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 .
Application Status
This action is written in response to applicant’s correspondence received 11/14/2025. Claims 1 and 21-39 are currently pending. Claims 27 and 39 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1, 21-26 and 28-38 are examined herein. The restriction requirement mailed 10/08/2025 is still deemed proper. Applicant elected the invention of Group I, the double-stranded siRNA analogue comprising a sense strand of SEQ ID NO: 3 and antisense strand of SEQ ID NO: 10, with traverse in the reply filed 11/14/2025.
Election/Restrictions
Applicant's election with traverse of the election of the duplex comprising SEQ ID NOs: 3 and 10 in the reply filed on is acknowledged. The traversal is on the ground(s) that, “the FdU…contained in the siRNA described in Wu is structurally distinct from the structure of “r” involved in the present application…Given these structural differences, a person skilled in the art would not have expected that replacement with “r” could produce technical effects similar or equivalent to those of FdU. Moreover, based on the fundamental mechanism of siRNA, replacing specific nucleoside(s) in an siRNA, particularly that in the antisense strand, with “r” would reduce the number of complementary base pairs. Consequently, a person skilled in the art would have no reasonable expectation that such replacement could enhance the efficacy of the unmodified siRNA.” Respectfully, this argument is not persuasive because it argues against Wu individually, when it is the combination of Wu (siRNA prodrugs incorporating one type of nucleoside analog to enhance siRNA cytotoxicity, thus providing a motivation to try incorporating other known nucleoside analogs into siRNA) with Galban-Garcia (providing a suggestion to use the nucleoside analog, ribavirin, to treat HBV) and Alnylam (providing the antisense sequence targeting HBV). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The requirement is still deemed proper and is therefore made FINAL.
Claims 27 and 39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/14/2025.
In light of the teachings of US PGPUB 2023/0220386 to An, discussed in the rejections of the claims under 35 U.S.C. § 102/103 below, the non-elected siRNA construct comprising the specific combination of SEQ ID NOs:3 and 4 is hereby rejoined. This reference clearly teaches a siRNA analogue duplex comprising both those sense and antisense sequences.
Claim Objections
Claim 35 recites the phrase, “the acid addition salt is selected from salts derived from inorganic acids, salts derived from inorganic acids”. The repetition of ‘inorganic’ appears to be a typographical error, and that the phrase was intended to recite inorganic and organic salts in the alternative. Appropriate correction is required. In the interests of customer service and compact prosecution, the phrase will be interpreted as reciting organic and inorganic salts.
Claim Rejections - 35 USC § 112(b)
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 26 is 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.
Claim 26 recites wherein the antisense strand comprises or consists of a number of sequences, all recited in the alternative. Claim 1, from which claim 26 depends, recites wherein the antisense strand comprises SEQ ID NO: 2. However, many of the sequences listed in claim 26 do not comprise SEQ ID NO: 2. For example, SEQ ID NO: 4 and SEQ ID NO: 2 share only 73.7% identity:
RESULT 1
US-18-001-244-4
Query Match 73.7%; Score 14; DB 1; Length 20;
Best Local Similarity 100.0%;
Matches 14; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 6 AGCGAAGUGCACAC 19
||||||||||||||
Db 5 AGCGAAGUGCACAC 18
This language renders the metes and bounds of the claim unclear because it causes the claim to encompass two mutually exclusive interpretations: the antisense strand must comprise SEQ ID NO: 2, according to claim 1, but if the antisense strand consists of SEQ ID NO: 4, then it cannot also comprise SEQ ID NO: 2.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 21-26 and 28-38 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US PGPUB 20230220386 to An (hereinafter ‘An’, earliest priority date 12/06/2019).
The applied reference has common inventors 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). This rejection under 35 U.S.C. 102(a)(2) 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) if the same invention is not being claimed; 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 in the reference 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.
Regarding claim 1, An teaches compound ‘r’ (disclosed as a ribavirin derivative) embedded in a siRNA (para [002]). By embedded, An means that, “an embedded group is connected to at least one nucleotide residue in the sequence, including the replacement of a nucleotide residue with an embedded group” (para [0066]).
An further teaches that the siRNA comprises an antisense strand comprising SEQ ID NO: 11, which comprises SEQ ID NO: 2 wherein one nucleotide residue has been replaced with ‘r’ (see e.g., claim 15 and Table 2):
RESULT 1
US-17-781-876B-11
Query Match 97.9%; Score 18.6; DB 1; Length 21;
Best Local Similarity 94.7%;
Matches 18; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UGUGAAGCGAAGUGCACAC 19
|||||:|||||||||||||
Db 1 UGUGARGCGAAGUGCACAC 19
Regarding claim 21, An teaches wherein all of the nucleotides and r in SEQ ID NO: 11 are modified (see Table 2 and the sequence listing on pp. 18-19, which show that all nucleotides of SEQ ID NO: 11 have either a methoxy or fluoro modification).
Regarding claim 22, An teaches that the modifications comprise methoxy and/or fluoro modifications and/or phosphorothioate linkages (see above).
Regarding claims 23-24, An teaches that the antisense strand, SEQ ID NO: 11, has had one nucleotide replaced with r (see above). An also teaches that the corresponding sense strand, SEQ ID NO: 9, has also had a single nucleotide replaced with r (Table 2).
Regarding claim 25, An teaches that the siRNA has a ‘UU’ overhang, as shown in Table 2:
PNG
media_image1.png
406
351
media_image1.png
Greyscale
Regarding claims 26, 31 (in part), and 38 (in part), An teaches the siRNA analogue with an antisense strand comprising SEQ ID NO: 4. Instant SEQ ID NO: 4 and prior art SEQ ID NO: 11 share the same nucleobase sequence:
RESULT 1
US-17-781-876B-11
Query Match 100.0%; Score 20.6; DB 1; Length 21;
Best Local Similarity 100.0%;
Matches 21; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UGUGARGCGAAGUGCACACUU 21
|||||||||||||||||||||
Db 1 UGUGARGCGAAGUGCACACUU 21
Regarding claim 31, An teaches the siRNA comprising sense strand SEQ ID NO: 9, which shares the same nucleobase sequence as SEQ ID NO: 3:
NASEQ2_01052026_120825
Query Match 100.0%; Score 18.6; DB 1; Length 19;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GRGUGCACUUCGCUUCACA 19
|||||||||||||||||||
Db 1 GRGUGCACUUCGCUUCACA 19
Therefore, An teaches a siRNA analogue comprising SEQ ID NOs: 3 (sense) and 4 (antisense).
Regarding claim 37, An teaches a method of treating hepatitis B in a subject:
[0044] In order to solve the above technical problems, the seventh technical solution of the present disclosure is to provide a method for treating viral hepatitis B, comprising administering the siRNA conjugate, the salt of the siRNA conjugate, the double-stranded siRNA conjugate or the salt of the double-stranded siRNA conjugate to patients or subjects in need thereof.
Regarding claim 38 (in part) , the instant specification discloses that SEQ ID NO: 2, SEQ ID NO: 4, and SEQ ID NO: 17 all share a nucleobase sequence, where SEQ ID NO: 4 is SEQ ID NO: 2 with ‘r’ at position 6 and SEQ ID NO: 17 is the further modified version thereof (Table 1, p. 34). As shown in Table 2 of An and Table 1 of the instant specification, instant SEQ ID NO: 17 and reference SEQ ID NO: 11, the antisense sequences, share the same base sequence and modification pattern, as do the sense sequences, instant SEQ ID NO: 3:
Table 2 of An:
PNG
media_image1.png
406
351
media_image1.png
Greyscale
Table 1 of the instant specification:
PNG
media_image2.png
124
567
media_image2.png
Greyscale
Regarding claims 27-30, An teaches a sense strand comprising a single r substitution at position 2 and the same modification pattern disclosed for SEQ ID NO: 16. Comparing An’s Table 2 and instant Table 1, An’s SEQ ID NO: 1 comprises the same nucleobase sequence as SEQ ID NO: 1; An’s SEQ ID NO: 9 comprises the same sense strand sequence with a single r substitution as SEQ ID NO: 3, the r-substituted version of SEQ ID NO: 1; and An’s SEQ ID NO: 9 also comprises the same modification pattern of SEQ ID NO: 16, the further modified version of SEQ ID NO: 1.
Regarding claim 31 and 38, An teaches the above sense strand paired with the previously discussed antisense strands in a single double-stranded siRNA analogue (see above).
Regarding claims 32-33, An teaches the siRNA conjugated to structure ‘L’, which is the same as structure ‘D’ in claim 33:
PNG
media_image3.png
533
680
media_image3.png
Greyscale
Regarding claims 34-36, An teaches a pharmaceutical composition comprising the siRNA and a salt, the salts including sodium, potassium, calcium, nitric acid, acetic acid, etc. (para [0081]).
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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, 21-26 and 28-38 are rejected under 35 U.S.C. 103 as being unpatentable over An (cited above). Although the invention is not identically disclosed or described as set forth in 35 U.S.C. 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 of the claimed invention to one having ordinary skill in the art to which the claimed invention pertains, the invention is not patentable.
An teaches the siRNA analogue comprising SEQ ID NO: 2 and the analogue comprising sense and antisense SEQ ID NOs: 3 and 4, respectively, as applied to claims 1, 21-26 and 28-38 above.
An does not teach the elected siRNA analogue comprising the particular combination of SEQ ID NOs: 3 (sense) and 10 (antisense).
However, An does teach the siRNA analogue with sense SEQ ID NO: 3 and with antisense SEQ ID NO: 4. SEQ ID NO: 4 differs from SEQ ID NO: 10 only in that the position of the r substitution differs by one nucleotide. SEQ ID NO: 4 has an r substitution at the 6th position. SEQ ID NO: 10 has an r substitution at 7th position. Furthermore, An’s general disclosure concerns siRNAs with r as an embedded group, and teaches embodiments wherein r is embedded in the sense and/or antisense strand (paras [0012-0014], [0018-0020], claims 1, 3-7)). An also notes that, “It will be apparent to those skilled in the art that various variations and improvements can be made to specific embodiments of the present disclosure.” (para [0090]). The repositioning of the single ‘r’ residue is one such variation. This is evidenced by the fact that An experimented with different positions for ‘r’ in the sense strand (see Table 1).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have tried substituting any one of the other finite number of positions present in the base nucleotide sequence of SEQ ID NO: 4, including the immediately adjacent positions such as position 7. Alnylam’s 21 nucleotide antisense sequence has a finite number of positions to try this substitution. Based on An’s disclosures, one having ordinary skill would have been motivated to try repositioning the r substituent to determine whether the effect observed by An could be improved if ‘r’ was placed elsewhere in the antisense strand. Given the finite number of possibilities, combined with An’s disclosures that embedding an ‘r’ residue in the sense and/or antisense strands of a siRNA enhanced its efficacy against HBV, and with An’s suggestion to try variants of the specific embodiments, one of ordinary skill could have pursed the known potential solutions with a reasonable expectation of success.
Claims 1, 21-26 and 28-38 are rejected under 35 U.S.C. 103 as being unpatentable over WIPO Publication 2018/195165 A1 to Alnylam Pharmaceuticals, Inc. (hereinafter ‘Alnylam’; of record, applicant’s submission), in view of WO 2004/084796 A2 to Pharmasset Ltd. (hereinafter ‘Pharmasset’; of record, applicant’s submission), Galban-García (Galban-García et al. Efficacy of ribavirin in patients with chronic hepatitis B. J Gastroenterol 2000; 35:347-352.), WIPO Publication No. 2021/067825 A1 to Sirnaomics,(hereinafter ‘Sirnaomics’; priority filing date 10/02/2019) and Peacock (Peacock et al., Chemical Modification of siRNA Bases to Probe and Enhance RNA Interference. J Org Chem. 2011 Aug 17;76(18):7295–7300.).
Regarding claim 1:
Alnylam teaches a RNAi agent (siRNA) with a sense strand and an antisense strand, the antisense strand comprising SEQ ID NO: 2 (SEQ ID NO: 25; p. 8 ln 19-21; claims 78-80, 83-86), shown in the below alignment:
RESULT 1
NASEQ2_01022026_155458
Query Match 100.0%; Score 19; DB 1; Length 21;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UGUGAAGCGAAGUGCACAC 19
|||||||||||||||||||
Db 1 UGUGAAGCGAAGUGCACAC 19
Alnylam further teaches that the RNAi agent is for treating hepatitis B (HBC) viral infection (p. 2 ln 20-22).
Alnylam further teaches that each of the nucleotides are independently modified or unmodified (see e.g., Table 3, which lists several exemplary embodiments, all of which have various combinations of modifications).
Alnylam does not teach compound ‘r’ (a derivative of ribavirin and nucleoside analog; or that nucleosides in the siRNA are substituted with ‘r’.
Pharmasset teaches compound r, ribavirin with a 2’-methoxy modification, used to treat Flaviviridae infections, including hepatitis C virus (HCV) (Abstract) (see p. 15, ln 10 to end of page).
Pharmasset does not teach that compound r can also be used to treat HBV.
Galban-García teaches that ribavirin is an effective treatment for HBV (p. 352):
We conclude that ribavirin therapy, at 1200 mg/day for 24 weeks, was shown to be effective in the seroconversion of HBeAg, negativization of HBV DNA, and reduction of liver inflammation and necrosis. The efficacy rate was greater than that reported in interferon studies. We conclude that ribavirin has therapeutic potential in chronic hepatitis B, even in patients who are non-responders to interferon.
Pharmasset and Galban-García do not teach substituting one or more nucleosides in Alnylam’s SEQ ID NO: 25 with compound r.
Sirnaomics teaches replacing at least one nucleotide residue in the antisense strand and/or the sense strand of a siRNA with a nucleoside analog (Abstract, Example 4 on pp. 21-22). Sirnaomics further provides a suggestion to treat viral diseases using the same approach, ie., by replacing nucleotide residues in the siRNA with antiviral nucleoside analogs (p. 15 ln. 9-12).
While Sirnaomics does not teach replacing nucleoside residues in the siRNA with compound r, Peacock teaches that a variety of nucleoside analogs have been successfully incorporated in siRNA. Chart 1 shows the structures of several exemplary analogs. Please note that the analogs have a variety of different structures. Table 1 shows the effects of modifying siRNA bases with these analogs. The majority (20 out of 27) either increased silencing activity (denoted with a ‘+’) or did not significantly affect it (+/-). In many cases, this held true even when placing the analog in the guide (antisense) strand (Id.). This would have given the ordinary artisan a reasonable expectation that at least one nucleotide residue in siRNA could be successfully replaced with a nucleoside analog.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have tried replacing at least one nucleotide residue in the antisense strand of Alnylam’s claimed siRNA for targeting HBV with compound r (a nucleoside analog, ribavirin). Alnylam shows that the siRNA comprising SEQ ID NO: 2 in its sense strand was effective at treating HBV. Respectively, Pharmasset and Galban-García teach compound r, a ribavirin derivative, and that ribavirin can be used to treat HBV, thus providing a motivation to pair Alnylam’s siRNA with ribavirin or a derivative thereof. Sirnaomics and Peacock show that nucleoside analogs can generally be incorporated into siRNA, either in the antisense or sense strand, without significantly changing its activity. Combined, the prior art would have led the ordinary artisan to try replacing at least one nucleotide in Alnylam’s siRNA sequence with ribavirin to addressed a recognize need in the art to design more effective treatments for HBV. Alnylam’s siRNA sequence was 21 nucleotides long, offering a finite number of identified solutions, and the ordinary artisan would have had a reasonable expectation of success due to Sirnaomics’ and Peacock’s success in replacing nucleotides in other siRNAs with a variety of structurally diverse nucleoside analogs.
Regarding claim 21, Alnylam teaches wherein substantially all of the nucleotides of the antisense strand are modified (claims 90-92), and Pharmasset teaches that r is modified (2’-O-methyl; see above).
Regarding claim 22, Alnylam and Pharmasset both teach methoxy modifications (see above).
Regarding claims 23 and 24, the combined references render obvious the replacement of at least one nucleotide in SEQ ID NO: 2 with r, at any position, as already described above.
Regarding claim 25, Alnylam teaches that SEQ ID NO: 2 has an overhang (UU, see above).
Regarding claim 26, because SEQ ID NO: 4 is merely SEQ ID NO: 2 with a single r substitution at position 6, SEQ ID NO: 4 is rendered obvious to try by the combination of all of the references cited in this rejection , as already described.
Regarding claims 28-30, Alnylam teaches that the corresponding sense strand to SEQ ID NO: 2 is SEQ ID NO: 1 (SEQ ID NO: 27; claims 81-86). SEQ ID NO: 27 has the same nucleobase sequence as SEQ ID NO: 1, except for an ‘r’ substitution at position 2:
RESULT 1
NASEQ2_01072026_084715
Query Match 93.5%; Score 17.4; DB 1; Length 19;
Best Local Similarity 94.7%;
Matches 18; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 GRGUGCACUUCGCUUCACA 19
| |||||||||||||||||
Db 1 GUGUGCACUUCGCUUCACA 19
However, this substitution in the sense strand is rendered obvious to try by the combination of all of the references cited in this rejection, as already described, with the same basic rationale applied to the r substitutions in the antisense strand.
Regarding claims 31 and 38, elected SEQ ID NOs: 3 and 10 have the nucleobase sequences of SEQ ID NOs: 1 and 2, but have been modified with single ‘r’ subtitutions. Therefore, Alnylam teaches the base nucleotide sequences of SEQ ID NOs: 3 and 10, as already described, while the ‘r’ substitutions are rendered obvious to try by the combination of all of the references cited in this rejection, as described above.
Regarding claims 32-34, Alnylam teaches the conjugate depicted in claim 33, linked to the 3’ end of the sense strand (claims 90-91 and 104).
Regarding claim 35-36, Alynlam teaches pharmaceutical compositions comprising the siRNA (p. 72, ln 35-37), including combinations of salts derived from inorganic acids and base addition salts (“sodium salt of lauric acid, capric acid and UDCA”; p. 84 ln 31-32).
Regarding claim 37, Alnylam teaches a method of treating hepatitis B comprising administering the siRNA (Abstract).
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/A.M.Z./Examiner, Art Unit 1636
/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636