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
Receipt of Arguments/Remarks filed on 04/27/2026 is acknowledged. Claims 3,4 and 80 were amended, claim 123 was canceled.
Applicant elected Group I (claims 3,4,9,13,15,21,28,42, 52,75,80,84,85,119,123 and 124) without traverse in the reply filed on 11/10/2025. Applicant elected 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 without traverse.
Claims 93,95,104,106,108 and 113 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
Claims 3,4,15,21,28,42,52,75,80,84,85,119 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.
Withdrawn Objections and Rejections
Applicant’s arguments and amendments, see page 15, filed 04/27/2026, with respect to the objection to claim 80, have been fully considered and are persuasive due to the amendment to claim 80 removing the extra comma. The objection to claim 80 has been withdrawn.
Applicant’s arguments and amendments, see page 15, filed 04/27/2026, with respect to the rejection(s) of claim(s) 3 and 4 under 35 U.S.C. 102(a)(1) as anticipated by Williams, as well as the 35 U.S.C. 103 rejection of claims 21,28,80,84,85,119 and 24 as being obvious over Williams, the 35 U.S.C. 103 rejection of claims 15,42,52 as obvious over Williams in view of Bettencourt, the 103 rejection of claim 75 as obvious over Williams in view of Jahns and Hassler have been fully considered and are persuasive due to the amendments to claims 3 and 4 requiring at least 18 contiguous nucleotides differing by no more than 3 nucleotides from the antisense sequence of SEQ ID NO: 1629, and the sense strand comprising at least 18 contiguous nucleotides differing by no more than three nucleotides from SEQ ID NO: 1540 such that Williams no longer anticipates claims 3 and 4 and therefore the claims that depend from claims 3 and 4 as well as their rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments requiring at least 18 contiguous nucleotides differing by no more than nucleotides from the recited sequences regarding a case of obviousness. See the new 103 rejections below.
Applicant’s arguments, see pages 23-24, filed 04/27/2026, with respect to the 35 U.S.C. 103 rejection of claim 75 as obvious over Williams in view of Manoharan has been fully considered and is persuasive, as Applicant has stated that Manoharan and the present application, no later than the effective filing date of the claimed invention, were subject to an obligation of assignment to the same entity, Alnylam Phamaceuticals, Inc, and therefore does not constitute prior art against the instant application. Therefore the 35 U.S.C. 103 rejection of claim 75 as obvious over Williams in view of Manoharan has been withdrawn.
Applicant’s arguments, see page 25, filed 04/27/2026, with respect to the Nonstatutory Double Patenting rejection of claims 3,4,15,21,28,42,52,75,80,84,85, 119,123 and 124 over claims 1-29 of U.S. Patent No. 12,516,322 in view of Almarsson, have been fully considered and are persuasive due the filing of the terminal disclaimer. The Nonstatutory Double Patenting rejection of claims 3,4,15,21,28,42,52,75,80,84,85, 119,123 and 124 has been withdrawn.
Rejections Necessitated By Amendment
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Interpretation: Any limitations that follow “optionally” are not being treated as required claim limitations.
Claims 3,4,15,21,28,52,80,84,85,119 and 124 are rejected under 35 U.S.C. 103 as being unpatentable over Williams (WO 2007107789, Published 27 September 2007), cited on an IDS dated 06/03/2025, in view of Kordasiewicz et al. (US 20160145617, Published 26 May 2016), cited on an IDS dated 11/10/2025.
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:
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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.
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Williams does not teach that the region of complementarity of the antisense strand comprises at least 18 contiguous nucleotides, differing by no more than 3 nucleotides from the antisense nucleotide sequence of SEQ ID NO: 1629.
Before the effective filing date, Kordasiewicz et al. taught antisense compounds for modulating expression of Tau mRNA and protein (paragraph 0011), including antisense oligonucleotides (paragraph 0011). Kordasiewicz et al. taught “Tau” means mammalian microtubule-associated protein tau (MAPT), including human microtubule-associated protein tau (MAPT) (paragraph 0193), and that “Antisense compound” means an oligomeric compound that is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. Examples of antisense compounds include single-stranded and double-stranded compounds, such as, antisense oligonucleotides, siRNAs, shRNAs, ssRNAs (paragraph 0104). Therefore, Kordasiewicz et al. taught the antisense compound includes double-stranded siRNA. Kordasiewicz et al. taught the antisense compound targeted to a Tau nucleic acid is 12-30 subunits in length (paragraph 0273). Table 9 of Kordasiewicz et al. taught sequences that target and inhibit Tau mRNA, including SEQ ID NO: 327 and having 64% inhibition, shown below:
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Alignment of SEQ ID NO: 327 (Db) of Kordasiewicz et al. is shown below with instant SEQ ID NO: 1629 (Qy), in which there are 20 contiguous nucleotides with no mismatches and 4 conservative substitutions. Therefore, Kordasiewicz et al. taught an antisense strand sequence meeting the limitations of instant claim 3.
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Shown below is the alignment of the antisense sequence of Williams (Qy) aligned with the antisense sequence of Kordasiewicz et al. of SEQ ID NO: 327 (Db):
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It would have been obvious to one of ordinary skill in the art before the effective filing date, to have substituted the antisense sequence of Williams with the antisense sequence of SEQ ID NO: 327 of Kordasiewicz et al. in the double-stranded short interfering nucleic acid molecule that down regulates expression of a MAPT gene of Williams to arrive at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success, as both Williams et al. and Kordasiewicz et al. pertain to inhibiting expression of Tau (MAPT) and both teach double-stranded oligonucleotide compounds and both share a common sequence with each other of 13 nucleotides. One of ordinary skill in the art would have been motivated to substitute the antisense sequence of Williams with the antisense sequence of SEQ ID NO: 327 of Kordasiewicz et al. in the double-stranded short interfering nucleic acid molecule that down regulates expression of a MAPT gene of Williams because the antisense sequence of Williams was taught to inhibiting Tau mRNA by 64% and because SEQ ID NO:327 of Kordasiewicz et al. shares 20 contiguous nucleotide with instant SEQ ID NO: 1629 (Qy).
Accordingly, the limitations of claim 3 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
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:
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Williams does not teach a sense strand sequence comprising at least 18 contiguous nucleotides differing by no more than 3 nucleotides from instant SEQ ID NO: 1540.
As discussed above, Kordasiewicz et al. taught antisense compounds including sequences that target and inhibit Tau mRNA, and that SEQ ID NO: 327 had 64% inhibition. While Kordasiewicz et al. does not specifically teach the corresponding sense sequence of the antisense sequence of SEQ ID NO: 327, Kordasiewicz et al. taught antisense compounds include single-stranded and double-stranded compounds, such as, antisense oligonucleotides, siRNAs, shRNAs, ssRNAs (paragraph 0104). Therefore, since Kordasiewicz et al. taught the antisense sequence of SEQ ID NO: 327 that has 20 contiguous nucleotides with no mismatches with instant SEQ ID NO: 1629, the corresponding sense strand sequence would necessarily meet the limitations of claim 4, part (b) for the sense strand sequence of instant SEQ ID NO: 1540.
Shown below is alignment of the sense strand sequence of instant SEQ ID NO: 1540 (Qy) with the antisense sequence of SEQ ID NO: 327 of Kordasiewicz et al. (Db):
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It would have been obvious to one of ordinary skill in the art before the effective filing date, to have substituted the sense sequence of Williams with a sense sequence corresponding to the antisense sequence of SEQ ID NO: 327 of Kordasiewicz et al. in the double-stranded short interfering nucleic acid molecule that down regulates expression of a MAPT gene of Williams to arrive at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success, as both Williams et al. and Kordasiewicz et al. pertain to inhibiting expression of Tau (MAPT) and both teach double-stranded oligonucleotide compounds and both share a common sequence with each other of 13 nucleotides. One of ordinary skill in the art would have been motivated to do so because Kordasiewicz et al. taught antisense compounds include single-stranded and double-stranded compounds, such as, antisense oligonucleotides and siRNAs and the antisense sequence of Williams was taught to inhibit Tau mRNA by 64% and SEQ ID NO:327 of Kordasiewicz et al. shares 20 contiguous nucleotide with instant SEQ ID NO: 1629 (Qy). The corresponding sense strand sequence would necessarily meet the limitations of claim 4, part (b) for the sense strand sequence of instant SEQ ID NO: 1540.
Accordingly, the limitations of claim 4 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Regarding claims 15 and 52 part (d), 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 wherein the lipophilic moiety is an aliphatic, alicyclic or polyalicyclic compound.
Kordasiewicz et al. taught antisense compounds may be covalently linked to one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotides and that typical conjugate groups include cholesterol moieties and lipid moieties (paragraph 0388).
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 and Kordasiewicz et al. to form a conjugate with one or more lipid moieties, including cholesterol moieties on the sense or antisense strand 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 Kordasiewicz et al. teaches covalently linking the antisense compounds to cholesterol and lipid moieties. One of ordinary skill in the art would have been motivated to do so because Kordasiewicz et al. taught antisense compounds may be covalently linked to one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotides and that typical conjugate groups include cholesterol moieties and lipid moieties (paragraph 0388).
Accordingly, the limitations of claims 15 and 52 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
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 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, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the dsRNA of Williams substituted with the antisense sequence of Kordasiewicz et al. with 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.
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).
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 substituted with the antisense sequence of Kordasiewicz et al. with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide a cell with the dsRNA c of Williams substituted with the antisense sequence of Kordasiewicz et al. 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.
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).
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 Williams substituted with the antisense sequence of Kordasiewicz et al. 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.
Response to Arguments
The modified 103 rejection above was necessitated by Applicant’s amendment requiring at least 18 contiguous nucleotides differing by no more than 3 nucleotides from the antisense nucleotide sequence of SEQ ID NO: 1629. The previous 35 U.S.C. 102(a)(1) rejection was withdrawn as well as the previous 35 U.S.C. 103 rejections, however new grounds of rejections are provided based on the amendments and a case of obviousness. Here, the Examiner is responding to Applicants arguments regarding the prior art used, since Williams was still used in the above 103 rejection.
Applicant argues on page 20 of response, that the Examiner acknowledges that Williams does not disclose or teach the sense and antisense strands of instant SEQ ID NOs: 1718 and 1807, and that none of the cited references discloses, suggests, or predicts a dsRNA agent with the sequences and modifications as set forth in antisense sequence SEQ ID NO: 1807 and sense sequence SEQ ID NO: 1718 i.e., modified sequences corresponding to the unmodified antisense and sense sequence of SEQ ID NOs 1629 and 1540, respectively. Applicant states the Examiner acknowledged that Williams does not teach the sense or antisense strand conjugated to one or more lipophilic moieties or where they are conjugated to, and does not teach terminal or chiral modifications at particular internucleotide linkages, and the Examiner acknowledges that Williams, NCBI reference sequence Accession No NM_001203252, Ui-Tei, Bettencourt, Maier, Ui-Tei II and Almarrsson do not teach the exact modification pattern of instantly claimed dsRNA agent of claim 123. Applicant summarizes the obviousness rationales used by the Examiner on page 21, and states that applicant submits that claim 3, from which claims 21,28,80,84,85,119 and 124 depend, is amended to focus on specific dsRNA agents not found in Williams and to require at least 18 contiguous nucleotides differing by no more than 3 nucleotides from the antisense sequence of SEQ ID NO: 1629.
The Examiner notes that as claim 123 has been canceled, none of the current claims requires a sequence with a specific modification pattern (SEQ ID NOs: 1718 and 1807 previously recited in now cancelled claim 123). While the Examiner agrees the cited references do not teach the claims as currently amended, the Examiner has provided a new case of obviousness using Williams in view of Kordasiewicz et al. which teaches the instant limitations of the at least 18 contiguous nucleotides differing by no more than 3 nucleotides from the antisense sequence of SEQ ID NO: 1629 recited in claim 3. In addition, Kordasiewicz et al. taught limitations of claims 15 and 52 as shown in the modified 103 rejection above.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Williams in view of Kordasiewicz et al. as applied to claims 3,4,15,21,28,52,80, 84,85,119 and 124 above, and further in view of Bettencourt et al. (US 20160115476, Published 28 April 2016).
The teachings of Williams and Kordasiewicz et al. as applicable to claims 3,4,15, 21,28,52,80,84,85,119 and 124 are described above. As stated 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) and Kordasiewicz et al. taught antisense compounds may be covalently linked to one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotides and that typical conjugate groups include cholesterol moieties and lipid moieties (paragraph 0388).
Williams and Kordasiewicz et al. do not teach 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 and Kordasiewicz et al. with one or more lipophilic moieties to internal positions of the dsRNA based on the teachings of Bettencourt et al. 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 Kordasiewicz et al. taught antisense compounds may be covalently linked to one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotides and that typical conjugate groups include cholesterol moieties and lipid moieties, 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 do so because Bettencourt et al. taught iRNA agents can be in the form of conjugates and may be attached at any suitable location in the iRNA molecule (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).
Accordingly, the limitations of claim 42 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 in view of Kordasiewicz et al. as applied to claims 3,4,15,21,28, 52,80,84,85,119 and 124 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 and Kordasiewicz et al. as applicable to claims 3,4,15,21,28, 52,80,84,85,119 and 124 are described above.
Williams and Kordasiewicz et al. do 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 taught 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:
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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 and Kordasiewicz et al. 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, Kordasiewicz et al., 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 do so 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.
Response to Arguments
Applicant argues on page 23 of response, that Jahns does not teach the chiral configurations at the specified strands and at the specified ends as claimed in claim 75, and that Hassler does not teach the particulars of the modification of instantly claimed 75, and even if Williams, Jahns, and Hassler were to be combined as suggested by the Examiner, one of ordinary skill in the art would not arrive at the dsRNA agents of amended claim 3, let alone narrower embodiments of claim 75.
While the 103 rejection of claim 75 as obvious over Williams in view of Jahns and Hassler has been withdrawn due to the amendments to claim 3, a new case of obviousness has been made based on the claim amendments to claim 3, using Williams in view of Kordasiewicz et al. and further in view of Jahns and Hassler. The Examiner stated that Jahns taught that the phosphorothioate group is chiral at phosphorus (Rp/Sp centers) and that a higher fraction of Rp PS linkages in an ORN surprisingly produces a more potent PS siRNA, and provided Hassler to show phosphorothioate linkages at the recited positions. As Jahns taught the phosphorothioate group is chiral at phosphorus and Hassler teach phosphorothioate groups at the recited positions, there would be a reasonable expectation of success in arriving at the instant claims.
Applicant also provides Secondary Considerations on pages 24-25 and states that the Applicant submits further objective evidence that rebuts any alleged predictability and reasonable expectation of success as suggested in the action, which evidence must be considered, and that there is data that the claimed dsRNA agents have unexpectedly improved properties not predictable from the prior art. Applicant submits that while design of dsRNA agents is based on the nucleotide sequence of the target mRNA, one cannot predict that any dsRNA that could possibly be made with have significant inhibitory activity, let alone be sufficiently efficacious so as to be relevant for clinical development. The present application provides experimental data showing high degree of inhibition for the claimed dsRNA agents both in vitro and in vivo, including Table 24 demonstrating high inhibition of MAPT mRNA in BE(2)-C cells at all doses tested, with 10nM resulting in 12% and 19% MAPT mRNA remaining for AD-1397072.1 and AD-1397072.2. AD-1397072.3 exhibited superior knockdown of MAPT mRNA in an in vivo mouse study shown in Table 29 and Example 3. Transgenic mice expressing human MAPT were administered subcutaneously a single dose of 3 mg/kg of the dsRNA agent. AD-1397072.3 was one of only 7 dsRNA in the study that exhibited greater than 70% knockdown in vivo. Applicant confirms AD-1397072.1, AD-1397072.2 and AD-1397072.3 are the same duplex prepared in separate batches as denoted by the number following the period. The unexpectedly high inhibitory activity of the presently claimed dsRNA could not have been predicted by the disclosure of Williams or with the additionally recited references.
The previous rejections have been withdrawn and new rejections provided based on the claim amendments. However, regarding Applicant’s argument about unexpected results, this is not found persuasive. Tables 24 and 29 and Example 3 do not make it clear if the duplexes of AD-1397072.1, AD-1397072.2, or AD-1397072.3 that have these results are the unmodified sequences or modified sequences. For Example, Table 16, page 197 shows AD-1397072.1 with unmodified sense and antisense sequences and Table 17, page 201 shows AD-1397072.1 with the modified sense and antisense sequences. Likewise, Table 20, page 211 shows AD-1397072.2 with the unmodified sense and antisense sequences, and Table 21 page 214 shows AD-1397072.2 with the modified sense and antisense sequences. The examples showing the effect and naming these duplexes do not describe whether the unmodified or modified sense and antisense sequences of the Duplex have these properties/effects to determine if these results are commensurate in scope with the claims. Claims 3 and 4 do not require any chemical modifications, and only require 18 contiguous nucleotides with no more than 3 nucleotides difference to the recited sequences. None of the instantly recited claims require the specific chemical modification pattern of the Duplex AD-1397072.1 shown in Table 17 or Duplex AD-1397072.2 shown in Table 21. In addition, the claims are directed to a product and do not recite administering in vitro or in vivo or any particular doses, and therefore the unexpected results are not commensurate in scope with the claims. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). Note: MPEP 716.02(d).
In addition, Applicant has not stated with the expected effect is to determine if the results are in fact unexpected. It appears the claimed invention works as intended. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02.
Conclusion
Claims 3,4,15,21,28,42,52,75,80,84,85,119 and 124 are rejected.
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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/STEPHANIE L SULLIVAN/ Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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