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
The action is written in response to the applicant’s correspondence received on 4/29/2026. Claims 1, 3-5, and 19-21 are currently pending.
Priority
The instant application claims foreign priority to EP24156795.7 with an effective filing date of 2/9/2024. The retrieval of Priority Documents in the instant application has been acknowledged.
Election/Restriction
Applicant’s election without traverse of the inventions of Group I (claims 1, 3, and 19), drawn to a siRNA agent, in the reply filed on 4/29/2026 is acknowledged.
Claims 4, 5, and 20-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/29/2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Claims 1, 3, and 9 are currently under examination on the merits.
Drawings
The drawings are objected to because all figures present use the word “FIGURE”. Individual patent drawing views should be generally labeled with the abbreviation “Fig.” followed by an Arabic numeral, please see MPEP and 37 CFR § 1.84(u)(1). Furthermore, Figs. 3, 4, 8, 11, and 12 has the word “Figure” oriented to the side of the drawings. The figure number should be placed directly below or associated with the respective view, oriented in the same upright direction as the view so it is clearly readable (see MPEP and 37 CFR § 1.84(u)(1)).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings are objected to under 37 CFR 1.83(a) because they fail to show the legend and data results (Figs.11 and 13-17), as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 recites “and (ii) a antisense strand having the sequence…”. “A” should be replaced with “an”.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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.
Claims 1, 3, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Bettencourt et al. (US 20190316137 A1, published 10/17/2019) in view of Schaeper (US 20220331351 A1, published 10/20/2022).
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Regarding claim 1, Bettencourt teaches angiopoietin-like 3 (ANGPTL3) iRNA compositions and methods of use (see abstract) wherein the present invention provides double-stranded RNAs for inhibiting expression of ANGPTL3. The dsRNAs comprise a sense strand and an antisense strand (see paragraph 0006). Bettencourt teaches SEQ ID NO: 44 which has 100% identity to SEQ ID NO: 11 of the instant application and Bettencourt teaches SEQ ID NO: 106, which has 100% identity to SEQ ID NO: 5 of the instant application, as shown below. It is noted that SEQ ID NO: 11 and 5 refer to RNA strands, however, sequences pulled from the instant application are presented as RNA strands with a methylated uracil, changing U to T.
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Bettencourt teaches where the dsRNA comprise at least one modified nucleotide, wherein said modified nucleotide is selected from the group consisting of 2’-O-methyl, 5’-phosphorothioate, 2’-deoxy-2’-fluoro modified nucleotide, etc. (see paragraph 0009). Looking to the instant specification for guidance, mX represents a 2’-O-methyl ribonucleotide, fX is a 2’-fluoro-ribonucleotide, and ps represents a phosphorothioate linkage (see page 23, of the instant specification).
Bettencourt also teaches where complementary sequences, as used herein, can be formed entirely from…modified nucleotides (see paragraph 0073).
Bettencourt further teaches where the dsRNA further comprises a ligand, where the ligand is conjugated to the 3’ end of the sense strand of the dsRNA, wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branch linker (see paragraph 0014). Paragraph 0014 also provides an exemplary ligand which has 3 branches, or is triantennary.
Regarding claim 3, teaches where the present invention also includes pharmaceutical compositions and formulations which include the iRNAs of the invention. Furthermore, iRNAs can be complexed to…pharmaceutically acceptable salt thereof (see paragraph 0217).
Regarding claim 19, Bettencourt teaches where “pharmaceutically-acceptable carrier” as used herein means a pharmaceutically-acceptable material, such as a …diluent (see paragraph 0097) and where pharmaceutical preparation of a vector can include the vector in an acceptable diluent (see paragraph 0202).
Regarding claim 1, Bettencourt does not teach where the triantennary ligand moiety is on the 5’ end of the sense strand and where the ligand moiety has the specific structure presented in claim 1 of the instant application.
Regarding claim 1, Schaeper teaches nucleic acids for inhibiting expression of tmprss6 and iron chelators (see abstract). Schaeper teaches where dsRNA able to complementarily bind expressed mRNA has been shown to be able to block gene expression and where interfering RNA such as siRNAs are oligonucleotide that prevent the formation of proteins by gene-silencing (see paragraph 0002). Schaeper teaches where the nucleic acid of the invention is meant to be a nucleic acid comprising two strands comprising nucleotides, where the nucleic acid may be an siRNA molecule (see paragraph 0107). Furthermore, Schaeper teaches where nucleic acids may be conjugated to a ligand, wherein the ligand may comprise (i) one or more N-acetyl galactosamine (GalNAc) moieties and derivatives thereof, and (ii) a linker (see paragraph 0065). Schaeper teaches a structure in Fig. 8C which is 100% identical to the claimed structure of the instant application, as shown below.
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Schaeper teaches where the double stranded nucleic acid contains a ligand conjugated to the sense strand (see paragraph 0232) and example 22, wherein the GalNAc ligand was conjugated to the 5’-end of the sense strand (see paragraph 0737).
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to combine the teachings of Bettencourt and Schaeper to arrive at a siRNA comprising a sense and antisense strand with oligonucleotide modifications conjugated to a GalNAc moiety, as described in the instant claim, on the 5’ end of the sense strand or a pharmaceutically acceptable salt thereof.
One would expect a reasonable chance of success as Bettencourt teaches the specific SEQ ID NOs of the instant application formulated into siRNA targeting ANGPTL3 and is conjugated with a GalNAc ligand moiety as it directs the RNAi agent to the site of interest, such as the liver (see paragraph 0083). Though the exact modifications of the sequence is not explicitly taught, Bettencourt teaches the 2’-O-methyl, 2’-fluoro, and phosphorothioate oligonucleotide modifications (see paragraph 0009 and page 23) and where sequences may be optimized for the effectiveness of iRNA by the introduction of modified nucleotides (see paragraph 0112). Furthermore, Bettencourt teaches where the entire complementary sequence can comprise of modified nucleotides (see paragraph 0073). Therefore, Bettencourt teaches routine optimization is important for generating and testing iRNA candidates. Absent evidence to the contrary, the routine optimization and experimentation taught by Bettencourt would allow one skilled in the art to arrive at SEQ ID NO: 11 and 5 of the instant application with the exact same modifications. Furthermore, Schaeper teaches a similar invention where siRNA is used to target a gene of interest with the GalNAc ligand moiety claimed in the instant application conjugated to the 5’-end of the sense strand. Though Bettencourt does not teach where the ligand is on the 5’ end of the sense strand, Schaeper teaches where the ligand broadly can be conjugated to the sense strand, and specifically teaches the 5’ end of the sense strand in example 22 (see paragraph 0737). One skilled in the art would recognize nucleotide modification as well as ligand position is part of the routine experimentation described in Bettencourt to further enhance iRNA effectiveness.
One would be motivated to combine said arts as ANGPTL3 plasma concentrations positively correlates with plasma HDL cholesterol and HDL phospholipid levels and where a reduction in ANGPTL3 expression has a protective effect against hyperlipidemia and atherosclerosis by promoting the clearance of triglycerides (taught by Bettencourt, see paragraph 0003). As Bettencourt already teaches that experimentation such as testing different sequences, modifications, and targeting to a particular location or cell type is important to improve inhibition efficiency, one skilled in the art would understand that the specific ligand taught by Schaeper would be tested in such experiments to further improve siRNA delivery.
In view of the foregoing, claims 1, 3, and 19 are rejected under 35 U.S.C. 103 as being prima facie obvious, before the effective filing date.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID YU whose telephone number is (571)272-1118. The examiner can normally be reached Monday-Friday 7:30 am -5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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