DETAILED ACTION
Response to Amendment
Applicant’s response to the office action filed on June 11, 2026 has been entered. The claims pending in this application are claims 24, 28-35, 38, 43-49, and 52-54 wherein claim 33 has been withdrawn due to the restriction requirement mailed on October 24, 2025. The objections and rejections not reiterated from the previous office action are hereby withdrawn in view of applicant’s amendment filed on June 11, 2026. Claims 24, 28-32, 34, 35, 38, 43-49, and 52-54 will be examined.
Drawings
New Figures 5, 7, 8, 9A to 9G, 11A to 11C, 13A, 15A, 16, 17, 19, 21, and 23-25 submitted on June 11, 2026 have been accepted and entered. However, since some nucleotide sequences in new Figures 11 D, 13B, 15B, and 15C submitted on June 11, 2026 do not have SEQ ID Nos, applicant is required to submit new Figures 11 D, 13B, 15B, and 15C in response to this office action. No new matter may be introduced in the required drawing. 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).
Claim Objections
Claim 31 is objected to because of the following informality: “a nucleotide sequence according to any one of SEQ ID NOs: 6-107” should be “the nucleotide sequence selected from SEQ ID NOs: 6-107.
Claim 38 is objected to because of the following informality: “a nucleotide sequence according to any one of SEQ ID NOs:108-143” should be “the nucleotide sequence elected from SEQ ID NOs: 108-143.
Claim 52 is objected to because of the following informality: “a nucleotide sequence according to any one of SEQ ID NOs: 202-481” should be “the nucleotide sequence elected from SEQ ID NOs: 202-302 or SEQ ID Nos: 303-481”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Scope of Enablement
Note the rejection is modified from the rejection under 35 U.S.C. 112(a) mailed on March 11, 2026 but some issues in the rejection under 35 U.S.C. 112(a) mailed on March 11, 2026 have been withdrawn in this rejection.
Claims 24, 28-32, 34, 35, 38, 43-49, and 52-54 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 performing step a) of claim 24, does not reasonably provide enablement for selecting guide RNAs for use in site-directed RNA editing using the methods recited in claims 24, 28-32, 34, 35, 38, 43-49, and 52-54. 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims”.
The Nature of The Invention
The claims are drawn to a high-throughput screening method for selecting guide RNAs for use in site-directed RNA editing. The invention is a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The Breadth of The Claims
Claims 24, 28-32, 34, 35, 38, 43-49, and 52-54 encompass a high-throughput screening method for selecting guide RNAs for use in site-directed RNA editing, the method comprising:
a) generating a plurality of fusion constructs, each fusion construct comprising a target sequence and a guide RNA sequence, wherein the target sequence is derived from a gene for which site-directed A-to-I RNA editing is desired, and wherein the guide RNA sequence comprises an antisense domain that is substantially complementary or perfectly complementary to the target sequence and a recruitment domain that recruits endogenous adenosine deaminases acting on RNA (ADARs) and/or engineered ADAR fusion proteins, wherein the recruitment domain comprises a first strand and a second strand that are substantially complementary or perfectly complementary to each other; b) expressing each of the plurality of fusion constructs in a distinct population of cells, wherein the cells express endogenous ADARs and/or at least one engineered ADAR fusion protein; and c) determining whether a fusion construct induces any kind of one or more modifications in a target nucleic acid isolated from the population of cells expressing the fusion constructs.
Working Examples
Although the specification provides 4 working examples (see pages 15-34 of US 2024/0110177 A1, which is US publication of this instant case), the specification provides no working example for selecting guide RNAs for use in site-directed RNA editing using the methods recited in claims 24, 28-32, 34, 35, 38, 43-49, and 52-54.
The Amount of Direction or Guidance Provided and The State of The Prior Art
The specification provides 4 working examples (see pages 15-34 of US 2024/0110177 A1, which is US publication of this instant case). However, the specification provides no working example for selecting guide RNAs for use in site-directed RNA editing using the methods recited in claims 24, 28-32, 34, 35, 38, 43-49, and 52-54. Furthermore, there is no experimental condition and/or experimental data in the specification to support the claimed invention. During the process of the prior art search, the examiner has not found any prior art which is related to select guide RNAs for use in site-directed RNA editing using the methods recited in claims 24, 28-32, 34, 35, 38, 43-49, and 52-54.
Level of Skill in The Art, The Unpredictability of The Art, and The Quantity of Experimentation Necessary
While the relative skill in the art is very high (the Ph.D. degree with laboratory experience), there is no predictability whether guide RNAs for use in site-directed RNA editing can be selected using the methods recited in claims 24, 28-32, 34, 35, 38, 43-49, and 52-54.
Since the specification teaches that “[I]n some aspects, provided herein are fusion constructs. In some embodiments, provided herein is a fusion construct comprising a target sequence and a guide RNA sequence. In some embodiments, the guide RNA sequence comprises an antisense domain that is substantially complementary or perfectly complementary to the target sequence. In some embodiments, the guide RNA sequence further comprises a recruitment domain that recruits endogenous adenosine deaminases acting on RNA (ADARs) and/or engineered ADAR fusion proteins. In some embodiments, the recruitment domain comprises a first strand and a second strand that are substantially complementary or perfectly complementary to each other”, “[F]IG. 2 shows design of endogenous ADAR-recruiting guide RNAs (gRNAs). ADARs, composed of a deaminase domain (ADAR-D) and multiple dsRNA-binding domains (dsRBDs), edit the R/G site located in a hairpin structure of GRIA2 pre-mRNA (left panel). Fusing a part of the hairpin structure (55 nt) to an antisense sequence (18-40 nt), complementary to a user-defined sequence, results in the generation of a gRNA which directs the ADAR enzyme to the target adenosine. The hairpin functions as ADAR-recruiting part enabling the interaction with the dsRBDs while the hybrid of the gRNA antisense domain and the target RNA is recognized by the deaminase domain catalyzing editing at the target site. To recruit ADAR, R/G gRNAs are either expressed from a plasmid or applied as a chemically modified antisense oligonucleotide (ASO)”, “[I]n some embodiments, the fusion construct comprises a target sequence. The target sequence is selected based upon the gene of interest (i.e., the gene for which site-directed A-to-I RNA editing is desired)”, “In some embodiments, the guide RNA sequence comprises a recruitment domain. The recruitment domain (also referred to herein as the ADAR-recruiting part), facilitates the interaction with the ADAR or ADAR fusion protein. The recruitment domain is configured to bind (i.e., recruit) one or more ADAR proteins or fusions thereof”, “In some embodiments, provided herein is a high-throughput screening method for selecting guide RNAs for use in site-directed RNA editing. In some embodiments, the method comprises generating a plurality of fusion constructs as described herein. The fusion constructs comprise a target sequence and a guide RNA sequence as described herein. In some embodiments, the target sequence is derived from a gene for which site-directed A-to-I RNA editing is desired”, “[T]he methods further comprise inducing expression of the fusion construct in a suitable cell. For example, the method may further comprise transfecting cells expressing adenosine deaminases acting on RNA (ADARs) or cells expressing ADAR fusion proteins with the fusion constructs. The method further comprises determining whether a fusion construct effectively induces one or more mutations in nucleic acid isolated from the cells relative to a control. Any suitable cells expressing ADARs or ADAR fusion proteins may be used”, and “[I]n some embodiments, determining whether a fusion construct induces one or more modifications in nucleic acid isolated from the population of cells expressing the fusion construct comprises sequencing the isolated nucleic acid. In sonic embodiments, the one or more modifications in nucleic acid isolated from the population of cells comprises a correction of the mutation (e.g. G to A point mutation, C to A point mutation, or to A point mutation) initially present in the target sequence. For example, RNA may be isolated from the cells and sequencing may be performed to determine whether the G to A point mutation initially present in the target sequence has been corrected. For example, successful recruitment of ADARs enables modification of selected adenine residues to inosine. Since inosine is biochemically interpreted as guanosine by the cellular machinery, A-to-I editing introduces A-to-G point mutations in RNA. Accordingly, point mutations present in the target sequence, such as a G to A point mutation present in the target sequence, may be corrected. For example, the adenosine residue originally present in the target sequence may be corrected to a guanine residue. Correction of the G to A point mutation indicates that the guide RNA sequence effectively induces site-directed RNA editing (i.e., site-directed A-to-I RNA editing)” (see Figure 2 and paragraphs [0005], [0025], [0088], [0096], [0113], [0114], and [0116] of US 2024/0110177 A1, which is US publication of this instant case), the specification teaches a fusion construct comprising a target sequence and a guide RNA sequence wherein the target sequence is derived from a gene for which site-directed A-to-I RNA editing is desired, the guide RNA sequence comprises an antisense domain that is substantially complementary or perfectly complementary to the target sequence and a recruitment domain comprising a first strand and a second strand that are substantially complementary or perfectly complementary to each other and binds to dsRNA binding domains of adenosine deaminases and clearly indicates that a RNA made by the target sequence of the fusion construct can be introduced A-to-G point mutations when the fusion construct is expressed in cells which express endogenous adenosine deaminase. However, the scope of the claims is much broader than the teaching of the specification. Since claim 24 does not require that the recruitment domain of the guide RNA sequence binds to dsRNA binding domains of adenosine deaminases and one or more modifications in a target nucleic acid isolated from the population of cells expressing the fusion constructs are A-to-G point mutations, if the recruitment domain of the guide RNA sequence do not bind to dsRNA binding domains of adenosine deaminases and one or more modifications in a target nucleic acid isolated from the population of cells expressing the fusion constructs are any kind of one or more modification such as a methylation, whether a fusion construct induces any kind of one or more modifications in a target nucleic acid isolated from the population of cells expressing the fusion constructs cannot be determined such that it is unpredictable how guide RNAs for use in site-directed RNA editing can be selected using the methods recited in claims 24, 28-32, 34, 35, 38, 43-49, and 52-54.
Case law has established that “(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that “[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art”. The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genentech Inc. v Novo Nordisk 42 USPQ2d 1001 held that “[I]t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement”.
In view of above discussions, the skilled artisan will have no way to predict the experimental results. Accordingly, it is concluded that undue experimentation is required to make the invention as it is claimed. The undue experimentation at least includes to test whether guide RNAs for use in site-directed RNA editing can be selected using the methods recited in claims 24, 28-32, 34, 35, 38, 43-49, and 52-54.
Conclusion
In the instant case, as discussed above, the level of unpredictability in the art is high, the specification provides one with no guidance that leads one to claimed methods. One of skill in the art cannot readily anticipate the effect of a change within the subject matter to which the claimed invention pertains. Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of any working example related to claimed invention and the no teaching in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
Response to Arguments
In page 9, second and third paragraphs of applicant’s remarks, applicant argues that “[T]he Examiner indicates that the claim is broader in scope than what is enabled by the application as filed. Solely to expedite prosecution, claim 24 is amended to recite that the target sequence is derived from a gene for which site-directed A-to-I RNA editing is desired, and that the guide RNA sequence comprises an antisense domain that is substantially complementary or perfectly complementary to the target sequence and a recruitment domain that recruits endogenous adenosine deaminases acting on RNA (ADARs) and/or engineered ADAR fusion proteins, wherein the recruitment domain comprises a first strand and a second strand that are substantially complementary or perfectly complementary to each other. The Examiner acknowledges on page 8 of the office action that such a method is described in the application as filed. Claim 24 further recites that the cells express endogenous ADARs and/or at least one engineered ADAR fusion protein, thus addressing how the recruitment domain can recruit ADARs and/or engineered ADAR fusion proteins in the population of cells”.
The above arguments have been fully considered but they are not persuasive toward the withdrawal of the rejection. In view of amended claim 24, since claim 24 does not require that the recruitment domain of the guide RNA sequence binds to dsRNA binding domains of adenosine deaminases and one or more modifications in a target nucleic acid isolated from the population of cells expressing the fusion constructs are A-to-G point mutations, if the recruitment domain of the guide RNA sequence do not bind to dsRNA binding domains of adenosine deaminases and one or more modifications in a target nucleic acid isolated from the population of cells expressing the fusion constructs are any kind of one or more modification such as a methylation, whether a fusion construct induces any kind of one or more modifications in a target nucleic acid isolated from the population of cells expressing the fusion constructs cannot be determined such that it is unpredictable how guide RNAs for use in site-directed RNA editing can be selected using the methods recited in claims 24, 28-32, 34, 35, 38, 43-49, and 52-54.
Conclusion
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.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph. D., whose telephone number is (571)272-0746. The examiner can normally be reached Monday to Friday, 9 AM to 5 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow, Ph.D., can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/FRANK W LU/
Primary Examiner, Art Unit 1683
August 26, 2026
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