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 .
Applicant’s response of 05/15/2026, including a declaration by Munefumi Tokugawa, Ph.D. has been received and entered into the application file.
Claims 1 and 4-9 are pending and under consideration.
Status of Prior Objections/Rejections
RE: Claim Rejections - 35 USC § 103
►Claims 1, 4,and 6-8 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0197762 A1 (Swayze; cited as reference 1 in the IDS filed 01/20/2022; of record) in view of Yamada et al., 2011 (cited as reference 13 in the IDS filed 01/20/2022; of record), as evidenced by Eckstein, 2014 (of record) and Masaki et al., 2018 (cited as reference 2 in the IDS filed 08/09/2024).
Applicant has traversed the rejection of record, asserting that a person of ordinary skill in the art would, starting from Swayze, have been dissuaded from modifying the 2’-modified nucleic acid in the wing region with MCE, as doing so would likely result in increased toxicity and reduced knockdown efficiency. Specifically, Applicant asserts that “nowhere does Swayze suggest reducing liver toxicity through replacement of 2’-modified nucleic acids…much less replacement of MOE with MCE” (page 7, paragraph 4).
In response, while the Examiner acknowledges that Swayze does not teach replacement of MOE with MCE, it is not found persuasive that Swayze does not suggest replacement of 2’-modified nucleic acids. As previously set forth, while Swayze teaches in part that toxicity reduction is achieved by decreasing the number of LNA residues in antisense oligonucleotides (as indicated by Applicant), Swayze also teaches that non-bicyclic (i.e. non-LNA) 2’-modified nucleosides (i.e. high affinity 2’-modified nucleosides and those that increase nuclease resistance) may be incorporated into the compounds disclosed therein to improve safety of said compounds (i.e. reducing toxicity) (paragraphs [0006], [0007], [0013], [0068], [0073], [0115], and [0116]). Thus, while Swayze does teach in part that toxicity reduction is achieved by decreasing the number of LNA residues in antisense oligonucleotides, this is not representative of the entirety of the disclosure of Swayze, which explicitly discloses incorporation of 2’-modified nucleosides (i.e. high affinity 2’-modified nucleosides) into the antisense oligonucleotides taught therein to reduce toxicity of said compounds. Therefore, while Swayze does not disclose incorporation of MCE, as previously set forth, Yamada discloses the development of oligonucleotides, including antisense oligonucleotides, containing new 2’-O-modified ribonucleosides (such as 2’-O-MCE) as nucleic acid drugs (abstract; Figure 1-2). Per Yamada, 2’-O-MCE oligonucleotides exhibited higher binding affinity for targeted RNAs, as well as increased nuclease resistance (page 3047, column 1, paragraphs 1 and 2), both of which constitute practical advantages motivating one of ordinary skill in the art to experiment with incorporating 2’-O-MCE oligonucleotides into therapeutic antisense oligonucleotides. As previously set forth, this motivation is further supported by Masaki, which discloses that antisense oligonucleotides comprising the MCE modification exhibit lower hepatotoxic potential as compared to antisense oligonucleotides having the MOE modification (abstract). While Masaki does not disclose and/or evaluate the instantly claimed bridged antisense nucleic acid, Swayze discloses bridged antisense nucleic acids, explicitly stating that the antisense oligonucleotides taught therein mitigate the toxicity of locked nucleic acid moieties while harnessing the potency imparted by the same by incorporating non-bicyclic high-affinity modified nucleotides (paragraph [0005]).
Therefore, based on the disclosure of Swayze, one of ordinary skill in the art would have been motivated to incorporate non-bicyclic high-affinity modified nucleotides into the bridged antisense nucleic acids taught therein, for example the MCE oligonucleotides of Yamada, which are known to exhibit higher binding affinity (per Yamada) and to exhibit lower hepatotoxic potential (per Masaki). Accordingly, it is considered that all the components and advantages thereof of the claimed invention were known in the prior art at the time of filing. Said another way, it is not found persuasive that it was unpredictable at the time of filing that MCE-modified nucleotides would confer advantages such as reduced toxicity to the antisense oligonucleotides disclosed in Swayze, as both Yamada and Masaki disclose that MCE-modified oligonucleotides confer advantages such as higher binding affinity and lower hepatotoxic potential. Per MPEP § 2143(I)(E), “[a] person of ordinary skill is also a person of ordinary creativity, not an automaton,” and thus when there are a finite number of identified, predictable solutions (i.e. possible nucleotide modifications), it would be obvious to a person of ordinary skill in the art to test possible solutions (i.e. possible nucleotide modifications) in order to optimize the function of the system being built (i.e. maximizing potency while minimizing toxicity as per Swayze).
With regard to the declaration of Munefumi Tokugawa, Ph.D. filed 05/15/2026, the declaration argues that the field of modified oligonucleotides for therapeutic use is unpredictable due to the complex behavior exhibited by small chemical modifications. Particularly, the declaration states that a persistent problem in the field was that while antisense nucleic acids incorporating artificial nucleic acid bases (such as LNA) can be clinically effective, they typically exhibit strong hepatotoxicity. Reducing LNA content is known to reduce toxicity at the cost of also reducing the potency of the oligonucleotide. Dr. Tokugawa asserts that the instant application surprisingly demonstrates that efficacy can be increased while toxicity is reduced without reducing the LNA content. Data is presented comparing the efficacy and hepatotoxicity of various embodiments of bridged antisense nucleic acids (see Table 1), wherein bridged antisense oligonucleotides containing MCE residues maintain equivalent knockdown activity while reducing hepatotoxicity relative to corresponding MOE-containing oligonucleotides in the presence of LNA. Dr. Tokugawa asserts that such an effect would not have been predictable from the prior art.
In response, this is not found persuasive. As set forth above, MCE modifications are known to exhibit higher binding affinity for targeted RNAs, as well as increased nuclease resistance (reviewed in Yamada; as set forth above) while reducing hepatotoxicity as compared to antisense oligonucleotides having the MOE modification (reviewed in Masaki; as set forth above). While the Examiner agrees that the instantly claimed antisense nucleic acids were not published in the field prior to the effective filing date of the instant application, the properties regarding efficacy and hepatotoxicity were well-known in the field. As set forth above, per MPEP § 2143(I)(E), “[a] person of ordinary skill is also a person of ordinary creativity, not an automaton,” and thus when there are a finite number of identified, predictable solutions (i.e. possible nucleotide modifications), it would be obvious to a person of ordinary skill in the art to test possible solutions (i.e. possible nucleotide modifications) in order to optimize the function of the system being built (i.e. maximizing potency while minimizing toxicity as per Swayze).
Additionally, the declaration filed 05/15/2026 discloses only a limited number of possible bridged antisense oligonucleotides. As disclosed at Table 1, the two tested bridged antisense nucleic acids comprising MCE modifications each comprise a single MCE-modified nucleotide; whereas, the instant claim set encompasses up to four MCE-modified nucleotides. Therefore, the data of the declaration is not commensurate in scope with the instant claim set and therefore cannot be applied to the full breadth of the claims. While dependent claim 4 further narrows the number of MCE-modified nucleotides to one to two, the declaration does not disclose bridged antisense oligonucleotides commensurate in scope with the instant claim set and therefore cannot be applied to the full breadth of the claims.
Accordingly, while Applicant’s arguments and declaration have been fully considered, they are not found persuasive. The rejection of record is hereby maintained.
►Claims 5 and 7 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0197762 A1 (Swayze; cited as reference 1 in the IDS filed 01/20/2022; of record) in view of Yamada et al., 2011 (cited as reference 13 in the IDS filed 01/20/2022; of record), as evidenced by Eckstein, 2014 (of record) and Masaki et al., 2018 (cited as reference 2 in the IDS filed 08/09/2024), as applied to claim 1 above, and further in view of Yamaguchi et al., 2015 (of record), as evidenced by US 2017/0044528 A1 (hereinafter Obika).
Applicant has traversed the rejection of record, asserting that Yamaguchi does not make up for the deficiencies of the cited prior art as set forth above. Applicant further asserts that Yamaguchi does not address or experimentally explore toxicity in vivo.
In response, while the Examiner acknowledges that Yamaguchi does not explore in vivo properties of the modifications taught therein, Yamaguchi nonetheless establishes that the modifications taught therein exhibit superior binding and nuclease resistance properties in vitro, thereby motivating in vivo experimentation, as “[a] person of ordinary skill is also a person of ordinary creativity, not an automaton” per MPEP § 2143(I)(E).
Accordingly, while Applicant’s arguments and declaration have been fully considered, they are not found persuasive. The rejection of record is hereby maintained.
►Claim 9 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0197762 A1 (Swayze; cited as reference 1 in the IDS filed 01/20/2022; of record) in view of Yamada et al., 2011 (cited as reference 13 in the IDS filed 01/20/2022; of record), as evidenced by Eckstein, 2014 (of record) and Masaki et al., 2018 (cited as reference 2 in the IDS filed 08/09/2024), as applied to claim 1 above, and further in view of Bennett, 2019 (of record).
Applicant has traversed the rejection of record, asserting that while Bennett confirms that antisense drugs can be therapeutically and commercially successful, it does not disclose, suggest, or motivate the specific combination of chemical features that are claimed in the present application.
In response, the Examiner agrees that Bennett does not disclose, suggest, or motivate the specific combination of chemical features that are claimed in the present application. However, Bennett is applied solely for the purpose of establishing that antisense drugs can be therapeutically and commercially successful. The prior art renders the chemical features of the instant application obvious, as set forth above, particularly in view of the principle that “[a] person of ordinary skill is also a person of ordinary creativity, not an automaton” per MPEP § 2143(I)(E).
Accordingly, while Applicant’s arguments and declaration have been fully considered, they are not found persuasive. The rejection of record is hereby maintained.
New/Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4,and 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0197762 A1 (Swayze; cited as reference 1 in the IDS filed 01/20/2022; of record) in view of Yamada et al., 2011 (cited as reference 13 in the IDS filed 01/20/2022; of record), as evidenced by Eckstein, 2014 (of record) and Masaki et al., 2018 (cited as reference 2 in the IDS filed 08/09/2024; of record).
With regard to instant claim 1, which recites “a bridged antisense nucleic acid comprising a gap region consisting of deoxyribonucleic acid of 5 to 15 bases and a wing region consisting of two to ten 2’,4’-modified nucleic acids at each of the 5’ and 3’-ends of the gap region, wherein one to four 2’-modified nucleic acids are supplementally added and/or inserted in at least one wing region, wherein the 2’-modified nucleic acid has the following structural formula:
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wherein R1 is H;
R2 is a methyl group;
R3 is H or the structure:
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wherein, the following bond structure:
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is the bonding point with the adjacent nucleic acid, or OH; and
X is S or O;
R4 is H or the bonding point with the adjacent nucleic acid; and
B represents a nucleobase residue optionally having a protecting group or a modifying group,” Swayze discloses antisense oligonucleotides with wing-gap-wing structures, in which the wing nucleic acids are modified such that at least one comprises a bridge between the 4’ and the 2’ position of the sugar (paragraph [0013]). These antisense oligonucleotides read on the instantly claimed bridged antisense nucleic acid and are disclosed to exhibit greater safety (and lower toxicity) than antisense oligonucleotides lacking modified nucleic acids (paragraphs [0005-0006]).
Specifically, the antisense oligonucleotide of Swayze comprises a deoxynucleotide gap region (paragraph [0006]) of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 nucleotides in length (paragraph [0010]), which reads on the instantly claimed “gap region consisting of deoxyribonucleic acid of 5 to 15 bases.” The antisense oligonucleotides of Swayze also comprise 5’ and 3’ wing regions, in which at least one of the nucleotides in the wing regions is a 4’ to 2’ bicyclic nucleotide (paragraph [0006]), with exemplary wing-gap-wing structures disclosed as 4-6-4, 3-6-3, 4-7-4, 3-7-3, 4-8-4, and 3-8-3 (paragraph [0071]), all of which read on the instantly claimed “wing region consisting of two to ten 2’,4’-modified nucleic acids at each of the 5’ and 3’-ends of the gap region. Finally, the wing regions of the antisense oligonucleotides of Swayze comprise at least one 2’ modified nucleotide (paragraph [0006]), which reads on the instantly claimed “one to four 2’-modified nucleic acids…supplementally added and/or inserted in at least one wing region.”
However, Swayze does not disclose the particular structures or compositions of the 2’ modified nucleic acids of instant claim 1.
Yamada et al., 2011 discloses the development of oligonucleotides, including antisense oligonucleotides, containing new 2’-O-modified ribonucleosides as nucleic acid drugs (abstract). These new 2’-O-modified ribonucleosides include 2-(N-methylcarbamoyl)ethyl (MCE), which is hereinafter referred to as 2’-O-MCE. Antisense oligonucleotides incorporating these modified nucleosides were found to function with better efficacy than other nucleic acid derivatives (abstract). These 2’-O-modified ribonucleosides are depicted in Figure 1-2 (page 3043) and are
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depicted below:
Positions R1, R2, R3, R4, and B will be considered individually.
Instant claim 1 recites that R1 is H and R2 is a methyl group. 2’-O-MCE of Yamada et al., 2011 comprises Hydrogen and a methyl group at positions R1 and R2, respectively, as is instantly claimed.
Instant claim 1 further recites that R3 is Hydrogen or the recited structure set forth above. While Yamada et al., 2011 does not disclose the recited structure at position R3 of 2’-O-MCE, they do disclose Hydrogen at position R3, which satisfies the claim limitation regarding position R3, meaning the Hydrogen of Yamada et al., 2011 reads on this limitation.
Instant claim 1 recites that R4 is “H or the bonding point with the adjacent nucleic acid.” While Yamada et al., 2011 does not disclose a bonding point with the adjacent nucleic acid at position R4 of 2’-O-MCE, they do disclose Hydrogen at position R4, which satisfies the claim limitation regarding position R4, meaning the Hydrogen of Yamada et al., 2011 reads on this limitation.
Finally, instant claim 1 recites that B “represents a nucleobase residue optionally having a protecting group or a modifying group.” Yamada et al., 2011 discloses a nucleobase residue at position B of 2’-O-MCE, which reads on the claim limitation regarding B.
Furthermore, Masaki et al., 2018 discloses that antisense oligonucleotides comprising the MCE modification (as taught in Yamada et al., 2011; depicted in Figure 1) exhibit lower hepatotoxic potential as compared to antisense oligonucleotides having the MOE modification (abstract), further motivating someone of ordinary skill in the art to utilize the modified nucleosides of Yamada et al., 2011 in the antisense oligonucleotides of Swayze to reduce the toxicity thereof.
Thus, the combined teachings of Swayze and Yamada et al., 2011 collectively disclose all the limitations of instant claim 1.
With regard to instant claim 4, which recites “one or two 2’-modified nucleic acids are added and/or inserted in each wing region” of the bridged antisense nucleic acid of claim 1, Swayze discloses that the wings of the wing-gap-wing antisense oligonucleotides described therein comprise at least one 2’ modified nucleotide (paragraph [0006]), which reads on the instantly claimed “one or two 2’-modified nucleic acids…added and/or inserted in each wing region.” Thus, Swayze discloses each and every additional limitation of instant claim 4.
With regard to claim 6, which recites “the bridged antisense nucleic acid according to claim 1…comprises one to four 2’,4’-modified nucleic acids,” Swayze discloses that the 5’ and 3’ wing regions of the wing-gap-wing antisense oligonucleotides described therein comprise at least one 4’ to 2’ bicyclic nucleotide (paragraph [0006]) with lengths of 1, 2, 3, or 4 nucleotides (paragraph [0010]). Exemplary wing-gap-wing structures are disclosed as 4-6-4, 3-6-3, 4-7-4, 3-7-3, 4-8-4, and 3-8-3 (paragraph [0071]), all of which read on the instantly claimed “the bridged antisense nucleic acid according to claim 1…compris[ing] one to four 2’,4’-modified nucleic acids.” Thus, Swayze discloses each and every additional limitation of instant claim 6.
With regard to instant claim 7, which recites “the bridged antisense nucleic acid according to [instant claim 1], wherein X is a sulfur atom,” the combined disclosures of Swayze and Yamada et al., 2011 teach every limitation of the bridged antisense oligonucleotide comprising 2’-modified nucleic acids in the wing region (instant claim 1), as set forth above. Additionally, Swayze discloses that the internucleoside linkages in the antisense oligonucleotide wing regions described therein may be phosphorothioate linkages (paragraph [0136]). To expand on this species of linkage, Eckstein, 2014 teaches that phosphorothioate linkages confer resistance against nucleases (page 377, column 1, paragraph 2) and phosphatases (page 383, column 1, paragraph 3), as well as improved oligonucleotide uptake (page 381, column 1, paragraph 2). In light of these conferred advantages, Eckstein, 2014 teaches that the majority of therapeutic oligonucleotides contain phosphorothioates (abstract), the structure of which is depicted in Figure 1 (page 375) and depicted below:
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Furthermore, Eckstein, 2014 teaches that phosphorothioate linkages have the structure depicted in Figure 11 (page 380), which is depicted below:
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Inclusion of S at position X of chemical structure 2 in instant claim 7 reads on the structure of phosphorothioates taught in Eckstein, 2014. Additionally, instant claim 1, from which instant claim 7 depends, recites that the bond structure of the chemical formula is the bonding point with the adjacent nucleic acid. This structure reads on the phosphorothioate linkages disclosed in Swayze and taught in Eckstein, 2014.
Finally, with regard to instant claim 8, which recites “the deoxyribonucleic acid [of the gap region of instant claim 1] has a base length of 8 to 10,” Swayze discloses that the deoxyribonucleic acid gap of the wing-gap-wing antisense oligonucleotides described therein has several possible ranges of lengths (i.e. between 6 and 18 nucleotides, between 8 and 16 nucleotides, or between 7 and 10 nucleotides), as well as discretely recited lengths, including 8, 9, or 10 nucleotides in length (paragraph [0010]). Additionally, exemplary wing-gap-wing structures are disclosed as 4-8-4 and 3-8-3 (paragraph [0071]), all of which read on the instantly “deoxyribonucleic acid [gap region with]…a base length of 8 to 10.” Thus, Swayze discloses each and every additional limitation of instant claim 8.
Given the reduction in antisense oligonucleotide toxicity associated with the structures and modifications disclosed in Swayze, and the increased antisense oligonucleotide efficacy associated with the 2’-modified nucleosides of Yamada et al., 2011 (which also reduce toxicity per the teachings of Masaki et al., 2018), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the 2’-modified nucleosides of Yamada et al., 2011 into the modified wing-gap-wing antisense oligonucleotides of Swayze to predictably produce an antisense oligonucleotide with increased efficacy and reduced toxicity. One would have been motivated to make such a modification in order to receive the expected benefit of generating a safer and more effective antisense oligonucleotide, which is especially relevant to therapeutic applications.
Additionally, given the reduction in antisense oligonucleotide toxicity associated with the structures and modifications disclosed in Swayze; the increased antisense oligonucleotide efficacy associated with the 2’-modified nucleosides of Yamada et al., 2011 (which also reduce toxicity per the teachings of Masaki et al., 2018); and the nuclease resistance and improved uptake of the phosphorothioate linkages disclosed in Swayze and taught in Eckstein, 2014, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the 2’-modified nucleosides of Yamada et al., 2011 into the modified wing-gap-wing antisense oligonucleotides with phosphorothioate linkages of Swayze to predictably produce an antisense oligonucleotide with increased efficacy, reduced toxicity, and increased bioavailability. One would have been motivated to make such a modification in order to receive the expected benefit of generating a safer and more effective antisense oligonucleotide, which is especially relevant to therapeutic applications.
Claims 5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0197762 A1 (Swayze; cited as reference 1 in the IDS filed 01/20/2022; of record) in view of Yamada et al., 2011 (cited as reference 13 in the IDS filed 01/20/2022; of record), as evidenced by Eckstein, 2014 (of record) and Masaki et al., 2018 (cited as reference 2 in the IDS filed 08/09/2024; of record), as applied to claim 1 above, and further in view of Yamaguchi et al., 2015 (of record), as evidenced by US 2017/0044528 A1 (hereinafter Obika; of record).
The combined disclosures of Swayze, Yamada et al., 2011, Eckstein, 2014, and Masaki et al., 2018 are described above and applied as before. However, these disclosures do not teach the 2’,4’-modified nucleic acid structures of instant claim 5.
With regard to instant claim 5, which recites “the bridged antisense nucleic acid according to claim 1, wherein the 2’,4’-modified nucleic acid is selected from the group consisting of the following:
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Wherein R5 and R8 each independently selected from the group consisting of H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups and substituted or unsubstituted aryl groups;
R6 is H or the structure:
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wherein, the following bond structure:
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is the bonding point with the adjacent nucleic acid, or OH; and X is S or O; R7 is H or the bonding point with the adjacent nucleic acid; and B represents a nucleobase residue optionally having a protective group or modifying group,” Swayze discloses bridged antisense oligonucleotides with wing-gap-wing structures, as set forth above, in which the wing nucleic acids comprise at least one 4’ to 2’ bicyclic nucleotide (i.e. a 2’,4’-modified nucleotide) (paragraph [0006]). Additionally, Yamada et al., 2011 discloses the development of oligonucleotides, including antisense oligonucleotides, containing new 2’-O-modified ribonucleosides as nucleic acid drugs (abstract). However, neither Swayze nor Yamada et al., 2011 discloses the particular structures or compositions of the 2’,4’-modified nucleic acids of instant claim 5.
Yamaguchi et al., 2015 discloses a novel bridged nucleic acid, scpBNA, which contains a spirocyclopropyl moiety at the methylene bridge of 2’,4’-bridged/locked nucleic acid (page 9739, column 2, paragraph 2). They found that incorporation of scpBNA into oligonucleotides resulted in increased nuclease resistance, excellent binding affinity toward complementary ssRNA, and improved RNA selectivity, all of which render these modified oligonucleotides highly amenable to antisense strategies, particularly antisense therapy, as the reported increased nuclease resistance is likely to translate to sustained systemic levels, as well as a longer half-life (page 9739, column 2, paragraph 2). The structure of scpBNA is depicted in Figure 1 (page 9737) and is inserted below:
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Positions R5, R6, R7, R8, and B will be considered individually in comparing scpBNA of Yamaguchi et al., 2015 to the 2’,4’-modified nucleic acid selected from the group of instant claim 5 (indicated within the black box below):
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Instant claim 5 recites that R5 and R8 are each “independently selected from the group consisting of H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups and substituted or unsubstituted aryl groups.” Given that R5 and R8 are not included in the above-indicated 2’,4’-modified nucleic acid of instant claim 5, the limitations regarding R5 and R8 will not be further considered.
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Instant claim 5 recites that R6 is Hydrogen or the structure shown to the right. While Yamaguchi et al., 2015 does not disclose the depicted structure at position R6 of scpBNA, they do disclose Hydrogen at position R6, which satisfies the claim limitation regarding position R6, meaning the Hydrogen of Yamaguchi et al., 2015 reads on this limitation.
Instant claim 5 recites that R7 is “H or the bonding point with the adjacent nucleic acid.” While Yamaguchi et al., 2015 does not disclose a bonding point with the adjacent nucleic acid at position R7 of scpBNA, they do disclose Hydrogen at position R7, which satisfies the claim limitation regarding position R7, meaning the Hydrogen of Yamaguchi et al., 2015 reads on this limitation.
Finally, instant claim 5 recites that B “represents a nucleobase residue optionally having a protecting group or a modifying group.” Yamaguchi et al., 2015 discloses a nucleobase residue at position B of scpBNA, which reads on the claim limitation regarding B.
Therapeutic oligonucleotides with relevance to nucleic acid drugs that comprise the scpBNAs disclosed in Yamaguchi et al., 2015 are known in the art. Obika discloses such therapeutic oligonucleotides, which were found to exhibit reduced toxicity following administration of the same (abstract; paragraph [0189]).
Thus, the combined teachings of Swayze, Yamada et al., 2011, and Yamaguchi et al., 2015 disclose all the limitations of instant claim 5, collectively disclosing an antisense oligonucleotide with reduced toxicity.
Given the reduction in antisense oligonucleotide toxicity associated with the structures and modifications disclosed in Swayze; the increased antisense oligonucleotide efficacy associated with the 2’-modified nucleosides of Yamada et al., 2011 (which also reduce toxicity per the teachings of Masaki et al., 2018); and the increased nuclease resistance, excellent binding affinity, and improved RNA selectivity associated with oligonucleotides incorporating the scpBNA of Yamaguchi et al., 2015 (which also reduce toxicity per the teachings of Obika), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the 2,4’-modified scpBNA of Yamaguchi et al., 2015 into the modified wing-gap-wing antisense oligonucleotides of Swayze to predictably produce an antisense oligonucleotide with increased nuclease resistance, excellent binding affinity, improved RNA selectivity, and reduced toxicity. One would have been motivated to make such a modification in order to receive the expected benefit of generating a safer and more effective antisense oligonucleotide, which is especially relevant to therapeutic applications.
With regard to instant claim 7, which recites “the bridged antisense nucleic acid according to [instant claim 5], wherein X is a sulfur atom,” the combined disclosures of Swayze, Yamada et al., 2011, and Yamaguchi et al., 2015 teach every limitation of the bridged antisense oligonucleotide comprising 2’,4’-modified nucleic acids in the wing region (instant claim 5), as set forth above. Additionally, Swayze discloses that the internucleoside linkages in the antisense oligonucleotide wing regions described therein may be phosphorothioate linkages (paragraph [0136]). To expand on this species of linkage, Eckstein, 2014 teaches that phosphorothioate linkages confer resistance against nucleases (page 377, column 1, paragraph 2) and phosphatases (page 383, column 1, paragraph 3), as well as improved oligonucleotide uptake (page 381, column 1, paragraph 2). In light of these conferred advantages, Eckstein, 2014 teaches that the majority of therapeutic oligonucleotides contain phosphorothioates (abstract), the structure of which is depicted in Figure 1 (page 375) and inserted below:
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Furthermore, Eckstein, 2014 teaches that phosphorothioate linkages have the structure depicted in Figure 11 (page 380), which is inserted below:
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Inclusion of S at position X in instant claim 7 reads on the structure of phosphorothioates taught in Eckstein, 2014. Additionally, instant claim 1, from which instant claim 7 depends, recites that the bond structure of the chemical formula is the bonding point with the adjacent nucleic acid. This structure reads on the phosphorothioate linkages disclosed in Swayze and taught in Eckstein, 2014. This structure reads on the phosphorothioate linkages disclosed in Swayze and taught in Eckstein, 2014.
Given the reduction in antisense oligonucleotide toxicity associated with the structures and modifications disclosed in Swayze; the increased antisense oligonucleotide efficacy associated with the 2’-modified nucleosides of Yamada et al., 2011 (which also reduce toxicity per the teachings of Masaki et al., 2018); the increased nuclease resistance, excellent binding affinity, and improved RNA selectivity associated with oligonucleotides incorporating the scpBNA of Yamaguchi et al., 2015 (which also reduce toxicity per the teachings of Obika); and the nuclease resistance and improved uptake of the phosphorothioate linkages disclosed in Swayze and taught in Eckstein, 2014, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the scpBNA of Yamaguchi et al., 2015 into the modified wing-gap-wing antisense oligonucleotides with phosphorothioate linkages of Swayze to predictably produce an antisense oligonucleotide with increased nuclease resistance, excellent binding affinity, improved RNA selectivity, reduced toxicity, and increased bioavailability. One would have been motivated to make such a modification in order to receive the expected benefit of generating a safer and more effective antisense oligonucleotide, which is especially relevant to therapeutic applications.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0197762 A1 (Swayze; cited as reference 1 in the IDS filed 01/20/2022; of record) in view of Yamada et al., 2011 (cited as reference 13 in the IDS filed 01/20/2022; of record), as evidenced by Eckstein, 2014 (of record) and Masaki et al., 2018 (cited as reference 2 in the IDS filed 08/09/2024; of record), as applied to claim 1 above, and further in view of Bennett, 2019 (of record).
The combined disclosures of Swayze, Yamada et al., 2011, Eckstein, 2014, and Masaki et al., 2018 are described above and applied as before. However, these disclosures do not teach the antisense nucleic acid drug of instant claim 9.
With regard to instant claim 9, which recites “an antisense nucleic acid drug with reduced toxicity by antisense nucleic acid modification, comprising the bridged antisense nucleic acid according to claim 1,” Swayze, Yamada et al., 2011, Eckstein, 2014, and Masaki et al., 2018 disclose each and every limitation of instant claim 1, as set forth above. While Swayze does disclose a wing-gap-wing antisense oligonucleotide with chemical modifications conferring increased potency and reduced toxicity (paragraphs [0014-0016]), they only disclose the administration of these antisense oligonucleotides in prodrug form, which is a therapeutic agent that is initially inactive (or less active) and subsequently activated within the body or cells thereof (paragraphs [0221-0222]).
However, Bennett, 2019 discloses that several antisense oligonucleotides are available as approved drugs, as well as that more are currently being developed (abstract). Bennett, 2019 discloses selected approved antisense drug species Inotersen, Patisiran, Eteplirsen, and Nusinersen (pages 314-318). These drugs are delivering major therapeutic benefits to affected patients (page 318, paragraph 5) and have become commercial successes (page 318, paragraph 3).
Given the increase in efficacy and reduction in antisense oligonucleotide toxicity associated with the structures and modifications disclosed in Swayze, the increased antisense oligonucleotide efficacy associated with the 2’-modified nucleosides of Yamada et al., 2011 (which also reduce toxicity per the teachings of Masaki et al., 2018), and the therapeutic and commercial success of antisense drugs disclosed in Bennett, 2019, it would have been obvious to someone of ordinary skill in the art to deliver the modified wing-gap-wing antisense oligonucleotides of Swayze and Yamada et al., 2011 in drug form (as opposed to the disclosed prodrug form) as per the disclosure of Bennett, 2019 to predictably provide an antisense oligonucleotide drug with increased efficacy and reduced toxicity. One would have been motivated to make such a modification in order to receive the expected benefit of generating a safer and more effective antisense oligonucleotide drug for therapeutic applications.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SARAH E ALLEN/Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
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