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 .
Election/Restrictions
Applicant’s election without traverse of species of triplet of FANA X1, X2, and X3 comprising claims 20 and 145 of Formula I in the reply filed on Feb 19, 2025 is acknowledged.
Claims 103, 107, and 147 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicants have since cancelled nonelected claims, making the species requirement moot.
Amendments
This action is in response to papers filed 3rd Jun 2026, in which the independent claims were amended with subject matter of claim 20, amendments made to other claims, no claims were canceled, and no new claims were added. All of the amendments have been thoroughly reviewed and entered.
Applicant has further amended:
Abstract and specification to overcome objections; the previous objections to the specification are withdrawn; however, the objection to the abstract is not withdrawn.
Applicant’s arguments, see Pgs. 8-11 filed 3rd Jun 2026, with respect to:
rejections of claims under 35 USC § 102 have been fully considered and are persuasive. The amendments have overcome the 35 USC § 102 rejection. The 35 USC § 102 rejection is withdrawn.
rejections of claims under 35 USC § 103 have been fully considered but are not persuasive for the reasons discussed in this office action. The 35 USC § 103 rejection is maintained.
NSDP rejections of claims are not persuasive for the reasons discussed in this office action; the NSDP rejection is maintained.
Arguments applicable to amended claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Status of Claims
Accordingly, claims 1,3,10-11,14-17, 28, and 145 are under examination on the merits in the instant application.
Specification
The disclosure remains objected to because of the following informalities:
The abstract of the disclosure is objected to because it is still not written as required by the MPEP. MPEP § 608.01(b), specifically says, “If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure”. In instant case, the abstract does not mention endogenous ADAR or the nature of the guide, which are key to the invention. Further, MPEP § 608.01C. Language and Format, specifically says:
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, "This disclosure concerns," "The disclosure defined by this invention," "This disclosure describes," etc.
In instant case, the abstract consists of the following two sentences:
First sentence
Second sentence
The present invention relates to methods and compositions for editing a GJB2
polynucleotide, [[e.g.,]] for example, a GJB2 polynucleotide comprising a SNP associated with autosomal recessive non-syndromic hearing loss.
The invention also relates to methods and compositions for treating or preventing autosomal recessive non-syndromic hearing loss in a subject.
37 C.F.R. 1.72 Title and abstract, states:
(b) A brief abstract of the technical disclosure in the specification must commence on a separate sheet, preferably following the claims, under the heading "Abstract" or "Abstract of the Disclosure." The sheet or sheets presenting the abstract may not include other parts of the application or other material. The abstract must be as concise as the disclosure permits, preferably not exceeding 150 words in length. The purpose of the abstract is to enable the Office and the public generally to determine quickly from a cursory inspection the nature and gist of the technical disclosure.
In instant case, the second sentence does not enable the nature and gist of the technical disclosure, as required by 37 C.F.R. 1.72.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Interpretation
The recitation of the independent claims are:
Claim 1
Claim 10
Claim 11
A method of editing a GJB2 polynucleotide comprising a single nucleotide polymorphism (SNP) associated with autosomal recessive non-syndromic hearing loss, the method comprising
A method of treating autosomal recessive non-syndromic hearing loss in a subject in need thereof, the method comprising
A method of treating autosomal recessive non-syndromic hearing loss in a subject in need thereof, the method comprising
contacting the GJB2 polynucleotide
with a guide oligonucleotide capable of effecting an adenosine deaminase acting on RNA (ADAR)-mediated adenosine to inosine alteration of the SNP associated with autosomal recessive non-syndromic hearing loss,
thereby editing the GJB2 polynucleotide wherein the guide oligonucleotide comprises…followed by remaining amendments.
contacting the GJB2 polynucleotide in a cell of the subject
with a guide oligonucleotide capable of effecting an adenosine deaminase acting on RNA (ADAR)-mediated adenosine to inosine alteration of the SNP associated with autosomal recessive non-syndromic hearing loss,
thereby treating the subject wherein the guide oligonucleotide comprises…followed by remaining amendments.
contacting the GJB2 polynucleotide in a cell
with a guide oligonucleotide capable of effecting an adenosine deaminase acting on RNA (ADAR)-mediated adenosine to inosine alteration of the SNP associated with autosomal recessive non-syndromic hearing loss,
and administering the cell to the subject,
thereby treating the subject wherein the guide oligonucleotide comprises…followed by remaining amendments.
The active steps are in bold. Because of the overlapping common limitations of the three claims, the three claims are being examined together.
Regarding claims 16-17, the recitation of “the pathogenic amino acid in GJB2 protein is isoleucine at position 37 and/or a premature stop codon at position 24” of claim 16 and corresponding limitation of claim 17 is being interpreted as, “SNPs are corrected to a V at position 37 and/or a W at position 24” and at the genomic level, this would be an A to G substitution (rs72474224(A) allele is changed to rs72474224(G) allele). See pg. 20, lines 15-17. Similarly for the alternative, the W24X variant (or mutation) is based on the potential change from tryptophan (encoded by rs104894396(G) allele) to a premature stop codon (encoded by the rs104894396(A) allele) at position 24 of the GJB2 protein. See pg. 20, lines 21-23.
The rejection of Claim(s) 1, 10-11, and 14-17 under 35 U.S.C. 102(a)(1) as being anticipated by Zhang (WO 2019/060746, IDS dated 05/18/2023) is withdrawn.
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 (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.
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 1,3,10-11,14-17, 28, and 145 remain rejected under 35 U.S.C. 103 as being unpatentable over Turunen et al., (US 2019/0218552 A1) in view of Li et al. (Biochemistry, 2006, 45:4141-4152) and Zhang (WO 2019/060746, IDS 5/18/2023), as discussed in the Non-Final Office Action dated 3/3/2026.
Regarding claims 1,3, 10-11, 14-17, 28, and 145, Turunen discloses a method of editing RNA, in a cell of a subject for correcting a genetic mutation via “the specific deamination of a target adenosine present in the target RNA sequence to an inosine”, wherein the method comprises administering to the cell comprising endogenous ADAR enzyme an antisense oligonucleotide comprising a central triplet comprising a second base (“C”) that is opposite of the target adenosine, wherein the oligonucleotide comprises at least 4 consecutive phosphorothioate linkages in the 5’ and 3’ termini and the remaining nucleotides are 2’-O-methyl modified, thereby treating a genetic disorder. See paragraphs 0001, 0011-0014, 0038-0040, 0082, 0096-0101; claims 1-18.
Turunen teaches that cells can be contacted with the antisense oligonucleotide ex vivo and “are then introduced into a living organism” for treatment. See paragraph 0075.
Turunen teaches that use of an antisense oligonucleotide that further comprises an ADAR recruitment portion that “acts in recruiting a natural ADAR enzyme present in the cell” is known in the art. See paragraph 0008.
Turunen exemplifies an oligonucleotide (“ADAR60-7”) having a modified triplex (e.g., YXZ) that has ribosyl moiety modified with 2’-F, which is “small enough not to cause steric interference with ADAR2” and is useful to “protect the AON from nucleases”. See paragraph 0110. See also the modifications in “ADAR60-7” disclosed in Figure 2 as reproduced below, wherein “*” represents phosphorothioate linkages and “(ucg)” represents 2’-fluoro RNA modified nucleotides for the triplet comprising the “C” base that is opposite of the target “A” base.
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Regarding the size of the guide oligonucleotide as amended, Turunen teaches, in a preferred aspect, the oligonucleotide according to the invention comprises 18 to 70 nucleotides [0066].
Turunen does not teach that the “C” base in the 2’-F modified RNA in the triplet “(ucg)” has the arabinose ring structure in Formula I, thereby forming 2’-fluoro-arabinonucleic acid (FANA).
Li teaches that 2’-fluoro-arabinonucleic acid (FANA) analogue “displays increased RNA affinity” compared to RNA or DNA such that “the observed trend for the stability of heteroduplexes between RNA and antisense oligonucleotides (AONs) is as follows: FANA > RNA > DNA > PS-DNA >> ANA”. See page 4141. See also the structure of FANA in Figure 1B as reproduced below and 0098 for description of sugar modifications.
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Neither Turunen nor Li disclose that the SNP to be edited is within the GJB2 gene or that “the pathogenic amino acid in GJB2 protein is isoleucine at position 37 and/or a premature stop codon at position 24”, wherein the “SNP is corrected to a valine at position 37 and/or a trp at position 24” at the genomic level, this would be an A to G substitution (rs72474224(A) allele is changed to rs72474224(G) allele). See pg. 20, lines 15-17. Similarly for the alternative, the W24X variant (or mutation) is based on the potential change from tryptophan (encoded by rs104894396(G) allele) to a premature stop codon (encoded by the rs104894396(A) allele) at
position 24 of the GJB2 protein. See pg. 20, lines 21-23.
However, Zhang, had taught ADAR-mediated correction of the GJB2 gene. Zhang taught various SNPs in GJB2 encompassing recited mutations. See ref sequences on pg. 249. Specifically, Zhang discloses a method of editing GJB2 mutation, wherein the mutation comprises one or more pathogenic G-to-A or C-to-T mutations / SNPs associated with nonsyndromic hearing loss [0836], in a cell of a subject with the disease via “targeted editing of specific single adenosines to inosines” [0961], wherein the method comprises administering to the cell a fusion ADAR enzyme and guide RNAs to result in correction of disease-relevant human mutations [01002]. Zhang teaches that cells can be contacted with the antisense oligonucleotide ex vivo and are then introduced into a living organism for treatment [0408-0412].
Regarding claim 14, Zhang teaches wherein the guide oligonucleotide comprises a nucleic acid sequence complementary to the target mRNA sequence ([0156]; the guide sequence is substantially complementary to the target sequence but comprises a non-pairing C corresponding to the A being targeted for deamination, resulting in an A-C mismatch in an RNA duplex formed by the guide sequence and the target sequence, [0388]).
Regarding claim 15, Zhang teaches wherein the guide oligonucleotide comprises a ADAR recruiting domain (For example, an sgRNA targeting locus A can be modified with MS2 loops, recruiting MS2-adenosine deaminase, [0400]).
Regarding claims 16-17, Zhang teaches wherein the GJB2 guide oligonucleotide comprises a various GJB2 SNP correcting mutations. See GJB2 encompassing recited mutations amongst the ref sequences on pg. 248. For e.g.,: NM_004004.5(GJB2):c.71G>A (p.Trp24Ter), NM_004004.5(GJB2):c.131G>A (p.Trp44Ter) and others.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the method of Turunen for editing the GJB2 SNPs known to cause the GJB2 pathogenic mutation responsible for non-syndromic hearing loss by replacing the non-2’-O-methyl (e.g., 2’-F) modified RNAs in the triplet comprising a cytosine base at position 2 of the triplet with FANA in all three positions of the triplet or only at position 2 of the triplet. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to enhance the stability and binding affinity of the “GJB2 SNP mutation”-editing guide oligonucleotide, thereby providing more effective editing of the mutation-causing base in GJB2, thereby correcting the GJB2 mutant allele in a subject having non-syndromic hearing loss for treating the subject in view of the art-recognized knowledge pertaining to the genetic link between the GJB2 SNP mutation and non-syndromic hearing loss as evidenced by Zhang, because use of a target base-editing guide oligonucleotide comprising non-2’-O-methyl modified nucleotides in the triplet comprising a base to be edited at position 2 was an art-recognized methodology as evidenced by Turunen, who taught that 2’-F ribosyl moiety for the triplet is useful to “protect the AON from nucleases”, wherein the fluoro moiety at position 2 (2’-F) of the ribose sugar ring was known to not interfere with the ADAR-mediated base editing because it is “small enough not to cause steric interference with ADAR2”, and because the 2’-fluoro-arabinonucleic acid (FANA) analogue modification was known to have a higher stability and binding affinity compared to RNA as taught by Li. As such, in view of the benefits associated with FANA analogues as taught by Li, one of ordinary skill in the art would have reasonably incorporated one, two, or three FANA analogues into the non-2’-O-methyl modified (e.g., 2’-F) triple RNA sequence for correcting the GJB2 SNP, wherein one of ordinary skill in the art would have pursued the finite number (seven) of readily identifiable positions (e.g., position 1 alone; position 2 alone; position 3 alone; positions 1-2; positions 1 and 3; positions 2-3; all positions 1-3) for FANA modification in the triplet, thereby arriving at the instantly claimed subject matter with a reasonable expectation of success. See MPEP 2144 II and 2143 I (E).
Regarding claim 145, the teachings of Turunen, Li, and Zhang discussed above as applied to claims 1,3,10-11,14-17, and 28 are similarly applied to claim 145.
In view of the foregoing, claims 1,3,10-11,14-17, 28, and 145 taken as a whole would have been prima facie obvious before the effective filing date.
Response to Arguments
Applicant's arguments filed on 3rd Jun 2026 have been fully considered but they are not persuasive.
1. Applicant argues that the claims as amended are not obvious because there is no motivation for one of ordinary skill in the art to arrive at the claimed subject matter by modifying the teachings of Turunen, whose oligonucleotides are already modified with 2’-F providing nuclease protection, wherein arabinose configuration is “among the various sugar modifications” that “may provide stability or affinity benefits”.
Applicant’s arguments are not found persuasive because the “increased RNA affinity” provided by Li’s FANA is not taught in Turunen’s 2’-F-modified oligonucleotide. As such, one of ordinary skill in the art desiring to further enhance the properties of Turunen’s oligonucleotide would have been motivated to use Li’s FANA within any of the GJB2 SNPS such as NM_004004.5 (GJB2):c.131 G>A (p.Trp44Ter) mutation-causing triplet sequence so as to enable the therapeutic oligonucleotide to bind to the disease-causing sequence, thereby effectively editing the disease-causing sequence. In addition, applicant’s argument that there are “various” modification choices to choose from is not found persuasive to show the asserted nonobviousness of using Li’s FANA in place of 2’-F because both FANA and 2’-F-RNA comprise fluorine (F) at the 2’ position of the sugar, which is taught to be “small enough not to cause steric interference with ADAR2”, wherein such property/feature of 2’-F is critical in providing the ADAR enzyme-mediated base editing for correcting the G>A mutation associated with nonsyndromic hearing loss. That is, one of ordinary skill in the art would have readily understood the significance of the small size of 2’-F in the ADAR-mediated base editing methodology thus would have been motivated to utilize a 2’-F-containing sugar modification or a similar modification known to be “small enough not to cause steric interference with ADAR2” in order to practice the art-recognized method of editing GJB2 mutation.
2. Applicant asserts that one of ordinary skill in the art would have been cautious of inserting a FANA at the triplet where ADAR editing occurs because the “steric implications would be unknown and certainly unpredictable” and one of ordinary skill in the art would have had “no reasonable expectation that such an orientation would be successful for an ADAR-editing oligonucleotide.”
However, Applicants have not provided any evidence such as a reference to show that FANA-containing base, unlike Turunen’s 2’-F base, was known to cause steric hindrance for ADAR-mediated base editing, nor is there any teaching in any of the cited references of record that the arabino configuration of FANA is unsuitable because it disrupts ADAR enzyme recruitment.
Arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant.
The Patent Office does not have the facilities and resources to provide the factual evidence needed in order to determine properties between the instantly claimed method for preventing obesity and the method of preventing or treating respiratory diseases taught by the prior art. In the absence of evidence to the contrary, the burden is upon the applicant to prove that the claimed method and associated method steps are different from the method and associated methods steps taught by the prior art, thereby establishing patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ2d 1922 (PTO Bd. Pat. App. & Int. 1989).
In the present case, Applicants provide no proof, only statements and arguments of counsel which are not considered evidence.
Li provide prior art citation to show wherein FANA has a far significantly higher RNA heteroduplex stability compared to arabinonucleic acids (ANA) as expressly disclosed at page 4141: “the observed trend for the stability of heteroduplexes between RNA and antisense oligonucleotides (AONs) is as follows: FANA > RNA > DNA > PS-DNA >> ANA”. Hence, ANA having 2’-F (thus FANA) was known to form a significantly stable heteroduplex with a complementary RNA compared to ANA without 2’-F, thereby providing a desirability of using FANA in a target RNA-binding oligonucleotide for stable target RNA binding activity. The mere fact that Li does not experimentally compare FANA with 2’-F RNA for RNA binding stability is not sufficient to show lack of a motivation to use FANA in place of 2’-F RNA because it has long been recognized in the relevant art that both FANA comprising 2’-F in the arabino configuration and 2’-F RNA have similar properties in terms of target RNA-binding affinity as evidenced by the long-held art-accepted scientific knowledge at page 4149 such that “a 2’-fluorine substituent, either in the ribo (2’F-RNA) or arabino configuration (FANA), promotes conformational properties that result in significantly higher RNA affinities of 2’-fluoro analogues compared to the corresponding oligonucleotides with a 2’-OH substituent (RNA and ANA, respectively).” (emphasis added).
Hence, in view of the art-accepted, art-recognized similar properties shared by FANA and 2’-F-RNA as expressly disclosed by Li, one of ordinary skill in the art would have had a sufficient reason to use the art-recognized alternative 2’-F-containing RNA in arabino configuration in place of 2’-F RNA so as not to disrupt the ADAR recruitment/binding for the ADAR-mediated base editing in the G>A mutation of the GJB2 RNA while improving or retaining the target RNA binding affinity and stability against nuclease compared to the 2’-F-containing base-editing oligonucleotide, thereby practicing Zhang and Turunen’s suggested method of editing GJB22 G>A mutation without the need “to cause steric interference with ADAR2”.
In view of the foregoing, this rejection is maintained.
Maintained Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1,3,10-11,14-17, 28, and 145 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,453,878 B2 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), as discussed in the Non-Final Office Action dated 3/3/2026.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘878 patent claims drawn to a method of treating a disorder in a subject in need thereof comprising administering an oligonucleotide that provides deamination of an adenosine in a target mRNA, wherein the oligonucleotide further comprises ADAR recruiting domains and comprises at least 20% 2’-O-methyl modified nucleotides and four terminal phosphorothioate linkages.
It is noted that the “disorder” being treated in the ‘878 patent claims is not limited to a specific disease, rather the dose and timing varies with the disease. See Detailed description (10) in the ‘878 patent specification where the disorder is described as a “genetic disease” and several examples are given. It would have been obvious to design the oligonucleotide of the ‘878 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refers (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘878 patent claims.
Claims 1,3,10-11,14-17, 28, and 145 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-24 and 26 of U.S. Patent No. 12,031,131 B2 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), as discussed in the Non-Final Office Action dated 3/3/2026.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘131 patent claims drawn to a method of treating a disorder in a subject in need thereof comprising administering an oligonucleotide that provides deamination of an adenosine in a target mRNA, wherein the oligonucleotide further comprises ADAR recruiting domains and comprises at least 20% 2’-O-methyl modified nucleotides and four terminal phosphorothioate linkages.
It would have been obvious to design the oligonucleotide of the ‘131 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘131 patent claims.
Claims 1,3,10-11,14-17, 28, and 145 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-19 and 21 of U.S. Patent No. 12,173,285 B2 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), as discussed in the Non-Final Office Action dated 3/3/2026.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over and overlap in scope with the ‘285 patent claim drawn to a method of treating a disorder comprising administering an oligonucleotide structure comprising “Formula I”, which is identical to “Formula I” claimed in the instant case, thereby satisfying the instantly claimed oligonucleotide.
It is noted that the “disorder” being treated in the ‘285 patent claims is not limited to a specific disease, rather the dose and timing varies with the disease. See Detailed description (10) in the ‘285 patent specification where the disorder is described as a “genetic disease” and several examples are given. It would have been obvious to design the oligonucleotide of the ‘285 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘285 patent claims.
The below rejections have been modified to address amendments:
Claims 1,3,10-11,14-17, 28, and 145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 17 of U.S. Patent No. 11,479,575 B2 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘575 patent claim drawn to a method of deaminating an adenosine in an mRNA in a cell comprising contacting the cell with an oligonucleotide having the structure satisfying the instantly claimed oligonucleotide. It would have been obvious to design the oligonucleotide of the ‘575 patent claim to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby deaminating the pathogenic amino acid in the mRNA encompassed by the ‘575 patent.
Furthermore, it would have been obvious to incorporate the FANA modification into X2 of the oligonucleotide used in the ‘150 claims in view of the combined teachings of Turunen and Li as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 1,3,10-11,14-17, 28, and 145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 17 of U.S. Patent No. 12,152,050 B2 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘050 patent claim drawn to a method of deaminating an adenosine in an mRNA in a cell comprising contacting the cell with an oligonucleotide having the structure satisfying the instantly claimed oligonucleotide.
It would have been obvious to design the oligonucleotide of the ‘050 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby editing the pathogenic mutant base encompassed by the ‘050 patent claims.
Claims 1,3,10-11,14-17, 28, and 145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-20 of U.S. Patent No. 12,448,620 B2 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘620 patent claims drawn to a method of treating a disorder in a subject in need thereof comprising administering an oligonucleotide that provides deamination of an adenosine in a target mRNA, wherein the oligonucleotide further comprises ADAR recruiting domains and comprises at least 20% 2’-O-methyl modified nucleotides and four terminal phosphorothioate linkages. It is noted that the “disorder” being treated in the ‘620 patent claims is not limited to a specific disease, rather the dose and timing varies with the disease. See Detailed description (10) in the ‘620 patent specification where the disorder is described as a “genetic disease” and several examples are given. It would have been obvious to design the oligonucleotide of the ‘620 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘620 patent claims.
Furthermore, it would have been obvious to incorporate the FANA modification into X2 of the oligonucleotide used in the ‘150 claims in view of the combined teachings of Turunen and Li as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 1,3,10-11,14-17, 28, and 145 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 52 and 61 of copending Application No. 18/290,062 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘062 claims drawn to a method of editing GJB2 for treating a disease comprising using an oligonucleotide targeting GJB2 that is capable of providing ADAR-mediated adenosine to inosine alteration in the target mRNA, wherein the oligonucleotide forms a double-stranded structure by further comprising an ADAR recruiting sequence. It would have been obvious to design the oligonucleotide of the ‘062 patent application claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘131 patent claims.
Furthermore, it would have been obvious to make and use the instantly claimed oligonucleotide in view of the combined teachings of Turunen and Li as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 1,3,10-11,14-17, 28, and 145 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41 and 50 of copending Application No. 18/570,918 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘918 claims drawn to a method of editing an SNP in a target sequence for treating a disease comprising using an oligonucleotide targeting the SNP and further comprises an ADAR recruiting sequence. It would have been obvious to design the oligonucleotide of the ‘918 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘918 patent claims.
Furthermore, it would have been obvious to incorporate one to three FANA modifications into X1, X2, and X3 of the oligonucleotide used in the ‘918 claims in view of the combined teachings of Turunen and Li as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 1,3,10-11,14-17, 28, and 145 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46 and 55 of copending Application No. 18/570,938 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘938 claims drawn to a method of editing an SNP in a target sequence for treating a disease comprising using an oligonucleotide targeting the SNP and further comprises an ADAR recruiting sequence. It would have been obvious to design the oligonucleotide of the ‘938 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘938 patent claims.
Furthermore, it would have been obvious to incorporate one to three FANA modification into X1, X2, and X3 of the oligonucleotide used in the ‘938 claims in view of the combined teachings of Turunen and Li as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 1,3,10-11,14-17, 28, and 145 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 74-75 of copending Application No. 18/927,268 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘268 claims drawn to a method of treating a disorder by deaminating an adenosine in a target mRNA comprising using an oligonucleotide that is capable of effecting ADAR-mediated adenosine to inosine alteration in the target mRNA. It is noted that the “disorder” being treated in the ‘268 patent claims is not limited to a specific disease, rather the dose and timing varies with the disease. See Detailed description (10) in the ‘268 patent specification where the disorder is described as a “genetic disease” and several examples are given. It would have been obvious to design the oligonucleotide of the ‘268 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘268 patent claims.
Furthermore, it would have been obvious to incorporate the FANA modification into X2 of the oligonucleotide used in the ‘150 claims in view of the combined teachings of Turunen and Li as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 1,3,10-11,14-17, 28, and 145 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-25 and 27 of copending Application No. 18/941,793 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘793 claims drawn to a method of treating a disorder by deaminating an adenosine in a target mRNA comprising using an oligonucleotide that is capable of effecting ADAR-mediated adenosine to inosine alteration in the target mRNA, wherein the oligonucleotide of the ‘793 claims comprises “Formula I”, which is identical to “Formula I” claimed in the instant case, thereby satisfying the instantly claimed oligonucleotide. It is noted that the “disorder” being treated in the ‘793 patent claims is not limited to a specific disease, rather the dose and timing varies with the disease. See Detailed description in the ‘793 patent specification where the disorder is described as a “genetic disease” and several examples are given. It would have been obvious to design the oligonucleotide of the ‘793 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘793 patent claims.
Furthermore, it would have been obvious to incorporate the FANA modification into X2 of the oligonucleotide used in the ‘150 claims in view of the combined teachings of Turunen and Li as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 1,3,10-11,14-17, 28, and 145 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-30 of copending Application No. 19/189,150 in view of in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘150 claims drawn to a method of editing a target mRNA comprising using an oligonucleotide that is capable of effecting ADAR-mediated adenosine to inosine alteration in the target mRNA. It would have been obvious to design the oligonucleotide of the ‘150 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘150 patent claims.
Furthermore, it would have been obvious to incorporate the FANA modification into X2 of the oligonucleotide used in the ‘150 claims in view of the combined teachings of Turunen and Li as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 1,3,10-11,14-17, 28, and 145 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 80-81 of copending Application No. 19/296,642 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘642 claims drawn to a method of treating a disorder by deaminating an adenosine in a target mRNA comprising using an oligonucleotide that is capable of effecting ADAR-mediated adenosine to inosine alteration in the target mRNA. It is noted that the “disorder” being treated in the ‘642 patent claims is not limited to a specific disease, rather the dose and timing varies with the disease. See Detailed description (10) in the ‘642 patent specification where the disorder is described as a “genetic disease” and several examples are given. It would have been obvious to design the oligonucleotide of the ‘642 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby treating the “disorder” encompassed by the ‘642 patent claims.
Furthermore, it would have been obvious to incorporate the FANA modification into X2 of the oligonucleotide used in the ‘150 claims in view of the combined teachings of Turunen and Li as explained in the §103 rejection above, which is fully incorporated by reference herein.
Claims 1,3,10-11,14-17, 28, and 145 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 33 of copending Application No. 19/493,944 in view of Zhang (WO 2019/060746, IDS dated 05/18/2023), Turunen et al. (US 2019/0218552 A1), and Li et al. (Biochemistry, 2006, 45:4141-4152).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the ‘944 claim drawn to a method of editing a target adenosine in a target RNA comprising using an oligonucleotide that is capable of effecting ADAR-mediated adenosine to inosine alteration in the target RNA It would have been obvious to design the oligonucleotide of the ‘944 patent claims to target the rs104894396 and rs72474224 SNPs of the GJB2 gene in view of Zhang. The guide RNAs described in Zhang target the SNPs at G71, resulting in a stop codon, and G109, resulting in an isoleucine at position 37, to which instant claim 16 refer (Zhang, paragraph 835) because it was an art-recognized goal to make and use a base-editing oligonucleotide targeting the pathogenic SNPs of the GJB2 gene for treatment of non-syndromic hearing loss as taught by Zhang, thereby edit the target adenosine encompassed by the ‘944 patent claims.
Furthermore, it would have been obvious to incorporate the FANA modification into X2 of the oligonucleotide used in the ‘150 claims in view of the combined teachings of Turunen and Li as explained in the §103 rejection above, which is fully incorporated by reference herein.
Response to Arguments
Applicant's arguments filed on 3rd Jun 2026 have been fully considered but they are not persuasive because: i) applicant did not address the merits of the provisional rejection where rejections where made in view of Zhang.
It is noted the response states that they will address the rejection at such time as the claims are otherwise considered allowable.
ii) applicant states that the rejections are moot in view of amendments to instant claims.
While amendments have overcome previous rejections, new rejections incorporating discussion from previous $103 rejections have been made in this Office Action.
Conclusion
No claim is allowed.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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