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
During a telephone conversation with Christopher Ramsey on 9/2/25 a provisional election was made without traverse to prosecute the invention of group I, claims 1-20. Affirmation of this election must be made by applicant in replying to this Office action.
Claims 21-22, 24-27, 29-32, 34-37, and 39-40 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
The election was affirmed in the response filed 1/20/2026.
Duplicate Claim Warning
Applicant is advised that should claim 6 be found allowable, claim 16 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Interpretation
The specification teaches that the fluorophore may be a “fluorescent nucleotide analog” (para 73). Where the amended claims require at least one fluorophore substituted at certain postion(s) the claim is interpreted to require a fluorescent nucleotide analog, consistent with the disclosure.
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.
Claim(s) 1, 2, 4, and 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stefanovic and Stefanovic (Biology 2014, 3, 281-294; doi:10.3390/biology3020281) in view of Bradrick and Marino (RNA (2004), 10:1459–1468).
Stefanovic teaches a composition with a first collagen mRNA nucleotide sequence that comprises SEQ ID NO: 1 and having a binding affinity for LARP6, the first collagen mRNA having a fluorescein label added at the 5’ end of the RNA (figure 1 description).
Stefanovic also provides an illustration which illustrates structure of the 5’stem-loop of collagen mRNA, and illustrates that A9 and U11 are nucleotides involved in binding LARP6.
Figure 1 from Stefanovic is copied below, with arrows added to highlight the nucleotides “in red” in the original figure.
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The reference does not teach a composition wherein the fluorophore is located at nucleotide position G10 of SEQ ID NO: 1. G10 is a nucleotide which is in the bulge illustrated in Figure 1.
Bradrick teaches a binding assay that measures protein-RNA binding which was developed by selectively substituting the highly fluorescent nucleoside analog 2-aminopurine (2-AP) for bulge bases in a hairpin (p. 1460, Figure 1A). These nucleotide positions are near the bases identified for peptide binding, but they are not identified as being important for peptide binding. Bradrick teaches that it was reasoned that substitution of 2-AP at these positions would be nonperturbing and provide sensitive probes of ligand interactions with TAR.
It would have been obvious before the effective filing date to have modified the probe taught by Stefanovic so as to have employed 2-AP nucleotides at positions near nucleotides identified as important for binding of LARP6, including the G10 position identified in Figure 1 of Stafanovic. One would have been motivated to make this modification by the teaching of Bradrick to use the highly fluorescent nucleotide analog to monitor placement, and the exemplification of the placement of the 2AP in a bulge position that was near but not exactly one of the nucleotides known to be important for binding. Following the teachings of Bradrick, there would have been a reasonable expectation of success at creating a sensor for monitoring RNA-protein interactions.
Claim(s) 6, 7, 9, 11, 12, 14, 16, 17, 19, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stefanovic in view of Bradrick as applied to claims 1, 4, and 5 above, and further in view of Zhang and Stefanovic (Int. J. Mol. Sci. 2016, 17, 419).
The teachings of Stefanovic in view of Bradrick are given previously in this office action and are fully incorporated here. These do not teach a molecule that is 90% identical to SEQ ID NO: 2.
Zhang teaches the sequence of the 5’SL of human collagen alpha 2(I), and identifies nucleotides critical for LARP6 binding (Figure 1). This 5’SL is identical to SEQ ID NO: 2, and G9 is a nucleotide sandwiched between nucleotides that are identified as critical for LARP6 binding.
It would have been obvious before the effective filing date to have modified the composition taught by Stafanovic so as to have included probes for both 5’SL of human collagen mRNA, as they both are bound by LARP6 with a similar binding constant (p. 4). Furthermore, it would have been obvious to have placed an 2AP at the G9 position of the collagen alpha 2(I) 5’SL in order to provide a probe that would be a sensor for monitoring binding of LARP6 to the 5’SL.
Response to Remarks
The rejection under 112a was overcome by amendment.
Applicant traverses the obviousness rejections.
Applicant argues that any modification Stefanovic must main its purpose of identifying compounds that can dissociate LARP6 from a complex with collagen 5’ stem loop RNA.
Applicant argues that there is no evidence that making the recited modification would yield an assay that can identify compounds that dissociate LARP6 from a complex with collagen 5’ stem loop RNA. However, this is a piecemeal analysis as Bradrick clearly shows that substituting a fluorescent nucleotide analog can be used to provide sensitive probes of ligand interactions. A person of ordinary skill has good reason to pursue the known options within his or her grasp. Here the primary reference clearly identified bulge positions, and Badrick provides clear suggestion to substitute 2-AP at bulge positions. Badrick provides evidence to suggest such a modification would be successful to provide an alternate probe.
Applicant argues that the reasonable expectation of success must be tied to achieving Stefanovic’s goal. The examiner maintains that it is tied to achieving Stefanovic’s goal, as the suggestion is to provide an alternate probe for use in the same system. Reasonable expectation of success does not require an absolute expectation of success.
Applicant argues that there is no suggestion to substitute a fluorophore at position G10 and/or C38. However, Badrick clearly suggests substituting nucleotides in the bulge, and G10 is clearly illustrated as one of a limited number of choices.
The rejection against claim 1 and its dependents in maintained for these reasons.
Conclusion
Claims 10 and 15 are free of the prior art. The prior art does not suggest modifying SEQ ID NO: 2 by substituting C37 for a pyrrolo-cytidine. The C37 position is taught in Zhang as being a position critical to the 5’SL binding LARP6.
Claims 10 and 15 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.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Rist and Marion teach that highly fluorescent dyes or nucleotide base analogs can serve as extremely sensitive probes in nucleic acid systems (p. 775). Local structural changes in RNA caused by protein binding can be assessed using 2-AP fluorescence, so long as specific protein recognition of the substituted adenine is not required. This supports that it would have not been obvious to have substituted the C38 position of SEQ ID NO: 1 or the C37 position of SEQ ID NO: 2 since these had been taught to be critical for binding LARP6.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682