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 .
Status of Claims/Application
The preliminary amendment dated 01/29/2024 is acknowledged. Claims 1, 2, 4, 5, 7, 10, 12 – 15, 29 – 31, 34, 35, 38, 40, and 42 – 44 are amended. Claims 3, 6, 8, 9, 11, 16 – 28, 32, 33, 36, 37, 39, 41, and 45 – 54 have been cancelled.
Claims 1, 2, 4, 5, 7, 10, 12 – 15, 29 – 31, 34, 35, 38, 40, and 42 – 44 are pending and are examined on the merits herein.
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The instant application is a National Stage Application of PCT/ US2022/039086, filed on 08/02/2022, and claims domestic benefit to U.S. provisional application no. 63/227,489, filed on 07/30/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted in the instant application on 08/19/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(4) because in Fig. 6A, 6B, and 6C reference character “Leucine (Leu)” has been used to designate both the first structure on the first row and the last structure on the second row of chemical modifications at the C-5 pyrimidine position of TNA. The last structure of the second row does not appear to be Leu. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term ThermoPol, LoBind, Millipore, Centricon, and NanoDrop which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 29, 31, and 43 are objected to because of the following informalities: for the usage “based-modified” as the instant specification uses this term only once [0008]. However, “base-modified” appears 30 times, with the first occurrence at [0006]. It is best if the disclosure uses the same term consistently. That term should be consistent with the usage in claims. 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 14, and 40 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.
Claim 14 recites “The monomer of claim 1, wherein the pyrimidine nucleotide base comprises a uracil base or a cysteine base”. As cysteine is an amino acid, and isn’t a pyrimidine nitrogenous base, the claim limitation is not clear. For examination purposes, cysteine base limitation will be interpreted as cytosine pyrimidine base as supported by the disclosure which refers to the preparation of triphosphate monomer with cytosine, and also targeting cytosine in the study of affinity agents for tumor necrosis factor-alpha ([0078], [0068], [0081], [0089]).
Claim 40 recites “The aptamer of claim 29, wherein the pyrimidine nucleotide base is bound to the C1’ position on the sugar moiety, wherein the pyrimidine nucleotide base comprises an uracil residue, a cystine residue, or a combination thereof”. As cystine is an oxidized dimer of the amino acid, cysteine, it isn’t a pyrimidine nitrogenous base. So, the claim limitation is not clear. For examination purposes, cystine base limitation will be interpreted as cytosine pyrimidine base as supported by the disclosure which refers to the preparation of triphosphate monomer with cytosine, and also targeting cytosine in the study of affinity agents for tumor necrosis factor-alpha ([0078], [0068], [0081], [0089]).
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1, 2, 4, 10, and 12 – 15 are rejected under 35 U.S.C. 103 as being unpatentable over Sau et al (A Scalable Synthesis of α-L-Threose Nuclei Acid Monomers, J. Org. Chem. 2016, 81, 2302−2307) (PTO-982) in view of WO 2018/005974 (IDS 08/19/2025) and McKenzie et al (Recent progress in non-native nucleic acid modifications, Chem. Soc. Rev., 2021, 50, 5126–5164) (IDS 08/19/2025).
Sau teaches that the recent advances in polymerase engineering have made
it possible to copy information back and forth between DNA and artificial genetic polymers composed of TNA (α-L-threofuranosyl-(3’,2’) nucleic acid), and a highly optimized chemical synthesis protocol for constructing multigram quantities of TNA nucleosides that can be readily converted to nucleoside 2’-phosphoramidites or 3’-triphosphates for solid-phase and polymerase-mediated synthesis, respectively (Abstract). TNA (α-L-threofuranosyl-(3’,2’) nucleic acid) is an artificial genetic polymer in which the natural ribose sugar found in RNA has been replaced by the tetrose sugar of α-L-threose. In contrast to natural DNA and RNA, which have a six-atom backbone repeat unit connected by 3’,5’-phosphodiester linkages, TNA has a backbone periodicity of five atoms (or bonds) with phosphodiester linkages occurring at the 2’ and 3’ vicinal positions of the threose sugar (pg. 2302, col.1, para. 1). Sau teaches that their approach involves a total of 10 chemical transformations with three crystallization and a single
chromatographic purification steps and results in an overall yield of 16−23% depending on the identity of the nucleoside (A, C, G, T), and demonstrate that this new strategy can be used to produce multigram quantities of TNA monomers required to explore the structural and functional properties of TNA polymers (pg. 2302, col. 2, para. 2).
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Sau teaches that Compounds 9a−d are key intermediates in the divergent synthesis of TNA nucleoside-3’-triphosphates and 2’-phosphoramidites. For L-threofuranosyl nucleoside 3’-triphosphates, compounds 9a−d can be phosphorylated using the standard Ludwig and Eckstein method, followed by treatment with concentrated NH4OH to remove the sugar and nucleobase protecting groups. For L-threofuranosyl nucleoside 2’-phosphoramidites, compounds 9a−d are tritylated with DMT-Cl and treated with 1 M NaOH for 20 min at 0 °C to remove the 2’-benzoyl group to obtain compounds 10a−d (pg. 2304, col. 2, para. 2)
The teachings of Sau differ from that of the instantly claimed invention in that Sau does not teach a base-modified XNA nucleoside monomer, wherein the pyrimidine nucleotide base comprises a chemical modification at position C-5 of the nucleobase.
WO’974 teaches oligonucleotides comprising modified nucleosides, such as aptamers that are capable of binding to target molecules, that comprise more than one type of base-modified nucleoside, and methods of making and using such aptamers (pg. 1, [0003]). WO’974 teaches an aptamer comprising at least one first 5-position modified pyrimidine and at least one second 5-position modified pyrimidine is provided, wherein the first 5-position modified pyrimidine and the second 5-position modified pyrimidine are different. In some embodiments, the first 5-position modified pyrimidine is a 5-position modified uridine and wherein the second 5-position modified pyrimidine is a 5-position modified cytidine. In some embodiments, the first 5-position modified pyrimidine is a 5-position modified cytidine and wherein the second 5-position modified pyrimidine is a 5-position modified uridine. In some embodiments, the 5-position modified uridine comprises a moiety at the 5-position selected from a naphthyl moiety, a benzyl moiety, a tyrosyl moiety, an indole moiety and a morpholino moiety. In some embodiments, the 5-position modified cytidine comprises a moiety at the 5-position selected from a naphthyl moiety, a benzyl moiety, a tyrosyl moiety, and a morpholino moiety. In certain embodiments, the moiety is covalently linked to the 5-position of the base via a linker comprising a group selected from an amide linker, a carbonyl linker, a propynyl linker, an alkyne linker, an ester linker, a urea linker, a carbamate linker, a guanidine linker, an amidine linker, a sulfoxide linker, and a sulfone linker (pg. 2, [0006]).
McKenzie is a review on recent progress in non-native nucleic acid modifications, and teaches that while nature harnesses RNA and DNA to store, read and write genetic information, the inherent programmability, synthetic accessibility and wide functionality of these nucleic acids make them attractive tools for use in a vast array of applications. In medicine, antisense oligonucleotides (ASOs), siRNAs, and therapeutic aptamers are explored as potent targeted treatment and diagnostic modalities, while in the technological field oligonucleotides have found use in new materials, catalysis, and data
storage. The use of natural oligonucleotides limits the possible chemical functionality of resulting technologies while inherent shortcomings, such as susceptibility to nuclease degradation, provide obstacles to their application. Modified oligonucleotides, at the level of the nucleobase, sugar and/or phosphate backbone, are widely used to overcome these limitations (Abstract). McKenzie teaches that perhaps the most generally tolerated modification in enzymatic incorporation is pendant addition at the C5 pyrimidine position, with the C7 position of adenine and guanine being other common modification targets. These positions are known to cause minimal disruption of Watson–Crick base pairing, as introduced bulky groups sit comfortably in the major groove (pg. 5136, col. 2, para. 2).
Regarding claim 1, it would have been obvious to combine Sau with WO’974 and McKenzie before the effective filing date of the claimed invention by using a pyrimidine nucleotide base with a chemical modification at the C-5 position as taught by WO’974 in the XNA monomer of Sau to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to use a nitrogenous base with a chemical modification because WO’974 teaches that modified nucleosides have been used as therapeutic agents, diagnostic agents, and for incorporation into oligonucleotides to improve their properties (e.g., stability) (pg. 1, [0004]). One of ordinary skill in the art will have a reasonable expectation of success as McKenzie teaches that modification at the C-5 positions are known to cause minimal disruption of Watson–Crick base pairing, as introduced bulky groups sit comfortably in the major groove (pg. 5136, col. 2, para. 2), and Sau teaches that TNA is capable of forming stable antiparallel Watson−Crick duplexes and shows efficient crosspairing with complementary strands of DNA and RNA (pg. 2302, col. 1, para. 1).
Regarding claim 2, Sau teaches the synthetic, non-natural sugar, threose.
Regarding claims 4, 10, and 12, Sau teaches the phosphorus group attached to the sugar moiety to be either a triphosphate or a phosphoramidite, and the triphosphate is attached at C3’ position and the phosphoramidite is attached at C2’ position of the threose sugar.
Regarding claims 13, and 14, Sau teaches from the Scheme 3 shown above that the pyrimidine base is bound to a C1’ position on the sugar moiety, and compound 9b has a cytosine base.
Regarding claim 15, WO’974 teaches the 5-position modified uridine comprises a moiety at the 5-position selected from a naphthyl moiety, a benzyl moiety, a tyrosyl moiety, an indole moiety and a morpholino moiety, and 5-position modified cytidine comprises a moiety at the 5-position selected from a naphthyl moiety, a benzyl moiety, a tyrosyl moiety and a morpholino moiety.
Claims 1, 2, 5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Augustyns et al (Incorporation of hexose nucleoside analogues into oligonucleotides: synthesis, base-pairing properties and enzymatic stability, Nucleic Acids Research, 1992, Vol. 20, No. 18 4711 – 4716) (PTO-892), in view of WO 2018/005974 (IDS 08/19/2025) and McKenzie et al (Recent progress in non-native nucleic acid modifications, Chem. Soc. Rev., 2021, 50, 5126–5164) (IDS 08/19/2025).
Augustyns teaches Oligonucleotides containing 1-(2,4-dideoxy-β-D-erythro-hexo-pyranosyl)thymine (2) and 1-(3,4-dideoxy-β-D-erythro-hexopyranosyl) thymine (3) were synthesized on a solid support using the phosphoramidite approach. The properties of these oligonucleotides were compared with the earlier reported characteristics of oligonucleotides containing 1-(2,3-dideoxy-β-D-erythro-hexopyranosyl) thymine (1). The order in enzymatic stability of end-substituted oligonucleotides is 3 > 1 > > 2 . The hybridization properties of the modified oligonucleotides are in reverse order: 2 > > 1 > 3 (Abstract).
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Augustyns teaches in conclusion that several oligomers have been synthesized containing one or more hexose nucleosides (1-3). Substitution with these nucleoside analogues in the middle of a 13-mer had a more pronounced effect on duplex stability than end-substitution. Apparently, when the hexose nucleoside is able to substitute the natural deoxyribose giving good hybridization properties, the modified oligonucleotide is also recognized by destructive exonucleases (pg. 4713, col. 2, para. 2).
The teachings of Augustyns differ from that of the instantly claimed invention in that Augustyns does not teach a base-modified XNA nucleoside monomer, wherein the pyrimidine nucleotide base comprises a chemical modification at position C-5 of the nucleobase.
The teachings of WO’974 and McKenzie are as discussed above.
Regarding claim 1, it would have been obvious to combine Augustyns with WO’974 and McKenzie before the effective filing date of the claimed invention by using a pyrimidine nucleotide base with a chemical modification at the C-5 position as taught by WO’974 in the XNA monomer of Augustyns to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to use a nitrogenous base with a chemical modification because WO’974 teaches that modified nucleosides have been used as therapeutic agents, diagnostic agents, and for incorporation into oligonucleotides to improve their properties (e.g., stability) (pg. 1, [0004]). One of ordinary skill in the art will have a reasonable expectation of success as McKenzie teaches that modification at the C-5 positions are known to cause minimal disruption of Watson–Crick base pairing, as introduced bulky groups sit comfortably in the major groove (pg. 5136, col. 2, para. 2), and Augustyns teaches that when the hexose nucleoside is able to substitute the natural deoxyribose it gives good hybridization properties to the oligonucleotide (pg. 4713, col. 2, para. 3).
Claims 1, 2, 4, 10, 12 – 15, 29 – 31, 34, 35, 38, 40, and 42 – 44 are rejected under 35 U.S.C. 103 as being unpatentable over Rangel et al (In vitro selection of an XNA aptamer capable of small-molecule recognition, Nucleic Acids Research, 2018, Vol. 46, No. 16 8057–8068) (IDS 08/19/2025) in view of WO 2018/005974 (IDS 08/19/2025) and McKenzie et al (Recent progress in non-native nucleic acid modifications, Chem. Soc. Rev., 2021, 50, 5126–5164) (IDS 08/19/2025).
Rangel teaches that despite advances in XNA evolution, the binding capabilities
of artificial genetic polymers are currently limited to protein targets, describes the expansion of in vitro evolution techniques to enable selection of threose nucleic acid (TNA) aptamers to ochratoxin A (OTA) (Abstract). Rangel teaches that there has been a growing interest in backbone modified nucleic acids, or xeno nucleic acids (XNA), as
these polymers are not readily recognized and degraded by nucleases, and thus are well-suited for in vivo applications (pg. 8057, col. 2, para. 2). Rangel teaches that an initial challenge is the limited availability of the building blocks and polymerases needed to create XNA polymers. For many non-natural nucleic acids, the phosphoramidites and triphosphates needed for solid phase and enzymatic synthesis, respectively, are neither commercially available nor easily synthesized (pg. 8058, col. 1, para. 1). Rangel teaches that direct selection using DNA-primed XNA libraries has provided hexitol nucleic acid (HNA) aptamers to hen-egg lysozyme and HIV trans-activating response RNA element, a (3’,2’)-α-L-threose nucleic acid (TNA) aptamers to human thrombin and HIV-reverse transcriptase, a 2’-deoxy-2’-fluoroarabinonucleotide (FANA) aptamer to HIV-1 reverse transcriptase, and a 2’-fluoromodified aptamer for human neutrophil elastase (HNE) (pg. 8058, col. 1, para. 1). Rangel teaches that using secondary structure predictions, they were able to minimize two of their aptamer sequences to a functional core <35 nt, a length that enables chemical synthesis using phosphoramidite monomers available
in their lab. Aptamer A04T.2, their shortest sequence at 31 nt, was found to have a KD of 71 ± 8 nM. This represents tighter binding than even the best DNA aptamer to OTA,
and is the first example of a TNA aptamer to be validated by chemical synthesis (pg. 8058, col. 2, para. 1). Rangel teaches that TNA triphosphates used for primer extension reactions were synthesized as described previously. TNA phosphoramidites were synthesized by published methods for solid phase synthesis of TNA polymers (pg. 8059, col. 1, para. 2).
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The teachings of Rangel differ from that of the instantly claimed invention in that Rangel does not teach a base-modified XNA nucleoside monomer, wherein the pyrimidine nucleotide base comprises a chemical modification at position C-5 of the nucleobase, wherein the chemical modification at position C-5 of the nucleobase are selected from a group consisting of phenylalanine side chain, a tryptophan side chain, a methyl side chain, a leucine side chain, a dioxol side chain, an isopentyl side chain, a dioxethyl side chain, a cyclopropyl side chain, a p-methoxy-phenyl side chain, a napthalene side chain, and a phenethyl side chain.
The teachings of WO’974, and McKenzie are as discussed above.
It would have been obvious to combine the teachings of Rangel with WO’974 and McKenzie before the effective filing date of the claimed invention by using a pyrimidine nucleotide base with a chemical modification at the C-5 position in the XNA monomer as taught by WO’974 to make the XNA aptamer of Rangel to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to use a nitrogenous base with a chemical modification because WO’974 teaches that modified nucleosides have been used as therapeutic agents, diagnostic agents, and for incorporation into oligonucleotides to improve their properties (e.g., stability) (pg. 1, [0004]). One of ordinary skill in the art will have a reasonable expectation of success as McKenzie teaches that modification at the C-5 positions are known to cause minimal disruption of Watson–Crick base pairing, as introduced bulky groups sit comfortably in the major groove (pg. 5136, col. 2, para. 2).
Regarding claims 2, 4, 10, 12 – 15, 30, 31, 34, 35, 38, 40, and 43, Rangel teaches TNA aptamers/polymers that bind to target small molecule or protein with high affinity and selectivity. The aptamers are made of TNA monomers consisting of a threose sugar, a nucleobase and a phosphorus group. The phosphorus group is either triphosphates or phosphoramidites which is attached to the C3’ or the C2’ of the sugar moiety respectively. The nucleobase is attached to the C1’ of the sugar moiety. Rangel teaches aptamers with cytosine and thymine pyrimidine nucleobases. Rangel teaches Aptamer A04T.2, their shortest sequence at 31 nt.
Regarding claim 42, WO’974 teaches the 5-position modified uridine comprises a moiety at the 5-position selected from a naphthyl moiety, a benzyl moiety, a tyrosyl moiety, an indole moiety and a morpholino moiety, and 5-position modified cytidine comprises a moiety at the 5-position selected from a naphthyl moiety, a benzyl moiety, a tyrosyl moiety and a morpholino moiety.
Regarding claim 44, Rangel teaches that (3’,2’)-α-L-threose nucleic acid (TNA) aptamers to human thrombin and HIV-reverse transcriptase have been made (pg. 8058, col. 1, para. 1).
Conclusion
Claims 1, 2, 4, 5, 7, 10, 12 – 15, 29 – 31, 34, 35, 38, 40, and 42 – 44 are rejected. No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANAKI ANANTH MAHADEVAN whose telephone number is (571)272-0230. The examiner can normally be reached Monday-Friday 8-5PM.
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/JANAKI ANANTH MAHADEVAN/ Examiner, Art Unit 1693
/SCARLETT Y GOON/ Supervisory Patent Examiner, Art Unit 1693
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