DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status and Withdrawn Rejections
Applicant’s amendment filed July 7, 2026, amending claims 1, 10, 11, 16, 17, 28, 129, 138 and 145, and cancelling claims 14-15, 19-20, 103, 107 and 147 is acknowledged. Claims 1, 3, 10-11, 16-17, 28, 129, 138, and 145 are pending. Claims 10-11 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Claims 1, 3, 16-17, 28, 129, 138 and 145 are under examination.
Applicant’s amendments, incorporating the limitations from canceled claim 20 into claim 1 overcomes the §102 rejection over Zhang and the §103 rejection over Turunen in view of Kurima. Additionally, removal of references to premature stop codons at position 389 in the TMC1 gene overcomes the §112(a) rejection.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Interpretation - Reiterated
The claims recite “a method of editing a TMC1 polynucleotide comprising a SNP associated with autosomal recessive non-syndromic hearing loss”. The Specification teaches that such a SNP is rs121908072 G>A that causes a D572N mutation in the TMC1 protein (¶ spanning pages 44-45). Applicant’s working example uses ADAR oligonucleotides to correct the G>A mutation (pages 130-131). However, Kurima classifies the G>A SNP that causes D572N as causative of a dominant form of hearing loss (Kurima et al., Nature Genetics (2002), 30: 277-284; of record). This is echoed by Nakanishi et al., (Auris Nasus Larynx (2014), 41: 399-408; Section 2; of record). Because Applicant’s working example is based on correcting the SNP that causes D572N, and the Specification lists the D572N as being a cause of an autosomal recessive form of non-syndromic hearing loss, even though it is actually a cause of autosomal dominant hearing loss, the method claims are interested as “a method of editing a TMC1 polynucleotide comprising a SNP associated with autosomal non-syndromic hearing loss”, without requiring the SNP to cause a recessive-type of inherited hearing loss.
Applicant does not provide any remarks regarding this interpretation.
It is suggested that references to “recessive” be removed from the claims.
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 1, 3, 16-17, 28, 129, 138 and 145 are rejected under 35 U.S.C. 103 as being unpatentable over Turunen (US 20190218552 A1, published July 18, 2019; of record) in view of Kurima (Kurima et al., Nature Genetics (2002), 30: 277-284; of record) and Dowler (Dowler et al., Nucleic Acids Research (2006), 34: 1669-1675; of record). This is a maintained rejection of claim 1 (former claim 20) and a new rejection of the remaining claims, necessitated by amendment.
Regarding claims 1, 16-17 and 28 Turunen teaches antisense oligonucleotides (AONs) that are capable of bringing about specific editing of an adenosine in a target RNA sequence (Abstract). Turunen teaches the AONs are capable of forming a double stranded complex with a target RNA sequence for the deamination of a target adenosine by an ADAR enzyme ([0011]). Turunen teaches a variety of disease ADAR-editing can be used to treat ([0012]). Turunen teaches ADAR-based editing can be used to edit pathogenic G>A mutations ([0014]). Turunen also teaches that the Central Triplet nucleotides (i.e., X1, X2 and X3), can be modified nucleotides, including non-standard or modified bases, and the sugars can be fluorinated at the 2’-position ([Fig 2, [0016]).
Turunen does not teach a mutation in TMC1 that causes autosomal non-syndromic hearing loss. Turunen does not teach AONs with arabinonucleic acids (ANA) or 2’-F arabinonucleic acids (FANA) (i.e., with Formula I).
Kurima teaches a 1714G>A mutation in the TMC1 gene that creates a D572N in the TMC1 protein and causes hearing loss (page 278, ¶4; Fig 4a). Kurima teaches the sequence surrounding the G>A SNP (Fig 4a).
Dowler teaches incorporating 2’-deoxy-2’-fluoro-beta-D-arabinonucleic acid (FANA) nucleotides (i.e., Formula I wherein R1 is a fluorine, a halogen) into small interfering RNAs (siRNAs). Dowler teaches that both AONs and siRNAs are routinely modified to enhance their stability, affinity with RNA, and biodistribution (page 1669, ¶2). Dowler teaches incorporating FANA nucleotides into siRNAs increased their stability in cells (page 1670, ¶2). Dowler teaches incorporating FANA nucleotides at several positions in the siRNAs (Table 1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the RNA-editing method and AON design principles of Turunen, with the modified nucleosides of Dowler at the central triplet, to design an AON that is capable of effecting an A[Wingdings font/0xE0]G ADAR edit in the TMC1 D572N encoding RNA. It would have amounted to applying a known method and known nucleotide modifications to edit a similar pathogenic mutation in RNA by known means to yield predictable results. The skilled artisan would have predicted that ADAR-based RNA-editing could be used to edit the 1714G>A SNP because Turunen teaches other disease-causing G>A SNPs can be edited by ADAR-recruiting AONs. One would have been motivated to do so to treat the known disease-causing SNP. The skilled artisan would have also predicted that the FANA nucleotides of Dowler could be used in the AONs because Turunen teaches that AONs can have modified sugars including with 2’ fluorinated sugars in the central triplet. One would have been motivated to have made the substitution because Dowler teaches incorporating the FANA nucleotides into other ssRNA therapeutics increases their stability and RNA affinity when delivered to cells.
Regarding claim 3, Turunen teaches endogenous ADAR enzymes are recruited to the double stranded RNA complex ([0010]-[0011]).
Regarding claims 129, 138 and 145 Turunen teaches AONs can having at least four phosphorothioate linkages at the 5’ and 3’ ends (Fig 2). Turunen teaches the nucleotides outside the central triplet are 2’-O-methyl modified (i.e., at least 20% of the nucleotides in A and B are 2’-O-methyl-nucleotides) ([0046]; [0016]).
Response to Arguments - §103
Applicant summarizes the §103 rejection for claim 20, which is equivalent to amended claim 1, and reviews the requirements for a determination of obviousness (pages 7-8). Applicant argues that the skilled artisan would not have been motivated to use the FANA nucleotides of Dowler in the AONs of Turunen, or had a reasonable expectation of success, because Dowler teaches using them in siRNAs which interact with Dicer and the RISC complex, which is mechanistically distinct from ADAR-mediated editing (page 8, ¶2-4). This argument has been fully considered but is not persuasive.
Dowler teaches that FANA nucleotides have been used in the both siRNAs and antisense oligonucleotides (AONs) (page 1669, ¶2). In fact, FANA nucleotides have been used in antisense oligonucleotides for nearly 15 years before the effective filing date of the claims, as evidenced by the publication date of the Dowler and references therein. Dowler teaches that the FANA nucleotides are effectively used in both siRNAs that use RISC-mediated interference and AONs that use RNAseH-mediated interference (page 1669, ¶1).
Turunen teaches 2’F-modifed nucleotides in ADAR AONs, and specifically in the central triplet. The sole difference between the 2’F-modified ribonucleotides and FANA nucleotides is the stereochemistry of the fluorine atom around the 2’-carbon.
Therefore, it was more likely than not that any nucleic acid-based hybridization process, like ADAR, could predictably incorporate FANA nucleotides. Given that FANA nucleotides increase the stability of oligonucleotides in vivo and increase hybridization/affinity between the antisense oligonucleotide and its target RNA, the skilled artisan would have been motivated to use them in any oligonucleotide-based therapy that requires target-RNA hybridization, including ADAR.
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, 16-17, 28, 129, 138 and 145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-18 of U.S. Patent No. 11453878 in view of Kurima (Kurima et al., Nature Genetics (2002), 30: 277-284) and Zhang (WO 2019005884 A1, published January 3, 2019).
Patented claim 10 recites A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of an oligonucleotide comprising the structure: [Am]-X1-X2-X3—[Bn], wherein each of A and B is a nucleotide; m and n are each, independently, an integer from 1 to 50, and A and B combined consist of 18 to 80 nucleotides; X1, X2, and X3 are each, independently, a nucleotide, wherein at least one of X1, X2, and X3 has the structure of any one of Formula I-IV, wherein when X1 has the structure of any one of Formulas I to IV, each of X2 and X3 is a ribonucleotide. Patented formula I reads on formula I in the examined claims. Patented claim 12 recites wherein halogen is fluoro. Patented claims 15 recites wherein at least 20% of the nucleotides of [Am] and [Bn] combined are 2′-O-methyl-nucleotides. Patented claim 17 recites wherein the oligonucleotide further comprises one or more adenosine deaminase acting on RNA (ADAR)-recruiting domains.
The patented claims do not recite methods of specifically editing a TMC polynucleotide for treating non-syndromic hearing loss.
Kurima teaches a 1714G>A mutation in the TMC1 gene that creates a D572N in the TMC1 protein and causes hearing loss (page 278, ¶4; Fig 4a). Kurima teaches the sequence surrounding the G>A SNP (Fig 4a).
Zhang teaches the ADAR editing can be used to treat a pathogenic G-to-A mutation/SNP associated with deafness, including the 1714G>A SNP that encodes for the D572N TMC1 allele ([01062]).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have use the patented method and oligonucleotides with formula I specifically to affect an A[Wingdings font/0xE0]G ADAR edit in the TMC1 D572N encoding RNA. It would have amounted to applying a known method to edit a similar pathogenic mutation in RNA by known means to yield predictable results. The skilled artisan would have predicted that ADAR-based RNA-editing could be used to edit the 1714G>A SNP because Zhang teaches TMC1 disease-causing G>A SNPs can be editing by ADAR and Kurima teaches the 1714G>A SNP causes non-syndromic hearing loss. One would have been motivated to do so to treat the known disease-causing SNP and because Zhang suggests it.
Claims 1, 3, 16-17, 28, 129, 138 and 145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 and 23-28 of U.S. Patent No. 12173285 in view of Kurima (Kurima et al., Nature Genetics (2002), 30: 277-284) and Zhang (WO 2019005884 A1, published January 3, 2019).
Patented claim 1 recites An oligonucleotide comprising the structure: [Am]-X1-X2-X3-[Bn], wherein each of A and B is a nucleotide; m and n are each, independently, an integer from 1 to 50, wherein A and B combined consist of 18 to 80 nucleotides, [Am] includes at least one phosphorothioate linkage, [Bn] includes at least one phosphorothioate linkage; X1, X2, and X3 are each, independently, a nucleotide, wherein at least one of X1, X2, and X3 has the structure of Formula I, wherein N1 is a nucleobase or hydrogen; and R1 is halogen or C1-C6 alkoxy; and the oligonucleotide comprises one or more adenosine deaminase acting on RNA (ADAR)-recruiting domains. Patented formula I is identical to formula I in claim 20. Patented claim 2 recites wherein at least 80%, at least 90%, or at least 95% of the nucleotides of [Am] and/or [Bn] include a nucleobase, a sugar, and an internucleoside linkage. Patented claim 9 recites wherein at least 30% of the nucleotides of [Am] and [Bn] combined are 2′-O-methyl-nucleotides. Patented claim 19 recites A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of an oligonucleotide of claim 1.
The patented claims do not recite methods of specifically editing a TMC polynucleotide for treating non-syndromic hearing loss.
Kurima teaches a 1714G>A mutation in the TMC1 gene that creates a D572N in the TMC1 protein and causes hearing loss (page 278, ¶4; Fig 4a). Kurima teaches the sequence surrounding the G>A SNP (Fig 4a). Zhang teaches the ADAR editing can be used to treat a pathogenic G-to-A mutation/SNP associated with deafness, including the 1714G>A SNP that encodes for the D572N TMC1 allele ([01062]).
The obviousness of using the patented oligonucleotides with formula I specifically to affect an A[Wingdings font/0xE0]G ADAR edit in the TMC1 D572N encoding RNA is recited above in paragraph 28.
Response to Arguments - NSDP
Applicant’s request to hold the nonstatutory double patenting rejections in abeyance is denied. The rejections will remain in place until they are overcome by amendment, terminal disclaimer, or otherwise.
Conclusion
No claims are allowable.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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