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 Status
This action is written in response to applicant’s correspondence received Sept 23, 2025. Claims 2-25, and 27-30 are currently pending and examined herein.
Priority
Acknowledgment is made of applicant's claim for priority based on a US Provisional Application
No. 63/313,423 filed on Feb 24, 2022.
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 12 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.
Claim 12 recites the limitation "said non-stop, non-start codon" in line 2. There is insufficient antecedent basis for this limitation in the claim. The first recitation of "non-stop, non-start codon" is in claim 11. It is unclear if this limitation is related to recitation in claim 11. It is unclear how this limitation is related to “editable codons” recited in claim 2.
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.
Claims 2-5, 8, 15-19, 21, and 23-30 are rejected under 35 U.S.C. 103 as being unpatentable over Jiang et al (WO 2022266117 A2; Provisional No. 6/210,829 Priority to June 15, 2021) and Garncarz et al (A high throughput screen to identify enhancers of ADAR-mediated RNA-editing; RNA Biology, 2013, 10(2):192-204; IDS received on Oct 17, 2024; IDS Non-Patent Literature Cite No. 13).
Regarding claim 2, Jiang teaches and RNA sensor system (i.e., a ssRNA sensor) comprising:
(a) a ssRNA sensor (i.e., a first region) comprising: (i) a region that is capable of binding to a ssRNA target to form a double-stranded RNA duplex that becomes a substrate for an adenosine deaminase (i.e., a nucleotide sequence configured to hybridize to a target RNA), and (ii) a stop codon (i.e., one or more editable codons); and
(b) a payload (i.e., a second region comprising a sequence encoding a protein) (Abstract).
However, Jiang does not teach a stem-loop sequence comprising one or more editable codons.
Garncarz teaches an editing substrate for adenosine deasminase acting on RNA (ADAR) introduced into the 5’ region of a His3 gene, shortly downstream of the AUG initiation codon (pg. 193, right-column, third paragraph). Garncarz further teaches the editing substrate is the stem loop containing the R/G editing site of glutamate receptor subunit B (GluR-B) and “was shortened and modified to contain an amber stop codon at the editing site” (Fig. 1A and C), wherein “HIS3 protein expression requires editing of the transcribed RNA leading to a conversion of the amber stop codon to a tryptophan” (Fig. 1A).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Jiang’s ssRNA sensor with a stem loop comprising editable codons as taught by Garncarz because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results given that the substituted component (stem-loop sequence comprising editable codon) and its function (editing substrate for ADAR or serves as recruiting domain for ADAR) were known in the art. One would have been motivated to have done so for the advantage of including one of the most prominent substrates of ADAR in mammals (Garncarz, pg. 192, left-column, first paragraph) in the ssRNA sensor to enhance ADAR binding and editing efficiency. One would have had a reasonable expectation of success in doing so because Jiang teaches a ssRNA sensor comprising an editing substrate for ADAR.
Regarding claim 3, Jiang teaches wherein one or more editable codons further comprises a stop codon (Abstract).
Regarding claim 4, Jiang teaches a composition comprising the RNA sensor system and a cell comprising target RNA ([0171]).
Regarding claim 5, Jiang teaches a method comprising: (a) supplying (i.e., combining) a target cell with (i) a ssRNA sensor comprising a stop codon and is capable of binding to a ssRNA target and (ii) a payload that is a self-dimerizing caspase; and (b) “the ssRNA target is enriched in expression in the specific cell or cell type” (claim 60, pg. 69). Jiang further describes the method comprising: (a) transfecting a target cell with “a dual reporter, single transcript targeting sensor” or an RNA sensor system comprising components previously discussed above as applied to claim 2; and (b) subjecting cells to doxycycline induction (i.e., subjecting said sensor RNA to conditions sufficient) for sensor to hybridize to target RNA (e.g., eGFP) and ADAR to edit TAG codon to TIG ([0171]-[0172]).
Regarding claim 8, Jiang teaches wherein the stop codon further comprises a TAG/UAG (claim 26; pg. 66)
Regarding claims 15 and 16, Jiang teaches wherein the payload (i.e., protein) comprises a reporter protein, a transcription factor, an enzyme, a therapeutic protein (claim 5; pg. 62), or a caspase (i.e., killing factor) ([0008]).
Regarding claim 17, Jiang teaches wherein the RNA sensor system is encapsulated in a lipid nanoparticle (claim 59; pg. 69)
Regarding claim 18, Jiang teaches the RNA sensor system is delivered via a viral vector ([0144]).
Regarding claim 19, the teachings of Jiang’s method regarding editing codons with ADAR is discussed above as applied to claim 5.
Regarding claim 21, Jiang teaches wherein said target RNA is a messenger RNA (e.g., IL6, eGFP) ([0186]).
Regarding claims 23 and 24, the obviousness to modify Jiang’s RNA sensor system to comprise a stem-loop sequence comprising editable codons is discussed above as applied to claim 2. Garncarz further teaches the editable stop codon is in a stem of GluR-B (instant claim 23) and the editable codon comprises at least one base that is mismatched with a sequence within the stem-loop sequence opposite of the editable codon (instant claim 24) (Fig. 1C).
Regarding claim 25, the obviousness to modify Jiang’s RNA sensor system to comprise a stem-loop sequence comprising editable codons is discussed above as applied to claim 2.
Jiang teaches a second version of RNA sensor system (RADARSv2) comprises out-of-frame stop codons ([0167]), which suggests that previous version of RNA sensor system comprises editable stop codons in-frame with payload (i.e., protein) and meets instantly recited claim limitation.
Nevertheless, Garncarz also teaches converting editable stop codon in GluR-B to a tryptophan codon enables functional HIS3 protein expression (pg. 193, right-column, third paragraph), suggesting that protein is in-frame with said editable stop codon.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the stop codon in the RNA sensor system of Jiang’s method to be in-frame as taught by Fraley because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results given that the substituted component (in-frame stop codon that is modified to be a non-stop codon) and its function (continuing translation of downstream sequences) were known in the art. One would have been motivated to have done so for the advantage of modulating expression of in-frame proteins and avoid translation of misfolded or aberrantly interrupted proteins. One would have had a reasonable expectation of success in doing so because Jiang teaches an RNA sensor system comprising editable stop codon to enable expression of a protein.
Regarding claim 27, the obviousness to modify Jiang’s RNA sensor system to comprise a stem-loop sequence comprising editable codons is discussed above as applied to claim 2. Jiang further teaches wherein ssRNA sensor configured to hybridize to target RNA is at least 60% complementarity to target RNA (FIG. 24).
Regarding claim 28, the obviousness to modify Jiang’s RNA sensor system to comprise a stem-loop sequence comprising editable codons is discussed above as applied to claim 2. Garncarz also teaches GluR-B stem-loop sequence is at least 12 base pairs in length (Fig. 1C).
Regarding claims 29 and 30, the obviousness to modify Jiang’s RNA sensor system to comprise a stem-loop sequence comprising editable codons is discussed above as applied to claim 2. Jiang further teaches “an AND gate” approach where the ssRNA sensor comprising nucleotide sequence that is configured to hybridize to two non-contiguous sequences within target RNA (instant claim 30), a portion hybridizing to “target 1” and another portion hybridizing to “target 2” (FIG. 65A), and a payload is expressed only if both target RNAs are present ([0211]). Jiang teaches wherein target 1 is IL6 and target 2 is EGFP (FIG. 65B).
However, Jiang does not explicitly teach wherein target RNA comprises an encoded gene fusion, Jiang does teach “AND gate sensor behaved in a target specific manner, requiring both targets to reach full activation…36-fold activation in the presence of both target transcripts with only 1.3-1.5-fold activation when only one target RNA was present (FIG. 65B).” ([0212])
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the ssRNA sensor of Jiang to target encoded gene fusion because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of detecting gene fusions or splice variants instead of individual genes as IL6 and EGFP. For this purpose, it would have been obvious to have designed ssRNA sensor comprising nucleotide sequences configured to hybridize to a gene fusion instead of ssRNA sensor configured to hybridize to individual gene transcripts given that the substituted component (gene fusion) and its function (encode a polypeptide) are known in the art. One would have had a reasonable expectation of success in doing so because Jiang already teaches a RNA sensor system comprising ssRNA sensors configured to hybridize to more than one target RNAs in an AND gate logic.
Claims 6-7, 9, 11, 13-14, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Jiang et al (WO 2022266117 A2; Provisional No. 6/210,829 Priority to June 15, 2021) and Garncarz et al (A high throughput screen to identify enhancers of ADAR-mediated RNA-editing; RNA Biology, 2013, 10(2):192-204; IDS received on Oct 17, 2024; IDS Non-Patent Literature Cite No. 13) as applied to claims 2 and 5 above, and further in view of Fraley et al (CA 3127243 A1; Published Date: Jul 30, 2020).
Regarding claims 6-7, 9, 11, and 13, the teachings of Jiang’s method is discussed above as applied to claim 5, and the obviousness to modify Jiang’s RNA sensor system to comprise a stem-loop sequence comprising editable codons is discussed above as applied to claim 2.
However, neither Jiang or Garncarz teaches “such that editing of said editable codon impairs expression” or “promotes expression of said second region of said sensor RNA”, or editable codons comprises a start codon, a non-stop, non-start codon, or 5’-AUA-3’.
Fraley teaches a method to deaminate adenosine in target mRNA by using guide oligonucleotides (ASO) designed to hybridize to target mRNAs, and wherein ASOs are incorporated with GluR-B (pg. 45) to “increase the recruitment of ADAR and increase the efficiency of editing” of target mRNA (pg. 1, lines 20-36). Fraley further teaches a list of editable codons including a start codon AUG (instant claim 9) to become IUG encoding for valine that impairs expression (instant claim 6), a non-stop, non-start codon AUA (instant claim 13) to become a start codon (instant claim 11) that promotes expression (instant claim 7).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the stop codon in the RNA sensor system of Jiang’s method to other editable codons as taught by Fraley because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results given that the substituted component (editable codons other than a stop codon) and its function (encode a canonical amino acid) were known in the art. One would have been motivated to have done so for the advantage of introducing various modified codons to further modulate expressions including impairing, initiating, and continuing expression. One would have had a reasonable expectation of success in doing so because Jiang teaches a method of using RNA sensor system that recruits ADAR modify editable codons at specific editing sites.
Regarding claim 14, the obviousness to modify Jiang’s RNA sensor system to comprise a stem-loop sequence comprising editable codons is discussed above as applied to claim 2. Jiang teaches wherein the ssRNA sensor comprises nucleotide sequences configured to hybridize to endogeneous transcripts (FIG. 1).
However, neither Jiang or Garncarz teach wherein nucleotide sequence is configured to hybridize to an untranslated region (UTR) of target RNA.
Fraley teaches designing ASO targeting 3’-UTR of human RAB7A gene (pg. 80; Example 1), demonstrating that the 3’-UTR is a known and suitable region for ssRNA with stem-loop sequences binding to achieve base editing.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the target RNA in Jiang’s RNA sensor system 3’-UTR as taught by Fraley because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results given that the substituted component (EGFP to 3’-UTR) and its function (an alternative and characterized target region for single-stranded RNA oligonucleotide hybridization) were known in the art. One would have been motivated to have done so for the advantage of detecting endogenous transcripts. One would have had a reasonable expectation of success in doing so because Jiang teaches RNA sensor system targeting transcripts expressed in cells.
Regarding claim 20, the obviousness to modify Jiang’s method to comprise a stem-loop sequence comprising editable codons in a ssRNA sensor is discussed above as applied to claim 5.
However, neither Jiang or Garncarz teaches administering sensor RNA to a patient.
Fraley teaches oligonucleotides are “formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.” (pg. 77, lines 5-7)
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the RNA sensor system in Jiang’s method to be in a pharmaceutical composition as taught by Fraley because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Each component in the combination performs the same function as they do separately: the RNA sensor system retains its known function of sequence-specific hybridization to target RNA and ADAR modifying editable codon to enable expression of a protein, while the pharmaceutical formulation retains its known function of facilitating delivery and administration to a patient. One would have been motivated to have done so for the advantage of delivering the RNA sensor system in vivo. One would have had a reasonable expectation of success in doing so because Fraley teaches the formulations of pharmaceutical composition.
Regarding claim 22, the obviousness to modify Jiang’s RNA sensor system to comprise a stem-loop sequence comprising editable codons is discussed above as applied to claim 2.
However, neither Jiang or Garncarz teaches wherein nucleotide sequence configured to hybridize to target RNA and stem-loop sequence comprising one or more editable codons are non-overlapping.
Fraley illustrates a stem-loop sequence (GluR-B) extended with an oligonucleotide (ASO) at the 3’-end, which demonstrates that the ASO and the stem-loop are structurally distinct and non-overlapping (pg. 45).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Jiang’s RNA sensor system to include Garncarz’s stem-loop sequence in the design as taught by Fraley because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Each component in the combination performs the same function as they do separately: the nucleotide sequence configured to hybridize to target RNA retains its known function of hybridizing to desired target RNA, while the stem-loop sequence retains its known function of comprising editable codons to promote or impair expression of a protein. One would have been motivated to have done so for the advantage of avoiding undesired interactions including misfolding of stem-loop sequence with nucleotide sequence configured to hybridize to target RNA and nonspecific hybridization to unintended targets. One would have had a reasonable expectation of success in doing so because Fraley teaches development of single nucleic acid sensors comprising components in the first region recited in claim 2.
Claims 10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Jiang et al (WO 2022266117 A2; Provisional No. 6/210,829 Priority to June 15, 2021) and Garncarz et al (A high throughput screen to identify enhancers of ADAR-mediated RNA-editing; RNA Biology, 2013, 10(2):192-204; IDS received on Oct 17, 2024; IDS Non-Patent Literature Cite No. 13) and Fraley et al (CA 3127243 A1; Published Date: Jul 30, 2020) as applied to claims 9 and 11 above, and further in view of Reff (WO 9411523A2; Published Date: May 26, 1994).
Regarding claims 10 and 12, the obviousness to modify Jiang’s RNA sensor system to comprise a stem-loop sequence comprising a start codon or non-stop, non-start codon is discussed above as applied to claims 9 and 11, respectively.
However, neither Jiang, Garncarz, or Fraley teaches wherein the stem-loop sequence further comprises a Kozak sequence operably linked to editable codons.
Reff teaches “utilization of a fully impaired consensus Kozak with a secondary structure (i.e., a so-called "stem-loop" or "hairpin") is beneficial viable to impairment of translation of protein…in such an embodiment, the start codon of the fully impaired consensus Kozak is most preferably located within the stem of a stem loop." (pg.23, lines 15-30) Reff further teaches "preferably, the out-of-frame start codon is part of a consensus Kozak." (pg. 7, lines 28) Schematic examples as follows:
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Jiang’s RNA sensor system further comprise a Kozak sequence in the stem-loop of Garncarz as taught by Reff because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Upon addition of a Kozak sequence to the stem-loop sequence, each component in the combination performs the same function as they do separately: the stem-loop sequence retains it known function of comprising editable codons to promote or impair expression of a protein, while the Kozak sequence retains its known function of impairing expression when combined with secondary structures as taught by Reff. One would have been motivated to have done so for the advantage of impairing expression of protein. One would have had a reasonable expectation of success in doing so because Reff teaches designs of Kozak sequences with stem-loops and Garncarz also teaches stem-loops sequences wherein the stem is modified (FIG. 1C).
Response to the Arguments
Applicant’s remarks received on Sept 23, 2025, were primarily directed to Daniel et al (RNA editing of non-coding RNA and its role in gene regulation; Biochimie, 2017, 117:22-27) and have been fully considered and is found persuasive. Therefore, prior rejections on claims 2-25, and 27-30 is withdrawn. However, claims 2-25, and 27-30 remain unpatentable as set forth in the current Office Action (see discussions above regarding 35 U.S.C. 103 rejection), particularly in view of Garncarz et al (A high throughput screen to identify enhancers of ADAR-mediated RNA-editing; RNA Biology, 2013, 10(2):192-204; IDS received on Oct 17, 2024; IDS Cite No. 13).
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to QIWEN SU-TOBON whose telephone number is (571)272-0331. The examiner can normally be reached Monday - Friday, 9:30am - 5:00pm.
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QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636