DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 9-25-25.
Claims 1-7, 10, 13-30 are pending in the instant application.
Election/Restrictions
Claims 15, 16, 19-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9-25-25.
Applicant’s election without traverse of Group I, claims 1-7, 10, 13, 14, 17, 18, a non-viral payload delivery system, a lipid nanoparticle, a single ionizable lipid N-(2-(cyclohex-1-en-1-ylamino)-1-(1-ethylpiperidin-4-yl)-2-oxoethyl)-N-(heptadecan-9-yl)palmitamide (P6), a single modular lipid, M1, a single first-type nucleic acid construct, [5' UTR]-[nsP1—4]-[SGP]-[GOJ]-[3' UTR]- [Poly A], a single SEQ ID NO, SEQ ID NO:42 and C2623A, wherein a and b are both 7, R3 = H; R4 = substituted heterocyclyl (1-ethylpiperidine); and R5 = carbocyclyl (cyclohexene); M1 is a compound according to Formula VIII: where R1 = sterol; R2 = C₂₄ alkyl; R3 = H; R4 = substituted heterocyclyl (1-ethylpiperidine); and R5 = the structure set forth as the third last structure listed on page 24 of the specification in the replies filed on7-11-25 and9-25-25 is acknowledged.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 17 is 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.
It is unclear whether the nucleotide substitutions recited in 17 a through g refer to mutations in all of the SEQ ID Nos. listed in claim 17, or are individual to each SEQ ID No.
Appropriate clarification is required.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7, 10, 13, 14, 17, 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The breadth of the claims:
The claims are drawn to compositions comprising a first type nucleic acid construct encoding a self-amplifying mRNA (sa-mRNA) or multiple self-amplifying mRNA (sa-mRNA) encoding at least one gene of interest (GOI) or a plurality of GOIs, a second type nucleic acid construct encoding an mRNA encoding at least one virus structural protein; and at least one payload delivery system, wherein the at least one payload delivery system is a non-viral payload delivery system, which payload is at least one nucleic acid construct, which virus structural protein encodes a viral capsid protein, a viral envelope protein, or a combination thereof, which first nucleic acid construct or second nucleic acid construct is a mRNA molecule, which first type nucleic acid construct is a sa- mRNA molecule or multiple sa-mRNA molecules, which non-viral payload delivery system is a lipidoid, a polymer, a core-shell nanoparticle, a nanoparticle mimic, a lipid nanoparticle (LNP), a polymeric nanoparticle, a micelle, liposome, an exosome, a virus-like particle (VLP), a lipoplex, a polyplex, a lipopolyplex, or a microbe, which ionizable lipid optionally comprises P6 of IVe, or salt or isomer thereof, and which LNP optionally comprises the modular lipi,d M1, or a salt or isomer thereof, which first type nucleic acid construct comprises an operably linked nucleic acid sequence comprising from 5' to 3':[5' UTR]-[nsP 1-4]-[SGP]-[GOI]-[3' UTR]-[Poly A] wherein, 5' UTR is a 5' untranslated region, nsP is a plurality of non-structural replicase domain sequences, SGP is a subgenomic promoter, GOI is one gene of interest or a plurality of genes of interest, 3' UTR is a 3' untranslated region, and Poly A is a poly A tail.
Teachings in the specification:
The specification teaches
[000163] While the standard viral genome encodes all the viral proteins required for viral replication, some viral variants contain mutations that result from either small mutations or drastic modifications of the viral genome, which may render the virus unable to complete a full replication cycle, called defective viral genome (DVG) (Vignuzzi, 2019, Nat Microbiol 4: 1075-1087). DVGs play complicated roles on interactions between the host cell and the virus (e.g. Rezelj, et al. 2021, Nat Commun 12: 2290). The oncolytic defective virus used in the experiments described in the following sections was a VEE (TC-83 strain) with a DVG engineered using with the structural proteins deleted for use as a cancer immunotherapy.
[000164] The sa-mRNA used in the experiments described in the following sections was derived from the viral genome of Venezuelan equine encephalitis virus (TC-83) and was engineered by replacing the subgenome that encodes structural proteins for capsids and envelopes with therapeutic payloads, as described in PCT/US2023/066903, which is fully incorporated herein by reference.
[000166] Notably, the composition used in the studies below, composed of LNPs encapsulating sa-mRNA encoding IL12 (SamRNA-IL12; SEQ ID NO: 41) in combination with a modified mRNA encoding the structural proteins from TC-83 strain of VEE (SEQ ID NO: 26), showed over 500x expression of IL12 in the intratumorally injection site compared to mice treated with a negative control (Fig. 3B). Furthermore, the composition of the disclosure dramatically enhanced central memory CD8 T cell presence in the tumor draining lymph node, showing 10x higher numbers of effective CD8 T cells in both tumor-draining lymph node (TDLN) and spleen (Figs. 4B-4C). Consequently, tumor growth was significantly suppressed in mice treated with the composition of the disclosure compared to the negative control (Fig. 5B), with 40-60% of the treated mice being tumor free after a single treatment with the composition of the disclosure. Importantly, the treatment showed reduced side effects such as body weight changes in the treated mice compared to mice treated with the negative control.
[000187] To understand the therapeutic efficacy of the composition of the disclosure on a different cancer type, a similar study was conducted using MC38 colon cancer cells in vivo. Six to eight weeks old C57B6L mice (5 replicates in each group) were subcutaneously inoculated with 0.5 million MC38 colon cancer cells. Seven days post inoculation, the mice were intratumorally injected with PBS as a negative control; an LNP comprising lipid components SV1 and P6 encapsulating SamRNA-mIL12 and a modified mRNA encoding capsid and envelop proteins from VEE virus; an LNP comprising lipid components SV1 and P6 encapsulating a sa-mRNA encoding GOI mIL18 (SEQ ID NO: 53) and a modified mRNA encoding capsid and envelop proteins from VEE virus; or an LNP comprising lipid components SV1 and P6 encapsulating a sa-mRNA encoding mIL18 mutant (SEQ ID NO: 54) and a modified mRNA encoding capsid and envelop proteins from VEE virus.
[000188] To investigate the roles of different capsids/envelops in determining the amplification efficiency for CATP, an evaluation of the capsids/envelops derived from three commonly used alphaviruses, including VEE, Sindbis virus (SIN), and Semliki Forest virus (SFV4) was conducted. Interestingly, the SFV4-derived capsids/envelops exhibited the strongest regression of tumor growth, as shown in Fig. 10B, resulting in a 60% tumor free rate with minimal weight changes, as shown in Fig. 8 and Fig. 10C. These findings suggest that CATP leveraging SFV4 capsids/envelops may generate oncolytic virus-like particles, in coincidence with other researchers' observations of oncolytic effects associated with SFV4 viruses.
[000189] To further enhance therapeutic efficacy, the therapeutic payloads were optimized by combining mouse IL-12 with mouse IL-18, as IL-18 enhances polarizations towards Type 1 inflammation in the presence of IL-12. However, IL-18 binding protein (IL-18BP) has been reported to be upregulated in solid tumors thereby inhibiting IL-18 activity. Therefore, wildtype mouse IL-18 was compared to a mutant form, which was designed to disrupt interactions with IL- 18BP.
000194] A study was conducted to produce sa-mRNA constructs. In one aspect, the first nucleic construct is an sa-mRNA designed using the method described herein. Directed evolution of SAM001 and SAM002 (SEQ ID NOs: 58 and 59 respectively), encoding GFP (SEQ ID NO: 24) and puromycin resistance gene (puromycin) (SEQ ID NO: 68) according to Tables 1-2 below, was performed at different concentrations (1 ug/ml or 10 ug/ml) of puromycin in C2C12 cells for 60 days.
[000195] RNA dependent RNA polymerases are known to have a high error rate, which will cause mutants of SAM002 to appear over time. The SAM002 construct as shown in Fig. 7 was divided into 8 contigs, marked 1-8 on Fig. 7, comprising SEQ ID NOs. 60-67. The 8 overlapping contigs facilitate cloning to a vector form suitable for Sanger DNA sequencing. As shown in Table 1, only 1 mutation was found at nsP4 in 1 ug/ml puromycin. In contrast, there were 6 mutations found in nsP2, nsP3, and nsP4 at 10 ug/ml puromycin. The 6 mutations were in the 2ⁿᵈ, 3ʳᵈ, 4th, 5th contigs. The 6 mutations of SAM002 is numbered as alleles 2, 4, 2, 2 respectively, which could form 32 variants. Tables 3-13 below show 66 variations of nucleic acid templates capable of producing 66 sa-mRNA variations produced using the method described above using SAM001 and SAM002 as immune memory.
[000197] A characterization study was conducted to study the expression level of the 66 sa-mRNA variants identified using the method described above. The 66 sa-mRNA variants were transcribed in vitro and transfected to C2C12 cells using a LNP comprising an ionizable lipid P6 as defined in PCT Patent Application No. PCT/US2023/017777 (P6-LNP), which is fully incorporated herein by reference. The transfected cells were performed by fluorescence-activated cell sorting (FACS) at day 1 and 3 post transfection. The percentages of GFP and mean fluorescent intensities (MFI), representing gene product expression of each variant, were analyzed. The percentage and MFI of GFP at day 3 were normalized compared to the data from day 1. Total RNA of the transfected cells was extracted and reverse transcribed as complementary DNA for quantification polymerase chain reaction (qPCR) by specific probes nsP3 and eGFP.
The specification, prior art and claims do not adequately describe the genus of nucleic acid constructs claimed, and/or fail to provide a representative number of species, and do not indicate what distinguishing attributes are concisely shared by the members of this genus, and further whereby predictable cascade amplifications of therapeutic payloads are obtained predictably in vitro or in vivo.
For the reasons stated above, the instant rejection for lacking adequate written description is proper.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-7, 14, 15, 16 and 18 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Badkar et al (WO 2023/057930).
Badkar et al (WO 2023/057930) teach compositions comprising self-amplifying mRNA (samRNA) comprising a first type nucleic acid construct encoding a self-amplifying mRNA (sa-mRNA) or multiple self-amplifying mRNA (sa-mRNA) encoding at least one gene of interest (GOI) or a plurality of GOIs, and nucleic acid construct encoding an mRNA encoding at least one virus structural protein; and at least one payload delivery system, wherein the at least one payload delivery system is a non-viral payload delivery system, which payload is at least one nucleic acid construct, which virus structural protein encodes a viral capsid protein, a viral envelope protein, or a combination thereof, which first nucleic acid construct or second nucleic acid construct is a mRNA molecule, which first type nucleic acid construct is a sa- mRNA molecule or multiple sa-mRNA molecules, which non-viral payload delivery system is a lipidoid, a polymer, a core-shell nanoparticle, a nanoparticle mimic, a lipid nanoparticle (LNP), a polymeric nanoparticle, a micelle, liposome, an exosome, a virus-like particle (VLP), a lipoplex, a polyplex, a lipopolyplex, or a microbe, 5' UTR is a 5' untranslated region, nsP is a plurality of non-structural replicase domain sequences, SGP is a subgenomic promoter, GOI is one gene of interest or a plurality of genes of interest, 3' UTR is a 3' untranslated region, and Poly A is a poly A tail (see esp. the abstract, pages 9-11, 25, 26, 28-30, 46-48, 51, 83-84, 107).
Claim(s) 1-7, 14, 15, 16 and 18 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Caramella et al (US 11,576,961).
Caramella et al (US 11,576,961) teach compositions comprising self-amplifying mRNA (samRNA) comprising a first type nucleic acid construct encoding a self-amplifying mRNA (sa-mRNA) or multiple self-amplifying mRNA (sa-mRNA) encoding at least one gene of interest (GOI) or a plurality of GOIs, a second nucleic acid construct encoding an mRNA encoding at least one virus structural protein; and at least one payload delivery system, wherein the at least one payload delivery system is a non-viral payload delivery system, which payload is at least one nucleic acid construct, which virus structural protein encodes a viral capsid protein, a viral envelope protein, or a combination thereof, which first nucleic acid construct or second nucleic acid construct is a mRNA molecule, which first type nucleic acid construct is a sa- mRNA molecule or multiple sa-mRNA molecules, which non-viral payload delivery system is a lipidoid, a polymer, a core-shell nanoparticle, a nanoparticle mimic, a lipid nanoparticle (LNP), a polymeric nanoparticle, a micelle, liposome, an exosome, a virus-like particle (VLP), a lipoplex, a polyplex, a lipopolyplex, or a microbe, 5' UTR is a 5' untranslated region, nsP is a plurality of non-structural replicase domain sequences, SGP is a subgenomic promoter, GOI is one gene of interest or a plurality of genes of interest, 3' UTR is a 3' untranslated region, and Poly A is a poly A tail (see esp. col. 1-12, 16, 63, 67-85, 91-161).
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Jane Zara
3-17-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
Prosecution Insights