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 7-30-26.
Claims 1-7, 10, 13-30 are pending in the instant application.
Claims 15, 16, 19-30 are withdrawn as being drawn to a non-elected invention or species.
Claims 1-7, 10, 13, 14, 17, 18 have been examined on their merits as set forth below.
Response to Arguments and Amendments
Withdrawn Rejections/Objections
Any objections or rejections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
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 for the reasons of record set forth in the Office action mailed 3-30-26, and as set forth below.
Applicant’s Arguments
The written description requirement is satisfied here for at least three reasons under either prong of the test. First, Example 6 identified 66 variations of nucleic acid templates capable of producing 66 samRNA variations that can be used as the first type nucleic acid construct of the composition of independent claim 1.
Second, numerous self-amplifying mRNAs, 5' untranslated regions, non-structural replicase domain sequences, subgenomic promoters, therapeutic GOIs, 3' untranslated regions and poly A tails are known in the art and "[i]nformation which is well known in the art need not be described in detail in the specification." MPEP §2163.II.A.2.
Paragraph [0221] of the specification…, which describes self-amplifying mRNAs, including the samRNAs used throughout the working examples of the instant application. Paragraph [0220] of the specification incorporated by reference several references with describe the standard viral genome and all the viral proteins required for viral replication (including nsP1-4 and virus structural proteins), furthermore, an exemplary nsP1-4 sequence is provided in the specification. Paragraph [0059] of the specification incorporated by reference U.S. Pat. No. 6,592,874, which describe subgenomic promoters and techniques for modifying them. The other components of the composition for cascade amplifications of therapeutic payloads (CATP) of the invention are also known in the art. For example, paragraph [0051] define "virus structural protein" as referring to a viral capsid protein, a viral envelope protein, a fragment thereof or a complex thereof and identifies several viruses that are known to be naturally enveloped (including, but not limited to Retroviridae, Coronaviridae, Herpesviridae, Hepadnaviridae, and Orthomyxoviridae). The nucleic acid and amino acid sequences of thousands of structural virus proteins are known in the art.
Additionally, paragraph [0070] of the specification…, which describe lipid nanoparticle compositions, a type of non-viral payload delivery system. Furthermore, paragraphs [0064] and [0065] of the specification describe delivery systems known in the art that can be used in the claimed composition. In short, the specification as filed, when read in view of the knowledge common to those skilled in the art and with the teachings of the incorporated-by-reference material included, lists hundreds and thousands of representative species such that a representative number of such species are described.
Furthermore, the examined claims are directed to a novel composition for cascade amplifications of therapeutic payloads comprising three components, one of which is a sa-mRNA, rather than to novel samRNAs. As discussed above, each component of the composition is described in the specification as filed using a representative number of species and reference to the prior art.
Third, each subheading in claim 1 (e.g., a first type nucleic acid construct encoding a sa- mRNA or multiple sa-mRNAs encoding at least one GOI or a plurality of GOIs) is the very same "structural features common to the members of the genus" that MPEP 2163 tells us constitutes and adequate written description. In other words, claim 1-all by itself, even if not a single word of the rest of the specification were not present-constitutes an adequate written description of the claimed invention.
Response to Applicant’s Arguments
The breadth of the claims:
The claims are broadly 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 of any viral structural protein; and at least one payload delivery system, comprising any non-viral payload delivery system, optionally comprising at least one nucleic acid construct, which virus structural protein optionally encodes a viral capsid protein, a viral envelope protein, or a combination thereof, which first nucleic acid construct or second nucleic acid construct is optionally 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 optionally 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 lipid 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…
[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.... 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...
Contrary to Applicant’s assertions, the specification, prior art and claims do not adequately describe the broad 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 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 properly maintained.
New Rejections
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.
Claim(s) 1-7, 14, 15 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Badkar et al (WO 2023/057930) and Caramella et al (US 11,576,961), the combination in view of Chavez et al (USPN 11,427,931) and R. Leeson (Viral Vectors 101: Systemic Capsids (2023)).
The claims are drawn to compositions for cascade amplifications of therapeutic payloads (CATP) comprising: a) 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; b) a second type nucleic acid construct encoding an mRNA encoding at least one virus structural protein; and c) at least one non-viral payload delivery system, 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].
Badkar et al (WO 2023/057930) teach compositions comprising nucleic acid constructs comprising self-amplifying mRNA (samRNA) or multiple self-amplifying mRNA (sa-mRNA) encoding at least one gene of interest (GOI) or a plurality of GOIs, and mRNA encoding at least one virus structural protein and at least one non-viral payload delivery system, which virus structural protein optionally encodes a viral capsid protein, which nucleic acid constructs comprise a mRNA molecule, a 5' UTR, a plurality of non-structural replicase domain sequences, a subgenomic promoter, 3' UTR, and a poly A tail (see esp. the abstract, pages 9-11, 25, 26, 28-30, 46-48, 51, 83-84, 107).
Caramella et al (US 11,576,961) teach compositions comprising nucleic acid constructs comprising mRNA 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 a nucleic acid encoding an mRNA encoding at least one virus structural protein and at least one non-viral payload delivery system, which payload is at least one nucleic acid construct, which virus structural protein encodes a viral capsid protein, which non-viral payload delivery system optionally comprises a polymer, a lipid nanoparticle (LNP), or a liposome, and which nucleic acid construct comprises a 5' UTR, a plurality of non-structural replicase domain sequences, a subgenomic promoter, one gene of interest or a plurality of genes of interest, a 3' UTR and a poly A tail (see esp. col. 1-12, 16, 63, 67-85, 91-161).
The primary references do not teach separate vectors for the first type and second type nucleic acid constructs.
Chavez et al (USPN 11,427,931) teach separate vectors expressing viral capsid proteins (see esp. bridging paragraph, columns 17 and 18, first paragraph column 18; bridging paragraphs, col. 22-23; last full paragraph, col. 27).
R. Leeson (Viral Vectors 101: Systemic Capsids (2023)) teaches dual expression vectors with one vector encoding a capsid protein (see page 3, “Dual expression” section).
It would have been obvious to design and optimize compositions for cascade amplifications comprising separate vectors or plasmids with one comprising self-amplifying mRNA encoding one or more genes of interest and further comprising a 5’ UTR, one or more non-structural viral proteins, a subgenomic promoter, the gene of interest, a 3’ UTR and a poly A tail because self-amplifying mRNA, and the components listed above, of the UTR’s, Poly A tail, promoter, and non-structural viral proteins were all taught in the prior art and routinely used for the expression of one of more genes of interest, as disclosed by . One would have been motivated to express viral structural proteins, including capsid or envelope proteins, on a separate vector or plasmid because the prior art taught the use of dual expression vectors for allowing promoters, genes of interest, etc to take up precious cargo space for expression in viral vectors, while dual expression systems accommodate larger, modular genetic payloads, as taught previously by Leeson. One of ordinary skill in the art would have reasonably expected dual vectors to enhance expression of genes of interest in target cells of interest, relying on the combined teachings of Badkar , Caramella, Chavez and Leeson.
For these reasons, the instant invention would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
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.
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Jane Zara
9-17-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
