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 .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/20/2025 and 02/27/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Application Status
This action is written in response to applicant’s correspondence received 01/20/2026. Claims 45-48, 50-56, and 58-66 are currently pending. Claims 49 and 57 have been cancelled. Accordingly, claims 45-48, 50-56, and 58-66 are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Interpretation
The amended claims recite a synthetic polyribonucleotide. The specification does not clearly and explicitly define the term “synthetic”. The broadest reasonable interpretation of the term encompasses polyribonucleotides which have been or can be synthesized. This includes both engineered structures and synthetic ones which share a base nucleotide sequence with a naturally occurring structure, but which have been synthesized instead of being isolated from an organism which produces it, such as via in vitro synthesis or in vivo in a host cell which has been engineered to express the polyribonucleotide.
The claims recite a “translation incompetent” circular polyribonucleotide. The specification does not explicitly define the term “translation incompetent”. However, the term is interpreted to mean that the circRNA lacks elements that would enable it to be translated into a protein, such as those typically present in translationally competent mRNAs. These would include elements such as a 5’ cap structure, poly-A tail, internal ribosomal entry site for mRNAs lacking a 5’ cap, start codon, a sequence encoding a protein for translation and expression, etc., per Wang (Wang et al. A viral sequence in the 3’-untranslated region mimics a 5’ cap in facilitating translation of uncapped mRNA. The EMBO Journal Vol.16 No.13 pp.4107–4116, 1997.; of record, cited in previous office action) (p. 4107):
Almost all eukaryotic cellular mRNAs contain a 5’m7G(5’)ppp(5’)N cap structure which is required for efficient initiation of translation.
When the first (or second in the case of leaky scanning) AUG codon is reached, the 60S ribosomal subunit joins and peptide elongation ensues.
The 3’ poly(A) tail, found on most eukaryotic cellular mRNAs, stimulates translation initiation.
In all these examples, the mRNA must have a 5’ cap in order for the 3’ element to function.
Picornaviral RNAs lack a 5’ cap structure and have an extremely long, highly structure 5’ UTR, including many AUG codons upstream of the start codon of the main open reading frame (ORF). Rather than scanning from the 5’ end, ribosomes bind internally in this long leader at the internal ribosomal entry site (IRES) just upstream of the start codon, in a cap-independent manner.
Claim Rejections - 35 USC § 112(a) – Written Description
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 45-48, 50-56 and 58-66 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The breadth of the claims:
The broadest reasonable interpretation of claim 45 reads on synthetic or naturally occurring circular RNAs which are translationally incompetent (e.g., does not comprise a start codon or other elements required for translation) and directly or indirect bind any nucleic acid as well as any protein via two distinct binding sites in the circRNA.
Claim 45 recites a method of forming a complex in a cell using a translation incompetent circular polyribonucleotide. The polyribonucleotide comprises a first binding site that binds any protein and a second binding site that binds any nucleic acid molecule. The genus of any protein is vast, including any protein produced by any cell in any organism, from prokaryotes to humans. The genus of any nucleic acid is also vast, encompassing any coding or non-coding RNA or DNA, natural or synthetic. This also includes nucleic acids which are linear when synthesized but may then be circularized. Either binding site in the circRNA may bind its target through any mechanism contemplated in the art. The circRNA may directly bind a nucleic acid target through complementary base baring or non-complementary interactions including but not limited to electrostatic interactions with phosphate groups in the backbone. For example, Khade & Joseph (Functional Interactions by Transfer RNAs in the Ribosome. FEBS Lett. 2010 January 21; 584(2): 420–426.) describe the interactions between tRNA molecules and ribosomes, noting several non-complementary interactions between nucleobases and the tRNA backbone (p. 3/12 §Functional Interactions in the P site):
Base G926 interacts with the phosphate group at the first position of the P site codon….Base m2G966 interacts with the backbone of P-tRNA at position 34.
The circRNA may also bind its nucleic acid target indirectly, i.e., through binding of a DNA- or RNA-binding protein which then binds the target. Regarding the function of binding any protein, the circRNA may do so directly or indirectly via comprising an aptamer component capable of binding the protein target, interacting with a nucleic-acid-binding protein which further interacts with a secondary protein, etc.
Claim 45 further requires that the protein and nucleic acid molecule (i.e., the target of the second binding site of the polyribonucleotide) interact with each other. This, again, is interpreted as encompassing both direct and indirect interactions.
The dependent claims limit the interactions between the second binding site to complementary nucleic acid interactions (claim 46, 50), the nucleic acid molecule to RNA (claims 51-52), DNA (claims 54-55), a microRNA (claim 58) the protein to an enzyme (claim 56), the action of the complex to gene regulation (claim 57), modulation of gene expression (claim 59; falling under the heading of gene regulation), or degradation of the target RNA (claim 60, considered to be a form of gene regulation/modulation of gene expression). Claim 61 and its dependents are broadly similar, but claim 61 limits the second binding site for binding a nucleic acid to a guide RNA sequence. The term ‘guide RNA sequence’ is given its plain meaning as one of ordinary skill in the art would understand it, and is interpreted as encompassing any CRISPR guide RNA sequence. This may include only the sequence of nucleotides which is complementary to a target sequence, or may include the entire guide RNA sequence, i.e., the crRNA together with the tracrRNA scaffold of a single guide RNA.
The teachings of the specification:
In contrast to the breadth of the claims, the specification exemplifies three specific systems using specific circRNA structures to target specific proteins and RNAs.
In Example 40 (para [0587-0597]), the specification describes a circular RNA including the HuR RNA binding aptamer motif (SEQ ID NO: 31) and an RNA binding aptamer motif (SEQ ID NO: 32) (para [0593]). Because there is no SEQ ID NO: given for the circular RNA itself, and because the specification uses the open-ended language, “includes”, it is not clear whether the circular RNA comprised further nucleotides.
In Example 41 (para [0598-0605]), the specification describes a circular RNA binding HuR and an unspecified DNA target. It is not clear whether this circular RNA included the same HuR binding motif (SEQ ID NO: 31) as the one in Example 40. It is also unclear what DNA is targeted, and it appears that the same binding motif (SEQ ID NO: 32) was used for both the previous RNA-binding aptamer and this DNA-binding aptamer.
The only other example provided that pertains to a circular RNA binding both a nucleic acid (a complementary sequence to 40-120 ATN1 expansion repeats) and a protein (Dcp2) is Example 8 (paras [0388-0393]. However, this example appears to be prophetic in nature.
Therefore, it appears that no complete sequence of a circRNA capable of binding a nucleic acid and a protein is disclosed. The partial sequences which are disclosed are specific to certain protein targets, i.e., Dcp2, HuR, but do not appear to share a common motif which is correlated with the binding of any protein in the genus of proteins. There is no core structure of the broad genus that has the desired activity of binding any protein and any nucleic acid.
The state of the art:
Lasda & Parker (Circular RNAs: diversity of form and function. RNA. 2014 Dec;20(12):1829–1842.) review the known structures and functions of naturally occurring non-coding circular RNAs. The genus is vast: in human cells alone, anywhere from 1,950 to 25,166 circRNAs are predicted to exist (see Table 2). The genus is also structurally and functionally variable, including viral genomes, various types of introns, rRNA precursors, permuted tRNAs, snoRNAs, and exonic circular RNAs (Table 1, p. 1830). Please note that these structures not only vary in function but that, in many cases, the function is not clear. For example, in the second-to-last column of Table 1, the authors list several possible functions, including transcription, genetic element mobility, and ceRNAs (sponges) for regulation of mRNA levels or translation. The genus of circular RNAs also includes synthetic circular RNAs, such as siRNAs for binding nucleic acids (Zhang et al. Circular siRNAs for Reducing Off-Target Effects and Enhancing Long-Term Gene Silencing in Cells and Mice. Mol Ther Nucleic Acids. 2017 Dec 19;10:237–24.) and aptamers for binding proteins (WIPO Publication 2018/237372 A1, para [0165]).
It is also relevant to note that, per Cigan (cited in the rejection under 35 U.S.C. 103 below), linear nucleic acid molecules may generally be linearized to provide resistance against degradation. Therefore, the breadth of the state of the art includes any translation incompetent nucleic acid molecule which may be linearized, including but not limited to significantly structurally and functionally diverse groups such as siRNAs, aptamers, etc.
Regarding the dependent claims:
Claims 50-52, 54-56, 58 and 62-63 limit the types of targets to DNA/RNA molecules, microRNA and enzymes, but these targets remain generically broad.
Claims 46-49 limit the structure of the circRNA and its effects, but do not narrow the breadth of the circRNA, nucleic acid target, or protein target.
Claims 53, 59-60 and 64-66 limit the function of the complex to some form of modulation of gene expression/degradation of a target molecule, but do not limit the breadth of the circRNA, nucleic acid target, or protein target structures.
Claim 61 limits the second binding site to a guide RNA sequence, but a guide molecule remains generic, and the claim does not narrow the breadth of the targets compared to claim 45.
Based on the generic breadth of the claimed proteins, nucleic acids and circular RNAs, the limited amount of guidance provided by the specification and the art, the high degree of variation among members of the claimed genus, and further the unpredictability in the art, one of ordinary skill in the art would conclude that Applicant was not in possession of the invention as broadly claimed.
Response to Arguments
Applicant's arguments filed 01/20/2026 have been fully considered but they are not persuasive for the reasons that follow.
Applicant argues that, “A skilled artisan would understand that the formation of a complex in a cell is not limited to a particular species of protein or nucleic acid included in the complex but is instead based on the method by which the complex is formed, e.g., by way of providing to a cell a synthetic translation incompetent circular polyribonucleotide that has binding sites for interacting with the protein and nucleic acid.” (Remarks, 01/20/2026, p. 6 1st full ¶). Respectfully, this argument is not persuasive because, as the Applicant notes, the polyribonucleotide must have binding sites for interacting with the protein and nucleic acid. In other words, the provision of the nucleotide to the cell is not sufficient. The structures of the components of the complex must also be able to perform the function of binding to one another and forming said complex.
Applicant also argues that, “…satisfaction of written description does not require an Applicant to teach aspects of the claimed invention that are well within the knowledge and skill of an ordinary artisan…it is not necessary for an Applicant to exemplify all possible options for implementing a claimed invention, in particular where features of the claimed invention are already known to those of skill in the art (e.g., the structure or physicochemical properties of a protein of interest and the nucleotide sequence of a nucleic acid of interest).” (Remarks, p. 6, 2nd and 3rd ¶). Respectfully, this is not persuasive because, as discussed in the above rejection, the claims do not merely encompass conventional, well-known proteins and nucleic acids. Instead, they are so broad as to encompass any protein and any nucleic acid, including proteins which are unknown or whose structures and physicochemical properties are not well-understood.
Conclusion
No claims are allowed at this time.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.M.Z./ Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636