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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 07/10/2025 is acknowledged. Claims 2,4-7,9,19,28 and 29 were/stand cancelled. Claims 1,3,8,10-18,20-24 and 30 were amended. Claims 1,3,8,10-18,20-27 and 30-34 are pending.
Applicant elected Group I (claims 1-29) without traverse in the reply filed on 01/07/2025. Claims 30-34 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1,3,8,10-18 and 20-27 are under examination.
Response to Arguments
Applicant’s amendments and arguments, see pages 8-9, filed 07/10/2025, with respect to the objection to the specification regarding the abstract being over 150 words and nucleotide sequences appearing in the specification missing SEQ ID NOs have been fully considered and are persuasive due to the amendment to the abstract to less than 150 words and identification of nucleotide sequences with SEQ ID NOs. The objection to the specification has been withdrawn.
Applicant’s amendments and arguments, see page 9, filed 07/10/2025, with respect to the rejection of claims 1-29 as indefinite under 35 U.S.C. 112(b) have been fully considered and are persuasive due to the amendment to claim 1 specifying “the targeting-editing guide” oligonucleotide in the preamble and at line 19. The 35 U.S.C. 112(b) rejection of claims 1-29 has been withdrawn.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
It is noted that Applicant cannot rely on the certified copy of the foreign priority application(s) to overcome a rejection based on intervening art because a translation of said application(s) has(have) not been made of record in accordance with 37 CFR 1.55. See MPEP 215 and 216.
Claim Objections
Claim 1 is objected to because of the following informalities: lines 24-25 recite “each of the first oligonucleotide and the third oligonucleotide is composed of all the nucleotide residues linked by phosphorothioate bond”. Bond should be plural, “bonds”. Claim 1 also recites “the oligonucleotide 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…”. The second recitation of “nucleotide” should be plural, and a space is missing between “2’-deoxy-2’-fluoronucleotide” and “residues”
Appropriate correction is required.
The following rejections have been updated and modified to reflect the amendments to the instant claims.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1,3,8,12,13,16-18 and 20-27 are rejected under 35 U.S.C. 103 as being unpatentable over Fukuda et al. (WO 2017010556), Published 19 January 2017 (wherein US 20180208924 is an English language equivalent) in view of Klein (WO 2016097212), Published 23 June 2016, and Jaschke et al. (Nucleic Acids Research 1994, Vol. 22, No. 22, pages 4810-4817).
Claim Interpretation: Claims 22-27 recite a product in the preamble of an intended use (A medicine; a therapeutic agent, a pharmaceutical composition), but the body of the claim merely recites the oligonucleotide according to claim 1 without any additional or further limitations to the oligonucleotide of claim 1. As no additional limitations regarding the structure of the oligonucleotide is recited in claims 22-27, a reference reading on claim 1 will also apply to claims 22-27.
Regarding claims 1 and 22-27, Fukuda et al. teaches introducing a site-directed RNA mutation and a target editing guide RNA to be used in the method and a target
RNA-target editing guide RNA complex [0001]. Fukuda et al. recites a 5’-target editing guide RNA represented by formula LVIA in claims 3 and 33:
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Fukuda et al. recites the 5’-target editing guide RNA comprises a 5’-antisense region configured from a 5’-terminal-side target recognition region, a target editing inducing base X (marked with a triangle), and an X-adjacent partial region of a core-side target recognition region, an ADAR (adenosine deaminase) binding region comprising an ADAR-adjacent partial region in the core-side target recognition region and an ADAR binding core region, and a guide-side decoupling region (Claims 3 and 33). The 5’-antisense region corresponds to the “first oligonucleotide”, the stem-loop structure formed by the “ADAR adjacent partial region of the core-side target recognition region”, the “guide-side decoupling region” and the “ADAR-binding core region” correspond to the stem-loop structure formed by the “second oligonucleotide”, the “third oligonucleotide” and the “first linking portion” recited in instant claim 1.
Fukuda et al. recites that the terminal-side target recognition region has a base sequence constructed from the same or different bases selected from adenine, cytosine, guanine and uracil and the number of bases constructing the base sequence is 40 to 20 and forms base-pairing by pairing with each constituent base of the terminal-side target complementary region in the target RNA; the target editing inducing base X, is a mismatched base with target base of the target RNA and consists of adenine, cytosine or guanine and indicates a base that induces target editing to an adenine base being the target base of the target RNA; the X adjacent partial region of the core-side target recognition region has a base sequence constructed from the same or different bases selected from adenine, cytosine, guanine and uracil and the number of bases is 1-10, and has the same number of bases of the base sequence of the guide-side target complementary region in the target RNA and forms a base-pairing; the ADAR binding region has an ADAR adjacent partial region of the core-side target recognition region, an ADAR binding core region and a guide-side decoupling region and each of the regions has a base sequence constructed from the same or different bases selected from adenine, cytosine, guanine and uracil and each number of the bases of the ADAR adjacent partial region of the core-side target recognition region and guide-side decoupling region is the same and is 10 or less; the ADAR binding core region has a base sequence constructed from the same or different bases selected from adenine, cytosine, guanine or uracil, has a stem-loop structure in the region and an incomplete ds RNA structure having a singular base pair or plurality of mismatched base pairs in addition to a plurality of base pairs and the number of bases is 20-30, and the ADAR binding core region has a structure connecting the guide-side decoupling region at a terminal side of the ADAR binding core region and the ADAR adjacent partial region of the target recognition region at the other side; the guide-side decoupling region has a base sequence constructed from the same or different bases selected from adenine, cytosine, guanine and uracil and number of bases 10 or less, and has a structure making a base-pairing with the ADAR adjacent partial region (claim 3).
Regarding claim 21, Fukuda et al. teaches the target base adenosine of the 3’-target RNA-5’-target editing guide RNA complex is converted to inosine by A-I editing through action of a double-stranded specific adenosine deaminase (ADAR) to obtain 3’-edited target RNA (Claim 3).
Fukuda et al. does not teach that at least one residue selected from a counter region composed of the target-corresponding nucleotide residue and one residue each on the 3’ and 5’ sides of the counter region is a nucleotide residue other than a natural-type ribonucleotide residue, or that the first linking portion consists of a polyalkyleneoxy group consisting of 1 to 8 alkyleneoxy units, that each of the first oligonucleotide and third oligonucleotide is composed of all the nucleotide residues linked by phosphorothioate bond, the oligonucleotide linked to the 5’ side of the target-corresponding nucleotide residue has a base sequence in which two types of modified nucleotides selected from the group consisting of 2’-deoxy-2’-fluoronucleotide residues, 2’-O-alkylribonucleotide residues, and bridged nucleotide residues are alternately linked, and each of the second and third oligonucleotides have a base sequence in which 2’-O-alkylribonucleotide residues are linked.
However, before the effective filing date, Klein recites an oligonucleotide construct for site-directed editing of a nucleotide in a target RNA sequence, wherein the oligonucleotide construct comprises a targeting portion comprising an antisense sequence complementary to a part of the target RNA and a recruiting portion capable of binding and recruiting an RNA editing entity naturally present in the cell and capable of performing editing of said nucleotide (claim 1). Klein further recites the oligonucleotide construct targeting portion comprises one or more 2’-O ribosyl substituted uridines, preferably 2’-OMe substituted uridines (claim 19), and teaches that various chemistries and modifications are known in the field of oligonucleotides that can readily be used, and that regular internucleosidic linkages between the nucleotides may be altered by mono-or di-thiolation of the phosphodiester bonds to yield phosphorothioate esters. In addition, ribose sugar modifications may be substitution of the 2’-O moiety with a lower alkyl and inhibit nuclease sensitivity and improve efficiency of hybridization (page 14, lines 13-22, page 17, lines 9-18).
Klein teaches a PEG (an alkyleneoxy unit) linker may link a recruiting portion at the 5’ or 3’ end to a targeting portion (page 14, lines 9-11).
Klein teaches the ribose sugar may be modified by substitution of the 2’-O moiety with a lower alkyl, alkenyl, alkynyl, methoxyethyl, or other substituent and is known for inhibiting nuclease sensitivity and improving efficiency of hybridization (page 14, lines 17-22). Klein teaches to prevent undesired editing of adenosines in the target RNA sequence in the region of overlap with the oligonucleotide construct, the targeting portion of the oligonucleotide construct can be chemically modified, and it has been shown in the art that 2’-O-methylation of the ribosyl-moiety of a nucleoside opposite an adenosine in the target RNA sequence dramatically reduces deamination of that adenosine by ADAR, and that by including 2’-methoxy (2’-OME) nucleotides in the desired position of the oligonucleotide construct, the specificity of editing may be dramatically improved (page 16, lines 2-9).
Klein teaches locked nucleic acid sequences (LNAs) comprising a 2’-4’ intramolecular bridge linkage inside the ribose ring may be applied, and exact chemistries and formats may depend from the oligonucleotide construct and the application and may be worked out according to the preferences of those of skill in the art (page 14, lines 23-29). Klein teaches both the targeting portion and recruiting portion may comprise or consist of nucleotides having chemical modifications that alter nuclease resistance, affinity of binding or other properties, and examples of chemical modifications are modifications of the sugar moiety, including cross-linking substituents within the sugar moiety (e.g. as in LNA or locked nucleic acids), by substitution of the 2’-O atom with alkyl groups…In addition the phosphodiester group of the backbone may be modified to yield phosphorothioate internucleosidic linkages (page 17, lines 9-18).
Regarding the first linking portion consisting of a polyoxyalkyeneoxy group consisting of 1 to 8 alkylene units in claim 1, Jaschke et al. teach the synthesis of oligonucleotide conjugates containing a varying number of ethylene glycol units attached to 3’-terminal, 5’-terminal and internal positions of the oligonucleotides and analysis thereof, and that the number and attachment sites of coupled ethylene glycol units greatly influence the hydrophobicity of the conjugates, and electrophoretic mobilities (Abstract).
Jaschke et al. teach chemical modification of antisense oligonucleotides have previously been performed but this study focuses on coupling polyethylene glycol (PEG) to oligonucleotides because it is non-toxic and non-immunogenic, and interacts in a complex manner with cellular membranes, and facilitates uptake of exogenous nucleic acids by different cells (Intro, page 4810).
Jaschke et al. teach the synthesis of various 3’-, 5’-, 3’,5’, and internally PEG-coupled oligonucleotides of length 5-18 nucleotides and whereby the degree of polymerization of PEG ranged from 5-120 for 3’-terminal coupling and from 5-32 for 5’-terminal and internal coupling (Results, page 4812). Jaschke et al. teach in all cases, coupling of PEG caused an increase in retention time, indicating increased hydrophobicity (page 4813, left column). Jaschke et al. teach that conjugate strategies using polymers as conjugate groups allow the modulation of molecular properties by the choice of the degree of polymerization, and the coupling strategy described herein uses a PEG polymer that contains only two reactive groups, and allows the incorporation of the conjugate group into oligonucleotides during automated synthesis at exactly defined positions with exactly defined stoichiometry and incorporation is possible at the 3’-terminal, 5’-terminal and internal positions, and it is possible to adjust the hydrophobicity of the conjugate by the selection of a suitable polymer size (Discussion, pages 4816-4817).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the target editing guide RNA of Fukuda et al. according to the teachings of Klein regarding the chemical modifications well known in the art for the purpose of trying to improve hybridization with the target sequence. It would have been obvious to modify the ADAR binding region of the target editing guide RNA of Fukuda et al. to link the core-side target recognition region and the guide-side decoupling region with the PEG of Jaschke et al., with a reasonable expectation of success. There would be a reasonable expectation of success as this would have amounted to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to try to modify at least one residue in the counter region of the target-corresponding nucleotide residue and two respective residues on the 3’ and 5’ sides with a chemical modification such as 2’-O ribosyl modifications, modified internucleoside linkages and other ribose sugar modifications well known in the art because Klein teaches these modifications provide properties such as inhibiting nuclease sensitivity due to its bulkiness and improving efficiency of hybridization. One of ordinary skill in the art would be motivated to provide a PEG 1-8 units as a linking portion between the core-side target recognition region and the guide-side decoupling region of Fukuda et al. because Jaschke et al. teach the desire for coupling polyethylene glycol (PEG) to oligonucleotides because it is non-toxic and non-immunogenic, and interacts in a complex manner with cellular membranes, and facilitates uptake of exogenous nucleic acids by different cells, and teach the synthesis of internally PEG-coupled oligonucleotides of length 5-18 nucleotides and whereby the degree of polymerization of PEG ranged from 5-32 for 5’-terminal and internal coupling (Results, page 4812) and that coupling of PEG caused an increase in retention time, indicating increased hydrophobicity (page 4813, left column). An ordinary artisan would be motivated to experiment with the number of PEG units because Jaschke et al. teach that conjugate strategies using polymers as conjugate groups allow the modulation of molecular properties by the choice of the degree of polymerization, and the coupling strategy described herein uses a PEG polymer that contains only two reactive groups, and allows the incorporation of the conjugate group into oligonucleotides during automated synthesis at exactly defined positions with exactly defined stoichiometry and incorporation is possible at the 3’-terminal, 5’-terminal and internal positions, and it is possible to adjust the hydrophobicity of the conjugate by the selection of a suitable polymer size.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the editing guide RNA of Fukuda et al. with the teachings of Klein et al. regarding phosphorothioate bonds with a reasonable expectation of success, as this would have amounted to applying a known technique of chemical modification with phosphorothioate bonds to a known oligonucleotide product ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to provide a phosphorothioate bond in the first oligonucleotide, the counter region or the target-corresponding nucleotide residue, or wherein each of the first, second and third oligonucleotides have nucleotide residues linked by a phosphorothioate bond, because Klein et al. teach that various chemistries and modifications are known in the field of oligonucleotides that can readily be used, and that regular internucleosidic linkages between the nucleotides may be altered by mono-or di-thiolation of the phosphodiester bonds to yield phosphorothioate esters, and that the exact chemistries and formats depend from oligonucleotide construct to oligonucleotide construct and from application to application and can be worked out in accordance with those of skill in the art (page 14, lines 13-16,26-29).
One of ordinary skill in the art would be motivated to modify the targeting editing guide oligonucleotide of Fukuda et al. to have two types of modified nucleotides selective from the group consisting of 2’-deoxy-2’-fluoronucleotide residues, 2’-O-alkylribonucleotide residues and bridged nucleotides residues alternatively linked, and each of the second and third oligonucleotide base sequence in which 2’-O-alkylribonucleotide residues are linked because Klein teaches both the targeting portion and recruiting portion may comprise or consist of nucleotides having chemical modifications that alter nuclease resistance, affinity of binding or other properties, and examples of chemical modifications are modifications of the sugar moiety, including cross-linking substituents within the sugar moiety (e.g. as in LNA or locked nucleic acids), by substitution of the 2’-O atom with alkyl groups…In addition the phosphodiester group of the backbone may be modified to yield phosphorothioate internucleosidic linkages (page 17, lines 9-18).
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the editing guide RNA of Fukuda et al. with the teachings of Klein et al. regarding a modified nucleotide residue containing a 2’-O-alkylribonucleotide residue or a bridged nucleotide residue, or in which bridged nucleotide residues and 2’-O-alkylribonucleotide residues are alternately linked with a reasonable expectation of success as this would have amounted to applying a known technique of chemical modification with 2’-O-alkylribonucleotide residues and/or bridged nucleotide residues to a known oligonucleotide product ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to provide 2’-O-alkylribonucleotide residues, bridged nucleotide residues, or bridged nucleotide residues and 2’-O-alkylribonucleotide residues alternately linked in the different parts of the oligonucleotide of Fukuda et al. because Klein teaches that various chemistries and modifications are known in the field of oligonucleotides that can readily be used and ribose sugar modifications are known in the art and inhibit nuclease sensitivity and improve efficiency of hybridization (page 14, lines 13-22, page 17, lines 9-18), and that the ribose sugar may be modified by substitution of the 2’-O moiety with a lower alkyl, alkenyl, alkynyl, methoxyethyl, or other substituent and is known for inhibiting nuclease sensitivity and improving efficiency of hybridization (page 14, lines 17-22). Klein teaches it has been shown in the art that 2’-O-methylation of the ribosyl-moiety of a nucleoside opposite an adenosine in the target RNA sequence dramatically reduces deamination of that adenosine by ADAR, and that by including 2’-methoxy (2’-OME) nucleotides in the desired position of the oligonucleotide construct, the specificity of editing may be dramatically improved (page 16, lines 2-9). In addition, Klein teaches locked nucleic acid sequences (LNAs) comprising a 2’-4’ intramolecular bridge linkage inside the ribose ring may be applied, and exact chemistries and formats may depend from the oligonucleotide construct and the application and may be worked out according to the preferences of those of skill in the art (page 14, lines 23-29). Klein teaches both the targeting portion and recruiting portion may comprise or consist of nucleotides having chemical modifications that alter nuclease resistance, affinity of binding or other properties, including locked nucleic acids (page 17, lines 9-11 and 13). Modifying the editing guide RNA of Fukuda et al. with the teachings of Klein et al. regarding a modified nucleotide residue containing a 2’-O-alkylribonucleotide residue or a bridged nucleotide residue, or in which bridged nucleotide residues and 2’-O-alkylribonucleotide residues are alternately linked.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the editing guide RNA of Fukuda et al. with the teachings of Klein et al. regarding a second linking portion containing an alkyleneoxy unit between the first oligonucleotide and second oligonucleotide with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide a linking portion containing an alkyleneoxy unit between the first and second oligonucleotide, because Klein et al. teach a PEG (an alkyleneoxy unit) linker may link a recruiting portion at the 5’ or 3’ end to a targeting portion (page 14, lines 9-11).
Accordingly, the limitations of claims 1,3,8,12,13,16-18 and 20-27 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant’s amendments and arguments, see pages 9-10, filed 07/10/2025, with respect to the rejection(s) of claim(s) 1-9,12,13 and 16-29 under 35 U.S.C. 103 as unpatentable over Fukuda et al. and Klein have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to claim 1 incorporating some of the limitations from claims 2,4-7 and 19 which art was not applied to previously due to the Markush language in claims 2 and 5, as well as limitations from the specification.
Applicant argues on page 9 that claim 1 has been amended to recite “wherein the first linking portion consists of a polyalkyleneoxy group consisting of 1 to 8 alkyleneoxy units”. The examiner applied art for previous claim 2 for the option of the first linking portion containing an oligonucleotide of 4 or 5 residues, which applicant has now amended to remove that option and require “wherein the first linking portion consists of a polyalkyleneoxy group consisting of 1 to 8 alkyleneoxy units” in amended claim 1.
Applicant also points out that the number of residues of the second oligonucleotide is 5 to 8 and the number of residues of the third oligonucleotide is 5 to 8. These limitations were present in previous claim 1. The examiner notes that as stated in the rejection above Fukuda et al. teaches “each number of the bases of the ADAR adjacent partial region of the core-side target recognition region and guide-side decoupling region is the same and is 10 or less” which the examiner interpreted as the second oligonucleotide and third oligonucleotide, respectively based on the claim interpretation section above. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Applicant also states on page 9 that the claimed target-editing guide oligonucleotide has a small number of nucleotides added to a target recognition site, having excellent stability in vivo, and is capable of inducing site-specific editing in a cell. See paragraph [0007] of the as-filed specification, and that neither Fukuda nor Klein teach this feature and the oligonucleotides of Fukuda and Klein tend to have a long total length.
This is not found persuasive because as shown in the rejection above, the claimed lengths of the different oligonucleotides of the target-editing guide oligonucleotide fall within the ranges disclosed by the prior art. Additionally, the property of having excellent stability in vivo is not a required claim limitation. Paragraph [0007] of the specification does not indicate that the “excellent stability” is unexpected or surprising, nor does it provide a comparison to the closest prior art.
“The arguments of counsel cannot take the place of evidence in the record.” In re Schulze, 346 F.2d 600, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 40 USPQ 2d 1685 (Fed. Cir. 1996), In re De Blauwe et al., 222 USPQ 191, (Fed. Cir. 1984). MPEP 716.01(c). Applicant has not provided any factual evidence establishing unobviousness.
Claims 10,11,14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Fukuda et al., Klein and Jaschke et al. as applied to claims 1,3,8,12,13,16-18 and 20-27 above, and further in view of Kalota et al. (Nucleic Acids Research, 2006, Vol. 34 No. 2, pgs 451-461).
The teachings of Fukuda et al., Klein and Jaschke et al. as applicable to claims 1,3,8,12,13,16-18 and 20-27 are described above.
Fukuda et al., Klein and Jaschke et al. do not teach an oligonucleotide having a nucleotide residue which is a 2’-deoxy-2’-fluoronucleotide residue.
However, before the effective filing date, Kalota et al. teach in order to be effective in vivo, antisense nucleic acids should be nuclease resistant, form stable ON/RNA duplexes and support ribonuclease H mediated heteroduplex cleavage (Abstract). Kalota et al. teach a chemical modification of 2’-deoxy-2’-fluoro-beta-D-arabinonucleic acid (2’F-ANA) that significantly enhances binding affinity to the target mRNA compared with native or PS-modified DNA, and that 2’F-ANA/RNA duplexes retain ability to activate RNase H (page 452, bottom left column to top right column). Kalota et al. teach incorporation of DNA into the 2’-F-ANA structure accelerates RNase H mediated RNA cleavage to a level that is superior to that observed with PS-DNA (page 452, right column). In addition, at later time points after transfections, intracellular concentration of PS-2-F-ANA chimera was considerably higher than the PS-DNA (page 459, left column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the editing guide RNA of Fukuda et al., Klein and Jaschke et al. and with the teachings of Kalota et al. regarding introduction of 2’-deoxy-2’-fluoronucleotide residues into specific parts of the oligonucleotide or wherein 2’-deoxy-2’-fluoronucleotide residues and 2’-O-alkylribonucleotide residues are alternately linked, or wherein 2’-deoxy-2’-fluoronucleotide residues and bridged nucleotide residues are alternately linked in the recited parts of the oligonucleotide with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so because Kalota et al. teach that modification with 2’-deoxy-2’-fluoro-beta-D-arabinonucleic acid (2’F-ANA) significantly enhances binding affinity to the target mRNA compared with native or PS-modified DNA and that 2’F-ANA/RNA duplexes retain ability to activate RNase H, and that increased intracellular concentration is higher for PS-2-F-ANA chimeras. The skilled artisan would be able to envision introduction of the 2’-deoxy-2’-fluoro-beta-D-arabinonucleic acid (2’F-ANA) modification into various parts and nucleotide residues of the oligonucleotide of Fukuda et al. and Klein et al. in addition to alternatively linking 2’-deoxy-2’-fluoro-beta-D-arabinonucleic acid (2’F-ANA) residues and 2’-O-alkylribonucleotide residues or alternatively linking 2’-deoxy-2’-fluoro-beta-D-arabinonucleic acid (2’F-ANA) residues and bridged nucleotide residues, in order to determine the locations and residues that maximize the properties of the guide RNA for inhibiting nuclease sensitivity and improving efficiency of hybridization. Modifying the editing guide RNA of Fukuda et al., Klein and Jaschke et al. with the teachings of Kalota et al. would make obvious the limitations of claims 10,11,14 and 15.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant’s arguments, see page 10, filed 07/10/2025, with respect to the rejection(s) of claim(s) 10,11,14 and 15 under 35 U.S.C. 103 as unpatentable over Fukuda et al. and Klein and further in view of Kolata et al. have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to claim 1 incorporating some of the limitations from claims 2,4-7 and 19 which art was not applied to previously due to the Markush language in claims 2 and 5, as well as limitations from the specification. Therefore, a new rejection based on the combination of references for the new 103 for amended claim 1 (Fukuda et al., Klein and Jaschke et al. and further in view of Kolata et al.) is being made.
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 1,3,8,10-18 and 20-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,643,658 in view of Fukuda et al., Klein, Jaschke et al. and Kalota et al. cited above in the 35 U.S.C. 103 rejections.
U.S. Patent No. 11,643,658 claims 1-4 recite an oligonucleotide for inducing site-specific editing of a target RNA, the oligonucleotide comprising a first oligonucleotide identifying the target RNA; and a second oligonucleotide linked to the 3’ side of the first oligonucleotide, wherein the first oligonucleotide is composed of a target-corresponding nucleotide residue corresponding to an adenosine residue in the target RNA, an oligonucleotide of 15-30 residues linked to the 5’ side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA, an oligonucleotide 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 oligonucleotide is composed of 2-24 nucleotide residues, the second oligonucleotide consists of a base sequence non-complementary to a base sequence corresponding to the target RNA, the second oligonucleotide has a base sequence capable of forming a stem-loop structure, and the second oligonucleotide contains a base sequence composed of consecutive guanine, uracil, and guanine in a region linked to a loop portion of the 5’-side stem portion and contains a base sequence capable of forming a complementary pair therewith in the 3’side stem portion.
Instant claims 1 and 21-27 recite an oligonucleotide comprising a first oligonucleotide identifying a target RNA; a second oligonucleotide linked to the 3'-side of the first oligonucleotide; a third oligonucleotide capable of forming a complementary pair with the second oligonucleotide; and a first linking portion linking the second oligonucleotide and the third oligonucleotide, wherein the first oligonucleotide is composed of a target-corresponding nucleotide residue corresponding to an adenosine residue in the target RNA, an oligonucleotide 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 oligonucleotide 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 oligonucleotide is 5 to 8, wherein the number of residues of the third oligonucleotide 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, the first linking portion consists of 1-8 alkyleneoxy units, each of the first and third oligonucleotides is composed of all nucleotide residues linked by phosphorothioate bonds, the oligonucleotide linked to the 5’- side has two types of modified nucleotides selected from the group consisting of 2’-deoxy-2’-fluoronucleotide residues, 2’-O-alkylribonucleotide residues, and bridged nucleotide residues alternately linked, and each of the second and third oligonucleotide has a base sequence in which 2’-O-alkylribonucleotide residues are linked. Dependent claims 3,8,10-18 and 20 recite further limitations regarding the second linking portion, modified nucleotide residues.
US Patent No. 11,643,658 does not recite a third oligonucleotide capable of forming a complementary pair with the second oligonucleotide, and a first linking portion linking the second oligonucleotide and the third oligonucleotide, or 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, or wherein the first linking portion consists of 1-8 alkyleneoxy units, each of the first and third oligonucleotides is composed of all nucleotide residues linked by phosphorothioate bonds, the oligonucleotide linked to the 5’- side has two types of modified nucleotides selected from the group consisting of 2’-deoxy-2’-fluoronucleotide residues, 2’-O-alkylribonucleotide residues, and bridged nucleotide residues alternately linked, and each of the second and third oligonucleotide has a base sequence in which 2’-O-alkylribonucleotide residues are linked.
However, regarding the above limitations, the teachings of Fukuda et al., Klein, Jaschke et al. and Kalota et al. are described above in the 103 rejections.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the oligonucleotide of US Patent No. 11,643,658 with the teachings of Fukuda et al., Klein, Jaschke et al. and Kalota et al. with a reasonable expectation of success, as this would have amounted to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to modify the oligonucleotide of US Patent No. 11,643,658 because Fukuda et al. teach the ADAR binding core region has a structure connecting the guide-side decoupling region at a terminal side of the ADAR binding core region and the ADAR adjacent partial region of the target recognition region at the other side and has a structure making a base-pairing with the ADAR adjacent partial region. One of ordinary skill in the art would have been motivated to try to modify at least one residue in the counter region of the target-corresponding nucleotide residue and two respective residues on the 3’ and 5’ sides with a chemical modification such as 2’-O ribosyl modifications, modified internucleoside linkages and other ribose sugar modifications well known in the art because Klein teaches these modifications provide properties such as inhibiting nuclease sensitivity due to its bulkiness and improving efficiency of hybridization.
One of ordinary skill in the art would be motivated to modify the oligonucleotide of US Patent No. 11,643,658 with a PEG of 1-8 units as a linking portion between the the second and third oligonucleotide because Jaschke et al. teach the desire for coupling polyethylene glycol (PEG) to oligonucleotides because it is non-toxic and non-immunogenic, and interacts in a complex manner with cellular membranes, and facilitates uptake of exogenous nucleic acids by different cells, and teach the synthesis of internally PEG-coupled oligonucleotides of length 5-18 nucleotides and whereby the degree of polymerization of PEG ranged from 5-32 for 5’-terminal and internal coupling (Results, page 4812) and that coupling of PEG caused an increase in retention time, indicating increased hydrophobicity (page 4813, left column). An ordinary artisan would be motivated to experiment with the number of PEG units because Jaschke et al. teach that conjugate strategies using polymers as conjugate groups allow the modulation of molecular properties by the choice of the degree of polymerization, and the coupling strategy described herein uses a PEG polymer that contains only two reactive groups, and allows the incorporation of the conjugate group into oligonucleotides during automated synthesis at exactly defined positions with exactly defined stoichiometry and incorporation is possible at the 3’-terminal, 5’-terminal and internal positions, and it is possible to adjust the hydrophobicity of the conjugate by the selection of a suitable polymer size.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the oligonucleotide of US Patent No. 11,643,658 with the teachings of Klein et al. regarding the phosphorothioate bonds with a reasonable expectation of success, as this would have amounted to applying a known technique of chemical modification with phosphorothioate bonds to a known oligonucleotide product ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to provide phosphorothioate bonds in all of the nucleotide residues of the first and third oligonucleotide or first and second oligonucleotide because Klein et al. teach that various chemistries and modifications are known in the field of oligonucleotides that can readily be used, and that regular internucleosidic linkages between the nucleotides may be altered by mono-or di-thiolation of the phosphodiester bonds to yield phosphorothioate esters, and the exact chemistries and formats depend from oligonucleotide construct to oligonucleotide construct and from application to application and can be worked out in accordance with those of skill in the art (page 14, lines 13-16,26-29).
It would have been obvious to one of ordinary skill in the art to modify the oligonucleotide of US Patent No. 11,643,658 to have two types of modified nucleotides in the 5’ side of the target-corresponding nucleotide residue selective from the group consisting of 2’-deoxy-2’-fluoronucleotide residues, 2’-O-alkylribonucleotide residues and bridged nucleotides residues alternatively linked, and each of the second and third oligonucleotide base sequence in which 2’-O-alkylribonucleotide residues are linked, or in which bridged nucleotide residues and 2’-O-alkylribonucleotide residues are alternately linked, or 2’-deoxy-2’-fluoronucleotide residues and 2’-O-alkylribonucleotide residues are alternately linked, and the other limitations regarding the specific sugar modifications at particular locations of the oligonucleotide with a reasonable expectation of success as this would have amounted to applying a known technique of chemical modification with 2’-O-alkylribonucleotide residues, 2’-deoxy-2’-fluoronucleotide residues and/or bridged nucleotide residues to a known oligonucleotide product ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Klein teaches both the targeting portion and recruiting portion may comprise or consist of nucleotides having chemical modifications that alter nuclease resistance, affinity of binding or other properties, and examples of chemical modifications are modifications of the sugar moiety, including cross-linking substituents within the sugar moiety (e.g. as in LNA or locked nucleic acids), by substitution of the 2’-O atom with alkyl groups (page 17, lines 9-18), and the ribose sugar may be modified by substitution of the 2’-O moiety with a lower alkyl, alkenyl, alkynyl, methoxyethyl, or other substituent and is known for inhibiting nuclease sensitivity and improving efficiency of hybridization (page 14, lines 17-22). Klein teaches it has been shown in the art that 2’-O-methylation of the ribosyl-moiety of a nucleoside opposite an adenosine in the target RNA sequence dramatically reduces deamination of that adenosine by ADAR, and that by including 2’-methoxy (2’-OME) nucleotides in the desired position of the oligonucleotide construct, the specificity of editing may be dramatically improved (page 16, lines 2-9). In addition, Klein teaches locked nucleic acid sequences (LNAs) comprising a 2’-4’ intramolecular bridge linkage inside the ribose ring may be applied, and exact chemistries and formats may depend from the oligonucleotide construct and the application and may be worked out according to the preferences of those of skill in the art (page 14, lines 23-29). Klein teaches both the targeting portion and recruiting portion may comprise or consist of nucleotides having chemical modifications that alter nuclease resistance, affinity of binding or other properties, including locked nucleic acids (page 17, lines 9-11 and 13). Kalota et al. teach that modification with 2’-deoxy-2’-fluoro-beta-D-arabinonucleic acid (2’F-ANA) that significantly enhances binding affinity to the target mRNA compared with native or PS-modified DNA and that 2’F-ANA/RNA duplexes retain ability to activate RNase H.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the oligonucleotide of US Patent No. 11,643,658 with the teachings of Klein et al. regarding a second linking portion containing an alkyleneoxy unit between the first oligonucleotide and second oligonucleotide with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide a linking portion containing an alkyleneoxy unit between the first and second oligonucleotide, because Klein et al. teach a PEG (an alkyleneoxy unit) linker may link a recruiting portion at the 5’ or 3’ end to a targeting portion (page 14, lines 9-11).
Accordingly, the limitations of claims 1,3,8,10-18 and 20-27 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 1,3,8,10-18 and 20-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of copending Application No. 17/905,881 (App 881) in view Klein, Jaschke et al. and Kalota et al. cited above in the 35 U.S.C. 103 rejections.
Claims 1-5 of App 881 recite an oligonucleotide that induces site-specific editing of a target RNA, comprising: a first oligonucleotide that identifies the target RNA, a second oligonucleotide linked to the 3' side of the first oligonucleotide, a third oligonucleotide having a base sequence capable of forming 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 target-corresponding 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 target-corresponding nucleotide residue and having a base sequence complementary to the target RNA.
Instant claims 1 and 21-27 recite an oligonucleotide comprising a first oligonucleotide identifying a target RNA; a second oligonucleotide linked to the 3'-side of the first oligonucleotide; a third oligonucleotide capable of forming a complementary pair with the second oligonucleotide; and a first linking portion linking the second oligonucleotide and the third oligonucleotide, wherein the first oligonucleotide is composed of a target-corresponding nucleotide residue corresponding to an adenosine residue in the target RNA, an oligonucleotide 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 oligonucleotide 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 oligonucleotide is 5 to 8, wherein the number of residues of the third oligonucleotide 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; the first linking portion consists of 1-8 alkyleneoxy units; each of the first and third oligonucleotides is composed of all nucleotide residues linked by phosphorothioate bonds; the oligonucleotide linked to the 5’- side has two types of modified nucleotides selected from the group consisting of 2’-deoxy-2’-fluoronucleotide residues, 2’-O-alkylribonucleotide residues, and bridged nucleotide residues alternately linked, and each of the second and third oligonucleotide has a base sequence in which 2’-O-alkylribonucleotide residues are linked. Dependent claims 3,8,10-18 and 20 recite further limitations regarding the second linking portion, modified nucleotide residues.
App 881 does not recite 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, or wherein the first