DETAILED ACTION
Receipt of Arguments/Remarks filed on January 22 2026 is acknowledged. Claim 15 was/stands cancelled. Claims 6-8, 10 and 11 were amended. Claims 1-14 and 16-21 are pending. Claims 13-14 and 16-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 1 2025. Claims 1-23 are directed to the elected invention.
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 .
Withdrawn Objections/Rejections
The objection to the drawings is withdrawn in light of Applicants’ arguments filed January 22 2026. The instant application only contains up to Fig. 5. The examiner regrets the confusion.
The amendments filed January 22 2026 has overcome the objection of claims 8 and 10. Firstly the Cl was replaced with C1 and the recitation to the table was removed.
The amendments filed January 22 2026 have overcome the rejection of claim 6 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The language which lacks written description were removed from the claim.
The amendments filed January 22 2026 are sufficient to overcome the rejection of claims 6 and 10-11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. The confusing words were removed from the claim 6. The broad recitation was removed from claim 10. Claim 11 was amended to recite just consists.
New Objections Necessitated by the Amendments filed January 22 2026 and Maintained Rejections
Claim Objections
Claim 8 is objected to because of the following informalities: the claim was amended to insert an additional dash “-“ between C and 10. The claim should recite C1-C10 to indicate the length of the alkyl chain. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: the claim is missing a word or punction between adenosine and the c.5882G>A. Currently the claim recites “wherein the target adenosine the c.5882G>A mutation in exon 42 of the human ABCA4.” Appropriate correction is required.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1-12 are rejected under 35 U.S.C. 103 as being unpatentable over Turunen et al. (WO2017220751, cited on PTO Form 1449) in view of Tanaka et al. (American Academy of Ophthalmology, 2018) and Allikmets et al. (Am. J. Hum. Genet. 2000) as evidenced by GenBank (NCBI Reference Sequence: NC_000001.11, 2018).
Applicant Claims
The instant application claims a RNA editing oligonucleotide (EON) capable of forming a double stranded complex with a target RNA molecule, wherein the EON when complexed with the target RNA molecule, is able to recruit and complex with an ‘Adenosine Deaminase Acting on RNA’ (ADAR) enzyme, thereby allowing the deamination by the ADAR enzyme of a target adenosine in the target RNA molecule, wherein the EON does not form an internal loop structure and wherein the target RNA molecule is a human ABCA4 pre-mRNA or mRNA
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Turunen et al. is directed to single-stranded RNA-editing oligonucleotides. Taught is a targeted approach to RNA editing using, in one embodiment, an antisense oligonucleotide (AON) capable of forming a double stranded complex with a target RNA in a cell, for the deamination of a specific target adenosine in said target RNA by a mammalian ADAR enzyme present in said cell; wherein said AON is complementary to a target RNA comprising the target adenosine, said AON optionally comprising one or more mismatches, wobbles and/or bulges with said target RNA; wherein the AON comprises one or more nucleotides with a sugar modification, provided that the nucleotide opposite the target adenosine comprises a ribose with a 2'-OH group or a deoxyribose with a 2'-H group (page 3, lines 30-40). The AONs do not comprise a portion that is capable of forming an intramolecular stem-loop structure (page 8, lines 10-14). The AON can be used for the treatment of genetic disorders such as Stargardt’s disease (claim 16).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Turunen et al. teach editing oligonucleotides which are single-stranded and form a double stranded complex with a target RNA, Turunen et al. does not expressly teach the target is ABCA4. However, this deficiency is cured by Tanaka et al.
Tanaka et al. is directed to the rapid-onset chorioretinopathy (ROC) phenotype of ABCA4 disease. Stargardt disease (STGD1) is the most common juvenile-onset macular dystrophy affecting 1 in 5 of 10 000 people worldwide. Since its discovery as the causative gene in 1997, more than 800 disease-causing mutations within the coding (50 exons) and noncoding regions of the ATP Binding Cassette Subfamily A Member 4 (ABCA4, Mendelian Inheritance in Man #601691) gene have been reported, giving rise to a large heterogeneous group of retinal dystrophies (page 89, first paragraph). The abundance of data from patients harboring c.5882G>A (p.G1961E) has revealed its association with a confined maculopathy, lower accumulation of lipofuscin (autofluorescence [AF]), and the long-term preservation of cone and rod function (page 89, second paragraph). The genotypic profile of ROC patients consisted of 21 unique variants. Four small deletions of 1-4 nucleotides resulting frameshifts and 7 nonsense variants resulting in premature stop codons were also detected (page 94, paragraph bridging columns).
Allikmets et al. is directed to further evidence for an association of ABCR alleles with age-related macular degeneration. Age-related macular degeneration (AMD) has been associated with both environmental and genetic factors. Previously the authors reported disease associated variants in the Stargardt disease gene, ABCR, in a subset of patients affected with this complex disease trait (page 487, first paragraph). Taught is data which tests the associations of AMD with two of the more common AMD-associated ABCR variants, G1961E and D2177N (page 487). Reports have indicated a higher rate of AMD in parents and grandparents of patients with recessive Stargardt disease harboring ABCR variants (page 489, last paragraph). The data confirms the association of the ABCR alleles G1961E and D2117N with7 AMD (page 490, last paragraph).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Turunen et al., Tanaka et al. and Allikmets et al. and utilize ABCA4 as the target mRNA. One skilled in the art would have been motivated to utilize ABCA4 as it is associated with disease causing mutations as taught by Tanaka et al. Since the mutations of the gene are well documented, one skilled in the art would have a reasonable expectation of success in targeting this particular gene in order to treat diseases associated with the mutations. Since Turunen et al. teaches the use of the editing oligonucleotides for treatment of diseases such as Stargardt disease there is a reasonable expectation of success. Rendering claim 1 obvious.
Regarding claim 2 and 4-5, Figure 13 of Turunen et al. teaches that AONs that have DNA nucleosides in the central triplet opposite the targeted adenosine and that such RNA editing may be further increased with additional mismatches are introduced. Central triplets include 5’-CCA-3’ (Figure 11). It is taught that the middle nucleotide does not have a 2’-O methyl modification and either or both surrounding nucleosides also do not have a 2’-O methyl modification (page 11, lines 1-5). This suggests at least one nucleotide in the central triplet comprises a modification (i.e. could be DNA) and that the middle nucleotide does not contain a 2’-OMe or 2’-MOE modification.
Regarding claim 3, Turunen et al. teaches that the editing enzyme is a cytidine deaminase and the ones most of interest include hADAR2 (page 19, lines 29-40).
Regarding claim 6-7, Turunen et al. claims the AON comprises at least one phosphorothioate linkage (claim 8). As claimed the 2, 3, 4, 5, or 6 terminal nucleotides of the 5' and 3' terminus of the AON are linked with phosphorothioate linkages (clam 9).
Regarding claim 8, the AON comprises 2’-O-alkyl group modifications preferably 2’-O-methyl which results in a 2’ modification of the sugar with an alkyl substitution which is interrupted with an O.
Regarding claim 9, Turunen et al. suggests that the target sequence can be a stop codon (figure 1, 11). Tanaka et al. teaches ABCA4 disease is associated with mutations. Specific mutations for the genotypic profile of ROC patients consisted of 21 unique variants. Four small deletions of 1-4 nucleotides resulting frameshifts and 7 nonsense variants resulting in premature stop codons were also detected (page 94, paragraph bridging columns).Therefore, one skilled in the art would have been motivated to target this particular modification in the ABCA4 disease as it is present in the genotypic profile of ROC patients.
Regarding claim 10, Tanaka et al. teaches data from patients harboring c.5882G>A (p.G1961E) has revealed its association with a confined maculopathy, lower accumulation of lipofuscin (autofluorescence [AF]), and the long-term preservation of cone and rod function (page 89, second paragraph). Allikmets et al. teaches data which tests the associations of AMD with two of the more common AMD-associated ABCR variants, G1961E and D2177N (page 487) which confirms the association of the ABCR alleles G1961E and D2117N with AMD. Therefore, one skilled in the art would have been motivated to target this particular mutation as it is a well-documented mutation which is associated with various conditions. One skilled in the art would have a reasonable expectation of success as Turunen et al. teaches that the target RNA sequence can be such that it is designed to edit a G>A mutation (page 5, lines 26-30).
Regarding claim 11, as set forth above, targeting the G1961E mutation is obvious. Turunen et al. teaches that the AON comprises one or more mismatches. These mismatches add to the RNA editing efficiency because it adds to the altered on/off rate of the AON with its target molecule and/or to the binding and/or recognition of the ADAR molecule (page 4, lines 14-20). Mismatches include U-C (aka T-C) (page 17, lines 20-24). As shown below: instantly claimed SEQ ID NO. 1 (Qy) 97% identical to the ABCA4 G1961E mutation (exon 42) (Db) wherein the instantly claimed sequence contains 1 mismatch:
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The sequence was obtained from the NCBI record for NC00001.11. As shown in the sequence information, the instantly claimed sequence is 97% identical to the antisense strand.
Therefore, one skilled in the art when designing AONs which target the ABCA4 G1961E mutation would have made an AON corresponding to SEQ ID NO. 1 as it would target this region of the ABCA4 gene. One skilled in the art would have been motivated to include a mismatch as it would be expected to add to the RNA editing efficiency as taught by Turunen et al. As taught by Turunen et al. the AON preferably comprises 18 to 50 nucleotides (page 11, lines 10-15).
Regarding claim 12, Turunen et al. claims a pharmaceutical composition comprising the AON and a pharmaceutically acceptable carrier (claim 14).
Response to Arguments
Applicants’ arguments filed January 22 2026 have been fully considered but they are not persuasive.
Applicants argue that none of the references appear to suggest use of an EON that does not form an internal loop to deaminate a target adenosine in the ABCA4 mRNA or pre-RNA. None of the cited reference appear to disclose evidence of the successful use of an EON that does not form an internal loop to deaminate a target adenosine in the ABCA4 mRNA or pre-mRNA. It is argued that the present claims are squarely within the unpredictable arts. The Office has not established a prima facie case of obviousness. This is because the office has filed to demonstrate that in combining the teachings of the cited prior art would have a reasonable expectation of success. As shown in the examples the inventors were able to provide EONs that were able to edit the target adenosine in exon 42 of the human ABCA4 (pre-)mRNA to an inosine in cells as well as in an in vitro biochemical setting.
Regarding Applicants arguments, firstly, as pointed out in the previous Office Action, Turunen et al. teaches that the AONs do not comprise a portion that is capable of forming an intramolecular stem-loop structure (page 8, lines 10-14). This reads on the EON does not form an internal loop structure. This concept is repeated throughout Turunen et al. including the claims. Therefore, the examiner cannot agree that the cited prior art does not suggest an EON that does not form an internal loop structure.
Regarding the argued unpredictability, obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. NOTE: MPEP 2143.02. Applicants do not point to what specifically is unpredictable except indicating that the Office has not demonstrated that there would be a reasonable expectation of success in making and using the EON of the present claims. As stated in the motivation statement, one skilled in the art would have been motivated to target ABCA4 as it is associated with disease causing mutations. Since mutations of the gene are well documented, one skilled in the art would have a reasonable expectation of success in targeting this particular gene in order to treat diseases associated with the mutations. Since Turunen et al. teaches the use of the editing oligonucleotide for treatment of diseases such as Stargardt disease the same disease taught by Tanaka et al. and Allikmets et al., the examiner cannot agree that there isn’t a reasonable expectation of success.
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 1-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10941402 in view of Turunen et al. (WO2017220751, cited on PTO Form 1449), Tanaka et al. (American Academy of Ophthalmology, 2018) and Allikmets et al. (Am. J. Hum. Genet. 2000) as evidenced by GenBank (NCBI Reference Sequence: NC_000001.11, 2018). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims an RNA editing oligonucleotide (EON) capable of forming a double stranded complex with a target RNA molecule, wherein the EON when complexed with the target RNA molecule, is able to recruit and complex with an 'Adenosine Deaminase Acting on RNA' (ADAR) enzyme, thereby allowing the deamination by the ADAR enzyme of a target adenosine in the target RNA molecule, wherein the EON does not form an internal loop structure and wherein the target RNA molecule is a human ABCA4 pre-mRNA or mRNA.
Patent ‘402 claims an antisense oligonucleotide (AON) capable of forming a double stranded complex with a target RNA sequence in a cell for the deamination of a target adenosine in the target RNA sequence by an ADAR enzyme present in the cell, wherein (i) the AON comprises a Central Triplet of 3 sequential nucleotides (reading on instant claim 2), (ii) the nucleotide directly opposite the target adenosine is the middle nucleotide of the Central Triplet, (iii) the middle nucleotide of the Central Triplet is a cytidine, (iv) 1, 2 or 3 nucleotides in the Central Triplet comprise a sugar modification and/or a base modification to render the AON more stable and/or more effective in inducing deamination of the target adenosine (reading on instant claim 4), (v) the AON does not comprise a 5′-terminal O6-benzylguanosine, (vi) the AON is not covalently linked to a SNAP-tag domain, (vii) the middle nucleotide does not have a 2′-O-methyl modification, and (viii) the AON does not comprise a portion that is capable of forming an intramolecular stem-loop structure that is capable of binding a mammalian ADAR enzyme (claim 1).
While Patent ‘402 claims forming a double stranded complex with a target RNA sequence, Patent ‘402 does not claim the target RNA sequence is a human ABCA4 pre-mRNA or mRNA. However, this deficiency is cured by Turunen et al., Tanaka et al. and Allikmets et al.
Turunen et al. is directed to single-stranded RNA-editing oligonucleotides (similar to patent ‘402). Taught is a targeted approach to RNA editing using, in one embodiment, an antisense oligonucleotide (AON) capable of forming a double stranded complex with a target RNA in a cell, for the deamination of a specific target adenosine in said target RNA by a mammalian ADAR enzyme present in said cell; wherein said AON is complementary to a target RNA comprising the target adenosine, said AON optionally comprising one or more mismatches, wobbles and/or bulges with said target RNA; wherein the AON comprises one or more nucleotides with a sugar modification, provided that the nucleotide opposite the target adenosine comprises a ribose with a 2'-OH group or a deoxyribose with a 2'-H group (page 3, lines 30-40). The AONs do not comprise a portion that is capable of forming an intramolecular stem-loop structure (page 8, lines 10-14). The AON can be used for the treatment of genetic disorders such as Stargardt’s disease (claim 16).
Tanaka et al. is directed to the rapid-onset chorioretinopathy (ROC) phenotype of ABCA4 disease. Stargardt disease (STGD1) is the most common juvenile-onset macular dystrophy affecting 1 in 5 of 10 000 people worldwide. Since its discovery as the causative gene in 1997, more than 800 disease-causing mutations within the coding (50 exons) and noncoding regions of the ATP Binding Cassette Subfamily A Member 4 (ABCA4, Mendelian Inheritance in Man #601691) gene have been reported, giving rise to a large heterogeneous group of retinal dystrophies (page 89, first paragraph). The abundance of data from patients harboring c.5882G>A (p.G1961E) has revealed its association with a confined maculopathy, lower accumulation of lipofuscin (autofluorescence [AF]), and the long-term preservation of cone and rod function (page 89, second paragraph). The genotypic profile of ROC patients consisted of 21 unique variants. Four small deletions of 1-4 nucleotides resulting frameshifts and 7 nonsense variants resulting in premature stop codons were also detected (page 94, paragraph bridging columns).
Allikmets et al. is directed to further evidence for an association of ABCR alleles with age-related macular degeneration. Age-related macular degeneration (AMD) has been associated with both environmental and genetic factors. Previously the authors reported disease associated variants in the Stargardt disease gene, ABCR, in a subset of patients affected with this complex disease trait (page 487, first paragraph). Taught is data which tests the associations of AMD with two of the more common AMD-associated ABCR variants, G1961E and D2177N (page 487). Reports have indicated a higher rate of AMD in parents and grandparents of patients with recessive Stargardt disease harboring ABCR variants (page 489, last paragraph). The data confirms the association of the ABCR alleles G1961E and D2117N with7 AMD (page 490, last paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘402, Turunen et al., Tanaka et al. and Allikmets et al. and utilize ABCA4 as the target mRNA. One skilled in the art would have been motivated to utilize ABCA4 as it is associated with disease causing mutations as taught by Tanaka et al. Since the mutations of the gene are well documented, one skilled in the art would have a reasonable expectation of success in targeting this particular gene in order to treat diseases associated with the mutations. Since patent ‘402 claims any target RNA and Turunen et al. teaches the use of the editing oligonucleotides similar to patent ‘402 for treatment of diseases such as Stargardt disease there is a reasonable expectation of success. Rendering claim 1 obvious.
Regarding claim 3, Patent ‘402 claims an ADAR enzyme. Turunen et al. teaches that the editing enzyme is a cytidine deaminase and the ones most of interest include hADAR2 (page 19, lines 29-40).
Regarding claim 5, Patent ‘402 claims the sugar modification is selected from the group consisting of deoxyribose (DNA), Unlocked Nucleic Acid (UNA) and 2′-fluororibose (claim 4).
Regarding claim 6-7, Patent ‘402 claims a phosphorothioate (claim 5). Patent ‘402 claims 2, 3, 4, 5, or 6 terminal nucleotides of the 5′ and 3′ terminus of the AON are linked with phosphorothioate linkages (claim 6).
Regarding claim 8, Patent ‘402 claims one or more nucleotides in the AON outside the Central Triplet comprise a modification selected from the group consisting of: DNA, a 2′-O-alkyl group, a 2′-O-methoxyethyl group, a 2′-F group, a 2′-NH.sub.2 group, an LNA and any combinations thereof (claim 8).
Regarding claim 9, Turunen et al. suggests that the target sequence can be a stop codon (figure 1, 11). Tanaka et al. teaches ABCA4 disease is associated with mutations. Specific mutations for the genotypic profile of ROC patients consisted of 21 unique variants. Four small deletions of 1-4 nucleotides resulting frameshifts and 7 nonsense variants resulting in premature stop codons were also detected (page 94, paragraph bridging columns).Therefore, one skilled in the art would have been motivated to target this particular modification in the ABCA4 disease as it is present in the genotypic profile of ROC patients.
Regarding claim 10, Tanaka et al. teaches data from patients harboring c.5882G>A (p.G1961E) has revealed its association with a confined maculopathy, lower accumulation of lipofuscin (autofluorescence [AF]), and the long-term preservation of cone and rod function (page 89, second paragraph). Allikmets et al. teaches data which tests the associations of AMD with two of the more common AMD-associated ABCR variants, G1961E and D2177N (page 487) which confirms the association of the ABCR alleles G1961E and D2117N with AMD. Therefore, one skilled in the art would have been motivated to target this particular mutation as it is a well-documented mutation which is associated with various conditions. One skilled in the art would have a reasonable expectation of success as Turunen et al. teaches that the target RNA sequence can be such that it is designed to edit a G>A mutation (page 5, lines 26-30). A similar mutation is claimed by patent ‘402 (claim 15).
Regarding claim 11, as set forth above, targeting the G1961E mutation is obvious. Turunen et al. teaches that the AON comprises one or more mismatches. These mismatches add to the RNA editing efficiency because it adds to the altered on/off rate of the AON with its target molecule and/or to the binding and/or recognition of the ADAR molecule (page 4, lines 14-20). Mismatches include U-C (aka T-C) (page 17, lines 20-24). As shown below: instantly claimed SEQ ID NO. 1 (Qy) 97% identical to the ABCA4 G1961E mutation (exon 42) (Db) wherein the instantly claimed sequence contains 1 mismatch:
PNG
media_image1.png
398
858
media_image1.png
Greyscale
The sequence was obtained from the NCBI record for NC00001.11. As shown in the sequence information, the instantly claimed sequence is 97% identical to the antisense strand.
Therefore, one skilled in the art when designing AONs which target the ABCA4 G1961E mutation would have made an AON corresponding to SEQ ID NO. 1 as it would target this region of the ABCA4 gene. One skilled in the art would have been motivated to include a mismatch as it would be expected to add to the RNA editing efficiency as taught by Turunen et al. As taught by Turunen et al. the AON preferably comprises 18 to 50 nucleotides (page 11, lines 10-15). Patent ‘402 claims the AON comprises 18 to 50 nucleotides (claim 12).
Regarding claim 12, Patent ‘402 claims a pharmaceutical composition comprising the AON and a pharmaceutically acceptable carrier (claim 20).
Claims 1-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 11851656 in view of Turunen et al., Tanaka et al. and Allikmets et al. as evidenced by GenBank (NCBI Reference Sequence: NC_000001.11, 2018). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims are set forth above.
Patent ‘656 claims antisense oligonucleotide (AON) comprising a Central Triplet of 3 sequential nucleotides (reading on instant claim 2), wherein (i) the AON is capable of forming a double stranded complex with a target RNA molecule in a cell comprising a target adenosine; (ii) the nucleotide directly opposite the target adenosine is the middle nucleotide of the Central Triplet; (iii) 1, 2 or 3 nucleotides in the Central Triplet comprise a sugar modification and/or a base modification (reading on instant claim 4) to render the AON more stable and/or more effective in inducing deamination of the target adenosine; with the proviso that the middle nucleotide does not have a 2′-O-methyl modification; (iv) the AON does not comprise a 5′-terminal O6-benzylguanosine; (v) the AON does not comprise a portion that is capable of forming an intramolecular stem-loop structure that is capable of binding a mammalian ADAR enzyme present in the cell; and, (vi) the AON can mediate the deamination of the target adenosine by the ADAR enzyme. (claim 1).
While Patent ‘656 claims forming a double stranded complex with a target RNA sequence, Patent ‘656 does not claim the target RNA sequence is a human ABCA4 pre-mRNA or mRNA. However, this deficiency is cured by Turunen et al., Tanaka et al. and Allikmets et al.
The teachings of Turunen et al., Tanaka et al. and Allikmets et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘656, Turunen et al., Tanaka et al. and Allikmets et al. and utilize ABCA4 as the target mRNA. One skilled in the art would have been motivated to utilize ABCA4 as it is associated with disease causing mutations as taught by Tanaka et al. Since the mutations of the gene are well documented, one skilled in the art would have a reasonable expectation of success in targeting this particular gene in order to treat diseases associated with the mutations. Since patent ‘656 claims any target RNA and Turunen et al. teaches the use of the editing oligonucleotides similar to patent ‘656 for treatment of diseases such as Stargardt disease there is a reasonable expectation of success. Rendering claim 1 obvious.
Regarding claim 3, Patent ‘656 claims an ADAR enzyme. Turunen et al. teaches that the editing enzyme is a cytidine deaminase and the ones most of interest include hADAR2 (page 19, lines 29-40).
Regarding claim 5, Patent ‘656 claims the sugar modification is selected from the group consisting of deoxyribose (DNA), Unlocked Nucleic Acid (UNA) and 2′-fluororibose (claim 7).
Regarding claim 6-7, Patent ‘656 claims a phosphorothioate (claim 8). Patent ‘656 claims 2, 3, 4, 5, or 6 terminal nucleotides of the 5′ and 3′ terminus of the AON are linked with phosphorothioate linkages (claim 9).
Regarding claim 8, Patent ‘656 claims one or more nucleotides in the AON outside the Central Triplet comprise a modification selected from the group consisting of: DNA, a 2′-O-alkyl group, a 2′-O-methoxyethyl group, a 2′-F group, a 2′-NH.sub.2 group, an LNA and any combinations thereof (claim 12).
Regarding claim 9, Turunen et al. suggests that the target sequence can be a stop codon (figure 1, 11). Tanaka et al. teaches ABCA4 disease is associated with mutations. Specific mutations for the genotypic profile of ROC patients consisted of 21 unique variants. Four small deletions of 1-4 nucleotides resulting frameshifts and 7 nonsense variants resulting in premature stop codons were also detected (page 94, paragraph bridging columns).Therefore, one skilled in the art would have been motivated to target this particular modification in the ABCA4 disease as it is present in the genotypic profile of ROC patients.
Regarding claim 10, Tanaka et al. teaches data from patients harboring c.5882G>A (p.G1961E) has revealed its association with a confined maculopathy, lower accumulation of lipofuscin (autofluorescence [AF]), and the long-term preservation of cone and rod function (page 89, second paragraph). Allikmets et al. teaches data which tests the associations of AMD with two of the more common AMD-associated ABCR variants, G1961E and D2177N (page 487) which confirms the association of the ABCR alleles G1961E and D2117N with AMD. Therefore, one skilled in the art would have been motivated to target this particular mutation as it is a well-documented mutation which is associated with various conditions. One skilled in the art would have a reasonable expectation of success as Turunen et al. teaches that the target RNA sequence can be such that it is designed to edit a G>A mutation (page 5, lines 26-30). A similar mutation is claimed by patent ‘656 (claim 22).
Regarding claim 11, as set forth above, targeting the G1961E mutation is obvious. Turunen et al. teaches that the AON comprises one or more mismatches. These mismatches add to the RNA editing efficiency because it adds to the altered on/off rate of the AON with its target molecule and/or to the binding and/or recognition of the ADAR molecule (page 4, lines 14-20). Mismatches include U-C (aka T-C) (page 17, lines 20-24). As shown below: instantly claimed SEQ ID NO. 1 (Qy) 97% identical to the ABCA4 G1961E mutation (exon 42) (Db) wherein the instantly claimed sequence contains 1 mismatch:
PNG
media_image1.png
398
858
media_image1.png
Greyscale
The sequence was obtained from the NCBI record for NC00001.11. As shown in the sequence information, the instantly claimed sequence is 97% identical to the antisense strand.
Therefore, one skilled in the art when designing AONs which target the ABCA4 G1961E mutation would have made an AON corresponding to SEQ ID NO. 1 as it would target this region of the ABCA4 gene. One skilled in the art would have been motivated to include a mismatch as it would be expected to add to the RNA editing efficiency as taught by Turunen et al. As taught by Turunen et al. the AON preferably comprises 18 to 50 nucleotides (page 11, lines 10-15). Patent ‘656 claims the AON comprises 18 to 50 nucleotides (claim 17).
Regarding claim 12, Patent ‘656 claims a pharmaceutical composition comprising the AON and a pharmaceutically acceptable carrier (claim 29).
Claims 1-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10988763 in view of Turunen et al., Tanaka et al. and Allikmets et al. as evidenced by GenBank (NCBI Reference Sequence: NC_000001.11, 2018). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘763 claims an antisense oligonucleotide (AON) capable of forming a double stranded complex with a target RNA in a cell for the deamination of a target adenosine present in the target RNA by an ADAR enzyme present in the cell, wherein: (a) the AON is complementary to a target RNA region comprising the target adenosine, and the AON comprises one or more mismatches, wobbles and/or bulges with the complementary target RNA region; (b) the AON comprises one or more nucleotides with one or more sugar modifications, provided that the nucleotide opposite the target adenosine comprises a ribose with a 2′-OH group, or a deoxyribose with a 2′-H group; (c) the AON does not comprise a portion that is capable of forming an intramolecular stem-loop structure capable of binding an ADAR enzyme; (d) the AON does not include a 5′-terminal O6-benzylguanine modification; (e) the AON does not include a 5′-terminal amino modification; and (f) the AON is not covalently linked to a SNAP-tag domain (claim 1). Genetic disorders which can be treated with the AON includes Stargardt’s Disease (claim 20).
While Patent ‘763 claims forming a double stranded complex with a target RNA sequence, Patent ‘763 does not claim the target RNA sequence is a human ABCA4 pre-mRNA or mRNA. However, this deficiency is cured by Turunen et al., Tanaka et al. and Allikmets et al.
The teachings of Turunen et al., Tanaka et al. and Allikmets et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘763, Turunen et al., Tanaka et al. and Allikmets et al. and utilize ABCA4 as the target mRNA. One skilled in the art would have been motivated to utilize ABCA4 as it is associated with disease causing mutations as taught by Tanaka et al. Since the mutations of the gene are well documented, one skilled in the art would have a reasonable expectation of success in targeting this particular gene in order to treat diseases associated with the mutations. Since patent ‘763 claims any target RNA and specifically claims Stargardt there is a reasonable expectation of success. Rendering claim 1 obvious.
Regarding claim 2 and 4-5, Patent ‘763 does not claim a central triplet. However, Figure 13 of Turunen et al. teaches that AONs that have DNA nucleosides in the central triplet opposite the targeted adenosine and that such RNA editing may be further increased with additional mismatches are introduced. Central triplets include 5’-CCA-3’ (Figure 11). It is taught that the middle nucleotide does not have a 2’-O methyl modification and either or both surrounding nucleosides also do not have a 2’-O methyl modification (page 11, lines 1-5). This suggests at least one nucleotide in the central triplet comprises a modification (i.e. could be DNA) and that the middle nucleotide does not contain a 2’-OMe or 2’-MOE modification. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘763, Turunen et al., Tanaka et al. and Allikmets et al. and utilize a central triplet in order to further increase the RNA editing as taught by Turunen et al.
Regarding claim 3, Patent ‘763 claims an ADAR enzyme. Turunen et al. teaches that the editing enzyme is a cytidine deaminase and the ones most of interest include hADAR2 (page 19, lines 29-40).
Regarding claim 6-7, Patent ‘763 claims a phosphorothioate (claim 8). Patent ‘763 claims 2, 3, 4, 5, or 6 terminal nucleotides of the 5′ and 3′ terminus of the AON are linked with phosphorothioate linkages (claim 9).
Regarding claim 8, Patent ‘764 claims all other nucleotides in the AON comprise 2’-O-alkyl group (claim 12).
Regarding claim 9, Turunen et al. suggests that the target sequence can be a stop codon (figure 1, 11). Tanaka et al. teaches ABCA4 disease is associated with mutations. Specific mutations for the genotypic profile of ROC patients consisted of 21 unique variants. Four small deletions of 1-4 nucleotides resulting frameshifts and 7 nonsense variants resulting in premature stop codons were also detected (page 94, paragraph bridging columns).Therefore, one skilled in the art would have been motivated to target this particular modification in the ABCA4 disease as it is present in the genotypic profile of ROC patients.
Regarding claim 10, Tanaka et al. teaches data from patients harboring c.5882G>A (p.G1961E) has revealed its association with a confined maculopathy, lower accumulation of lipofuscin (autofluorescence [AF]), and the long-term preservation of cone and rod function (page 89, second paragraph). Allikmets et al. teaches data which tests the associations of AMD with two of the more common AMD-associated ABCR variants, G1961E and D2177N (page 487) which confirms the association of the ABCR alleles G1961E and D2117N with AMD. Therefore, one skilled in the art would have been motivated to target this particular mutation as it is a well-documented mutation which is associated with various conditions. One skilled in the art would have a reasonable expectation of success as Turunen et al. teaches that the target RNA sequence can be such that it is designed to edit a G>A mutation (page 5, lines 26-30).
Regarding claim 11, as set forth above, targeting the G1961E mutation is obvious. Turunen et al. teaches that the AON comprises one or more mismatches. Patent ‘763 claims mismatches as well. These mismatches add to the RNA editing efficiency because it adds to the altered on/off rate of the AON with its target molecule and/or to the binding and/or recognition of the ADAR molecule (page 4, lines 14-20). Mismatches include U-C (aka T-C) (page 17, lines 20-24). As shown below: instantly claimed SEQ ID NO. 1 (Qy) 97% identical to the ABCA4 G1961E mutation (exon 42) (Db) wherein the instantly claimed sequence contains 1 mismatch:
PNG
media_image1.png
398
858
media_image1.png
Greyscale
The sequence was obtained from the NCBI record for NC00001.11. As shown in the sequence information, the instantly claimed sequence is 97% identical to the antisense strand.
Therefore, one skilled in the art when designing AONs which target the ABCA4 G1961E mutation would have made an AON corresponding to SEQ ID NO. 1 as it would target this region of the ABCA4 gene. One skilled in the art would have been motivated to include a mismatch as it would be expected to add to the RNA editing efficiency as taught by Turunen et al. As taught by Turunen et al. the AON preferably comprises 18 to 50 nucleotides (page 11, lines 10-15). Patent ‘763 claims the AON comprises 18 to 70 nucleotides (claim 13).
Regarding claim 12, Patent ‘763 claims a pharmaceutical composition comprising the AON and a pharmaceutically acceptable carrier (claim 14).
Claims 1-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-41 of U.S. Patent No. 11649454 in view of Turunen et al., Tanaka et al. and Allikmets et al. as evidenced by GenBank (NCBI Reference Sequence: NC_000001.11, 2018). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘454 claims an antisense oligonucleotide (AON) capable of forming a double stranded complex with a target RNA in a cell, wherein: a) the AON is complementary to a target RNA region comprising a target adenosine, wherein the AON nucleotide opposite the target adenosine in the double stranded complex formed between the AON and the target RNA is a cytidine or a uridine; b) the AON comprises one or more nucleotides with one or more sugar modifications, provided that the AON nucleotide opposite the target adenosine does not comprise a 2′-OMe modification; c) the AON does not comprise a portion that is capable of forming an intramolecular stem-loop structure capable of binding an Adenosine Deaminases Acting on RNA (ADAR) enzyme; d) the AON does not include a 5′-terminal O6-benzylguanine modification; e) the AON does not include a 5′-terminal amino modification; f) the AON is not covalently linked to a SNAP-tag domain; and g) the AON is shorter than 100 nucleotides; and wherein formation of the double stranded complex between the AON and the target RNA results in the deamination of the target adenosine by an ADAR enzyme present in the cell. (claim 1). Genetic disorders which can be treated with the AON includes Stargardt’s Disease (claim 19).
While Patent ‘454 claims forming a double stranded complex with a target RNA sequence, Patent ‘454 does not claim the target RNA sequence is a human ABCA4 pre-mRNA or mRNA. However, this deficiency is cured by Turunen et al., Tanaka et al. and Allikmets et al.
The teachings of Turunen et al., Tanaka et al. and Allikmets et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘454, Turunen et al., Tanaka et al. and Allikmets et al. and utilize ABCA4 as the target mRNA. One skilled in the art would have been motivated to utilize ABCA4 as it is associated with disease causing mutations as taught by Tanaka et al. Since the mutations of the gene are well documented, one skilled in the art would have a reasonable expectation of success in targeting this particular gene in order to treat diseases associated with the mutations. Since patent ‘454 claims any target RNA and specifically claims Stargardt there is a reasonable expectation of success. Rendering claim 1 obvious.
Regarding claim 2 and 4-5, Patent ‘454 does not claim a central triplet. However, Figure 13 of Turunen et al. teaches that AONs that have DNA nucleosides in the central triplet opposite the targeted adenosine and that such RNA editing may be further increased with additional mismatches are introduced. Central triplets include 5’-CCA-3’ (Figure 11). It is taught that the middle nucleotide does not have a 2’-O methyl modification and either or both surrounding nucleosides also do not have a 2’-O methyl modification (page 11, lines 1-5). This suggests at least one nucleotide in the central triplet comprises a modification (i.e. could be DNA) and that the middle nucleotide does not contain a 2’-OMe or 2’-MOE modification. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘763, Turunen et al., Tanaka et al. and Allikmets et al. and utilize a central triplet in order to further increase the RNA editing as taught by Turunen et al.
Regarding claim 3, Patent ‘454 claims an ADAR enzyme. Turunen et al. teaches that the editing enzyme is a cytidine deaminase and the ones most of interest include hADAR2 (page 19, lines 29-40).
Regarding claim 6-7, Patent ‘454 claims a phosphorothioate (claim 8). Patent ‘454 claims 2, 3, 4, 5, or 6 terminal nucleotides of the 5′ and 3′ terminus of the AON are linked with phosphorothioate linkages (claim 9).
Regarding claim 8, Patent ‘454 claims all other nucleotides in the AON comprise 2’-O-alkyl group (claim 24).
Regarding claim 9, Turunen et al. suggests that the target sequence can be a stop codon (figure 1, 11). Tanaka et al. teaches ABCA4 disease is associated with mutations. Specific mutations for the genotypic profile of ROC patients consisted of 21 unique variants. Four small deletions of 1-4 nucleotides resulting frameshifts and 7 nonsense variants resulting in premature stop codons were also detected (page 94, paragraph bridging columns).Therefore, one skilled in the art would have been motivated to target this particular modification in the ABCA4 disease as it is present in the genotypic profile of ROC patients.
Regarding claim 10, Tanaka et al. teaches data from patients harboring c.5882G>A (p.G1961E) has revealed its association with a confined maculopathy, lower accumulation of lipofuscin (autofluorescence [AF]), and the long-term preservation of cone and rod function (page 89, second paragraph). Allikmets et al. teaches data which tests the associations of AMD with two of the more common AMD-associated ABCR variants, G1961E and D2177N (page 487) which confirms the association of the ABCR alleles G1961E and D2117N with AMD. Therefore, one skilled in the art would have been motivated to target this particular mutation as it is a well-documented mutation which is associated with various conditions. One skilled in the art would have a reasonable expectation of success as Turunen et al. teaches that the target RNA sequence can be such that it is designed to edit a G>A mutation (page 5, lines 26-30).
Regarding claim 11, as set forth above, targeting the G1961E mutation is obvious. Turunen et al. teaches that the AON comprises one or more mismatches. Patent ‘454 claims mismatches as well. These mismatches add to the RNA editing efficiency because it adds to the altered on/off rate of the AON with its target molecule and/or to the binding and/or recognition of the ADAR molecule (page 4, lines 14-20). Mismatches include U-C (aka T-C) (page 17, lines 20-24). As shown below: instantly claimed SEQ ID NO. 1 (Qy) 97% identical to the ABCA4 G1961E mutation (exon 42) (Db) wherein the instantly claimed sequence contains 1 mismatch:
PNG
media_image1.png
398
858
media_image1.png
Greyscale
The sequence was obtained from the NCBI record for NC00001.11. As shown in the sequence information, the instantly claimed sequence is 97% identical to the antisense strand.
Therefore, one skilled in the art when designing AONs which target the ABCA4 G1961E mutation would have made an AON corresponding to SEQ ID NO. 1 as it would target this region of the ABCA4 gene. One skilled in the art would have been motivated to include a mismatch as it would be expected to add to the RNA editing efficiency as taught by Turunen et al. As taught by Turunen et al. the AON preferably comprises 18 to 50 nucleotides (page 11, lines 10-15). Patent ‘454 claims the AON comprises 18 to 50 nucleotides (claim 13).
Regarding claim 12, Patent ‘454 claims a pharmaceutical composition comprising the AON and a pharmaceutically acceptable carrier (claim 14).
Claims 1-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12275937 in view of Turunen et al., Tanaka et al. and Allikmets et al. as evidenced by GenBank (NCBI Reference Sequence: NC_000001.11, 2018). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘937 claims an oligonucleotide composition comprising an oligonucleotide capable of forming a double stranded complex with a target nucleic acid molecule in a cell, and capable of recruiting an eukaryotic adenosine deaminase enzyme, wherein the target nucleic acid molecule comprises a target adenosine for deamination by the enzyme, wherein the oligonucleotide comprises a nucleotide referred to as nucleotide position 0, which is opposite the target adenosine and which is a cytidine, a deoxycytidine, a uridine, or a deoxyuridine, wherein the internucleotide linkage numbering is such that linkage number 0 is the linkage 5′ from nucleotide position 0, and wherein the nucleotide positions and the linkage positions in the oligonucleotide are both positively (+) and negatively (−) incremented towards the 5′ and 3′ ends, respectively, wherein the oligonucleotide comprises at least one internucleotide linkage which is predominantly an Rp or an Sp stereospecific configuration (reading on instant claim 6) according to Formula ##STR00002## wherein X is —S.sup.−, —Se.sup.−, or —BH.sub.3.sup.−, wherein the oligonucleotide is at least 13, 14, 15, 16 or 17 nucleotides in length, wherein the at least one internucleotide linkage with predominantly an Rp configuration is at linkage position +4, −1, −3, and/or −6, and wherein the at least one internucleotide linkage with predominantly an Sp configuration is at linkage position +10.
While Patent ‘937 claims forming a double stranded complex with a target RNA sequence, Patent ‘937 does not claim the target RNA sequence is a human ABCA4 pre-mRNA or mRNA. However, this deficiency is cured by Turunen et al., Tanaka et al. and Allikmets et al.
The teachings of Turunen et al., Tanaka et al. and Allikmets et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘937, Turunen et al., Tanaka et al. and Allikmets et al. and utilize ABCA4 as the target mRNA. One skilled in the art would have been motivated to utilize ABCA4 as it is associated with disease causing mutations as taught by Tanaka et al. Since the mutations of the gene are well documented, one skilled in the art would have a reasonable expectation of success in targeting this particular gene in order to treat diseases associated with the mutations. Since patent ‘937 claims any target RNA there is a reasonable expectation of success. Rendering claim 1 obvious.
Regarding claim 2 and 4-5, Patent ‘937 does not claim a central triplet. However, Figure 13 of Turunen et al. teaches that AONs that have DNA nucleosides in the central triplet opposite the targeted adenosine and that such RNA editing may be further increased with additional mismatches are introduced. Central triplets include 5’-CCA-3’ (Figure 11). It is taught that the middle nucleotide does not have a 2’-O methyl modification and either or both surrounding nucleosides also do not have a 2’-O methyl modification (page 11, lines 1-5). This suggests at least one nucleotide in the central triplet comprises a modification (i.e. could be DNA) and that the middle nucleotide does not contain a 2’-OMe or 2’-MOE modification. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘763, Turunen et al., Tanaka et al. and Allikmets et al. and utilize a central triplet in order to further increase the RNA editing as taught by Turunen et al.
Regarding claim 3, Patent ‘937 claims an ADAR enzyme. Turunen et al. teaches that the editing enzyme is a cytidine deaminase and the ones most of interest include hADAR2 (page 19, lines 29-40).
Regarding claim 7, Patent ‘937 claims the at least one internucleotide linkage that is an unmodified phosphodiester is at linkage position +5, +6, +7, +8, −4, and/or −5 (claim 3).
Regarding claim 8, Patent ‘937 claims all other nucleotides in the AON comprise 2’-O-methylgroup (claim 4 or 5).
Regarding claim 9, Turunen et al. suggests that the target sequence can be a stop codon (figure 1, 11). Tanaka et al. teaches ABCA4 disease is associated with mutations. Specific mutations for the genotypic profile of ROC patients consisted of 21 unique variants. Four small deletions of 1-4 nucleotides resulting frameshifts and 7 nonsense variants resulting in premature stop codons were also detected (page 94, paragraph bridging columns).Therefore, one skilled in the art would have been motivated to target this particular modification in the ABCA4 disease as it is present in the genotypic profile of ROC patients.
Regarding claim 10, Tanaka et al. teaches data from patients harboring c.5882G>A (p.G1961E) has revealed its association with a confined maculopathy, lower accumulation of lipofuscin (autofluorescence [AF]), and the long-term preservation of cone and rod function (page 89, second paragraph). Allikmets et al. teaches data which tests the associations of AMD with two of the more common AMD-associated ABCR variants, G1961E and D2177N (page 487) which confirms the association of the ABCR alleles G1961E and D2117N with AMD. Therefore, one skilled in the art would have been motivated to target this particular mutation as it is a well-documented mutation which is associated with various conditions. One skilled in the art would have a reasonable expectation of success as Turunen et al. teaches that the target RNA sequence can be such that it is designed to edit a G>A mutation (page 5, lines 26-30).
Regarding claim 11, as set forth above, targeting the G1961E mutation is obvious. Turunen et al. teaches that the AON comprises one or more mismatches. These mismatches add to the RNA editing efficiency because it adds to the altered on/off rate of the AON with its target molecule and/or to the binding and/or recognition of the ADAR molecule (page 4, lines 14-20). Mismatches include U-C (aka T-C) (page 17, lines 20-24). As shown below: instantly claimed SEQ ID NO. 1 (Qy) 97% identical to the ABCA4 G1961E mutation (exon 42) (Db) wherein the instantly claimed sequence contains 1 mismatch:
PNG
media_image1.png
398
858
media_image1.png
Greyscale
The sequence was obtained from the NCBI record for NC00001.11. As shown in the sequence information, the instantly claimed sequence is 97% identical to the antisense strand.
Therefore, one skilled in the art when designing AONs which target the ABCA4 G1961E mutation would have made an AON corresponding to SEQ ID NO. 1 as it would target this region of the ABCA4 gene. One skilled in the art would have been motivated to include a mismatch as it would be expected to add to the RNA editing efficiency as taught by Turunen et al. As taught by Turunen et al. the AON preferably comprises 18 to 50 nucleotides (page 11, lines 10-15). Patent ‘454 claims the AON comprises 18 to 50 nucleotides (claim 13).
Regarding claim 12, Patent ‘937 claims a pharmaceutical composition comprising the AON and a pharmaceutically acceptable carrier (claim 9).
Claims 1-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, 19 and 21-22 of copending Application No. 17429796 (USPGPUB No. 20220127609) in view of Turunen et al., Tanaka et al. and Allikmets et al. as evidenced by GenBank (NCBI Reference Sequence: NC_000001.11, 2018). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘796 claims an editing oligonucleotide (EON) capable of forming a double stranded complex with a target nucleic acid molecule in a cell, and capable of recruiting an enzyme with nucleotide deaminase activity, wherein the target nucleic acid molecule comprises a target nucleotide for deamination by the enzyme with nucleotide deaminase activity, wherein the EON comprises a nucleotide, referred to as nucleotide position 0, which is opposite the target nucleotide and which forms a mismatch with the target nucleotide, and wherein the internucleotide linkage numbering is such that linkage number 0 is the linkage 5' from nucleotide position 0, and wherein the nucleotide positions and the linkage positions in the EON are both positively (+) and negatively (-) incremented towards the 5' and 3' ends, respectively, wherein (i) the EON comprises at least one phosphonoacetate internucleotide linkage and at least one internucleotide linkage that is not a phosphonoacetate internucleotide linkage, and/or (ii) the EON comprises at least one nucleotide comprising an unlocked nucleic acid (UNA) ribose modification and at least one nucleotide not comprising a UNA ribose modification (claim 1). Stargardt’s disease is claimed (claim 17).
While copending ‘796 claims forming a double stranded complex with a target RNA sequence, copending ‘796 does not claim the target RNA sequence is a human ABCA4 pre-mRNA or mRNA. However, this deficiency is cured by Turunen et al., Tanaka et al. and Allikmets et al.
The teachings of Turunen et al., Tanaka et al. and Allikmets et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘796, Turunen et al., Tanaka et al. and Allikmets et al. and utilize ABCA4 as the target mRNA. One skilled in the art would have been motivated to utilize ABCA4 as it is associated with disease causing mutations as taught by Tanaka et al. Since the mutations of the gene are well documented, one skilled in the art would have a reasonable expectation of success in targeting this particular gene in order to treat diseases associated with the mutations. Since copending ‘796 claims any target RNA and specifically claims Stargardt there is a reasonable expectation of success. Rendering claim 1 obvious.
Regarding claim 2 and 4-5, copending ‘796 does not claim a central triplet. However, Figure 13 of Turunen et al. teaches that AONs that have DNA nucleosides in the central triplet opposite the targeted adenosine and that such RNA editing may be further increased with additional mismatches are introduced. Central triplets include 5’-CCA-3’ (Figure 11). It is taught that the middle nucleotide does not have a 2’-O methyl modification and either or both surrounding nucleosides also do not have a 2’-O methyl modification (page 11, lines 1-5). This suggests at least one nucleotide in the central triplet comprises a modification (i.e. could be DNA) and that the middle nucleotide does not contain a 2’-OMe or 2’-MOE modification. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘796, Turunen et al., Tanaka et al. and Allikmets et al. and utilize a central triplet in order to further increase the RNA editing as taught by Turunen et al.
Regarding claim 3, copending ‘796 claims an ADAR enzyme. Turunen et al. teaches that the editing enzyme is a cytidine deaminase and the ones most of interest include hADAR2 (page 19, lines 29-40).
Regarding claim 6-7, copending ‘796 claims a phosphonoacetate (claim 3). Copending ‘796 claims at least one phosphonoacetate internucleotide linkage is at linkage position +19, +18, +17, +16, +15, +14, +10, +9, +5, +4, +3,+2, +1, 0, -6, -7, -8, -9, -10, -11 and/or -12 (claim 2).
Regarding claim 8, copending ‘796 claims all other nucleotides in the AON comprise 2’-O-methylgroup (claim 10).
Regarding claim 9, Turunen et al. suggests that the target sequence can be a stop codon (figure 1, 11). Tanaka et al. teaches ABCA4 disease is associated with mutations. Specific mutations for the genotypic profile of ROC patients consisted of 21 unique variants. Four small deletions of 1-4 nucleotides resulting frameshifts and 7 nonsense variants resulting in premature stop codons were also detected (page 94, paragraph bridging columns).Therefore, one skilled in the art would have been motivated to target this particular modification in the ABCA4 disease as it is present in the genotypic profile of ROC patients.
Regarding claim 10, Tanaka et al. teaches data from patients harboring c.5882G>A (p.G1961E) has revealed its association with a confined maculopathy, lower accumulation of lipofuscin (autofluorescence [AF]), and the long-term preservation of cone and rod function (page 89, second paragraph). Allikmets et al. teaches data which tests the associations of AMD with two of the more common AMD-associated ABCR variants, G1961E and D2177N (page 487) which confirms the association of the ABCR alleles G1961E and D2117N with AMD. Therefore, one skilled in the art would have been motivated to target this particular mutation as it is a well-documented mutation which is associated with various conditions. One skilled in the art would have a reasonable expectation of success as Turunen et al. teaches that the target RNA sequence can be such that it is designed to edit a G>A mutation (page 5, lines 26-30).
Regarding claim 11, as set forth above, targeting the G1961E mutation is obvious. Turunen et al. teaches that the AON comprises one or more mismatches. These mismatches add to the RNA editing efficiency because it adds to the altered on/off rate of the AON with its target molecule and/or to the binding and/or recognition of the ADAR molecule (page 4, lines 14-20). Mismatches include U-C (aka T-C) (page 17, lines 20-24). As shown below: instantly claimed SEQ ID NO. 1 (Qy) 97% identical to the ABCA4 G1961E mutation (exon 42) (Db) wherein the instantly claimed sequence contains 1 mismatch:
PNG
media_image1.png
398
858
media_image1.png
Greyscale
The sequence was obtained from the NCBI record for NC00001.11. As shown in the sequence information, the instantly claimed sequence is 97% identical to the antisense strand.
Therefore, one skilled in the art when designing AONs which target the ABCA4 G1961E mutation would have made an AON corresponding to SEQ ID NO. 1 as it would target this region of the ABCA4 gene. One skilled in the art would have been motivated to include a mismatch as it would be expected to add to the RNA editing efficiency as taught by Turunen et al. As taught by Turunen et al. the AON preferably comprises 18 to 50 nucleotides (page 11, lines 10-15). Copending ‘796 claims the EON is at least 10-32 and less than 100 nucleotides (claim 13).
Regarding claim 12, copending ‘796 claims a pharmaceutical composition comprising the AON and a pharmaceutically acceptable carrier (claim 16).
Response to Arguments
Applicant's arguments filed January 22 2026 are acknowledged. The rejections are maintained since applicant has not made any substantive arguments traversing the rejection.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636