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 .
DETAILED ACTION
2. Claims 1 – 2, 5 – 6, 16 – 17, 29 – 30, 34 – 38, 40, 43 – 45, 50, 70, 83, 132, and 143 are pending in this application. Applicant’s preliminary amendment, filed June 20, 2023, is entered, wherein claims 1 – 2, 5 – 6, 16 – 17, 34 – 38, 40, 43 – 45, 50, 70, 83, 132, and 143 are amended and claims 3 – 4, 7 – 15, 18 – 28, 31 – 33, 39, 41 – 42, 46 – 49, 51 – 69, 71 – 82, 84 – 131, 133 – 142, and 144 are canceled.
Priority
3. This application is a continuation application of PCT/US21/28486, filed April 21, 2021, which claims benefit of domestic applications 63/013,456 and 63/020,473, filed April 21, 2020 and May 5, 2020, respectively.
Election/Restrictions
4. Applicant’s election without traverse of group IV, claims 29 – 30, 34 – 38, 40, 50, 70, 83, and 143, drawn to a self-amplifying expression system, filed November 7, 2025, is acknowledged. The following species was elected by Applicant without traverse in the reply filed on November 7, 2025, with claims 29 – 30, 34 – 38, 40, 50, 70, 83, and 143 reading on the elected species:
(i) A specific compound of formula (I) or formula (II) with its corresponding substituents recited in claims 1 – 2, 5, 38, and 40:
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Claims 1 – 2, 5 – 6, 16 – 17, 43 – 45, and 132 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected invention, there being no allowable generic or linking claim.
Therefore, claims 29 – 30, 34 – 38, 40, 50, 70, 83, and 143 are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/20/2025 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 30 and 50 are objected to because of the following informalities:
Claim 30, line 7, “,” should be replaced with “and”.
Claim 50, line 10, “and” should be inserted immediately after “combination thereof;”. Appropriate correction is required.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
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 29 – 30, 34 – 37, 50, 70, 83, and 143 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (US20190134184A1) in view of Rabideau et al. (WO2019/036682A1).
a. Regarding claims 29 – 30, 34 – 37, 50, 70, 83, and 143, Yu et al. teach a self-replicating RNA molecule (also referred to as a self-amplifying mRNA, or SAM molecule) comprising the construct (para. [0012]), which is useful as components of immunogenic compositions (para. [0009]). The self-amplifying mRNA (SAM) background consists of VEE TC-83 replicon encoding the viral nonstructural proteins 1 – 4 (nsP1-4), followed by the subgenomic promotor, and either Zika prME or Zika CprME. Yu et al. disclose a SAM-Zika construct (Fig 5):
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wherein the construct is from 5’ to 3’ and has a 5’m7G-ppp cap followed by endogenous non-coding regions of a flavivirus genome, followed by nonstructural genes of the flavivirus genome followed by a subgenomic promotor operably linked to nonstructural proteins prME (para. [0032]). The 5’ end of the RNA may be capped with a modified ribonucleotide with the structure m7G(5’) ppp(5’) N (cap 0 structure) or a derivative thereof, wherein the 5’cap of the RNA molecule may be further modified by a 2’-O-Methyltransferase which results in the generation of a cap 1 structure (m7Gppp[m2’-O] N) (para. [0079]). Modified nucleobases which can be incorporated into modified nucleosides and nucleotides and be present in the RNA molecules include m5U (5-methyluridine) and m6A (N6-methyladenosine) (para. [0081]). Non-naturally occurring forms of polypeptides may comprise one or more heterologous amino acid sequences (e.g. another antigen sequence, another signal sequence, a detectable tag, or the like) in addition to a Zika virus prME antigen sequences. For example, a polypeptide may be a fusion protein (para. [0071]). The nucleic acid may comprise one or more heterologous nucleic acid sequences (e.g. a sequence encoding another antigen and/or a control sequence such as a promotor or an internal ribosome entry site (para. [0077]). A self-replicating RNA molecule may have a 3’ poly-A tail (para. [0090]). The self-replicating RNA molecule may encode a single heterologous polypeptide antigen (i.e. a Zika virus prME antigen) (para. [0094]). In some embodiments, a method is provided for inducing an immune response against a Zika virus infection in a subject in need thereof comprising administering to the subject an immunologically effective amount of a composition comprising one or more of the constructs, vectors, or self-replicating RNA molecules (para. [0020]).
However, Yu et al. do not explicitly teach that N1 is a modified adenosine, N2 is a uridine or modified uridine.
Rabideau et al. teach RNA polymerase variants, which increases transcription efficiency while reducing the number of double-stranded RNA contaminants and run-on transcripts produced during an in vitro transcription reaction (Abstract). Rabideau et al. disclose methods of capping a mRNA with cap analogs, such as trinucleotides, co-transcriptionally in an in vitro transcription assay using a T7 RNA polymerase variant described. In some embodiments, greater than 90% of the RNA produced includes a functional cap, and the RNA produced does not elicit a substantial cytokine response, even in the absence of post-IVT purification (page 3, para. 5; page 4, para. 1). The cap analog is m7GpppA2’OMepU (page 12, para. 3).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the self-amplifying RNA constructs as taught by Yu et al., which encode antigens such as Zika prME or CprMe and incorporate elements like 5’ capping and m6A modifications with the capping methods using trinucleotide cap analogs in view of Rabideau et al. because Yu et al. disclose that modified nucleobases such as m6A and m5U may be incorporated into RNA, and that the 5’ end may include a cap structure to improve RNA function and immunogenicity and Rabideau et al. teach that co-transcriptional capping of RNA using trinucleotide cap analogs improves transcription efficiency and reduces undesirable double-stranded RNA byproducts. One would have been motivated to combine the self-amplifying RNA constructs as taught by Yu et al., which encode antigens such as Zika prME or CprMe and incorporate elements like 5’ capping and m6A modifications with the capping methods using trinucleotide cap analogs in view of Rabideau et al. because the combination will further enhance the transcription yield and capping efficiency of the SAM RNA product as disclosed by Rabideau et al. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to combine the self-amplifying RNA constructs as taught by Yu et al., which encode antigens such as Zika prME or CprMe and incorporate elements like 5’ capping and m6A modifications with the capping methods using trinucleotide cap analogs in view of Rabideau et al. because Rabideau et al. disclose the trinucleotide capping approach that would improve the efficiency and quality of the RNA products disclosed by Yu et al., thereby rendering the claimed combination obvious.
Claims 38 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (US20190134184A1) in view of Rabideau et al. (WO2019/036682A1) as applied to claims 29 – 30, 34 – 37, 50, 70, 83, and 143 above, and further in view of Brown (Wiley-Vch, Cop, 2012, Reference included with PTO-892).
b. Regarding claims 38 and 40, Yu et al. and Rabideau et al. teach the limitations discussed above.
However, these references do not teach the elected species:
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Brown teaches that one of the most common monovalent isosteric replacements is the substitution of hydrogen with fluorine. These atoms have similar van der Waals radii but different electronic effects, fluorine being the most electronegative element in the periodic table. Due to the high strength of the C-F bond, fluorine is often introduced to achieve metabolic stability (page 17, 2.3.1 Monovalent Atoms and Groups, para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the H of Methyl in m7GpppA2’OMepU as taught by Rabideau et al. with F in view of Brown because Brown teaches that -F is the most common replacement for hydrogen. One would have been motivated to substitute the H of Methyl in m7GpppA2’OMepU as taught by Rabideau et al. with F in view of Brown because Brown teaches that the introduction of F will lead to metabolic stability. Such substitution will yield predictable and improved results. Therefore, a person of ordinary skill in the art would have had a reasonable expectation of success to substitute the H of Methyl in m7GpppA2’OMepU as taught by Rabideau et al. with F in view of Brown because Rabideau et al. teach the trinucleotide capping analog and Brown teaches that the replacement of H by F will lead to predictable and improved products.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 29 – 30, 34, 50, 70, and 83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 5, 50, 52, 70, and 75 of copending Application No. 18/658,604 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘604 anticipates the claimed invention.
a. Independent claim 29 is directed to a self-amplifying expression system, wherein the self-amplifying expression system comprises a self-amplifying backbone, wherein the self-amplifying backbone comprises one or more polynucleotide sequences of a self-replicating RNA virus; and wherein the self-amplifying expression system comprises a nucleic acid sequence, wherein each element is linked from 5’ to 3’, described by the formula:
m7G-ppp-N1-N2-Nv,
wherein m7G is a 7-methylguanylate (m7G) cap, ppp is a triphosphate bridge, N1 is a first nucleotide of the self-amplifying backbone corresponding to a first endogenous 5’nucleotide of the self-replicating RNA virus, N2 is a second nucleotide of the self-amplifying backbone corresponding to a second endogenous 5’nucleotide of the self-replicating RNA virus, and Nv comprises (1) one or more additional nucleic acid sequence of the self-amplifying backbone, and (2) a cassette comprising at least one exogenous nucleic acid sequence for delivery, and wherein the cassette is operably linked to the self-amplifying backbone. Dependent claim 30 is directed to the composition, wherein the composition for delivery of the self-amplifying expression system comprises (A) the self-amplifying expression system, wherein the self-amplifying expression system comprises one or more self-amplifying mRNA (SAM) vectors, wherein the one or more SAM vectors comprise: (a) the self-amplifying backbone, wherein the self-amplifying backbone comprises: (i) at least one promotor nucleotide sequence and (ii) at least one polyadenylation (poly(A)) sequence; and (b) the cassette. Dependent claim 34 is directed to the composition, wherein N1 is a modified nucleotide. Dependent claim 50 is directed to the composition, wherein the at least one exogenous nucleic acid sequence for delivery comprises: (i) the polypeptide-encoding nucleic acid sequence, wherein the polypeptide-encoding nucleic acid sequence encodes (a) the antigen-encoding nucleic acid sequence, wherein the antigen-encoding nucleic acid sequence comprises an epitope capable of stimulating a B cell response and (b) a full-length protein or functional portion thereof. Dependent claim 70 is directed to the composition, wherein the self-replicating RNA virus is a flavivirus. Dependent claim 83 is directed to the composition, wherein the at least one promotor nucleotide sequence is a native promotor nucleotide sequence encoded by the self-replicating RNA virus, optionally wherein the native promotor nucleotide sequence is a subgenomic promotor nucleotide sequence.
‘604 teaches a composition for delivery of a self-expression system comprising a single-stranded RNA (ssRNA) vector, wherein the ssRNA vector comprises a m7G cap, a poly(A) tail, a self-amplifying backbone, and one or more modified nucleosides, wherein the self-amplifying backbone comprises a polynucleotide that is a self-replicating RNA virus, such as alphavirus; the ssRNA vector is produced by in vitro transcription, wherein the m7G cap analog comprises a trinucleotide m7G-ppp-A-U cap analog; the ssRNA vector comprises a cassette comprising at least one nucleic acid sequence for delivery, wherein the at least one nucleic acid sequence comprises a polypeptide-encoding nucleic acid sequence, wherein the polypeptide-encoding nucleic acid sequence is an antigen-encoding nucleic acid sequence, wherein the cassette is operably linked to or operably inserted into the self-amplifying backbone; the self-amplifying backbone comprises a polynucleotide that is a self-replicating RNA virus comprising at least one nucleic acid sequence from 5’ to 3’, described by the formula:
m7G-ppp-N1-N2-Nv,
wherein m7G is a 7-methylguanylate (m7G) cap, ppp is a triphosphate bridge, N1 is a first nucleotide of the self-amplifying backbone corresponding to a first endogenous 5’nucleotide of the self-replicating RNA virus, N2 is a second nucleotide of the self-amplifying backbone corresponding to a second endogenous 5’nucleotide of the self-replicating RNA virus, and Nv comprises (1) one or more additional nucleic acid sequence of the self-amplifying backbone, and (2) a cassette comprising at least one nucleic acid sequence for delivery, and wherein the cassette is operably linked to the self-amplifying backbone (claims 2, 50, and 52). The one or more modified nucleosides comprises m5C, m6A, 2’-O-Me, s2U, and m5U (claims 5 and 52). The composition for delivery of the self-amplifying expression system comprises the self-amplifying expression system, wherein the self-amplifying expression system comprises one or more self-amplifying mRNA (SAM) vectors, wherein the one or more SAM vectors comprise (a) the self-amplifying backbone, wherein the self-amplifying backbone comprises the nucleic acid sequence, wherein the self-amplifying backbone sequence comprises a subgenomic promoter nucleotide sequence and a poly(A) sequence, and the cassette comprises at least one antigen-encoding nucleic acid sequence comprising an epitope-encoding nucleic acid sequence (claim 70). The at least one nucleic acid sequence for delivery comprises the polypeptide-encoding nucleic acid sequence, wherein the polypeptide-encoding nucleic acid sequence encodes an epitope capable of stimulating a B cell response or the polypeptide-encoding nucleic acid sequence encodes a full-length protein or functional portion thereof (claim 75).
For these reasons above, ‘604 anticipates the claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693