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 species 1 recited in claims 16 and 27 (i.e. SEQ ID NO: 63) for the sense strand and species 25 recited in claim 26 (i.e. SEQ ID NO: 42) for the antisense strand in the reply filed 05/01/2026 is acknowledged. Following a search of the prior art, the species election is hereby withdrawn.
Claims 1-32 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 07/11/2022.
Information Disclosure Statement
Receipt of an information disclosure statement on 06/10/2024 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Drawings
The drawings filed 07/11/2023 are accepted.
Claim Objections
Claims 2-7, 14, 16, 22, 25-27, and 30 are objected to because of the following informalities:
With regard to claims 2, 4, 5, 7, 14, 16, 22, 26, and 27, all of these claims recite modifications such as “2’-F modification[s]” and “2’-O-methyl modification[s],” none of which are preceded by an article such as “a” as required by standard grammatical and/or linguistic conventions. It would be remedial to amend the instant claims such that the recited modifications are properly preceded by an article such as “a,” thereby comporting with standard grammatical and/or linguistic conventions.
As an example, instant claim 2 recites “the isolated oligonucleotide of claim 1, wherein the first modification is modification of the sugar moiety of the at least one nucleotide at the 2’-position selected from 2’-F modification, 2’-CN modification, 2’-N3 modification, 2’-deoxy modification, and an equivalent thereof, and a combination thereof,
preferably wherein the first modification is 2’-F modification, 2’-CN modification, 2’-N3 modification, or 2’-deoxy modification, or a stereoisomer thereof,
more preferably wherein the first modification is 2’-F modification, 2’-CN modification, or 2’-N3 modification, or a stereoisomer thereof,
even more preferably wherein the first modification is 2’-F modification or a stereoisomer thereof,” which lacks articles preceding the recited modifications.
It would be remedial to amend instant claim 2 such that it recites “the isolated oligonucleotide of claim 1, wherein the first modification is modification of the sugar moiety of the at least one nucleotide at the 2’-position selected from a 2’-F modification, a 2’-CN modification, a 2’-N3 modification, a 2’-deoxy modification, and an equivalent thereof, and a combination thereof,
preferably wherein the first modification is a 2’-F modification, a 2’-CN modification, a 2’-N3 modification, or a 2’-deoxy modification, or a stereoisomer thereof,
more preferably wherein the first modification is a 2’-F modification, a 2’-CN modification, or a 2’-N3 modification, or a stereoisomer thereof,
even more preferably wherein the first modification is a 2’-F modification or a stereoisomer thereof” (bolded emphasis added).
It would be remedial to amend all of claims 2, 4, 5, 7, 14, 16, 22, 26, and 27 to properly include articles such as “a” preceding the instantly claimed modifications.
With regard to claims 3 and 6, both claims recite a number of possible modifications suitable for the claimed second and fourth modifications, respectively. Regarding the first clause of each claim (i.e. the portion of the claim preceding the “preferably” limitations), while the structure of the instant claim language is not technically incorrect, the structure hampers interpretation and introduces confusion. It appears that Applicant is claiming modification of a sugar moiety of a nucleotide, wherein said sugar moiety comprises a modification at the 2’-position, wherein said modification is selected from a:
2’-C1-C6 alkyl;
2’-OR modification, wherein R is a C1-C6 alkyl optionally substituted with C1-C6 alkoxy, acetamide, phenyl, or heteroaryl, wherein the heteroaryl comprises a 5- or 6-membered ring and 1 or 2 heteroatoms selected from N, O, and S;
2’-amino; and
morpholino replacement.
However, the structure of the instant claim language substantially blurs these recited modifications together. It would be remedial to clearly delineate the claimed modifications such that it is clear on first read which modifications are being claimed, for example by separating the claimed modifications with semicolons rather than commas, as commas are used both to separate claimed modifications and to further expand on the claimed modifications, and therefore do not clearly delineate the claimed modifications.
Regarding the limitations reciting “preferably,” as set forth above regarding claims 2, 4, 5, 7, 14, 16, 22, 26, and 27, none of the recited modifications are preceded by an article such as “a” as required by standard grammatical and/or linguistic conventions. It would be remedial to amend the instant claims such that the recited modifications are properly preceded by an article such as “a,” thereby comporting with standard grammatical and/or linguistic conventions, as set forth above.
With particular regard to claim 22, the terminal punctuation mark of claim 22 is a comma, which is not grammatically correct. It would be remedial to amend instant claim 22 such that the terminal punctuation mark is a period, which is grammatically correct.
Regarding claim 25, the opening clause “the isolated oligonucleotide of claim 17, wherein in the antisense strand” lacks a colon following “in the antisense strand,” thereby failing to comport with standard grammatical and/or linguistic conventions. It would be remedial to amend the instant claim to include a colon following “in the antisense strand,” as in instant claims 23 and 24, thereby comporting with standard grammatical and/or linguistic conventions.
Regarding claim 30, which recites “the isolated oligonucleotide of claim 1, comprising one or more non-natural base-containing nucleotide, a locked nucleotide, or an abasic nucleotide,” first, the recitation of “one or more” necessarily embraces both single and multiple of the recited nucleotide species. It would be remedial to amend the instant claim to reflect this duality, for example by reciting “one or more non-natural base-containing nucleotide(s), locked nucleotide(s), or abasic nucleotide(s).” Second, the structure of instant claim 30 is inconsistent with the other claims. For purposes of internal consistency, it would be remedial to amend instant claim 30 such that it is consistent with the other claims, for example by reciting “the isolated oligonucleotide of claim 1, wherein the isolated oligonucleotide comprises one or more non-natural base-containing nucleotide(s), locked nucleotide(s), or abasic nucleotide(s).” This is merely an example set forth by the Examiner and is not intended to be limiting.
Appropriate correction is required.
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 2-7, 22, and 31 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.
Regarding claims 2-7, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It would be remedial to amend the instant claim language to remove the phrase “preferably,” thereby clearly delineating the metes and bounds of protection sought by the instant claim set.
Claim 22, which depends from instant claim 17, recites the limitation "the at least seven nucleotides, at least six nucleotides, at least five nucleotides, at least four nucleotides, or at least three nucleotides" (bolded emphasis added) in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Instant claim 17, from which instant claim 22 depends, recites “at most” (bolded emphasis added) seven, six, five, four, or three nucleotides. It would be remedial to amend the instant claim language such that there is sufficient antecedent basis for each and every claim term. For purposes of examination and in the interest of compact prosecution, the Examiner has interpreted instant claim 22 to recite “the at most seven nucleotides, at most six nucleotides, at most five nucleotides, at most four nucleotides, or at most three nucleotides” (bolded emphasis added), which is consistent with the recitation of instant claim 17.
With regard to claim 31, which recites “the terminal nucleotide at the 5’ end [of the isolated oligonucleotide of claim 1] comprises a phosphate mimic,” the Examiner notes that those of ordinary skill in the art are aware that the isolated oligonucleotide of claim 1 is double stranded, and each strand comprises a 5’ end. Thus, the isolated oligonucleotide of claim 1 comprises two terminal nucleotides-one at each 5’ end of each strand. It is therefore unclear which terminal nucleotide at which 5’ end is claimed to comprise a phosphate mimic. It would be remedial to amend the instant claim language to clearly define which terminal nucleotide at which 5’ end is claimed to comprise a phosphate mimic. For purposes of examination, and in the interest of compact prosecution, the Examiner has interpreted instant claim 31 to recite that either terminal nucleotide at either 5’ end comprises a phosphate mimic.
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 1-8, 11, 14, 16-19, 22, and 29-32 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 2019/0292547 A1 (hereinafter Li).
With regard to claim 1, which recites “an isolated oligonucleotide comprising:
a sense strand comprising X1 nucleotides, wherein at least one nucleotide is modified with a first modification,
each of the remaining nucleotides is independently modified with a second modification, and
X1 is an integer selected from 13-36,
wherein the first modification and the second modification are different; and
an antisense strand comprising X2 nucleotides, wherein at least one nucleotide is modified with a third modification,
each of the remaining nucleotides is independently modified with a fourth modification, and
X2 is an integer selected from 18-31,
wherein the third modification and the fourth modification are different,”
Li discloses double stranded RNAi agents comprising a sense strand and an antisense strand (paragraph [0014]). Per Table 5, one such duplex is AD04419, which comprises antisense strand AM05612 (Table 3) and sense strand AM05616 (Table 4), both of which are 21 nucleotides in length and comprise at least one 2’-O-methyl modification and at least one 2’-F modification (paragraphs [0388] and [0399]). Both AM05612 and AM05616 are exclusively comprised of modified nucleotides, wherein said modified nucleotides are modified either with a 2’-O-methyl modification or a 2’-F modification, as instantly claimed. Thus, Li anticipates each and every limitation of instant claim 1.
With regard to claims 2-4, which respectively recite “the isolated oligonucleotide of claim 1, wherein the first modification is…2’-F” …”the second modification is…2’-O-methyl,” and “wherein the first modification is 2’-F…and the second modification is 2’-O-methyl,” as set forth above, Li discloses the duplex RNAi agent AD04419 (Table 5), which comprises antisense strand AM05612 (Table 3) and sense strand AM05616 (Table 4), both of which are comprised of 2’-O-methyl and 2’-F modified nucleotides (paragraphs [0388] and [0399]), as instantly claimed. Thus, Li anticipates each and every limitation of instant claims 2-4.
With regard to claims 5-7, which respectively recite “the isolated oligonucleotide of claim 1, wherein the third modification is…2’F”…”the fourth modification is…2’-O-methyl,” and wherein the third modification is 2’F…and the fourth modification is 2’-O-methyl,” as set forth above, Li discloses the duplex RNAi agent AD04419 (Table 5), which comprises antisense strand AM05612 (Table 3) and sense strand AM05616 (Table 4), both of which are comprised of 2’-O-methyl and 2’-F modified nucleotides (paragraphs [0388] and [0399]), as instantly claimed. Thus, Li anticipates each and every limitation of instant claims 5-7.
With regard to claim 8, which recites “the isolated oligonucleotide of claim 1, wherein in the sense strand at least three nucleotides are modified with the first modification…”, the sense strand disclosed in Li and set forth above (AM05616 (Table 4)) comprises three 2’-F modified nucleotides, as instantly claimed. Thus, Li anticipates each and every limitation of instant claim 8.
With regard to claim 11, which recites “the isolated oligonucleotide of claim 8, wherein the at least three nucleotides, the at least four nucleotides, or the at least five nucleotide modified with the first modification are located from position 10 to position 15 from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand,” as set forth above, Li discloses the duplex RNAi agent AD04419 (Table 5), which comprises antisense strand AM05612 (Table 3) and sense strand AM05616 (Table 4), both of which are comprised of 2’-O-methyl and 2’-F modified nucleotides (paragraphs [0388] and [0399]). Sense strand AM05616 (Table 4) comprises three 2’-F modified nucleotides, which are located from positions 11-13 from the nucleotide complementary to the first nucleotide at the 5’ terminus of the antisense strand, as instantly claimed. Thus, Li anticipates each and every limitation of instant claim 11.
With regard to 14, which recites “the isolated oligonucleotide, wherein the at least three nucleotides, the at least four nucleotides, or the at least five nucleotides are modified with [a] 2’-F modification,” as set forth above, sense strand AM05616 (Table 4) of the duplex RNAi agent AD04419 (Table 4) of Li comprises three 2’-F modified nucleotides, as instantly claimed. Thus, Li anticipates each and every limitation of instant claim 14.
With regard to claim 16, which recites “the isolated oligonucleotide of claim 1, wherein the sense strand comprises nucleotides modified with 2’-F modification, and nucleotides modified with 2’-O-methyl modification, according to the formula:
5’ (M)g(F)f(M)e(F)d(M)c(F)b(M)a 3’,
wherein M is [a] 2’-O-methyl modified nucleotide, F is [a] 2’-F modified nucleotide, and each of a, b, c, d, e, f, and g are any one of 0-16, and indicates the number of consecutive nucleotides modified with the modification, and wherein the sense strand is any one of:
5’ (M)0(F)0(M)0(F)0(M)8(F)3(M)10 3’…”,
as set forth above, sense strand AM05616 (Table 4) of the duplex RNAi agent AD04419 (Table 4) of Li comprises three 2’-F modified nucleotides. Furthermore, sense strand AM05616 (Table 4) comprises 18 2’-O-methyl modified nucleotides. The pattern of modified nucleotides in sense strand AM05616 (Table 4) is 5’ (M)8(F)3(M)10 3’, which reads on species a) of instant claim 16. Thus, Li anticipates each and every limitation of instant claim 16.
With regard to claims 17-19, which respectively recite “the isolated oligonucleotide of claim 1, wherein in the antisense strand at most seven nucleotides…” “six nucleotides…” or “five nucleotides are modified with the third modification,” as set forth above, Li discloses the duplex RNAi agent AD04419 (Table 5), which comprises antisense strand AM05612 (Table 3) and sense strand AM05616 (Table 4). Antisense strand AM05612 (Table 3) comprises five 2’-F modified nucleotides, as instantly claimed. Thus, Li anticipates each and every limitation of instant claims 17-19.
With regard to claim 22, which recites “the isolated oligonucleotide of claim 17, wherein the at [most-see section Claim Rejections - 35 USC § 112(b)] seven nucleotides…are modified with [a] 2’-F modification,” as set forth above, antisense strand AM05612 (Table 3) comprises five 2’-F modified nucleotides, which is at most seven nucleotides, as instantly claimed. Thus, Li anticipates each and every limitation of instant claim 22.
With regard to claim 29, which recites “the isolated oligonucleotide of claim 1, wherein the sense strand comprises at least one nucleotide having a modified phosphate backbone, and/or the antisense strand comprises at least one nucleotide having a modified phosphate backbone,” Li further discloses that the duplex RNAi agents taught therein (such as AD04419 (Table 5)) comprise non-standard linkages or backbones such as phosphorothioate linkages (paragraph [0372]). Thus, Li anticipates each and every limitation of instant claim 29.
With regard to claim 30, which recites “the isolated oligonucleotide of claim 1, comprising one or more non-natural base-containing nucleotide[(s)]…locked nucleotide[(s)], or…abasic nucleotide([s]),” Li further discloses that the duplex RNAi agents taught therein (such as AD04419 (Table 5)) comprise one or more abasic nucleotides or locked nucleotides (paragraph [0369]). Thus, Li anticipates each and every limitation of instant claim 30.
With regard to claim 31, which recites “the isolated oligonucleotide of claim 1, wherein the terminal nucleotide at the 5’ end comprises a phosphate mimic,” per the instant specification, an example of a suitable phosphate mimic is vinyl phosphonate (paragraph [0031]), which is disclosed at paragraph [0369] of Li. Table 3 of Li discloses various antisense sequences associated with the duplex RNAi agents taught therein, including AM05055 (Table 3), which is the antisense strand of duplex AD04005 (Table 5). The sense strand associated with the same duplex is AM05064 (Table 4). Both the sense and antisense strands of duplex AD04005 (Table 5) comprise 2’-O-methyl and 2’-F modified nucleotides (Tables 3 and 4) and are 21 nucleotides in length, as recited at instant claim 1. Furthermore, antisense strand AM05055 (Table 3) comprises a terminal vinyl phosphonate deoxyribonucleotide (paragraph [0426]), as instantly claimed. Thus, Li anticipates each and every limitation of instant claim 31.
With regard to claim 32, which recites “the isolated oligonucleotide of claim 1, wherein in the sense strand or the antisense strand or both, a terminal or internal nucleotide is linked to a targeting ligand…”, Li further discloses that the duplex RNAi agents taught therein may be conjugated or linked to a targeting group such as an asialoglycoprotein receptor ligand or an N-acetyl-galactosamine targeting ligand (paragraph [0326]). Thus, Li anticipates each and every limitation of instant claim 32.
Claims 1-18, 22, and 29-32 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2020/243702 A2 (hereinafter Das; as cited in Applicant IDS).
With regard to claim 1, which recites “an isolated oligonucleotide comprising:
a sense strand comprising X1 nucleotides, wherein at least one nucleotide is modified with a first modification,
each of the remaining nucleotides is independently modified with a second modification, and
X1 is an integer selected from 13-36,
wherein the first modification and the second modification are different; and
an antisense strand comprising X2 nucleotides, wherein at least one nucleotide is modified with a third modification,
each of the remaining nucleotides is independently modified with a fourth modification, and
X2 is an integer selected from 18-31,
wherein the third modification and the fourth modification are different,”
Das discloses modified double-stranded RNAi constructs (abstract; paragraph [0017]; Table 2). Duplex D-2000 of Das comprises a sense sequence and an antisense sequence (SEQ ID NOs: 161 and 162, respectively), wherein both the sense and antisense sequences comprise 2’-O-methyl and 2’-F modified nucleotides (paragraph [0177]) and both sequences are 21 nucleotides in length. Thus, Das anticipates each and every limitation of instant claim 1.
With regard to claims 2-4, which respectively recite “the isolated oligonucleotide of claim 1, wherein the first modification is…2’-F” …”the second modification is…2’-O-methyl,” and “wherein the first modification is 2’-F…and the second modification is 2’-O-methyl,” as set forth above, Das discloses modified double-stranded RNAi constructs (abstract; paragraph [0017]; Table 2). Duplex D-2000 of Das comprises a sense sequence and an antisense sequence (SEQ ID NOs: 161 and 162, respectively), wherein both the sense and antisense sequences comprise 2’-O-methyl and 2’-F modified nucleotides (paragraph [0177]), as instantly claimed. Thus, Das anticipates each and every limitation of instant claims 2-4.
With regard to claims 5-7, which respectively recite “the isolated oligonucleotide of claim 1, wherein the third modification is…2’F”…”the fourth modification is…2’-O-methyl,” and wherein the third modification is 2’F…and the fourth modification is 2’-O-methyl,” as set forth above, Das discloses modified double-stranded RNAi constructs (abstract; paragraph [0017]; Table 2). Duplex D-2000 of Das comprises a sense sequence and an antisense sequence (SEQ ID NOs: 161 and 162, respectively), wherein both the sense and antisense sequences comprise 2’-O-methyl and 2’-F modified nucleotides (paragraph [0177]), as instantly claimed. Thus, Das anticipates each and every limitation of instant claims 5-7.
With regard to claims 8-10, which respectively recite “the isolated oligonucleotide of claim 1, wherein in the sense strand at least three nucleotides are modified with the first modification…”, “at least four nucleotides are modified with the first modification…”,” and “at least five nucleotides are modified with the first modification…”, the sense strand disclosed in Das and set forth above (SEQ ID NO: 161 (Table 2)) comprises five 2’-F modified nucleotides, as instantly claimed. Thus, Das anticipates each and every limitation of instant claims 8-10.
With regard to claim 11, which recites “the isolated oligonucleotide of claim 8, wherein the at least three nucleotides, the at least four nucleotides, or the at least five nucleotides modified with the first modification are located from position 10 to position 15 from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand…”, as set forth above, the sense strand disclosed in Das (SEQ ID NO: 161 (Table 2)) comprises five 2’-F modified nucleotides, wherein said 2’-F modified nucleotides are located at positions 10-13 and 15 from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand. Thus, Das anticipates each and every limitation of instant claim 11.
With regard to claim 12, which recites “the isolated oligonucleotide of claim 8, wherein one of the at least four nucleotides modified with the first modification is located at position 10 from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand…”, as set forth above, the sense strand disclosed in Das (SEQ ID NO: 161 (Table 2)) comprises five 2’-F modified nucleotides, wherein said 2’-F modified nucleotides are located at positions 10-13 and 15 from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand. Thus, Das anticipates each and every limitation of instant claim 12.
With regard to claim 13, which recites “the isolated oligonucleotide of claim 8, wherein not all of the at least three nucleotides modified with the first modification are consecutively located,” as set forth above, the sense strand disclosed in Das (SEQ ID NO: 161 (Table 2)) comprises five 2’-F modified nucleotides, four of which are consecutively located and one of which is located separate from the other four (positions 10-13 and 15 from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand). Thus, Das anticipates each and every limitation of instant claim 13.
With regard to claim 14, which recites “the isolated oligonucleotide of claim 8, wherein the at least three nucleotides…are modified with [a] 2’-F modification,” as set forth above, the sense strand disclosed in Das (SEQ ID NO: 161 (Table 2)) comprises five 2’-F modified nucleotides. Thus, Das anticipates each and every limitation of instant claim 14.
With regard to claim 15, which recites “the isolated oligonucleotide of claim 8, wherein in the sense strand…
at most five nucleotides are modified with the first modification at positions 10, 11, 12, 13 and 15, from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand…”, as set forth above, the sense strand disclosed in Das (SEQ ID NO: 161 (Table 2)) comprises five 2’-F modified nucleotides, wherein said 2’-F modified nucleotides are located at positions 10-13 and 15 from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand. Thus, Das anticipates each and every limitation of instant claim 15.
With regard to claim 16, which recites “the isolated oligonucleotide of claim 1, wherein the sense strand comprises nucleotides modified with 2’-F modification, and nucleotides modified with 2’-O-methyl modification, according to the formula:
5’ (M)g(F)f(M)e(F)d(M)c(F)b(M)a 3’,
wherein M is [a] 2’-O-methyl modified nucleotide, F is [a] 2’-F modified nucleotide, and each of a, b, c, d, e, f, and g are any one of 0-16, and indicates the number of consecutive nucleotides modified with the modification, and wherein the sense strand is any one of:…
5’ (M)0(F)0(M)6(F)1(M)1(F)4(M)9 3’…”,
as set forth above, the sense strand disclosed in Das (SEQ ID NO: 162 (Table 2)) comprises five 2’-F modified nucleotides and sixteen 2’-O-methyl modified nucleotides. The pattern of modified nucleotides in sense strand SEQ ID NO: 161 (Table 2) is 5’ (M)6(F)1(M)1(F)4(M)9 3’, which reads on species i) of instant claim 16. Thus, Das anticipates each and every limitation of instant claim 16.
With regard to claims 17 and 18, which respectively recite “the isolated oligonucleotide of claim 1, wherein in the antisense strand at most seven nucleotides…” or “six nucleotides are modified with the third modification…”, as set forth above, Das discloses modified double-stranded RNAi constructs (abstract; paragraph [0017]; Table 2). Duplex D-2000 of Das comprises a sense sequence and an antisense sequence (SEQ ID NOs: 161 and 162, respectively), wherein both the sense and antisense sequences comprise 2’-O-methyl and 2’-F modified nucleotides (paragraph [0177]). Antisense strand SEQ ID NO: 162 (Table 2) of Das comprises six 2’-F modified nucleotides, as instantly claimed. Thus, Li anticipates each and every limitation of instant claims 17 and 18.
With regard to claim 22, which recites “the isolated oligonucleotide of claim 17, wherein the at [most-see section Claim Rejections - 35 USC § 112(b)] seven nucleotides…are modified with [a] 2’-F modification,” as set forth above, Das discloses modified double-stranded RNAi constructs (abstract; paragraph [0017]; Table 2). Duplex D-2000 of Das comprises a sense sequence and an antisense sequence (SEQ ID NOs: 161 and 162, respectively), wherein both the sense and antisense sequences comprise 2’-O-methyl and 2’-F modified nucleotides (paragraph [0177]). Antisense strand SEQ ID NO: 162 (Table 2) of Das comprises six 2’-F modified nucleotides, as instantly claimed. Thus, Das anticipates each and every limitation of instant claim 22.
With regard to claim 29, which recites “the isolated oligonucleotide of claim 1, wherein the sense strand comprises at least one nucleotide having a modified phosphate backbone, and/or the antisense strand comprises at least one nucleotide having a modified phosphate backbone,” Das further discloses that the duplex RNAi agents taught therein (such as the first duplex of Table 2) comprise modified linkages or backbones such as phosphorothioate linkages (paragraph [0010]). Thus, Das anticipates each and every limitation of instant claim 29.
With regard to claim 30, which recites “the isolated oligonucleotide of claim 1, comprising one or more non-natural base-containing nucleotide[(s)]…locked nucleotide[(s)], or…abasic nucleotide([s]),” Das further discloses that the duplex RNAi agents taught therein (such as the first duplex of Table 2) comprise one or more locked nucleotides (paragraph [0152]). Thus, Das anticipates each and every limitation of instant claim 30.
With regard to claim 31, which recites “the isolated oligonucleotide of claim 1, wherein the terminal nucleotide at the 5’ end comprises a phosphate mimic,” per the instant specification, an example of a suitable phosphate mimic is vinyl phosphonate (paragraph [0031]), which is disclosed at paragraph [0049] of Das. Per the disclosure of Das, in some embodiments of the RNAi constructs of the invention, the 5’ end of the sense strand, the antisense strand, or both the antisense and sense strands comprise a 5’-vinylphosphate moiety. Thus, Das anticipates each and every limitation of instant claim 31.
With regard to claim 32, which recites “the isolated oligonucleotide of claim 1, wherein in the sense strand or the antisense strand or both, a terminal or internal nucleotide is linked to a targeting ligand…”, Das further discloses that the duplex RNAi agents taught therein may be conjugated or linked to a targeting group such as an N-acetyl-galactosamine targeting ligand (paragraph [0088]). Thus, Das anticipates each and every limitation of instant claim 32.
Claims 1-9, 11, 13, 16-19, 22, 26, 27, 29, 30, and 32 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 2019/0350962 A1 (hereinafter Chan).
With regard to claim 1, which recites “an isolated oligonucleotide comprising:
a sense strand comprising X1 nucleotides, wherein at least one nucleotide is modified with a first modification,
each of the remaining nucleotides is independently modified with a second modification, and
X1 is an integer selected from 13-36,
wherein the first modification and the second modification are different; and
an antisense strand comprising X2 nucleotides, wherein at least one nucleotide is modified with a third modification,
each of the remaining nucleotides is independently modified with a fourth modification, and
X2 is an integer selected from 18-31,
wherein the third modification and the fourth modification are different,”
Chan discloses double stranded RNAi agents (abstract) such as those recited at claim 1, which comprises sense strand SEQ ID NO: 10 and antisense strand SEQ ID NO: 7. Both SEQ ID NOs: 10 and 7 exclusively comprise 2’-O-methyl modified nucleotides and 2’-F modified nucleotides. Additionally, SEQ ID NO: 10 is 21 nucleotides in length, while SEQ ID NO: 7 is 23 nucleotides in length. Thus, Chan discloses each and every limitation of instant claim 1.
With regard to claims 2-4, which respectively recite “the isolated oligonucleotide of claim 1, wherein the first modification is…2’-F” …”the second modification is…2’-O-methyl,” and “wherein the first modification is 2’-F…and the second modification is 2’-O-methyl,” as set forth above, Chan discloses double stranded RNAi agents (abstract) such as those recited at claim 1, which comprises sense strand SEQ ID NO: 10 and antisense strand SEQ ID NO: 7. Both SEQ ID NOs: 10 and 7 exclusively comprise 2’-O-methyl modified nucleotides and 2’-F modified nucleotides. Thus, Chan anticipates each and every limitation of instant claims 2-4.
With regard to claims 5-7, which respectively recite “the isolated oligonucleotide of claim 1, wherein the third modification is…2’F”…”the fourth modification is…2’-O-methyl,” and wherein the third modification is 2’F…and the fourth modification is 2’-O-methyl,” as set forth above, Chan discloses double stranded RNAi agents (abstract) such as those recited at claim 1, which comprises sense strand SEQ ID NO: 10 and antisense strand SEQ ID NO: 7. Both SEQ ID NOs: 10 and 7 exclusively comprise 2’-O-methyl modified nucleotides and 2’-F modified nucleotides. Thus, Chan anticipates each and every limitation of instant claims 5-7.
With regard to claims 8 and 9, which respectively recite “the isolated oligonucleotide of claim 1, wherein in the sense strand at least three nucleotides are modified with the first modification…”, and “at least four nucleotides are modified with the first modification…”, the sense strand disclosed in Chan and set forth above (SEQ ID NO: 10) comprises four 2’-F modified nucleotides, as instantly claimed. Thus, Chan anticipates each and every limitation of instant claims 8 and 9.
With regard to claim 11, which recites “the isolated oligonucleotide of claim 8, wherein the at least three nucleotides, the at least four nucleotides, or the at least five nucleotides modified with the first modification are located from position 10 to position 15 from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand…”, as set forth above, the sense strand disclosed in Chan (SEQ ID NO: 10) comprises four 2’-F modified nucleotides, wherein said 2’-F modified nucleotides are located at positions 11-13 and 15 from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand. Thus, Chan anticipates each and every limitation of instant claim 11.
With regard to claim 13, which recites “the isolated oligonucleotide of claim 8, wherein not all of the at least three nucleotides modified with the first modification are consecutively located,” as set forth above, the sense strand disclosed in Chan (SEQ ID NO: 10) comprises four 2’-F modified nucleotides, three of which are consecutively located and one of which is located separate from the other three (positions 11-13 and 15 from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand). Thus, Chan anticipates each and every limitation of instant claim 13.
With regard to claim 16, which recites “the isolated oligonucleotide of claim 1, wherein the sense strand comprises nucleotides modified with 2’-F modification, and nucleotides modified with 2’-O-methyl modification, according to the formula:
5’ (M)g(F)f(M)e(F)d(M)c(F)b(M)a 3’,
wherein M is [a] 2’-O-methyl modified nucleotide, F is [a] 2’-F modified nucleotide, and each of a, b, c, d, e, f, and g are any one of 0-16, and indicates the number of consecutive nucleotides modified with the modification, and wherein the sense strand is any one of:…
5’ (M)0(F)0(M)5(F)1(M)1(F)3(M)10 3’…”,
as set forth above, the sense strand disclosed in Chan (SEQ ID NO: 10) comprises four 2’-F modified nucleotides and seventeen 2’-O-methyl modified nucleotides. The pattern of modified nucleotides in sense strand SEQ ID NO: 10 is 5’ (M)6(F)1(M)1(F)3(M)10 3’, which reads on species b) of instant claim 16. Thus, Chan anticipates each and every limitation of instant claim 16.
With regard to claims 17-19, which respectively recite “the isolated oligonucleotide of claim 1, wherein in the antisense strand at most seven nucleotides…” “six nucleotides…” or “five nucleotides are modified with the third modification,” as set forth above, Chan discloses double stranded RNAi agents (abstract) such as those recited at claim 1, which comprises sense strand SEQ ID NO: 10 and antisense strand SEQ ID NO: 7. Antisense strand SEQ ID NO: 7 comprises five 2’-F modified nucleotides, as instantly claimed. Thus, Chan anticipates each and every limitation of instant claims 17-19.
With regard to claim 22, which recites “the isolated oligonucleotide of claim 17, wherein the at [most-see section Claim Rejections - 35 USC § 112(b)] seven nucleotides…are modified with [a] 2’-F modification,” as set forth above, Chan discloses double stranded RNAi agents (abstract) such as those recited at claim 1, which comprises sense strand SEQ ID NO: 10 and antisense strand SEQ ID NO: 7, wherein both the sense and antisense sequences comprise 2’-O-methyl and 2’-F modified nucleotides. Antisense strand SEQ ID NO: 7 of Chan comprises five 2’-F modified nucleotides, as instantly claimed. Thus, Chan anticipates each and every limitation of instant claim 22.
With regard to claim 26, which recites “the isolated oligonucleotide of claim 1, wherein the antisense strand comprises nucleotides modified with [a] 2’-F modification, and nucleotides modified with [a] 2’-O-methyl modification, according to the formula:
3’ (M)a(F)b(M)c(F)d(M)e(F)f(M)g(F)h(M)i(F)j(M)k(F)l(M)m(F)n(M)o 5’,
Wherein M is [a] 2’-O-methyl modified nucleotide, F is [a] 2’-F modified nucleotide, and each of a, b, c, d, e, f, g, h, i, j, k, l, m, n, and o are any one of 0-16, and indicates the number of consecutive nucleotides modified with the modification, wherein the antisense strand is any one of:…
5) 3’ (M)0(F)0(M)0(F)0(M)7(F)1(M)1(F)1(M)4(F)1(M)2(F)1(M)3(F)1(M)1 5’…”
as set forth above, the antisense strand disclosed in Chan (SEQ ID NO: 7) comprises five 2’-F modified nucleotides and eighteen 2’-O-methyl modified nucleotides. The pattern of modified nucleotides in sense strand SEQ ID NO: 7 is 3’ (M)7(F)1(M)1(F)1(M)4(F)1(M)2(F)1(M)3(F)1(M)1 5’, which reads on species 5) of instant claim 26. Thus, Chan anticipates each and every limitation of instant claim 26.
With regard to claim 27, which recites “the isolated oligonucleotide of claim 26, wherein the sense strand comprises nucleotides modified with 2’-F modification, and nucleotides modified with 2’-O-methyl modification, according to the formula:
5’ (M)g(F)f(M)e(F)d(M)c(F)b(M)a 3’,
wherein M is [a] 2’-O-methyl modified nucleotide, F is [a] 2’-F modified nucleotide, and each of a, b, c, d, e, f, and g are any one of 0-16, and indicates the number of consecutive nucleotides modified with the modification, and wherein the sense strand is any one of:…
5’ (M)0(F)0(M)5(F)1(M)1(F)3(M)10 3’…”,
as set forth above, the sense strand disclosed in Chan (SEQ ID NO: 10) comprises four 2’-F modified nucleotides and seventeen 2’-O-methyl modified nucleotides. The pattern of modified nucleotides in sense strand SEQ ID NO: 10 is 5’ (M)6(F)1(M)1(F)3(M)10 3’, which reads on species b) of instant claim 27. Thus, Chan anticipates each and every limitation of instant claim 27.
With regard to claim 29, which recites “the isolated oligonucleotide of claim 1, wherein the sense strand comprises at least one nucleotide having a modified phosphate backbone, and/or the antisense strand comprises at least one nucleotide having a modified phosphate backbone,” Chan further discloses that the duplex RNAi agents taught therein (such as the duplex of claim 1) comprise modified linkages or backbones such as phosphorothioate linkages (paragraph [0182]; claim 1). Thus, Chan anticipates each and every limitation of instant claim 29.
With regard to claim 30, which recites “the isolated oligonucleotide of claim 1, comprising one or more non-natural base-containing nucleotide[(s)]…locked nucleotide[(s)], or…abasic nucleotide([s]),” Chan further discloses that the duplex RNAi agents taught therein (such as the duplex of claim 1) may comprise one or more locked nucleotides (paragraph [0192]). Thus, Chan anticipates each and every limitation of instant claim 30.
With regard to claim 32, which recites “the isolated oligonucleotide of claim 1, wherein in the sense strand or the antisense strand or both, a terminal or internal nucleotide is linked to a targeting ligand…”, Chan further discloses that the duplex RNAi agents taught therein may be conjugated or linked to a targeting group such as an N-acetyl-galactosamine targeting ligand (paragraphs [0028] and [0029]). Thus, Chan anticipates each and every limitation of instant claim 32.
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 20, 21, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292547 A1 (hereinafter Li), as applied to claims 1, 8, and 17 above, and further in view of US 2020/0087663 A1 (hereinafter Khvorova).
Claims 20, 21, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/243702 A2 (hereinafter Das; as cited in Applicant IDS), as applied to claims 1, 8, and 17 above, and further in view of US 2020/0087663 A1 (hereinafter Khvorova).
Claims 20, 21, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0350962 A1 (hereinafter Chan), as applied to claims 1, 8, and 17 above, and further in view of US 2020/0087663 A1 (hereinafter Khvorova).
The disclosures of Li, Das, and Chan are respectively described above and applied as before (see section Claim Rejections - 35 USC § 102). However, these disclosures do not teach the specified modifications of instant claims 20, 21, and 23-25.
With regard to claims 20 and 21, which respectively recite “the isolated oligonucleotide of claim 17, wherein at most four nucleotides…” or “…at most three nucleotides are modified with the third modification,” as set forth above, Li, Das, and Chan all disclose duplex RNAi agents. However, none of the duplex RNAi agents of Li, Das, and Chan comprise at most three or four nucleotides modified with the third modification, as instantly claimed. This deficiency is cured by Khvorova. Khvorova discloses 2’-O-methyl-rich duplex RNAi agents having reduced 2’-F modifications at Example 3. Pattern 1A comprises a sense strand (SEQ ID NO: 4) and antisense strand (SEQ ID NO: 3), wherein the antisense strand comprises two “xN” residues, which are disclosed to be 2’-fluoro modified nucleotides (paragraphs [0123]-[0125]). Per Khvorova, the O-methyl rich siRNAs disclosed therein with minimal 2’-F modifications acquired unexpected improvements in efficacy properties in vitro and showed either increased or similar guide strand accumulation in the liver, kidney, and placenta in vivo (paragraphs [0344] and [0345]). Thus, Khvorova discloses that minimal 2’-F modification of the antisense strand (i.e. two 2’-F modifications) unexpectedly improve the efficacy in vitro while increasing or maintaining guide strand accumulation in the liver, kidney, and placenta in vivo (paragraphs [0344] and [0345]). Thus, it is considered that Khvorova discloses each and every additional limitation of instant claims 20 and 21.
With regard to claim 23, which recites “the isolated oligonucleotide of claim 17, wherein in the antisense strand:
at most five nucleotides are modified with the third modification at positions 2, 3, 6, 14 and 16, from the nucleotide complementary to the first nucleotide at the 5’ terminus of the antisense strand, or
at most five nucleotides are modified with the third modification at positions 2, 6, 7, 14 and 16, from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand,” as set forth above, Li, Das, and Chan all anticipate the oligonucleotide of claim 17. However, none of Li, Das, and Chan disclose the recited modification pattern. However, Li, Das, Chan, and Khvorova all disclose numerous duplex RNAi species (Li: Table 5; Das: Table 2; Chan: Table 1; Khvorova: Figure 1), which all comprise different modification patterns. Based on these disclosures, it is clearly routine to optimize duplex RNAi agent function by varying the design/placement of the modifications contained therein. Per MPEP 2144.05(I)(A), “it is not inventive to discover the optimum or workable ranges by routine experimentation” (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Therefore, it is considered that it would have been obvious, based on the state of the art and the disclosures of Li, Das, Chan, and Khvorova to modify the design/placement of the modifications taught therein to optimize duplex RNAi agent function, thereby arriving at the instant invention.
With regard to claim 24, which recites “the isolated oligonucleotide of claim 17, wherein in the antisense strand:
at most six nucleotides are modified with the third modification at positions 2, 3, 6, 8, 9 and 16, from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand, or
at most six nucleotides are modified with the third modification at positions 2, 3, 5, 8, 9 and 16, from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand,” as set forth above, Li, Das, and Chan all anticipate the oligonucleotide of claim 17. However, none of Li, Das, and Chan disclose the recited modification pattern. However, Li, Das, Chan, and Khvorova all disclose numerous duplex RNAi species (Li: Table 5; Das: Table 2; Chan: Table 1; Khvorova: Figure 1), which all comprise different modification patterns. Based on these disclosures, it is clearly routine to optimize duplex RNAi agent function by varying the design/placement of the modifications contained therein. Per MPEP 2144.05(I)(A), “it is not inventive to discover the optimum or workable ranges by routine experimentation” (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Therefore, it is considered that it would have been obvious, based on the state of the art and the disclosures of Li, Das, Chan, and Khvorova to modify the design/placement of the modifications taught therein to optimize duplex RNAi agent function, thereby arriving at the instant invention.
With regard to claim 25, which recites “the isolated oligonucleotide of claim 17, wherein in the antisense strand[:]
at most seven nucleotides are modified with the third modification at positions 2, 3, 5, 7, 9, 14 and 16, from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand, or
at most seven nucleotides are modified with the third modification at positions 2, 3, 5, 7, 10, 14 and 16, from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand,” as set forth above, Li, Das, and Chan all anticipate the oligonucleotide of claim 17. However, none of Li, Das, and Chan disclose the recited modification pattern. However, Li, Das, Chan, and Khvorova all disclose numerous duplex RNAi species (Li: Table 5; Das: Table 2; Chan: Table 1; Khvorova: Figure 1), which all comprise different modification patterns. Based on these disclosures, it is clearly routine to optimize duplex RNAi agent function by varying the design/placement of the modifications contained therein. Per MPEP 2144.05(I)(A), “it is not inventive to discover the optimum or workable ranges by routine experimentation” (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Therefore, it is considered that it would have been obvious, based on the state of the art and the disclosures of Li, Das, Chan, and Khvorova to modify the design/placement of the modifications taught therein to optimize duplex RNAi agent function, thereby arriving at the instant invention.
Given that Li, Das, and Chan all disclose duplex RNAi species, all of which comprise different modification patterns, and that Khvorova discloses that minimal 2’-F modification of the antisense strand (i.e. two 2’-F modifications) of siRNA duplexes unexpectedly improves the efficacy in vitro while increasing or maintaining guide strand accumulation in the liver, kidney, and placenta in vivo, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to reduce the number of 2’-F modifications in the antisense strand (per Khvorova) as well as to modify the design/placement of the modifications taught by the art to predictably improve RNAi construct efficacy and optimize its function. One would have been motivated to make such a modification in order to receive the expected benefit of improving RNAi duplex efficacy and optimizing its function.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/243702 A2 (hereinafter Das; as cited in Applicant IDS), as applied to claims 1, 8, and 15 above, and further in view of US 2020/0087663 A1 (hereinafter Khvorova).
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0350962 A1 (hereinafter Chan), as applied to claims 1, 8, and 15 above, and further in view of US 2020/0087663 A1 (hereinafter Khvorova).
The disclosures of Das and Chan are respectively described above and applied as before (see section Claim Rejections - 35 USC § 102). However, these disclosures do not teach the specified modifications of instant claim 28.
With regard to claim 28, which recites “the isolated oligonucleotide of claim 15, wherein in the antisense strand:
at most five nucleotides are modified with the third modification at positions 2, 3, 6, 14 and 16, from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand… or
at most seven nucleotides are modified with the third modification at positions 2, 3, 5, 7, 10, 14 and 16, from the nucleotide complementary to the first nucleotide at the 5’-terminus of the antisense strand,” as set forth above, Das, and Chan all anticipate the oligonucleotide of claim 15. Furthermore, as set forth above, Khvorova discloses 2’-O-methyl-rich duplex RNAi agents, including those having reduced 2’-F modifications at Example 3. However, none of Das, Chan, or Khvorova disclose the recited modification pattern. However, Das, Chan, and Khvorova all disclose numerous duplex RNAi species (Das: Table 2; Chan: Table 1; Khvorova: Figure 1), which all comprise different modification patterns. Based on these disclosures, it is clearly routine to optimize duplex RNAi agent function by varying the design/placement of the modifications contained therein. Per MPEP 2144.05(I)(A), “it is not inventive to discover the optimum or workable ranges by routine experimentation” (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Therefore, it is considered that it would have been obvious, based on the state of the art and the disclosures of Das, Chan, and Khvorova to modify the design/placement of the modifications taught therein to optimize duplex RNAi agent function, thereby arriving at the instant invention.
Given that Das and Chan both disclose duplex RNAi species, all of which comprise different modification patterns, and that Khvorova discloses that minimal 2’-F modification of the antisense strand (i.e. two 2’-F modifications) of siRNA duplexes unexpectedly improves the efficacy in vitro while increasing or maintaining guide strand accumulation in the liver, kidney, and placenta in vivo, 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 design/placement of the modifications taught by the art to predictably improve RNAi construct efficacy and optimize its function. One would have been motivated to make such a modification in order to receive the expected benefit of optimizing RNAi duplex function.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 29, 31, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 3 of U.S. Patent No. 11,286,488 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Instant claim 29 recites that the isolated oligonucleotide claimed therein comprises at least one nucleotide having a modified phosphate backbone. Instant claim 31 recites that the isolated oligonucleotide claimed therein comprises a phosphate mimic at the 5’ terminal nucleotide. Finally, instant claim 32 recites that the isolated oligonucleotide claimed therein is linked to a targeting ligand.
In comparison, claim 1 of patent ‘488 recites an oligonucleotide comprising a sense strand (SEQ ID NO: 2) and an antisense strand (SEQ ID NO: 1), wherein all positions of each strand are modified either with a 2’-F modification or a 2’-O-methyl modification, wherein both strands are of defined lengths that read on the lengths recited in the instant application, wherein the oligonucleotide comprises phosphorothioate linkages, wherein the oligonucleotide comprises a phosphate mimic at position 1 of the antisense strand, and wherein the oligonucleotide is linked to a targeting ligand such as GalNAc. Claims 2 and 3 of patent ‘488 are drawn to compositions comprising said oligonucleotide.
Given that both the instant and patented applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification, wherein the oligonucleotide comprises at least one phosphorothioate linkage, wherein the oligonucleotide comprises a terminal phosphate mimic, and wherein the oligonucleotide is linked to a targeting ligand, it is considered that the instant and patented applications are not patentably distinct.
Claims 1-7, 29, 31, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,661,604 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Instant claim 29 recites that the isolated oligonucleotide claimed therein comprises at least one nucleotide having a modified phosphate backbone. Instant claim 31 recites that the isolated oligonucleotide claimed therein comprises a phosphate mimic at the 5’ terminal nucleotide. Finally, instant claim 32 recites that the isolated oligonucleotide claimed therein is linked to a targeting ligand.
In comparison, claims 1 and 5 of patent ‘604 recite an oligonucleotide comprising a sense strand (SEQ ID NO: 2) and an antisense strand (SEQ ID NO: 1), wherein all positions of each strand are modified either with a 2’-F modification or a 2’-O-methyl modification and wherein both strands are of defined lengths that read on the lengths recited in the instant application. Patented claims 2 and 6 further recite conjugation of said oligonucleotide to a GalNac moiety. Patented claims 3, 5 and 8 further recite that said oligonucleotide comprises at least one phosphorothioate linkage. Patented claims 4 and 7 further recite that said oligonucleotide comprises a terminal phosphate mimic.
Given that both the instant and patented applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification, wherein the oligonucleotide comprises at least one phosphorothioate linkage, wherein the oligonucleotide comprises a terminal phosphate mimic, and wherein the oligonucleotide is linked to a targeting ligand, it is considered that the instant and patented applications are not patentably distinct.
Claims 1-7, 29, 31, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 27, 28, 36, 40, 42, 44, 46, 48, 53, 56, 65, 66, 67, 84, 94, and 101 of copending Application No. 18/316,529 (reference application; corresponds to US 2023/0416742 A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Instant claim 29 recites that the isolated oligonucleotide claimed therein comprises at least one nucleotide having a modified phosphate backbone. Instant claim 31 recites that the isolated oligonucleotide claimed therein comprises a phosphate mimic at the 5’ terminal nucleotide. Finally, instant claim 32 recites that the isolated oligonucleotide claimed therein is linked to a targeting ligand.
In comparison, copending claims 1, 4, 27, 28, and 36 are drawn to an RNAi oligonucleotide comprising a sense strand (15 to 50 nucleotides in length; sequences are defined at copending claims 65, 67, 84, and 94) and an antisense strand (15 to 30 nucleotides in length; sequences are defined at copending claims 66, 67, 84, and 94), wherein each and every nucleotide is modified with either a 2’-O-methyl modification or a 2’-F modification. Copending claims 40, 42, and 44 further recite that the RNAi oligonucleotide claimed therein comprises at least one modified internucleotide linkage (i.e. phosphorothioate). Copending claim 46 further recites that the antisense strand comprises a phosphate analog at the 5’ nucleotide. Copending claims 48, 53, 56 further recite that the RNAi oligonucleotide claimed therein is conjugated to one or more targeting ligands. Copending claim 101 recites a pharmaceutical composition comprising the RNAi oligonucleotide claimed therein.
Given that both the instant and copending applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification, wherein the oligonucleotide comprises at least one phosphorothioate linkage, wherein the oligonucleotide comprises a terminal phosphate mimic, and wherein the oligonucleotide is linked to a targeting ligand, it is considered that the instant and copending applications are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7, 29, 31, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 27, 28, 36, 40, 42, 44, 46, 48, 53, 56, 65, 66, 67, 83, 92, and 98 of copending Application No. 18/316,561 (reference application; corresponds to US 2023/0416743 A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Instant claim 29 recites that the isolated oligonucleotide claimed therein comprises at least one nucleotide having a modified phosphate backbone. Instant claim 31 recites that the isolated oligonucleotide claimed therein comprises a phosphate mimic at the 5’ terminal nucleotide. Finally, instant claim 32 recites that the isolated oligonucleotide claimed therein is linked to a targeting ligand.
In comparison, copending claims 1, 4, 27, 28, 36, and 92 are drawn to an RNAi oligonucleotide comprising a sense strand (15 to 50 nucleotides in length; sequences defined at copending claims 65, 67, and 83) and an antisense strand (15 to 30 nucleotides in length; sequences defined at copending claims 66, 67, and 83), wherein each and every nucleotide is modified with either a 2’-O-methyl modification or a 2’-F modification. Copending claims 40, 42, and 44 further recite that the RNAi oligonucleotide claimed therein comprises at least one modified internucleotide linkage (i.e. phosphorothioate). Copending claim 46 further recites that the antisense strand comprises a phosphate analog at the 5’ nucleotide. Copending claims 48, 53, 56 further recite that the RNAi oligonucleotide claimed therein is conjugated to one or more targeting ligands. Copending claim 98 recites a pharmaceutical composition comprising the RNAi oligonucleotide claimed therein.
Given that both the instant and copending applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification, wherein the oligonucleotide comprises at least one phosphorothioate linkage, wherein the oligonucleotide comprises a terminal phosphate mimic, and wherein the oligonucleotide is linked to a targeting ligand, it is considered that the instant and copending applications are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7, 16, 26, and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 18, 19, and 42-49 of copending Application No. 18/585,697 (reference application; corresponds to US 2024/0309383 A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Furthermore, instant claims 16 and 27 define a sense strand modification pattern of species l), which comprises 5’ (M)0(F)0(M)5(F)1(M)1(F)4(M)9 3’ and instant claim 26 defines an antisense strand modification pattern of species 25), which comprises 3’ (M)0(F)0(M)6(F)1(M)1(F)1(M)3(F)1(M)2(F)1(M)1(F)1(M)1(F)2(M)1 5’.
In comparison, copending claim 1 is drawn to an isolated oligonucleotide comprising a sense strand (defined at copending claim 19) and an antisense strand (defined at copending claim 18), wherein the strands are of defined lengths that read on the lengths recited in the instant application. The patterns of modifications of these strands are defined at copending claims 42 (wherein the sequences are defined at copending claims 44 and 46) and 43 (wherein the sequences are defined at copending claims 45 and 46) and are identical to those recited at instant claims 16, 26, and 27, as set forth above. Copending claims 47-49 are drawn to a vector, a delivery system, and a pharmaceutical composition comprising the claimed isolated oligonucleotide.
Given that both the instant and copending applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification in specified patterns, it is considered that the instant and copending applications are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7, 16, 26, 27, 29, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 30, 41-48, and 52-56 of copending Application No. 18/593,706 (reference application; corresponds to US 2024/0309380 A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Furthermore, instant claims 16 and 27 define a sense strand modification pattern of species l), which comprises 5’ (M)0(F)0(M)5(F)1(M)1(F)4(M)9 3’ and instant claim 26 defines an antisense strand modification pattern of species 25), which comprises 3’ (M)0(F)0(M)6(F)1(M)1(F)1(M)3(F)1(M)2(F)1(M)1(F)1(M)1(F)2(M)1 5’. Instant claim 29 recites that the isolated oligonucleotide claimed therein comprises at least one nucleotide having a modified phosphate backbone. Finally, instant claim 32 recites that the isolated oligonucleotide claimed therein is linked to a targeting ligand.
In comparison, copending claims 1 and 30 are drawn to an isolated oligonucleotide comprising a sense strand and an antisense strand of defined lengths that read on the lengths recited in the instant application, wherein the sequences of each modified with 2’-F and 2’-O-methyl in patterns defined at copending claims 41 and 52 (antisense) and 42 and 53 (sense) that are identical to those recited at instant claims 16, 27, and 27, as set forth above. Per copending claims 43-45, the isolated oligonucleotide further comprises at least one phosphorothioate internucleotide linkage and a conjugated targeting ligand. Copending claims 46-48 and 54-56 are drawn to a vector, a delivery system, and a pharmaceutical composition comprising the claimed isolated oligonucleotide.
Given that both the instant and copending applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification in specified patterns, wherein the oligonucleotide comprises at least one phosphorothioate linkage, and wherein the oligonucleotide is linked to a targeting ligand, it is considered that the instant and copending applications are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7, 29, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 22, 23, and 32-37 of copending Application No. 18/650,710 (reference application; corresponds to US 2024/0301421 A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Instant claim 29 recites that the isolated oligonucleotide claimed therein comprises at least one nucleotide having a modified phosphate backbone. Finally, instant claim 32 recites that the isolated oligonucleotide claimed therein is linked to a targeting ligand.
In comparison, copending claims 15, 32, and 35 are both drawn to isolated oligonucleotides consisting of an antisense strand and a sense strand of defined lengths that read on the lengths recited in the instant application, wherein both the sense and antisense strands are fully modified with 2’-O-methyl and 2’-F modifications, comprise phosphorothioate linkages, and wherein the sense strand is linked to a GalNAc targeting ligand. Copending claims 22, 23, 33, 34, 36, and 37 are drawn to delivery systems and pharmaceutical compositions comprising the isolated oligonucleotides claimed therein.
Given that both the instant and copending applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification, wherein the oligonucleotide comprises at least one phosphorothioate linkage, and wherein the oligonucleotide is linked to a targeting ligand, it is considered that the instant and copending applications are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7, 16, 29, 31, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 and 27-29 of copending Application No. 18/653,253 (reference application; corresponds to US 2024/0294916 A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Furthermore, instant claim 16 defines a sense strand modification pattern of species l), which comprises 5’ (M)0(F)0(M)5(F)1(M)1(F)4(M)9 3’. Instant claim 29 recites that the isolated oligonucleotide claimed therein comprises at least one nucleotide having a modified phosphate backbone. Instant claim 31 recites that the isolated oligonucleotide claimed therein comprises a phosphate mimic at the 5’ terminal nucleotide. Finally, instant claim 32 recites that the isolated oligonucleotide claimed therein is linked to a targeting ligand.
In comparison, copending claims 1-4 are drawn to an isolated oligonucleotide comprising an antisense strand and a sense strand of defined lengths that read on the lengths recited in the instant application. Copending claims 5 and 9-21 subsequently define modification patterns comprising 2’-F, 2’-O-methyl and phosphorothioate linkages in defined patterns. The pattern of the sense strand modifications recited at copending claim 11 is identical to that recited at instant claim 16, as set forth above. Copending claim 6 recites that the isolated oligonucleotide comprises a terminal phosphate mimic, and copending claims 7, 8, and 27-29 recite that the isolated oligonucleotide is linked to a targeting ligand such as GalNAc. Copending claims 22-24 are respectively drawn to a vector, a delivery system, and a pharmaceutical compositions comprising the isolated oligonucleotide.
Given that both the instant and copending applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification in defined patterns, wherein the oligonucleotide comprises at least one phosphorothioate linkage, wherein the oligonucleotide comprises a terminal phosphate mimic, and wherein the oligonucleotide is linked to a targeting ligand, it is considered that the instant and copending applications are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7, 16, 26, 27, 29, 31, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 8, 9, 11-13, 15-20, 22, and 23 of copending Application No. 18/750,463 (reference application; corresponds to US 2025/0027089 A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Furthermore, instant claims 16 and 27 define a sense strand modification pattern of species l), which comprises 5’ (M)0(F)0(M)5(F)1(M)1(F)4(M)9 3’ and instant claim 26 defines an antisense strand modification pattern of species 25), which comprises 3’ (M)0(F)0(M)6(F)1(M)1(F)1(M)3(F)1(M)2(F)1(M)1(F)1(M)1(F)2(M)1 5’. Instant claim 29 recites that the isolated oligonucleotide claimed therein comprises at least one nucleotide having a modified phosphate backbone. Instant claim 31 recites that the isolated oligonucleotide claimed therein comprises a phosphate mimic at the 5’ terminal nucleotide. Finally, instant claim 32 recites that the isolated oligonucleotide claimed therein is linked to a targeting ligand.
In comparison, copending claims 1 and 4-6 are drawn to an isolated oligonucleotide comprising a sense strand and an antisense strand of defined lengths that read on the lengths recited in the instant application. Copending claims 8 and 15-19 subsequently define modification patterns comprising 2’-F, 2’-O-methyl, phosphorothioate linkages, and terminal phosphate mimic nucleotides. The pattern of the antisense strand modifications recited at copending claim 15 and the pattern of the sense strand modifications recited at copending claim 16 are identical to that recited at instant claims 16, 26, and 27, as set forth above. Copending claim 9 further recites that the antisense strand comprises a phosphate mimic. Copending claims 11-13 further recite that the isolated oligonucleotide claimed therein is linked to a targeting ligand such as GalNAc. Copending claims 20, 22, and 23 are respectively drawn to a vector, a delivery system, and a pharmaceutical composition comprising the isolated oligonucleotide claimed therein.
Given that both the instant and copending applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification in defined patterns, wherein the oligonucleotide comprises at least one phosphorothioate linkage, wherein the oligonucleotide comprises a terminal phosphate mimic, and wherein the oligonucleotide is linked to a targeting ligand, it is considered that the instant and copending applications are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7, 29, 31, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/217,052 (reference application; corresponds to US 2025/0283091 A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Instant claim 29 recites that the isolated oligonucleotide claimed therein comprises at least one nucleotide having a modified phosphate backbone. Instant claim 31 recites that the isolated oligonucleotide claimed therein comprises a phosphate mimic at the 5’ terminal nucleotide. Finally, instant claim 32 recites that the isolated oligonucleotide claimed therein is linked to a targeting ligand.
In comparison, copending claim 1 is drawn to an isolated oligonucleotide comprising a sense strand and an antisense strand of defined lengths that read on the lengths recited in the instant application. Copending claims 2-9 further recite that the isolated oligonucleotide comprises modified nucleotides, specifically wherein all of the nucleotides are modified either with a 2’-F or 2’-O-methyl modification. Copending claims 10-13 further recite that the isolated oligonucleotide comprises at least one modified internucleotide linkage, such as a phosphorothioate linkage. Copending claims 14 and 15 further recite that the terminal uridine of the antisense strand comprises a phosphate analog. Copending claims 16-20 further recite that the isolated oligonucleotide is linked to a targeting ligand such as a GalNAc moiety.
Given that both the instant and copending applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification, wherein the oligonucleotide comprises at least one phosphorothioate linkage, wherein the oligonucleotide comprises a terminal phosphate mimic, and wherein the oligonucleotide is linked to a targeting ligand, it is considered that the instant and copending applications are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7, 29, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5 and 6 of copending Application No. 19/572,773 (reference application; corresponds to US 2026/0209764 A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-7 are drawn to an isolated oligonucleotide, wherein said isolated oligonucleotide comprises a sense strand comprising 13-35 nucleotides, wherein at least one nucleotide is modified with a first modification and each of the remaining nucleotides is independently modified with a different second modification, and an antisense strand comprising 18-31 nucleotides, wherein at least one nucleotide is modified with a third modification and each of the remaining nucleotides is independently modified with a different fourth modification. The first and third modifications are recited to be 2’-F modifications, and the second and fourth modifications are recited to be 2’-O-methyl modifications. Instant claim 29 recites that the isolated oligonucleotide claimed therein comprises at least one nucleotide having a modified phosphate backbone. Finally, instant claim 32 recites that the isolated oligonucleotide claimed therein is linked to a targeting ligand.
In comparison, copending claim 5 is drawn to an siRNA comprising an antisense strand and a sense strand, both of defined lengths that read on those of the instant application, wherein the sense and antisense strands are fully modified with 2’-O-methyl and 2’-F modifications, comprise phosphorothioate linkages, and are linked to a targeting ligand, as recited in the instant application. Copending claim 6 is further drawn to a pharmaceutical composition comprising the siRNA claimed therein.
Given that both the instant and copending applications recite oligonucleotides comprising sense and antisense strands of specified lengths, wherein each and every nucleotide is modified either with a 2’-F modification or a 2’-O-methyl modification, wherein the oligonucleotide comprises at least one phosphorothioate linkage and wherein the oligonucleotide is linked to a targeting ligand, it is considered that the instant and copending applications are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Claims 2-7, 14, 16, 22, 25-27, and 30 are objected to.
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/SARAH E ALLEN/Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
Prosecution Insights