ngwuluka et al discloses Metformin-loaded solid lipid nanoparticles (SLN) as a chemotherapeutic agent that where optimized, and characterized for particle size, zeta potential, drug entrapment, structure, crystallinity, thermal behavior, morphology, and drug release (abstract).
It would have been obvious for one of ordinary skill in the art to modify Liu’s pH-sensitive liposome substrate with the GC or Metformin substrates or PLGA shell of Ding or Ngwuluka et al based on the design of liposomal cargo (nucleic acids, DNA) or therapy in order to achieve release of encapsulated POLR2A siRNAs and other cancer therapeutics with a reasonable expectation of success.
Claims 21, 22 and 33-41 are rejected under 35 U.S.C. 103(a) as being unpatentable over Liu et al in view of Lu et al, Mook et al, Shah et al as evidenced by Clark et al, Ding et al, Lin et al, and Ngwuluka et al as applied to claims 21, 22 and 33-38, 40 and 41 above, and further in view of Brinker et al (WO 2018/187287). This rejection is maintained for reasons made of record in the Office Actions dated 9/25/2024 and 3/14/2025.
The teachings of Liu, Lu, Lin, Ding and Mook et al are as above and applied as before.
The teachings of Liu, Lu, Lin, Ding and Mook do not teach PLGA that is PEGylated.
Brinker et al discloses a mesoporous silica nano particle (MSNP) core wrapped in a supported lipid bilayer (SLB) (page 2, lines 19-25; Figure 11) and one or more non-integrating vectors (claim 1), wherein lipid bilayer is comprised of various lipids including PEGylated lipids such as PEGylated DOPE or PEGylated DSPE ( claim 24).
It would have been obvious for one of ordinary skill in the art to modify the shell of a pH activated nanoparticle rendered obvious by the combined teachings of Liu, Lu, Ding and Mook et al to incorporate PEGylated PLGA based on the design of PEGylated lipids as taught by Brinker et al for the same or similar purpose, i.e. liposomal drug delivery. It would have been obvious for the skilled artisan to do this because of the known benefit of generating improved biocompatibility and biodegradability liposomal cancer therapeutics for administration as taught by Ding and Brinker et al. Given the teachings of the cited references and the level of skill of the ordinary skilled artisan at the time of applicants’ invention, it must be considered, absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Response to Arguments
Applicant's arguments filed 9/9/2025 have been fully considered but they are not persuasive. Applicants essentially assert that: 1) the substitution rationale for combining Liu, Lu and Mook et al is faulty; 2) none of the cited references teach that an siRNA would work in their system; 3) RNAs are too large, as compared to doxorubicin, to be encapsulated or delivered by liposomes
Regarding 1), a substitution rationale is not relied upon to combine these references. The motivation provided above, i.e. to provide breast cancer therapeutics, is not specifically argued by applicant’s.
Regarding 2) and 3), the combination of references teaches that siRNAs, DNA’s and other nucleic acids are routinely delivered by liposomes, including pH-sensitive liposomes (Lu and Ding et al). Absent any reasoning or evidence as to why pH-sensitive liposomes bearing siRNAs would not perform just as well, if not better, than prior art liposomes for siRNA delivery, applicants opinion is not convincing. Further, Liu et al teaches the broad applicability of their system as not specific to doxorubicin delivery, but rather due to “enhanced cellular uptake” and “endosomal escape”. Contrary to applicants assertions, small (and large) RNAs, DNAs, and nucleic acids in general are routinely encapsulated in or within liposomes and then are delivered to the intended target cell.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
/MICHAEL D BURKHART/ Primary Examiner, Art Unit 1638