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 .
Status of Application/Amendments/Claims
Applicant’s response filed on 9/8/2026 has been considered. Claims 89-93 are newly added. Claims 70, 74-76 and 87 have been canceled. Claims 69, 73 and 93 have been amended. Claims 69, 71-73, 77-86 and 88-93 are pending. Claims 86 and 88 are withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 69, 71-73, 77-85 and 89-93 are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application 371 of PCTCN2021096122 filed on 5/26/2022 under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 5/26/2022.
Withdrawn Claim Rejections and Objections
The objection to claim 1 has been withdrawn in light of applicants claim amendments defining the acronym DKC1.
The 35 U.S.C. 112(b) rejection of claims 73-76 has been withdrawn in light of applicants claim amendments to independent claim 69 and 73, describing that the scaffold sequence comprises one or more mutations.
The 35 U.S.C. 102(a)(1) and 102(a)(2) rejections of claims 69, 73-79 and 81-85 over Klein have been withdrawn in light of applicants claim amendments describing DKC1 protein localization in the cytoplasm of the host cell.
New Claim Rejections - 35 USC § 112b
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.
Claims 73, 79 and 89-92 are 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 pre-AIA the applicant regards as the invention. This rejection is newly applied to address applicants claim amendments filed on 9/8/2026.
Claims 73-76 describe gsnoRNA sequences which are “derived from” wild type H/ACA-snoRNA scaffold sequences. Wild type H/ACA gsnoRNA are a class of small noncoding RNAs which exhibit highly conserved hairpin-hinge-hairpin-tail architecture which act as a structural scaffold for assembling proteins like DKC1 to form pseudouridylation complexes. Although the claims have been amended to recite that the scaffold sequence comprises one or more mutations, the claims recite that the scaffold sequence comprises a sequence derived from, indicating that the one or more mutations are in addition to other changes from the wild type H/ACA gsnoRNA. Similarly, claim 79 describes the intron sequence and the second exon sequence derived from a naturally-occurring gene. It is unclear what “derived from” would indicate to one of ordinary skill in the art. “Derived from” could convey several different meanings to one of ordinary skill including degree of gsnoRNA sequence similarity, structural homology any number of core structural characteristics (bipartite hairpins, Hbox, ACA box). Please note that the language of a claim must make it clear what subject matter the claim encompasses to adequately delineate its "metes and bounds", see MPEP 2173. Claims 89-92 are rejected for their dependency on indefinite claim 73. Notably, claim 93 is excluded since the scaffold sequences are described with their Seq ID NO.
Response to Traversal
Although the rejection is newly applied in modified form, some of applicant’s arguments are still relevant and are addressed below.
Applicant traverses the rejection by arguing that the specification does not use “derived from” as an open-ended reference to any sequence or structure exhibiting some degree of similarity to wild type H/ACA gsnoRNA. Applicant points to newly added claims 89-92 which describe further structural and sequence-based definitions of the claimed scaffold sequence and its modifications.
These arguments have been fully considered, but are not found persuasive since although the claims have been amended to recite that the scaffold sequence comprises one or more mutations, the claims recite that the scaffold sequence comprises a sequence derived from, indicating that the one or more mutations are in addition to other changes from the wild type H/ACA gsnoRNA. “Derived from” could still convey several different meanings to one of ordinary skill including degree of gsnoRNA sequence similarity, structural homology any number of core structural characteristics (bipartite hairpins, Hbox, ACA box).
Claim Interpretation
Claim 73 describes a gsnoRNA sequences which are “derived from” wild type H/ACA-snoRNA scaffold sequences. Taking the broadest reasonable interpretation, derived from reads broadly on any sequence or structural similarity to the wild type H/ACA-snoRNA scaffold sequences with one or more mutation.
Maintained 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 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.
Claims 69, 71-73, 77-85 and 89-91 are rejected under 35 U.S.C. 103 as being unpatentable over Klein et al. US 2021/0010002, published 1/14/2021, priority date 3/27/2018 (hereinafter Klein, reference of record) in view of Heiss et al. WO 99/54449, published 10/28/1999, machine translation provided (hereinafter Heiss) and Angrisani et al. "A new human dyskerin isoform with cytoplasmic localization." Biochimica et Biophysica Acta (BBA)-General Subjects 1810.12 (2011): 1361-1368 (hereinafter Angrisani). This rejection is applied in modified form and newly applied to claims 89-91 to address applicants claim amendments on 9/8/2026. A response to applicant’s traversal is found below.
Claim 69: Klein discloses a method for editing a target RNA in a host cell by converting a uridine to a pseudouridine (Klein, para 8). Klein presents this as a strategy to replace uridine with pseudouridine in stop codons to suppress translation termination, which could be harnessed to mediate readthrough of premature termination codons which are the cause of several genetic disorders (Klein, para 35 and examples 2-4 and claim 15). Klein achieves this by using an engineered guide RNA with the correct structural motif to recruit a host endogenous dyskerin complex (DKC1) that catalyzes the isomerization of uridine to pseudouridine (Klein, para 5, 58). Klein does not describe a DKC1 protein which is introduced and localizes in the cytoplasm of a host cell.
Claims 73 and 89-90: Klein discloses the basic structure of the wild type H/ACA-snoRNA ACA19 which comprises two hairpin structures within which the internal target-binding loops are located as well as the H box between the hairpins and the ACA box at the 3’ end (Klein, para 18 and Fig 4). Klein describes non-natural modifications in the ribose moiety, which reads on “mutation” as recited in newly amended claim 73 (Klein, claim 6).
Claims 74-76: Klein discloses the basic structure of the wild type H/ACA-snoRNA ACA19 (Klein, para 18, 36 and Fig 4). As stated in the claim interpretation section, “derived from” is given its broadest reasonable interpretation and reads on any sequence or structural similarity to the wild type H/ACA-snoRNA scaffold sequences. Thus, the disclosure of ACA19 and the other gsnoRNA embodiments provided in para 18 and 19 read on gsnoRNA sequences which are derived from those listed in claim 73 given their shared sequence and structural homology.
Claims 77-78, 80 and 85: Klein discloses the use of a viral vector or plasmid for introducing the nucleic acid encoding the gsnoRNA and dyskerin into a eukaryotic host cell (Klein, para and claim 10-13). Klein discloses the use of a U6 or H1 promoter for expression (Klein, para 36, 47).
Claim 79: Klein discloses encoding the gsnoRNA in an intron sequence which is located between a first exon sequence and a second exon sequence which are derived from a naturally-occurring gene (Klein, claims 9, 19, 25).
Claims 81-82: Klein discloses gsnoRNA comprising chemically modified nucleosides and/or inter-nucleosidic linkages and 5’ cap modifications (Klein, para 8, 45 and claim 3).
Claims 83-84: Klein discloses target RNA including mRNA (Klein, para 54, 61-63). Klein discloses targeting sequences wherein modification of the target uridine to pseudouridine causes the stop codon to be translated as a coding codon (Klein, para 116-117).
Klein does not describe a DKC1 protein which localizes in the cytoplasm of a host cell, comprises the amino acid sequence of SEQ ID NO: 88 or is delivered to the host cell via a viral vector.
Claims 69, 70 and 72: However, engineered human dyskerin isoforms with cytoplasm localization are known in the art as shown by Angrisani. Angrisani used bioinformatics and molecular analysis to identify a DKC1 splice variant able to encode for a truncated form of dyskerin and was able to show stable transduction (Angrisani, abstract).
Claim 71: Similarly, Heiss discloses novel human dyskerin isoforms including one with 100% local similarity to instant SEQ ID NO: 88 (Heiss, sequence search results shown below, claim 8, Fig 1B)
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Claim 80: Both Heiss and Angrisani describe viral expression of the dyskerin isoforms (Heiss, claim 4-6; Angrisani pg 1362).
It would have been prima facie obvious to one of ordinary skill in the art to deliver a dyskerin isoform comprising the amino acid sequence of SEQ ID NO: 88 and/or that localizes in the cytoplasm of a host cell as described by Heiss and Angrisani in the method of RNA editing described by Klein. It would have been a matter of combining prior art elements according to known methods to yield predictable results since the claimed dyskerin isoforms are known in the prior art and are unique in their ability to localize in the cytoplasm rather than the traditional nuclear/nucleolar gsnoRNA pathways that rely on endogenous dyskerin. One would be motivated to make this combination in order to achieve RNA editing outside the nucleus and thus regulate post-transcriptional mRNA networks which are present in the cytoplasm. One would have a reasonable expectation of success given that both Heiss and Angrisani demonstrated that dyskerin isoforms which localize in the cytoplasm can be transduced effectively through viral expression and would therefore be compatible with the programable gsnoRNA editing pathways described by Klein. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the instant rejection by arguing that the cited references do not provide a reasonable expectation of success. Applicant states that the 514 amino acid sequence taught by Heiss corresponds to the canonical full-length DKC1 form and not the 420 amino acid alternatively spliced cytoplasmic isoform described by Angrisani. Applicant states that Heiss does not disclose that the protein can interact with the engineered gsnoRNA and mediate targeted RNA pseudouridylation as claimed.
These arguments have been fully considered, but are not found persuasive since one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references, see MPEP 2145. The prior art shows that engineered human dyskerin isoforms with cytoplasm localization are known in the art as shown by Angrisani. Angrisani used bioinformatics and molecular analysis to identify a DKC1 splice variant able to encode for a truncated form of dyskerin and was able to show stable transduction (Angrisani, abstract). Furthermore, the specific alternatively spliced variant in claim 71 is fully disclosed by Heiss, who describes a novel human dyskerin isoforms including one with 100% local similarity to instant SEQ ID NO: 88 (Heiss, sequence search results shown below, claim 8, Fig 1B). Importantly, claim 71 states that the DKC1 protein “comprises” seq id 88, which may include longer variants.
Applicant further argues that the claimed combination produces unexpected improvements in RNA editing activity. Applicant points to para 259 and Fig 7D-7F which compares the effects of canonical DKC1 isoform 1 and cytoplasmically localized DKC1 isoform 3 which shows a 2.5 fold increase. Applicant argues that the comparative results provide evidence that the combination recited in amended claim 69 was not predictable in ivew of the prior art given the substantially greater enhancement when a cytoplasmically localized DKC1 isoform was introduced into eh same gsnoRNA-mediated editing system.
These arguments have been fully considered, but are not found persuasive since whether the unexpected results are the result of unexpected improved results or a property not taught by the prior art, the objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support, see MPEP 716.02(d). The unexpected results are directed to specific gsnoRNA scaffold sequences and cannot be generalized to any gsnoRNA in a predictable manner. Furthermore, the benefits of delivering a dyskerin isoform comprising the amino acid sequence of SEQ ID NO: 88 that localizes in the cytoplasm of a host cell as described by Heiss and Angrisani in the method of RNA editing described by Klein were reported in the prior art. It would have been a matter of combining prior art elements according to known methods to yield predictable results since the claimed dyskerin isoforms are known in the prior art and are unique in their ability to localize in the cytoplasm rather than the traditional nuclear/nucleolar gsnoRNA pathways that rely on endogenous dyskerin. One would be motivated to make this combination in order to achieve RNA editing outside the nucleus and thus regulate post-transcriptional mRNA networks which are present in the cytoplasm.
Claims 91-93 are rejected under 35 U.S.C. 103 as being unpatentable over Klein (supra) in view of Heiss (supra) and Angrisani (supra) as applied to claims 69, 71-73, 77-85 and 89-91 above in further view of De Zoysa et al. "Guide-substrate base-pairing requirement for box H/ACA RNA-guided RNA pseudouridylation." RNA 24.8 (2018): 1106-1117 (hereinafter De Zoysa). This rejection is newly applied to address applicants claim amendments filed on 9/8/2026.
A description of Klein, Heiss and Angrisani can be found above with respect to claims 69, 71-73, 77-85 and 89-91. The collection of cited art does not describe a gsnoRNA scaffold sequence comprising one or more substitution mutations in nucleotides of a polyU sequence in the wild type H/ACA-snoRNA, wherein the gsnoRNA comprises 14 or 15 nucoeitdes between the nucleotide residue in the guide region that hybridizes to the target uridine and the H/ACA box, or a gsnoRNA comprising a scaffold sequence selected from the group consisting of SEQ ID Nos: 3, 6-12, 15-19, 22-36, 71-84, 171 and 177-192.
Claims 91-93: Klein discloses SEQ ID NO: 5 (sequence search results shown below) which is a full-length ACA19 snoRNA that has two hairpins, internal target-binding loops, a H box between the hairpins and an ACA box at the 3’ end (Example 1, SEQ ID NO: 5). The polyU sequence can be observed below.
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Sequence alignment between instant Seq ID NO: 18 and SEQ ID NO: 5 from Klein
Claims 91-93: De Zoysa describes generating engineered gsnoRNA AVA19 variants and showed that relatively minor nucleotide alterations can alter substrate specificity and change which target uridine is pseudouridylated (De Zoysa, pg 1109). De Zoysa presents predictable methods for generating mutants via nucleotiode substitutions within the polyU sequence to modulate functionality and substrate specificity of human box H/AVA guide RNAs (De Zoysa, discussion).
It would have been prima facie obvious to one of ordinary skill in the art to alter the gsnoRNA polyU sequence of Klein to match that instant Seq ID NO: 18 using the predictable techniques outlined by De Zoysa. It would have been a matter of combining prior art elements according to known methods to yield predictable results since De Zoysa establishes that mutations and substitutions in a H/ACA snoRNA guide can alter its interaction with a target uridine and its pseudouridylation activity. One would be motivated to make this combination in order to change which target uridine is pseudouridylated. One would have a reasonable expectation of success given that the scaffold sequence is can be readily modified through mutational substitutions and each structural change can be evaluated for its functional outcome using the techniques outlined by De Zoysa. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
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 extension fee 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 ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
