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 .
Application Status
This action is written in response to applicant’s correspondence received on 06/08/2026. Claims 1-19 are currently pending. Claims 14-19 are withdrawn from prosecution as being drawn to nonelected
subject matter. Accordingly, claims 1-13 are examined herein.
Election/Restrictions
Claims 14-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being
drawn to a nonelected Groups II & III, there being no allowable generic or linking claim. Accordingly, claims 1-13 are examined herein. The restriction requirement mailed on 04/08/2026 is still deemed proper. Applicant's elected Group I without traverse in the reply filed on 06/08/2026.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
This application is a 371 of PCT/US2022/015604 filed on 02/08/2022, which has PRO 63/186,899 filed on 05/11/2021, and PRO 63/147,371 filed on 02/09/2021.
Drawings
The drawing is objected to because 37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG.”. In the current case, the view number for Figure 1 is preceded by the word "Figure" instead of the abbreviation "FIG.".
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the terms Ciaramella, BioNTech, Pfizer, New England Biolabs, Promega, TriLink, Avanti Polar Lipids, Sigma, Jackson Laboratories, IDT, Luminex, Gibco, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 3 & 4 are objected to because of the following informalities: Missing “.” at the end of the claims. Each claim is required to begin with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations, see MPEP §608.01(m).
Appropriate correction is required.
Claim 8 is objected to because of the recitation “…nucleotide sequences that encode …further encodes …”. The recited “encodes” should be “encode” based on the plural form of “sequences”.
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:
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.
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 1, 3-6, 13 are rejected under 35 U.S.C. 103 as being unpatentable over Ruth (WO920813, published on 02/06/1992), in view of Sarnow (US5766903, issued on 06/16/1998). The rejection of claim 3 is evidenced by Moore (Methods Mol Biol. 1999;118:11-9).
Claim interpretation: The recitation “optionally” and “and/or” are interpreted that the limitations “optionally comprising nucleotide sequences encoding one or more linkers or spacers” and “and/or a Kozak sequence” are not required.
Ruth (1992) teaches a single stranded circular nucleic acid comprising between 30 and 2200 nucleotides (Page 40, Claim 16). The range “between 30 and 2200 nucleotides” reads on the claimed range of “comprising 30 to 3300 nucleotides” in the instant claim 1. Ruth further teaches circularizing one linear polynucleotides into circular polynucleotides (Page 12, lines 16-19; Figure 3L), and describes circularizing 2 or more linear polynucleotides (Page 13, lines 10-14; Figure 3N). Some embodiments fall within the range circularizing between 1 and 40 synthetic single-stranded oligonucleotide sequences ligated together (Page 12, lines 34) using T4 DNA ligase (Page 29, lines 16). Despite that Ruth teaches cloning the circular polynucleotides into vectors for producing RNA, DNA, and polypeptides in vitro and in vivo (Page 24, lines 20-34), Ruth does not teach any example of circular RNA (circRNA) and using it as a “vaccine vector” comprising both one “coding region” comprising nucleotide sequences encoding at least one “immunogen” and a “non-coding region” comprising an “internal ribosome entry site (IRES)”.
However, Sarnow (1998) teaches a circular RNA, i.e. circRNA (Front page, Abstract, lines 2-3) comprising an internal ribosome entry site (IRES) element that engages a eukaryotic ribosome (Claim 1), instead of encoding a polypeptide or RNA, i.e. being non-coding (FIG. 2, IRES is outside of the coding region between the initiator codon AUG and the termination codon UAA; Claim 18; Column 7, lines 56-57; Column 17, 2nd ¶), and comprising an RNA coding sequencing encoding a polypeptide (Claim 13; FIG. 2, the region between AUG and UAA codons). Sarnow further teaches the embodiment of delivery the circRNA as a vaccine (Column 14, lines 28-29), i.e. as a vaccine vector, by encoding immunogenic “antigen” (Claim 17), i.e. immunogen.
Regarding claim 1, it would have been obvious to persons having ordinary skills in the art (PHOSITAs) before the effective filing date of the claimed invention to have modified the circular polynucleotide taught by Ruth by incorporating the detailed elements taught by Sarnow to achieve the functions of a known vaccine vector structure in a circRNA embodiment. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results, because of the same structures and congruent outcomes using circRNA as a vector for delivery of encoded immunogenic polypeptides. One would have been motivated to do so because Sarnow demonstrates functional examples and support circRNA vectors can be used to translate multi-cistronic polypeptides, including immunogenic antigens (Examples 1-5). One would have reasonable expectation of success because of the known functions associated with the known circRNA structure.
Regarding claim 3, the recitation “wherein ligation does not introduce extraneous RNA fragments containing dsRNA” is explained in the specification as ligation of one or multiple short oligonucleotides using T4 ligase, which does not introduce extraneous double-stranded (ds) RNA fragments containing immune-activating dsRNA (Page 5, lines 26-30). Both Ruth (Page 29, lines 16; Page 30, line 19) and Sarnow (Column 16, Example 2, line 31) use T4 DNA ligase to circularize linear single stranded polynucleotides (RNA in the case of Sarnow). As evidenced by Moore (1999), using T4 DNA ligase to connect the 5’ monophosphate (P) and the 3’ hydroxyl (-OH) of the linear RNA termini, brought together by a splint DNA oligonucleotide complementary to both termini, have been long demonstrated in the art, “because this enzyme is specific for nicks in double-stranded duplexes, production of undesired side products is kept to a minimum”. There is no possibility of introducing extraneous RNA fragments containing double stranded RNA (dsRNA) formation when using T4 DNA ligase because the covalent bond formed between the 5’ P and the 3’-OH, under the catalysis of T4 DNA ligase, does not involve introducing extraneous nucleotides, as evidenced by Moore (Page 15, Figure 1). Hence, Ruth and Sarnow both teach the claimed circRNA vaccine vector of claim 1, wherein ligation does not introduce extraneous RNA fragments containing dsRNA.
Regarding claim 4, Sarnow (1998) teaches a strategy of eliminating stop codon immediately following the open reading frame (ORF) of the coding region in the circRNA (EMCV-ORF-IRES/VP3; Column 15, 2nd ¶) to determine if continuous translation is feasible and proves it (Column 18, Example 5, last 2 lines), resulting in “extremely long protein species” (Column 18, line 39).
Regarding claim 5, Ruth (1992) teaches in Figure 3, the embodiment N of circularizing two or more nucleic acid fragments (o and p in Figure 3) and describes between 15-1100 bases in length (Page 5, line 24). Combined with the teachings of Sarnow, at least some embodiments can be circRNAs comprised of two or more, within the claimed 1-40, synthetic RNA oligonucleotide sequences, each with a length in the range of 40-150 nucleotides.
Regarding claim 6, Sarnow further teaches that the IRES element “is at least about 250 base pairs in length” (Claim 9), 250 is within the claimed “300 or fewer nucleotides” range.
Regarding claim 13, Sarnow further teaches a delivery vehicle embodiment of “liposome” (Column 2; 4th ¶, line 29).
Claims 2 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Ruth (1992), in view of Sarnow (1998), further in view of CuraVac (US20190040378A1, published on 02/07/2019; Listed on IDS filed on 08/07/2023), as evidenced by NCI Dictionary of Cancer Terms (Print listed in PTO-892; www.cancer.gov/publications/dictionaries/cancer-terms/def/cytotoxic-t-cell; Accessed in 2026).
The teachings of Ruth (1992) and Sarnow (1998) have been discussed above as applied to claims 1, 3-6, 13, and are applied here in. Neither Ruth nor Sarnow teaches at least one immunogen encoded by the circRNA of claim 1 induces cell-mediated immunity in at least one cell type selected from the group consisting of immunogen-specific CD4+ T cells and immunogen-specific CD8+ killer T cells.
However, Fotin-Mleczek (2019) teaches that a circRNA construct encoding “T helper Epitopes (TH)” is used as a vaccine vector and it induces cell-mediated immunity in both CD4+ T helper (Th) cells and CD8+ cytotoxic T lymphocytes (CTLs; Page 94, ¶[0141]). As evidenced by National Cancer Institute Dictionary of Cancer Terms, CTLs are also known as killer T cells (NCI_2026_Dictionary of Cancer Terms_Definition of CTL.pdf is attached and listed in PTO-892 form). Fotin-Mleczek further teaches that the circRNA encoding at least one tumor antigen (Page 150, ¶[0788]).
Regarding claim 2, it would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have modified the circular polynucleotide taught by Ruth and Sarnow to further augment and refine the vaccine vector features of the circRNA based on the teachings of Fotin-Mleczek. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results because of the same structures and congruent outcomes using circRNA as a vaccine vector for delivery of encoded immunogens. One would have been motivated to do so because Fotin-Mleczek demonstrates functional examples proving that circRNA vaccine vectors can induce specific immune responses in vivo (Pages 149-154; Examples 1-4). One would have reasonable expectation of success because of the known functions associated with the known circRNA structure.
Claims 7, 9 are rejected under 35 U.S.C. 103 as being unpatentable over Ruth (1992), in view of Sarnow (1998), further in view of Atabekov (US8257945B2, Issued on 0904/2012).
The teachings of Ruth (1992) and Sarnow (1998) have been discussed above as applied to claims 1, 3-6, 13, and are applied here in. Neither Ruth nor Sarnow teaches the source options of the IRES.
However, Atabekov (2012) teaches that a 148-nucleotide region upstream of the CP gene of crTMV RNA contained an internal ribosome entry site (IRESCP148; Column 3, lines 13-17, 27-32), as well as 228- and 75-nt regions upstream of the MP gene of crucifer-infecting Tobamovirus (crTMV) and TMV U1 RNAs contained IRES elements (IRESMP 75CR or IRESMP 228CR; Column 3, 3rd ¶, lines 1-3).
Regarding claim 7, it would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have modified the circular polynucleotide taught by Ruth and Sarnow to further refine the size and source of the non-coding IRES region to optimize the structure and efficiency of the circRNA vaccine vector based on the teachings of Atabekov (2012). It would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results because of the same structures and congruent outcomes using IRES-dependent RNA translation to optimize the gene expression performance of a vaccine vector. Optimizing the size and gene expression levels of a vector is routine in the art. One would have been motivated to do so because Atabekov demonstrates examples proving that novel short IRES sequences from Tobacco mosaic tobamovirus (TMV) and crRMV enable efficient gene expression (Columns 11, 12; Examples 1-3). One would have reasonable expectation of success because of the known functions associated with IRES.
Regarding claim 7, Atabekov teaches a 148-nucleotide IRES, and a 75-nucleotide IRESMP 75CR, both of which are within the claimed “150 or fewer nucleotides” range.
Regarding claim 9, Atabekov teaches crTMV IRES (Column 3, 3rd ¶, lines 1-3).
Claims 8, 11, 12 are rejected under 35 U.S.C. 103 as being unpatentable over Ruth (1992), in view of Sarnow (1998), further in view of Sette (US7888472B2, issued on 02/15/2011) and Ciaramella (US20190008938A1, published on 01/10/2019; Listed on IDS filed on 08/07/2023).
The teachings of Ruth (1992) and Sarnow (1998) have been discussed above as applied to claims 1-7, 9, 10, 13, and are applied here in. Neither Ruth nor Sarnow teaches the coding region comprising nucleotide sequences encoding one or more linkers or spacers, which further encode a peptide cleavage site or structural peptide linker, or that the coding region encodes a plurality of peptide immunogens, wherein the peptide immunogens are separated by linkers comprising peptide cleavage sites or structural peptide linkers.
However, Sette (2011) teaches the concept of “Immunodominance” in designing multiepitope vaccines because only a small fraction of the many thousand possible peptides that are encoded by a complex foreign pathogen ends up in a peptide form capable of binding to MHC Class I antigens and thus of being recognized by T cells (Column 2, 3rd ¶). Sette further teaches structural peptide linkers in the coding region of a claimed multi-epitope nucleic acid and peptide vaccines wherein a plurality of peptide immunogens are separated by linkers comprising structural peptide linkers (FIG. 9A-9C; SEQ ID NOs: 222-224), e.g. GAAA, NAAA, KAAA, etc. Sette does not teach linkers comprising peptide cleavage sites or a linker-less peptide concatemer.
However, Ciaramella (2019) teaches “an mRNA cancer vaccine, comprising: an mRNA having an open reading frame encoding a concatemeric cancer antigen comprised of 2-100 peptide epitopes, … interspersed by cleavage sensitive sites; or the mRNA encoding each peptide epitope is linked directly to one another without a linker…” (Claim 1).
Regarding claim 8, it would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have modified the circular polynucleotide taught by Ruth and Sarnow to further incorporate structural linkers in the coding region between multiple immunogens based on the teachings of Sette (2011) such that the chance of stimulating cognate immune cell can be increased thereby improving the immunogenicity of a vaccine vector for augmented immunodominance in T cell-based immune response. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results because of the same structures and congruent outcomes using multi-epitope immunogen translation to augment the immunodominance of the vaccine vector. Diversifying the immunogen expression of a vaccine vector to improve immunodominance is known in the art. One would have been motivated to do so because Sette demonstrates effective examples improving the immune response both in vitro and in vivo (Examples 1-3). One would have reasonable expectation of success because of the known functions of multi-epitope vaccines associated with the multi-linker structures, as Ciaramella (2019) provides independent support for such a well-established structure-function association involving structural linkers or cleavage sites. Although neither Sette nor Ciaramella uses circRNA as the base structure, since Sarnow teaches circularizing linear RNA to form circRNA without modifying the internal structures of single stranded linear RNA molecule (Front page, Abstract, line 6; Column 17, Example 3), all the linear structural teachings from Sette and Ciaramella can be readily incorporated into the circRNA structure and provide the same level of reasonable expectation for success for simple combinations of known techniques that lead to predictable results, because linear RNAs are simply the precursors of circRNAs taught by Sarnow (Fig. 1).
Regarding claim 11, Sette further teaches a coding region of the vaccine vector encoding a plurality of peptide epitopes or immunogens, wherein the peptide immunogens are separated by structural peptide linkers, such as GAAA, KAAA, NAAA, etc (FIG. 9A-9C; SEQ ID NOs: 222-224). In addition, Ciaramella teaches “peptide epitopes, … interspersed by cleavage sensitive sites …” (Claim 1).
Regarding claim 12, Ciaramella further teaches alternative embodiments wherein “the mRNA encoding each peptide epitope is linked directly to one another without a linker…” (Claim 1).
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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