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 .
Claims 1-7 are pending.
Status of the Application
Applicant’s response and amendment filed 29 December 2025 are acknowledged and entered.
Applicant has amended Claims 1 and 4.
Response to Amendment
Applicant has amended the Drawing to overcome Objections; the objections to the Drawings are withdrawn.
Applicant has amended the Spec. to overcome Objections to the Nucleic acid disclosures; the objections to the Nucleic acid disclosures are withdrawn.
Applicant has amended the Spec. to overcome Objections; the objections are maintained.
Applicant has amended Claims 1 and 4 to overcome Objections; the objections are withdrawn.
Applicant has amended Claim 4 to overcome the 112(a) Written Description rejection; the 112(a) Written Description rejection is withdrawn.
Claims 1-7 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. A certified copy of JP 2020-043253 is present in the application file. A certified English translation has now been filed and is in the application file as of 29 December 2025.
Specification
The disclosure is objected to because of the following informalities:
Some text in the following ¶ is so blurry, small, and/or faded it is not legible: Formulas and SEQ in ¶34, ¶52, ¶54, ¶57, ¶60, ¶63, ¶66, ¶68, ¶94, ¶105-106, ¶108, ¶115-116, ¶118, ¶123-124, ¶126, and ¶138. The text in the formulas and SEQ ID NO labels in ¶68, ¶81, ¶94, ¶105, ¶108, ¶115, ¶118, ¶123, ¶126, and ¶137 is blurry.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites …a first linkage group that links…. Claim 2 recites …a second linkage group that links…. Claims 3 and 5 also recite linkage group. The Spec. does not provide any definition for what is considered a linkage group, but it does teach (p. 12 ¶39) the first linkage group only needs to have the function of linking the first oligont and the third oligont and may be a nt chain of any arbitrary sequence or may be consisted of a molecular structure other than nt, such as an alkyleneoxy structural unit. Therefore, in the interest of compact prosecution, a linkage group is interpreted as any kind of structure that can link one nt to another.
Claim 1 recites:
An oligonucleotide that induces site-specific editing of a target RNA, comprising:
a first oligonucleotide that complements the target RNA,
a second oligonucleotide linked to the 3' side of the first oligonucleotide,
a third oligonucleotide having a base sequence that forms a complementary strand with the second oligonucleotide, and
a first linkage group that links the 5' end of the first oligonucleotide and the 3' end of the third oligonucleotide,
wherein the first oligonucleotide consists of:
a nucleotide residue that corresponds to an adenosine residue in the target RNA,
a 10 to 24 residue oligonucleotide linked to the 5' side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA, and
a 2 to 7 residue oligonucleotide linked to the 3' side of the nucleotide residue and having a base sequence complementary to the target RNA.
Then Claims 2-5 each refer to the oligonucleotide of Claim 1 which could be interpreted to refer to any of the recited oligont (the first, second, third, the 10-24 residue oligont, or the 2-7 residue oligont). In each instance for Claims 2-5, the oligonucleotide of Claim 1 is interpreted to refer to the oligont that induces site-specific editing of a target RNA (and which comprises all the different recited parts).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4 and 6-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by International Publication Number WO 2016/097212, published 23 June 2016 (“WO212”, of record on IDS). This rejection is maintained.
WO212, drawn to targeted RNA editors, teaches (§Abstract) an oligont that comprises a targeting portion and a recruiting portion that recruits a nucleic acid editing entity such as ADAR. WO212 teaches (same §) the oligont directs the editing entity to a preselected target site by means of the targeting portion which is just another way of saying their oligont is site-specific. WO212 teaches (pp. 2-3 L30-10) ADAR mediates site-specific A to I editing in a target RNA.
WO212 teaches (Fig. 2; p. 4 L10-25; p. 18 L24-36) their invention comprises (1) a targeting portion comprising an antisense oligont that is complementary to the target site in the RNA sequence to be edited and (2) a recruiting portion that may comprise a dsRNA in the form of a hairpin and which recruits the editing enzyme. WO212 teaches (p. 4 L10-25) the hairpin can be 5’ or 3’ of the targeting portion. Fig. 2 is shown here:
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Together, the figure and text describe a first oligont that identifies a target RNA and a second oligont linked to the 3’side of the first oligont. Although WO212’s second oligont comprises a hairpin, it is the exact same structure as what is recited in the instant claims as: a third oligont having a base sequence capable of forming a complementary strand with the second oligont. Therefore WO212 discloses a structure that encompasses the limitation of the third oligont having a base sequence capable of forming a complementary strand with the second oligont.
WO212 teaches (p. 7 L25-32) the recruiting portion may be an aptamer selected for its ability to bind the editing entity and can be fused to the targeting portion of the oligont with any kind of linker including PO, PS, peptide, or PEG linkages.
Regarding the length of what is claimed as the “first oligont”, WO212 teaches that the targeting portion is complementary to the target RNA: (pp. 5-6 L33-12) it is represented by the formula called SEQ ID NO 8: N1N2N3N4N5N6N7N8N9N10N11N12N13N14N15N16N17CN18N19N20, wherein N1 to N20 are A/G/C/U depending on the complementary sequence in the target RNA, and wherein C is cytidine opposite the adenosine in the target RNA that is targeted for deamination. Therefore WO212 discloses a target-corresponding nt residue that corresponds to an adenosine residue in the target RNA.
The formula SEQ ID NO 8 shows N1 to N17 are on the 5’side of the targeting-corresponding nt residue and N18 to N20 are on the 3’side of the target-corresponding nt residue. Regarding linkages, WO212 teaches (p. 15 L12-29) linkages between nt can be PO or PS linkages. Therefore WO212 discloses a 17-residue oligont linked to the 5’side of the target-corresponding nt residue, which falls within the claimed range of 10-24 residues for the structure on the 5’side of the target-corresponding residue. And, WO212 discloses a 3-residue oligo linked to the 3’side of the target-corresponding nt residue, which falls within the claimed range of 2-7 residues for the structure on the 3’side of the target-corresponding nt residue.
Regarding Claim 1’s linkage between the first oligont and the third oligont, WO212 teaches (p. 5 L30-32) the recruiting portion may be linked at the 5’ or 3’end to a targeting portion, optionally via a linker “L” that comprises one or more nucleotides, an oligopeptide, or another chemical linker, such as [PEG].
Therefore WO212 anticipates all the limitations of Claim 1.
Regarding Claims 2-3, WO212 teaches (pp. 14-15 L1-11) the recruiting portion of the oligont can comprise a stem loop segment. Then WO212 teaches (same §) a specific sequence of the recruiting portion that includes a 5-nt loop. As explained, the oligont comprising a hairpin is the exact same structure as what is recited in the instant claims: a third oligont that forms a complementary strand with the second oligont. Since the two sides of the recruiting portion are connected via a 5-nt loop, they are connected by a linkage group comprising a nt chain of 5 residues, which falls within the claimed range of 4-20 residues. Therefore WO212 anticipates all the limitations of Claims 2-3.
Regarding Claim 4, WO212 teaches (pp. 14-15 L25-11) shortening the recruiting portion (vs. known ADAR-recruiting sequences) because doing so may be convenient from a manufacturability or cost of good perspective. WO212 teaches (same §) at least three sequences (SEQ ID NOs 6-7 and 25) that comprise the entire recruiting portion (i.e., what is claimed as second and third oligonts). Those SEQ ID NOs comprise 11-14 residues (SEQ ID NOs 6-7) or 20 residues (SEQ ID NO 25) 5’ of the 5-nt loop sequence. Therefore WO212 teaches a second oligont that contains a number of residues within the claimed range of 2-30 residues, thereby anticipating all the limitations of Claim 4.
Regarding Claim 6, WO212 teaches (p. 8 L6-15) their invention provides methods for site-specific editing of target RNA sequences in a cell. WO212 teaches (Example 1, starts on p. 32; Figs. 4-7) they successfully used their oligos to edit a point mutation-induced stop codon within GFP. That example discusses that their oligont restored GFP fluorescence in tested cells, indicating that target RNA was contacted with their oligont in the presence of ADAR2. The example also discusses that they transfected cells with a plasmid encoding ADAR2, further indicating that target RNA was contacted by their oligont in the presence of ADAR2. Therefore WO212 anticipates limitations of Claim 6.
Regarding Claim 7, the same example discusses that they administered the oligont and ADAR2-encoding plasmid to HeLa cells, which are a kind of eukaryotic cells. Therefore WO212 anticipates limitations of Claim 7.
Therefore WO212 anticipates all the limitations of Claims 1-4 and 6-7.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2016/097212, published 23 June 2016 (“WO212”, of record on IDS) in view of US Patent Application Publication No. US 2015/0057333, published 26 February 2015 (“US333”). This rejection is maintained.
Note: references to p# in WO refer to the PDF p#.
WO212, drawn to targeted RNA editors, teaches (§Abstract) an oligont that comprises a targeting portion and a recruiting portion that recruits a nucleic acid editing entity such as ADAR. WO212 teaches (same §) the oligont directs the editing entity to a preselected target site by means of the targeting portion which is just another way of saying their oligont is site-specific. WO212 teaches (pp. 2-3 L30-10) ADAR mediates site-specific A to I editing in a target RNA.
WO212 teaches (Fig. 2; p. 4 L10-25; p. 18 L24-36) their invention comprises (1) a targeting portion comprising an antisense oligont that is complementary to the target site in the RNA sequence to be edited and (2) a recruiting portion that may comprise a dsRNA in the form of a hairpin and which recruits the editing enzyme. WO212 teaches (p. 4 L10-25) the hairpin can be 5’ or 3’ of the targeting portion. Fig. 2 is shown here:
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Together, the figure and text describe a first oligont that identifies a target RNA and a second oligont linked to the 3’side of the first oligont. Although WO212’s second oligont comprises a hairpin, it is the exact same structure as what is recited in the instant claims as: a third oligont having a base sequence capable of forming a complementary strand with the second oligont. Therefore WO212 discloses a structure that encompasses the limitation of the third oligont having a base sequence capable of forming a complementary strand with the second oligont.
WO212 teaches (p. 7 L25-32) the recruiting portion may be an aptamer selected for its ability to bind the editing entity and can be fused to the targeting portion of the oligont with any kind of linker including PO, PS, peptide, or PEG linkages.
Regarding the length of what is claimed as the “first oligont”, WO212 teaches that the targeting portion is complementary to the target RNA: (pp. 5-6 L33-12) it is represented by the formula called SEQ ID NO 8: N1N2N3N4N5N6N7N8N9N10N11N12N13N14N15N16N17CN18N19N20, wherein N1 to N20 are A/G/C/U depending on the complementary sequence in the target RNA, and wherein C is cytidine opposite the adenosine in the target RNA that is targeted for deamination. Therefore WO212 discloses a target-corresponding nt residue that corresponds to an adenosine residue in the target RNA.
The formula SEQ ID NO 8 shows N1 to N17 are on the 5’side of the targeting-corresponding nt residue and N18 to N20 are on the 3’side of the target-corresponding nt residue. Regarding linkages, WO212 teaches (p. 15 L12-29) linkages between nt can be PO or PS linkages. Therefore WO212 discloses a 17-residue oligont linked to the 5’side of the target-corresponding nt residue, which falls within the claimed range of 10-24 residues for the structure on the 5’side of the target-corresponding residue. And, WO212 discloses a 3-residue oligo linked to the 3’side of the target-corresponding nt residue, which falls within the claimed range of 2-7 residues for the structure on the 3’side of the target-corresponding nt residue.
Regarding Claim 1’s linkage between the first oligont and the third oligont, WO212 teaches (p. 5 L30-32) the recruiting portion may be linked at the 5’ or 3’end to a targeting portion, optionally via a linker “L” that comprises one or more nucleotides, an oligopeptide, or another chemical linker, such as [PEG].
Therefore WO212 teaches limitations of Claim 1.
Regarding Claims 2-3, WO212 teaches (pp. 14-15 L1-11) the recruiting portion of the oligont can comprise a stem loop segment. Then WO212 teaches (same §) a specific sequence of the recruiting portion that includes a 5-nt loop. As explained, the oligont comprising a hairpin is the exact same structure as what is recited in the instant claims: a third oligont that forms a complementary strand with the second oligont. Since the two sides of the recruiting portion are connected via a 5-nt loop, they are connected by a linkage group comprising a nt chain of 5 residues, which falls within the claimed range of 4-20 residues. Therefore WO212 teaches limitations of Claims 2-3.
Regarding Claim 4, WO212 teaches (pp. 14-15 L25-11) shortening the recruiting portion (vs. known ADAR-recruiting sequences) because doing so may be convenient from a manufacturability or cost of good perspective. WO212 teaches (same §) at least three sequences (SEQ ID NOs 6-7 and 25) that comprise the entire recruiting portion (i.e., what is claimed as second and third oligonts). Those SEQ ID NOs comprise 11-14 residues (SEQ ID NOs 6-7) or 20 residues (SEQ ID NO 25) 5’ of the 5-nt loop sequence. Therefore WO212 teaches a second oligont that contains a number of residues within the claimed range of 2-30 residues, thereby teaching limitations of Claim 4.
Regarding Claim 6, WO212 teaches (p. 8 L6-15) their invention provides methods for site-specific editing of target RNA sequences in a cell. WO212 teaches (Example 1, starts on p. 32; Figs. 4-7) they successfully used their oligos to edit a point mutation-induced stop codon within GFP. That example discusses that their oligont restored GFP fluorescence in tested cells, indicating that target RNA was contacted with their oligont in the presence of ADAR2. The example also discusses that they transfected cells with a plasmid encoding ADAR2, further indicating that target RNA was contacted by their oligont in the presence of ADAR2. Therefore WO212 teaches limitations of Claim 6.
Regarding Claim 7, the same example discusses that they administered the oligont and ADAR2-encoding plasmid to HeLa cells, which are a kind of eukaryotic cells. Therefore WO212 teaches limitations of Claim 7.
WO212 does not teach why an artisan would use a first linkage group to connect the 5’end of the first oligont to the 3’end of the third oligont, or that the first linkage group (i.e., the linkage group between the first oligont that identifies the RNA and the third oligont) comprises a nt chain of 8-50 residues (i.e., limitations of Claim 5).
However, regarding a justification for connecting the 5’end of the first oligont to the 3’end of the third oligont and regarding Claim 5: US333, drawn to duplex RNAi compositions, teaches (¶3-4) oligont are subject to nuclease degradation when applied to biological systems but that they designed a way to improve oligont stability to nucleases. US333 teaches (¶7, Fig. 1) double-stranded (ds) oligont comprising the following structure:
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.
US333 teaches (same ¶) each of X and Y can comprise a loop structure consisting of about 4 to about 20 nucleotides. US333 teaches (¶146) that structure comprising loop structures at its 5’ or 3’ends is stable against nucleases. Therefore US333 teaches nt loops that “tie up” an oligont’s “free ends” increase its resistance to nucleases. And, US333 teaches nt loops comprising a chain of a number of nt residues (i.e. ≈4 to ≈20) that falls within the range recited in Claim 5 (i.e., 8-50).
WO212 teaches a structure for RNA editing comprising targeting and enzyme-recruiting portions linked together, nucleotide linkers, and permits linking the recruiting portion to the targeting portion. US333 teaches oligont are subject to nuclease degradation but that linking the 5’ and 3’ends of the oligont to produce a loop comprising a chain of ≈4 to ≈20 nt can stabilize the oligont against nucleases.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify WO212’s oligont for RNA editing with US333’s teachings about incorporating a nt chain comprising ≈4 to ≈20 residues to form loops connecting the ends of an oligont. They would have done so for the benefit of improving the RNA editing oligont by increasing its stability and reducing degradation by nucleases. One would have been motivated to do so with a reasonable expectation of success because WO212’s oligont for RNA editing is comprised of RNA, and an artisan would have known it is susceptible to nuclease degradation at its “free” ends. The teachings of US333 would have led the artisan to add US333’s nt chain of ≈4 to ≈20 residues to the WO212 oligont’s free ends to form loops and reduce that nuclease degradation. They would have placed the nt chain of ≈4 to ≈20 residues at the free ends, which would have placed the nt chain between the 5’end of the first oligont and the 3’end of the third oligont. In doing so, they would have produced an oligont for RNA editing comprising all the limitations of the claimed invention, including the first linkage group comprising a chain of ≈4 to ≈20 residues that links the 5’end of the first oligont and the 3’end of the third oligont. Altogether, Claims 1-7 would have been obvious in view of WO212 and US333.
Claim(s) 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over WO212 and US333 as applied to claims 1-7 above, and further in view of Harvard (2018. The Molecular Basis of Enzymatic Catalysis. Chapter 7 in DNA Structure and Chemistry. Available online at projects.iq.harvard.edu/files/lifesciences1abookv1/files/7_-_dna_structure_chemistry_revised_9-24-2018.pdf. Accessed via the Wayback Machine on 23 September 2025, “Harvard”), Kuttan (and Bass. 2012. Mechanistic insights into editing-site specificity of ADARs. PNAS 109[48]:E3295–E3304, “Kuttan”),Thomas (and Beal. 2017. How do ADARs bind RNA? New protein-RNA structures illuminate substrate recognition by the RNA editing ADARs. Bioessays 39[4]:1600187, “Thomas”), and Tan (et al. 2019. Engineering of high-precision base editors for site-specific single nucleotide replacement. Nat. Comm. 10:439, “Tan”). This rejection is maintained.
The teachings of WO212 and US333 as applicable to Claim(s) 1-7 have been described above.
WO212 and US333 do not teach further reasons why an artisan would have wanted to use a linker to link the 5’end of the first oligont and the 3’end of the third oligont.
However, other references provide further motivation for linking the 5’end of the first oligont and the 3’end of the third oligont:
Harvard, drawn to a text book chapter about the molecular basis of enzymatic catalysis, teaches that (Fig. 3) the probability that molecules collide in the right orientation contributes to reaction rate. Harvard teaches (§Enzymes use proximity and orientation effects to increase reaction rate, entire §) enzymes use proximity and orientation effects to increase reaction rate and (¶3, Fig. 5) a requirement of two parties reacting is that they are forced into an optimal orientation.
Kuttan, drawn to mechanistic insights into editing-site specificity of ADARs, teaches that a specific portion of the ADAR enzyme is important for editing. Kuttan teaches (§Author Summary ¶1) ADAR [editing] preferences derive from the effects of neighboring nucleotides on the ability of the target adenosine to flip out of the dsRNA helix and into the ADAR active site. Kuttan teaches (same §, ¶2) their studies emphasize the loop containing certain residues is important for base flipping and promiscuity of base flipping abilities corresponds with decrease in specificity and vice versa. Kuttan teaches (same §, ¶3) all the mutants they tested bound dsRNA with the same affinity and [editing] preferences do not derive from differential binding but that an increase in base flipping correlated with a higher deamination rate for all proteins and their data suggest that preferences are based on the effects of nearest neighbors. Kuttan teaches (same §, ¶5) a highly conserved loop close to the ADAR enzyme’s active site that has an important role in determining ADAR preferences.
Kuttan’s teachings indicate that interaction between the conserved loop and the target nucleotides determines editing specificity. That indicates that the orientation of binding between the ADAR enzyme and the target is important for editing specificity.
Thomas, drawn to an overview of how ADARs bind RNA, teaches (§How can RNA binding and deaminase domains bind simultaneously?-dsRBD binding is required for editing of some substrates ¶2) interaction of the ADAR catalytic domain and RNA within a certain region of the enzyme is critical for base flipping which is essential to achieve the RNA conformation required for catalysis.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify WO212 and US333’s oligont for inducing site-specific editing, including WO212’s teaching about linking the recruiting portion’s 3’end to the targeting portion, with the teachings about enzyme–substrate orientation of Harvard, teachings about ADAR’s conserved active loop of Kuttan, and teachings about RNA interacting with ADAR’s catalytic domain of Thomas for the benefit of using a linker to control the orientation between the ADAR-recruiting portion of the oligo and the targeting portion of the RNA editing oligont, which would ultimately control the orientation between the recruited ADAR enzyme and the target RNA (because the target RNA would be complemented by the targeting portion of the RNA editing oligont). One would have been motivated to do so with a reasonable expectation of success because teachings in the art indicate that it was common knowledge that the orientation between an enzyme (i.e., ADAR) and its substrate (i.e., the target RNA) affects rate reaction. WO212 teaches (pp. 6-7 L20-18) the structures of the recruiting loop and ADAR were known, so an artisan would have wanted to control the geometry between the enzyme and the target RNA to ensure the enzyme’s conserved base flipping loop would be in optimal conformation with the nucleotide targeted for editing.
To this end, Tan teaches (§Results-Rigid linkers improve precision of APOBEC1-based editors, entire §; Fig. 1; Suppl. Fig. 1) the positioning on the target sequence of a nickase relative to a deaminase other than ADAR, and the connection between those two domains determines the width of the editing window and the precision of the editor. An artisan would have readily realized that Tan’s single guideRNA is of fixed proportion and holds the nickase at a fixed distance, forming a single entity. The artisan would have understood that Tan’s linker length and rigidity determines the geometry between the deaminase and the guideRNA/nickase (and, therefore the target RNA, since it is complemented by the guideRNA), and that geometry determines the width of the editing window and the precision of the editor.
Therefore it would have been obvious to use a linker between WO212 and US333’s targeting RNA and ADAR-recruiting hairpin (i.e., between the first and second/third oligont) to similarly control the geometry between the deaminase and the target RNA. Doing so would have produced the limitations of Claims 1-7.
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 1-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-6 of U.S. Patent No. 11,643,658 (“US658”) in view of US Patent Application Publication No. US 2015/0057333, published 26 February 2015 (“US333”). This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The US658 claims are drawn to an oligont for inducing site-specific editing of a target RNA, the oligont comprising a first oligont that identifies the target, comprises a target-corresponding nt residue that corresponds to an adenosine residue in the target, a 15-30-mer linked to the 5’side of the target-corresponding nt residue and a 3-4-mer oligo linked to the 3’side of the target corresponding nt residue; a second oligont linked to the 3’side of the first oligont and which is composed of 2-24 nt residues and forms a stem loop structure; wherein the oligont has certain structural requirements; wherein the site-specific editing is caused by an enzymatic reaction of adenosine deaminase; and to methods of using the oligont including in a eukaryotic cell.
The instant claims are drawn to an oligont that induces site-specific editing of a target RNA, comprising: a first oligo nt that identifies the target RNA and consists of a nt that corresponds to an adenosine residue in the target, a 10-24 residue oligont linked to the 5’side of the nt that corresponds to an adenosine residue in the target and a 2-7 residue oligont linked to the 3’side of the nt that corresponds to an adenosine residue in the target; a second oligont linked to the 3’side of the first oligont, wherein the second oligont can comprise 2-30 residues; a third oligont comprising a base sequence that can complement the second oligo; wherein a first linkage group links the 5’end of the first oligont and the 3’end of the third oligont, wherein the first linkage group can comprise a nt chain of 8-50 residues; and which can further comprise a second linkage group that links the 3’end of the second oligont to the 5’end of the third oligont and wherein the second linkage group can comprise a nt chain of 4-20 residues.
Both claims sets are directed to oligont for inducing site-specific editing of a target RNA, including in a eukaryotic cell. Although the US658 claims do not recite a third oligont, they recite that the second oligont forms a stem loop. That describes a structure that is exactly the same as what is claimed: a second oligont linked to the 3’side of the first oligont and which forms a complementary strand with the third oligont, and wherein a linkage group connects the 3’end of the second oligont with the 5’end of the third oligont.
The US658 claims do not recite that the oligont for RNA editing comprises a first linkage group that links the 5’end of the first oligont and the 3’end of the third oligont.
However, US333 teaches (¶3-4, ¶7, ¶146, and Fig. 1) a ≈4 to ≈20-residue loop that connects two oligos, forming a loop, and which blocks the ends and thereby reduces degradation by nucleases.
It would therefore have been obvious to modify the oligont for RNA editing of the US658 claims with the teachings of US333 for the benefit of reducing degradation by nucleases. In doing so, they would have used a ≈4 to ≈20-residue chain to connect the free ends of the oligont for RNA editing of the US658 claims and that would mean using the ≈4 to ≈20-residue chain to link the 5’end of the first oligont to the 3’end of the third oligont.
Therefore the claimed invention would have been obvious in view of the US658 claims and US333.
Claims 1-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,390,865 (“US865”) in view of US Patent Application Publication No. US 2015/0057333, published 26 February 2015 (“US333”). This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The US865 claims are drawn to a method for introducing a site-directed RNA mutation comprising reacting a target RNA with a target-editing guideRNA having SEQ ID NO 99 and the following formula:
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to produce the following formula:
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,
wherein target base adenosine (A*) of the resulting 3'-target RNA-5'-target editing guide RNA complex is converted to inosine (P) by A-I editing by action of double- stranded specific adenosine deaminase (ADAR), wherein SEQ ID NO 99 corresponds to the ADAR-binding core region. The US865 claims recite that the targeting region comprises 20-40 nt 5’ of the targeted adenosine and 1-10 nt 3’ of the targeted adenosine. Although the US865 claims don’t recite a third nt, they comprise the exact same structures as what is recited in the instant claims. Furthermore, the structure of XXXVIIA shows the second oligont comprises 18 nt and the nt loop connecting the second and third oligont comprises 4 nt. The US865 claims recite that the action of ADAR is derived from intravital ADAR mechanism which simply means that the oligont recruits endogenous ADAR.
Persons of ordinary skill know that ADAR occurs in animals, so they would understand that the method should be used in eukaryotic cells.
The instant claims are drawn to an oligont that induces site-specific editing of a target RNA, comprising: a first oligo nt that identifies the target RNA and consists of a nt that corresponds to an adenosine residue in the target, a 10-24 residue oligont linked to the 5’side of the nt that corresponds to an adenosine residue in the target and a 2-7 residue oligont linked to the 3’side of the nt that corresponds to an adenosine residue in the target; a second oligont linked to the 3’side of the first oligont, wherein the second oligont can comprise 2-30 residues; a third oligont comprising a base sequence that can complement the second oligo; wherein a first linkage group links the 5’end of the first oligont and the 3’end of the third oligont, wherein the first linkage group can comprise a nt chain of 8-50 residues; and which can further comprise a second linkage group that links the 3’end of the second oligont to the 5’end of the third oligont and wherein the second linkage group can comprise a nt chain of 4-20 residues.
Both claims sets are directed to oligont for inducing site-specific editing of a target RNA, including in a eukaryotic cell. Although the US865 claims do not recite a third oligont, they show that the second oligont forms a stem loop. That describes a structure that is exactly the same as what is claimed: a second oligont linked to the 3’side of the first oligont and which forms a complementary strand with the third oligont, and wherein a linkage group connects the 3’end of the second oligont with the 5’end of the third oligont.
The US865 claims do not recite that the oligont for RNA editing comprises a first linkage group that links the 5’end of the first oligont and the 3’end of the third oligont or that the second oligont is linked to the 3’side of the first oligont.
However, US333 teaches (¶3-4, ¶7, ¶146, and Fig. 1) a ≈4 to ≈20-residue loop that connects two oligos, forming a loop, and which blocks the ends and thereby reduces degradation by nucleases.
It would therefore have been obvious to modify the oligont for RNA editing of the US865 claims with the teachings of US333 for the benefit of reducing degradation by nucleases. In doing so, they would have used a ≈4 to ≈20-residue chain to connect the free ends of the oligont for RNA editing of the US865 claims and that would mean using a ≈4 to ≈20-residue chain to link the 5’end of the first oligont to the 3’end of the third oligont and a second linkage group comprising a ≈4 to ≈20-residue chain to link the 3’end of the first oligont to the 5’end of the second oligont.
Therefore the claimed invention would have been obvious in view of the US865 claims and US333.
Claims 1-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of copending Application No. 17631727 (“App727”) in view of International Publication Number WO 2016/097212, published 23 June 2016 (“WO212”, of record on IDS) and US333. This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The App727 claims are drawn to a guideRNA for editing a target RNA sequence, comprising an antisense nt sequence complementary to a target RNA, an ADAR-recruiting nt sequence, and at least one functional nt sequence; wherein the antisense and the ADAR recruiting sequences are connected with each other, wherein the functional sequence is further connected with the 5’terminal side of the antisense nt; wherein the functional nt sequence is associated with intracellular stabilization, can form a loop or possess other structural properties including specific SEQ ID NOs; wherein the ADAR-recruiting sequence consists of 14-34 nt and can comprise a stem loop consisting of 4-5 nt; wherein the linker can be 15-25 nt; wherein the system can edit target RNA, including by modifying an adenosine[Wingdings font/0xE0]inosine, and wherein the system can be used to treat a disease;
The instant claims are drawn to an oligont that induces site-specific editing of a target RNA, comprising: a first oligo nt that identifies the target RNA and consists of a nt that corresponds to an adenosine residue in the target, a 10-24 residue oligont linked to the 5’side of the nt that corresponds to an adenosine residue in the target and a 2-7 residue oligont linked to the 3’side of the nt that corresponds to an adenosine residue in the target; a second oligont linked to the 3’side of the first oligont, wherein the second oligont can comprise 2-30 residues; a third oligont comprising a base sequence that can complement the second oligo; wherein a first linkage group links the 5’end of the first oligont and the 3’end of the third oligont, wherein the first linkage group can comprise a nt chain of 8-50 residues; and which can further comprise a second linkage group that links the 3’end of the second oligont to the 5’end of the third oligont and wherein the second linkage group can comprise a nt chain of 4-20 residues.
Both claims sets are directed to oligont for inducing site-specific editing of a target RNA, including in a eukaryotic cell. Although the App727 claims do not recite a third oligont, they describe that the ADAR-recruiting region forms a stem loop. That describes a structure that is exactly the same as what is claimed: a second oligont linked to the 3’side of the first oligont and which forms a complementary strand with the third oligont, and wherein a linkage group connects the 3’end of the second oligont with the 5’end of the third oligont. In addition, the size ranges of each component read on the ranges of the instant claims. The App727 claims recite that the ADAR recruiting portion comprises certain SEQ ID NOs that comprise 14-34 nt and that the functional nt sequence comprises certain SEQ ID NOs that can comprise 21-36 nt. Those lengths read on the lengths of the second linkage group (4-20 nt), the second oligont (2-30 nt), and the first linkage group (8-50 nt).
The App727 claims don’t recite that the target corresponding oligont comprises a 10-24 residue oligont 5’ of a target-corresponding residue and a 2-7 residue nt 3’ of the target corresponding residue but WO212 teaches a similar invention to what is claimed and teaches that their targeting portion is complementary to the target RNA. WO212 teaches (pp. 5-6 L33-12) it is represented by the formula called SEQ ID NO 8: N1N2N3N4N5N6N7N8N9N10N11N12N13N14N15N16N17CN18N19N20, wherein N1 to N20 are A/G/C/U depending on the complementary sequence in the target RNA, and wherein C is cytidine opposite the adenosine in the target RNA that is targeted for deamination. Therefore WO212 discloses a target-corresponding nt residue that corresponds to an adenosine residue in the target RNA, which is recited in the instant claims.
The formula SEQ ID NO 8 shows N1 to N17 are on the 5’side of the targeting-corresponding nt residue and N18 to N20 are on the 3’side of the target-corresponding nt residue. Regarding linkages, WO212 teaches (p. 15 L12-29) linkages between nt can be PO or PS linkages. Therefore WO212 discloses a 17-residue oligont linked to the 5’side of the target-corresponding nt residue, which falls within the claimed range of 10-24 residues for the structure on the 5’side of the target-corresponding residue. And, WO212 discloses a 3-residue oligo linked to the 3’side of the target-corresponding nt residue, which falls within the claimed range of 2-7 residues for the structure on the 3’side of the target-corresponding nt residue.
The App727 claims are not 100% clear that there is a first linkage group that links the 5’end of the antisense oligont to the 3’end of the ADAR-recruiting oligont.
However, US333 teaches (¶3-4, ¶7, ¶146, and Fig. 1) a ≈4 to ≈20-residue loop that connects two oligos, forming a loop, and which blocks the ends and thereby reduces degradation by nucleases.
It would therefore have been obvious to modify the oligont for RNA editing of the App727 claims with the teachings of WO212 and US333 for the benefit using a targeting formula demonstrated (in WO212 Examples, start at p. 32 L20; Figs. 4-7) to be effective and benefit of reducing degradation by nucleases. In doing so, they would have used the same targeting structure of WO212 and a ≈4 to ≈20-residue chain of US333 to connect the free ends of the oligont for RNA editing of the App727 claims and that would mean using a ≈4 to ≈20-residue chain to link the 5’end of the first oligont to the 3’end of the third oligont and a second linkage group comprising a ≈4 to ≈20-residue chain to link the 3’end of the first oligont to the 5’end of the second oligont.
Therefore the claimed invention would have been obvious in view of the App727 claims, WO212, and US333.
This is a provisional nonstatutory double patenting rejection.
Claims 1-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 8, 10-18, 20-27, and 30-34 of copending Application No. 17616430 (“App430”) in view of US333. This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The App430 claims are drawn to target-editing guide oligont, or a pharmaceutically acceptable salt thereof, comprising: a first oligont identifying a target RNA; a second oligont linked to the 3'-side of the first oligont; a third oligont capable of forming a complementary pair with the second oligont; and a first linking portion linking the second oligont and the third oligont, wherein the first oligont is composed of a target-corresponding nucleotide residue corresponding to an adenosine residue in the target RNA, an oligont of 10 to 30 residues linked to the 5'-side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA, and an oligont of 3 to 6 residues linked to the 3'-side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA, wherein the number of residues of the second oligont is 5 to 8, wherein the number of residues of the third oligont is 5 to 8, wherein at least one residue selected from a counter region composed of the target-corresponding nucleotide residue and two respective residues on the 3'- and 5'-sides thereof is a nucleotide residue other than a natural ribonucleotide residue, and wherein the target-editing guide oligont or a pharmaceutically acceptable salt thereof induces site-specific editing for the target RNA, wherein the first linking portion consists of a polyalkyleneoxy group consisting of 1 to 8 alkyleneoxy units, each of the first oligont and the third oligont is composed of all the nucleotide residues linked by phosphorothioate bond, the oligont linked to the 5'-side of the target-corresponding nucleotide residue has a base sequence in which two types of modified nucleotide selected from the group consisting of 2'-deoxy-2'-fluoronucleotideresidues, 2'-O-alkylribonucleotide residues, and bridged nucleotide residues are alternately linked, and each of the second oligont and the third oligont has a base sequence in which 2'-O-alkylribonucleotide residues are linked; to the target-editing oligont comprises a second linking portion between the first and second oligont; and to methods of treating a disease by administering the oligont to a warm-blooded animal including wherein the disease is treatable by converting an adenosine residue in a target RNA into an inosine residue.
The instant claims are drawn to an oligont that induces site-specific editing of a target RNA, comprising: a first oligo nt that identifies the target RNA and consists of a nt that corresponds to an adenosine residue in the target, a 10-24 residue oligont linked to the 5’side of the nt that corresponds to an adenosine residue in the target and a 2-7 residue oligont linked to the 3’side of the nt that corresponds to an adenosine residue in the target; a second oligont linked to the 3’side of the first oligont, wherein the second oligont can comprise 2-30 residues; a third oligont comprising a base sequence that can complement the second oligo; wherein a first linkage group links the 5’end of the first oligont and the 3’end of the third oligont, wherein the first linkage group can comprise a nt chain of 8-50 residues; and which can further comprise a second linkage group that links the 3’end of the second oligont to the 5’end of the third oligont and wherein the second linkage group can comprise a nt chain of 4-20 residues.
Both claims sets are directed to oligont for inducing site-specific editing of a target RNA, including in a eukaryotic cell. Although the App430 claims do not recite the same numbering as the claimed invention, they recite all the same components. Only what is the first linking portion linking the second and third oligont in the App430 claims is what is called the second linkage group in the instant claims. What is called the second linking portion between the first and second oligont in the App430 claims is what is referred to as a second oligont linked to the 3’side of the first oligont in the instant claims. Although the App430 claims recite species of linkages, those encompass the linkages of the instant claims because a species reads on an entire genus comprising that species. Furthermore, at least the instant independent claim does not specify what the linkage groups are comprised of. The instant claims recite slightly different ranges for the number of residues on either side of the target-corresponding residue, but those ranges overlap with the ranges of the App430 claims.
The App430 claims do not recite that the oligont for RNA editing comprises a first linkage group that links the 5’end of the first oligont and the 3’end of the third oligont.
However, US333 teaches (¶3-4, ¶7, ¶146, and Fig. 1) a ≈4 to ≈20-residue loop that connects two oligos, forming a loop, and which blocks the ends and thereby reduces degradation by nucleases.
It would therefore have been obvious to modify the oligont for RNA editing of the App430 claims with the teachings of US333 for the benefit of reducing degradation by nucleases. In doing so, they would have used a ≈4 to ≈20-residue chain to connect the free ends of the oligont for RNA editing of the App430 claims and that would mean using the ≈4 to ≈20-residue chain to link the 5’end of the first oligont to the 3’end of the third oligont.
Therefore the claimed invention would have been obvious in view of the App430 claims and US333.
This is a provisional nonstatutory double patenting rejection.
Claims 1-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 17754196 (“App196”) in view of WO212 (of record on IDS) and US333. This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The App196 claims are drawn to a site-specific target-editing RNA, comprising: a first oligont that identifies a target RNA; a second oligont linked to the 5'-side of the first oligont, wherein the first oligont consists of a target-corresponding nucleotide residue corresponding to an adenosine residue in the target RNA, wherein the target-corresponding nt residue does not form a base pair with the adenosine to be edited, an oligont of 10 to 24 residues, linked to the 3'-side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA, and an oligont of 3 to 6 residues, linked to the 5'-side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA; wherein the second oligont has 2 to 10 residues and forms a complementary strand with the target RNA, and the target RNA and the second oligont contain at least one base pair that does not form a stable base pair or at least one base is inserted in the target RNA and/or the second oligont; wherein the second oligont has 4 to 8 residues; wherein the site-specific editing is caused by an enzymatic reaction with adenosine deaminase 1 (ADAR1); and to methods for site-specific editing of a target RNA using the site-specific target-editing RNA, including in a eukaryotic cell or subject who has a hereditary disease.
The instant claims are drawn to an oligont that induces site-specific editing of a target RNA, comprising: a first oligo nt that identifies the target RNA and consists of a nt that corresponds to an adenosine residue in the target, a 10-24 residue oligont linked to the 5’side of the nt that corresponds to an adenosine residue in the target and a 2-7 residue oligont linked to the 3’side of the nt that corresponds to an adenosine residue in the target; a second oligont linked to the 3’side of the first oligont, wherein the second oligont can comprise 2-30 residues; a third oligont comprising a base sequence that can complement the second oligo; wherein a first linkage group links the 5’end of the first oligont and the 3’end of the third oligont, wherein the first linkage group can comprise a nt chain of 8-50 residues; and which can further comprise a second linkage group that links the 3’end of the second oligont to the 5’end of the third oligont and wherein the second linkage group can comprise a nt chain of 4-20 residues.
Both claims sets are directed to oligont for inducing site-specific editing of a target RNA, including in a eukaryotic cell. Although the App196 claims recite species features of the site-specific target-editing RNA, those encompass the structures of the instant claims because a species reads on an entire genus comprising that species. The instant claims recite slightly different ranges for the number of residues on either side of the target-corresponding residue, but those ranges overlap with the ranges of the App196 claims. Although the App196 claims do not recite a third oligont, they recite that the second oligont forms double-stranded structure with the target RNA. The structure of the App196 claims can be interpreted to encompass the claimed structure because in the claimed structure, the only required linkers are nt linkers and the only linkages between nt are inter-nt linkages. In either claim set there is no requirement that each oligont begin and end at a certain point. The claimed third strand is only capable of forming a complementary strand with the second oligont. The second oligont in the App196 claims only has to form a complementary strand with the target but nothing in the claim requires how any specific amount of the second oligont to form a complementary strand with the target, so it could be as few as a single nt which would allow for part of the second oligont to form a complementary strand with the target and the remaining part to form a hairpin. In such case, the structure of the App196 claims would encompass the claimed structure because nothing in the claims dictates where one oligont ends and another begins, provided each oligont meets the length requirements.
Additionally, although the App196 claims recite that the order of the components is different vs. the instant claims (i.e., in the App196 claims, the second oligont is linked to the 5’side—rather than the 3’side—of the first oligont), it would have been obvious to an artisan to alter the order of components depending on the target. That point is demonstrated by WO212: WO212 teaches (Fig. 2; p. 4 L10-25; p. 18 L24-36) their invention comprises (1) a targeting portion comprising an antisense oligont that is complementary to the target site in the RNA sequence to be edited and (2) a recruiting portion that may comprise a dsRNA in the form of a hairpin and which recruits the editing enzyme. WO212 teaches (p. 4 L10-25) the hairpin can be 5’ or 3’ of the targeting portion. Fig. 2 is shown here:
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Together, WO212’s figure and text describe a first oligont that identifies a target RNA and a second oligont linked to the 3’side of the first oligont. The figure also shows that the second oligont (i.e., the recruiting portion) may be placed on either the 3’side or the 5’side of the targeting portion; that indicates that it would have been obvious to alter the orientation recited in the App196 claims and make it the same as what is recited in the instant claims. WO212’s text and Fig. 2 clearly show/describe a second oligont linked to the 3’end of the first oligont and whose structure can be interpreted to encompass a third oligont and second linkage group that connects the second and third oligont. Furthermore, an artisan would have been motivated to add an ADAR-recruiting oligont to the structure of the App196 claims because WO212 shows that structure successfully edits RNA target.
The App196 claims don’t recite anything about the second oligont’s stem loop. However, WO212 teaches (pp. 14-15 L1-11) the recruiting portion of their oligont can comprise a stem loop segment. WO212 teaches (same §) that structure recruits ADAR1 and describes SEQ ID NOs that are based on structures that recruit ADAR1 (which is claimed in App196’s Claim 5). Then WO212 teaches (same §) a specific sequence of the recruiting portion that includes a 5-nt loop. The oligont comprising a hairpin is the exact same structure as what is recited in the instant claims: a third oligont that forms a complementary strand with the second oligont. Since the two sides of the recruiting portion are connected via a 5-nt loop, they are connected by a linkage group comprising a nt chain of 5 residues, which falls within the claimed range of 4-20 residues.
The App196 claims do not recite that the oligont for RNA editing comprises a first linkage group that links the 5’end of the first oligont and the 3’end of the third oligont.
However, US333 teaches (¶3-4, ¶7, ¶146, and Fig. 1) a ≈4 to ≈20-residue loop that connects two oligos, forming a loop, and which blocks the ends and thereby reduces degradation by nucleases.
It would therefore have been obvious to modify the oligont for RNA editing of the App196 claims with the teachings of US333 for the benefit of reducing degradation by nucleases. In doing so, they would have used a ≈4 to ≈20-residue chain to connect the free ends of the oligont for RNA editing of the App196 claims and that would mean using the ≈4 to ≈20-residue chain to link the 5’end of the first oligont to the 3’end of the third oligont. It would have been obvious to use the teachings of WO212 for the benefit of using a nt structure demonstrated to recruit ADAR.
Therefore the claimed invention would have been obvious in view of the App196 claims, WO212, and US333.
This is a provisional nonstatutory double patenting rejection.
Claims 1-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 18187880 (“App880”) in view of US333. This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The App880 claims are drawn to an oligont for inducing site-specific editing of a target RNA, the oligont comprising: a first oligont identifying the target RNA; and a second oligont linked to the 3' side of the first oligont, wherein the first oligont comprises a target-corresponding nucleotide residue corresponding to an adenosine residue in the target RNA, an oligont of 15 to 30 residues linked to the 5' side of the target corresponding nucleotide residue and having a base sequence complementary to the target RNA, and an oligont of 3 or 4 residues linked to the 3' side of the target corresponding nucleotide residue and having a base sequence complementary to the target RNA, wherein the second oligont comprises 2 to 24 nucleotide residues, and wherein the second oligont comprises a base sequence non-complementary to a base sequence corresponding to the target RNA; wherein the second oligont can form a stem loop structure; wherein site-specific editing is caused by an enzymatic reaction of an adenosine deaminase; to methods for target RNA site-specific editing comprising bringing the oligonucleotide according to claim 1 into contact with a target RNA in the presence of adenosine deaminase, including within a eukaryotic cell; and to manufacturing methods of producing the oligont.
The instant claims are drawn to an oligont that induces site-specific editing of a target RNA, comprising: a first oligo nt that identifies the target RNA and consists of a nt that corresponds to an adenosine residue in the target, a 10-24 residue oligont linked to the 5’side of the nt that corresponds to an adenosine residue in the target and a 2-7 residue oligont linked to the 3’side of the nt that corresponds to an adenosine residue in the target; a second oligont linked to the 3’side of the first oligont, wherein the second oligont can comprise 2-30 residues; a third oligont comprising a base sequence that can complement the second oligo; wherein a first linkage group links the 5’end of the first oligont and the 3’end of the third oligont, wherein the first linkage group can comprise a nt chain of 8-50 residues; and which can further comprise a second linkage group that links the 3’end of the second oligont to the 5’end of the third oligont and wherein the second linkage group can comprise a nt chain of 4-20 residues.
Both claims sets are directed to oligont for inducing site-specific editing of a target RNA, including in a eukaryotic cell. Although the App880 claims do not recite a third oligont, they recite that the second oligont forms a stem loop. That describes a structure that is exactly the same as what is claimed: a second oligont linked to the 3’side of the first oligont and which forms a complementary strand with the third oligont, and wherein a linkage group connects the 3’end of the second oligont with the 5’end of the third oligont. The instant claims recite slightly different ranges for the number of residues on either side of the target-corresponding residue, but those ranges overlap with the ranges of the App880 claims.
The App880 claims do not recite that the oligont for RNA editing comprises a first linkage group that links the 5’end of the first oligont and the 3’end of the third oligont.
However, US333 teaches (¶3-4, ¶7, ¶146, and Fig. 1) a ≈4 to ≈20-residue loop that connects two oligos, forming a loop, and which blocks the ends and thereby reduces degradation by nucleases.
It would therefore have been obvious to modify the oligont for RNA editing of the App880 claims with the teachings of US333 for the benefit of reducing degradation by nucleases. In doing so, they would have used a ≈4 to ≈20-residue chain to connect the free ends of the oligont for RNA editing of the App880 claims and that would mean using the ≈4 to ≈20-residue chain to link the 5’end of the first oligont to the 3’end of the third oligont.
Therefore the claimed invention would have been obvious in view of the App880 claims and US333.
This is a provisional nonstatutory double patenting rejection.
Claims 1-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of copending Application No. 18265756 (“App756”) in view of WO212 (of record on IDS) and US333. This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The App756 claims are drawn to target-editing guide oligont, or a pharmaceutically acceptable salt thereof, comprising: a first oligont identifying a target RNA; a second oligont linked to the 5'-side of the first oligont, wherein the first oligont consists of a target-corresponding nucleotide residue corresponding to an adenosine residue in the target RNA, an oligont of 10 to 24 residues, linked to the 3'-side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA, and an oligont of 3 to 6 residues, linked to the 5'-side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA; wherein the second oligont has no nucleotide residue corresponding to a nucleotide residue of the target RNA or has a nucleotide residue which does not form a complementary pair with a nucleotide residue of the target RNA, at the 3'-end thereof; wherein a number of residues in the second oligont is 2 to 10, and at least the nucleotide residues other than at the 3'-end form a double-stranded structure complementary to the target RNA, a counter region consisting of the target-corresponding nucleotide residue and each one residue at the 3'-side and the 5'-side thereof is contained, the nucleotide residue linked to the 3'-side of the target-corresponding nucleotide residue is a 2'-deoxynucleotide residue, the third nucleotide residue counted in the 3'-direction from the target-corresponding nucleotide in the oligont linked to the 3'-side of the target-corresponding nucleotide residue is a 2'-deoxy-2'-fluoronucleotide residue, and the oligont or pharmaceutically acceptable salt thereof induces site-specific editing for the target RNA; wherein the site-specific editing is due to an enzyme reaction by ADAR1; wherein the linkages or nt can comprise various modifications; and to delivery molecules comprising the oligont.
The instant claims are drawn to an oligont that induces site-specific editing of a target RNA, comprising: a first oligo nt that identifies the target RNA and consists of a nt that corresponds to an adenosine residue in the target, a 10-24 residue oligont linked to the 5’side of the nt that corresponds to an adenosine residue in the target and a 2-7 residue oligont linked to the 3’side of the nt that corresponds to an adenosine residue in the target; a second oligont linked to the 3’side of the first oligont, wherein the second oligont can comprise 2-30 residues; a third oligont comprising a base sequence that can complement the second oligo; wherein a first linkage group links the 5’end of the first oligont and the 3’end of the third oligont, wherein the first linkage group can comprise a nt chain of 8-50 residues; and which can further comprise a second linkage group that links the 3’end of the second oligont to the 5’end of the third oligont and wherein the second linkage group can comprise a nt chain of 4-20 residues.
Both claims sets are directed to oligont for inducing site-specific editing of a target RNA, including in a eukaryotic cell. Although the App756 claims do not explicitly recite that the target corresponding nt residue corresponds to an adenosine residue in the target RNA, they do recite that in their system, the enzyme responsible for the reaction is ADAR1, and artisan knows that ADAR1 will edit a targeted adenosine residue. Although the App756 claims recite species of linkages, those encompass the linkages of the instant claims because a species reads on an entire genus comprising that species. Furthermore, at least the instant independent claim does not specify what the linkage groups are comprised of. The instant claims recite slightly different ranges for the number of residues on either side of the target-corresponding residue, but those ranges overlap with the ranges of the App756 claims. Although the App756 claims do not recite a third oligont, they recite that the second oligont forms double-stranded structure. Note that the exact structure of the App756 claims’ second oligont is not clear because the claims recite that the second oligont has no nt residue corresponding to a nt residue of the target RNA or has a nt residue that does not form a complementary pair with a nt residue of the target RNA but also recites that a number of nt residues in the second oligont form a double-stranded structure complementary to the target RNA. Therefore, until the App756 are clarified, the App756 claims are interpreted as describing a structure that self-complements and, therefore, is exactly the same as what is claimed: a second oligont linked to the first oligont and which forms a complementary strand with the third oligont, and wherein a linkage group connects the 3’end of the second oligont with the 5’end of the third oligont.
Additionally, although the App756 claims recite that the order of the components is different vs. the instant claims (i.e., in the App756 claims, the second oligont is linked to the 5’side—rather than the 3’side—of the first oligont), it would have been obvious to an artisan to alter the order of components depending on the target. That point is demonstrated by WO212: WO212 teaches (Fig. 2; p. 4 L10-25; p. 18 L24-36) their invention comprises (1) a targeting portion comprising an antisense oligont that is complementary to the target site in the RNA sequence to be edited and (2) a recruiting portion that may comprise a dsRNA in the form of a hairpin and which recruits the editing enzyme. WO212 teaches (p. 4 L10-25) the hairpin can be 5’ or 3’ of the targeting portion. Fig. 2 is shown here:
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Together, WO212’s figure and text describe a first oligont that identifies a target RNA and a second oligont linked to the 3’side of the first oligont. The figure also shows that the second oligont (i.e., the recruiting portion) may be placed on either the 3’side or the 5’side of the targeting portion; that indicates that it would have been obvious to alter the orientation recited in the App756 claims and make it the same as what is recited in the instant claims. Furthermore, no matter how the confusing language in the App756 claims is interpreted, WO212’s text and Fig. 2 clearly show/describe a second oligont linked to the 3’end of the first oligont and whose structure can be interpreted to encompass a third oligont and second linkage group that connects the second and third oligont.
In addition, the App756 claims don’t recite anything about the second oligont’s stem loop. However, WO212 teaches (pp. 14-15 L1-11) the recruiting portion of their oligont can comprise a stem loop segment. WO212 teaches (same §) that structure recruits ADAR1 and describes SEQ ID NOs that are based on structures that recruit ADAR1 (which is claimed in App756’s Claim 4). Then WO212 teaches (same §) a specific sequence of the recruiting portion that includes a 5-nt loop. The oligont comprising a hairpin is the exact same structure as what is recited in the instant claims: a third oligont that forms a complementary strand with the second oligont. Since the two sides of the recruiting portion are connected via a 5-nt loop, they are connected by a linkage group comprising a nt chain of 5 residues, which falls within the claimed range of 4-20 residues.
The App756 claims do not recite that the oligont for RNA editing comprises a first linkage group that links the 5’end of the first oligont and the 3’end of the third oligont.
However, US333 teaches (¶3-4, ¶7, ¶146, and Fig. 1) a ≈4 to ≈20-residue loop that connects two oligos, forming a loop, and which blocks the ends and thereby reduces degradation by nucleases.
It would therefore have been obvious to modify the oligont for RNA editing of the App756 claims with the teachings of US333 for the benefit of reducing degradation by nucleases. In doing so, they would have used a ≈4 to ≈20-residue chain to connect the free ends of the oligont for RNA editing of the App756 claims and that would mean using the ≈4 to ≈20-residue chain to link the 5’end of the first oligont to the 3’end of the third oligont. It would have been obvious to use the teachings of WO212 for the benefit of using a nt structure demonstrated to recruit ADAR.
Therefore the claimed invention would have been obvious in view of the App756 claims, WO212, and US333.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 29 December 2025 have been fully considered but they are not persuasive. Arguments that are no longer relevant are not addressed.
Spec.
Passages and text in the Spec. are still blurry and should be clear.
102/103
Applicant argues against the 102 rejection on pp. 8-9. They argue that their claims read on WO212 Fig. 2B and WO212 discloses that (p. 5 L30-32, also cited in Remarks) the recruiting portion may be linked at the 5’ or 3’ end to a targeting portion, optionally via a linker…. They argue that Fig. 2B shows the case where the recruiting portion is linked at the 5’ end to the targeting portion whereas their claim requires that the second oligont (i.e., what WO212 calls the recruiting portion, which also encompasses the instantly claimed third oligont, as explained in the rejection) is linked to the 3’ side of the first oligont that complements the target RNA (i.e., the targeting portion), and their claim also requires a first linkage group that links the 5’ end of the first oligont (i.e., the targeting portion) and the 3’ end of the third oligont (i.e., the 3’end of the hairpin, wherein the hairpin comprises the second and third oligonts). Applicant argues that WO212 fails to teach the structure of what is recited in the instant claims because Fig. 2B shows the 5’end of the first oligont is linked to the 3’end of the third oligont.
Those arguments are not found persuasive for several reasons. First, the arguments assume that WO212 Figs. 2A and 2B show every potential embodiment. There is no reason to make that assumption and Applicant cites nothing to substantiate it. Note that WO212 discloses (p. 32 L17-18) all embodiments illustrated in the drawings may be combined, as explained in the detailed description of the invention herein [emphasis added].
Furthermore, Fig. 2A also shows only one potential embodiment. The orientation of Fig. 2A could be flipped so that the 5’ end of the targeting portion were “exposed” and the 3’end of the targeting portion forms a single oligont with the 5’end of the recruiting portion; WO212 permits such an orientation because it teaches (p. 4 L19-20) the hairpin may reside upstream or downstream of the targeting portion and (p. 19 L22-24) the invention provides for the use of an oligont construct that consists of a single oligont comprising both the targeting portion and the recruiting portion for editing. In such a case, the passage Applicant describes (i.e., WO212 p. 5 L3-32) reads on instant Claim 1 because it allows that the recruiting portion may be linked at the 5’ or 3’ end to a targeting portion.
Applicant hasn’t presented any discussion of why that is an inappropriate reading of WO212 or why it isn’t embodied by the teachings of WO212.
Applicant argues against the 103 rejection on pp. 9-10. Applicant hasn’t responded to the assertion that connecting via a 4- to 20-mer linker (i.e., the instantly claimed “first linkage group”) the 5’ end of the targeting oligont (i.e., “first oligont”) and the 3’ end of the recruiting oligont (i.e., “third oligont”) would have been obvious and would have had the benefit of imparting stability to nucleases.
However, they argue that that the tertiary structure of the oligont for editing is crucial for its function. They describe that they tried various linker lengths and those didn’t work (they specifically mention 4-6 nt linkers) or worked poorly (they specifically mention 10 nt linkers). The rationale intended with that particular argument is unclear because only dependent Claim 5 recites any length requirement for the first linkage group, namely that it comprises a nt chain of 8-50 residues.
Not only does the open language of Claim 5 (i.e., comprises) allow for lengths at least 8 residues and longer than 50 residues, the length requirement appears only in a dependent claim. Therefore the other claims allow linkers that are shorter than 8 or longer than 50 residues. Furthermore, even though Claim 5 does require a linker that comprises 8-50 residues, that range encompasses linkers that are 10-mer which is exactly the length that Applicant argues worked poorly (i.e., in Applicant’s terms, editing efficiency was dramatically decreased). In addition, the linker length taught in US333—4 to 20 nt—encompasses lengths that are encompassed by Claim 5. We emphasize that Claim 1 recites no length requirement for the “first linkage group” so even if Applicant’s arguments were found persuasive (which they are not), they would have no bearing on Claims besides for Claim 5.
Furthermore, Applicant hasn’t presented any evidence why linkage lengths within the range of 11-20—encompassed by their own Claim 5!—would not be successful.
Then Applicant argues (p. 9, final ¶) their results show linking via a linker the 5’end of the first oligont and 3’end of the third oligont means it is still possible to stably maintain a conformation suitable for editing induction whereas combining the cited references would obtain far more than predictable results.
Applicant hasn’t provided any evidence for those statements. All that is required for an obviousness rejection is a reasonable expectation of success and Applicant hasn’t provided any evidence that wouldn’t result from modifying the references. Furthermore, if a first linkage group of 4-20 nt wouldn’t allow for successful editing, why does Applicant’s dependent Claim 5 recite linker lengths that overlap with that range?
ATTORNEY ARGUMENTS CANNOT TAKE THE PLACE OF EVIDENCE
The 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 inventor or at least one joint inventor.
See MPEP § 2145 generally for case law pertinent to the consideration of applicant’s rebuttal arguments.
MPEP §716.01(c)
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., any specific tertiary structure, level of editing efficiency, or first linkage group length requirements beyond lengths that overlap with 8-50 nt) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Claim 1 is deemed obvious because US333 indicates would have been obvious to add linkage groups to prevent nucleases from digesting the free ends of the editing compositions of WO212.
NSDP
The arguments against the NSDP rejections are not persuasive for the same reasons the arguments against the 103 rejection are not persuasive. Briefly, it would have been obvious to modify all of the patented or copending claims with the teachings of US333 about (¶3-4, ¶7, ¶146, and Fig. 1) a ≈4 to ≈20-residue loop that connects two oligos, forming a loop, and which blocks the ends and thereby reduces degradation by nucleases. One would have done so for the benefit of preventing nuclease degradation of the compounds of the patented or copending claims. Therefore the NSDP rejections are maintained.
Conclusion
Claims 1-7 are rejected.
THIS ACTION IS MADE FINAL. 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.
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RUTHIE S ARIETI
Examiner (Ruth.Arieti@uspto.gov)
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636