DETAILED ACTION
Applicant’s amendment and response received on 1/27/26 has been entered. Claims 1-2, 9-15, 18-20, 24-30, and 45-46 are pending in this application.
Applicant’s election of Group II, claims 11-15, 18-20, 24-30, and 45-46, without traverse, is acknowledged. Applicant’s further election of the species Filamin A as the species of Filamin, SEQ ID NO:56 as the species of oligonucleotide construct sequence, SEQ ID NO:30 as the species of RNA editing entity, and lambda N protein as the species of recruiting domain without traverse is also acknowledged. After further consideration, it is noted that the election of species for the species of recruiting domain is withdrawn.
Claims 1-2, 9-10, 14, and 18-19 are therefore withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/27/26.
Claims 11-13, 15, 20, 24-30, and 45-46 are therefore under examination based on the election invention and the elected species. As noted in the previous office action, claim 45 is not a generic claim but rather recites in the alternative both of the inventions of Groups I and II. In view of applicant’s election of Group II, claim 45, and claim 46 which depends on claim 45, have been examined only to the extent that they recite the elected invention. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/2/22 (2) and 10/6/22 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner and initialed and signed copies of the 1449s are attached to this action.
Claim Objections
Claims 45-46 are objected to for the following reasons. Claim 45 depends in part on a large number of canceled claims. Appropriate correction is required.
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.
Claims 12, 15, 20, 24-28, and 45-46 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 lacks proper antecedent basis for “the target sequence” in line 3. Claim 12 depends on claim 11; however, neither claim recites the requisite antecedent basis for “ target sequence”. As such, there is insufficient antecedent basis for this limitation in the claim. It is noted that claim 11 refers to Filamin A RNA. It is suggested that applicant amend claim 11 to recite “Filamin A RNA target sequence” in order to provide antecedent basis for “the target sequence” in claim 12 in order to overcome this rejection. Claim 20 depends on claim 12 and is thus included in this rejection.
Claim 15 lacks proper antecedent basis for “the target RNA”. Claim 15 depends on claim 11; however neither claim provides the requisite antecedent basis for “target RNA”. As such, there is insufficient antecedent basis for this limitation in the claim. It is suggested that applicant amend claim 15 to recite Filamin A RNA.
Claim 24 lacks proper antecedent basis for “the target RNA” and for “the cell” recited in lines 2 and 3 respectively. Claim 24 depends on claim 11; however neither claim provides the requisite antecedent basis for “target RNA” or “the cell”. As such, there is insufficient antecedent basis for these limitations in the claim. It is suggested that applicant amend claim 24 to recite Filamin A RNA, and to recite “a cell”. Claims 25-28 and 45-46 depend on claim 24 and thus are included in this rejection.
Claim 45 recites a method of treatment which depends upon a number of claims recited in the alternative. Some of these claims have been withdrawn as being drawn to a non-elected invention. However, some of these claims upon which claim 45 depends have been canceled. It is noted that the metes and bounds of the method of claim 45 as it pertains to the use of products of canceled claims cannot be determined because the structure of any such products is unknown. As such, claim 45 as a whole is indefinite as the metes and bounds of the products to be administered cannot be determined. The same applies to claim 46 which depends on claim 45.
Claim 45 is further considered indefinite for reciting the administration of “the RNA editing entity not naturally present in the cell as defined in any one of claims 24-28”. Claims 24-28 are drawn to a oligonucleotide construct, not an RNA editing entity not naturally present in a cell. Claim 24 depends on claim 11, which is drawn to the oligonucleotide construct, and further recite a functional activity for the oligonucleotide construct in recruiting an RNA editing entity not naturally present in a cell. However, the functional activity and elements recited as part of the functional activity are not actually elements present in the pharmaceutical composition of claim 11. As such, neither claim 24 nor claim 11 define any RNA editing entity not naturally present in a cell as these claims are drawn to oligonucleotide constructs as a pharmaceutical composition. It is further noted that applicant has elected for examination the invention which is an oligonucleotide construct. Thus, the recitation in claim 45 regarding the administration of the RNA editing entity as defined in any one of claims 24-28 is confusing and indefinite. Applicant is also advised that if the claim is amended to clearly recite a method of administering an RNA editing entity that this subject matter does not correspond to the elected subject matter. Claim 46 depends on claim 45 and thus in included in this rejection.
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.
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 11-13, 15, 20, 24-30, and 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over Fukoda et al. (2017) Sci. Rep., Vol. 7, 41478;doi:10.1038/srep41478, pages 1-13, in view of Vogel et al. (2019) Curr. Opin. Biotech., Vol. 55, 74-80, Merkle et al. (2019) Nat. Biotech., Vol. 37, 133-138, Jain et al. (2018) EMBO, Vol. 37:e94813; doi:10.15252/embj.201694813, pages 1-15, Shallev et al. (2018) RNA, Vol. 24, 828-840, U.S. Patent Application Publication 2022/0195416 (2022), hereafter referred to as Wang et al., with an effective filing date of 04/18/19, and GenEmbl Accession Number AK304255 (2008) Homo sapiens cDNA FLJ57038 compete cds-Filamin A.
Fukoda et al. teaches a site specific guide RNA editing system for adenosine (A) to inosine (I) RNA editing which uses an oligonucleotide construct comprising a gRNA capable of inducing A-I mutations by guiding the human adenosine deaminase acting on RNA (ADAR) to the target site (Fukoda et al., abstract). More specifically, Fukoda et al. teaches RNA editing gRNA oligonucleotides which comprise a protein-recruiting region for recruiting hADAR2 (ARR) and an antisense region (ASR) which hybridizes to the target RNA (Fukoda et al., pages 2-3 and Figure 1). Fukoda et al. provides detailed guidance as to the ARR for recruiting hADAR2 and further provides detailed guidance for designing the ASR portion of the gRNA to target a specific A in the target RNA sequence (Fukoda et al., Figure 1 and pages 2-3). Fukoda et al. demonstrated success in specifically targeting and editing an A to I in a target RNA transcript using the ARR-ASR gRNA in cells transformed to express hADAR2 (Fukoda et al., pages 6-7, and Figure 5). Fukoda et al. teaches that their system is a generally applicable mutagenesis approach for A-to-I mutations.
Vogel et al. supplements Fukoda et al. by teaching several site-specific RNA editing systems such as 1) a system comprising a gRNA oligonucleotide comprising a site specific targeting sequence which has been chemically conjugated to O6-benzylguanine (BG) and an ADAR fusion protein comprising ADAR fused to a SNAP-tag, 2) a system comprising a gRNA oligonucleotide comprising a site specific targeting sequence and a stem loop boxB segment which non-covalently associates with an ADAR-lambdaN peptide fusion protein or an ADAR2 E/Q-lambda fusion protein, and 3) a system comprising a gRNA oligonucleotide comprising a site specific targeting sequence and a stem loop DR segment which non-covalently associates with an ADAR2 E/Q deaminase domain-dCAS13b fusion protein (Vogel et al., pages 74-75 and Figure 1). Note that in 2) above, the oligonucleotide has a sugar modification comprising conjugation to O6-benzylguanine.
Merkle et al. further supplements Fukoda et al. and Vogel al. by teaching two methods of RNA editing which recruit endogenous ADAR where the first method involves the use of plasmid encoding a gRNA comprising a targeting domain and an ADAR recruiting domain which recruits either endogenous ADAR1 or ADAR2 in a cell which naturally expresses ADAR, and a second method which involves the use of a chemically stabilized antisense oligonucleotide (RESTORE) which comprises a targeting domain and an ADAR recruiting domain for either endogenous ADAR1 or ADAR2, wherein the chemical modification is a 2'-O-methylation (Merkle et al., page 133). Note that the 2’-O-methylation is a sugar modification. Merkle et al. reported high levels of A to I editing at three different target sequences, including two disease relevant transcripts, in cells naturally expressing ADAR (Merkle et al., page 134-135, Figures 2 and 3). Merkle et al. teaches that this method has several advantages such as low off-target editing, and the fact that the anti-sense oligonucleotides can be delivered in vivo for therapeutic purposes (Merkle et al., page 137).
Thus, all of Fukoda et al., Vogel et al., and Merkle et al. teach site specific gene editing systems which utilize a targeting oligonucleotide capable of recruiting either endogenous ADAR1 or ADAR2 (Fukoda et al. and Merkle et al.) or recruit a non-naturally occurring ADAR (Vogel et al.), and which were demonstrated to be capable of site specific RNA editing of a target A in a target RNA transcript to an I in a cell. Further, as noted above, Merkle et al. teaches that such site specific RNA editing oligonucleotides can be delivered in vivo for therapeutic purposes. Fukoda et al., Vogel et al., and Merkle et al., while teaching the general applicability of the site specific RNA editing systems for A to I RNA editing of a target RNA transcript in cells in vitro or in vivo, do not teach or suggest that the target RNA transcript is Filamin A, that the A to I edit occurs in an A at a position corresponding to position 7247 of SEQ ID NO:7, or that the editing oligonucleotide can be used to treat a disease, or more specifically an inflammatory disease. However, at the time of filing, Jain et al. teaches that Filamin A RNA transcripts are naturally edited by ADAR which produces a specific A-to-I edit in exon 42 of the Filamin A RNA which results in a Q2341R amino acid exchange in the Filamin A protein in Ig-repeat 22 (Jain et al., page 2). Note that the Q2341R amino acid exchange involving the A to I editing of the A in the codon coding for Q in Ig-repeat 22 of exon 42 to an I which codes for R occurs at a position in human Filamin A which corresponds to position 7247 of SEQ ID NO:7. Jain et al. further teaches that reduced Filamin A editing is associated with cardiovascular disease (Jain et al., pages 2-3 and Figure 1). In addition, Shallev et al. teaches that A to I gene editing plays a critical role in immune responses where reduced A to I gene editing has been linked to autoimmune and inflammation (Shallev et al., page 829). Shallev et al. further specifically shows that FLNA (Filamin A) ADAR mediated editing is reduced in patients with psoriasis, a chronic inflammatory disease (Shallev et al., page 833, Figure 4). In addition, at the time of filing, the sequence of human Filamin A, which comprises sequence which is 100% identical to SEQ ID NO:56 was known. GenEmbl Accession Number AK304255, for example, discloses the sequence of human Filamin A which comprises sequence which is 100% identical to SEQ ID NO:56 (AK304255, page 2). Further, the sequence for ADAR was also known, including a catalytic domain sequence of ADAR with 91.2% sequence identity to SEQ ID NO:30 (Wang et al., see SEQ ID NO:3).
Therefore, in view of the specific teachings of Fukoda et al., Vogel et al., and Merkle et al. for several site specific RNA editing systems which comprises an oligonucleotide construct which comprises an antisense targeting sequence for binding to a target sequence in a target RNA transcript and which was shown by all three references as being capable of either recruiting endogenous ADAR or recruiting a non-naturally occurring ADAR for A to I RNA editing of the target sequence, the further teachings of Merkle et al. that such site specific RNA editing can be used in vivo for therapeutic purposes, the teachings of Jain et al. and Shallev et al. that Filamin A (FLNA) RNA transcripts naturally undergo ADAR mediated A to I RNA editing at a position corresponding to position 7247 of SEQ ID NO:7, and that a decrease in this specific editing is associated with both cardiovascular disease and psoriasis, and further the detailed teachings and guidance provided by Fukoda et al. for designing an oligonucleotide construct capable of targeting a specific A in a target RNA transcript, it would have been prima facie obvious to the skilled artisan at the time of filing to make an oligonucleotide construct according to Fukoda et al., Vogel et al., or Merkle et al. where the oligonucleotide construct targets a position in Filamin A, and more specifically a Filamin A sequence as set forth in GenEmbl Accession Number AK304255 which comprises sequence which is 100% identical to SEQ ID NO:56, corresponding to position 7247 of SEQ ID NO:7 for A to I editing, and where the oligonucleotide construct is capable of recruiting an ADAR, including an ADAR as taught by Wang et al. which has 91.2% sequence identity to SEQ ID NO:30, with a reasonable expectation of success, and further to use such an oligonucleotide for treating cardiovascular disease or psoriasis in vivo by administering the oligonucleotide also with a reasonable expectation of success.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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