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 .
DETAILED ACTION
Applicant's amendments and remarks filed on February 11, 2026 under 37 C.F.R. §1.116, in reply to the final rejection, are acknowledged.
This action is NON-FINAL due to new grounds of rejection not necessitated by amendment; therefore, the finality of the last Office action is withdrawn and prosecution is hereby reopened.
Claims 3-4, 7, 13-14, 17, 21, 26, 31-55, and 58 have been canceled. Claims 1, 2, 20, 25, 28, 30, and 60 were amended. Claims 1, 2, 5, 6, 8-12, 15, 16, 18-20, 22-25, 27-30, 56, 57, 59, and 60 are pending. Claims 56 and 57 are withdrawn.
Claims 1, 2, 5, 6, 8-12, 15, 16, 18-20, 22-25, 27-30, 59, and 60 are examined on the merits herein.
Priority
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 17, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections
In view of Applicant’s amendments and response, the objection to the specification is withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(b) rejection is withdrawn.
Specification
The substitute specification filed on October 16, 2025 has been entered.
Claim Objections
Claims 1 and 28 are objected to because of the following informalities:
Claim 1 recites in part “each of R10, R11, R12, R13, R14 or R15” and should recite “each of R10, R11, R12, R13, R14 and R15” (emphasis added).
Claim 28 recites in part “or iC5f2-M3S” and should recite “siC5f2-M3S” (emphasis added).
Appropriate correction is required.
Response to Arguments
Applicant's arguments filed February 11, 2026 have been fully considered but they are not persuasive.
Applicant asserts that claim 28 was amended to insert the contents which were inadvertently omitted in the previous amendment. Claim 28 previously recited in part “or iC5f2-M3” and amended claim 28 now recites in part “or iC5f2-M3S”; however, claim 28 should recite “siC5f2-M3S” (emphasis added).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 5, 6, 8-12, 15, 16, 18-20, 59, and 60 are rejected under 35 U.S.C. 103 as being obvious over Brown et al. (US 10,954,517; reference previously cited by the Examiner) in view of Zhang et al. (US Patent No. 11,633,482; reference previously cited by the Examiner).
The applied reference has a common assignee and joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Regarding claims 1, 2, 5, 6, 8-11, 59, and 60, Brown et al. is directed to methods and compositions for the specific inhibition of complement component 5(C5) by double-stranded RNA. Brown et al. teaches SEQ ID NO: 19839 which is 19 nucleotides in length and is a human anti-C5 DsiRNA [column 955]. SEQ ID NO: 19839 has a 100% match to instant SEQ ID NO: 1 and a 100% complementarity to instant SEQ ID NO: 2 as shown in the alignments below. Further, Brown et al. teaches that one or more strands of the DsiRNA molecule independently comprises 19 to 35 nucleotides that are complementary to a target (C5) nucleic acid molecule [column 32, lines 42-47]. Brown et al. also teaches that siRNA comprises between 19 and 23 nucleotides and typically has 2 bp overhangs on the 3’ ends of each strand such that the duplex region in the siRNA comprises 17-21 nucleotides. Typically, the antisense strand of the siRNA is sufficiently complementary with the target sequence of the C5 gene/RNA [column 21, second full paragraph]. Brown et al. teaches that a GalNAc moiety, a cholesterol and/or a cholesterol targeting ligand can be attached to a nucleic acid, dsNA or hybridization complex [column 6, second paragraph].
SEQ ID NO: 1 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Brown et al., SEQ ID NO: 19839 1 CUUCAUUCAUACAGACAAA 19
SEQ ID NO: 2 1 UUUGUCUGUAUGAAUGAAG 19
:::|:|:|:|:|||:||||
Brown et al., SEQ ID NO: 19839 19 TTTGTCTGTATGAATGAAG 1
Regarding claim 12, Brown et al. teaches SEQ ID NO: 19839 which is 19 nucleotides in length and has 100% complementarity to instant SEQ ID NO: 2 as shown in the alignment below. Claim 12 depends on claim 1 which requires that the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 2. Claim 12 further limits the nucleotide difference limitation of claim 1; however, claim 12 does not exclude a nucleotide sequence that does not have any nucleotide differences. Thus, Brown et al. meets the limitations of claim 12 because it has 100% complementarity to instant SEQ ID NO: 2.
SEQ ID NO: 2 1 UUUGUCUGUAUGAAUGAAG 19
:::|:|:|:|:|||:||||
Brown et al., SEQ ID NO: 19839 19 TTTGTCTGTATGAATGAAG 1
Regarding claims 15, 16, and 18, Brown et al. teaches SEQ ID NO: 19839 which is 19 nucleotides in length and has a 100% match to instant SEQ ID NO: 3 and 100% complementarity to instant SEQ ID NO: 4 as shown in the alignments below. Brown et al. also teaches that the ends of the DsiRNA agent have one or more overhangs [column 22, lines 1-2]. Specifically, an anti-C5 DsiRNA agent is asymmetric with a 3’ overhang on the antisense strand [column 1306, third full paragraph]. Brown et al. also teaches that siRNA comprises between 19 and 23 nucleotides and typically has 2 bp overhangs on the 3’ ends of each strand such that the duplex region in the siRNA comprises 17-21 nucleotides [column 21, second full paragraph].
SEQ ID NO: 3 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Brown et al., SEQ ID NO: 19839 1 CUUCAUUCAUACAGACAAA 19
SEQ ID NO: 4 1 UUUGUCUGUAUGAAUGAAG 19
:::|:|:|:|:|||:||||
Brown et al., SEQ ID NO: 19839 19 TTTGTCTGTATGAATGAAG 1
Regarding claim 19, Brown et al. teaches SEQ ID NO: 19839 (designated as Db below) which is 19 nucleotides in length and has a 100% match to instant SEQ ID NO: 5 (designated as Qy below) as shown in the alignment below. While Brown et al. teaches the complement of the sense strand is 19 nucleotides long, rather than 21 nucleotides long as in instant SEQ ID NO: 6, it would have been obvious to one of ordinary skill in the art to have arrived at SEQ ID NO: 6 based on the teachings of Brown et al. regarding that DsiRNA agents can have a 3’ overhang on the antisense strand and siRNAs typically have 2 bp overhangs on the 3’ ends of each strand.
Qy 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Db 1 CUUCAUUCAUACAGACAAA 19
Regarding claim 20, instant SEQ ID NO: 1 is the same as instant SEQ ID NO: 9 as set forth on page 64 in the instant specification which corresponds to siC5a1. Brown et al. SEQ ID NO: 19839 has a 100% match to instant SEQ ID NO: 1 as previously shown in the alignment above. While Brown et al. teaches the complement of the sense strand is 19 nucleotides long, rather than 21 nucleotides long as in instant SEQ ID NO: 10, it would have been obvious to one of ordinary skill in the art to have arrived at SEQ ID NO: 10 based on the teachings of Brown et al. regarding that DsiRNA agents can have a 3’ overhang on the antisense strand and siRNAs typically have 2 bp overhangs on the 3’ ends of each strand.
However, Brown et al. does not teach the Formula 308 or 403.
Zhang et al. claims a compound represented by Formula (321) which is similar to instantly claimed Formula (308). As claimed, M1 can be an N-acetylgalactosamine [claim 6]. As claimed is R4 which is capable of binding to an oligonucleotide via a phosphodiester bond [claim 7]. As claimed is a conjugate of Formula (1) which is the same as instant Formula 308 [claim 14]. The conjugate of Formula (1) is represented by Formula (3) – (22) which is the same as instant claim 9 [claim 23]. Oligonucleotide as claimed are siRNA [claim 24] which have sense and antisense strands [claim 25].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zhang et al. and Brown et al. and conjugate the siRNA to the conjugate of Zhang et al. One skilled in the art would have been motivated to utilize this conjugate as it allows for release of a separate antisense strand of the siRNA blocking translation as taught by Zhang et al. [column 128, second full paragraph].
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claims 22-25 and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (US 10,954,517; reference previously cited by the Examiner) in view of Zhang et al. (US Patent No. 11,633,482; reference previously cited by the Examiner) as applied to claims 1, 2, 5, 6, 8-12, 15, 16, 18-20, 59, and 60 above, and further in view of Khvorova et al. (Nature Biotechnology 2017; reference cited by Applicant).
Regarding claims 22-25 and 27-30, the teachings of Brown et al. and Zhang et al. are discussed above. Brown et al. also teaches that substitutions and/or modifications such as deoxy-modifications and 2’-O-alkyl modifications can be made at specific residues within a DsiRNA agent [column 22, third full paragraph]. Further, Brown et al. teaches that stabilizing modifications (e.g., 2’-O-Methyl, phosphorothioate, deoxyribonucleotides, including dNTP base pairs, 2’-F, etc.) can be incorporated within any double stranded nucleic acid [column 34, first full paragraph]. Brown et al. teaches SEQ ID NO: 19839 which is 19 nucleotides in length and has a 100% match to instant SEQ ID NO: 13 (claim 25), SEQ ID NO: 25 (claim 28), and SEQ ID NO: 49 (claim 30) as shown in the alignments below. While Brown et al. teaches the complement of the sense strand is 19 nucleotides long, rather than 21 nucleotides long as in instant SEQ ID NO: 14 (claim 25), instant SEQ ID NO: 26 (claim 28), and instant SEQ ID NO: 50 (claim 30), it would have been obvious to one of ordinary skill in the art to have arrived at SEQ ID NOS: 14, 26, and 50 based on the teachings of Brown et al. regarding that DsiRNA agents can have a 3’ overhang on the antisense strand and siRNAs typically have 2 bp overhangs on the 3’ ends of each strand.
SEQ ID NO: 13 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Brown et al., SEQ ID NO: 19839 1 CUUCAUUCAUACAGACAAA 19
SEQ ID NO: 25 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Brown et al., SEQ ID NO: 19839 1 CUUCAUUCAUACAGACAAA 19
SEQ ID NO: 49 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Brown et al., SEQ ID NO: 19839 1 CUUCAUUCAUACAGACAAA 19
However, Zhang et al. and Brown et al. do not teach that each nucleotide in the sense strand and the antisense strand is independently a fluoro modified nucleotide or a non-fluoro modified nucleotide.
Khvorova et al. is directed to the chemical evolution of oligonucleotide therapies of clinical utility. Oligonucleotide therapeutics comprise a diverse class of drugs, including small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), microRNAs, aptamers, and others. As these all work by different mechanisms, the activity and pharmacokinetic properties can to some extent be optimized inde-pendently (Fig. 1) [page 238, left column]. Although base sequence and the precise pattern of chemical modi-fications can affect the global properties of an oligonucleotide and its trafficking, cellular uptake, and other behaviors, the ability to sepa-rately optimize the pharmacophore and dianophore, at least to some extent, is a key advantage of oligonucleotide drugs [page 238, right column]. Chemical modification of siRNA is absolutely necessary to achieve clinical utility [page 242, left column]. Many different chemical configurations have been used to stabilize siRNAs, particularly combinations of 2’-OMe, 2’-F and phosphorothioate. 2’-F is the best mimic of the 2’-OH group by size and charge and is generally well tolerated and has been used extensively as a primary guide strand modification. Often, the guide strand is modified with 2’-F and the sense strand with 2’-OMe. Modifications typically interfere with silencing activity by making the duplex too stable, which prevents removal of the passenger strand and interferes with proper loading of guide strand, or by forcing the nucleic acid into a suboptimal geometry. Either modification (2’-F or 2’-OMe) is tolerated in any individual position of an siRNA, but a fully modified 2′-OMe guide strand is completely inactive, and a fully modified 2′-F guide strand often has substan-tially reduced activity. When 2′-OMe and 2′-F modifications are alternated, however, the combination creates a compound ideally suited for RISC assembly and function [page 243, left column]. Figure 3 shows alternating 2’-F-2’-OMe RNA pattern. Khvorova et al. shows in Figure 2 the methoxy modified replaces the 2’-hydroxy with a methoxy group (claim 23). Furthermore, Khvorova et al. shows in Figure 2 the 2’-OMe-RNA, 2’-F-RNA, and 5’-phosphorothioate have structures as recited in instant Formula (4) and Formula (5) (claim 29).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zhang et al., Brown et al., and Khvorova et al. and utilize a combination of 2’-OMe, 2’-F and phosphorothioate. One skilled in the art would have been motivated to utilize this specific combination of modifications as Khvorova et al. teaches that this is a particular combination known to stabilize siRNAs. Since Zhang et al. and Brown et al. suggests modifications can be utilized there is a reasonable expectation of success. With regards to the positions of the modification, Khvorova et al. teaches that a totally modified siRNA often has substantially reduced activity and that one can tune modification patterns in order to optimize binding and activity. Therefore, one skilled in the art would have been motivated to manipulate the modification locations on the siRNA in order to determine the optimal stability and activity of the siRNA.
Claims 1, 2, 5, 6, 8-12, 15, 16, 18-20, 59, and 60 are rejected under 35 U.S.C. 103 as being obvious over Brown et al. (US 10,954,517; reference previously cited by the Examiner) in view of Zhang et al. (US Patent No. 12,497,622).
The applied reference has a common assignee and joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Regarding claims 1, 2, 5, 6, 8-11, 59, and 60, Brown et al. is directed to methods and compositions for the specific inhibition of complement component 5(C5) by double-stranded RNA. Brown et al. teaches SEQ ID NO: 19839 which is 19 nucleotides in length and is a human anti-C5 DsiRNA [column 955]. SEQ ID NO: 19839 has a 100% match to instant SEQ ID NO: 1 and a 100% complementarity to instant SEQ ID NO: 2 as shown in the alignments below. Further, Brown et al. teaches that one or more strands of the DsiRNA molecule independently comprises 19 to 35 nucleotides that are complementary to a target (C5) nucleic acid molecule [column 32, lines 42-47]. Brown et al. also teaches that siRNA comprises between 19 and 23 nucleotides and typically has 2 bp overhangs on the 3’ ends of each strand such that the duplex region in the siRNA comprises 17-21 nucleotides. Typically, the antisense strand of the siRNA is sufficiently complementary with the target sequence of the C5 gene/RNA [column 21, second full paragraph]. Brown et al. teaches that a GalNAc moiety, a cholesterol and/or a cholesterol targeting ligand can be attached to a nucleic acid, dsNA or hybridization complex [column 6, second paragraph].
SEQ ID NO: 1 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Brown et al., SEQ ID NO: 19839 1 CUUCAUUCAUACAGACAAA 19
SEQ ID NO: 2 1 UUUGUCUGUAUGAAUGAAG 19
:::|:|:|:|:|||:||||
Brown et al., SEQ ID NO: 19839 19 TTTGTCTGTATGAATGAAG 1
Regarding claim 12, Brown et al. teaches SEQ ID NO: 19839 which is 19 nucleotides in length and has 100% complementarity to instant SEQ ID NO: 2 as shown in the alignment below. Claim 12 depends on claim 1 which requires that the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 2. Claim 12 further limits the nucleotide difference limitation of claim 1; however, claim 12 does not exclude a nucleotide sequence that does not have any nucleotide differences. Thus, Brown et al. meets the limitations of claim 12 because it has 100% complementarity to instant SEQ ID NO: 2.
SEQ ID NO: 2 1 UUUGUCUGUAUGAAUGAAG 19
:::|:|:|:|:|||:||||
Brown et al., SEQ ID NO: 19839 19 TTTGTCTGTATGAATGAAG 1
Regarding claims 15, 16, and 18, Brown et al. teaches SEQ ID NO: 19839 which is 19 nucleotides in length and has a 100% match to instant SEQ ID NO: 3 and 100% complementarity to instant SEQ ID NO: 4 as shown in the alignments below. Brown et al. also teaches that the ends of the DsiRNA agent have one or more overhangs [column 22, lines 1-2]. Specifically, an anti-C5 DsiRNA agent is asymmetric with a 3’ overhang on the antisense strand [column 1306, third full paragraph]. Brown et al. also teaches that siRNA comprises between 19 and 23 nucleotides and typically has 2 bp overhangs on the 3’ ends of each strand such that the duplex region in the siRNA comprises 17-21 nucleotides [column 21, second full paragraph].
SEQ ID NO: 3 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Brown et al., SEQ ID NO: 19839 1 CUUCAUUCAUACAGACAAA 19
SEQ ID NO: 4 1 UUUGUCUGUAUGAAUGAAG 19
:::|:|:|:|:|||:||||
Brown et al., SEQ ID NO: 19839 19 TTTGTCTGTATGAATGAAG 1
Regarding claim 19, Brown et al. teaches SEQ ID NO: 19839 (designated as Db below) which is 19 nucleotides in length and has a 100% match to instant SEQ ID NO: 5 (designated as Qy below) as shown in the alignment below. While Brown et al. teaches the complement of the sense strand is 19 nucleotides long, rather than 21 nucleotides long as in instant SEQ ID NO: 6, it would have been obvious to one of ordinary skill in the art to have arrived at SEQ ID NO: 6 based on the teachings of Brown et al. regarding that DsiRNA agents can have a 3’ overhang on the antisense strand and siRNAs typically have 2 bp overhangs on the 3’ ends of each strand.
Qy 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Db 1 CUUCAUUCAUACAGACAAA 19
Regarding claim 20, instant SEQ ID NO: 1 is the same as instant SEQ ID NO: 9 as set forth on page 64 in the instant specification which corresponds to siC5a1. Brown et al. SEQ ID NO: 19839 has a 100% match to instant SEQ ID NO: 1 as previously shown in the alignment above. While Brown et al. teaches the complement of the sense strand is 19 nucleotides long, rather than 21 nucleotides long as in instant SEQ ID NO: 10, it would have been obvious to one of ordinary skill in the art to have arrived at SEQ ID NO: 10 based on the teachings of Brown et al. regarding that DsiRNA agents can have a 3’ overhang on the antisense strand and siRNAs typically have 2 bp overhangs on the 3’ ends of each strand.
However, Brown et al. does not teach the Formula 308 or 403.
Zhang et al. claims a siRNA conjugate of Formula (308) which is the same as instantly claimed Formula (308). The conjugate is represented by Formula (403) – (422) which is the same as instant claim 9. Oligonucleotide as claimed are siRNA which have sense and antisense strands.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zhang et al. and Brown et al. and conjugate the siRNA to the conjugate of Zhang et al. One skilled in the art would have been motivated to utilize this conjugate as it allows for release of a separate antisense strand of the siRNA blocking translation as taught by Zhang et al. [column 83].
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claims 22-25 and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (US 10,954,517; reference previously cited by the Examiner) in view of Zhang et al. (US Patent No. 12,497,622) as applied to claims 1, 2, 5, 6, 8-12, 15, 16, 18-20, 59, and 60 above, and further in view of Khvorova et al. (Nature Biotechnology 2017; reference cited by Applicant).
Regarding claims 22-25 and 27-30, the teachings of Brown et al. and Zhang et al. are discussed above. Brown et al. also teaches that substitutions and/or modifications such as deoxy-modifications and 2’-O-alkyl modifications can be made at specific residues within a DsiRNA agent [column 22, third full paragraph]. Further, Brown et al. teaches that stabilizing modifications (e.g., 2’-O-Methyl, phosphorothioate, deoxyribonucleotides, including dNTP base pairs, 2’-F, etc.) can be incorporated within any double stranded nucleic acid [column 34, first full paragraph]. Brown et al. teaches SEQ ID NO: 19839 which is 19 nucleotides in length and has a 100% match to instant SEQ ID NO: 13 (claim 25), SEQ ID NO: 25 (claim 28), and SEQ ID NO: 49 (claim 30) as shown in the alignments below. While Brown et al. teaches the complement of the sense strand is 19 nucleotides long, rather than 21 nucleotides long as in instant SEQ ID NO: 14 (claim 25), instant SEQ ID NO: 26 (claim 28), and instant SEQ ID NO: 50 (claim 30), it would have been obvious to one of ordinary skill in the art to have arrived at SEQ ID NOS: 14, 26, and 50 based on the teachings of Brown et al. regarding that DsiRNA agents can have a 3’ overhang on the antisense strand and siRNAs typically have 2 bp overhangs on the 3’ ends of each strand.
SEQ ID NO: 13 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Brown et al., SEQ ID NO: 19839 1 CUUCAUUCAUACAGACAAA 19
SEQ ID NO: 25 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Brown et al., SEQ ID NO: 19839 1 CUUCAUUCAUACAGACAAA 19
SEQ ID NO: 49 1 CUUCAUUCAUACAGACAAA 19
|||||||||||||||||||
Brown et al., SEQ ID NO: 19839 1 CUUCAUUCAUACAGACAAA 19
However, Zhang et al. and Brown et al. do not teach that each nucleotide in the sense strand and the antisense strand is independently a fluoro modified nucleotide or a non-fluoro modified nucleotide.
Khvorova et al. is directed to the chemical evolution of oligonucleotide therapies of clinical utility. Oligonucleotide therapeutics comprise a diverse class of drugs, including small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), microRNAs, aptamers, and others. As these all work by different mechanisms, the activity and pharmacokinetic properties can to some extent be optimized inde-pendently (Fig. 1) [page 238, left column]. Although base sequence and the precise pattern of chemical modi-fications can affect the global properties of an oligonucleotide and its trafficking, cellular uptake, and other behaviors, the ability to sepa-rately optimize the pharmacophore and dianophore, at least to some extent, is a key advantage of oligonucleotide drugs [page 238, right column]. Chemical modification of siRNA is absolutely necessary to achieve clinical utility [page 242, left column]. Many different chemical configurations have been used to stabilize siRNAs, particularly combinations of 2’-OMe, 2’-F and phosphorothioate. 2’-F is the best mimic of the 2’-OH group by size and charge and is generally well tolerated and has been used extensively as a primary guide strand modification. Often, the guide strand is modified with 2’-F and the sense strand with 2’-OMe. Modifications typically interfere with silencing activity by making the duplex too stable, which prevents removal of the passenger strand and interferes with proper loading of guide strand, or by forcing the nucleic acid into a suboptimal geometry. Either modification (2’-F or 2’-OMe) is tolerated in any individual position of an siRNA, but a fully modified 2′-OMe guide strand is completely inactive, and a fully modified 2′-F guide strand often has substan-tially reduced activity. When 2′-OMe and 2′-F modifications are alternated, however, the combination creates a compound ideally suited for RISC assembly and function [page 243, left column]. Figure 3 shows alternating 2’-F-2’-OMe RNA pattern. Khvorova et al. shows in Figure 2 the methoxy modified replaces the 2’-hydroxy with a methoxy group (claim 23). Furthermore, Khvorova et al. shows in Figure 2 the 2’-OMe-RNA, 2’-F-RNA, and 5’-phosphorothioate have structures as recited in instant Formula (4) and Formula (5) (claim 29).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zhang et al., Brown et al., and Khvorova et al. and utilize a combination of 2’-OMe, 2’-F and phosphorothioate. One skilled in the art would have been motivated to utilize this specific combination of modifications as Khvorova et al. teaches that this is a particular combination known to stabilize siRNAs. Since Zhang et al. and Brown et al. suggests modifications can be utilized there is a reasonable expectation of success. With regards to the positions of the modification, Khvorova et al. teaches that a totally modified siRNA often has substantially reduced activity and that one can tune modification patterns in order to optimize binding and activity. Therefore, one skilled in the art would have been motivated to manipulate the modification locations on the siRNA in order to determine the optimal stability and activity of the siRNA.
Conclusion
No claims are allowed.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637