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 amendment dated 06/01/2026 is acknowledged. Claims 3 – 4 and 9 – 13 are amended. Claims 1 – 18 are currently pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-13 and 16-18 drawn to an oligonucleotide primer; and Applicant’s election of species without traverse of the following structure, which is presented in claims 9-13 in the reply filed on 06/01/2026 is acknowledged.
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Claims 14 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II and Group III respectively, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/01/2026.
The requirement is still deemed proper and is therefore made FINAL.Claims 1-13 and 16-18 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 continuation-in-part (CIP) Application of PCT/ CN2023/091598, filed on 04/28/2023, and claims priority to Chinese Patent Application No. CN202210480431.7, filed on 05/05/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted in the instant application
on 11/28/2023 and 03/31/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Objections
The structures in claim 1 contain illegible text and need to be amended for legibility.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1 recites “R1 and R2 are independently selected from the group consisting of H, OH, alkyl, O-alkyl, and halogen”. Although claim 5 further recites O-alkyl is substituted or unsubstituted, based on the instant specification which defines “O-alkyl” and discloses that O-alkyl groups may be substituted or unsubstituted (pg. 14, [0061]), the claim 1 limitation has the same scope. Thus, claim 5 depends on claim 1 and fails to further limit it. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 – 13 and 16 – 18 are rejected under 35 U.S.C. 103 as being unpatentable over Sikorski et al (The identity and methylation status of the first transcribed nucleotide in eukaryotic mRNA 5’ cap modulates protein expression in living cells, Nucleic Acids Research, 2020, Vol. 48, No. 4, 1607 – 1626) (PTO-892) in view of US 2020/0040026 (PTO-892).
Sikorski teaches that 7-methylguanosine 5’ cap on mRNA is necessary for efficient protein expression in vitro and in vivo and teaches trinucleotide 5’ cap analogs (m7GpppN(m)pG), which are utilized by RNA polymerase T7 to initiate transcription from templates carrying ф6.5 promoter and enable production of mRNAs differing in
the identity of the first transcribed nucleotide (N = A, m6A, G, C, U) and its methylation status (±2’-O-methylation) (Abstract).
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Sikorski teaches the structures of trinucleotide cap analogs synthesized in Figure 1 shown above (pg. 1609). Among those, m7GpppAmpG (2) is the closest to the elected species from the instant claims. Sikorski teaches how efficiently the trinucleotide cap
analogs were incorporated into RNA during in vitro transcription (IVT) with the highest
capping efficiency was observed for trinucleotides featuring a purine nucleotides at the position of the first transcribed nucleotide (‘purine trinucleotides’): m7GpppAmpG (90%),
m7GpppApG (89%), m7GpppGmpG (86%), m7GpppGpG (80%), while the lowest capping efficiencies were observed for pyrimidine trinucleotides: m7GpppUmpG (56%), m7GpppUpG (56%), m7GpppCmpG (54%) and m7GpppCpG (60%), comparable to the capping efficiencies obtained for m7GpppG (69%) and m2 7,3’-OGpppG (56%). The high capping efficiencies for purine trinucleotides result likely from the fact that these nucleotides are able to pair with two nucleotides in the DNA template, which is thermodynamically preferred over single-base pair annealing taking place in the case
of GTP, m7GpppG-derived dinucleotides, or pyrimidine trinucleotides (Figure 2B) (col. 1-2, pg. 1614). A typical initiation event in in vitro transcription involves annealing of guanosine from the cap analog with +1 cytosine in the antisense strand of the template. Exceptions are A-trinucleotides, which can anneal with both –1 and +1 sites forming A–T and G–C pairs thereby providing more efficient capping, and G-trinucleotides, which can anneal with +1 and +2 sites forming two G–C pairs thereby providing more efficient capping and 1 nt shorter main transcription product (Figure 2, pg. 1616).
The teachings of Sikorski differ from the instantly claimed invention in that Sikorski does not teach a seco-ribose with the m7G nucleotide of the trinucleotide analog m7GpppAmpG (2).The circled feature in the following figure from Sikorski shows the position that differs from the elected species. The arrows are added to help visualize the trinucleotide analog, m7GpppAmpG (2).
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US’026 teaches a trinucleotide cap analog comprising m7G(5′)p3-N1pN2 for increased efficiency of in vitro transcription of m7G(5′)p3-RNA, wherein m7G is N7-methylguanosine or analog, (5′)p3 is a 5′,5′-triphosphate bridge, and N1 or N2 or both ribonucleotide analogs linked to each other by a phosphate, p, and wherein the trinucleotide cap analog increases the efficiency of in vitro transcription (Abstract).
US’026 teaches a compound of formula m7G(5′)p3-N1pN2, wherein m7G is a ribonucleotide consisting of N7-methylguanine and a ribose or a modified ribose wherein one or both of the ribose 2′ or 3′ carbons has a fluoro or a C1-C6 alkoxy substituent; N1 comprises a seco (UNA) ribose optionally substituted at the 2′ or 3′ carbons with one or more fluoro or C1-C6 alkoxy substituents, and a base selected from the group consisting of adenine, among others; wherein the seco (UNA) ribose moiety is a seco (UNA) ribose or a modified seco (UNA) ribose, and wherein one or both of the seco (UNA) ribose 2′ or 3′ carbons has a fluoro or a C1-C6 alkoxy substituent; and N2 consists of (i) a base and (ii) a ribose moiety, wherein the base is selected from the group consisting of adenine, uridine, guanine, cytosine, among others; wherein the m7G ribonucleotide is linked at its 5′-OH to the triphosphate bridge, wherein the triphosphate bridge is linked to a 5′-OH of the N1 ribonucleotide, wherein N1 nucleotide is linked via its 3′-OH to a phosphate, p, and wherein the phosphate is linked to a 5′-OH of the N2 ribonucleotide; or a salt or solvated form thereof (pg. 1, col. 2, [0014]). The base of N1 is adenine (pg. 2, col. 1, [0016]). The base of N2 is guanine (pg. 2, col. 1, [0023]). The compound is m7G(5′)p3-seco-2′-OMeA-G, wherein seco-2′-OMeA is 2′-O-methyladenosine-seco(UNA)ribose and G is guanosine (pg. 2, col. 1, [0027]). One or both of the 2′-OH or the 3′OH groups of the ribose group of the m7G ribonucleotide are substituted by fluoro or C1-C6 alkoxy group, or the ribose is substituted by bicyclic (LNA) or seco (UNA) ribose (pg. 2, col. 2, [0032]). A method of synthesizing mRNA in vitro from DNA by using the trinucleotide cap analog to initiate transcription. In some embodiments, the in vitro transcription uses a DNA-dependent RNA polymerase (pg. 2, col. 2, [0033]). FIG. 13 teaches the synthesis of secoguanine (43) (pg. 3, col. 1, [0049]). FIG. 15 teaches the synthesis of trinucleotide cap analog, m7G(5′)pppm62′-OMeAp-seco-2′-OMeG (47) (pg. 3, col. 2, [0051]). US’026 teaches in the section on mRNA synthesis that the trinucleotide cap analogs are used for improving the synthesis of 5′ capped RNA molecules in in vitro transcription reactions. Substitution of cap analog for a portion of the GTP in a transcription reaction results in the incorporation of the cap structure into a corresponding fraction of the transcripts. Transcription of RNA usually starts with a nucleotide triphosphate (usually a purine, A or G). When transcription occurs in vitro, it typically includes a phage RNA polymerase such as T7, T3 or SP6, a DNA template
containing a phage polymerase promoter, nucleotides (ATP, GTP, CTP and UTP) and a buffer containing magnesium salt. The synthesis of capped RNA includes the incorporation of a cap (e.g., m7GpppG) or a cap analog in the transcription reaction (pg. 7, col. 2, [104 – 105]).
It would have been obvious to combine Sikorski and US’026 before the effective filing date of the instantly claimed invention by substituting the seco (UNA) ribose modification in the m7G nucleotide as taught by US’026 in the place of ribose in the trinucleotide cap analog m7GpppAmpG (2) of Sikorski to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the sugar in the m7G nucleotide of the cap analog of Sikorski to a seco-ribose and have a reasonable expectation of success as US’206 teaches the synthesis of trinucleotide cap analogs for improved in vitro mRNA synthesis and translation of m7G(5′)p3-RNA and teaches the synthesis of secoguanine (43) in FIG. 13 (pg. 3, col. 1, [0049]).
Regarding claim 17, Sikorski teaches in the analysis of short RNAs obtained by in vitro transcription (IVT) using T7 RNA polymerase in presence of different cap analogs. (A) IVT RNAs were obtained by a standard protocol (DNA template with ф6.5 promoter, 0.5 mM ATP, GTP, CTP, 0.125 mM GTP, 0.75 mM cap analog), gel-purified, trimmed at the 3’ end by DNAzyme 10–23, and analyzed in 15% PAA gel and (B) A-trinucleotides, which can anneal with both –1 and +1 sites forming A–T and G–C pairs thereby providing more efficient capping, and G-trinucleotides, which can anneal with +1 and +2 sites forming two G–C pairs thereby providing more efficient capping and 1 nt shorter main transcription product (Figure 2, pg. 1616).
Conclusion
Claims 1-13 and 16-18 are rejected. No claims are 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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/J.A.M./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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