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
Claims 1-12, 15-16, 18-19, 21, 26, 28, 32-33 are under consideration.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/07/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(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 26 and 28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the Specification, while being enabling for treating a SARS-CoV-2 infection, does not reasonably provide enablement for preventing SARS-CoV-2 or its variants, Delta and Omicron infection. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Here, instant claim 26 is broadly drawn to a method for preventing or treating a SARS-CoV-2 infection in an individual, comprising administering to the individual an effective amount of the circRNA of instant claim 1. The full scope of the term ‘preventing’ also reads upon complete prevention or prophylaxis of SARS-CoV-2 infection. Instant claim 28 further limits claim 26, wherein the SARS-CoV-2 infection is caused by Delta or Omicron variant of SARS-CoV-2.
The level of skill in the art is high and would include, e.g., Ph.D. level scientists, physicians. Liu et al (Liu)(14 Nov 2021) conducted a systematic review and meta-analysis on the effectiveness and safety of SARS-CoV-2 vaccines. Liu found that the vaccine effectiveness or “VE” did not support 100% prevention alone or with a booster. Liu teaches “For the first dose of SARS-CoV-2 vaccines, the pooled VE was 41% (95% CI: 28-54%) for the prevention of SARS-CoV-2 infection, 52% (95% CI: 31-73%) for the prevention of symptomatic COVID-19, 66% (95% CI: 50-81%) for the prevention of hospital admissions, 45% (95% CI: 42-49%) for the prevention of ICU admissions, and 53% (95% CI: 15-91%) for the prevention of COVID-19-related death” (p. 4-5, Table 1). Liu also teaches “For the second dose of SARS-CoV-2 vaccines, the pooled VE was 85% (95% CI: 81-89%) for the prevention of SARS-CoV-2 infection, 97% (95% CI: 97-98%) for the prevention of symptomatic COVID-19, 93% (95% CI: 89-96%) for the prevention of hospital admissions, 96% (95% CI: 93-98%) for the prevention of ICU admissions, and 95% (95% CI: 92-98%) for the prevention of COVID-19-related death (Table 1). VE was 94% (95% CI: 78-98%) in ≥ 21 days after the second dose for the prevention of SARS-CoV-2 infection, higher than other subgroups, regardless of 2 dose group (p. 4-5, Table 1). For the prevention of symptomatic COVID-19, VE was also relatively higher in 21 days after the second dose (99%, 95% CI: 94-100%). Liu further teaches “In the fully vaccinated groups (over 14 days after the second dose), the pooled VE was 85% (95% CI: 80-91%) for the prevention of Alpha variant of SARS-CoV-2 infection, 54% (95% CI: 35-74%) for the Gamma variant, and 74% (95% CI: 62-85%) for the Delta variant. There was only one study…focused on the Beta variant, which showed the VE was 75% (95% CI: 71-79%) for the prevention of the Beta variant of SARS-CoV-2 infection. BNT162b2 vaccine had the highest VE in each variant group; 92% (95% CI: 90-94%) for the Alpha variant, 62% (95% CI: 2-88%) for the Gamma variant, and 84% (95% CI: 75-92%) for the Delta variant” (p. 6).
With respect to the Omicron variant, Karim et al. (Karim)(11 Dec 2021) teaches “The principal concerns about omicron include whether it is more infectious or severe than other VoCs and whether it can circumvent vaccine protection. Although immunological and clinical data are not yet available to provide definitive evidence, we can extrapolate from what is known about the mutations of omicron to provide preliminary indications on transmissibility, severity, and immune escape. Omicron has some deletions and more than 30 mutations, several of which (eg, 69–70del, T95I, G142D/143–145del, K417N, T478K, N501Y, N655Y, N679K, and P681H) overlap with those in the alpha, beta, gamma, or delta VoCs. These deletions and mutations are known to lead to increased transmissibility, higher viral binding affinity, and higher antibody escape. Some of the other omicron mutations with known effects confer increased transmissibility and affect binding affinity. Importantly, the effects of most of the remaining omicron mutations are not known, resulting in a high level of uncertainty about how the full combination of deletions and mutations will affect viral behaviour and susceptibility to natural and vaccine-mediated immunity”(p. 2126) .
As such, there appears to be a high degree of unpredictability for the prevention of SARS-CoV-2 infection, to include the Delta and Omicron variants.
The Specification exemplifies mouse immunization/challenge studies with the circRNA such as in Figures 2A-2O, macaque immunization/challenge studies for SARS-CoV-2 infection such as in Figures 5A-5J, and vaccination studies of mice for serum interrogation for neutralization assays with the SARS-CoV-2 pseudovirus (VSV-based SARS-CoV-2 (Delta) or (Omicron) such as in Figures 12 and 13. The Specification, however, does not include any human clinical trial data. Whilst animal studies can provide valuable data and generally precede human clinical trials, they are generally not seen as a replacement for human clinical trials. Winkler et al. (Winkler)(April 2021) teaches “Animal COVID-19 models should ideally provide a full recapitulation of COVID-19 pathophysiology represented by an array of the clinical phenotypes and their sequelae and be widely available. Current high demand for experimental animals exceeds capacity of commercial breeders impeding the investigative progress and verification of the existing findings. The limited lethality across SARS-CoV-2/COVID-19 models constitute a critical shortcoming (Fig, 1, Table 2). To maximize translational value, several key model design elements need to be contemplated: i) severe COVID-19 phenotypes (short and long-term), ii) aged animals as they correspond to the most commonly affected patient demographic, iii) the most frequent COVID-19-related comorbidities (e.g. diabetes, obesity, cardiovascular), iv) sex effects. The lack of those components fails to provide an adequate clinical outcome match-up with the most severe COVID-19 patients” (p. 4).
Thus, an undue amount of experimentation, including extensive human clinical trials, would still be required to use the invention based on the content of the disclosure.
Taken together, the Specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with the claims.
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.
Claims 15, 18 are 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.
See claims 15, 18 as submitted 07/08/2024.
Claim 15: The phrase, “comprising a polyAC or polyA sequence disposed at the 5’ end of the IRES sequence is unclear. It is unclear what meaning is being attributed to “disposed”.
Claim 18: The phrase, “comprising a 3’ exon sequence recognizable by a 3’ catalytic Group I intron” is unclear. It is unclear what “recognizable” means in the context of the exon sequences and the intron fragments.
Claim Rejections - 35 USC § 103
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.
Claims 1-3, 7-8, 10, 12, 16, 21, 26, 28 are rejected under 35 U.S.C. 103 as being unpatentable over Qu et al. (Qu)(See PTO-892 Notice of References Cited) in view of Kumar et al. (Kumar) (See PTO-892 Notice of References Cited).
See claims 1-3, 7-8, 10, 12, 16, 21, 26, 28 as submitted 07/08/2024.
Regarding claims 1, 2, and 3, Qu teaches a circular RNA (circRNA) vaccine that encodes the trimeric RBD of SARS-CoV-2 spike protein (p. 1, Abstract). Qu also teaches variant construct - circRNA vaccine encoding RBD/K417N-E484K-N501Y derived from the B.1.351/501Y.V2 variant, termed as circRNARBD-501Y.V2. Qu further teaches “the coding sequence of circular RNA can be quickly adapted to deal with any emerging SARS-CoV-2 variants, such as the recently reported B.1.1.7/501Y.V1, B.1.351/501Y.V2, and P.1 variants” (p. 8).
Regarding claims 7 and 8, Qu teaches The signal peptide sequence of human tissue
plasminogen activator (tPA)…was fused to the N-terminus of RBD to ensure the secretion
of antigens, and the trimerization motif of bacteriophage T4 fibritin protein (foldon)…was fused
to its C terminus, mimicking the natural conformation of SARS-CoV-2 Spike 90 trimers, which have a superior hACE2 binding capacity to the monomeric RBD counterparts (p. 3).
Regarding claim 10, Qu teaches a Kozak sequence operably linked to the nucleic acid sequence encoding the antigenic polypeptide as shown in Figure 1. A. (p. 9).
Regarding claim 12, Qu teaches “in this construct, the IRES element was placed before the RBD-coding sequence to initiate its translation” (p. 4).
Regarding claim 16, Qu teaches “Although circRNA lacks the essential elements for cap-
dependent translation, it can be engineered to enable protein translation through internal ribosome entry site (IRES) or the m6A modification incorporated to its 5’ UTR region”(p. 3).
Regarding claim 21, Qu teaches a circRNA vaccine (Abstract, p. 1).
Regarding claim 26, Qu teaches “Lipid nanoparticle-encapsulated circRNARBD elicited potent and sustained neutralizing antibodies, as well as Th1-biased T cell responses in mice. Notably, antibodies from mice immunized with circRNA encoding RBD variant (K417N-E484K-501Y) effectively neutralized B.1.351 variant. Moreover, we developed therapeutic circRNAs, encoding SARS-30 CoV-2 neutralizing nanobodies or hACE2 decoys, which could effectively neutralize SARS-CoV-2 pseudovirus. Our study suggests that circular RNA holds the potential to become a novel vaccine and therapeutic platform (p 1-2).
Qu does not teach an antigenic polypeptide of a SARS-CoV-2 variant, wherein the SARS-CoV-2 variant is a Delta variant or an Omicron variant.
Regarding claims 1 and 28, Kumar, however, teaches the “term “variant of concern” (VOC) for SARS‐CoV‐2 (which produces COVID‐19) refers to viral variants with mutations in their spike protein receptor‐binding domain (RBD) that dramatically improve binding affinity in the RBD‐hACE2 complex while also causing fast dissemination in human populations” (p.2). Kumar also teaches two VOCs - the Delta variant (B.1.617.2) and the Omicron variant (B.1.1.529) (p. 2). Kumar further teaches Table 1 (p. 5) which shows Spike protein mutation in Delta and Omicron variants compared to wild‐type (Wuhan‐Hu‐1), noting receptor‐binding domain as residues 319–541 (p.5) for comparison.
One of ordinary skill in the art would have been motivated to substitute the Delta and Omicron variants as taught by Kumar for those originally taught by Qu in order to quickly develop a therapeutic or a vaccine against the emerging SARS-CoV-2 variants of concern circulating globally (See MPEP 2143, Rationale B. Simple substitution of one known element for another to obtain predictable results and Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for developing circular RNA comprising a nucleic acid sequence encoding an antigenic polypeptide, e.g., RBD, of the SARS-CoV-2 variants – Delta or Omicron as taught by Kumar. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, and coronavirus field, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Qu in view of Kumar as applied to claims 1-3, 7-8, 10, 12, 16, 21, 26, and 28 and further in view of Lee et al. (Lee)(WO2021211279A1)(See PTO-892 Notice of References Cited).
See claim 4 as submitted 07/08/2024.
Qu and Kumar teach claim 3 but do not teach wherein the RBD comprises amino acid residues 319 to 542 of a full-length S protein of SARS-CoV-2, wherein the numbering is based on SEQ ID NO: 1.
Lee, however, teaches an isolated or purified SARS-CoV-2 Receptor Binding Domain (RBD) polypeptide and cells for producing such a polypeptide, as well as compositions and methods thereof. Lee also teaches SEQ ID NO: 5 with a 100% identity to that of instant application’s amino acid residues 319-542 of SEQ ID NO: 1 (see result 20, us-18-727-308-1-copy-319-542.align750.rag, 7/15/2026, see in supplementary contents tab).
One of ordinary skill in the art would have been motivated to use SEQ ID NO: 5 for the RBD component as taught by Lee because its length (amino acid span) enables the mutations observed for both the Delta and the Omicron variants, but particularly for the Omicron variant which has a large number of mutations as evidenced by Kumar in their Table 1 (p. 5) (See MPEP 2143, Rationale A. Combining prior art elements according to known methods to yield predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for using SEQ ID NO: 5 for RBD as taught by Lee. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, protein biology, immunology, and coronavirus studies, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Qu in view of Kumar as applied to claims 1-3, 7-8, 10, 12, 16, 21, 26, and 28, and further in view of Sahin et al. (Sahin)(EP3901260-A1)(See PTO-892 Notice of References Cited).
See claim 9 as submitted 07/08/2024.
Qu and Kumar teach claim 8 but they do not specifically teach where in the Fd domain comprises the amino acid sequence of SEQ ID NO: 3.
Sahin, however, teaches methods comprising administering to a subject RNA encoding a peptide or protein comprising an epitope of SARS-CoV-2 spike protein (S protein) for inducing an immune response against coronavirus S protein, in particular S protein of SARS-CoV-2, in the subject, i.e., vaccine RNA encoding vaccine antigen (Abstract). Sahin also teaches “According to certain embodiments, a trimerization domain is fused, either directly or through a linker, e.g., a glycine/serine linker, to a SARS-CoV-2 S protein, a variant thereof, or a fragment thereof, i.e., the antigenic peptide or protein” [0308] and teaches SEQ ID NO: 10 with 100% identity to that of instant application SEQ ID NO: 3 (see result 2, us-18-727-303-3.align750.rag, 07/15/2026, in supplemental contents tab).
One of ordinary skill in the art would have been motivated to use SEQ ID NO: 10 for the Fd domain as taught by Sahin since the domain allows the trimerization of the antigenic peptide as encoded by the RNA and may elicit a higher immune response and provide improved stability to the composition (See MPEP 2143, Rationale A. Combining prior art elements according to known methods to yield predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success adding the Fd domain sequence as taught by Sahin. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, protein biology, immunology, and coronavirus studies, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Qu in view of Kumar as applied to claims 1-3, 7-8, 10, 12, 16, 21, 26, and 28, and further in view of Costello et al. (Costello)(See PTO-892 Notice of References Cited).
See claim 11 as submitted 07/08/2024.
Qu and Kumar teach claim 1 but do not teach wherein an “In-frame 2A peptide coding sequence operably linked to the 3’ end of the nucleic acid sequence encoding the antigenic polypeptide.
Costello, however, teaches EPO expression from linear, circular and infinite circular mRNAs. Costello also teaches an in-frame 2A peptide coding sequence operably linked to the 3’ end of a nucleic acid sequence encoding an antigen, e.g., “EPO” and self-cleavage of the resulting protein into homogenous monomeric units (p. 288, Figure 3).
One of ordinary skill in the art would have been motivated to combine the teachings of Qu and Kumar with those of Costello in order to increase the abundance of the protein, to ensure more homogeneity of the protein (e.g., minimize multimeric variants), and with the improved homogeneity, to better retain functionality of the protein (See MPEP 2143, Rationale A. Combining prior art elements according to known methods to yield predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for combining the teachings of Qu, Kumar and Costello’s addition of an in-frame 2A peptide for improved antigen production. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, protein biology, immunology, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Qu in view of Kumar as applied to claims 1-3, 7-8, 10, 12, 16, 21, 26, and 28, and further in view of Wesselhoeft et al. (Wesselhoeft)(See PTO-892 Notice of References Cited).
See claim 15 as submitted 07/08/2024.
Qu and Kumar teach claim 12 but do not teach a polyAC or polyA sequence disposed at the 5’ end of the IRES sequence.
Wesselhoeft, however, teaches the use of exogenous circRNA for robust and stable protein expression in eukaryotic cells (p. 1, Abstract). Wesselhoeft teaches the addition of an internal polyA sequence or a polyAC spacer control upstream of an IRES (p. 4-5, Fig. 3a). Wesselhoeft also teaches that this addition improved protein expression in all constructs (p. 4).
One of ordinary skill in the art would have been motivated to combine the teachings of Qu, Kumar and Wesselhoeft, particularly with the inclusion of a polyA sequence or a polyAC spacer upstream of an IRES as taught by Wesselhoeft in order to achieve better protein expression of the antigenic polypeptide (e.g., the spike RBD) and consequently increase the immunogenic response in a subject (See MPEP 2143, Rationale A. Combining prior art elements according to known methods to yield predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success combining the teachings of Qu, Kumar with Wesselhoeft’s addition of an internal polyA sequence or a polyAC spacer. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, protein biology, immunology, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Qu in view of Kumar as applied to claims 1-3, 7-8, 10, 12, 16, 21, 26, and 28, and further in view of Obi et al. (Obi)(See PTO-892 Notice of References Cited) and Chang et al. (Chang)(WO2017222911A1)(as cited on the IDS submitted 10/07/2024).
See claim 18 as submitted 07/08/2024.
Qu and Kumar teach claim 1. Qu also teaches Fig. 1A. showing both the 3’ Intron fragment and the 5’ intron fragment flanking the IRES-SP-RBD-T4 sequence (p. 9, Figure 1).
Regarding claim 18, Obi, teaches “Ribozymes are RNAs that perform the catalytic actions typical of protein enzymes. The use of certain ribozymatic sequences constitutes a third strategy for producing circRNAs in vitro. The most popular of these methods rely on the autocatalytic activity of group I introns naturally found within the rRNA, tRNA, and mRNA genes of bacteria and non-metazoan eukaryotes. Group I introns splice themselves out without assistance from the spliceosome or other proteins, and instead rely on magnesium and a free guanosine nucleotide to initiate the splicing reaction in vivo. This process results in joining of the flanking exons and circularization of the intervening intron to produce an intronic circRNA” (p. 7). Obi also teaches generation of circRNA by the PIE method, and more specifically, Group I Intron – PIE splicing mechanism in Fig. 4B (p. 34). Obi also teaches the permuted T4 td and Anabaena pre-tRNA genes have become staple backbones in the field for circularization of a wide assortment of exonic sequences inserted between the group I intron halves (p. 7).
Chang further teaches reference claim 1. a) which recites producing a recombinant nucleic acid encoding the target RNA to be made circular, wherein the recombinant nucleic acid comprises in 5 ' to 3' order: i) a 3' portion of an exogenous intron comprising a 3' splice site, ii) a nucleic acid sequence encoding the target RNA, and iii) a 5 ' portion of an exogenous intron comprising a 5' splice site. Chang teaches reference claim 5 which recites a “self-splicing Group 1 intron”. And, Chang teaches reference claim 6, wherein the self-splicing Group I intron is from a phage T4 thymidylate synthase (td) gene (as mentioned previously by Obi).
One of ordinary skill in the art would have been motivated to combine the teachings as taught by Qu and Kumar with those of Obi and Chang who teach different constructs to produce a recombinant nucleic acid encoding a target RNA to successfully generate a circRNA for both antigenic expression and increasing immunogenicity of a target RNA(See MPEP 2143, Rational A. Combining prior art elements according to known methods to yield predictable results and Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for using ribozymatic sequences, the autocatalytic activity of group I introns and splicing and binding events as taught by Obi and Chang. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, protein biology, immunology, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Qu in view of Kumar as applied to claims 1-3, 7-8, 10, 12, 16, 21, 26, and 28, and further in view of Huang et al. (Huang)(WO2021147025A1)(See PTO-892 Notice of References Cited).
See claim 19 as submitted 07/08/2024.
Qu and Kumar teach claim 1 but do not teach a plurality of circRNAs of claim 1 wherein the antigenic polypeptides corresponding to the plurality of circRNAs are different with respect to each other,
Huang, however, teaches strategies for designing vaccines for 2019-nCov using spike protein and the fragments predicted as neutralizing epitopes (p. 2). Huang also teaches that in other embodiments, the recombinant protein vaccines comprise one or more different polypeptides p. 4-5).
One of ordinary skill in the art would have been motivated to make a composition with a plurality of circRNAs each with a different antigenic polypeptide as taught by Huang, in order to make a multi-epitope vaccine and to generate a broader, and possibly more robust immune response, such as both increasing neutralizing antibody titer while also inducing, for example, T-cell immunity (See MPEP 2143, Rationale A. Combining prior art elements according to known methods to yield predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for making a plurality of different circRNAs with different polypeptides or fragments as taught by Huang. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, protein biology, immunology, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claims 32 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Qu in view of Kumar as applied to claims 1-3, 7-8, 10, 12, 16, 21, 26, and 28, and further in view of Chang et al. (Chang)(as cited in IDS submitted 10/07/2024).
See claims 32 and 33 as submitted 07/08/2024.
Qu and Kumar teach claim 1 but do not specifically teach a linear RNA capable of forming the circRNA of claim 1 or a nucleic acid construct comprising a nucleic acid sequence encoding the linear RNA of claim 32.
Regarding claim 32, Chang, however, teaches “Circular RNAs can be produced from linear RNAs in a number of ways. In one embodiment, circular RNAs are produced from a linear RNA by backsplicing of a downstream 5' splice site (splice donor) to an upstream 3' splice site (splice acceptor)….Alternatively, circular RNAs can be produced in vitro from a linear RNA by chemical or enzymatic ligation of the 5' and 3' ends of the RNA (p. 23)
Regarding claim 33, Chang teaches “In one embodiment, the circular RNA is produced from a recombinant nucleic acid encoding the target RNA to be made circular. The method comprises: a) producing a recombinant nucleic acid encoding the target RNA to be made circular, wherein the recombinant nucleic acid comprises 5’ to 3’ order” (p. 2).
One of ordinary skill in the art would have been motivated to construct a linear RNA capable of forming the circRNA as well as the nucleic acid construct comprising a nucleic sequence encoding the linear RNA as taught by Chang, as it lends itself to more precise sequence engineering and because with respect to linear RNA constructs, there already exists well-established large scale production platforms using in vitro transcription. Thus, one could take advantage of the existing IVT infrastructure while still delivering a circRNA product by incorporating one of the circularization strategies (See MPEP 2143, Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for constructing a linear RNA capable of forming the circRNA as well as the nucleic acid construct comprising a nucleic sequence encoding the linear RNA as taught by Chang. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, protein biology, immunology, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
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.
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Claims 1, 32 and 33 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 12, 26, 36, and 37 of U.S. Patent No. 12662671 in view of Qu and Kumar.
See claims 1, 32 and 33 as submitted 07/08/2024.
U.S. Patent No. 12662671 teaches:
Claim 1: 1. A linear RNA, comprising from the 5' end to the 3' end:(a) a first portion of an RNA element;(b) an effector RNA sequence; and(c) a second portion of the RNA element; wherein the RNA element is an internal ribosomal entry site (IRES) or a portion thereof; wherein the first portion of the RNA element and the second portion of the RNA element associate with each other to form a double-stranded region of at least 4 base pairs (bp) long; wherein the 5' end of the first portion of the RNA element and the 3' end of the second portion of the RNA element form a nick in the double-stranded region; and wherein the nick can be ligated by an RNA ligase.
Claim 11: The linear RNA of claim 1, wherein the effector RNA sequence is a coding RNA sequence.
Claim 12: The linear RNA of claim 11, wherein the coding RNA sequence encodes a therapeutic polypeptide.
Claim 26: A method of preparing a circRNA, comprising:(a) contacting the linear RNA of claim 1 with an RNA ligase under conditions that allow ligation of the nick in the linear RNA to provide a circularized RNA product; and(b) isolating the circularized RNA product, thereby providing the circRNA.
Claim 36: A circRNA formed by ligation of the nick in the linear RNA of claim 1.
Claim 37: A nucleic acid construct comprising a nucleic acid sequence encoding the linear RNA of claim 1.
U.S. Patent No. 12662671 does not teach an antigenic polypeptide of a SARS-CoV-2 variant, wherein the SARS-CoV-2 variant is a Delta variant or an Omicron variant.
Qu and Kumar, however, as noted above, teach an antigenic polypeptide of a SARS-CoV-2 variant and the Delta and Omicron variants.
One of ordinary skill in the art would have been motivated to combine the teachings of U.S. Patent No. 12662671 (linear RNA, method of preparing a circRNA) with those of Qu (circular RNAs comprising a nucleotide sequence encoding an antigenic polypeptide of a SARS-CoV-2 variant) and Kumar (details about the SARS-CoV-2 variants, Delta and Omicron) to arrive at a linear RNA capable of forming a circRNA comprising a nucleic acid sequence encoding an antigenic polypeptide of a SARS-CoV-2 variant, wherein the SARS-CoV-2 variant is a Delta variant or an Omicron variant. Similarly, one would have been motivated to combine the teachings to arrive at a nucleic acid construct comprising a nucleic acid sequence encoding the linear RNA (See MPEP 2143, Combining prior art elements according to known methods to yield predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for combining the teachings of U.S. Patent No. 12662671 with Qu and Kumar. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, protein biology, immunology, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claims 1, 26 and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 27, 34 of copending Application No. 18832465 in view of Qu and Kumar.
See claims 1, 26 and 28 as submitted 07/08/2024.
Copending Application No. 18832465 teaches:
Claim 1: A method of treating or preventing a disease or condition in an individual, comprising administering to the individual an effective amount of a circular RNA (circRNA) comprising a nucleic acid sequence encoding a therapeutic polypeptide, wherein the circRNA is a naked circRNA.
Claim 2: The method of claim 1, wherein the disease or condition is an infection.
Claim 3: The method of claim 2, wherein the infection is a coronavirus infection.
Claim 27: The method of claim 5[[26]], wherein the antigenic polypeptide comprises a Spike (S) protein or a fragment thereof of a coronavirus.
Claim 34: The method of claim 5[[33]], wherein the therapeutic polypeptide is a receptor protein and wherein the receptor protein is an ACE2 receptor.
Copending Application No. 18832465 does not specifically teach SARS-CoV-2 or its variants Delta and Omicron.
Qu and Kumar, however, teaches both SARS-CoV-2, spike protein, RBD, and the variants Delta and Omicron.
One of ordinary skill in the art would have been motivated to combine the teachings of Copending Application No. 18832465, particularly the method, with those of Qu and Kumar as related to SARS-CoV-2, the spike protein RBD and the Delta and Omicron variants, to in order to develop a method of treating infections caused by SARS-CoV-2, its known variants, not to mention emerging variants, during the global pandemic (See MPEP 2143, Rationale A. Combining prior art elements to known methods to yield predictable results and Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for combining the teachings as taught by both the Copending Application No. 18832465 and Qu and Kumar. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, protein biology, immunology, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 7-12, 15-16, 18-19, 21, 26, 28, 32-33 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-6, 10-17, 21-22, 32, 34-35, 38-41, 45-46 of copending application 18022488.
See claims 1-4, 7-12, 15-16, 18-19, 21, 26, 28, 32-33 as submitted 07/08/2024.
Copending application 18022488 teaches:
Claims 1-6: a circular RNA (circRNA) constructs with Kozak sequences, IRES, polyAC or polyA sequence, Group I intron fragments, m6A modification motif sequence.
Claims 10-17: therapeutic protein for treating or preventing an infection, viral infection, coronavirus, SARS-CoV-2, antigenic polypeptide, Spike protein or a fragment, RBD, multimerization domain.
Claims 21-22: receptor protein, ACE2 receptor.
Claim 32: a composition comprising a plurality of circRNAs of claim 1, wherein the therapeutic polypeptides corresponding to the plurality of circRNAs are different with respect to each other.
Claims 34-35: a circRNA vaccine, a pharmaceutical composition.
Claims 38-41: a method of treating or preventing, coronavirus infection, SARS-CoV-2.
Claims 45-46: a linear RNA capable of forming a circRNA and a nucleic acid construct comprising a nucleic acid sequence encoding the linear RNA.
Although the claims at issue are not identical, they are not patentably distinct from each other because both instant claims 1-12, 15-16, 18-19, 21, 26, 28, 32-33 of 18727308 and claims 1-6, 10-17, 21-22, 32, 34-35, 38-41, 45-46 of copending application 18022488 recite a circular RNA (circRNA) comprising a nucleic acid sequence encoding a therapeutic polypeptide, wherein the therapeutic polypeptide is selected from the group consisting of an antigenic polypeptide, a functional protein, a receptor protein, and a targeting protein, and the viral infection emphasis is on SARS-CoV-2.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
Claims 5 and 6 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
SEQ ID NO: 18 (claim 5) and SEQ ID NO: 19 (claim 6) are free of the prior art of record.
Conclusion
No claims allowed.
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/C.C./Examiner, Art Unit 1672
/M FRANCO G SALVOZA/Primary Examiner, Art Unit 1672
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