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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/24/2026 has been entered.
All previous rejection not reiterated in this office action are withdrawn.
Claims 43-45, 53-56, 58, 60 and 61 are currently under examination.
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.
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.
Claim(s) 43-45, 53-56, 58, 60, 61 is/are rejected under 35 U.S.C. 103 as being unpatentable over Marquardt (WO2018/0681462, IDS), as evidenced by (US 2015/0064235), in view of Metelev (US 7,045,609).
Marquardt discloses a method for characterizing a mRNA comprising: contacting an mRNA with an RNase H enzyme, and an isolated nucleic acid; physically separating a cleaved 5’ untranslated region (UTR) from the mRNA; generating a signature profile of the mRNA by detecting cleaved mRNA 5’UTR; comparing the signature profile with a known RNA signature profile, and determine the Cap structure of the mRNA based upon the comparison (page 7, 3rd paragraph). Marquardt discloses that the isolated nucleic acid sequence has the formula from 5’ to 3’: [R]qD1D2D3D4[R]p, wherein R is a modified RNA nucleotide such as 2’-O-methyl-modified RNA nucleotide (page 20, lines 18-19), D is a deoxyribonucleotide base, and each of q and p are independently an integer between 0 to 50, and wherein the hybridization of the isolated nucleic acid to a mRNA in the presence of RNase H results in cleavage of the mRNA (page 4, lines 26-32). Marquardt discloses in some embodiments, hybridization of the isolated nucleic acid to a mRNA in the presence of RNase H results in cleavage of the mRNA 5’ UTR, or results in liberation of an intact mRNA Cap (page 5, line 18-19). Marquardt discloses in some embodiment, the hybridization of the guide strand to mRNA 5’ UTR may be between 1 to 50 nucleotides upstream of the first nucleotide of the initiation codon (page 22, lines 14-18). Since it is known in prior art that mammalian mRNA has 5’ UTR has 100 or more nucleotides long (as evidenced by the teaching from Lodish, Harvey, Molecular cell biology, 2003, page 113, bridging paragraph of 1st and 2nd col), the binding of the guide strand would be downstream of the 1st 6 nucleotides of the test mRNA. Marquardt teaches an RNA may comprise naturally occurring nucleotide and/or modified nucleotides with chemical modifications well known in the art including those listed in US 2015/0064235 (page 17-18, bridging paragraph). ‘235 publication teaches modification in internucleoside linkage that includes substitute phosphate moiety to phosphorothioate DNA and RNA have increased nuclease resistance and subsequently a longer half-life in a cellular environment, and reduced the innate immune response through weaker binding/activation of cellular innate immune molecules (paragraph [0461]).
However, Marquardt specifically teach R comprises a phosphorothioate modification.
Metelev teaches hybrid oligonucleotides having phosphorothioate or phosphorodithioate internucleotide linkages, and both deoxyribonucleosides and ribonucleosides or 2’substituted ribonucleotides, wherein said hybrid oligonucleotides have superior properties of duplex formation with RNA, nuclease resistance and RNase H activation (abstract). Metelev teaches an oligonucleotide comprising a deoxyribonucleotide, a 2’-substitued ribonucleotide, and a phosphorothioate internucleotide linkage that comprises at least four contiguous deoxyribonucleotides (col.17, claim 2).
It would have been obvious to an ordinary skilled in the art that to make the modification of phosphorothioate linkage in the guide oligo taught by Marquardt because ‘235 publication (that is incorporated in Marquardt’s teaching) teaches phosphorothioate linkage gives stability to oligonucleotides against serum or intracellular nucleases, and reduced innate immune response, wherein Metelev demonstrates that oligonucleotides having 2’-O-methyl modification and phosphorothioate modification activates RNase H cleavage of mRNA (with at least four consecutive deoxynucleotides), the ordinary skilled in the art would be motivated to use such modification in the guide strand [R]qD1D2D3D4[R]p taught by Marquardt to improve RNase H cleavage reaction. The ordinary skilled in the art would have reasonable expectation of success to make claimed modifications to the guide strand following combined teaching from Marquardt (including ‘235 publication cited by Marquardt) and Metelev. Therefore, the claimed invention of claim 43 and claim 45 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claim 44, Marquardt discloses the guide strand may hybridize to a mRNA 5’UTR between 1 nucleotide and about 100 nucleotides upstream of the first nucleotide of the initiation codon (page 22, line 11-14). Since mammalian 5’UTR is at least 100 nucleotides, assuming a 100 nucleotides, hybridization of 75-94 nucleotides upstream of the first nucleotide of the initiation codon (encompassed by between 1-100) would meet this claim limitation.
Regarding claim 53, Marquardt discloses D1 and D2 are unmodified DNA nucleotides (page 21, lines 5-6).
Regarding claim 54, Marquardt discloses D3, D4, or D3 and D4 are modified DNA nucleotides (page 1, line 8).
Regarding claim 55, Marquardt discloses that the modified DNA nucleotide is 5-nitroindole or Inosine, 4-nitroindole, 6-nitroindole, 3-nitropyrrole or 2-thio-thiamine.
Regarding claim 56, Marquardt discloses that a plurality of guide nucleic acid hybridizes to different regions of the mRNA simultaneously, including 5’UTR, ORF and 3’UTR (page 24, lines 10-14).
Regarding claim 58, Marquardt discloses the mRNA in mixed in a buffer comprising Tris and urea (page 27, lines 28-29).
Regarding claim 60, Marquardt discloses that the test mRNA is an in vitro transcribed mRNA (page 5, lines 31-33).
Regarding claim 61, Marquardt discloses that the test mRNA encodes a therapeutic protein (page 1, line 27-29).
Response to Arguments
Applicant argues that the combined teaching from Marquardt, Bancel and Metelev does not provide a guide strand that hybridizes to the test mRNA at a position that is downstream from nucleotides 1-6 of the test mRNA, and that does not hybridize to any of the first 6 nucleotides of the test mRNA. Applicant argues even if the missing feature was taught by the cited references and one of ordinary skilled in the art were motivated to combine the references, one could not have predicted the result of said combination, because hybridization of the guide strand to the targe mRNA at a position that is downstream from nucleotide 1-6 of the test mRNA results in a method having various surprising advantages not taught by the cited references. Applicant states that the present application describes the ability to direct RNase H cleavage with high specificity is critical for directing retention times of the RNase H target fragments, such as Cap fragments, which allows one or prevent undesired co-elution with other fragments. Applicant alleges that the working example demonstrates that the claimed method offers higher sensitivity and/specificity of RNase cleavage than is achieved with using previously described methods. Applicant states that example 2 describes result of digesting of Cap regions of target mRNAs using RNase H according to the claimed method does not result in cleavage 3’ or 5’ of the cut site. Applicant alleges these results indicate that the claimed method using guide RNAs configured to bind at the relative positions described in claim 1 results in both highly specific cleavage and highly efficient release of Caps from mRNA. Applicant asserts that Figure 3 demonstrates that there is no overlap with Cap fragments, and Cap fragments generally have retention times shorter than 4 min, whereas guides 7, 7a, 8 and 9 show distinguishable retention times. Applicant asserts that this allows for surprising efficient quantification of Caps in samples using different RNAs.
The above argument has been considered but deemed unpersuasive. While Marquardt does not use the same word as claimed in claim 43 “wherein guide strand hybridizes to the test mRNA at a position that is downstream from nucleotides 1-6 of the test mRNA, and the guide strand does not hybridize to any of the first nucleotides of the test mRNA,” it would have been obvious to an ordinary skilled in the art that this aspect is taught by Marquardt because Marquardt teaches embodiments that hybridization of the isolated nucleic acid [R]qD1D2D3D4[R]p, which has the same structure as claimed in claim 43, results in liberation of an intact mRNA Cap, cleavage of the mRNA 3’ UTR, or cleavage of mRNA ORF by RNAse H, and no cleavage of the 5’UTR or 3’UTR of the mRNA (page 5, 16-30). At least when there is no cleavage of 5’UTR, the isolated nucleic acid cannot hybridize to the first 6 nucleotides of the mRNA, because RNase H would cleave the hybridized position. With regard to the teaching from example 2, Example 2 teaches “increased levels of RNase H Cap signal was detected for Cap variants described as NO: 7, 7a, 8 and 9,” and “the ability to direct RNase H specificity and flexibility in the length of the RNase H guide strand significantly advances one’s ability to direct retention times of RNase H target fragment.” There is no teaching in this example for demonstrating superior results from hybridization not at any of the 1-6 nucleotides of mRNA. Example 3 teaches modification to guide 7, 7a, 8 and 9 were tested in RNase H assays, it is unclear how this example demonstrates the alleged superior result of higher sensitivity and/specificity of RNase cleavage than is achieved with using previously described methods, presumably, when the hybridization occurs at nucleotides 1-6 of mRNA. Therefore, for reason discussed in previous rejection and set forth above, this rejection is still considered proper and thus maintained.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637
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