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 .
Election/Restrictions
Applicant’s election without traverse of claims 1-3, 45, 68, 78, 79, 83, 85, 87-89, 134, 157, 158, and 166 (Group I) in the reply filed on 12/17/2025 is acknowledged.
Claims 71, 72, 169-171, and 176 (Group II) and claim 134 were cancelled in the reply filed on 12/17/2025. New claims 177-184 were added in the reply filed on 12/17/2025 and encompass the elected invention.
The Examiner acknowledges the election of species in the reply filed on 12/17/2025. Regarding species C and D of the reply filed 12/17/2025, the election of species is hereby withdrawn in view of US 2020/0362341 A1 (hereinafter Khvorova; as cited in the IDS filed 12/17/2025), which discloses identical dsRNA modification patterns to the instant application, as set forth below (see section Claim Rejections - 35 USC § 103). Furthermore, regarding species F-I of the reply filed 12/17/2025, the election of species is hereby withdrawn in view of Khvorova. the Examiner notes that the elected L2 linker was cancelled in the amended claim set filed 12/17/2025 (see amended instant claim 158). Additionally, Applicant did not elect a specific structure selected from formulas (I-1)-(I-9) at claim 158. However, Khvorova teaches identical dsRNA modification patterns and formulas of compounds comprising the same as the instant application, as set forth below (see section Claim Rejections - 35 USC § 103), thereby obviating the necessity of the election of species previously set forth.
Accordingly, claims 1-3, 45, 68, 78, 79, 83, 85, 87-89, 157, 158, 166, and 177-184 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest effective filing date to which the instant application is entitled is 03/11/2022.
Information Disclosure Statement
Receipt of information disclosure statements on 06/06/2024 and 12/17/2025 is acknowledged. The signed and initialed PTO-1449‘s have been mailed with this action.
Drawings
The drawings received on 03/10/2023 are acceptable.
Specification
The disclosure is objected to because of the following informalities:
The formatting of Table 1 splits the top row between pages 99 and 100. It would be remedial to format Table 1 such that each row is depicted in its entirety on a single page.
The formatting of Table 2 splits the depicted terminal R groups and their associated labels (R5 and R6) between pages 102 and 103. It would be remedial to format Table 2 such that each group and label associated with the same is depicted in its entirety on a single page.
The instant specification discloses Table 1, Table 2, Table 4, Table 5, Table 6, and Table 7. There is no Table 3. It would be remedial to number the Tables in consecutive, ascending numerical order.
Appropriate correction is required.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1, 2, 87, 88, 157, 158, 180, and 184 are objected to because of the following informalities:
Claim 1 recites a range of SEQ ID NOs, specifically “SEQ ID NOs: 15, 1-14, and 16-19.” The claimed range may more clearly be recited as “SEQ ID NOs: 1-19.” For purposes of clarity, it would be remedial to amend the instant claim such that it recites “SEQ ID NOs: 1-19.”
Claim 2 recites a range of SEQ ID NOs, specifically “SEQ ID NOs: 34, 20-33, and 35-38.” The claimed range may more clearly be recited as “SEQ ID NOs: 20-38.” For purposes of clarity, it would be remedial to amend the instant claim such that it recites “SEQ ID NOs: 20-38.”
Claim 87 recites “wherein the substantially complementary sequence comprises sufficient complementarity to the APP mRNA to direct target-specific silencing of an APP mRNA” (bolded emphasis added), which is inconsistent with similar recitations throughout the instant claim set. For example, instant claim 1 recites “wherein the substantially complementary sequence comprises sufficient complementarity to the APP nucleic acid sequence to direct target-specific silencing of an APP mRNA” (bolded emphasis added), which is both more clear and more consistent with linguistic conventions in the field. It would be remedial to amend the instant claim language to be consistent with similar recitations throughout the instant claim set (as in instant claim 1) that are more clear and more consistent with linguistic conventions in the field.
Claim 88 does not comport with standard grammatical and/or linguistic conventions. Specifically, the comma separating the preamble from the body of the claim is not followed by a space, as it grammatically proper. In order to comport with standard grammatical and/or linguistic conventions, it would be remedial to amend the instant claim to include a space separating the preamble from the body of the claim.
Claim 157 recites “wherein the substantially complementary sequence comprises sufficient complementarity to the APP nucleic acid to direct target-specific silencing of an APP mRNA” (bolded emphasis added), which is inconsistent with similar recitations throughout the instant claim set. For example, instant claim 1 recites “wherein the substantially complementary sequence comprises sufficient complementarity to the APP nucleic acid sequence to direct target-specific silencing of an APP mRNA” (bolded emphasis added), which is both more clear and more consistent with linguistic conventions in the field. It would be remedial to amend the instant claim language to be consistent with similar recitations throughout the instant claim set (as in instant claim 1) that are more clear and more consistent with linguistic conventions in the field.
Claim 158 does not comport with standard grammatical and/or linguistic conventions. The recitation of “the compound of claim 157, the compound has a structure…” is grammatically improper, as it lacks a transition word such as “wherein” separating the preamble of the claim from the body of the claim. It would be remedial to amend the instant claim to include a transition word such as “wherein” separating the preamble of the claim from the body of the claim, for example by reciting “the compound of claim 157, wherein the compound has a structure…” (bolded emphasis added). This is merely an example set forth by the Examiner and is not intended to be limiting.
Claims 180 and 184 both recite a number of 5’ modifications, including 5’ phosphate, 5’ alkylene phosphonate, and 5’ alkenyl phosphonate. Only the modification of “a 5’-alkyl phosphonate” (bolded and underlined emphasis added) is recited with the emphasized dash. For purposes of consistency, it would be remedial to amend the instant claim such that all 5’ modifications are recited consistently, with or without the emphasized dash set forth above.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3, 85, 87-89, 157, 158, 166, and 181-184 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 3 is drawn to a dsRNA molecule targeting an APP nucleic acid sequence comprising an antisense strand comprising full complementarity to or complementary to at least 10, 11, 12, or 13 of the APP nucleic acid sequence defined by any one of SEQ ID NOs: 1-19, all of which are 50 nucleotides in length. The rejected claim thus comprises a set of dsRNA molecules targeting an APP nucleic acid sequence comprising an antisense strand up to 50 nucleotides in length.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes antisense sequences targeting APP mRNA (Table 5), all of which are 20 nucleotides in length, which is less than 50 nucleotides in length. No description is provided of antisense sequences that are 50 nucleotides in length, as is encompassed by the instant claim language.
It is known that the length of dsRNA agents (such as siRNAs) has an impact on silencing efficiency. While there is some debate over the “best length” for such dsRNA agents, agents with lengths of 19-29 nucleotides have been found to effectively silence their targets. Effective siRNA design includes considering the length of the agent, as shorter lengths may lead to unspecific binding, while longer lengths can induce immune responses in mammals (Fakhr et al., 2016: page 75, column 1, paragraph 1). In view of the disclosed examples and the accepted principles in the field reflected in the prior art and set forth above, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claim 3.
Claims 85, 87-89, 166, and 181-184 are broadly drawn to a set of branched RNA compounds comprising two or more RNA molecules. Claims 157 and 158 are also drawn to a compound comprising multiple nucleic acid molecules (specifically 2, 3, 4, 5, 6, 7, or 8 nucleic acid molecules). The rejected claims thus comprise a set of branched RNA compounds that comprise up to an unlimited number of RNA molecules, as well as a set of compounds comprising 2-8 nucleic acid molecules.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes a panel of siRNAs comprising a sense and antisense strand (Example 1: paragraphs [0465]-[0468]), as well as in vivo administration of a di-siRNA to mice (Example 2: paragraphs [0469] and [0470]). No description is provided of a compound comprising more than two RNA (or other nucleic acid) molecules.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of di-siRNAs comprising a first sense strand linked to an identical second sense strand (and their associated antisense strands). The results are not necessarily predictive of a branched RNA compound comprising up to an unlimited number of RNA molecules. Thus, it is impossible for one to extrapolate from the single example described herein those branched RNA compounds comprising up to an unlimited number of RNA molecules that would necessarily meet the structural/functional characteristics of the rejected claims. While the instant specification does describe a di-siRNA comprising a first sense strand linked to an identical second sense strand (and their associated antisense strands), the instant claim language encompasses compounds comprising up to eight nucleic acid molecules, which are not described in the instant specification.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of branched RNA compounds comprising up to an unlimited number of RNA molecules. While the prior art does disclose branched RNA compounds comprising multiple RNA molecules (see Aviñó et al., 2011; as cited in the IDS filed 12/17/2025), the instant specification only describes a di-siRNA molecule, as set forth above.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 5, 87-89, 157, 158, 166, and 181-184.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 45, 68, 78, 79, 83, 85, 87-89, 157, 158, 166, and 177-184 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 2, 78, 79, 87-89, and 157 all recite that the nucleic acid compounds recited therein comprise “a sequence substantially complementary” to an APP nucleic acid sequence. Claims 45, 68, 83, 85, 158, 166, and 177-184 all depend therefrom and therefore inherit this recitation. While the term “substantially complementary” is defined in the claims as “comprising sufficient complementarity to the APP nucleic acid sequence to direct target-specific silencing of an APP mRNA” (see instant claim 1), it is not clear what level of target-specific silencing of an APP mRNA would satisfy the requirements of the instant claim language. dsRNA molecules targeting APP for inhibition of its expression and/or activity are known in the art, as disclosed in US 2020/0339991 A1 (hereinafter Milstein; see abstract and paragraphs [0005] and [0176]). Under broadest reasonable interpretation, inhibition of APP reads on silencing of APP. However, not all dsRNA molecules equally inhibit APP expression and/or activity, as shown in Figures 2A and 2B of Milstein. It is thus not clear what level of target-specific silencing of an APP mRNA would necessarily infringe on the instantly claimed “target-specific silencing of an APP mRNA” achieved by the dsRNA agents comprising “a sequence substantially complementary” to an APP nucleic acid sequence. Therefore, by extension, it is also not clear what dsRNA molecules comprising “a sequence substantially complementary” to an APP nucleic acid sequence would necessarily infringe on the instantly claimed dsRNA molecules.
With further regard to claims 177 and 181, the term “about” in claims 177 and 181 is a relative term which renders the claims indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In the absence of a clear definition of “about,” the bounds of the lengths of the instantly claimed sense and antisense strands are not clearly defined such that one of ordinary skill in the art would be reasonably apprised of the metes and bounds of protection sought by the instant claim language.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 68, 78, 79, 85, 87-89, 157, 166, and 177-184 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 2020/033991 A1 (hereinafter Milstein).
With regard to claim 1, which recites “a double stranded RNA (dsRNA) molecule comprising a sense strand and an antisense strand, each strand with a 5’ end and a 3’ end, wherein the antisense strand comprises a sequence substantially complementary to an amyloid precursor protein (APP) nucleic acid sequence of any one of SEQ ID NOs: [1-19], wherein the substantially complementary sequence comprises sufficient complementarity to the APP nucleic acid sequence to direct target-specific silencing of an APP mRNA,” Milstein discloses double stranded RNA agents and compositions targeting the APP gene (abstract). As depicted in Figure 14A, these double-stranded RNA agents each comprise a sense strand and an antisense strand, wherein both the sense and antisense strands include a 5’ end and a 3’ end, as instantly claimed. Milstein discloses specific dsRNA duplexes at Table 3, including AD-392885, which includes a sense sequence (SEQ ID NO: 1311) and an antisense sequence (SEQ ID NO: 1312). As shown in the alignment of Appendix I, antisense sequence SEQ ID NO: 1312 is complementary to instant SEQ ID NO: 15, as elected by Applicant in the reply filed 12/17/2025. Furthermore, the agents taught in Milstein are further disclosed to specifically target RNAs of the target APP gene for inhibition of the same (paragraph [0745]). Thus, Milstein anticipates each and every limitation of instant claim 1.
With regard to claim 2, which recites “the antisense strand [of the dsRNA molecule of claim 1] comprises a sequence substantially complementary to the APP nucleic acid sequence of any one of SEQ ID NOs: [20-38], wherein the substantially complementary sequence comprises sufficient complementarity to the APP nucleic acid sequence to direct target-specific silencing of an APP mRNA,” as set forth above, SEQ ID NO: 1312 of Milstein is an antisense sequence of a dsRNA duplex targeting APP for specific inhibition of the same (abstract; Table 3; paragraph [0745]). Furthermore, as shown in the alignment of Appendix II SEQ ID NO: 1312 of Milstein is complementary to the APP nucleic acid sequence of SEQ ID NO: 34, as elected by Applicant in the reply filed 12/17/2025. Thus, Milstein anticipates each and every limitation of instant claim 2.
With regard to claim 3, which recites “the antisense strand [of the dsRNA molecule of claim 1] comprises complementarity to at least 10, 11, 12, or 13 contiguous nucleotides of the APP nucleic acid sequence of any one of SEQ ID NOs: 1-19,” as set forth above and shown in the alignment of Appendix I, antisense sequence SEQ ID NO: 1312 is complementary to instant SEQ ID NO: 15, as elected by Applicant in the reply filed 12/17/2025. SEQ ID NO: 1312 of Milstein is 23 nucleotides in length, and SEQ ID NO: 1312 of Milstein is complementary to 23 contiguous nucleotides of the APP nucleic acid sequence of instant SEQ ID NO: 15. Given that complementarity to 23 contiguous nucleotides of the APP nucleic acid sequence of instant SEQ ID NO: 15 reads on the instantly claimed complementarity to at least 10-13 contiguous nucleotides, Milstein anticipates each and every limitation of instant claim 3.
With regard to claim 68, which recites “a pharmaceutical composition for inhibiting expression of an amyloid precursor protein (APP) gene in an organism comprising the dsRNA molecule of claim 1 and a pharmaceutically acceptable carrier,” as set forth above, Milstein anticipates the dsRNA molecule of claim 1. Milstein further discloses that the RNAi agents taught therein can be incorporated into pharmaceutical compositions suitable for administration, said pharmaceutical compositions additionally comprising a pharmaceutically acceptable carrier (paragraph [0584]). Thus, Milstein anticipates each and every limitation of instant claim 68.
With regard to claim 78, which recites “a vector comprising a regulatory sequence operably linked to a nucleotide sequence that encodes a double stranded RNA (dsRNA) molecule substantially complementary to an amyloid precursor protein (APP) nucleic acid sequence of SEQ ID NOs: 1-19, wherein the substantially complementary sequence comprises sufficient complementarity to the APP nucleic acid sequence to direct target-specific silencing of an APP mRNA,” as set forth above, Milstein discloses dsRNA agents specifically targeting APP for inhibition of the same, said dsRNA agents comprising a sense strand and an antisense strand such as antisense strand SEQ ID NO: 1312, which is complementary to instant SEQ ID NO: 34 within instant SEQ ID NO: 15 (abstract; Table 3; paragraph [0745]; Appendices I and II). Milstein further discloses that the RNAi agents taught therein may be delivered via a vector comprising regulatory elements such as promoters or enhancers to ensure expression of the RNAi agent encoded in said vector (paragraphs [0577]-[0601]). Thus, Milstein anticipates each and every limitation of instant claim 78.
With regard to claim 79, which recites “the dsRNA molecule [of the vector of claim 78] comprises a sense strand and an antisense strand, wherein the antisense strand comprises the sequence substantially complementary to the APP nucleic acid sequence of SEQ ID NOs: 1-19,” as set forth above, the dsRNA agents disclosed in Milstein comprise sense and antisense strands such as antisense strand SEQ ID NO: 1312, which is complementary to instant SEQ ID NO: 15 (abstract; Table 3; paragraph [0745]; Appendices I and II), as elected by Applicant in the reply filed 12/17/2025. Thus, Milstein anticipates each and every limitation of instant claim 79.
With regard to claim 85, which recites “a branched RNA compound comprising two or more of the dsRNA molecules of claim 1 covalently bound to one another, optionally wherein: the dsRNA molecules are covalently bound to one another by way of a linker, a spacer, a branching point, or a combination thereof,” as set forth above, Milstein anticipates the dsRNA molecule of claim 1. Milstein further discloses that the dsRNA agents taught therein may be multimeric, wherein each multimer contains at least two RNAi duplexes connected by a linker (paragraph [0360]). Thus, Milstein anticipates each and every limitation of instant claim 85.
With regard to claim 87, which recites “a branched RNA compound comprising: two or more RNA molecules comprising 15 to 35 nucleotides in length, and a sequence substantially complementary to an amyloid precursor protein (APP) mRNA, wherein the substantially complementary sequence comprises sufficient complementarity to the APP mRNA to direct target-specific silencing of the APP mRNA, wherein the two or more RNA molecules are connected to one another by one or more moieties independently selected from a linker, a spacer, and a branching point,” as set forth above, Milstein discloses dsRNA agents specifically targeting APP for inhibition of the same, said dsRNA agents comprising a sense strand and an antisense strand such as antisense strand SEQ ID NO: 1312, which is 20 nucleotides in length and is complementary to instant SEQ ID NO: 34 within instant SEQ ID NO: 15 (abstract; Table 3; paragraph [0745]; Appendices I and II). Furthermore, as set forth above, Milstein additionally discloses that the dsRNA agents taught therein may be multimeric, wherein each multimer contains at least two RNAi duplexes connected by a linker (paragraph [0360]). Thus, Milstein anticipates each and every limitation of instant claim 87.
With regard to claims 88 and 89, which respectively recite “the sequence substantially complementary to the APP mRNA [of the branched RNA compound of claim 87], wherein the sequence substantially complementary to the APP mRNA is an APP nucleic acid sequence of any one of SEQ ID NOs: 1-19,” or “SEQ ID NOs: 20-38,” as set forth above, the dsRNA agents taught in Milstein target APP for inhibition of the same and comprise a sense strand and an antisense strand such as antisense strand SEQ ID NO: 1312, which is 20 nucleotides in length and is complementary to instant SEQ ID NO: 34 within instant SEQ ID NO: 15 (abstract; Table 3; paragraph [0745]; Appendices I and II), as elected by Applicant in the reply filed 12/17/2025. Thus, Milstein anticipates each and every limitation of instant claims 88 and 89.
With regard to claim 157, which recites “a compound of formula (I): L – (N)n
wherein: L comprises an ethylene glycol chain, an alkyl chain, a peptide, an RNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or combinations thereof…and N is a double stranded nucleic acid comprising 15 to 35 bases in length comprising a sense strand and an antisense strand; wherein: the antisense strand comprises a sequence complementary to an amyloid precursor protein (APP) nucleic acid sequence of any one of SEQ ID NOs: 1-19, wherein the substantially complementary sequence comprises sufficient complementarity to the APP nucleic acid [sequence] to direct target-specific silencing of an APP mRNA; the sense strand and the antisense strand each independently comprises one or more chemical modifications; and n is 2, 3, 4, 5, 6, 7, or 8,” as set forth above, the dsRNA agents taught in Milstein target APP for inhibition of the same and comprise a sense strand and an antisense strand such as antisense strand SEQ ID NO: 1312, which is 20 nucleotides in length and is complementary to instant SEQ ID NO: 34 within instant SEQ ID NO: 15 (abstract; Table 3; paragraph [0745]; Appendices I and II), as elected by Applicant in the reply filed 12/17/2025. Milstein further discloses that the dsRNA agents taught therein may be conjugated to a ligand such as polyethylene glycol, which reads on the instantly claimed ethylene glycol chain of L (paragraph [0416]). Furthermore, as set forth above, Milstein additionally discloses that the dsRNA agents taught therein may be multimeric, wherein each multimer contains at least two RNAi duplexes connected by a linker (paragraph [0360]). Thus, Milstein anticipates each and every limitation of instant claim 157.
With regard to claim 166, which recites “a pharmaceutical composition for inhibiting expression of an amyloid precursor protein (APP) gene in an organism, comprising a branched RNA compound of claim 87, and a pharmaceutically acceptable carrier,” as set forth above, Milstein anticipates the branched RNA compound of claim 87. Additionally, as set forth above, Milstein further discloses that the RNAi agents taught therein can be incorporated into pharmaceutical compositions suitable for administration, said pharmaceutical compositions additionally comprising a pharmaceutically acceptable carrier (paragraph [0584]). Thus, Milstein anticipates each and every limitation of instant claim 166.
With regard to claims 177 and 181, which respectively recite that “the dsRNA molecule of claim 1” and “the branched RNA compound of claim 181” comprise an antisense strand comprising “about 15 nucleotides to about 25 nucleotides in length and/or [a] sense strand compris[ing] about 15 nucleotides to about 25 nucleotides in length,” as set forth above, Milstein anticipates the dsRNA molecule of claim 1 and the branched RNA compound of claim 181. Furthermore, Milstein discloses specific dsRNA duplexes at Table 3, including AD-392885, which includes a sense sequence 21 nucleotides in length (SEQ ID NO: 1311) and an antisense sequence 23 nucleotides in length (SEQ ID NO: 1312). Thus, Milstein anticipates each and every limitation of instant claims 177 and 181.
With regard to claims 178 and 182, which respectively recite “the dsRNA molecule of claim 1” and “the branched RNA compound of claim 181, wherein the antisense strand and/or the sense strand comprise at least one modified nucleotide, optionally wherein the modified nucleotide comprises a 2’-O-methyl modified nucleotide, a 2’-deoxy-2’-fluoro modified nucleotide, an abasic nucleotide, a 2’-amino-modified nucleotide, a 2’-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, or a mixture thereof, ” as set forth above Milstein anticipates the dsRNA molecule of claim 1 and the branched RNA compound of claim 181. Milstein further discloses that the dsRNA agents taught therein include at least one modified nucleotide in both the sense and antisense strands (paragraphs [0014] and [0018]). These modified nucleotides include 2’-O-methyl modified nucleotides, 2’-fluoro modified nucleotides, morpholino nucleotides, and phosphoramidates (paragraph [0020]), among others. Thus, Milstein anticipates each and every limitation of instant claims 178 and 182.
With regard to claims 179 and 183, which respectively recite “the dsRNA molecule of claim 1” and “the branched RNA compound of claim 181, wherein the antisense strand and/or the sense strand comprise at least one modified internucleotide linkage, optionally wherein the modified internucleotide linkage comprises a phosphorothioate internucleotide linkage,” as set forth above Milstein anticipates the dsRNA molecule of claim 1 and the branched RNA compound of claim 181. Milstein further discloses that the dsRNA agents taught therein include at least one phosphorothioate internucleotide linkage (paragraphs [0054] and [0068]). Thus, Milstein anticipates each and every limitation of instant claims 179 and 183.
With regard to claims 180 and 184, which respectively recite “the dsRNA molecule of claim 1” and “the branched RNA compound of claim 181, wherein the antisense strand comprises a 5’ phosphate, a 5’-alkyl phosphonate, a 5’ alkylene phosphonate, or a 5’ alkenyl phosphonate, optionally wherein the 5’ alkylene phosphonate is a 5’ vinyl phosphonate,” as set forth above Milstein anticipates the dsRNA molecule of claim 1 and the branched RNA compound of claim 181. Milstein further discloses that the dsRNA agents taught therein may include a 5’-alkenyl phosphonate that is a vinyl phosphonate at the 5’ terminus (paragraph [0556]; Table 9). Thus, Milstein anticipates each and every limitation of instant claims 180 and 184.
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.
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 45, 83, and 158 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/033991 A1 (hereinafter Milstein) as applied to claims 1, 78, and 157 above, and further in view of US 2020/0362341 A1 (hereinafter Khvorova; as cited in the IDS filed 12/17/2025).
The disclosure of Milstein is described above and applied as before. However, this disclosure does not teach the dsRNA molecule structure of instant claim 45, the rAAV comprising an AAV capsid of instant claim 83, or the compound structure of instant claim 158.
With regard to claim 45, which recites “the dsRNA molecule of claim 1, wherein:” the structure of said dsRNA molecule is selected from the structures set forth in A-G of instant claim 45, wherein the structure of “A” is “(1) the antisense strand comprises alternating 2’-methoxy-ribonucleotides and 2’-fluoro-ribonucleotides; (2) the nucleotides at positions 2 and 14 from the 5’ end of the antisense strand are not 2’-methoxy-ribonucleotides; (3) the nucleotides at positions 1-2 to 1-7 from the 3’ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages; (4) a portion of the antisense strand is complementary to a portion of the sense strand; (5) the sense strand comprises alternating 2’-methoxy-ribonucleotides and 2’-fluoro-ribonucleotides; and (6) the nucleotides at positions 1-2 from the 5’ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages,” as set forth above, Milstein anticipates the dsRNA molecule of claim 1. However, Milstein does not disclose the specific structures recited at instant claim 45. However, this deficiency is cured by Khvorova, which discloses dsRNA molecules comprising a sense strand and an antisense strand targeting ApoE to reduce its expression and activity (abstract; paragraphs [0003], [0005], and [0010]). Thus, the dsRNA molecules of Milstein and Khvorova both comprise sense and antisense strands and target a specific sequence to inhibit its expression and function. Khvorova discloses a number of modifications to the structure of the dsRNA molecules taught therein. These modifications include alternating 2’-methoxy-ribonucleotides and 2’-fluoro-ribonucleotides, nucleotides at positions 2 and 14 from the 5’ end that are not 2’-methoxy-ribonucleotides, and connection of the nucleotides at positions 1-2 to 1-7 from the 3’ end to adjacent nucleotides via phosphorothioate linkages (paragraphs [0024]-[0025], [0072]-[0076]). These double-stranded, chemically-modified nucleic acids comprise a first and second oligonucleotide, wherein a portion of the first oligonucleotide (i.e. the antisense strand) is complementary to a portion of the second oligonucleotide (i.e. the sense strand) (paragraphs [0334] and [0423]). Thus, Milstein and Khvorova disclose each and every limitation of instant claim 45.
With regard to claim 83, which recites “an isolated cell or a recombinant adeno-associated virus (rAAV) comprising the vector of claim 78, wherein the rAAV comprises an AAV capsid,” as set forth above, Milstein anticipates the vector of claim 78. However, while Milstein discloses an AAV vector to deliver the dsRNA agents taught therein, Milstein does not disclose the rAAV comprising an AAV capsid as recited at instant claim 83. However, this deficiency is cured by Khvorova, which discloses dsRNA molecules comprising a sense strand and an antisense strand targeting ApoE to reduce its expression and activity (abstract; paragraphs [0003], [0005], and [0010]), as set forth above. Khvorova further discloses that the dsRNA agents (i.e. siRNAs) taught therein can be delivered via rAAVs comprising an AAV capsid (paragraphs [0504] and [0511]). Thus, Milstein and Khvorova disclose each and every limitation of instant claim 83.
With regard to claim 158, which recites the compound of claim 157, [wherein] the compound has a structure selected from formulas (I-1)-(I-9),” as set forth above, Milstein anticipates the compound of claim 157. However, Milstein does not disclose the structure of formulas (I-1)-(I-9) recited at instant claim 158. However, this deficiency is cured by Khvorova, which discloses dsRNA molecules comprising a sense strand and an antisense strand targeting ApoE to reduce its expression and activity (abstract; paragraphs [0003], [0005], and [0010]), as set forth above. Khvorova further discloses compounds comprising the dsRNA agents taught therein, wherein the compounds have structures selected from formulas (I-1)-(I-9) (paragraphs [0089]-[0097]), which are identical to formulas (I-1)-(I-9) of the instant application. Thus, Milstein and Khvorova disclose each and every limitation of instant claim 158.
Given that Milstein discloses dsRNA agents targeting APP for inhibition and compounds comprising the same, wherein the APP-inhibiting dsRNA agents and compounds treat a subject suffering from APP-associated diseases such as Alzheimer’s disease and cerebral amyloid angiopathy (paragraphs [0005] and [0007]), and that Khvorova discloses modified structures of dsRNA agents and compounds comprising the same that are applicable to the treatment or management of an amyloid-related disease such as Alzheimer’s disease (paragraphs [0167]-[0168]), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the APP-targeting dsRNA agents and compounds comprising the same disclosed in Milstein as disclosed in Khvorova to predictably treat or manage an amyloid-related disease such as Alzheimer’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of treating or managing an amyloid-related disease such as Alzheimer’s disease.
Conclusion
No claims are allowed.
Claims 1, 2, 87, 88, 157, 158, 180, and 184 are objected to.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637