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 and Election
Applicant’s amendments filed August 24, 2026, amending claims 12, 18-19, 25, 27, 37, 44-46, 48-49, canceling claims 1, 3, 8, 10, 23, 33, and adding new claims 51-53 is acknowledged. Applicant’s election without traverse of IRES species iCVB3 in the reply filed on August 24, 2026 is acknowledged.
Claims 12, 17-21, 25, 27, 37, 44-46, 48-49 and 51-53 are pending and under examination.
Drawings
The drawings are objected to because the lines, shadings, numbers and letters of FIGs. 2, 5A, 7D, 8, 10A-B, 11, 13A-B, 14, 16-D, 17C, 18A-B and 19 are not sufficient to provide satisfactory reproduction characteristics. 37 CFR 1.84(l) states that “all drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.” In the instant case, the text in the FIGs listed above is either light grey or otherwise not sufficiently dense and dark to permit satisfactory reproduction characteristics or is very small and of poor resolution.
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 term NanoLuc®, which is a trade name or a mark 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 18 and 37 are objected to because of the following informalities:
Claim 18 recites “so that the aptamer is spatially proximal to [] portion of the modified iCVB3 IRES responsible for translation initiation”. There is an article missing before “portion”. It is suggested that “a” be used as the article.
Claim 37 recites “2’-0-methylcytidine (20MeC)”. The zeroes should be Os because the “O” represents an oxygen atom. The correct spelling and abbreviation is 2’-O-methyldcytidine and 2OMe.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 12, 17-21, 25, 27, 37, 44-46, 48-49 and 52 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 a circular RNA molecular comprising SEQ ID NO 107, does not reasonably provide enablement for an iCVB3 IRES comprising any aptamer or placed anywhere within the iCVB3 IRES sequences. 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.
Exemplary factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (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. See MPEP 2164.01(a). All of these factors were considered, along with others, and a sufficient number are addressed below so as to create a prima facie case.
Nature of the Invention and Breadth of Claims – Claim 12
Claim 1 is drawn to a circular RNA (circRNA) comprising a modified iCVB3 IRES sequence that comprises an aptamer. According to the specification the wildtype iCVB3 IRES sequence is 736 nucleotides in the length. The claims are not limited to how the CVB3 IRES is modified compared to the wildtype other than including an aptamer. Thus, the claims encompass circRNA molecules comprising a large genus of modified CVB3 IRES. An aptamer is defined as a short, single stranded DNA or RNA molecule that can selectively bind to a specific target ([0072]). Other than being “short” and “single stranded”, an aptamer only identifies a polynucleotide by function. A definition by function does not suffice to define the genus because it is only an indication of what the polynucleotide does (i.e., bind to another molecule), rather than what it is. As such, “an aptamer” is interpreted as any short (~20-200 nucleotides) polynucleotide sequence. Accordingly, enablement of the method requires one skilled in the art to be able to use the genus of circRNA molecules comprising a CBV3 IRES and any polynucleotide sequence that merely has the function of binding to any other molecule.
Guidance in the Specification
The specification provides a series of experiments incorporating a specific eIF4G aptamer, which was first described in Tusup et al., EPH Int. J. Med. Health Sci 4 (2018): 29-35, into the wildtype CVB3 IRES ([00203]-[00205] and [00205]-[00218]). Applicant found that incorporation of the aptamer having SEQ ID NO 99 specifically within the distal and proximal loops of domain IV either maintained or increased translation of a reporter gene from the IRES (FIG 10A). However, introduction of the eIF4G-binding aptamer in any other domain completely abolished the function of the IRES (FIG 10A). As such, it is not clear what a CBV3 IRES sequence comprising the eIF4G-aptamer inserted in domains, I, II, III, V, VI or VII could be used for. Applicant does not attempt to incorporate any other eIF4G-binding aptamer, or any other aptamer into the CBV3 IRES. Based on Applicant’s results that deleting portions of the IRES (FIG 7A) or inserting sequences into IRES domains (FIGs 6B and 10A), it appears that engineering IRES sequences is not a predictable endeavor. As such, it is unpredictable what other aptamer sequences can be included in the CBV3 IRES that would at least maintain the IRES’s translation promoting activity.
Although Applicants may argue that it is possible to screen for functional CBV3 IRES’s with other aptamer sequences or alternatively screen for functions for CBV3 IRES’s having the eIF4G aptamer in different domain as claimed, the court found in that screening assays are not sufficient because they are merely a wish or plan for obtaining the claimed chemical invention. Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004.
Accordingly, in view of the Specification it is not clear how the skilled artisan would use many species of the genus of circRNA molecules comprising a modified CBV3 IRES comprising a generic aptamer.
State of the Prior Art
Stewart (US 20190307785 A1) discloses circRNA having the CVB3 IRES and additional sequences, such as spacer elements, splicing elements, and URE/CSE elements (Examples 44-48 and 55). However, none of these types of elements would be considered aptamers by the skilled artisan, given their length, and none of the elements are incorporated within the CBV3 IRES, either structurally or functionally. Kruse (US 20160083747 A1) describes an eIF4E-recruiting aptamer (SEQ ID NO 3) within the context of a circRNA, but does not combine the aptamer with a known IRES. Kruse also suggests developing a novel IRES that binds directly to eIF4G, thereby skipping the necessary recruitment by eIF4E ([0086]). However, this disclosure does not provide the sequence of any eIF4G aptamer or suggest combining the theoretical aptamer with an already known IRES.
Roberts and Wieden review attempts at engineering viral IRES (Biotechnology and Genetic Engineering Reviews (2018), 34: 60-75). Roberts reports only one previous attempt to combine a known IRES sequence with an RNA aptamer, in which the aptamer was placed upstream of the IRES to regulate translation (page 69, ¶1). A thorough search of the prior art found no disclosure of engineering a known IRES by inserting a polynucleotide sequence within the IRES sequence. Thus, in view of the prior art, it would be highly unpredictable how one skilled in the art would use many species within the genus of circRNA molecules comprising a modified CBV3 IRES comprising a generic aptamer.
Experimentation Required
In order to practice the invention, one skilled in the art would need to create an extensive library of aptamer sequences and insert them within various portions of the CVB3 IRES sequence. Once designed, the skilled artisan would need to screen them for a function. However, since it is not clear what, if any function, the IRES-aptamer sequence would have, it isn’t even clear what assays would need to be preformed to determine a function. Such assay development and subsequent screening to find a function for most of the claimed IRES-aptamer genus would be undue.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant, and the lack of working examples of other aptamers inserted within the CBV3 IRES, it is the conclusion that an undue experimentation would be required to use the invention across its entire claimed scope.
Dependent claims
Claims 17-20, 25, 27, 37, 44-46 and 48-49 do not limit the sequence of the aptamer and are rejected for the reasons described above for claim 12.
Claim 21 limits the aptamer sequence to having SEQ ID NO 99. However, claim 21 still allows insertion of the aptamer at any location within the CBV3 IRES. Applicant found that insertion of the aptamer having SEQ ID NO 99 at most sites in the CBV3 IRES resulted in a completely nonfunctional IRES sequence. As such, the skilled artisan would not know how to use most of the circRNAs comprising nonfunctional IRES-aptamer combinations.
Claim 52 is limited to the modified CVB3 IRES having 90% identity to SEQ ID NO 107, which allows 77 out of the 776 nucleotides to be altered. Thus claim 52 encompasses a genus of 10144 different sequences. Souii teaches the structure of the CBV3 IRES and the roles of various domains in translation initiation (Souii et al., Mol Biotechnol (2013), 55: 179-202). Souii teaches that most of the nucleotide positions hybridize with other nucleotides to form secondary structures (Fig 1), which are important for interactions with other domains and the translational machinery (throughout). Given 1) Applicant’s data showing that deletions of any domain and insertion of an aptamer into most domains abolishes translation function, 2) the lack of testing nucleotide substitutions at positions within the wild type CBV3, and 3) understanding in the art that the primary sequence of the IRES promotes secondary structure, which is required for its function, it is more likely that not that most of the species within that genus of 10144 different sequences would not function to initiate translation. As such, it is not predictable how the skilled artisan would use the circRNAs comprising the nonfunctional modified IRES sequences.
Allowable Subject Matter
Claims 51 and 53 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.
Claims 51 and 53 encompass a circRNA comprising a modified iCBV3 IRES having an aptamer comprising SEQ ID NO 99 inserted into the proximal loop of domain IV. Claim 53 further requires the IRES to comprise SEQ ID NO 107, which is the sequence of the wild type CBV3 IRES having the aptamer with SEQ ID NO 99 inserted into the proximal loop of domain. See FIG. 10A. Applicant demonstrates that this modified CBV3-aptamer promotes translation from the IRES within the context of a circRNA.
The closest prior art is Stewart (US 20190307785 A1), which discloses circRNAs having the CVB3 IRES and additional sequences, such as spacer elements, splicing elements and URE/CSE elements (Examples 44-48 and 55). However, none of these types of elements would be considered aptamers by the skilled artisan, given their length, and none of the elements are incorporated within the CBV3 IRES, either structurally or functionally.
Tusup developed an eIF4G-recuiting aptamer having SEQ ID NO 99 and demonstrated its ability to drive translation from a linear mRNA (EPH Int. J. Med. Health Sci 4 (2018): 29-35; Apt 17). Kruse (US 20160083747 A1) suggests developing a novel IRES that binds directly to eIF4G ([0086]). However, neither Tusup nor Kruse suggest combining eIF4G-recruiting aptamers with a known viral IRES or inserting them within the sequence of an IRES. As such, it would not have been obvious to insert Tusup’s eIF4G-recruiting aptamer into Stewart’s circRNA comprising the CBV3 IRES.
Conclusion
Claims 51 and 53 are objected to. Claims 12, 17-21, 25, 27, 37, 44-46, 48-49 and 52 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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