DETAILED ACTION
Claims 1-10, 12, 19-20, 22, 39-40, 42-43, 46 and 48 are currently pending.
Claims 11, 13-18, 21, 23-38, 41, 44-45, 47 and 49-53 are cancelled.
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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-10, 12, 19, 20 and 22), and Group I species of the polyribonucleotide is bound to the circular polyribonucleotide by direct binding (claim 6), in the reply filed on January 2, 2026 is acknowledged.
Claims 5, 7-8, 39-40, 42-43, 46 and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 2, 2026.
Priority
Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application PCT/US2021/015742, filed January 29, 2021, which claims the benefit of provisional application No. 62/967,547, filed January 29, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/22/2023, 8/3/2023, 7/18/2024, 1/2/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification, at paragraphs [0166], [0177], [0276] and [0327], are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
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.
Claim 10 is 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.
Regarding claim 10 and the limitation “wherein the polyribonucleotide or 5’ modified guanosine cap of the polyribonucleotide recruits a ribosome”, it is noted this limitation renders claim 10 indefinite since the claim appears to recite the intended use of the claimed composition. It is unclear if the claim requires the presence of a ribosome.
In the interest of compact prosecution, although claim 10 states that the “polyribonucleotide recruits a ribosome” or the “5’ modified guanosine cap of the polyribonucleotide recruits a ribosome”, these limitations are interpreted as being directed to intended use which does not further define or limit the composition, per se. Compositions are defined by their physical, structural, and chemical properties, not by an intended use or application. See, e.g., Ex parte Masham, 2 USPQ2d 1647 (1987) and In re Hack 114, USPQ 161. See MPEP 2111.02
However, despite the above interpretation, such treatment does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action. The rejection to claim 10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, stands and must be addressed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 6, 9-10, 12, 19, 20 and 22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
The rationale set forth below conforms to current Office practice for examination of claims under § 101.
These claims are analyzed for eligibility in accordance with their broadest reasonable interpretation. All of the claims are directed to a statutory category, e.g., a composition (Step 1: YES).
The next part of the analysis involves whether the claimed invention recites or is directed to one or more judicial exceptions (Step 2A, prong one).
Claim 1: Claim 1 is directed to a pharmaceutical composition comprising:
(a) a polyribonucleotide comprising a 5' modified guanosine cap and a first binding region;
(b) a circular polyribonucleotide; and
(c) a pharmaceutically acceptable excipient.
As is recognized by the instant specification, the excipient encompasses non-carrier aqueous solvents such as phosphate buffered saline (paragraphs [0360]) or solvents including water, or isotonic agents such as sucrose or trehalose ([0426]).
Further regarding a circular polyribonucleotide, it is noted that Legnini et al (see IDS 5/22/2023) notes that studies show that circular RNA (circular polyribonucleotides) are commonly produced by thousands of genes (INTRODUCTION, left col, page 22), and circular RNA (circRNA) is highly conserved across species and particularly abundant in mammalian neuronal tissues. Legnini et al specifically identifies circRNAs that are regulated during murine and human muscle differentiation, and whose expression is altered in Duchenne muscular dystrophy (DMD) myoblasts (INTRODUCTION, right col, page 22).
As to the recited polyribonucleotide comprising a 5' modified guanosine cap and a first binding region, it is noted that Filipowicz et al., (see PTO-892) evidences that native messenger RNA (from Artemia salina embryos) comprises a 5’ modified guanosine cap and a cap binding region (first binding region), wherein the cap binding protein(s) may influence the initiation of protein synthesis by promoting ribosomal binding of cap-containing messengers through recognition of the modified guanosine cap, m7GpppN (ABSTRACT). Filipowicz further notes that many viral and eukaryotic mRNAs have a m7G(5’)pppN cap at the 5’ end, and this cap is important for translation, as well as being required for binding the messenger to 40S or 80S ribosomes (first paragraph, left col, page 1559).
Xie further teaches native microRNAs (miRNAs, polyribonucleotides) that are gene regulators and produced from primary transcripts, wherein the pre-miRNAs have 5’ modified guanosine cap, i.e., 7-methylguanosine-capped, and binding region for exporting via the PHAX-exportin 1 pathway (Summary, page 1568; Introduction, page 1568-1569).
Thus, the claim recites a combination of natural products.
The claim as a whole, considering all claim elements both individually and in combination, does not amount to significantly more. There is no indication in the specification that in combining an excipient comprising water or sucrose with either the polyribonucleotide comprising a 5' modified guanosine cap and a first binding region or circular RNA, that any characteristics (structural, functional, or otherwise) are developed by either the polyribonucleotide comprising a 5' modified guanosine cap and a first binding region, or circular RNA, that are not present in the individual parts. The combination does not improve or change in any way each components natural functioning. Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception.
There is no indication in the specification that the limitations recited in dependent claims 2-4, 6, 9-10, 12, 19-21 and 22 limit the claimed composition in such a way that is markedly different in structure, or biological and/or pharmacological function from their natural counterparts.
Accordingly, the claims are directed to an exception (Step 2A, prong one: YES). Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101.
The next part of the analysis involves whether the claimed invention recites additional elements that integrate the judicial exception into a practical application (Step 2A, prong two).
Given the claims are directed to a composition, the claims do not recite additional steps that integrate the judicial exception into a practical application (Step 2A, prong two: No).
The final part of the analysis involves whether the claimed invention, as a whole, recite something “significantly more” than the judicial exceptions (Step 2B).
In view of the above and considered as a whole, the claimed composition does not have markedly different characteristics from what occurs in nature and such elements discussed above are not significantly more than the indicated judicial exceptions. Thus, the claims do not qualify as eligible subject matter, and are rejected under 35 U.S.C. 101 (Step 2B: NO).
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.
Claim(s) 1-3, 6-10, 12, 19-20 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/118919 (“WO ‘919”, IDS 5/22/2023), as evidenced by Cowling et al., (Biochem J. (2010) 425, 295-302; see PTO-892) (“Cowling”).
WO ‘919 teaches of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a circular polyribonucleotide, wherein the circular polyribonucleotide encodes a regulatory nucleic acid (e.g., micro RNA) that is substantially or fully complementary to all or a fragment of an endogenous gene or gene product (e.g., mRNA, i.e., polyribonucleotide comprising a 5’-modified guanosine). The regulatory nucleic acid may complement sequences at the boundary between introns and exons, in between exons, or adjacent to exons, to prevent the maturation of newly-generated nuclear RNA transcripts of specific genes into mRNA for transcription. The regulatory nucleic acids that are complementary to specific genes can hybridize (i.e., first binding region) with the mRNA (i.e., second binding region) for that gene and prevent its translation. The antisense regulatory nucleic acid can be DNA, RNA, or a derivative or hybrid thereof ([0027], [0184]-[0186]). WO’919 teaches the mRNA comprises modified nucleosides, including 7-methyl-guanosine ([0311]). It is further noted that Cowling evidences that eukaryotic mRNA is modified by the addition of the 7-methylguanosine ‘cap’ to the first transcribed nucleotide (Abstract and Introduction).
Thus, the mRNA disclosed in WO ‘919 is considered to comprise a 5’-modified guanosine cap, specifically comprising 7-methyl-guanosine (as recited in claim 20).
WO ‘919, at paragraph [0188], further teaches that known miRNA binding sites (i.e., first binding region) are within mRNA 3' UTRs and the miRNAs target sites with near-perfect complementarity to nucleotides 2-8 (claim 19) from the miRNA's 5' end, known as the seed region (i.e., polynucleotide is bound to the circular polyribonucleotide by direct binding, as recited in claim 6).
It is noted that, although paragraphs [0184]-[0186] and [0188] do not exemplify the presence of a pharmaceutically acceptable excipient, it is noted that WO ‘919 (at paragraph [0044]), clearly teaches the disclosed invention includes a method of producing pharmaceutical compositions comprising the disclosed circular polyribonucleotides. Thus, WO ‘919 does render obvious a pharmaceutically acceptable excipient, that is, WO ‘919 teaches the limitations required by the current claims and as all limitations are found in one reference it is held that inclusion of a pharmaceutically acceptable excipient for therapeutic purposes is within the scope of the teachings of WO ‘919, and thus renders the invention of claim 1 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to include a pharmaceutically acceptable excipient. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by WO ‘919.
Regarding claim 2, WO ‘919 teaches the miRNA sequence of the circular polyribonucleotide is complementary to disclosed mRNA and reads on the second binding region.
Regarding claim 3, WO ‘919 teaches the miRNA sequence of the circular polyribonucleotide is complementary to disclosed mRNA and reads on the first binding region specifically binds to the second binding region.
Regarding claims 6 and 19, as noted above, WO ‘919, at paragraph [0188], further teaches that the miRNAs target sites with near-perfect complementarity to nucleotides 2-8 (claim 19) from the miRNA's 5' end, known as the seed region (i.e., polynucleotide is bound to the circular polyribonucleotide by direct binding, as recited in claim 6).
Regarding claim 9, WO ‘919 teaches the circular polyribonucleotide encodes a regulatory nucleic acid (e.g., micro RNA) that is substantially or fully complementary to all or a fragment of an endogenous mRNA, i.e., polyribonucleotide comprising a 5’-modified guanosine. The regulatory nucleic acid may complement sequences at the boundary between introns and exons, in between exons, or adjacent to exons, to prevent the maturation of newly-generated nuclear RNA transcripts of specific genes into mRNA for transcription. The regulatory nucleic acids that are complementary to specific genes can hybridize (i.e., first binding region) with the mRNA (i.e., second binding region) for that gene and prevent its translation. The antisense regulatory nucleic acid can be RNA ([0027], [0184]-[0186]). Thus, the teachings of WO ‘919 meet the limitations of claim 9.
Regarding claim 10 and the limitation “wherein the polyribonucleotide or 5’ modified guanosine cap of the polyribonucleotide recruits a ribosome”, it is noted as set forth above at the rejection under 35 USC 112(b), these limitations are interpreted as being directed to intended use which does not further define or limit the composition, per se. Compositions are defined by their physical, structural, and chemical properties, not by an intended use or application. Please note that it is well settled that “intended use” of a composition or product will not further limit claims drawn to a composition or product. See, e.g., Ex parte Masham, 2 USPQ2d 1647 (1987) and In re Hack 114, USPQ 161. See MPEP 2111.02
Therefore, claim 10 is included in the rejection of claim 1.
Regarding claim 12, WO ‘919 teaches the circular RNA comprises expression sequence for miRNA ([0027] and [0184]-[0186]), thus meeting the limitation of claim 12.
Regarding claim 19, WO ‘919, at paragraph [0188], teaches miRNAs target sites with near-perfect complementarity to nucleotides 2-8, thus the first binding region of the endogenous mRNA is considered to have complementary sequence to the miRNA sequence of the circular RNA, thus meeting the limitation of claim 19.
Regarding claims 20 and 22, as set forth above at the rejection of claim 1, WO’919 teaches the mRNA comprises modified nucleosides, including 7-methyl-guanosine ([0311]). It is further noted that Cowling evidences that eukaryotic mRNA is modified by the addition of the 7-methylguanosine ‘cap’ to the first transcribed nucleotide (Abstract and Introduction). Thus, the mRNA disclosed in WO ‘919 is considered to comprise a 5’-modified guanosine cap, specifically comprising 7-methyl-guanosine, thus meeting the limitations of claims 20 and 22.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over WO ‘919 (set forth above), as evidenced by Cowling, as applied to claims 1-3, 6, 9-10, 12, 19-20 and 22 above, and further in view of Tusup et al., (EPH-International Journal of Medical and Health Science, Volume-3, Issue-3, Sep, 2017, pages 20-24; see PTO-892) (“Tusup”).
The teaching of WO ‘919, as evidenced by Cowling, is set forth above.
Regarding claim 4, it is noted that, although paragraphs [0184]-[0186] and [0188] of WO ‘919 do not further teach the mRNA driving expression in the circular RNA when bound to the circular RNA, it is noted that paragraphs [0046]-[0047] of WO ‘919 teaches the disclosed invention includes a method for protein expression, comprising translating at least a region of the circular polyribonucleotide, wherein translation takes place in vitro, and would thus produce in vitro translated mRNA.
Tusup is directed to increasing the functionality of in vitro transcribed mRNA (ivt mRNA) and teaches of adding aptamer sequences that bind the EIF4G protein (recruit ribosomes) to the 5’ UTR of in vitro transcribed mRNA (Abstract).
Tusup teaches that aptamers that bind EIF4G have been identified for blocking translation in tumor cells, and in further researching those aptamers that did not block translation, Tusup utilized said aptamers for bringing the EIF5G to the 5’ end of the ivt mRNA and enhancing translation. Thus, Tusup suggests the addition of said aptamer sequence to mRNA that will be in vitro translated, thus providing a universal method for improving mRNA-based therapies (INTRODUCTION, page 21).
Tusup further teaches that 5’ capped mRNAs with the aptamer 17 sequence exhibited several fold increases in luciferase activity compared with mRNAs without a 5’ aptamer sequence (Results and Discussion, page 21; Conclusion; Figure 2).
Thus, Tusup has established it was well-known that 5’ capped mRNA (polyribonucleotide comprising a 5’ modified guanosine cap) modified to comprise specific aptamer sequences enhance translation and drive expression of in vitro translated RNA.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the 5’ capped mRNA modified to comprise specific aptamer sequences, as taught by Tusup, with the circular RNA disclosed by WO ‘919.
The person of ordinary skill in the art would have been motivated to modify the circular RNA composition of WO ‘919 to include the 5’ capped mRNA modified to comprise specific aptamer sequences for the predictable result of successfully enhancing in vitro translation and increasing circular RNA protein expression for future therapeutic use, thus meeting the limitation of claim 4.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of WO ‘919 and Tusup because each of these teachings are directed at in vitro translation of RNA for mRNA therapeutic uses.
Conclusion
No claim is allowed. No claim is free of prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633