DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/22/2026 has been entered. Claims 1-43 are cancelled. Claims 44-66 are pending in this application. Claims 54, 55, and 57-61 are withdrawn. Claims 44-53, 56, and 62-66 are currently under examination.
Priority
This application is a CON of 16/793,808 filed on 02/18/2020, now PAT 11548876, which is a CON of PCT/US2018/000316 filed on 08/17/2018 and claims US PRO 62/547,687 filed on 08/18/2017.
Withdrawn Claim Objections/Rejections
The objection of claims 44, 51, and 62 because incorrect recitations, as set forth on page 3 of the Non-Final Rejection mailed on 10/01/2025, is withdrawn in view of amended claims.
The rejection of claim 49 under 35 U.S.C. 112(b), as set forth on page 4 of the Non-Final Rejection mailed on 10/01/2025, is withdrawn in view of amended claim.
Claim Objections
Claim 44 is objected to because of the following informalities: In claim 44, change the incorrect recitation “support and binding” (line 12) to “support for binding” because the “binding” does not apply to the preceding chromatographic column; and insert the missing word “chromatographic” immediately before the recitation “column or the” (line 14) to be consistent with the preceding and subsequent “chromatographic column”. 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 44-53, 56, and 62-66 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. Claims 45-53, 56, and 62-66 depend from claim 44.
Claim 44 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are: Claim 44 recites “the target oligonucleotide comprises a 5'-0H end and/or a 3'-0H end”, which encompasses oligonucleotide having both 5’-OH and 3’-OH and thus it is confusing because such oligonucleotide would not attach to the solid support, as required in the synthesizing step. Applicant is advised to change the above recitation “and/or” to “or”.
Claim Rejections - 35 USC § 102/103
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.
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.
(I) Claims 44, 45, and 47-52 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Fang et al. (Nucleic Acids Research, Vol. 31, No. 2., p. 708-715, 2003, hereinafter referred to as Fang ‘2003) incorporated by Wincott et al. (Nucleic Acids Research, Vol. 23, No. 14, p. 2677-2684, 1995, hereinafter referred to as Wincott ‘1995).
With regard to structural limitations “a method comprising: synthesizing the target oligonucleotide (or RNA; or comprising 2’-OH protecting t-butyldimethylsilyl group, a phosphorous protecting group, and a nucleobase protecting group) on a solid support and obtaining a mixture comprising the target oligonucleotide and truncated oligonucleotides; reacting the target oligonucleotide at the 5’OH or the 3’-OH end with an orthoester linker (or attached to the 5’OH or the 3’-OH of the target oligonucleotide), and thereby forming an oligonucleotide-orthoester linker conjugate, wherein the orthoester linker (defined as “an orthoester compound that is capable of attaching to a biopolymer such as an oligonucleotide” in the specification) comprises an affinity tag (or one or more groups in the orthoester linker; or a biotin tag) at the time of conjugation or the affinity tag is added in a second reaction after the conjugation reaction; cleaving the oligonucleotide-orthoester linker conjugate and the truncated oligonucleotides from the solid support; loading the oligonucleotide-orthoester linker conjugate and the truncated oligonucleotides onto a chromatographic column or an affinity capture support for binding the oligonucleotide-orthoester linker conjugate by the affinity tag to the affinity capture support; washing off the truncated oligonucleotides from the chromatographic column or the affinity capture support; eluting the oligonucleotide-orthoester linker conjugate from the chromatographic column or the affinity capture support; and cleaving the orthoester linker from the oligonucleotide-orthoester linker conjugate, thereby obtaining the purified target oligonucleotide” (claims 44, 45, and 47-52):
Fang ‘2003 disclosed that to test the binding efficiency of biotinylated DNA to streptavidin or avidin media, attempts were made to separate 7 from the failure sequences, generated during synthesis, by NeutrAvidinTM mediated affinity purification. Because in every synthetic cycle, failure sequences are capped, only the full-length sequence is biotinylated, and affinity purification followed by fluoride cleavage should give high quality full-length DNA 9 (Scheme 2, avidin bead not shown).
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Since the DNA obtained by strategy A with unoptimized yield contains more failure sequences, it was chosen as our substrate for this study. One portion was dried on a SpeedVac, dissolved in TTL buffer, and incubated with NeutrAvidinTM coated microspheres for 1 h at room temperature with gentle shaking. The non-biotinylated failure sequences were washed away by TES buffer and water. The beads were dried by washing with anhydrous acetone and THF sequentially, and suspended in dry THF. The cleaving reagent, pyridine/HF, was then added and incubated at room temperature for 1 h with gentle shaking. DNA 9 is then washed down with water, dried, redissolved in water. Biotinyl oligonucleotide 7 was synthesized on an ABI DNA/RNA synthesizer. Biotinyl phosphoramidite 1 (
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) was coupled for 15 min. The CPG was dried under a nitrogen flow. To the 0.30 mmol portion in a screw-capped 5 ml vial was added K2CO3 in anhydrous methanol (0.05 M, 1.0 ml), and the resulting suspension was gently shaken at r.t. for 24 h. Supernatant was transferred to Eppendorf tubes by pipette, and the CPG was washed with NH4OAc (0.5 M, 500 ml) and water (100 ml 3 3). The supernatant, washing buffer and water were combined, and dried on a SpeedVac (page 713, Scheme 2 and right col., para. 2; page 714, left col., para. 1; page 710, left col., para. 4; right col., para. 1). The 5’-end biotinylated oligonucleotide 7 (Scheme 2) was synthesized in an automated DNA/RNA synthesizer, using two common base protection and post-synthetic cleavage/deprotection strategies (A and B). Normal synthetic cycles were used, except that the biotinylated phosphoramidite 1 was coupled for 15 min. Cleavage/deprotection was performed under UltraMild conditions (0.05 M K2CO3 in MeOH, r.t., 24 h). The resulting solution was neutralized by NH4OAc buffer (0.5 M), and dried on a SpeedVac. In strategy B, A, G and C were protected by benzoyl, isobutyryl and acetyl groups, respectively. These conditions have been used for 2’-OH alkylsilyl protected RNA deprotection to minimize unwanted early desilylation (Ref. # 45: Wincott et al. Nucleic Acids Res., 23, 2677-2684, 1995). The current method may also be readily adapted to biotinylation and purification of synthetic RNA when the 2’-OHs are protected by alkylsilyl groups considering that the 2’-OH protecting groups can be removed under the same conditions for breaking the linker by fluoride ion (page 713, left col., para. 2; page 714, left col., para. 2). The key silyl acetal linkage was formed by addition of diisopropyldichlorosilane to a solution of the tertiary alcohol 5 in DMF in the presence of diisopropylethylamine and imidazole at 0°C. Subsequent addition of thymidine in DMF gave product 6 in 92% yield after flash chromatography.
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. A more convenient way is to synthesize a biotinylated phosphoramidite, and incorporate this into the oligonucleotide during automated solid phase synthesis. Phosphoramidite reagents are available that allow one to label either the 3’- or 5’-end. An acid-labile linker for biotinylation at the 5’-end of DNA has been reported. This reagent has to be attached to the 5’-end of DNA in a separate step (page 708. Left col., para. 1; right col., para. 1). Wincott ‘1995 (incorporated by the reference here) disclosed improvements In the synthesis, deprotectlon and purification of oligoribonucleotides. These advances allow for reduced synthesis and deprotectlon times, while improving product yield. Coupling times are reduced by half using 5-ethylthlo-1H-tetrazole (S-ethyttetrazole) as the activator. Base and 2'-O-t-butyldlmethylsllyl (TBDMS) deprotectlon with methylamlne (MA) and anhydrous triethylamlne/ hydrogen fluoride In N-methylpyrrolldlnone (TEA•HF/NMP), respectively (page 2677, Abstract).
Thus, these teachings of Fang ‘2003 incorporated by Wincott ‘1995 anticipate Applicant’s claims 44, 45, and 47-52 because the silyl acetal linkage is formed at the 5’-OH of oligonucleotide or the biotinyl phosphoramidite 1 attaches to the 5’-OH of oligonucleotide. In an alternation, the 3’-OH biotinylation is obvious to skilled artisan as suggested by the Fang ‘2003 above.
Applicant’s Arguments/Remarks filed on 05/22/2026 have been fully considered. Applicant argued “Fang '2003 describes methods wherein the biotinyl affinity tag is introduced during the last monomer addition of the target oligonucleotide synthesis… the biotinyl tag is not incorporated onto the full-length oligonucleotide, but instead is incorporated with the final nucleotide during the last cycle of the oligonucleotide synthesis, precluding the universality of the tag introduction… Scheme 2 of Fang '2003 discloses the two oligonucleotides of the reference (biotinylated oligonucleotide Compound 7 and full length target oligonucleotide Compound 9). Neither of these groups, nor any other compounds of Fang '2003, have any orthoester group, which has the form -C(R1)(OR2)3” (p. 10, para. 1; p. 11, para. 3), and “Wincott '1995 does not disclose or suggest orthoester linkers, oligonucleotide-orthoester linker conjugates optionally comprising an affinity tag, or any methods of purifying target oligonucleotides using same” (p. 12, para. 3).
In response, these arguments are not persuasive because of the following reasons. First, the “orthoester linker” is broadly defined as “an orthoester compound that is capable of attaching to a biopolymer such as an oligonucleotide” in the specification (p. 25, [0073]), which does not exclude a nucleotide monomer or does not limited to the argued “-C(R1)(OR2)3”, and thus encompasses the compound 1 of Fang ‘2003. Second, the “target oligonucleotide” is not specifically defined and thus encompasses any oligonucleotide with one extra nucleotide for special purpose, such as cloning or mismatch priming. Lastly, the Wincott ‘1995, cited by Fang ‘2003, is incorporated by the reference to teach claim 51, as described above. To overcome this 102/103 rejection, Applicant may include additional limitation, such as specific structure of the “orthoester linker”, in independent claim 44.
(II) Claims 44, 45, 47-52, 62, and 64 are rejected under 35 U.S.C. 103 as being unpatentable over Karwowski et al. (Nucleosides, Nucleotides, amJ. Nucleic Acids, 24 (5- 7):1111-1114, 200.5, hereinafter referred to as Karwowski ‘2005, also listed in IDS filed on 11/14/2022) incorporated by Reese (Tetrahedron 58:8893–8920, 2002, hereinafter referred to as Reese ‘2002).
With regard to structural limitations “a method comprising: synthesizing the target oligonucleotide (or RNA; or comprising 2’-OH protecting t-butyldimethylsilyl group, a phosphorous protecting group or deprotecting step, and a nucleobase protecting group) on a solid support and obtaining a mixture comprising the target oligonucleotide and truncated oligonucleotides; reacting the target oligonucleotide at the 5’OH or the 3’-OH end with an orthoester linker (or attached to the 5’OH or the 3’-OH of the target oligonucleotide; or
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, wherein each of R1, R2, R3, R4, R5, R6 and R7 is independently H, C1-C24 heteroalkyl, or any substituted equivalents; R8 and R9 are H; X is methyl; n is 0; at least one of R1, R2, R3, R4, R5, R6 and R7 comprises an affinity tag) and thereby forming an oligonucleotide-orthoester linker conjugate, wherein the orthoester linker (defined as “an orthoester compound that is capable of attaching to a biopolymer such as an oligonucleotide” in the specification) comprises an affinity tag (or one or more groups in the orthoester linker; or a hydrophobic tag with a cLogP value of at least 3) at the time of conjugation; cleaving the oligonucleotide-orthoester linker conjugate and the truncated oligonucleotides from the solid support; loading the oligonucleotide-orthoester linker conjugate and the truncated oligonucleotides onto a chromatographic column; washing off the truncated oligonucleotides from the chromatographic column; eluting the oligonucleotide-orthoester linker conjugate from the chromatographic column; and cleaving the orthoester linker from the oligonucleotide-orthoester linker conjugate, thereby obtaining the purified target oligonucleotide” (claims 44, 45, 47-52, 62, and 64):
Karwowski ‘2005 disclosed 4,5-bis(ethoxycarbonyl)-[1,3}dioxolan-2-yl as a new protecting for the 2'-hydroxyl function. This cyclic orthoester-type group is compatible with the DMTr strategy for oligonucleotide synthesis. Post-synthetic conversion of the moiety of this protecting group with an amine resulted information of a new amide moiety that is more stable to acid deprotection in aqueous solution, but it can still be easily removed by treatment with acids in organic solvents. Synthesis of dinucleotide UpU via 5'-O-DMT-2'-O-[4,5-bis(ethoxycarbonyl)-[1,3]dioxolan-2-yl]uridine as a substrate.
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. Since the backbone structures of compounds 6 and 7 were used in the new strategy for oligonucleotide synthesis, their stability under acidic conditions which are necessary for deprotection of the DMT group from the 5'-hydroxyl function. Compound 6 was stable in a dry solution of DCA and in acetic acid-water solution. During the creation of the internucleotide bond, no unexpected signals in 31P NMR analysis are found. The crude product was analyzed by RP HPLC. The difference in the retention time between 10 and the dinucleotide with a DMT protecting group is big enough to purify each of them. The RNA synthesis with the t-butyldimethylsilyl 2'-protecting group did not have a significant difference in the retention time. Future work will continue to implement this strategy for the solid-phase synthesis of RNA (page 1111, Abstract; page 1112, para. 6; page 1113, Figure 2; para. 3 and 4). Many chemical strategies have been developed for oligoribonucleotide synthesis (Ref. # 1, Reese 2002) (page 1111, para. 1). Reese ‘2002 (incorporated by the reference here) disclosed that TBDMS protecting group has been used very widely in the solid phase synthesis of RNA sequences. Relatively pure monomeric phosphoramidites of general structure 151 (
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), which are contaminated with at most very small quantities of isomeric 3’-O-TBDMS-2’-phosphoramidites, are available commercially. The general protocol of RNA synthesis is very similar to that of solid phase DNA synthesis. In order to ensure that the 2’-O-TBDMS protecting groups remain largely intact until the final unblocking step, it is advisable that the adenine, cytosine and guanine residues should be protected with relatively labile acyl groups that are removable by treatment with ammonia or methylamine under very mild conditions. In the final unblocking step, the 2’-O-TBDMS protecting groups are best removed by treatment with triethylamine trihydrofluoride (page 8913, right col., para. 1). The TBDMS protecting group nevertheless suffers from a notable disadvantage in that it readily undergoes base-catalyzed migration (as in the conversion of 137a into 140a and vice versa; Scheme 20:
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). For this reason, 2’-O-TBDMS ribonucleoside derivatives with free 3’-hydroxy functions (e.g. 137a) must be handled with care. Acyl groups, which are the most common base-labile protecting groups for hydroxy functions, very readily undergo base-catalyzed migration. However, unlike mixtures of 2’- and 3’-O-TBDMS ribonucleoside derivatives, mixtures of isomeric 2’ and 3’-O-acyl ribonucleoside derivatives (e.g. 137b and 140b: R1=Me) are not generally easily separable by chromatography (page 8911, right col., Scheme 20; page 8912, left col., para. 1 and 2).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to protect 5’-OH or 3’-OH end of RNA with
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for facilitating purification of RNA oligonucleotide containing the 4,5-bis(ethoxycarbonyl)-[1,3}dioxolan-2-yl at either end of the oligonucleotide because Karwowski ‘2005 incorporated by Reese ‘2002 teach (a) the compound 6:
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is the orthoester linker comprising affinity tag and is compatible with the solid phase synthesis of RNA sequences using 2’-O-TBDMS protecting group, (b) difference in the retention time between 10 and the dinucleotide with a DMT protecting group is big enough to purify each of them, (c) 2’-O-TBDMS ribonucleoside derivatives with free 3’-hydroxy functions (e.g. 137a) must be handled with care, and (d) 2’-protecting group is removable by treatment with triethylamine trihydrofluoride, described above, to purify full-length oligonucleotide containing the 4,5-bis(ethoxycarbonyl)-[1,3}dioxolan-2-yl at either end of the oligonucleotide. Thus, one of skill in the art would have a reasonable expectation that by protecting 5’-OH or 3’-OH end of RNA with
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for facilitating purification of RNA oligonucleotide containing the 4,5-bis(ethoxycarbonyl)-[1,3}dioxolan-2-yl at either end of the oligonucleotide as taught by Karwowski ‘2005 incorporated by Reese ‘2002, one would achieve Applicant’s claims 44, 45, 47-52, 62, and 64.
Applicant’s Arguments/Remarks filed on 05/22/2026 have been fully considered. Applicant argued “as disclosed in Karwowski '2005… the orthoester group was installed at the time of coupling the monomer to which it is attached. Moreover, Karwowski's orthoester composition does not include an affinity tag… Karwowski '2005 at least do not involve the step of "reacting the target oligonucleotide at the 5'-OH end or the 3'-OH end… silent on the features of "loading the oligonucleotide-orthoester linker conjugate and the truncated oligonucleotides onto a chromatographic column… washing off the truncated oligonucleotides… eluting the oligonucleotide-orthoester linker conjugate… and cleaving the orthoester linker from the oligonucleotideorthoester linker conjugate” (p. 13, para. 3 to 4; p. 14, para. 1), and “teaching of Reese '2002 or derived therefrom would necessarily require that any full length target oligonucleotide comprises the orthoester group as it would have been incorporated as part of the oligonucleotide synthesis” (p. 14, para. 2).
In response, these arguments are not persuasive because of the following reasons. As indicated above, the compound 6:
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is the orthoester linker comprising affinity tag, in which the ethyl (Et) tag is cleavable from the EtCOO. The Et tag is encompassed by the recited “ C1-C24 alkyl” in claim 62. This obviousness rejection has been revised above to provide disclosures that would motivate skilled artisan to protect 5’-OH or 3’-OH end of RNA with
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for facilitating purification of RNA oligonucleotide containing the 4,5-bis(ethoxycarbonyl)-[1,3}dioxolan-2-yl at either end of the oligonucleotide, described above.
(III) Claims 44-53, 56, and 62-66 are rejected under 35 U.S.C. 103 as being unpatentable over Karwowski et al. (Nucleosides, Nucleotides, amJ. Nucleic Acids, 24 (5- 7):1111-1114, 200.5, hereinafter referred to as Karwowski ‘2005, also listed in IDS filed on 11/14/2022) incorporated by Reese (Tetrahedron 58:8893–8920, 2002, hereinafter referred to as Reese ‘2002) in view of Pearson et al. (J. Org. Chem. 70, 7114-7122, 2005, hereinafter referred to as Pearson ‘2005, also listed in IDS filed on 11/14/2022) and Martin (US 5,969,116, Oct. 19, 1999, hereinafter referred to as Martin ‘116). Claims 44, 45, 47-52, 62, and 64 are rejected here because they have been rejected under 103 above and the disclosure of Karwowski ‘2005 incorporated by Reese ‘2002 are thus incorporated to its entirety here.
Karwowski ‘2005 incorporated by Reese ‘2002 did not explicitly disclosed the limitations (A) “the affinity tag is reacted with the oligonucleotide-orthoester linker conjugate in a second reaction after the conjugation reaction (or conducted before or after the oligonucleotide-orthoester linker conjugate is cleaved from the solid support)”, “an affinity capture support and binding the oligonucleotide-orthoester linker (or the phosphorous protecting group is deprotected before reacting the oligonucleotide with the orthoester linker) conjugate by the affinity tag to the affinity capture support; washing off the truncated oligonucleotides from the affinity capture support; eluting the oligonucleotide-orthoester linker conjugate from the affinity capture support (or target RNA comprises at least 70 nucleotides)”, and (B) “a fluorous tag (or at least one of R1, R2, R3, R4, R5, R6 and R7 is a fluorosubstituted alkyl; or
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, elected);”, required by claims 44, 46, 53, 56, and 63-66.
With regard to the structural limitations (A) and (B) above, Pearson ‘2005 disclosed fluorous-tagged oligonucleotides (for example,
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), which were subjected to solid-phase extraction using a pH-stable fluorinated adsorbent. On-column detritylation afforded the purified oligonucleotides. The fluorous affinity purification method offers one-pass loading without ammonia removal, high selectivity for the removal of failure sequences, high recoveries (typically 70-100%), and the ability to purify long oligonucleotides (e.g., 50-100-mers). A popular purification strategy uses RP adsorbent. Reversed-phase HPLC is often performed on oligonucleotides with a 4,4’-dimethoxytrityl (DMT) group on the 5’-terminus. The DMT group allows retention of the target oligonucleotide, allowing failure sequences (which have no DMT group) to be washed off with an appropriate eluant. In a common strategy, target molecules are retrieved from mixtures by attaching temporary fluorous tags and then employing a fluorous separation technique such as fluorous chromatography to separate the tagged molecules from other nontagged organic compounds. The interaction of a fluorous-tagged molecule with a perfluorinated surface is very strong, facilitating solid-phase extraction techniques. Synthesis of 5’-O-FDMT Nucleoside Phosphoramidites (
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):
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. The FDMT method requires only one fluorous chain (rather than two in the FMMT group) to accomplish the purification of oligonucleotides (page 7114, Abstract; right col., para. 2; page 7115, right col., para. 1; page 7116, left col., para. 1; right col., Figure 1; page 7117, left col., Scheme 1).
With regard to structural limitation of (B) above, Martin ‘116 disclosed that nucleosides having polyol derivatives as side chains of the 2'-OH group increase the binding affinity for complementary RNA not only in the case of relatively short chains but also in the case of relatively long chains. Analogously to 2'-OH-modified oligoribonucleotides, the compounds are like-wise distinguished by their outstanding resistance to nuclease. Compounds of formula I:
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; wherein R1 and R2 are each independently of the other hydrogen or a protecting group; R3 is a radical of formula Ia (
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), lb (
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, R5 is hydrogen, C1-C10alkyl, -CH2-O-R6 or a radical of formula lb; Z in the case of -CH2- is unsubstituted or substituted by one or more identical or different substituents selected from C1-C10alkyl) or lc. Examples of further 2'-OH modifications:
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, R3 is
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,
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, or
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(page 3/33, col. 1, lines 38-65; col. 2, lines 1-36; page 14/33).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the first EtOOC-, second EtOOC-, and Et of -OEt components of
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as taught by Karwowski ‘2005 with ---
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, H, and isostere CH2CF3, in view of Pearson ‘2005 and Martin ‘116 to improve the purification of fluorous-tagged oligonucleotides in solid-phase extraction to afford high selectivity for the removal of failure sequences because (i) Karwowski ‘2005 teaches that the
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moiety is required for hydroxyl group protection, (ii) Pearson ‘2005 teaches that one fluorous chain is sufficient to accomplish the purification of oligonucleotides; and Martin ‘116 teaches that the ---
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attached to the
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moiety is also used as hydroxyl group protecting group, described above. Thus, one of skill in the art would have a reasonable expectation that by substituting the first EtOOC-, second EtOOC-, and Et of -OEt components of
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as taught by Karwowski ‘2005 with ---
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, H, and isostere CH2CF3, in view of Pearson ‘2005 and Martin ‘116 to improve the purification of fluorous-tagged oligonucleotides in solid-phase extraction to afford high selectivity for the removal of failure sequences, one would achieve Applicant’s claims 44-53, 56, and 62-66. "Exemplary rationales that may support a conclusion of obviousness include: (B) Simple substitution of one known element for another to obtain predictable results". See MPEP § 2143 [R-01.2024] [I].
Applicant’s Arguments/Remarks filed on 05/22/2026 have been fully considered. Applicant argued “Pearson '2005 relies on the same approach previously disclosed in Fang '2003, in which a modified monomer phosphoramidite containing the affinity tag is used when adding the final nucleotide during oligonucleotide synthesis, and is therefore different from the presently pending claims for the reasons provided above. Martin '116 discloses ribonucleotide analogues having 2' -OH groups etherified by polyol derivatives, along with methods of preparing same and oligonucleotides comprising same” (p. 16, para. 4), and “nothing in Karwowski '2005, Reese '2002, or Pearson '2005 suggests that an orthoester group be used as a linker between an oligonucleotide and an affinity tag, alteration of a DMTr group of a monomer phosphoramidite to a monomer-independent orthoester group; or alteration of the method of synthesizing the oligonucleotides provided therein in a manner omitting the modified phosphoramidites and introducing a separate reaction involving the full length target oligonucleotide and an orthoester group to introduce an affinity tag” (p. 18, para. 3).
In response, these arguments are not persuasive because of the following reasons. As indicated in the preceding 103 rejection above, the compound 6:
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is the orthoester linker comprising affinity tag, in which the ethyl (Et) tag is cleavable from the EtCOO. The motivation to protect 5’-OH or 3’-OH end of RNA with
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for facilitating purification of RNA oligonucleotide containing the 4,5-bis(ethoxycarbonyl)-[1,3}dioxolan-2-yl at either end of the oligonucleotide is described above. The teachings of Pearson and Martin further motivate skilled artisan to substitute the first EtOOC-, second EtOOC-, and Et of -OEt components of
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143
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as taught by Karwowski ‘2005 with ---
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, H, and isostere CH2CF3, in view of Pearson ‘2005 and Martin ‘116 for improving the purification of fluorous-tagged oligonucleotides in solid-phase extraction to afford high selectivity for the removal of failure sequences, described above. To overcome the current obviousness rejection, Applicant is advised to include additional limitation that is not taught by the reference.
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 44-53, 56, and 62-66 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 13, and 19-23 of U.S. Patent No. 11,299,483 (Dellinger et al., Apr. 12, 2022, also listed in IDS filed on 11/14/2022). Although the claims at issue are not identical, they are not patentably distinct from each other because Pat ‘483 claims “A method of purifying a target oligonucleotide, comprising: synthesizing the target oligonucleotide on a solid support and obtaining a mixture comprising the target oligonucleotide and truncated oligonucleotides; reacting the target oligonucleotide with an orthoester linker, and thereby forming an oligonucleotide-orthoester linker conjugate (or the orthoester linker is attached at the 5'-hydroxyl or at the 3'-hydroxyl of the target oligonucleotide), wherein the orthoester linker either comprises an affinity tag at the time of conjugation or the affinity tag is reacted with the oligonucleotide-orthoester linker conjugate in a second reaction after the conjugation reaction; cleaving the oligonucleotide-orthoester linker conjugate and the truncated oligonucleotides from the solid support; loading the oligonucleotide-orthoester linker conjugate and the truncated oligonucleotides onto a chromatographic column or an affinity capture support and binding the oligonucleotide-orthoester linker conjugate by the affinity tag to the affinity capture support; washing off the truncated oligonucleotides from the column or the affinity capture support; eluting the target oligonucleotide from the chromatographic column or the affinity capture support; and cleaving the orthoester linker from the target oligonucleotide, thereby obtaining the purified target oligonucleotide” (claims 1, 4, and 5), encompassing claim 1 of this Application because the eluting and cleaving in either reversed order or in one single step is obvious to skilled artisan. Also, claims 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 19, 20, 21, 22, and 23 of Pat ‘483 read specifically on claims 45, 46, 47, 48, 49, 50, 51, 52, 53, 56, 62, 63, 64, 65, and 66 of this Application, respectively.
Applicant’s Arguments/Remarks filed on 05/22/2026 have been fully considered. Applicant argued “the nonstatutory double patenting rejection be held in abeyance until the presently pending rejections have been overcome” (p. 20, para. 1).
In response, this double patenting rejection is thus maintained, as requested.
Conclusion
No claims are allowed.
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/YIH-HORNG SHIAO/Primary Examiner, Art Unit 1691
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