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 .
Applicant’s response of 07/27/2026, including a substitute specification, has been received and entered into the application file.
Claims 1, 45, 68, 157, 158, 178, and 182-184 were amended in the claim set filed 07/27/2026.
Claims 2, 3, 78, 79, 83, 87-89, 177, and 181 were canceled in the claim set filed 07/27/2026.
Claims 185-189 were added in the claim set filed 07/27/2026.
Accordingly, claims 1, 45, 68, 85, 157, 158, 166, 178-180, and 182-189 are pending and under consideration.
Election/Restrictions
Applicant’s previous 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 previously acknowledged 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 Regarding species C and D of the reply filed 12/17/2025, the election of species was previously withdrawn in view of US 2020/0362341 A1 (hereinafter Khvorova; as cited in the IDS filed 12/17/2025), which discloses identical dsRNA modification patterns to the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 Furthermore, regarding species F-I of the reply filed 12/17/2025, the election of species was previously withdrawn in view of Khvorova. The Examiner previously noted 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.
Information Disclosure Statement
Receipt of an information disclosure statement on 07/27/2026 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Status of Prior Objections/Rejections
RE: Specification
►The disclosure was previously objected to for various informalities.
The substitute specification filed 07/27/2026 has obviated the basis of the objections of record. The objections of record are hereby withdrawn.
RE: Claim Objections
►Claims 1, 2, 87, 88, 157, 158, 180, and 184 were previously objected to for various informalities.
The cancellation of claims 2, 87, and 88 render the objections thereof moot.
The amendments to the instant claim set filed 07/27/2026 have obviated the basis of the objections of record. The objections of record are hereby withdrawn.
RE: Claim Rejections - 35 USC § 112(a)
►Claims 3, 85, 87-89, 157, 158, 166, and 181-184 were previously 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.
The cancellation of claims 3, 87-89, and 181 renders the rejection thereof moot.
The amendments to the instant claim set filed 07/27/2026 have obviated the basis of the rejection of record. The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 112(b)
►Claims 1, 2, 45, 68, 78, 79, 83, 85, 87-89, 157, 158, 166, and 177-184 were previously 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.
The cancellation of claims 2, 78, 79, 83, 87-89, 177, and 181 renders the rejection thereof moot.
The amendments to the instant claim set filed 07/27/2026 have obviated the basis of the rejection of record. The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 102
►Claims 1-3, 68, 78, 79, 85, 87-89, 157, 166, and 177-184 were previously rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 2020/0339991 A1 (hereinafter Milstein).
Applicant has traversed the rejection of record, asserting that Milstein does not recite the combination of features recited in the amended independent claims.
In response, this is found persuasive. The rejection of record is hereby withdrawn. However, new grounds of rejection necessitated by amendment are set forth below.
RE: Claim Rejections - 35 USC § 103
►Claims 45, 83, and 158 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0339991 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).
Applicant has traversed the rejection of record, asserting that Khvorova does not cure the deficiencies of Milstein regarding the amended instant claim set. Applicant further asserts that there is no reason, suggestion, or motivation to lead a skilled artisan to combine these references.
In response, it is noted that KSR forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http://www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 USPQ2d 1385 (2007): “Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.”
Therefore, the claimed invention, as a whole, is prima facie obvious.
However, regarding the amended claim limitations, this argument is found persuasive. The rejection of record is hereby withdrawn. However, new grounds of rejection necessitated by amendment are set forth below.
New/Maintained Grounds of Objection/Rejection
Claim Objections
Claims 157 and 158 are objected to because of the following informalities:
Amended claim 157 lacks a conjunction such as “and” properly separating the recitations defining “L” and “N.” It would be remedial to amend instant claim 157 to include a conjunction such as “and” separating said recitations.
Amended claim 158 recites “the compound of claim 157, having a structure of formula (I-1):…” followed by a table listing formulas I-1 to I-9. While it appears Applicant intended to delete formulas I-2 to I-9, these formulas are still listed. Furthermore, formula I-1 is listed twice: once in the text of the claim body and once in the table of the claim body. It would be remedial to amend the instant claim such that formula I-1 is listed once and that the recited formulas and recited scope are commensurate.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 45 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Amended claim 45 depends from amended claim 1, which recites an “antisense strand compris[ing] 21-25 nucleotides in length and a sequence of SEQ ID NO: 59, [wherein the] nucleotides at positions 4-6, 16, and 20 from the 5’ end of the antisense strand are 2’-fluoro-ribonucleotides.” However, A(1) of amended claim 45 recites “the antisense strand comprises alternating 2’-methoxy-ribonucleotides and 2’-fluoro-ribonucleotides” (bolded emphasis added). The antisense strand required by amended instant claim 1 thus comprises 2’-fluoro-ribonucleotides at positions 4-6, which is incompatible with alternating 2’-methoxy-ribonucleotides and 2’-fluoro-ribonucleotides, as recited at amended instant claim 45. It would be remedial to amend the instant claim language such that this incompatibility is resolved.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1, 45, 68, 85, 157, 158, 166, 178-180, and 182-188 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0339991 A1 (hereinafter Milstein; of record) in view of US 2020/0362341 A1 (hereinafter Khvorova; as cited in the IDS filed 12/17/2025; of record), WO 2009/078685 A2 (hereinafter Lee), and Yuan et al., 2012 (hereinafter Yuan), as evidenced by Foster et al., 2018 (hereinafter Foster).
With regard to amended instant claim 1, which recites “a double stranded RNA (dsRNA) molecule for specific silencing of an amyloid precursor protein (APP) gene comprising a sense strand and an antisense strand, each strand with a 5’ end and a 3’ end, wherein:
the antisense strand and the sense strand are fully chemically modified,
the antisense strand comprises 21-25 nucleotides in length and a sequence of SEQ ID NO: 59,
[wherein] nucleotides at positions 4-6, 16, and 20 from the 5’ end of the antisense strand are 2’-fluoro-ribonucleotides, and
the sense strand comprises 15-20 nucleotides in length,”
as previously set forth, 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 the Appendix, antisense sequence SEQ ID NO: 1312 comprises a sequence of instant SEQ ID NO: 59. The Examiner notes that the phrasing “comprises…a sequence of SEQ ID NO: 59” (bolded and underlined emphasis added) embraces a sequence that shares at least a dinucleotide with the instantly claimed sequence. In the instant case, SEQ ID NO: 1312 of Milstein comprises 90.5% identity to instant SEQ ID NO: 59 (as shown in the alignment of the Appendix). 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]).
Milstein further discloses that both strands of the dsRNA agents taught therein may be fully chemically modified (paragraphs [0019] and [0339]). Additionally, SEQ ID NO: 1312 of Milstein is 23 nucleotides in length, which falls within the instantly claimed range of 21-25 nucleotides for the antisense strand. Per Table 4, duplex AD-392885 (which comprises SEQ ID NO: 1312) mediates effective knockdown of APP in vitro.
Regarding the specified positions of 2’-fluoro-ribonucleotides in the antisense strand, while Milstein does not explicitly disclose this pattern of modification, Milstein discloses that 2’-fluoro-ribonucleotides may be incorporated at a number of positions, for example at positions 2, 14, and 16 from the 5’ terminus of the antisense strand (paragraphs [0120], [0129], and [0486]). Khvorova also discloses therapeutic dsRNA agents (albeit with a different target), wherein said dsRNA agents comprise 2’-fluoro-ribonucleotides are a number of positions, including a region of three contiguous nucleotides (paragraph [0026]). Therefore, while neither Milstein nor Khvorova disclose the instantly claimed modification pattern, both of these disclosures establish that 2’-fluoro modifications may be incorporated at a number of positions within therapeutic dsRNA molecules, thereby motivating someone of ordinary skill in the art to practice routine optimization to optimize the modification pattern of 2’-fluoro-ribonucleotides, as instantly claimed (see MPEP § 2144.05.I.A). This is supported by the disclosure of Foster, which teaches a screening paradigm for the optimization of siRNA designs based on a positions model for chemical modifications, thereby expanding the therapeutic potential of RNAi therapeutics (abstract; page 714, column 1, paragraph 4-page 714, column 2, paragraph 1)
Regarding the instantly claimed length of the sense strand, Milstein discloses that the sense strand comprises at least 15 contiguous nucleotides and further that each strand of the dsRNA agents taught therein may range from 17-19 nucleotides in length (paragraphs [0012] and [0279]), which falls within the instantly claimed range. While Milstein discloses a number of possible length ranges for the sense strand (as set forth above), Lee specifically discloses double-stranded RNA molecules comprising a 19-21 nucleotide antisense strand and a 15-19 nucleotide sense strand (abstract). Furthermore, Yuan specifically teaches that shortening the sense strand of a dsRNA agent improves strand specificity and overcomes off-target gene-expression effects while retaining the efficacy of said dsRNA agent (abstract; page 531, column 2, paragraph 3). Therefore, based on the disclosures of Lee and Yuan, one of ordinary skill in the art would have been motivated to select a shortened sense strand sequence as compared to the antisense strand sequence, as instantly claimed.
Thus, it is considered that the prior art discloses and/or motivates each and every limitation of amended instant claim 1.
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, Khvorova, Lee, Yuan, and Foster collectively disclose the dsRNA molecule of claim 1. Khvorova further 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. While the gene targets of Milstein and Khvorova differ, the principles by which these dsRNA agents function are the same. 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]).
With regard to claim 68, which recites “a pharmaceutical composition for inhibiting expression of the 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, Khvorova, Lee, Yuan, and Foster collectively disclose 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]).
With regard to claim 85, which recites “a branched RNA compound comprising two dsRNA molecules of claim 1 covalently bound to one another, optionally wherein
the two 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, Khvorova, Lee, Yuan, and Foster collectively disclose 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]).
With regard to amended claim 157, which recites “a compound for specific silencing of an amyloid precursor protein (APP) gene of formula (I)…wherein:
L comprises an ethylene glycol chain, an alkyl chain, a peptide, an RNA, a DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or combinations thereof[,]
N is a double stranded nucleic acid comprising a sense strand and an antisense strand, each strand with a 5’ end and a 3’ end, wherein:
the antisense strand and the sense strand are fully chemically modified,
the antisense strand comprises 21-25 nucleotides in length and a sequence of SEQ ID NO: 59,
[wherein] nucleotides at positions 4-6, 16, and 20 from the 5’ end of the antisense strand are 2’-fluoro-ribonucleotides; and
the sense strand comprises 15-20 nucleotides in length; and
n is 2,” as set forth above and regarding the instantly claimed “N,” 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 the Appendix, antisense sequence SEQ ID NO: 1312 comprises a sequence of instant SEQ ID NO: 59. The Examiner notes that the phrasing “comprises…a sequence of SEQ ID NO: 59” (bolded and underlined emphasis added) embraces a sequence that shares at least a dinucleotide with the instantly claimed sequence. In the instant case, SEQ ID NO: 1312 of Milstein comprises 90.5% identity to instant SEQ ID NO: 59 (as shown in the alignment of the Appendix). 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]).
Milstein further discloses that both strands of the dsRNA agents taught therein may be fully chemically modified (paragraphs [0019] and [0339]). Additionally, SEQ ID NO: 1312 of Milstein is 23 nucleotides in length, which falls within the instantly claimed range of 21-25 nucleotides for the antisense strand.
Regarding the specified positions of 2’-fluoro-ribonucleotides in the antisense strand, while Milstein does not explicitly disclose this pattern of modification, Milstein discloses that 2’-fluoro-ribonucleotides may be incorporated at a number of positions, for example at positions 2, 14, and 16 from the 5’ terminus of the antisense strand (paragraphs [0120], [0129], and [0486]). Khvorova also discloses therapeutic dsRNA agents (albeit with a different target), wherein said dsRNA agents comprise 2’-fluoro-ribonucleotides are a number of positions, including a region of three contiguous nucleotides (paragraph [0026]). Therefore, while neither Milstein nor Khvorova disclose the instantly claimed modification pattern, both of these disclosures establish that 2’-fluoro modifications may be incorporated at a number of positions within therapeutic dsRNA molecules, thereby motivating someone of ordinary skill in the art to practice routine optimization to optimize the modification pattern of 2’-fluoro-ribonucleotides, as instantly claimed (see MPEP § 2144.05.I.A). This is supported by the disclosure of Foster, which teaches a screening paradigm for the optimization of siRNA designs based on a positions model for chemical modifications, thereby expanding the therapeutic potential of RNAi therapeutics (abstract; page 714, column 1, paragraph 4-page 714, column 2, paragraph 1)
Regarding the instantly claimed length of the sense strand, Milstein discloses that the sense strand comprises at least 15 contiguous nucleotides and further that each strand of the dsRNA agents taught therein may range from 17-19 nucleotides in length (paragraphs [0012] and [0279]), which falls within the instantly claimed range. While Milstein discloses a number of possible length ranges for the sense strand (as set forth above), Lee specifically discloses double-stranded RNA molecules comprising a 19-21 nucleotide antisense strand and a 15-19 nucleotide sense strand (abstract). Furthermore, Yuan specifically teaches that shortening the sense strand of a dsRNA agent improves strand specificity and overcomes off-target gene-expression effects while retaining the efficacy of said dsRNA agent (abstract; page 531, column 2, paragraph 3). Therefore, based on the disclosures of Lee and Yuan, one of ordinary skill in the art would have been motivated to select a shortened sense strand sequence as compared to the antisense strand sequence, as instantly claimed.
Regarding the instantly claimed compound, 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. 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]).
With regard to claim 158, which recites the compound of claim 157, having a structure of formula (I-1),” as set forth above, Milstein, Khvorova, Lee, Yuan, and Foster collectively disclose the compound of claim 157. However, Milstein does not disclose the structure of formula (I-1) 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.
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,” 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]).
With regard to claims 178 and 182, which respectively recite “the dsRNA molecule of claim 1,” and “the branched RNA compound of claim 85, wherein the antisense strand and/or the sense strand further comprise at least one modified nucleotide comprising a 2’-O-methyl modified nucleotide, a 2’-deoxy-modified nucleotide, a locked 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 further discloses that both strands of the dsRNA agents taught therein may be fully chemically modified (paragraphs [0019] and [0339]), including with 2’-O-methyl modifications (Table 1). Additional modifications include a morpholino nucleotide, a phosphoramidate, a 2’-deoxy-modified nucleotide, and other such modifications per paragraph [0020] of Milstein.
With regard to claims 179 and 183, which respectively recite “the dsRNA molecule of claim 1,” and “the branched RNA compound of claim 85, 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,” Milstein further discloses that the dsRNA agents taught therein include at least one phosphorothioate internucleotide linkage (paragraphs [0054] and [0068]).
With regard to claims 180 and 184, which respectively recite “the dsRNA molecule of claim 1” and “the branched RNA compound of claim 85, 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,” 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).
With regard to claim 185, which recites “the dsRNA molecule of claim 1, wherein the sense strand comprises at least 65% 2’-O-methyl modified nucleotides and the antisense strand comprises 50% to 80% 2’-O-methyl modified nucleotides,” as set forth above, Milstein discloses duplex AD-392885, which comprises sense strand 1311 and antisense strand 1312. The modified sequences thereof correspond to SEQ ID NOs: 582 and 583, respectively. The sense strand comprises 76% 2’-O-methyl modified nucleotides, while the antisense strand comprises 82% 2’-O-methyl modified nucleotides (see Table 2A). While 82% is outside of the claimed 50%-80% range, Milstein discloses a number of possible modified antisense sequences targeting APP. Therefore, it is considered that it would have been within the realm of routine optimization via routine experimentation to optimize the modification pattern thereof to maximize efficacy of the same (see MPEP § 2144.05.I.A). This is supported by the disclosure of Foster, which teaches a screening paradigm for the optimization of siRNA designs based on a positions model for chemical modifications, thereby expanding the therapeutic potential of RNAi therapeutics (abstract; page 714, column 1, paragraph 4-page 714, column 2, paragraph 1)
With regard to claim 186, which recites “the dsRNA molecule of claim 1, wherein the nucleotide at one or more positions of 3, 7, 9, 11, and 13 from the 3’ end of the sense strand is not a 2’-methoxy-ribonuclotide,” as set forth above, Milstein discloses duplex AD-392885, which comprises sense strand 1311 and antisense strand 1312. Sense strand 1311 of Milstein comprises a 2’-fluoro modified nucleotide at positions 11 and 13 from the 3’ end of said sense strand (Table 2A). Thus, sense strand 1311 of Milstein comprises nucleotides that are not a 2’-methoxy-ribonucleotide at positions 11 and 13 from the 3’ end of said sense strand, as instantly claimed.
With regard to claim 187, which recites “the dsRNA molecule of claim 1, wherein the nucleotides at positions 4, 5, and 6 from the 3’ end of the sense strand are 2’-methoxy-ribonucleotides,” as set forth above, Milstein discloses duplex AD-392885, which comprises sense strand 1311 and antisense strand 1312. Sense strand 1311 of Milstein comprises 2’-O-methoxy-ribonucleotides at positions 4, 5, and 6 from the 3’ end of said sense strand (Table 2A), as instantly claimed.
With regard to claim 188, which recites “the dsRNA molecule of claim 1, wherein the antisense strand is 21 nucleotides in length and the sense strand is 16 nucleotides in length, as set forth above, Lee specifically discloses double-stranded RNA molecules comprising a 19-21 nucleotide antisense strand and a 15-19 nucleotide sense strand (abstract). Lee explicitly discloses dsRNA agents comprising antisense strands consisting of 21 nucleotides in length and sense strands consisting of 16 nucleotides in length (Example 5). Per Lee, when the dsRNA agent taught therein comprises an antisense strand consisting of 21 nucleotides in length, the dsRNA molecule shows high gene silencing efficiency (page 17, lines 4-7). This structure showed high gene silencing efficiency (page 17, lines 12-16). Additionally, as set forth above, Yuan specifically teaches that shortening the sense strand of a dsRNA agent improves strand specificity and overcomes off-target gene-expression effects while retaining the efficacy of said dsRNA agent (abstract; page 531, column 2, paragraph 3). Therefore, based on the disclosures of Lee and Yuan, one of ordinary skill in the art would have been motivated to select a shortened sense strand sequence of 16 nucleotides as compared to the antisense strand sequence of 21 nucleotides, as instantly claimed.
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]), that Lee discloses therapeutic dsRNA molecules comprising a 19-21 nucleotide antisense strand and a 15-19 nucleotide sense strand (specifically that 16 nucleotides in length facilitates robust dsRNA activity), that Yuan further discloses that shortened sense strands improve strand specificity and overcome off-target effects, 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 Lee, Yuan, and Khvorova and via routine optimization as evidenced by Foster to predictably generate a therapeutic dsRNA molecule capable of treating or managing 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.
Allowable Subject Matter
Claim 189 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 189 recites “the antisense strand [of the dsRNA molecule of claim 188] comprises the sequence of SEQ ID NO: 904” (bolded emphasis added). Instant SEQ ID NO: 904 is free of the prior art. The Examiner notes that the phrasing “the sequence of SEQ ID NO: 904” (bolded emphasis added) requires SEQ ID NO: 904 in its entirety, to which the prior art is silent. However, claim 189 depends from rejected claims 1 and 188.
Conclusion
Claims 1, 45, 68, 85, 157-158, 166, 178-180, and 182-188 are rejected.
Claim 189 is objected to.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-F 8-5.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
