DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 1-14 are pending.
Status of the claims: claim(s) 5-6, 10, and 12 were amended in the reply filed 06/24/2026.
Applicant’s arguments filed 06/24/2026 have been thoroughly reviewed, but are not persuasive for the reasons that follow. Any rejections and objections not reiterated in this action have been withdrawn. This action is FINAL.
Election/Restrictions
Applicant’s election without traverse of sense strand SEQ ID NO: 67 and antisense strand SEQ ID NO: 68, in the reply filed on 02/10/2026, is acknowledged.
Claim(s) 1-4, 9, 11, and 13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/10/2026.
Claim(s) 5-8, 10, 12, and 14 are under consideration.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 for application KR10-2020-0178838, filed 12/18/2020.
Response to Arguments – Specification
The previous objection to the specification for containing the following trademarks/tradenames without a proper symbol, i.e., Lipofectamine 2000 (Page 24, Line 8), (Page 39, Line 13), (Page 40, Line 23); and Lipofectamine RNAiMAX (Page 28, Line(s) 7, 12, 17), (Page 32, Line(s) 6 and11), (Page 36, Line 17), has been withdrawn in view of Applicant’s amendments filed 06/24/2026.
Claim Objections – New
Minor informalities
Claim 6 is objected to because of the following informalities: It is of note that SEQ ID NO: 74 and 76 are not the elected species, however, the claim has been amended to remove most of the non-elected species besides SEQ ID NO: 74 and 76. These sequences are identical/ redundant sequences. It would be remedial to include only one of the sequences in the claim.
Claim 10 is objected to because of the following informalities:
The letter list of (j), (k), and (m) all contain an indentation leaving a large space between the letter and start of the sequence. (l) contains multiple spaces between the letter list and start of the sequence. It would be remedial to amend the claims to remove the additional spacing for consistency. See (c)-(d) and (g)-(i) as references.
(g) and (h) are identical/redundant sequences/modifications. It would be remedial to remove one.
Claim 12 is objected to because of the following informalities: (j) and (k) are identical/redundant. It would be remedial to remove one.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) – indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim(s) 5-8, 10, 12 and 14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This is a new rejection necessitated by the amendments filed on 06/24/2026.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 5 recites the broad recitation “the sense strand has a length of 15nt to 17nt”, and the claim also recites “consists of a sequence selected from the group consisting of SEQ ID NOs: 67, 73 and 75” which is the narrower statement of the range/limitation.
It is unclear whether the claim is attempting to claim a fragment of SEQ ID NOs: 67, 73, and 75, however, the recitation of “consists of” suggests that the claim is referring to the entire sequence. SEQ ID NO: 67 is 16 nucleotides, SEQ ID NO: 73 is 16 nucleotides, and SEQ ID NO: 75 is 17 nucleotides. Therefore, it is unclear what it means to refer to a sense strand that has a length of 15 nucleotides if none of the SEQ ID NOs have a length of 15 nucleotides.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim(s) 6-8, 10, 12, and 14 are rejected for being dependent upon claim 5.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 5-8 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over
Hinkle et al (US 2017/0349900 A1; published December 7th, 2017; see PTO 892 filed 03/24/2026) in view of Chang et al (Asymmetric Shorter-duplex siRNA Structures Trigger Efficient Gene Silencing With Reduced Nonspecific Effects, Molecular Therapy, vol 17, issue 4, pages 725-732, published January 20th, 2009). This is a new rejection that is necessitated by amendment to the claims in the reply filed on 06/24/2026.
Hinkle et al teaches, “… RNAi agents, e.g., double- stranded RNAi agents, targeting the hepatitis B virus (HBV) genome, and methods of using such RNAi agents to inhibit expression of one or more HBV genes and methods of treating subjects having an HBV infection and/or HBV-associated disorder, e.g., chronic hepatitis B infection.”, (Abstract).
Regarding claim(s) 5-7 Hinkle et al teaches, “Accordingly, in one aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis B virus (HBV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double- stranded region, wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: l, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:2, wherein substantially all of the nucleotides of said sense strand and substantially all of the nucleotides of said antisense strand are modified nucleotides, wherein said sense strand is conjugated to a ligand attached at the 3 '-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.”, (paragraph [0014]).
Furthermore, Hinkle et al teaches, “Based on these assays, RNAi agents targeting five sites in the HBV X ORF (nucleotides 1551, 1577, 1580, 1806, and 1812 of GenBank Accession No. NC_003977.1 were selected for lead optimization and additional agents were designed and synthesized. These additional agents are evaluated in in vitro assays as described above. A detailed list of the additional unmodified sense and antisense strand sequences targeting the HBV X ORF is shown in Table 25. A detailed list of the additional modified sense and antisense strand sequences targeting the HBV X ORF is shown in Table 26.”, (paragraph [0705] and Figure 2).
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Hinkle et al teaches “AD-66808 and AD 66809” (see figure 2 below), which are double stranded RNAi agents with a sense strand and an antisense strand. SEQ ID NO: 67 (sense) of the instant application is 100% identical to nucleotides 4-19 of SEQ ID NOs: 1207 and 1208. SEQ ID NO: 68 (antisense) of the instant application is 100% identical to nucleotides 1-19 of SEQ ID NOs: 1263 and 1264 (see table 25 above).
Hinkle et al further teaches, “As used herein, the term “nucleotide overhang” refers to at least one unpaired nucleotide that protrudes from the duplex structure of an iRNA, e.g., a dsRNA. For example, when a 3′-end of one strand of a dsRNA extends beyond the 5′-end of the other strand, or vice versa, there is a nucleotide overhang. A dsRNA can comprise an overhang of at least one nucleotide; alternatively, the overhang can comprise at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides or more. A nucleotide overhang can comprise or consist of a nucleotide/nucleoside analog, including a deoxynucleotide/nucleoside. The overhang(s) can be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5′-end, 3′-end or both ends of either an antisense or sense strand of a dsRNA.”, (paragraph [0234]).
Further, “…The RNAi may also have a blunt end, located at the 5′-end of the antisense strand (or the 3′-end of the sense strand) or vice versa. Generally, the antisense strand of the RNAi has a nucleotide overhang at the 3′-end, and the 5′-end is blunt. While not wishing to be bound by theory, the asymmetric blunt end at the 5′-end of the antisense strand and 3′-end overhang of the antisense strand favor the guide strand loading into RISC process.”, (paragraph [0312]).
Regarding claim 8, Table 26 of Hinkle et al teaches various modifications to the sense and antisense strands, including 2’-Fluro, 2’-MOE, and phosphorothioate modifications. Table 27 and Figure 2 of Hinkle et al teaches in vivo screening of AD-66808 and AD-66809.
Moreover, “In certain aspects of the invention, the double-stranded RNAi agents of the invention include agents with chemical modifications as disclosed, for example, in WO 2013/075035, filed on Nov. 16, 2012, the entire contents of which are incorporated herein by reference. As shown herein and in PCT Publication No. WO 2013/075035, a superior result may be obtained by introducing one or more motifs of three identical modifications on three consecutive nucleotides into a sense strand and/or antisense strand of an RNAi agent, particularly at or near the cleavage site. In some embodiments, the sense strand and antisense strand of the RNAi agent may otherwise be completely modified. The introduction of these motifs interrupts the modification pattern, if present, of the sense and/or antisense strand. The RNAi agent may be optionally conjugated with a GalNAc derivative ligand, for instance on the sense strand. The resulting RNAi agents present superior gene silencing activity. More specifically, it has been surprisingly discovered that when the sense strand and antisense strand of the double-stranded RNAi agent are completely modified to have one or more motifs of three identical modifications on three consecutive nucleotides at or near the cleavage site of at least one strand of an RNAi agent, the gene silencing activity of the RNAi agent was superiorly enhanced.”, ([0305] to [0306]).
“In one embodiment, the RNAi agent comprises the pattern of the alternating motif of 2′-O-methyl modification and 2′-F modification on the sense strand initially has a shift relative to the pattern of the alternating motif of 2′-O-methyl modification and 2′-F modification on the antisense strand initially, i.e., the 2′-O-methyl modified nucleotide on the sense strand base pairs with a 2′-F modified nucleotide on the antisense strand and vice versa. The 1 position of the sense strand may start with the 2′-F modification, and the 1 position of the antisense strand may start with the 2′-O-methyl modification. The introduction of one or more motifs of three identical modifications on three consecutive nucleotides to the sense strand and/or antisense strand interrupts the initial modification pattern present in the sense strand and/or antisense strand. This interruption of the modification pattern of the sense and/or antisense strand by introducing one or more motifs of three identical modifications on three consecutive nucleotides to the sense and/or antisense strand surprisingly enhances the gene silencing activity to the target gene.”, (see paragraph [0338] to [0339]).
Regarding claim 14, Hinkle et al teaches, “In one aspect, the present invention provides methods of treating a subject having a Hepatitis B virus (HBV) infection. The methods include administering to the subject a therapeutically effective amount of the double stranded RNAi agent of the invention, or the composition of the invention, or the vector of the invention, or the pharmaceutical composition of the invention, thereby treating said subject. In another aspect, the present invention provides methods of treating a subject having a Hepatitis B virus (HBV)-associated disorder. The methods include administering to the subject a therapeutically effective amount of the double stranded RNAi agent of the invention, or the composition of the invention, or the vector of the invention, or the pharmaceutical composition of the invention, thereby treating said subject.”, (paragraphs [0078] to [0079]).
Despite, Hinkle et al teaching the claimed SEQ ID NOs: 67 and 68 (found in table 25 above), double stranded RNAi agents, modifications such as 2’-MOE, 2’-F, alternating 2’MOE/2’F, trivalent GalNac additions at the 3’ end of the sense strand, blunt ends, and overhangs, Hinkle et al does not explicitly teach that the sense strand consisting of 16 (of SEQ ID NO:67).
Hinkle et al suggests, “The skilled person is well aware that dsRNAs having a duplex structure of between about 20 and 23 base pairs, e.g., 21, base pairs have been hailed as particularly effective in inducing RNA interference (Elbashir et al., EMBO 2001, 20:6877-6888). However, others have found that shorter or longer RNA duplex structures can also be effective (Chu and Rana (2007) RNA 14:1714-1719; Kim et al. (2005) Nat Biotech 23:222-226). In the embodiments described above, by virtue of the nature of the oligonucleotide sequences provided in any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26, dsRNAs described herein can include at least one strand of a length of minimally 21 nucleotides. It can be reasonably expected that shorter duplexes having one of the sequences of any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26 minus only a few nucleotides on one or both ends can be similarly effective as compared to the dsRNAs described above. Hence, dsRNAs having a sequence of at least 15, 16, 17, 18, 19, 20, or more contiguous nucleotides derived from one of the sequences of any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26, and differing in their ability to inhibit the expression of a HBV gene by not more than about 5, 10, 15, 20, 25, or 30% inhibition from a dsRNA comprising the full sequence, are contemplated to be within the scope of the present invention.”, (see paragraph [0277]).
Moreover, “While a target sequence is generally about 15-30 nucleotides in length, there is wide variation in the suitability of particular sequences in this range for directing cleavage of any given target RNA. Various software packages and the guidelines set out herein provide guidance for the identification of optimal target sequences for any given gene target, but an empirical approach can also be taken in which a “window” or “mask” of a given size (as a non-limiting example, 21 nucleotides) is literally or figuratively (including, e.g., in silico) placed on the target RNA sequence to identify sequences in the size range that can serve as target sequences. By moving the sequence “window” progressively one nucleotide upstream or downstream of an initial target sequence location, the next potential target sequence can be identified, until the complete set of possible sequences is identified for any given target size selected. This process, coupled with systematic synthesis and testing of the identified sequences (using assays as described herein or as known in the art) to identify those sequences that perform optimally can identify those RNA sequences that, when targeted with an iRNA agent, mediate the best inhibition of target gene expression. Thus, while the sequences identified, for example, in any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26 represent effective target sequences, it is contemplated that further optimization of inhibition efficiency can be achieved by progressively “walking the window” one nucleotide upstream or downstream of the given sequences to identify sequences with equal or better inhibition characteristics. Further, it is contemplated that for any sequence identified, e.g., in any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26, further optimization could be achieved by systematically either adding or removing nucleotides to generate longer or shorter sequences and testing those sequences generated by walking a window of the longer or shorter size up or down the target RNA from that point. Again, coupling this approach to generating new candidate targets with testing for effectiveness of iRNAs based on those target sequences in an inhibition assay as known in the art and/or as described herein can lead to further improvements in the efficiency of inhibition. Further still, such optimized sequences can be adjusted by, e.g., the introduction of modified nucleotides as described herein or as known in the art, addition or changes in overhang, or other modifications as known in the art and/or discussed herein to further optimize the molecule (e.g., increasing serum stability or circulating half-life, increasing thermal stability, enhancing transmembrane delivery, targeting to a particular location or cell type, increasing interaction with silencing pathway enzymes, increasing release from endosomes) as an expression inhibitor.”, (see paragraphs [0279] to [0280]).
Despite Hinkle et al suggesting that the base sequence can be modified by adding or removing nucleotides from one or both sides, Hinkle et al does not explicitly teach that the sense strand consists of 16 nucleotides (of claim 5) or antisense consists of 19 nucleotides (of claim 6).
Chang et al teaches asymmetric shorter-duplex siRNA structures. More specifically, “In this study, we report on the identification of truncated siRNA backbone structures with duplex regions shorter than 19 bp (referred to as asymmetric shorter-duplex siRNAs or asiRNAs) that can efficiently trigger gene silencing in human cell lines. Importantly, this asiRNA structure significantly reduces nonspecific effects triggered by conventional 19+2 siRNA scaffold, such as sense-strand–mediated off-target gene silencing and saturation of the cellular RNAi machinery.”, (abstract).
Regarding claim(s) 5 and 6, Chang et al teaches, “The length of the guide (antisense; AS) strand of these siRNAs was fixed to 19 nt, but the passenger (sense)-strand length was varied. This process yielded several siRNA structures with duplex regions shorter than 19 bp and AS strands with 3′-overhangs of various lengths (Figure 1a). We named these as 17+2A, 16+3A, 15+4A, 14+5A, and 13+6A, which refer to a 17-bp duplex with a 2-nt 3′-overhang on the AS strand, a 16-bp duplex with 3-nt 3′-overhang on the AS strand, a 15-bp duplex with 4-nt 3′-overhang on the AS strand, a 14-bp with 5-nt 3′-overhang on the AS strand, and a 13-bp duplex with 6-nt 3′-overhang on the AS strand, respectively.”, (p.726, col 2, para 1).
asiRNA of 16+3 showed comparable silencing expression to conventional 19+2
Moreover, “To our surprise, two structures with duplexes shorter than 19 bp, 17+2A and 16+3A, showed silencing activity comparable to that of the conventional 19+2 siRNA at both tested concentrations (Figure 1b).”, (p.726, col 2, para 1).
The asiRNA of 16+3 can be guidance for many different targets
Further, Chang et al teaches, “We then tested whether active asiRNA structures can be designed for other mRNA targets. siLamin 19+2 (ref. 1), siSurvivin 19+2 (ref. 24), and siIntegrin 19+2 (ref. 25), which are con ventional 19+2 siRNAs that target the LaminA/C, Survivin, and Integrin αv subunit, respectively, were converted to asiRNA structures (Supplementary Figure S4). The gene-silencing efficiencies of these asiRNA structures were then compared with those of their corresponding 19+2 structures in HeLa cells (Figure 1c–e). The 17+2A and 16+3A asiRNA structural variants efficiently reduced the amounts of LaminA/C, Survivin, and Integrin mRNAs at all concentrations tested, and silencing efficiencies were comparable to those of the 19+2 structures (Figure 1c–e). IC50 values of active 16+3A asiRNAs were either almost identical to those of the 19+2 siRNAs (in the case of siTIG3 and siSurvivin), or slightly increased, about twofold higher than those of the 19+2 siRNAs (in the case of siLamin and siIntegrin).”, (p. 727, col 1, para 2).
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Similar phenotypic changes with 16+3A asiRNA compared to conventional 19+2
Chang et al teaches, “Supplementary Figure S8b showed that the 19+2 and 16+3A siRNAs induced the production of a similar percentage of polyploid cells. Therefore, siSurvivin 16+3A not only silenced Survivin mRNAs to the same extent as did the 19+2 siRNA (Figure 1c), but also induced similar phenotypic changes.”, (p.727, col 1, para 3).
Similar serum stability of asiRNAs compared to conventional 19+2
Chang et al teaches, “Because asiRNAs have a shortened duplex region and longer overhangs than 19+2 structures, we tested whether it might be more susceptible to degradation by serum nucleases than the latter. Supplementary Figure S10 shows that both 19+2 and 16+3A siRNAs have similar kinetics of degradation when incubated with serum, suggesting that the serum stability of asiRNAs is comparable to that of conventional 19+2 siRNAs.”, (p.727, col 2, para 3).
Reduced off-target silencing with 16+3A asiRNA compared to conventional 19+2
Further, “In contrast, 16+3A siTIG3 and siSurvivin yielded significantly reduced gene-silencing activity by their sense strands (Figure 3a,b). These data demonstrate that asiRNAs display less sense-strand–mediated off-target silencing than 19+2 siRNAs. . . As shown in Supplementary Figure S11b, both symmetric (16+3) siRNAs showed stronger sense-mediated off-target silencing activities than their corresponding asymmetric (16+3A) siRNAs. These results demonstrate that reduced sense off-target silencing is most efficiently achieved in asymmetric structures.”, (p. 728, col 1-2, para 1-2).
Reduced AGO2 saturation with 16+3A asiRNA
Chang et al teaches, “Our observation that asiRNAs have little or reduced competition with 19+2 structures (Figure 4a,b) suggests that cellular RNAi machinery saturation may be reduced or prevented with our asiRNA structures.”, (p.729, col 1 para 2 to col 2 para 1).
asiRNA of 17+2A or 16+3A show less inhibition of endogenous microRNAs in cells
Chang et al teaches, “These results suggest that the exogenous 19+2 siTIG3 interferes with miR-21-mediated luciferase gene silencing. Importantly, the corresponding 17+2A and 16+3A structures showed less inhibition of miR-21 activity, with the 15+4A showing almost no inhibition of miR-21 activity in cells (Figure 4c). These findings demonstrate that asiRNAs have less or no inhibition of endogenous miRNA activity.”, (p.729, col 2, para 1).
Lastly, Chang et al teaches, “In conclusion, the asymmetric shorter-duplex siRNA structures described in this report showed gene-silencing activities that are comparable to the conventional 19+2 siRNA structures. Importantly, our asiRNA strcuture provides several advantages, which includes reduced sense-strand–mediated off-target gene silencing, reduced saturation of the cellular RNAi machinery, and a reduction in production costs. Our findings provide a new structural scaffold for designing silencing RNA duplex that can potentially overcome nonspecific effects evoked by siRNAs, a significant challenge in broad RNAi applications in functional genomics and therapeutics.”, (p.730, col 2, para 3).
Therefore, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to modify the teachings of Hinkle et al, i.e., SEQ ID NOs: 1207 or 1208 and SEQ ID NOs: 1263 or 1264 (as shown in table 25 above) with the teachings of Hinkle et al and Chang et al, i.e., a sense strand (SEQ ID NOs: 1207 or 1208) having 16 nucleotides and an antisense strand (SEQ ID NOs: 1263 or 1264) having 19 nucleotides, to yield the predictable results of an asymmetric dsRNA having a sense strand of 16 nucleotides (reading on “consists of SEQ ID NO: 67” of claim 5) and an antisense strand of 19 nucleotides (reading on “consists of SEQ ID NO: 68” of claim 6). One of skill in the art could have looked to the teachings of Hinkle et al and found duplexes AD-66808 and AD 66809 in figure 2 and the top of table 25. One could have found where Hinkle et al teaches that “further optimization could be achieved by systematically either adding or removing nucleotides to generate longer or shorter sequences and testing those sequences generated by walking a window of the longer or shorter size up or down the target RNA from that point.” One of skill could have looked to Chang et al for teachings on optimization of dsRNA and found that a 16-nucleotide sense strand and a 19-nucleotide antisense strand, that are asymmetrical, with a blunt end on the 5’ end of the antisense sense strand have the following characteristics:
comparable silencing expression to conventional 19+2 sequences;
can be designed for any target;
similar phenotypic changes;
similar serum stability;
reduced off-target silencing;
reduced AGO2 saturation;
less or no inhibition of endogenous microRNAs; and
reduced production cost.
One of skill in the art could have looked to the teachings of Hinkle et al and Chang et al to arrive at the claimed invention with a high likelihood of success.
Accordingly, claim(s) 5-8 and 14 are unpatentable over Hinkle et al in view of Chang et al.
Claim(s) 10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Hinkle et al (supra) in view of Chang et al (supra) as applied to claim(s) 5-8 and 14 above, and further in view of Khvorova and Watts (The chemical evolution of oligonucleotide therapies of clinical utility, Nature Biotechnology, Vol 35, Issue 3, Published February 27th, 2017; cited on the PTO 892 form filed 03/24/2026). This rejection was made in the prior Office action mailed 03/24/2026 and has been rewritten to address the amendments to the claims in the reply filed 06/24/2026.
All limitations taught in Hinkle et al in view of Chang et al from the above rejection apply herein.
Hinkle et al further teaches, “In one embodiment, a double-stranded RNAi agent comprises 6-8 phosphorothioate internucleotide linkages.”, (paragraph [0341]).
Chang et al teaches, “The asiRNAs used in this study only have modifications to the backbone structure and do not contain any chemical modifications. Further chemical modification of asiRNAs can be expected to add additional benefits.”, (p. 730, col 1, para 2)
Hinkle et al and Chang et al do not teach (1) a 5’-phosphate group linkage on the antisense strand, (2) the alternating modifications of 2’-MOE and 2’-Fluro with a stretch of three identical modifications in the middle of either the antisense or sense stand as claimed, and (3) phosphorothioate bond locations.
Khvorova and Watts teach multiple designs that enable effective targeting to the liver.
More specifically, Khvorova and Watts teach, (1) “The 5′-phosphate of a siRNA guide strand is essential for recognition by RISC. siRNAs with a 5′-hydroxyl are efficiently phosphorylated and loaded onto Ago2 inside cells. Blocking phosphorylation of the 5′-hydroxyl in siRNA prevents RISC loading and activity. Chemical modification (e.g., 2′-OMe or 2′-F) of the 5′-ribose of the guide strand can interfere with intracellular phosphorylation but the activity of these 5′-modified guide strands can be restored if a 5′-phosphate is introduced chemically...”, (Page 243, column 2, paragraph 3).
“Phosphatase-resistant analogs of the 5′-phosphate can improve in vivo efficacy. Ionis modified the 5′ end of single-stranded siRNA (ss-siRNA) with E-vinyl phosphonate (5′-E-VP), which substitutes the bridging oxygen with carbon in the context of a double bond (Fig. 2). The 5′-E-VP is in a suitable conformation for RISC binding, whereas the other stereoisomer (5′-Z-VP) shows reduced activity due to inappropriate positioning of the phosphonate. In this context, 5′ chemical stabilization was absolutely essential for the in vivo efficacy of ss-siRNAs”, (Page 243, column 2, paragraph 4).
“5′-E-VP has a major impact on the in vivo efficacy of GalNAc-conjugated siRNAs, discussed below. The effect is not specific to GalNAc: phosphate stabilization of hydrophobically modified siRNAs significantly enhances the distribution, accumulation, and retention of intact oligonucleotide in primary and secondary tissues, and extends the duration of effect beyond a month after injection (R. Haraszti, L. Roux, and A.K., unpublished data). In the absence of lipid formulation, therefore, metabolic stabilization of the 5′-phosphate is essential for stability, biodistribution, activity, and duration of effect of therapeutic siRNAs in vivo. Notably, phosphate stabilization also increases the accumulation of guide strand in tissues, probably because it provides additional protection from XRN1-mediated hydrolysis. XRN1 is the primary cellular nuclease that rapidly degrades 5′-phosphorylated RNA and DNA, but it does not recognize metabolically stable 5′-phosphate analogs (R. Haraszti, L. Roux, and A.K., unpublished data).”, (Page 244, column 1, paragraph 1).
“For best results, GalNAc conjugation requires a metabolically stable oligonucleotide scaffold; that is, modification of every nucleotide to remove all ribose moieties and metabolic stabilization of the 5′-phosphate. The resulting GalNAc-conjugated siRNA and ASO compounds show exceptional stability and duration of effect, allowing monthly or even semiannual subcutaneous injections.”, (Page 244, column 1, paragraph 5).
Further, Khvorva and Watts teach, (2) “The 2-F and 2-OMe modifications favor the C3′-endo ribose conformation and support the A-form helical structure of the guide strand, which positions the target mRNA into the cleavage center of RISC. But both modifications introduce slight structural distortions. 2′-F-RNA slightly overwinds the duplex (leading to more stacking and higher Tm), and 2′-OMe-RNA slightly underwinds the duplex (less stacking). Either modification 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 substantially 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, column 1, paragraph 3).
“Thermodynamic or structural tuning may further enhance the efficacy of modified siRNAs. Many of the advanced clinical compounds carry additional stretches of 2′-OMe and 2′-F (for example, three of either modification in a row, or sometimes longer stretches of 2′-OMe) in the context of the alternating 2′-F–2′-OMe-RNA pattern (Fig. 3). The pattern was designed to chemically mimic the sinusoidal thermodynamic stability described for highly functional siRNAs.”, (Page 243, column 1, paragraph 4)).
Khvorva and Watts teach, (3), “Additional nuclease stability is conferred by backbone modifications. Limited phosphorothioates are tolerated by Ago2, and phosphorothioate modifications at both ends of both strands of an siRNA duplex are incorporated into many of the leading clinical candidates. This simple combination of backbone and sugar modification provides additional resistance to exonucleases—the primary effectors of RNA degradation—and an order-of-magnitude increase in oligonucleotide accumulation in vivo.”, (Page 243, column 2, paragraph 2).
Lastly, Figure 3 of Khvorva and Watts teach the evolution of RNAi technologies. Specifically teaching a double-stranded modified RNAi agent, with a blunt end, overhangs, alternating modifications of 2’-MOE and ‘2-F, a stretch of three identical modifications, phosphorothioate bonds, a trivalent GalNac, and a 5’ phosphate modification. See below.
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined teachings of Hinkle et al in view of Chang et al, i.e., an asymmetrical siRNA consisting of a 16 nucleotide sense strand and a 19 nucleotide antisense strand (reading on instant SEQ ID NOs: 67 and 68, respectively), with the teachings of Khvorova and Watts, i.e., to add a 5’-phosphate group linkage on the antisense strand, alternate the 2’-MOE and 2’-F modifications with at least one stretch on either/or both strands of three identical modifications, and have between 6-8 phosphorothioate bonds in the RNAi agent (2 on the sense strand, and 6 on the antisense strand) to yield the predictive results of an asymmetrical siRNA modified consisting of a 16 nt sense stand and 19 nt antisense strand (reading on the modifications (c)-(d) and (g)-(i) of claim 10; and (c)-(d) and (g)-(k) of claim 12).
One of skill in the art could look to the combined teachings of Hinkle et al and Chang et al and see that Chang et al teaches that further chemical modifications can be expected to add additional benefits. One of skill could look to the teachings of Hinkle et al and Khvorova and Watts for various chemical modification to asymmetric siRNA and find that (1) a 5’-E-VP or 5’P on the longer strand, i.e., the antisense stand, improves in vivo efficacy, stability, biodistribution, nuclease stability and is essential when paired with (2) a 3’ GalNac on the shorter strand, i.e., the sense strand, which is proper metabolic stabilization. Further, the teachings of Khvorova and Watts extend past that of the 5’ or 3’ end modifications into nucleotide chemical modifications, one of skill could find that (3) when the sense strand and antisense strand of the double-stranded RNAi agent are completely modified to have one or more motifs of three identical modifications on three consecutive nucleotides at or near the cleavage site of at least one strand of an RNAi agent, the gene silencing activity of the RNAi agent was superiorly enhanced, which also chemically mimics sinusoidal thermodynamic stability described for highly functional siRNAs. One would find in the teachings of Khvorova and Watts that (4) chemical modifications (e.g., 2′-OMe or 2′-F) of the 5′-ribose of the guide strand can interfere with intracellular phosphorylation but the activity of these 5′-modified guide strands can be restored if a 5′-phosphate is introduced chemically as taught by (1). Lastly, one could find that Khvorova and Watts teaches that (5) nuclease stability is conferred through backbone modifications, and limited phosphorothioates are tolerated by Ago2, thus, modifying the terminal ends of the siRNA duplex has been a going model for enhanced stability while maintaining Ago2 tolerance, and has already been a design incorporated into many of the leading clinical candidates. Thus, one of skill could look to the combined teachings of Hinkle et al and Chang et al and find teachings of Khvorova and Watts for chemical modifications of clinically relevant asymmetric siRNA and arrive at the claimed invention with a high likelihood of success.
Thus, claim(s) 10 and 12, are rejected as being unpatentable over Hinkle et al in view of Chang et al in further view of Khvorova and Watts.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claim(s) 5-8 and 14 under 35 U.S.C 103 as being unpatentable over Hinkle et al (supra), and The previous rejection of claim(s) 10 and 12 under 35 U.S.C 103 as being unpatentable over Hinkle et al (supra) in view of Khvorova and Watts (supra), Applicant’s argument on pages 9-17 of the reply filed 06/22/2026 has been fully considered but is not persuasive for at least the following reasons:
Applicant contends that the presently amended claims are not obvious for a variety of reasons, and that Hinkle or the combination of Hinkle and Khvorova and Watts do not teach or suggest that presently amended claims. Applicant contends that neither reference, alone nor in the combination proposed in the Office Action (filed 03/24/2026), teaches or suggests the specific claimed sense and antisense sequences, the terminal sequence changes recited in the claims, or the markedly superior HBV inhibitory effects demonstrated in the present Specification. The combination proposed in the Office Action also lacks a reasoned motivation to arrive at the pending claims and lacks a reasonable expectation of success.
Applicant provides seven arguments throughout the remarks filed 06/24/2026.
Argument (1): Comparing the amended claims and the cited references. Applicant admits that Hinkle relates to HBV iRNA compositions and methods of inhibiting HBV using the same and describes double stranded RNAi agents such as "AD-66808" and "AD-66809." (a) Applicant contends that Hinkle does not teach or suggest any RNAi agent having the same sequence as asiHBV-082 of SEQ ID NOs: 67 and 68, asiHBV-103 of SEQ ID NOs: 73 and 74, or asiHBV-107 of SEQ ID NOs: 75 and 76 of the present application, nor does Hinkle describe the markedly superior effects of those specific agents. (b) Applicant contends that Khvorova and Watts does not teach or suggest the features recited in the pending claims, including the asiHBV-082 core sequence, the terminal changes that produce asiHBV-103 and asiHBV-107, or the HBV inhibitory effects demonstrated in the present Specification.
Response (1): (a) Applicant is reminded that SEQ ID NOs: 67 and 68 are the elected species of sequences, therefore any argument related to unelected species, which were not examined, will not be responded to in this action. As the claims stood in the Office Action filed 03/24/2026, Hinkle did comprise the sequences of SEQ ID NO: 67 and 68 (see table 25). The 35 U.S.C. 103 rejection has been rewritten to address the amendment which now recites consists of. (b) Khvorova and Watts do teach the modifications found in claim (s) 10 and 12 and do not need to necessarily teach that base sequence. General chemical modifications are well-known and routine in the art of siRNA production. Also, the combination of Hinkle et al and Khvorova and Watts does not necessarily need to demonstrate the HBV inhibitory effects because the combined teachings to yield the predictable results of the previously claimed modifications of the sequences would inherently produce those effects.
Argument (2): The claimed sense and antisense strand sequences could not have been readily derived from Hinkle. (a) Applicant contends that Hinkle does not describe the presently claimed sequence pairs. For example, Hinkle SEQ ID NO: 1208 includes terminal "guc" residues that are not present in the claimed SEQ ID NOs: 67 and 73. Applicant contends that Hinkle frames such changes as an empirical optimization process that requires synthesis and testing of candidate sequences, and that Hinkle therefore confirms the unpredictability of terminal changes rather than providing a reasonable expectation that the particular claimed terminal deletions, additions, and substitutions would produce a superior HBV RNAi agent. (b) Applicant contends that Hinkle itself describes that truncation alters inhibitory activity by no more than about 5 percent to 30 percent. (See Hinkle, paragraph [0277]) Yet, as discussed below, OLX703A- 082 and OLX703A-046 differ by only two to three terminal nucleotides but exhibit a marked difference in efficacy exceeding the approximately 30 percent range that Hinkle presumes. The effect of such terminal changes is therefore unpredictable. One of ordinary skill in the art could not have predicted that modifying Hinkle's sequences to arrive at OLX703A-082, OLX703A- 103, or OLX703A-107 would yield operative agents, much less agents with markedly superior HBV inhibitory activity.
Response (2): (a) The prior recitation of “comprises” encompassed the terminal “guc” of SEQ ID NO: 1208. Hinkle explicitly states, “It can be reasonably expected that shorter duplexes having one of the sequences of any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26 minus only a few nucleotides on one or both ends can be similarly effective as compared to the dsRNAs described above.”, (para [0277]). (b) As for “Hinkle itself describes that truncation alters inhibitory activity by no more than about 5 percent to 30 percent” (remarks above by applicant”, Hinkle et al states verbatim, “Hence, dsRNAs having a sequence of at least 15, 16, 17, 18, 19, 20, or more contiguous nucleotides derived from one of the sequences of any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26, and differing in their ability to inhibit the expression of a HBV gene by not more than about 5, 10, 15, 20, 25, or 30% inhibition from a dsRNA comprising the full sequence, are contemplated to be within the scope of the present invention.” Applicant argues that “OLX703A- 082 and OLX703A-046 differ by only two to three terminal nucleotides but exhibit a marked difference in efficacy exceeding the approximately 30 percent”, however, Applicant does not demonstrate the control of the “full sequence” in any of the figures that is explicitly recited by Hinkle as a condition for the percent inhibition. However, if we are looking at the comparison of OLX703A- 082 and OLX703A-046, Figures 8 and 9 show less than a
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30% difference between the two.
Argument (3): The markedly superior effects of the claimed HBV asiRNA agents could not have been readily derived from Hinkle. (a) Applicant contends that Example 5 and FIG. 13 of the present Specification confirm that OLX703A-082 has markedly superior effects compared to other siRNAs. Although OLX703A-082 and OLX703A-046 have similar sequences as shown below, OLX703A-082 exhibits markedly superior efficacy. This demonstrates that deleting, adding, or altering two to three nucleotides at the terminus of an siRNA sequence can produce a marked difference in efficacy. (b) Applicant contends that Example 7 and FIG. 19 of the present Specification confirm that OLX703A-082, as well as OLX703A-103 and OLX703A-107 in which one or two nucleotides are added to the terminus thereof, also exhibit markedly superior efficacy and that these data are not predictable by simply shortening or extending the prior art RNAi sequence and that these specific terminal configurations produce unexpectedly strong activity. (c) Applicant contends that OLX703A-082, OLX703A-103, and OLX703A-107 are chemically modified, which could not be readily derived from Hinkle.
Response (3): (a/b/c) In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., compounds OLX703A-082, OLX703A-103, and OLX703A-107) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
(a/b/c) claim(s) 5-8 and 14 do not require the chemical modifications as presented by OLX703A-082, OLX703A-103, and OLX703A-107 found in Examples 7 and 8 of the instant specification (the main compounds of Applicant’s arguments). Claim 5 requires a sequence. Khvorova and Watts teach the modifications, however, Applicant is not arguing the combination of Hinkle and Khvorova and Watts teaching the compounds of OLX703A-082, OLX703A-103, and OLX703A-107, Applicant argues the Hinkle does not.
Further, (a) When looking to the sequence of SEQ ID NO: 67 compared to SEQ ID NO: 33, SEQ ID NO: 33 does not only remove a nucleotide from the 5’ end (which is consistent with the teachings of Hinkle et al), it also adds a “g” into the sequence before the “a” at the 3’ end, which Applicant did not bold and underline like the other modification differences in the sequences (See highlights below):
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Hinkle teaches the removal or addition of sequences to the end of the strand, not inside the strand. This additional “g” potentially aids in the reason as to why 082 is “markedly superior” and thus cannot be directly compared for expression purposes in the context of adding and removing on the strand ends. Further, Hinkle teaches a “walking window” and a “g” would not be found if a window were being walked up and down the sequences of Hinkle because it is a different sequence with a “g”.
(b) Compound asiHBV-103 and asiHBV-107 do not relate to the elected species of SEQ ID NOs: 67 and 68, so for the purpose of this response, only compound asiHBV-082 will be addressed. Applicant contends that the efficacy/activity of asiHBV-082 is not predictable by simply shortening or extending the prior art RNAi sequence, however, Applicant does not have the prior art compound as a control to compare to the asiHBV-082, so the argument of predictability, efficacy, and expression comparison is mute.
Argument (4): Khvorova and Watts does not cure the deficiencies of Hinkle with respect to claims 10 and 12. (a) Applicant contends that Khvorova and Watts is a general review of oligonucleotide therapeutic chemistry and that it does not teach or suggest the claimed asiHBV-082, asiHBV-103, or asiHBV-107 sequences, and it does not bridge the gap between Hinkle's AD-66808 or AD-66809 agents and the pending claims. Applicant contends that chemical modification of siRNA is highly context dependent and that a modification pattern that may improve stability or delivery in one sequence context can alter duplex stability, guide strand loading, cleavage efficiency, nuclease susceptibility, tissue distribution, or off target behavior in another sequence context. Further, Applicant contends that one of ordinary skill in the art would not have had a reasonable expectation that applying generalized chemical modification teachings from Khvorova and Watts to a sequence modified from Hinkle would yield the particular chemically modified agents of claims 10 and 12 with the markedly superior activity demonstrated in the present Specification.
Response (4): (a) In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of skill in the art would look to the teachings of Khvorova and Watts and apply those teachings to the sequences as taught by Hinkle et al. Khvorova and Watts need not contain the sequences to be applicable to the sequences of Hinkle et al.
Argument(s) (5-7): (5) There was no motivation to combine the cited references in the manner proposed by the Office Action. (6) There was no reasonable expectation of success. (7) The pending claims are patentable over the cited combinations.
(5a) Applicant contends that the Office Action's reasoning appears to rest on the view that Hinkle and Khvorova and Watts relate generally to RNAi agents and chemical modifications and that a general overlap in field, however, does not provide a specific reason to modify Hinkle's HBV RNAi agents to arrive at the exact claimed sequences and terminal configurations. Applicant contends that Hinkle describes many HBV RNAi agents and many possible optimization directions and that the Office Action does not identify any description in Hinkle that would have directed one of ordinary skill in the art specifically to remove the terminal "guc" sequence from Hinkle SEQ ID NO: 1208, to replace the terminal "uu" of Hinkle SEQ ID NO: 1264 with "gg" for the asiHBV-103 and asiHBV-107 antisense strands, and to retain the asiHBV-082 core as claimed nor does Khvorova and Watts supply that missing motivation. Applicant contends that Khvorova and Watts addresses general chemical strategies for oligonucleotide therapeutics and does not identify the claimed HBV target sequence, the asiHBV-082 core, the specific terminal substitutions of claims 5 and 6, or the specific chemically modified sequence combinations of claims 10 and 12.
(6b) Applicant contends that even if one of ordinary skill in the art had selected Hinkle as a starting point and had considered Khvorova and Watts, there would have been no reasonable expectation of success in arriving at the pending claims and that the data in the present Specification show that small terminal changes can cause large and unpredictable differences in activity. OLX703A-082 and OLX703A-046 differ by only two to three terminal nucleotides, yet OLX703A-082 shows markedly superior activity, and that this difference exceeds the approximate 30 percent range that Hinkle itself suggests for truncation effects.
(7c) Applicant contends that for claims 5 and 6, Hinkle does not teach or suggest the presently claimed sense and antisense strand sequences, and one of ordinary skill in the art would not have had a motivation or reasonable expectation of success in modifying Hinkle to arrive at asiHBV-082, asiHBV-103, or asiHBV-107. Applicant contends that claims 7 and 8 depend on claim 5 and recite further features of the RNAi agent and that these claims are patentable for at least the same reasons as claim 5, and the additional features do not remedy the Office Action's failure to establish that the specific claimed sequences would have been obvious. Applicant contends that claim 14 recites a method of ameliorating or treating a disease caused by HBV infection by administering an effective amount of the RNAi agent of claim 5 and is patentable for at least the same reasons as claim 5. Applicant contends that for claims 10 and 12, the addition of Khvorova and Watts does not remedy Hinkle's failure to teach or suggest the claimed sequences, the claimed terminal changes, or the unexpected activity of OLX703A-082, OLX703A-103, and OLX703A-107, and that Khvorova and Watts provides, at most, general chemical modification concepts and does not provide a motivation to make the specific claimed agents or a reasonable expectation that those agents would provide the markedly superior HBV inhibitory activity demonstrated in the present Specification. Lastly, Applicant contends that the cited references, as combined in the Office Action, do not provide a motivation to arrive at the pending claims and do not provide a reasonable expectation of success.
Response (5-7): (5a and 7c) It is of note that asiHBV-103 and asiHBV-107 are not elected species and thus the argument directed to these will not be responded to. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Applicant contends that Hinkle describes many HBV RNAi agents and many possible optimization directions and that the Office Action does not identify any description in Hinkle that would have directed one of ordinary skill in the art specifically to remove the terminal "guc" sequence from Hinkle SEQ ID NO: 1208, however, as pointed to throughout this response, Hinkle et al in [0277-0280] teaches, “It can be reasonably expected that shorter duplexes having one of the sequences of any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26 minus only a few nucleotides on one or both ends can be similarly effective as compared to the dsRNAs described above. Hence, dsRNAs having a sequence of at least 15, 16, 17, 18, 19, 20, or more contiguous nucleotides derived from one of the sequences of any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26, and differing in their ability to inhibit the expression of a HBV gene by not more than about 5, 10, 15, 20, 25, or 30% inhibition from a dsRNA comprising the full sequence, are contemplated to be within the scope of the present invention. . . Thus, while the sequences identified, for example, in any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26 represent effective target sequences, it is contemplated that further optimization of inhibition efficiency can be achieved by progressively “walking the window” one nucleotide upstream or downstream of the given sequences to identify sequences with equal or better inhibition characteristics. Further, it is contemplated that for any sequence identified, e.g., in any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26, further optimization could be achieved by systematically either adding or removing nucleotides to generate longer or shorter sequences and testing those sequences generated by walking a window of the longer or shorter size up or down the target RNA from that point.” Further, one of skill in the art would look to the teachings of Khvorova and Watts and apply those teachings to the sequences as taught by Hinkle et al. Khvorova and Watts need not contain the sequences to be applicable to the sequences of Hinkle et al.
(6b) This argument has been responded to in 2(b) and 3(a) and reiterated here. When looking to the sequence of SEQ ID NO: 67 compared to SEQ ID NO: 33, SEQ ID NO: 33 does not only remove a nucleotide from the 5’ end (which is consistent with the teachings of Hinkle et al), it also adds a “g” into the sequence before the “a” at the 3’ end, which Applicant did not bold and underline like the other modification differences in the sequences (See highlights below):
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Hinkle teaches the removal or addition of sequences to the end of the strand, not inside the strand. This additional “g” potentially aids in the reason as to why 082 is “markedly superior” and thus cannot be directly compared for expression purposes in the context of adding and removing on the strand ends. Further, Hinkle teaches a “walking window” and a “g” would not be found if a window were being walked up and down the sequences of Hinkle because it is a different sequence with a “g”.
As for “Hinkle itself describes that truncation alters inhibitory activity by no more than about 5 percent to 30 percent” (remarks above by applicant”, Hinkle et al states verbatim, “Hence, dsRNAs having a sequence of at least 15, 16, 17, 18, 19, 20, or more contiguous nucleotides derived from one of the sequences of any one of Tables 3, 4, 6, 7, 12, 13, 22, 23, 25, and 26, and differing in their ability to inhibit the expression of a HBV gene by not more than about 5, 10, 15, 20, 25, or 30% inhibition from a dsRNA comprising the full sequence, are contemplated to be within the scope of the present invention.” Applicant argues that “OLX703A- 082 and OLX703A-046 differ by only two to three terminal nucleotides but exhibit a marked difference in efficacy exceeding the approximately 30 percent”, however, Applicant does not demonstrate the control of the “full sequence” in any of the figures that is explicitly recited by Hinkle as a condition for the percent inhibition. However, if we are looking at the comparison of OLX703A- 082 and OLX703A-046, Figures 8 and 9 show less than 30% difference between the two (see figures above).
(7c) As for motivation to be provided, Hinkle teaches that one would be motivated to modifying length to improve efficiency of inhibition. As for the modifications taught by Khvorova and Watts, as stated in the Office Action mailed 03/24/2026, One would have been motivated to make such modifications because of the following:
First, the GalNac moiety requires a metabolically stable oligonucleotide, and for proper
metabolic stabilization, the 5′-phosphate is essential for stability, biodistribution, activity, and duration of effect of therapeutic siRNAs in vivo (as taught by Khvorova and Watts).
Second, chemical modification (e.g., 2-OMe or 2′-F) of the 5′-ribose of the guide strand
can interfere with intracellular phosphorylation but the activity of these 5-modified guide strands can be restored if a 5′-phosphate is introduced chemically (as taught by Khvorova and Watts).
Third, when the sense strand and antisense strand of the double-stranded RNAi agent are completely modified to have one or more motifs of three identical modifications on three consecutive nucleotides at or near the cleavage site of at least one strand of an RNAi agent, the gene silencing activity of the RNAi agent was superiorly enhanced, which also chemically mimics sinusoidal thermodynamic stability described for highly functional siRNAs (as taught by both Hinkle et al and Khvorova and Watts).
Fourth, nuclease stability is conferred through backbone modifications, and limited phosphorothioates are tolerated by Ago2, thus, modifying the terminal ends of the siRNA duplex has been a going model for enhanced stability while maintaining Ago2 tolerance, and has already been a design incorporated into many of the leading clinical candidates (as taught by Khvorova and Watts).
Thus, the argument provided has not provided substantial reasoning as to why Hinkle is not obvious over claims 5-8 and 14, and why Hinkle in view of Khvorova and Watts are not obvious claims 10 and 12.
Conclusion
No claims allowed.
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.
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/L.M.T./ Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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