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 .
Response to Amendment/Status of Claims
Claims 3,4,21,93 and 104 have been amended, claims 9 and 13 have been canceled. Claims 124 and 124 are new. Claims 3,4,15,21,28,42,52,75,80,84,85,93, 95,104,106,108,113,119,123 and 124 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 3,4,9,13,15,21,28,42, 52,75,80,84,85,119,123 and 124) in the reply filed on 11/10/2025 is acknowledged.
Claims 93,95,104,106,108 and 113 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11/10/2025.
Applicant’s election without traverse of the species of the antisense strand of SEQ ID NO: 1629 which corresponds to positions 512-534 and the sense strand of SEQ ID NO: 1540 which corresponds to positions 1063-1085 in Table 16 and is the duplex AD-1397072 in the reply filed on 11/10/2025 is acknowledged.
Claims 3,4,9,13,15,21,28,42,52,75,80,84,85,119,123 and 124 are under examination.
Priority
This application is a 371 of PCT/US2021/024858 filed 3/30/2021, which claims benefit of 63/164,467 filed 03/22/2021 and claims benefit of 63/002,030 filed 03/30/2020.
Claim Objections
Claim 80 is objected to because of the following informalities: line 2 of part (a) has two adjacent comas (“antisense strand, ,”). Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 123 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 123 recites “the dsRNA agent of claim 3, wherein the sense strand comprise the sequence and all the modifications of SEQ ID NO: 1718, and the antisense strand comprises the sequence and all the modifications of SEQ ID NO: 1807”. Page 201 of the instant specification shows the sequence and chemical modification pattern of the recited sequences. The Tables on pages 157-159 describe the abbreviations. The instant specification does not describe or define what “(G2p)” means in the antisense sequence below (SEQ ID NO: 1807).
PNG
media_image1.png
37
695
media_image1.png
Greyscale
Therefore, claim 123 is indefinite as neither the claim nor the instant specification provides guidance as to what “G2p” is and therefore the scope of the claim cannot be determined. For purposes of compact prosecution, the examiner is interpreting (G2p) to mean “guanosine monophosphate”.
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.
Claims 3 and 4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Williams (WO 2007107789, Published 27 September 2007), cited on an IDS dated 06/03/2025.
Regarding claim 3, Williams teach double-stranded RNA compounds capable of mediating RNA interference (page 5, lines 17-18, page 10, line 1), including double-stranded short interfering nucleic acid molecules that down regulate expression of a MAPT gene, and teach the double-stranded nucleic acid molecule has an antisense strand and a sense strand (page 12, lines 4-6, page 15, lines 4,5,10-14). Williams teach the following double-stranded RNA in Figure 8:
PNG
media_image2.png
75
555
media_image2.png
Greyscale
The antisense strand (bottom strand) when read 5’-3’ is shown aligned below (Db) with instant SEQ ID NO: 1629 (Qy), and has 15 contiguous nucleotides, and differs by 1 nucleotide from the antisense sequence of instant SEQ ID NO: 1629.
PNG
media_image3.png
128
475
media_image3.png
Greyscale
Regarding claim 4, part (b), the sense strand (top strand) of Williams (Db) comprises at least 15 contiguous nucleotide differing by no more than 1 nucleotide from instant SEQ ID NO: 1540 (Qy), and alignment thereof is shown below:
PNG
media_image4.png
116
472
media_image4.png
Greyscale
Claim Rejections - 35 USC § 102/103
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.
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 21,28,80,84,85,119 and 124 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over by Williams (WO 2007107789, Published 27 September 2007) as applied to claims 3 and 4 above.
Claim Interpretation: Any limitations that follow “optionally” are not being treated as required claim limitations.
The teachings of Williams as applicable to claim 3 have been described above in the 35 U.S.C. 102(a)(1) rejection.
Regarding claim 21, Williams teach the dsRNA agent comprises at least one modified nucleotide, and chemical modifications are well known in the art capable of increasing stability, availability, and/or cell uptake of the siNA and that a skilled person will be aware of other types of chemical modifications which may be incorporated into RNA molecules (Page 11, lines 5-9).
Regarding claim 28 part (a), Williams teach modifications can be used to provide improved resistance to degradation or improved uptake and such modifications include phosphorothioate internucleotide linkages (Page 11, lines 11-12). Williams teach either or both of the sense or antisense strand comprises one or more, for example 1,2,3,4,5,6,7,8,9,10 or more phosphorothioate internucleotide linkages (page 12, lines 25-28).
Regarding claim 80, part (a), Williams teach the 5’ end of the fragment comprising said antisense region can optionally include a phosphate group, and therefor teaches the dsRNA comprises a phosphate at the 5’ end of the antisense strand (page 12, lines 22-24).
Regarding claim 84, Williams teach cells comprising the siRNA duplexes, in which siRNAs are introduced into cells by any transfection technique known in the art (page 19, lines 17,18,25,26). Williams teach checking the specificity of the siRNA interference using cell cultures expressing target genes and that the cells are incubated with the corresponding siRNA duplexes followed by analysis of gene expression levels, and that for linking siRNA knockdown to specific phenotypes in cultured cells, it is necessary to demonstrate the decrease of the targeted protein or reduction of the targeted mRNA (page 19, lines 15-20).
Regarding claims 85 and 119, Williams teach the siNAs of the invention may be formulated into pharmaceutical compositions by any of the techniques known in the art (page 21, lines 3-4), and may be administered as known in the art (page 21, lines 14-15).
Regarding claim 124, Williams teach the siRNAs of the invention may contain one or more modified nucleotides, and chemical modifications well known in the art are capable of increasing stability, availability and/or cell uptake of the siRNA, and teach modifications include 2’-O-methyl ribonucleotides, 2’-deoxy-fluoro-ribonucleotides, 2’-deoxy ribonucleotides (page 11, lines 5-7,12-15), one or more locked nucleic acid (LNA) nucleotides (page 13, lines 23-24).
Therefore, claims 21,28,80,84,85,119 and 124 are anticipated by Williams.
In the alternative, Williams does not explicitly teach that the double-stranded RNA comprising SEQ ID NO: 215 in Figure 8 has the limitations as recited in claims 21,28,80,84,85,119 and 124.
However, Williams teaches “the siNAs of the invention” can comprise the limitations as described above, and teaches the above benefits of the limitations.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, that the dsRNA of Williams shown in Figure 8, comprising SEQ ID NO: 215 would comprises at least one modified nucleotide, including 2’-O-methyl ribonucleotides, 2’-deoxy-fluoro-ribonucleotides or 2’-deoxy ribonucleotides, or one or more locked nucleic acid (LNA) nucleotides, or at least one phosphorothioate internucleotide linkage, or a 5’ phosphate with a reasonable expectation of success. There would be a reasonable expectation of success, because this would amount to applying a known technique of chemical modification to a known product (siRNA) ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to provide the dsRNA of Williams with such modifications, because Williams teach chemical modifications are well known in the art capable of increasing stability, availability, and/or cell uptake of the siNA, including 2’-O-methyl ribonucleotides, 2’-deoxy-fluoro-ribonucleotides, 2’-deoxy ribonucleotides (page 11, lines 5-7,12-15), one or more locked nucleic acid (LNA) nucleotides (page 13, lines 23-24), and that modifications can be used to provide improved resistance to degradation or improved uptake and such modifications include phosphorothioate internucleotide linkages (Page 11, lines 11-12) and that either or both of the sense or antisense strand comprises one or more, for example 1,2,3,4,5,6,7,8,9,10 or more phosphorothioate internucleotide linkages.
Accordingly, the limitations of claims 21,28,80 and 124 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, for a cell to contain the dsRNA of Williams shown in Figure 8, comprising SEQ ID NO: 215 with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide a cell with the dsRNA comprising SEQ ID NO: 215 in order to determine the specificity of the dsRNA on the expression of the MAPT target gene and because Williams teach cells comprising the siRNA duplexes (page 19, lines 17,18,25,26) and teach checking the specificity of the siRNA interference using cell cultures expressing target genes and that the cells are incubated with the corresponding siRNA duplexes followed by analysis of gene expression levels, and that for linking siRNA knockdown to specific phenotypes in cultured cells, it is necessary to demonstrate the decrease of the targeted protein or reduction of the targeted mRNA (page 19, lines 15-20).
Accordingly, the limitations of claim 84 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to provide a pharmaceutical composition comprising the dsRNA of Figure 8, comprising SEQ ID NO: 215 with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so in order to provide a composition to be administered to a subject for treatment, and because Williams teach the siNAs of the invention may be formulated into pharmaceutical compositions by any of the techniques known in the art (page 21, lines 3-4), and may be administered as known in the art (page 21, lines 14-15).
Accordingly, the limitations of claim 85 and 119 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 15,42 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Williams as applied to claims 3 and 4, above, and further in view of Bettencourt et al. (US 20160115476, Published 28 April 2016).
The teachings of Williams as applicable to claims 3 and 4 are described above.
Williams teaches an siRNA molecule of the invention may be complexed with a cationic lipid or helper lipid molecule (page 21, lines 29-30).
Williams does not teach wherein the sense strand, the antisense strand or both the sense and the antisense strand is conjugated to one or more lipophilic moieties, or that the lipophilic moieties are conjugated to one or more internal positions on at least one strand in the double stranded region of the dsRNA.
Before the effective filing date, Bettencourt et al. taught iRNA agents and that they can be in the form of conjugates and may be attached at any suitable location in the iRNA molecule, e.g. at the 3’ end or the 5’ end of the sense or antisense strand (paragraph 0348). Bettencourt et al. taught that the iRNA agent is chemically linked to one or more conjugates, which may confer functionality by enhancing the activity, cellular distribution or cellular uptake of the iRNA, and that such moieties include lipid moieties such as a cholesterol moiety, cholic acid, a thiocholesterol, a phospholipid (paragraph 0349). Bettencourt et al. taught lipid conjugates can increase resistance to degradation of the conjugate, increase targeting or transport into the target cell or cell membrane and/or be used to adjust binding to a serum protein (paragraph 0364) or can be used to modulate the binding of the conjugate to a target tissue (paragraph 0365). Bettencourt et al. teach that 3’ ligand conjugated strands can be synthesized using a solid support containing the corresponding ligand, and for example the introduction of cholesterol unit in the sequence is performed from a hydroxyprolinol-cholesterol phosphoramidite (paragraph 0668). Bettencourt et al. taught conjugation of ligands to the 5’ end and/or internal positions is achieved by using appropriately protected ligand-phosphoramidite building block (paragraph 0688).
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the dsRNA of Williams to form a conjugate with one or more lipophilic moieties at the 3’ end or the 5’ end of the sense or antisense strand, or conjugation of the lipophilic moieties to internal positions of the dsRNA with a reasonable expectation of success. There would be a reasonable expectation of success, because Williams suggests an siRNA molecule of the invention may be complexed with a cationic lipid or helper lipid molecule, and both Williams and Bettencourt pertain to dsRNA for inhibiting gene expression of a target gene and therefore are in the same field of endeavor. One of ordinary skill in the art would have been motivated to modify the sense strand or antisense strand of the dsRNA of Williams by conjugating to one or more lipophilic moieties, or for one or more lipophilic moieties to be conjugated to one or more internal positions on at least one strand in the ds region of the dsRNA agent, because Bettencourt et al. teach iRNA agents can be in the form of conjugates and may be attached at any suitable location in the iRNA molecule, e.g. at the 3’ end or the 5’ end of the sense or antisense strand (paragraph 0348) and that conjugation of ligands to the 5’ end and/or internal positions is achieved by using appropriately protected ligand-phosphoramidite building block (paragraph 0688) and teach the benefits of such a lipophilic conjugation which include enhancing the activity, cellular distribution or cellular uptake of the iRNA and that lipid conjugates can increase resistance to degradation of the conjugate, increase targeting or transport into the target cell or cell membrane and/or be used to adjust binding to a serum protein (paragraph 0364) or can be used to modulate the binding of the conjugate to a target tissue (paragraph 0365). One of ordinary skill in the art would have been motivated to provide a lipophilic moiety that is an aliphatic, alicyclic or polyalicyclic compound because Bettencourt et al. teach lipid moieties may confer functionality by enhancing the activity, cellular distribution or cellular uptake of the iRNA, and that such moieties include lipid moieties such as a cholesterol moiety, cholic acid, a thiocholesterol, a phospholipid (paragraph 0349).
Accordingly, the limitations of claims 15,42 and 52 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 75 is rejected under 35 U.S.C. 103 as being unpatentable over Williams as applied to claims 3 and 4 above, and further in view of Jahns et al. (Nature Communications, 6:6317,Published 6 March 2015) and Hassler et al. (Nucleic Acids Research, 2018, Vol. 46, No. 5, pages 2185-2196).
Claim Interpretation: As claim 75 recites the dsRNA agent of claim 3, further comprising, the limitations of (a),(b),(c),(d) or (e) which each recite terminal, chiral modifications at specific positions of the internucleotide linkages at each of the 5’ and 3’ ends of each of the antisense and sense strands, merely require that chiral modification at the recited internucleotide linkage position but may have more of the chiral modifications at additional internucleotide linkages, as the language “comprising” is non-limiting.
The teachings of Williams as applicable to claims 3 and 4 are described above.
Williams does not teach specific terminal, chiral modifications occurring at the specified internucleotide linkages as in (a),(b),(c),(d), or (e) recited in instant claim 75.
Before the effective filing date, Jahns et al. taught that an established means of improving pharmacokinetic properties of oligoribonucleotides is to exchange their phosphodiester linkages for phosphorothioates, and that the phosphorothioate group is chiral at phosphorus (Rp/Sp centers) (Abstract). Jahns et al. teach a study of whether the control of stereochemistry of PS ORN strands in a siRNA can be exploited to improve their pharmacological properties, and that the choice of the activating agent during the synthesis of PS RNA shifts the Rp/Sp ratio in the PS linkages and when assembled into duplexes (Page 2, right column). Jahns et al. taught that distinct tetrazole activators produce a stereogenic bias during the solid-phase synthesis of PS ORNs, and this bias substantially influences the biophysical and biological properties of the duplex. Specifically, compared with tetrazole, ribonucleoside coupling catalysed by BTT yields a higher fraction of Rp PS linkages in an ORN, as evidenced by elevated Tms which surprisingly this produces a more potent PS siRNA (Discussion, page 7).
Hassler et al. taught a variety of chemical modification patterns have been explored to improve siRNA stability, and teach systematically comparing the distribution, tissue accumulation, and efficacy of partially and fully modified siRNAs (Intro, page 2185). Hassler et al. taught a fully-modified siRNA, with phosphorothioate internucleotide linkages at the first and second internucleotide linkage at the 5’ end of the antisense strand, and the 7 internucleotide linkages at the 3’ end of the antisense strand, as well as phosphorothioate internucleotide linkages at the first and second internucleotide linkages of the 5’ end of the sense strand (Figure 1 A), with the red showing the phosphorothioate internucleotide linkages below:
PNG
media_image5.png
45
376
media_image5.png
Greyscale
Hassler et al. taught the single-strand region of the guide strand contains phosphorothioate linkages, providing additional stabilization and enhancing
cellular internalization (page 2189, left column), and that two phosphorothioate linkages were added to both 5’ and 3’ ends of the passenger and guide strands to provide additional resistance to exonucleases (page 2189, left column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the dsRNA of Williams based on the teachings of Jahns et al. and Hassler et al. to comprise the terminal, chiral modifications at the recited internucleotide linkages at the recited ends of the antisense and sense strand and in the recited Rp or Sp configurations with a reasonable expectation of success. There would be a reasonable expectation of success, because both Williams, Jahns et al. and Hassler et al. pertain to dsRNA agents that are for inhibiting target gene expression, and Williams suggests modifications can be used to provide improved resistance to degradation or improved uptake and such modifications include phosphorothioate internucleotide linkages, and because this would amount to applying a known technique of chirally-modified phosphorothiaote internucleotide linkages to a known product (siRNA) ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to modify the dsRNA of Williams based on the teachings of Jahns et al. and Hassler et al. because Jahns et al. taught that the phosphorothioate group is chiral at phosphorus (Rp/Sp centers) and taught determining whether the control of stereochemistry of PS ORN strands in a siRNA can be exploited to improve their pharmacological properties as well as whether the choice of the activating agent during the synthesis of PS RNA shifts the Rp/Sp ratio in the PS linkages, and because Hassler et al. taught systematically comparing the distribution, tissue accumulation, and efficacy of partially and fully modified siRNAs with phosphorothiaote linkages at the first and second internucleotide linkage at the 5’ end of the antisense strand, and the 7 internucleotide linkages at the 3’ end of the antisense strand, as well as phosphorothioate internucleotide linkages at the first and second internucleotide linkages of the 5’ end of the sense strand (Figure 1 A). Therefore, the ordinary artisan would have been motivated by Jahns et al. and Hassler et al. to arrive at a dsRNA with the terminal, chiral modifications as recited in instant claim 75 based on the teachings Jahns et al. and Hassler et al. in order to test the dsRNAs for their pharmacological properties to arrive at a dsRNA with improved resistance to degradation or improved uptake.
Accordingly, the limitations of claim 75 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 75 is rejected under 35 U.S.C. 103 as being unpatentable over Williams as applied to claims 3 and 4 above, and further in view of Manoharan et al. (WO 2019126651, Published 27 June 2019, Filed 21 Dec 2018).
The applied reference has a common applicant 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).
The teachings of Williams as applicable to claims 3 and 4 are described above.
Williams does not teach the specific terminal, chiral modifications occurring at the specified internucleotide linkages as in (a),(b),(c),(d), or (e) recited in instant claim 75.
Before the effective filing date, Manoharan et al. taught chirally-modified dsRNA having site specific (e.g. terminal) chirally-modified internucleotide linkages that are advantageous for inhibition of target gene expression (Field of Invention, page 1). Manoharan et al. taught the discovery that by selecting the chirality of phosphorus atom of phosphorothioate linkages at the termini of a modified dsRNA, the number of internucleotide phosphorothioate backbone modifications within each strand of dsRNA agent may be reduced while simultaneously maintaining or improving the in vivo pharmacological properties, such as the stability of dsRNA agents against nucleases and gene silencing potency (RISC loading) (Summary, page 2). Manoharan et al. taught chiral modification to the internucleotide linkage may occur at the 5’ end, the 3’ end, or both the 5’ end and 3’ end, and may occur on the sense strand, antisense strand, or both (page 3, bottom paragraph). Manoharan et al. taught the chirally-modifed dsRNA agent comprises a terminal, chiral modification occurring at the first internucleotide linkage from the 3’ end of the antisense strand, having the linkage phosphorous atom in Sp configuration, a terminal, chiral modification occurring at the first internucleotide linkage at the 5’ end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modification occurring at the first internucleotide linkage at the 5’ end of the sense strand, having the linkage phosphorus atoms in either Rp or Sp configuration (pages 12-13). Manoharan et al. also taught the same limitations as recited in instant claim 75 part (b),(c),(d) and (e) on page 13 of Manoharan et al.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the dsRNA of Williams based on the teachings of Manoharan et al. to comprise the terminal, chiral modifications at the recited internucleotide linkages at the recited ends of the antisense and sense strand and in the recited Rp or Sp configurations with a reasonable expectation of success. There would be a reasonable expectation of success, because both Williams and Manoharan et al. pertain to dsRNA agents that are for inhibiting target gene expression and would amount to applying a known technique of chirally- modified internucleotide linkages to a known product (siRNA) ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to modify the dsRNA of Williams based on the teachings of Manoharan et al. regarding the specific recited positions on the 5’ end or 3’ end of the antisense and sense strands and in the recited Rp or Sp configuration as recited in claim 75, because Manoharan et al. teach the exact same limitations at the same positions, and that by selecting the chirality of phosphorus atom of phosphorothioate linkages at the termini of a modified dsRNA, the number of internucleotide phosphorothioate backbone modifications within each strand of dsRNA agent may be reduced while simultaneously maintaining or improving the in vivo pharmacological properties, such as the stability of dsRNA agents against nucleases and gene silencing potency (RISC loading) (Summary, page 2).
Accordingly, the limitations of claim 75 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claim 123 is rejected under 35 U.S.C. 103 as being unpatentable over Williams as applied to claims 3 and 4 above, and further in view of NCBI Reference Sequence Accession number NM_001203252 (Homo sapiens MAPT, transcript variant 8 mRNA, 05 Feb 2011), Ui-Tei (Front Genet. 11 June 2013; 4;107), Bettencourt et al. (US 20160115476, Published 28 April 2016), Maier et al. (US 20170275626, Published 28 Sept 2017), Ui-Tei et al. (Nucleic Acids Res. 11 Feb 2008; 36(7):2136-2151), and Almarrson et al. (WO 2015038892, Published 19 March 2015).
Claim Interpretation: Page 201 of the instant specification shows the sequence and chemical modification pattern of the recited sequences. The Tables on pages 157-159 describe the abbreviations. It is noted that the nucleotide sequence of the sense strand of SEQ ID NO: 1718 is the same as the nucleotide sequence as instant SEQ ID NO: 1540, and the antisense nucleotide sequence of SEQ ID NO: 1807 is the same as the antisense nucleotide sequence of SEQ ID NO: 1629, with the difference being the modifications.
PNG
media_image1.png
37
695
media_image1.png
Greyscale
The instant specification does not describe or define what “(G2p)” means in the above antisense sequence (SEQ ID NO: 1807). For purposes of compact prosecution, the examiner is interpreting (G2p) to mean “guanosine monophosphate”.
The above chemical modification motif can be summarized as below:
Sense strand: positions 1-5,7,8,12-21 2’-OMe; positions 9-11 2’-F, position 6 Chd (2’-O-hexadecyl-cytidine-3’-phosphate).
Antisense strand: positions 1,3,4,6,8-13,15,17-23 2’-OMe; positions 2,14,16 2’-F; position 5 dA; position. 7 G2p (guanosine monophosphate).
The teachings of Williams as applicable to claims 3 and 4 are described above.
Williams does not teach the sense strand comprises the sequence and all the modifications of SEQ ID NO: 1718, and the antisense strand comprises the sequence and all the modification of SEQ ID NO: 1807.
A blast search of the sense sequence of SEQ ID NO: 1540 shows that nucleotides 1-20 of instant SEQ ID NO: 1540 aligns with nucleotides 514-533 of Homo sapiens microtubule associated protein tau (MAPT), transcript variant 8, mRNA of NM_001203252.
PNG
media_image6.png
205
724
media_image6.png
Greyscale
Likewise, a blast search of the antisense sequence of instant SEQ ID NO: 1629 shows nucleotides 2-23 of instant SEQ ID NO: 1629 aligns with nucleotides 533-512 of Homo sapiens microtubule associated protein tau (MAPT), transcript variant 8, mRNA of NM_001203252.
PNG
media_image7.png
232
727
media_image7.png
Greyscale
The mRNA sequence of the Homo sapiens microtubule-associated protein tau (MAPT), transcript variant 8 of NCBI Reference sequence NM_001203252 was publicly available (05 Feb 2011) before the effective filing date and the mRNA sequence is shown below.
PNG
media_image8.png
895
506
media_image8.png
Greyscale
PNG
media_image9.png
726
515
media_image9.png
Greyscale
Before the effective filing date, Ui-Tei taught examining the relationship between siRNA sequence and its ability to give rise to RNAi in mammalian cells, and empirically defined the practical characteristics of highly functional siRNAs as follows: (1) A or U residues at nucleotide position 1; (2) four to seven A/Us at nucleotide positions 1–7; and (3) G/C at position 19, with the nucleotide position measured from the 5’ -end of the guide strand (page 1, middle column; Conclusion, page 3).
Bettencourt et al. taught iRNA agents and that they can be in the form of conjugates, e.g. a carbohydrate conjugate which may serve as a targeting moiety and/or ligand, attached to the 3’ end of the sense strand of the dsRNA, and the conjugate make be attached by a linker (paragraph 0027). Bettencourt et al. taught the conjugate comprises one or more acetylgalactosamine (GalNAc) derivatives, which targets the RNAi agents to a particular cell (paragraph 0028), and teaches the RNAi agent is conjugated to L96 shown below:
PNG
media_image10.png
139
438
media_image10.png
Greyscale
This is the exact same structure for instant L96 shown on page 158 of the instant specification.
Bettencourt et al. taught Duplexes with L96 attached at the 3’ end of the sense strand (Table 7 page 79):
PNG
media_image11.png
242
826
media_image11.png
Greyscale
Bettencourt taught iRNA agents chemically linked to one or more ligands, moieties or conjugates which may confer functionality, by enhancing the activity, cellular distribution or cellular uptake of the RNAi, and such moieties include a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (paragraph 0349) and taught that oligonucleotides can contain the nucleotide (Chd) or “2’-O-hexadecyl-cytidine-3’-phosphate” (Table 1, page 67).
Maier et al. taught dsRNA agents comprising a sense strand and antisense strand with various motifs, the sense strand having a length of 21 nucleotides with a GalNAc ligand attached through a trivalent branched linker to the 3’ end of the sense strand, and taught 2’-OMe modifications at positions 1-6,8,10,12-21, 2’F modifications at position 7 and 9, and phosphorothioate internucleotide linkages between nt positions 1 and 2 and 2 and 3, and taught the antisense strand having a length of 23 nucleotides, 2’-OME modifications at positions 1,3,7,9,11,13,15,17,19-23 and 2’-F modifications at positions 2,4-6,8,10,12,14,16 and 18; phosphorothioate internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraphs 0150-0158). Maier et al. also taught dsRNA agents comprising a sense strand comprising 2’-F modifications at positions 10 and 11 (paragraph 0171) and a sense strand comprising 2’-F modifications at positions 9-11 and 2’-OMe modifications at positions 1-6,8 and 12-21 (paragraph 0198) and phosphorothioate internucleotide linkages between nt positions 1 and 2 and 2 and 3, and an antisense strand comprising 2’-F modifications at positions 2,6,9,14 and 16, and 2’-OMe modifications at positions 1,3-5,7,8,10-13,15 and 17-23 (paragraph 0202) and phosphorothioate internucleotide linkages between positions 1 and 2 and 2 and 3, and between positions 21 and 22 and 22 and 23 counting from the 5’ end (paragraph 0203).
Maier et al. taught dsRNA agents with a 5’-VP on the antisense strand (paragraphs 0052,0056), and the presence of a 5’-VP generally improves the in vivo activity (Paragraph 0247, Fig. 17).
Maier et al. taught the inventors found that having 2’-OMe modifications at nucleotide positions 2 and 14 from the 5’ end of the antisense strand dampened gene silencing activity (paragraph 0261).
Ui-Tei et al. also taught siRNA based RNA interference and examined effects of systematic deoxy-ribonucleotide substitutions of highly functional siRNAs on gene silencing, and found that the 5’ end and the 5’ proximal “seed” arm of the guide strand were found capable of being replaced with cognate deoxyribonucleotides with little or no loss of gene-silencing activity, and without substantial off-target effect (page 2137, left column). While DNA substitution only of the passenger strand (i.e. sense strand) had a minimal silencing effect (Figure 1F,1G, page 2139). Ui-Tei et al. taught that DNA-RNA hybrid is less stable thermodynamically than RNA duplex and demonstrate that the calculated Tm in the “seed” region of DNA modified siRNA was considerably lower than that of cognate unmodified siRNA (page 2145), and taught a reduction in seed-sequence based off-target effect in gene silencing due to transfection with functional DNA-modified siRNAs and as well as decreased off-target effect by genome-wide analysis (pages 2145-2146, Fig. 6). Therefore, replacing RNA with DNA within the seed region of the antisense strand can reduce off-target silencing effects.
Almarrson et al. taught nucleic acid based compounds or polynucleotides, including non-coding) that have chemical and/or structural features that avoid problems in the art, features that are useful for optimizing nucleic acid-based therapeutics while retaining structural and functional integrity, overcoming the threshold of expression, avoiding deleterious bio-responses (paragraph 0007). Almarrson et al. taught non-coding polynucleotides of the invention include those that reduce protein expression, including siRNA and RNAi constructs (paragraph 000180). Almarrson et al. taught modifications that are useful in the present invention include those in Table 4 (page 101) and which includes 2’-O-ribosylguanosine (phosphate) (Gr(p)) on page 108.
Therefore, it was known in the prior art to provide a dsRNA wherein the sense strand has heavy 2'-O-methyl modifications in the 5' and 3' regions and 2’-F in positions 9-11, and to conjugate the GalNAc structure of formula L96 to the 3’ end of the sense strand, and incorporate 2'-O-hexadecyl nucleoside (e.g., cytosine). Similarly, it was known in the art to formulate the antisense strand having a 5' VP and a mixture of 2'-O-methyl and 2'-F with at least 7 consecutive 2'-O-methyl in the 3' region of the antisense, a deoxy nucleotide in the seed region, as well as 2’-O-ribosylguanosine (phosphate) modifications in siRNA, as well as the phosphorothioate internucleotide linkages at the recited positions in the sense and antisense sequences.
Although the cited art does not specifically teach the exact modification pattern, it would have been obvious for one ordinarily skilled in the art to perform routine optimization of the pattern to achieve improved results. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05 provides In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."
In the instant case, the focus is in the change of form, or substitution of equivalents over the prior art. Substitution of equivalents in terms of identifying optimal locations, both in terms of potency and reduced toxic effects, for 2’F and 2’-OMe modifications in dsRNA, since varying 2’-F and 2’-OMe positions in a double stranded nucleic acid for optimal or better results in known in the prior art.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to have modified the dsRNA of Williams in view of NCBI Reference Sequence Accession number NM_001203252, Ui-Tei , Bettencourt et al., Maier et al., Ui-Tei et al, and Almarrson et al. and arrived at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the iRNA agent targeting MAPT of Williams to arrive at the instant sequences of SEQ ID NO: 1718 and 1807 because the mRNA sequence of MAPT was publicly available, and instant nucleotides 1-20 aligns with nucleotides 514-533 of Homo sapiens microtubule associated protein tau (MAPT), transcript variant 8, mRNA of NM_001203252, and instant nucleotides 2-23 aligns with nucleotides 533-512 of Homo sapiens microtubule associated protein tau (MAPT), transcript variant 8, mRNA of NM_001203252. One of ordinary skill in the art could have arrived at 100% identity to the instant claimed sequences based on Ui-Tei teaching that highly functional siRNAs have A or U residues at nucleotide position 1. One of ordinary skill in the art would have been motivated to arrive at the specific modification pattern based on the combined teachings of Bettencourt et al. that cetylgalactosamine (GalNAc) derivatives targets the RNAi agents to a particular cell (paragraph 0028) and teaches the RNAi agent is conjugated to L96 at the 3’ end of the sense strand, and that oligonucleotides can contain the nucleotide (Chd) or “2’-O-hexadecyl-cytidine-3’-phosphate” (Table 1, page 67), and Maier et al. teaching the phosphorothioate, 2’-O-Me, 2’-F at specific positions, and a 5’-VP on the antisense strand which improves the in vivo activity and
that having 2’-OMe modifications at nucleotide positions 2 and 14 from the 5’ end of the antisense strand dampened gene silencing activity (paragraph 0261). Ui-Tei et al. teaching that replacing RNA with DNA within the seed region of the antisense strand can reduce off-target silencing effects, and Almarrson et al. teaching optimizing nucleic acid-based therapeutics while retaining structural and functional integrity, overcoming the threshold of expression, avoiding deleterious bio-responses (paragraph 0007), including siRNA and RNAi constructs (paragraph 000180), and modifications include 2’-O-ribosylguanosine (phosphate).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3,4,9,13,15,21,28,42,52,75,80,84,85,119,123 and 124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 12,516,322 (‘322) (Issued 6 Jan 2026) in view of Almarrson et al. (WO 2015038892, Published 19 March 2015).
The instant specification does not describe or define what “(G2p)” means in the above antisense sequence (SEQ ID NO: 1807). For purposes of compact prosecution, the examiner is interpreting (G2p) to mean “guanosine monophosphate”.
Claims 1-3 and 26-29 of ‘322 recite a dsRNA agent comprising a sense strand and antisense strand, wherein the antisense region comprises the nucleotide sequence of SEQ ID NO: 1011, and the sense strand comprises the nucleotide sequence of SEQ ID NO: 1007.
PNG
media_image12.png
46
390
media_image12.png
Greyscale
PNG
media_image13.png
41
385
media_image13.png
Greyscale
Claims 4-25 of ‘322 recite a dsRNA agent for inhibiting expression of MAPT wherein the antisense strand comprises a region of complementarity to an mRNA encoding Tau, and wherein the region of complementarity comprises at least nucleotides 2-18 of the antisense sequence of SEQ ID NO: 1003, or wherein the antisense strand comprises SEQ ID NO: 1003. Claim 5 recites the sense strand comprises SEQ ID NO: 999, and claims 10-25 recite specific nucleotide modifications, and some claims recite specific positions of the modifications.
PNG
media_image14.png
37
325
media_image14.png
Greyscale
The sequences (SEQ ID NO: 999 and 1003) of the sense and antisense strands of ‘322 are almost the same as instant SEQ ID NOs: 1540 and 1629, and therefore are not patentably distinct. In addition, the modification patterns of SEQ ID NOs: 1007 and 1011 of ‘322 above are almost the same as the modification pattern recited in instant claim 123, see below:
PNG
media_image1.png
37
695
media_image1.png
Greyscale
‘322 does not recite that the antisense strand comprises (G2p).
Almarrson et al. taught nucleic acid based compounds or polynucleotides, including non-coding) that have chemical and/or structural features that avoid problems in the art, features that are useful for optimizing nucleic acid-based therapeutics while retaining structural and functional integrity, overcoming the threshold of expression, avoiding deleterious bio-responses (paragraph 0007). Almarrson et al. taught non-coding polynucleotides of the invention include those that reduce protein expression, including siRNA and RNAi constructs (paragraph 000180). Almarrson et al. taught modifications that are useful in the present invention include those in Table 4 (page 101) and which includes 2’-O-ribosylguanosine (phosphate) (Gr(p)) on page 108.
Therefore, it would have been obvious to have modified the dsRNA agent of ‘322 regarding the antisense sequence in view of the modification taught in Almarrson et al. to arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the dsRNA agent of ‘322 targeting MAPT with a 2’-O-ribosylguanosine (phosphate) modification in the antisense strand because Almarrson et al. taught siRNA molecules and chemical modifications including 2’-O-ribosylguanosine (phosphate) useful for optimizing nucleic acid-based therapeutics while retaining structural and functional integrity, overcoming the threshold of expression, avoiding deleterious bio-responses.
Conclusion
Claims 3,4,9,13,15,21,28,42,52,75,80,84,85,119,123 and 124 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 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, Ram R 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.
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.
/STEPHANIE L SULLIVAN/ Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636