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 .
DETAILED ACTION
Claims 1-20, filed April 6, 2023 are currently pending in the instant application.
Response to Election/Restriction
Applicant's election with traverse of Group I, claims 1-9 and 13-20, directed to a method for analyzing a higher-order structure of RNA; and Applicant’s election with traverse of Species as follows:
Species (A): wherein the barcode sequence forms a structure comprising a plurality of base pairs (claim 4); and
Species (B): wherein the structure comprising a plurality of base pairs is a complementary double-stranded structure (claim 5), in the reply filed March 17, 2026 is acknowledged.
Response to Traversals:
The traversal of is on the grounds that: (a) Applicant elects Invention I with traverse (Applicant Remarks, pg. 1, first full paragraph); and (b) the recited structures represent obvious variants of a common inventive concept and do not impose a serious search burden (Applicant Remarks, pg. 1, third full paragraph).
Regarding (a), no arguments were provided with regard to Applicant’s traversal of Groups I-IV. Thus, the restriction requirement with respect to Groups I-IV is proper.
Regarding (b), MPEP 806.04(f) states (in part): “Claims to different species are mutually exclusive if one claim recites limitations disclosed for a first species but not a second, while a second claim recites limitations disclosed only for the second species and not the first. This may also be expressed by saying that to require restriction between claims limited to species, the claims must not overlap in scope.” Species (A) includes claims 4 and 5, wherein claim 4 recites barcodes that do not form a base pair, and claim 5 recites a barcode sequence comprising a plurality of base pairs. Species (B) includes claims 5-8 and 13-20, where each claim recites a different barcode base-pair structure (e.g., base pairs in a stem-loop structure, base pairs deposited in PDB, base pairs in a triple chain structure, etc.). Thus, the structures and/or functions of the base pairs are patentably distinct a priori, such that the species are mutually exclusive. Moreover, the species require different fields of search, which creates a serious search and examination burden on the Examiner. Thus, the restriction is proper.
Claims 10, 11 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 3, 6-8 and 13-20 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on April 6, 2026.
The restriction requirement is still deemed proper and is therefore made FINAL.
The claims will be examined insofar as they read on the elected species.
Therefore, claims 1, 2, 4, 5 and 9 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed November 22, 2022 is a CON of PCT/JP2021/042250, filed November 17, 2021, which claims the benefit Japanese Patent Application JP2020-191550, filed November 18, 2020.
Acknowledgment is made of Applicant's claim for foreign priority based on an application filed in the Japan on November 18, 2020; and of Applicant’s filing of the certified copy of Japanese Patent Application JP2020-191550 on November 8, 2023 as required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on April 6, 2023; September 5, 2023; February 5, 2024; March 5, 2024; July 10, 2024 and October 29, 2025 have been considered. Initialed copies of the IDSs accompany this Office Action.
Claim Objections/Rejections
Claim Interpretation: “barcode sequences has a structure that has a reduced reactivity with the RNA modification reagent” is interpreted to refer to a barcode sequence having any structure.
Specification Objection
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code – see, e.g. paragraphs [0006]; [0024] and [0030] (instant as-filed Specification). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112(b)
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 1, 2, 4, 5 and 9 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1, 2 and 4 are indefinite for the recitation of the term “the RNA probes” such as recited in claim 1, lines 6 and 9. There is insufficient antecedent basis for the term “the RNA probes” in the claim because claim 1, line 3 recites the term “one or a plurality of RNA probes.” The Examiner suggests that Applicant amend claim 1 to recite, for example, “a sequence of the one or the plurality of RNA probes.”
Claim 1 is indefinite for the recitation of the term “detecting a position and a frequency of modified nucleotides in a sequence” such as recited in claim 1, lines 8-9 because claim 1(b) does not recite that any nucleotides are modified by contacting the RNA probes with an RNA modification reagent and, thus, the metes and bounds of the claim cannot be determined.
Claims 1 and 2 are indefinite for the recitation of the term “step” such as recited in claim 1, line 9 because claim 1 recites (a), (b), and (c), such that claim 1 does not recite “step” (a), etc. and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “the barcode sequences has a structure that has a reduced activity with the RNA modification reagent” such as recited in claim 1, lines 11-13 because it is unclear what barcode structures having a reduced activity are encompassed by the recited limitation given the different types of RNA, the number of modification sites, and the vast number of chemical reagents that can modify RNA (in all combinations). For example, it is known that more than 170 chemical modifications of RNA have been characterized as evidenced by Zhang (Abstract); large families of RNA-modifying enzymes can modify a variety of RNA types (e.g., mRNA, tRNA, piRNA ncRNA, miRNA, etc.) are known in the art as evidenced by Storm (pg. 1, entire page); as well as, drugs and chemicals that alkylate and acylate RNA as evidenced by Drablos (Abstract, lines 1-3) and Velema (Abstract) and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “reduced activity” such as recited in claim 1, line 12 because the term “reduced” is a relative term that renders the claim indefinite. The term “reduced” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite amount of ‘reduction’ in reactivity with the RNA modification reagent as compared to some other value, such that a “reduced reactivity” is determined or detected, such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention.
Claim 4 is indefinite for the recitation of the term “selectively modified an unbound nucleotide in the RNA probe” such as recited in claim 4, lines 3-4 because claim 4 depends from instant claim 1, wherein claim 1 does not recite selective modification, bound and/or unbound nucleotides, and/or the modification of an unbound nucleotide in the RNA probe and, thus, the metes and bounds of the claim cannot be determined.
Claims 5 and 9 are indefinite insofar as they ultimately depend from instant claim 1.
Claim Rejections - 35 USC § 112(d)
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 4 is rejected under 35 U.S.C. 112(d) 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 4 recites (in part): “wherein the barcode sequence forms a structure comprising a plurality of base pairs in a case where the RNA modification reagent selectively modifieds and unbound nucleotide in the RNA probe” in lines 1-4 because claim 4 depends from claim 1, wherein claim 1 does not recite modifying a barcode sequence, selective modification, and/or the modification of an unbound nucleotide in the RNA probe. Thus, claim 4 is an improper dependent claim 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.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 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 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.
Claims 1, 2, 4, 5 and 9 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Smola et al. (hereinafter “Smola”) (Nature Protocols, 2015, 10(11), 1643-1669).
Regarding claims 1, 2, 4, 5 and 9, Smola teaches the selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) chemistries exploit small electrophilic reagents that react with 2′-hydroxyl groups to interrogate RNA structure at single-nucleotide resolution; and mutational profiling (MaP) identifies modified residues by using reverse transcriptase to misread a SHAPE-modified nucleotide and then counting the resulting mutations by massively parallel sequencing, such that the SHAPE-MaP approach measures the structure of large and transcriptome-wide systems as accurately as can be done for simple model RNAs (interpreted 2’-hydroxyl acylation as encompassing RNA modification reagents; and synthesizing cDNA, claims 1 and 2) (Abstract, lines 1-5). Smola teaches that SHAPE electrophiles are added to the folded RNA (or virus or cell) and then incubated until the reagent has either reacted with RNA or degraded via hydroly-sis with water (five hydrolysis half-lives, Fig. 1b,c), wherein two con-trol reactions are performed in parallel: a no-reagent control and a denaturing control (interpreted as contacting the RNA probe and an RNA modification reagent, claim 1b) (pg. 1645, col 1, last partial paragraph). Figure 2 is shown below:
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Smola teaches that cellular or viral RNAs that were obtained by gentle extraction to maintain secondary structure should be DNase-treated following SHAPE modifica-tion, before reverse transcription (interpreted as RNA to be analyzed; and interpreting a secondary structure as an RNA comprising a structural motif, claims 1a and 9) (pg. 1645, col 2, last partial paragraph, lines 7-10). Smola teaches in Figure 2, an overview of SHAP-MaP and ShapeMapper, the method comprising: (a) RNA is treated with a SHAPE reagent that reacts at conformationally dynamic nucleotides; (b) Specialized reverse transcription conditions—the MaP strategy—allow the polymerase to read through chemical adducts in the RNA and to record the site as a nucleotide noncomplementary to the original sequence in the cDNA; (c) the resulting cDNA is processed through one of three workflows including barcoding (Figure 4) and subjected to massively parallel sequencing; (d–f) ShapeMapper then aligns sequenced reads back to the target sequence (d), calculates mutation rates; (e) and generates SHAPE reactivity profiles (f), wherein SHAPE reactivities can be used to model secondary structures, visualize competing and alternative structures and quantify any process that modulates local nucleotide RNA dynamics (interpreting (a) as contacting RNA probes and an RNA modification agent in claim 1b, and showing that the RNA has at least one structural motif of claim 9; (b) as synthesizing cDNA using RNA as a template, and reverse transcription in claim 2c1; (c) sequencing as a workflow that includes barcoding the probes as recited in claim 1a, determining nucleotide sequences in claim 2c2, barcodes forming base pairs in claim 4; (d) as alignment and mutation counting in claim 2c2; (e) and (f) are interpreted to provide mutation rates for detecting a position and frequency of mutations in claim 2c3; and interpreting SHAPE reagents to selectively modify unbound nucleotides in single-stranded regions, claims 1, 2, 4, 5 and 9) (pg. 1645, Figure 2; and pg. 1647, Figure 4). Smola teaches that Figure 4 is an overview of workflows useful for converting RNAs modified with SHAPE reagents into libraries compatible with massively parallel sequencing, wherein RNAs are modified with a SHAPE reagent and subjected to reverse transcription under MaP conditions, during which adduct-induced mutations are recorded in the cDNA strand, such that one of three workflows is then used to construct high-quality libraries for sequencing and recovery of the SHAPE chemical probing information (interpreted as synthesizing cDNA, sequencing to determine nucleotide sequences comprising mutations; barcoding probes; and forming base pairs, claims 1, 2 and 5) (pg. 1647, Figure 4). Figure 4 is shown below:
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Smola teaches in Figure 1 that SHAPE reagents include 1M7, 1M6 and NMIA, wherein 1M6 and NMIA are selective for nucleobases that have one face available for stacking and that achieve a reaction competent conformation on a slow time scale, respectively (interpreting SHAPE reagents 1M6 and NMIA selectively modify unbound nucleotides in single-stranded regions, claim 4) (Figure 1). Smola teaches that low SHAPE reactivity across a region of RNA is indicative of stable base pairing (interpreted as barcodes having reduced reactivity with the RNA modification reagent, claim 1) (pg. 1645, col 1, first partial paragraph, lines 1-2).
Smola meets all the limitations of the claims and, therefore, anticipates the claimed invention.
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 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 may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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.
Claims 1, 2, 4, 5 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Smola et al. (hereinafter “Smola”) (Nature Protocols, 2015, 10(11), 1643-1669) in view of Saito et. al. (hereinafter “Saito”) (US Patent No. 12091775, issued September 17, 2024; and International Application WO2018/003809, published January 4, 2018).
The teachings of Smola as applied to claims 1, 2, 4, 5 and 9 are described supra.
Smola does not specifically exemplify additional instances of a barcode forming base pairs (claim 4, in part).
Regarding claim 4 (in part), Saito teaches an RNA probe containing RNA functional structural units is prepared by the following steps: (1) recognizing one or more stem structures contained in the RNA based on RNA sequence information; (2) extracting a motif region with reference to the one or more recognized stem structures; (3) adding an assistive stem region to the extracted motif region; and (4) adding a barcode region, which represents a complementary sequence to a DNA barcode sequence, to the assistive stem region; and a method for detecting a protein-binding RNA by using an RNA probe containing RNA functional structural units (interpreted as preparing RNA probes; attaching a barcode sequence comprising base pairs; and inherently having a structure with reduced reactivity with RNA modification reagents, claim 1) (Abstract). Saito teaches the analysis of the functions of large RNA structural units containing a plurality of loop structures, which have been heretofore difficult to analyze; and since the RNA functional structural units can be extracted based only on RNA sequence information, it is possible to analyze the functional structural units extracted from a wide variety of RNAs (col 3, lines 56-62). Saito teaches adding a first assistive stem portion sequence (interpreted as a ssRNA barcode) and a second assistive stem portion sequence (interpreted as a ssRNA barcode) to the extracted motif region, wherein the second assistive stem portion sequence is complementary to the first assistive stem portion sequence and hybridizes to the first assistive stem portion sequence to form a double-stranded assistive stem (interpreting the hybridized assistive stem base-pairs as forming barcode base-pairs, claim 1) (col 2, lines 49-55). Saito teaches an RNA microarray prepared by hybridizing a microarray having DNA barcode sequences immobilized on a support with the RNA probe library (interpreting the hybridized DNA barcode sequence to the RNA probe as forming barcode base-pairs, claim 1) (col 3, lines 32-34). Saito teaches that the barcode region which represents a complementary sequence to a DNA barcode sequence is added to the assistive stem (Figures 2b and 2c), wherein the DNA barcode sequence of the present invention, it is possible to use tags (JP 1998-507357 A and JP 2002-518060 A), zip codes (JP 2001-519648 A) or normalized orthogonal sequences (JP 2012-181813 A), barcode sequences (Xu, Q. et al., Proc. Natl. Acad. Sci., Vol. 106, pp. 2289-2294, 2009), or the like, such that the term "motif region" refers to a functional structural unit for an RNA to interact with a target substance, wherein the DNA barcode sequence desirably has less cross-reactivity (cross-hybridization); and preferably has a sequence of 20 to 30 bases, and particularly preferably 25 bases (interpreted as a double-stranded structure; a forming a plurality of base pairs; and reduced reactivity, claim 4) (col 6, lines 28-41). Saito teaches that the extracted RNA probe is contacted with a microarray having DNA barcode sequences immobilized on a support, and the RNA probe hybridized with the DNA barcode sequences is identified (interpreting the barcode to comprise base pairs, claim 4) (col 9, lines 43-46). Saito teaches that RNA structure data of the HIV-1 genome used data analyzed by SHAPE-MaP (col 13, lines 1-4).
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Moreover, it is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of producing RNA probes containing RNA functional structural units as exemplified by Saito, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of mutational profiling using SHAPE chemistries and mutational profiling as disclosed by Smola to include the RNA probes comprising a motif region, an assistive stem region, a barcode region, and a DNA barcode sequence as taught by Saito with a reasonable expectation of success in identifying modified residues; in producing a thorough and robust strategy for higher order RNA structure probing at multiple scales; and/or in identifying specific RNA probes hybridized to the DNA barcode sequence. Moreover, it would have been prima facie obvious for one of ordinary skill in the art to analyze the RNA structure data obtained by the methods of Saito using the SHAPE-MaP method disclosed by Smola with a reasonable expectation of success in converting the RNA structure information into secondary structure information.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103(a) as obvious over the art.
Conclusion
Claims 1, 2, 4, 5 and 9 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
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/AMY M BUNKER/Primary Examiner, Art Unit 1684