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 .
DETAILED ACTION
2. Claims 1, 3 – 5, 7, 9 – 10, 53, 57, 59, 61, 65, 67 – 69, 71, 73 – 74, 110, and 116 are pending in this application. Applicant’s preliminary amendment, submitted October 4, 2024, is entered, wherein claims 3 – 5, 7, 9 – 10, 61, 67 – 69, 71, 73 – 74, 110, and 116 are amended and claims 2, 6, 8, 11 – 52, 54 – 56, 58, 60, 62 – 64, 66, 70, 72, 75 – 109, and 111 – 115 are canceled.
Claims 1, 3 – 5, 7, 9 – 10, 53, 57, 59, 61, 65, 67 – 69, 71, 73 – 74, 110, and 116 are examined on the merits herein.
Priority
3. This application is a national stage application of PCT/US2022/037262, filed July 15, 2022, which claims benefit of domestic applications 63/222,090 and 63/236,029, filed July 15, 2021 and August 23, 2021, respectively.
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/222,090 and 63/236,029, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The prior-filed applications, 63/222,090 and 63/236,029, do not provide support for the limitations the structures of Formulae (IV), (VI), (VII), (VIII), and (IX) of claim 1; the structure of Formula (IVb) of claim 57; the structures of Formulae VIb, VIIb, VIIIb, and IXb of claim 59; and the structures of Formulae (V), (VIx), (VIIx), (VIIIx), and (IXx) of claim 65. Thus, the priority date of claims 1, 57, 59, and 65 and the dependent claims 3 – 5, 7, 9 – 10, 53, 61, 67 – 69, 71, 73 – 74, 110, and 116 is July 15, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/09/2024, 04/17/2025, 03/17/2026, and 05/06/2026 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the application contains two different abstracts. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claims 1, 7, 9 – 10, 53, 57, 59, 61, 65, 71, 73, 110, and 116 are objected to because of the following informalities:
Claim 1, line 1, “,” should be inserted immediately after “(VIII)”.
Claim 1, line 15, “indepently” should read “independently”.
Claims 7 and 71, lines 2 – 4, “is selected independently from the group consisting of…or” should read “is selected independently from the group consisting of…and”
Claim 9, line 1, “,’ should be inserted immediately after “3”.
Claim 10, line 2, “,” should be inserted immediately after “benzyl”.
Claims 53, 57, and 59, lines 4 and 8, respectively, “,” should be inserted immediately after “(ii)”.
Claim 53, line 16, “or” should be removed.
Claim 61, line 2, “a first compound” should read “the first compound”.
Claim 65, line 2, “,” should be inserted immediately after “(VIIIx)”.
Claim 73, line 2, “,” should be inserted immediately after “3”.
Claim 110, line 3, “an oligonucleotide” should read “the oligonucleotide”.
Claim 116, line 5, “an oligonucleotide” should read “the oligonucleotide”.
Claim 116, line 6, “a target gene” should read “the target gene”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3 – 5, 7, 9 – 10, 53, 57, 59, 61, 65, 67 – 69, 71, 73 – 74, 110, and 116 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.
a. Claim 1 recites “(e.g., phenyl)”, “(e.g., selected independently…(PEGs))”, “(e.g., methoxy)”, “(e.g., methoxyethyl)”, “(e.g., -C(O)CH2CH2C(O)-)”, (e.g., cyclopropylphosphonate)”, “(R(OH)(O)P…etc…)”, “(R(OH)(O)P…ethoxymethyl, etc…)”, “(e.g., HO[-(CH2)a…independently 1-10)”, “(phosphorothioate,…((HO)2(O)P-S-5’)”, “(R(OH)(O)P-O-5’…propyl, etc…)”, “(R(OH)(O)P-O-5’…ethoxymethyl, etc…)”, and “(e.g., GalNac)”. The phrases are written within a parenthesis. It is unclear whether the parenthetical phrase is limiting and is intended to define the substituents or is merely providing non-limiting descriptive information. Thus, the metes and bounds of the claim are not clear and the phrases render the claim indefinite. Claims 3 – 5, 7, 9 – 10, 53, 57, 59, and 61 depend from claim 1 and are, therefore, indefinite.
b. Claims 53, 57, and 59 recite “(e.g., phenyl)”, “(e.g., when Q is…1 or 2)”, “(e.g., phenyl or naphthyl)”, “(e.g., 1, 2, or 3)”, “(e.g., when Y is…1 or 2)”, “(e.g., when QH is...1 or 2)”, and “(e.g., when YH is…1 or 2)”. The phrases are written within a parenthesis. It is unclear whether the parenthetical phrase is limiting and is intended to define the substituents or is merely providing non-limiting descriptive information. Thus, the metes and bounds of the claim are not clear and the phrases render the claim indefinite.
c. Claim 65 recites “(e.g., methoxy)”, “(e.g., 2-methoxyethyl)”, (e.g., morpholin-1-yl…pyrrolidine-1-yl)”, “(e.g., cyclopropylphosphonate…P-O-5’)”, “[(RP)(OH)…propyl)]”, “[(RP1)(OH)…ethoxymethyl]”, “(e.g., HO[-(CH2)a…-5’”, and “(e.g., GalNac)”. The phrases are written within a parenthesis. It is unclear whether the parenthetical phrase is limiting and is intended to define the substituents or is merely providing non-limiting descriptive information. Thus, the metes and bounds of the claim are not clear and the phrases render the claim indefinite. Claims 67 – 69, 71, 73 – 74, 110, and 116 depend from claim 65 and are, therefore, indefinite.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3 – 5, and 9 – 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Manoharan et al. (US2015/0203847A1, See PTO-892).
a. Manoharan et al. teach a compound (Figure 10):
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which corresponds to the claimed Formula (III), wherein R1 is:
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wherein a’ is 1, RB is N, n is 2, and RC is:
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wherein b’ is 1, L is absent, and RL is C1-30 alkenyl; R4 is hydrogen; and R32, R33, and R35 are protected hydroxy. Thus, the disclosure of Manoharan et al. addresses independent claim 1 and dependent claims 3 – 5 and 9 – 10.
For these reasons, Manoharan et al. anticipate the claimed invention.
Claims 1 and 53 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Manoharan et al. (US2015/0203847A1, See PTO-892).
b. Manoharan et al. teach the compound (Figure 10):
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which corresponds to the claimed compound of Formula (IIIc), wherein R4 is hydrogen; R32, R33, and R35 are protected hydroxy; Q is -CH2N-; m is 2; and Z is
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Thus, the disclosure of Manoharan et al. addresses independent claim 1 and dependent claim 53.
For these reasons, Manoharan et al. anticipate the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 1 are rejected under 35 U.S.C. 103 as being unpatentable over Takeuchi et al. (US5773607, See PTO-892).
c. Takeuchi et al. teach compound (45):
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which corresponds to the claimed Formula (III), wherein R1 is N3; R4 is hydrogen; R33 and R35 are hydroxyl; and R32 is halogen.
It would have been prima facie obvious for a person of ordinary skill before the effective filing date of the claimed invention to modify the halogen as taught by Takeuchi et al. into a different configuration because it is well established that position isomers are prima facie structurally obvious. The isomer is expected to be preparable by the same method and to have generally the same properties. This expectation is deemed the motivation for preparing the position isomers. For example, “Position isomerism has been used as a tool to obtain new and useful drugs” (Englehardt) and “Position isomerism is a fact of close structural similarity” (Mehta, emphasis in the original). Note also In re Jones, 21 USPQ2d 1942, which states at 1943 “Particular types or categories of structural similarity without more, have, in past cases, given rise to prima facie obviousness”; one of those listed is “adjacent homologues and structural isomers”. Position isomers are the basic form of close “structural isomers.” Similar is In re Schechter and LaForge, 98 USPQ 144, 150, which states “a novel useful chemical compound which is homologous or isomeric with compounds of the prior art is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compounds.” One of ordinary skill in the art would have had a reasonable expectation of success to modify the halogen as taught by Takeuchi et al. into a different configuration because position isomerism is a common practice to obtain new and useful compounds.
Claims 1 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Manoharan et al. (US2015/0203847A1, See PTO-892).
d. Manoharan et al. teach a compound (Figure 10):
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which corresponds to the claimed Formula (III), wherein R1 is:
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wherein a’ is 1, RB is N, n is 2, and RC is:
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wherein b’ is 1, L is absent, and RL is C1-30 alkenyl; R4 is hydrogen; and R32, R33, and R35 are protected hydroxy. Thus, the disclosure of Manoharan et al. addresses independent claim 1. Manoharan et al. disclose that the “click” chemistry has recently emerged as an efficient strategy to conjugate carbohydrates, peptides, and proteins, fluorescent labels, and lipids to oligonucleotides (para. [0026]). The invention relates to compounds that can be used as a ribose replacement or can be used as universal base to conjugate various ligands to oligonucleotides, e.eg. iRNA agents, through “click” chemistry (para. [0027]). Manoharan et al. disclose the 3’-conjugation of ligand to antagomirs, antisense oligonucleotides, and siRNAs using click chemistry (Figure 4):
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as well as 5’-conjugation of ligand to antagomirs, antisense oligonucleotides and siRNAs using click chemistry (Figure 5):
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wherein R is ligand (para. [0054]). General examples of ligand include lipids, steroids, vitamins, sugars, proteins, peptides, polyamines, and peptide mimics (para. [0279]). To be precise, ligands can be proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies. Ligand can also include non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-glucosamine multivalent mannose, multivalent fucose, or aptamers (para. [0283]). Moreover, the compound comprising the ligand, e.g. the click-carrier compound can be present in any position of the oligosaccharide, e.g. an iRNA agent. In some embodiments, click-carrier compound can be present at the terminus, such as a 5’ or 3’ terminal of the iRNA agent. Click-carrier compounds can also present at an internal position of the iRNA agent (para. [0305]).
With respect to claim 7, Manoharan et al. teach that R is a ligand and that suitable ligands include lipids, steroids, vitamins, sugars, proteins, peptides, polyamines, peptide mimics, carbohydrates, antibodies, and aptamers. Manoharan et al. further teach that click-carrier compounds comprising the ligand may be present at any position of the iRNA agent, including a 5’ or 3’ terminus or an internal position. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select one of the disclosed ligands of Manoharan et al., such as lipid, carbohydrate, vitamin, peptide protein, polyamine, or antibody, as RL in the triazole-containing substituent of the claimed compound. One of ordinary skill in the art would have had a reasonable expectation of success because Manoharan et al. teach azide-alkyne click chemistry as a modular and efficient method for conjugating such ligands to oligonucleotides.
Claim 61 is rejected under 35 U.S.C. 103 as being unpatentable over Manoharan et al. (US2015/0203847A1, See PTO-892).
e. Manoharan et al. teach the compound (Figure 10):
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which corresponds to the claimed compound of Formula (IIIc), wherein R4 is hydrogen; R32, R33, and R35 are protected hydroxy; Q is -CH2N-; m is 2; and Z is
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Thus, the disclosure of Manoharan et al. reads on independent claim 1 and dependent claim 53. Manoharan et al. teach the synthesis as shown below (page 96, Example 12):
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Thus, Manoharan et al. teach a composition obtained from an azide-alkyne cycloaddition reaction and the linoleyl-N3 reagent, which reads on the limitations “a composition that is an azide-alkyne cycloaddition (AAC) reaction product” and “ a second compound of the formula RL-L-N3, wherein L is a linker and RL is a ligand”.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to react
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with the disclosed linoleyl-N3 reagent under the AAC conditions of Manoharan et al. to obtain the corresponding triazole-linked conjugate because Manoharan et al. explicitly teach azide-alkyne cycloaddition of the alkyne-containing nucleoside compound with linoleyl-N3, thereby providing the claimed AAC reaction product. One of ordinary skill in the art would have had a reasonable expectation of success because Manoharan et al. provide the starting alkyne compound, the azide reagent, the AAC reaction conditions, and the resulting triazole-linked product. The substitution/use of linoleyl-N3 as the second compound merely applies the disclosed click chemistry method of Manoharan et al. to its disclosed reactants for their intended purpose, yielding the predictable AAC conjugation product.
Claims 65, 67 – 69, 71, 73 – 74, and 110 are rejected under 35 U.S.C. 103 as being unpatentable over Manoharan et al. (US2015/0203847A1, See PTO-892).
f. Manoharan et al. teach an oligonucleotide comprising at least one subunit of formula (I) at one or more positions that occur at 1 – 6 nucleotides from either end of the oligonucleotide (claim 1):
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Manoharan et al. teach that the oligonucleotide further comprises at least one subunit represented by formula (IV) (claim 4):
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Manoharan et al. disclose an exemplary compound (Figure 10):
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which corresponds to the claimed Formula (III), wherein R1 is:
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wherein a’ is 1, RB is N, n is 2, and RC is:
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wherein b’ is 1, L is absent, and RL is C1-30 alkenyl; R4 is hydrogen; and R32, R33, and R35 are protected hydroxy. Thus, the disclosure of Manoharan et al. addresses independent claim 65 and dependent claims 67 – 69 and 73 – 74. Manoharan et al. disclose that the “click” chemistry has recently emerged as an efficient strategy to conjugate carbohydrates, peptides, and proteins, fluorescent labels, and lipids to oligonucleotides (para. [0026]). The invention relates to compounds that can be used as a ribose replacement or can be used as universal base to conjugate various ligands to oligonucleotides, e.eg. iRNA agents, through “click” chemistry (para. [0027]). Manoharan et al. disclose the 3’-conjugation of ligand to antagomirs, antisense oligonucleotides, and siRNAs using click chemistry (Figure 4):
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as well as 5’-conjugation of ligand to antagomirs, antisense oligonucleotides and siRNAs using click chemistry (Figure 5):
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wherein R is ligand (para. [0054]). General examples of ligand include lipids, steroids, vitamins, sugars, proteins, peptides, polyamines, and peptide mimics (para. [0279]). To be precise, ligands can be proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies. Ligand can also include non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-glucosamine multivalent mannose, multivalent fucose, or aptamers (para. [0283]). Moreover, the compound comprising the ligand, e.g. the click-carrier compound can be present in any position of the oligosaccharide, e.g. an iRNA agent. In some embodiments, click-carrier compound can be present at the terminus, such as a 5’ or 3’ terminal of the iRNA agent. Click-carrier compounds can also present at an internal position of the iRNA agent (para. [0305]). Manoharan et al. disclose that the oligonucleotide is a double-stranded oligonucleotide (claim 15), wherein the double stranded oligonucleotide is a double stranded siRNA (claim 16). Moreover, Manoharan et al. also disclose that pharmaceutical compositions containing the oligonucleotide of the invention, such as iRNA agent, and a pharmaceutically acceptable carrier, wherein the composition is useful for treating a disease caused by expression of a target gene and is administered in a dosage sufficient to inhibit expression of the target gene (para. [0477]). Manoharan et al. further teach that an iRNA agent may include a duplex comprising a hybridized sense and antisense strand, in which the antisense strand and/or the sense strand may include one or more of the modifications described (para. [0401]).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the exemplary compound of Manoharan et al. into the backbone of an oligonucleotide at a position 1 – 6 nucleotides from either end because Manoharan et al. explicitly teach that oligonucleotides comprising formula (I) subunits located 1 – 6 nucleotides from either end and further teach formula (IV) triazole-containing subunits. The exemplary compound is a triazole-linked alkenyl-containing nucleoside subunit falling within that disclosed genus. One of ordinary skill in the art would have had a reasonable expectation of success in incorporating the exemplary compound into the disclosed oligonucleotide of Manoharan et al. because Manoharan et al. teach that such modified nucleoside subunits are suitable for incorporation into oligonucleotides through conventional internucleotide linkages, thereby predictably yielding the claimed modified oligonucleotide.
Regarding the proviso recited in claim 65, it would have been satisfied because Manoharan et al. teach the modified subunit as part of an oligonucleotide, thereby requiring internucleotide linkage to a preceding and/or subsequent nucleotide as recited.
With respect to claim 71, Manoharan et al. teach that R is a ligand and that suitable ligands include lipids, steroids, vitamins, sugars, proteins, peptides, polyamines, peptide mimics, carbohydrates, antibodies, and aptamers. Manoharan et al. further teach that click-carrier compounds comprising the ligand may be present at any position of the iRNA agent, including a 5’ or 3’ terminus or an internal position. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select one of the disclosed ligands of Manoharan et al., such as lipid, carbohydrate, vitamin, peptide protein, polyamine, or antibody, as RL in the triazole-containing substituent of the claimed compound. One of ordinary skill in the art would have had a reasonable expectation of success because Manoharan et al. teach azide-alkyne click chemistry as a modular and efficient method for conjugating such ligands to oligonucleotides.
Regarding claim 110, Manoharan et al. further disclose that the oligonucleotide may be a double stranded oligonucleotide and that the double stranded oligonucleotide may be a double stranded siRNA. A double stranded siRNA necessarily comprises a first oligonucleotide strand and a second oligonucleotide strand that are substantially complementary to one another so as to hybridize and form the siRNA duplex. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to prepare the modified oligonucleotide of claim 65 as one strand of the disclosed double stranded siRNA of Manoharan et al. One of ordinary skill in the art would have had a reasonable expectation of success because Manoharan et al. explicitly teach double stranded siRNA comprising the disclosed modified oligonucleotides and duplex formation by substantially complementary strands is routine and predictable.
With respect to claim 116, Manoharan et al. disclose pharmaceutical compositions comprising the oligonucleotide of the invention, such as an iRNA agent, and a pharmaceutically acceptable carrier, wherein the composition is administered in an amount sufficient to inhibit expression of a target gene. Manoharan et al. further teach that an iRNA agent may comprise a duplex including hybridized sense and antisense strands and that the disclosed oligonucleotides may be double stranded oligonucleotides, including double stranded siRNA. Because the iRNA agent comprises hybridized sense and antisense strands and is administered to inhibit expression of a target gene, one of ordinary skill in the art would have understood that the antisense strand is complementary to the target gene transcript, thereby satisfying the limitation that the oligonucleotide is complementary to a target gene.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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