DETAILED ACTION
The examiner for your application at the USPTO has changed. Examiner Abigail VanHorn can be reached at 571-270-3502.
Election/Restrictions
Applicants’ election without traverse of Group I in the reply filed on June 22 2026 is acknowledged. Claims 1, 3-21, 34, 46-56 and 61 are pending in the application. Claims 34, 46-56 and 61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 22 2026. Accordingly, claims 1 and 3-21 are being examined on the merits herein.
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 .
Priority
This application is a 371 of PCT/US2022/031150 (05/26/2022) which claims benefit of 63/194,681 (05/28/2021) as reflected in the filing receipt issued on April 16 2024.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on November 17 2023 and June 25 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112-Indefiniteness
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.
Claim 3 is 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.
Claim 3 as currently written is vague and indefinite. Claim 3 depends from claim 1. Claim 1 as amended recites an oligonucleotide adapter coupled to a 1’ position of the ribose by a linker (which equates to a nucleobase with a linker that extends from). Claim 3 recites the modified nucleotide comprises a nucleobase coupled to a 1’ position of the ribose wherein the linker extends from the nucleobase. Since claim 1 already requires an oligonucleotide coupled to the 1’ position, the scope of claim 3 is not clear as it already recites the same limitation in claim 1.
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.
Claim(s) 21 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Routh et al. (J. Mol. Biol., 2015, cited on PTO Form 1449).
The instant application claims an oligo-modified nucleic acid analogue composition, comprising: a modified nucleotide comprising: a ribose; a 5' phosphate group coupled to the ribose; a 3' reactive group coupled to the ribose; and an oligonucleotide adapter coupled to a 3' position of the ribose by a linker and terminating in a 3' oligonucleotide end
Routh et al. is directed to clickseq, a fragmentation-free next-generation sequencing via click-ligation of adaptors to stochastically terminated 3’-azido cDNAs. Shown in Figure 1 B) is shown the copper-catalyzed cycloaddition of a 5’-hexnyl modified adaptor DNA to a 3’-azido blocked cDNA fragment
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. Thus, this figure shows a ribose with a 5’ phosphate, a 3’ reactive group (N3) coupled to the ribose and an DNA (aka oligonucleotide) adaptor coupled to a 3’ position of the ribose by a linker terminating in a 3’ oligonucleotide end.
Claim(s) 1, 3-4, 7-9, 12-13, 16 and 19-20 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Lubys et al. (USPGPUB No. 20200399633) as evidenced by Bollu et al. (J. Org. Chem., 2019).
The instant application claims an oligo-modified nucleic acid analogue composition, comprising: a modified nucleotide comprising: a ribose; a 5' phosphate group coupled to the ribose; a 3' reactive group coupled to the ribose; and an oligonucleotide adapter coupled to a 1' position of the ribose by a linker and terminating in a 5' oligonucleotide end.
Lubys et al. is directed to an oligonucleotide-tethered nucleotides. Claimed (claim 19) is an oligonucleotide-tethered nucleotide of formula (A):
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Fig. 9 and 10 shows a cycloaddition (click) reaction with an oligonucleotide. It is taught that in an alternative embodiment the oligonucleotide with alkyne group attached to the phosphate of the 5’ terminus of the oligonucleotide via hexynyl linker was used in a click reaction with compound 9 indicating that the exemplified reaction is a reaction at the 3’ terminus of the oligonucleotide which would result in terminating in a 5’ oligonucleotide end (paragraph 0484). The oligonucleotides are taught as being adapter sequences (paragraph 0302; 0249; 0344; 0449).
Regarding claims 1, 3, 12-13, 16 and 19-20, Luby et al. exemplifies a ribose, a 5’ phosphate group, shown in Fig. 9 is a 3’-OH reading on reactive group and shown in Fig. 9/10 is an oligonucleotide coupled to a 1’ position of the ribose by a linker and terminating in a 5’ oligonucleotide. As shown in Fig. 9/10 is a nucleobase coupled to the 1’ position of the ribose. As shown in Fig 10, the linker is attached at the end of the oligonucleotide. While the examiner indicated above that Luby et al. is interpreted as attaching to the 3’ end resulting in termination of the 5’ end, since there are only two ends, one skilled in the art would immediately envision attaching the linker to either end of the oligonucleotide. Note: MPEP 2131.
Regarding claim 4, as shown in formula A is NB which corresponds to nucleobase. The nucleobase include cytosine, guanine, thymine, uracil, inosine, 7-deaza-adenine and 7-deazaguanine (example 14; paragraph 0584; table 1).
Regarding claim 7, as shown in Fig. 9/10, the linker comprises a carbon chain comprising two or more carbons wherein the oligonucleotide is coupled directly to the carbon chain. It is noted that the recitation comprising allows for other atoms to be present in the linker.
Regarding claims 8-9, as shown in Fig. 9/10 the linker comprises an amide bond (C(O)-NH). As evidenced by Bollu et al., amides are readily cleaved/hydrolyzed by enzymes such as proteases (page 5596, left column, first paragraph).
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 5-6, 10-15 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lubys et al. as applied to claims 1, 3-4, 7-9, 12-13, 16 and 19-20 above.
Applicant Claims
The instant application claims the composition comprises a plurality of modified nucleotides comprising a mix of nucleotide base. The instant application claims the composition comprises a plurality of unmodified nucleotides, the unmodified nucleotides comprising one or more of uracil, thymine, cytosine, adenine, or guanine. The instant application claims the 5' oligonucleotide end is reactive with the 3' reactive group to couple the 5' oligonucleotide end to the ribose at a 3' position. The instant application claims the composition comprises a reversible blocker on the 5' oligonucleotide end or the 3' reactive group. The instant application claims the 5' oligonucleotide end comprises a phosphate group or an alkyne group. The instant application claims the 3' reactive group comprises a hydroxyl group or an azide. The instant application claims the oligonucleotide adapter comprises a primer binding site, a capture site, an index, or a combination thereof. The instant application claims the oligonucleotide adapter is coupled to an affinity binder. The instant application claims the oligonucleotide adapter comprises a sequence hybridized to a recognition sequence extending from the linker. The instant application claims the oligonucleotide adapter comprises a forked adapter
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Lubys et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Lubys et al. suggests more than one modified nucleotide and unmodified nucleotide can be used, a mixture is not expressly taught. While Lubys et al. suggest various reactive groups for the 3’ position, Lubys et al. does not expressly teach the 5’ oligonucleotide end is reactive with the 3’ reactive group. While Lubys et al. teaches the oligonucleotide can be a primer or splint oligonucleotide, Lubys et al. does not expressly exemplify the adapter having a primer binding site, affinity binder, recognition sequence or forked adapter.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 5-6, Lubys et al. claims the oligonucleotide-tethered nucleotide is a dideoxynucleotide wherein the dideoxynucleotide is chosen from dideoxyadenosine triphosphate, dideoxyguanosine triphosphate, dideoxythymidine triphosphate, dideoxyuridine triphosphate, dideoxycytidine triphosphate, and any combination thereof (claim 4) suggest mixtures. Taught is a reaction mixture containing oligonucleotide-tethered deoxycytinine and unmodified dATP, DTTP and dGTP (paragraph 0491). Taught is at least one oligonucleotide-tethered nucleotide and at least one nucleotide not tethered to an oligonucleotide (claim 2). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to utilize a plurality of modified nucleotides comprising a mix of nucleotide bases and a plurality of unmodified nucleotides. One skilled in the art would have been motivated to utilize this plurality as Lubys et al. teaches a mixture of oligonucleotide-tethered nucleotide and unmodified nucleotides. Therefore, to arrive at the claimed invention one would just need to select more than one of the modified and unmodified nucleotides which is suggested by Lubys et al.
Regarding claim 10 and 12-13, Lubys et al. shows in claim 19, X can be N3 (corresponding to the 3’ position). As shown in Figure 10, the oligonucleotide can be terminated with a hexynyl linker. It is taught that that this can be attached at either the 5’ terminal end or 3’ end or both (paragraph 0299). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to utilize a 3’ N3 and a hexynyl linker attached at the 5’-terminal end. This would allow via the taught click chemistry coupling of the 5’ end of the oligonucleotide to the ribose at the 3’ position.
Regarding claim 11, Lubys et al. teaches blocking groups that prevent extension of the 3’ end are taught. These include a 3’ amino, a 3’ phosphate, a dideoxy (paragraph 0357). Lubys et al. teaches that the 3’ position of the ribose can be H (dideoxy) (see also Fig. 10) and amino. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date to utilize a hydrogen or amino at the 3’ position of the ribose when it is desired to prevent extension as taught by Lubys et al.
Regarding claims 14-15 and 17, Lubys et al. universal handles at the 5’ end or 3’ end (paragraph 0550; 0553; 0658). Universal sequences are taught as known sequences e.g. a primer binding site (paragraph 0450; 0451). It is taught that the tethered oligonucleotide may comprise an affinity tag (e.g. biotin) (paragraph 0206; 0263; Fig. 32). As claimed the primer, the tethered oligonucleotide or both comprise a random sequence, a target-specific sequence or both (claim 15). As claimed one or more of the primer, the tethered oligonucleotide, or the splint oligonucleotide comprises a universal handle, a universal sequence, a unique molecular identifier, an adapter sequence, a promoter sequence, a barcode sequence, an index sequence, or any combination thereof (claim 16). Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date to utilize any of the specifically taught primer sequences including those with universal sequences, affinity tags and random/target-specific sequences as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding claim 18, the instant specification provides no limiting definition of a fork adapter. Lubys et al. teaches annealing a splint oligonucleotide to the tethered oligonucleotide (claim 8; paragraph 0377; 0395). It is taught that one or more of the primer, the tethered oligonucleotide, or the splint oligonucleotide comprises a universal handle, a universal sequence, a unique molecular identifier, an adapter sequence, a promoter sequence, a barcode sequence, an index sequence, or any combination thereof (claim 16). It would have been obvious to one of ordinary skill in the art before the effective filing date to utilize a splint oligonucleotide with the oligonucleotide-tethered nucleotide. One skilled in the art would have been motivated to utilize a splint as Lubys et al. specifically teaches and claims they can be utilized. It is noted that the splint necessarily has a split which results in a fork.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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