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 in each of species I, II, III, IV, and V in the reply filed on 04/02/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
STATUS OF CLAIMS
Claims 1-5 and 10-25 are pending.
Claims 6-9 and 26-47 are cancelled.
Claims 11-12, 15-16, 19, and 22-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/02/2026.
Upon further consideration, species XYZ, is also examined in addition to the elected species. Accordingly, claims 13-14, that read on species XYZ, are examined.
Therefore, claims 1-5, 10, 13-14, 17-18, 20-21, and 24-25 are under examination in this office action.
Priority
Applicant’s claim for the benefit of a prior-filed application, 63/132,545, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c), with filing date 12/31/2020 is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/29/2023 and 10/31/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
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.
(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 1-5, 10, 13-14, 20-21, and 24-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Semenyuk A. et. al., (J. Am. Chem. Soc., 2006, 128(38), pgs. 12356–12357 and supplemental information, provided in IDS).
Regarding claims 1-5, 10, 13-14, and 20-21, Semenyuk teaches “a novel hydroxyl protecting group,” tert-Butyldithiomethyl (DTM), that is “cleavable under reductive conditions,” and is useful “for the protection of 2‘-OH during solid-phase RNA synthesis,” see pg. 12356 3rd paragraph. Semenyuk further teaches “2‘-O-DTM Protected Amidites,” which meet the limitations of formula (I) of claims 1, 10, and 13-14; formula (II) of claims 2 and 3; and formulas IIa and IIb of claims 4-5 and 20-21 (see scheme 1, reproduced below for convenience, and entire article and all of supporting information).
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Further regarding claim 1, Semenyuk teaches oligonucleotides comprising one or more 2’-modified nucleosides wherein the nucleoside has a structure of formula (I) (see title: “Synthesis of RNA Using 2′-O-DTM Protection,” see FIG. 1: “Identity and purity of RNA synthesized according to the DTM method,” and see pg. 12357 last para: “2′-O-DTM-protected oligonucleotides”).
Further regarding claim 3, Semenyuk further teaches synthesis of specific unmodified and modified nucleobases such as: 5'-O-(4,4'-Dimethoxytrityl)-2'-O-(tert-butyldithiomethyl)uridine and N2-isobutyryl-O6-diphenylcarbamoyl-2’-O-(tert-butyldithiomethyl)guanosine, among many others (see supporting information pgs. S15 and S21, respectively, and all of supporting information).
Further regarding claim 21, Semenyuk further teaches the “2‘-O-DTM Protected Amidites” with a phosphate at the 3’-position, see supporting information pg. S27 and reproduced below for convenience.
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Regarding claims 24-25, Semenyuk teaches both single and double stranded 2′-O-DTM-protected oligonucleotides, see Figure 1 legend (a) and (d).
In general, Semenyuk teaches “the choice of a 2′-OH protecting group is of crucial importance for chemical synthesis” of oligonucleotides.” Semenyuk further teaches that the 2′-OH protecting group “limits the range and dictates the nature of all other groups used for protection of remaining functionalities,” and “consequently, the origin of most shortcomings is related to the chemical characteristics of this particular protecting group.” See 1st paragraph.
Claims 1-5, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cook P. et. al., (US 20040048826 A1).
Regarding claims 1-5 and 10, Cook teaches oligonucleotides comprising one or more 2’-O modified nucleosides that meet the limitations of formula (I) of claims 1 and 10; formula (II) of claims 2 and 3; and formulas IIa and IIb of claims 4-5. For example, claim 10 recites: “an oligomer comprising at least one subunit having the structure:
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wherein X is R1—(R2)n;
R1 is C1-C20 alkyl, C2-C20 alkenyl, or C2-C20 alkynyl;
R2 is halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, imidazole, N-phthalimido, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetic properties of oligonucleotides;
T3 and T5 independently are OH or a further subunit of said oligomer that is joined to said structure; and
n is an integer from 0 to about 6.”
Thus, when selecting, for example, methyl for R1 and NH-alkyl for R2, one could arrive at O-CH2-NH(CH2CH3) when an ethyl group is selected as the alkyl group; thereby, satisfying formula 1. Furthermore, O-CH2-NH(CH2CH3) applied to the structure taught in claim 10 of Cook, formulas II, IIa, and IIb are satisfied.
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:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. 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.
Claims 1-5, 10, 17-18, and 20-21, are rejected under 35 U.S.C. 103 as being unpatentable over Cook et. al., (US 20040048826 A1) in view of Manoharan M. et. al., (US 20030113769 A1), Fukuyama, T et. al., (Tetrahedron Letters 38 (1997): 5831-5834), and Mercurio ME, et. al., (J Org Chem. 2016 Dec 2;81(23):11612-11625).
As established in the above 102 rejection of claims 1-5 and 10, Cook teaches an oligonucleotide comprising one or more 2’-O-modified nucleosides. Specifically, Cook teaches a 2’-O-modification of the formula 2’-O-CH2-NH-R, where R is an alkyl group. Cook’s disclosure of “alkyl” inherently encompasses the ethyl group of the elected species in current claims 17-18 and 20-21.
Cook does not explicitly disclose the 2-nitrobenzenesulfonyl (oNBS) protecting group on the nitrogen.
Manoharan teaches aminooxy functionalized oligomers. Specifically, Manoharan teaches “an oligomer comprising a plurality of nucleotide units of the structure:
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wherein:
Bx is a purine or pyrimidine heterocyclic base;
each T1 and T2 is, individually, OH, a protected hydroxyl, a nucleotide, a nucleoside or an oligonucleotide;
T3 is H, OH, a protected hydroxyl or a sugar substituent group; said oligomer further comprising at least one group, R, therein; said R group occurring at the 5′-end, the 3′-end, in lieu of at least one T3 or as a substituent on at least one Bx; said R group having one of the formulas:
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wherein: each Z is, independently, a single bond, O or a phosphate; each Q is, independently, H, C1-C10 alkyl or a nitrogen protecting group; each T0 is, independently, a bond or a linking moiety; each L is, independently, a chemical functional group, a conjugate group or a solid support material; or Q, T0 and L, together, are a chemical functional group; each m is, independently, an integer from 1 to about 10; and each n is, independently, an integer from 1 to about 6.” Manoharan further teaches that a protecting group “renders a chemical functionality of a molecule inert to specific reaction conditions and can later be removed from such functionality in a molecule without substantially damaging the remainder of the molecule,” see [0078]. For example, “the aminooxy functionality is masked with a protecting group…” see [0057].
Mercurio teaches the use of the oNBS group as a switchable protecting group for amines specifically within the context of modified nucleopeptide synthesis on solid phase resin, see pgs. 11614 last paragraph and 11615 first paragraph.
Fukuyama teaches that the oNBS group is the preferred reagent for the selective and efficient N-alkylation of amines to form secondary amines (e.g., N-ethyl amines), see pg. 5831.
Regarding claims 17-18 and 20-21, it would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to modify the 2’-O-scaffolds of Cook and Manoharan with a oNBS protecting group taught by Fukuyama and Mercurio to arrive at the species comprising the nitrobenezenesulfonamide. A PHOSITA seeking to produce the N-ethylated modification according to Cook’s scaffold would naturally look to the Fukuyama-Nosyl strategy to achieve selective and efficient N-ethylation. The claimed nitrobenezenesulfonamide structure is the direct and expected intermediate of this well-known chemical process. Manoharan provides the specific motivation to use nitrogen protecting groups in oligonucleotide synthesis, teaching that such groups render a chemical functionality inert to certain reaction conditions and are used specifically to mask amino-based functionalities. A PHOSTITA would follow this teaching to protect the amine in Cook during iterative steps of oligonucleotide synthesis. Furthermore, as evidenced by Mercurio, the oNBS group is recognized as an effective protecting group for amines in the field of oligonucleotide chemistry on solid phase. A PHOSITA would be motivated to retain or specifically attach the oNBS group on the nitrogen during the assembly of oligonucleotides to prevent side reactions with phosphoramidite reagents. The combination involves the application of a known nitrogen protecting group to a known oligonucleotide modification for its established purpose of making the amine functionality, thereby preventing side reactions. A PHOSITA would have had a reasonable expectation of success to produce stable, protected 2’-amino modified oligonucleotides.
Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Cook et. al., (US 20040048826 A1) in view of Manoharan M. et. al., (US 20030113769 A1), Fukuyama, T et. al., (Tetrahedron Letters 38 (1997): 5831-5834), and Mercurio ME, et. al., (J Org Chem. 2016 Dec 2;81(23):11612-11625) as applied to claim 1 above, and further in view of Tachas G. et. al., (US20060178325A1).
Neither Cook, Manoharan, Fukuyama, or Mercurio explicitly teach the 2’modified oligonucleotides can be single- or double-stranded.
Tachas teaches that 2’-modified oligonucleotides “may be introduced in the form of single-stranded, double-stranded, circular or hairpin oligomeric compounds and may contain structural elements such as internal or terminal bulges or loops,” see [0044]. Tachas further teaches that single-stranded antisense compounds which are “DNA-like” elicit RNAse H,” and that “activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide-mediated inhibition of gene expression,” see [0044]. Tachas further teaches that “in many species the introduction of double-stranded structures, such as double-stranded RNA (dsRNA) molecules, has been shown to induce potent and specific antisense-mediated reduction of the function of a gene or its associated gene products,” see [0045].
It would have been obvious to a PHOSITA before the effective filing date to make the 2-modified oligonucleotides of Cook as either single or double stranded. One would have been motivated to do so in order to enhance the efficacy oligonucleotide-mediated inhibition of gene expression. One would have had a reasonable expectation of success because Tachas successfully employed both single- and double-stranded oligonucleotides.
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
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/COREY LANE BRETZ/Patent Examiner, 1635/1600
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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