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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims1-15 and 18-20, in the reply filed on 09/08/2025 is acknowledged. The traversal is on the ground(s) that no serious burden is upon the Office to examine all of the claims together. This is not found persuasive because the restriction is based on a lack of unity, and burden is not an element to be considered. The Remarks do not contest the teaching of the reference cited to establish a lack of unity.
The requirement is still deemed proper and is therefore made FINAL.
Claims 16 and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-20 are pending.
Claims 1-15 and 18-20 are under examination on the merits.
Priority
This application 17/920,597 filed on 10/21/2022 is a 371 national phase of PCT/JP2021/01599 filed on 04/20/2021, and claims the benefit of provisional Japanese Patent Application No. 2020-076369, filed on 04/22/2020.
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. Receipt of certified copies of papers required by 37 CFR 1.55 is acknowledged. It is noted that foreign priority is not perfected as no English translation was provided for the foreign priority document received on 10/21/2022. In order to perfect the foreign priority claim, please provide a certified English copy.
In the absence of a translated copy, the priority date of claim 1 and its dependents is determined to be 04/20/2021, the filing date of the 371 national phase application PCT/JP2021/01599.
Drawings
The drawings are objected to because Figure 1 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. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. 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.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because it does not contain a “Sequence Listing XML” as a separate part of the disclosure. A “Sequence Listing XML” is required because the filing date of the US application is after 07/01/2022.
Required response - Applicant must provide:
• A “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2.; together with
o A statement that indicates the basis for the amendment, with specific references to particular parts of the application as originally filed, as required by 37 CFR 1.835(a)(3);
o A statement that the “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(a)(4)
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(a)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Interpretation
Claim 1 recites “the oligonucleotide probe has a hybridization sequence with respect to a target sequence of the nucleic acid”. A “sequence with respect to” is interpreted as a sequence capable of binding to the target sequence of the nucleic acid.
Claims 11, 12 and 18 recite the limitation “protein RNA”. This phrase is interpreted as mRNA or messenger RNA.
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 4 and 18-20 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 4 recites the limitation “tissue sections collected from a cultured cell”. It is unclear how tissue sections could be collected from a cultured cell.
Claims 18-20 are similarly indefinite because they directly or indirectly depend from claim 4.
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 (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 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 1-7, 9, and 10 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Pierce et al., (US PGPub 2011/0288148. On IDS dated 09/18/2024).
Regarding claim 1, Pierce teaches cross-linking (e.g. triggered covalent) probes to covalently bind probes to nucleic acid targets (Abstract) that can be used for detecting the presence of a target nucleic acid in a sample (para 45). The crosslinkable probes (oligonucleotide probes) comprise a target initiator region (hybridization sequence) that can bind to a target nucleic acid (para 54) and cross-linkers that covalently bond the probe to the target (para 27). Crosslinkers in the probe may be selected from 4-Thio-dT and CNV-K (para 13), which are capable of covalent bonding.
Pierce teaches combining a target nucleic acid with the cross-linking probe to allow for the initiator region (hybridization sequence) to hybridize to the target sequence (paras 104 and 189 and Figs. 1A and 1B).
Pierce further teaches activating the cross-linkers by photo-activation (para 104), by irradiating the cell or tissue to cross-link the crosslinker probe to the target, resulting in a cross-linked target (an authentic cross-linked hybridization product having a crosslinked structure) (para 189).
Pierce teaches denaturing by an ultrastringent wash (denaturing) would completely eliminate nucleic acid hybridization in the sample, thus causing any non-crosslinked probes to dissociate from their binding sites (para 75). This includes probes that are hybridized but not cross-linked (non-specific hybridization product) (para 136).
Regarding claim 2, Pierce teaches an ultrastringent wash that would be strong enough to destabilize all base-pairing between the probe (hybridization sequence) and the sample (para 75), as encompassed by the required dissociation of the authentic hybridization product and the authentic crosslinked hybridization product as in claim 2.
Regarding claim 3, Pierce teaches the method comprises in situ hybridization (para 45).
Regarding claim 4, Pierce teaches adding the cross-linking probe to cells or tissue that are believed to include the target nucleic acid (para 189), including in fixed cells or tissues (para 147) and normal and pathological tissues (para 8). One would recognize that in situ in tissues involves tissue sections or “the like”.
Regarding claim 5, Pierce teaches denaturing using an ultrastringent wash comprising 75% formamide (para 75).
Regarding claim 6, Pierce teaches denaturing using an ultrastringent wash at 70 degrees (para 75).
Regarding claim 7, Pierce teaches chemical denaturants such as organic cosolvents, or urea (para 75).
Regarding claim 9, Pierce teaches irradiating with 365 nm UV light (paras 199 and 201).
Regarding claim 10, Pierce teaches a target initiator region (hybridization sequence) that is two to 1000 nucleotides (para 54).
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.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al., (US PGPub 2011/0288148. On IDS dated 09/18/2024) in view of Morrison et al., (US PGPub 2015/0291999).
Regarding claim 8, the teachings of Pierce as they relate to claims 1 and 7 are stated in the 102 rejection above in this office action and are incorporated herein.
Pierce teaches chemical denaturants such as formamide, organic cosolvents, or urea (para 75) but does not teach the denaturant other than formamide is tetramethylammonium chloride.
Morrison teaches a chemical denaturant selected from a list including formamide and tetramethylammonium chloride (paras 9 and 85 and claim 6). Morrison states that the choice of denaturant is not bound to a particular theory, i.e. can be chosen as desired.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pierce and Morrison to arrive at the instantly claimed invention. The modification would have entailed choosing tetramethylammonium chloride as the denaturant. One would have been motivated to perform the substitution by the specifics of the annealing temperature and probe Tm (Morrison para 9). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al., (US PGPub 2011/0288148. On IDS dated 09/18/2024) in view of Kononen et al. (US PGPub 2006/0166253).
Regarding claim 11, the teachings of Pierce as they relate to claim 1 are stated in the 102 rejection above in this office action and are incorporated herein.
Pierce teaches target nucleic acids may include mRNA (protein RNA) (para 90), but does not teach the target sequence comprises an RNA sequence in human HER2 protein mRNA.
Kononen teaches erbB2 (HER2) mRNA in situ hybridization on a tissue array (para 50 and Fig. 10) comprising breast cancer specimens (para 54) using oligonucleotide probes directed against erbB2 mRNA (para 89).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pierce and Kononen to arrive at the instantly claimed invention. The modification would have entailed selecting HER2 mRNA of Kononen as the target nucleic acid in the method of Pierce. One would have been motivated to select HER2 to assay expression in breast cancer samples. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al., (US PGPub 2011/0288148. On IDS dated 09/18/2024) in view of Dalerba et al. (US PGPub 2018/0094322).
Regarding claim 12, the teachings of Pierce as they relate to claim 1 are stated in the 102 rejection above in this office action and are incorporated herein.
Pierce teaches target nucleic acids may include mRNA (protein RNA) (para 90), but does not teach the target sequence comprises an RNA sequence in Satb2 protein mRNA.
Dalerba teaches predicting cancer responsiveness using biomarkers (Abstract). Dalerba teaches identifying markers that are useful (alone or in combination with CDX2) in assessing and predicting responsiveness of cancer, e.g., CRC, to treatment with an EGFR inhibitor (para 9 and Table 1). Dalerba teaches that expression level can be determined by in situ hybridization using an oligonucleotide complementary to a portion of the mRNA (para 36). Satb2 is identified as a marker whose mRNA expression levels are positively correlated to those of CDX2 in human colorectal tissues (Table 1, eighth entry).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pierce and Dalerba to arrive at the instantly claimed invention. The modification would have entailed selecting Satb2 mRNA of Dalerba as the target nucleic acid in the method of Pierce. One would have been motivated by the use of Satb2 mRNA as a biomarker for predicting cancer responsiveness to treatment in a patient. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al., (US PGPub 2011/0288148. On IDS dated 09/18/2024) in view of Aloisi et al. (WO 2008/125366).
Regarding claim 13, the teachings of Pierce as they relate to claim 1 are stated in the 102 rejection above in this office action and are incorporated herein.
Pierce teaches target nucleic acids may include viral nucleic acids (para 76), but does not teach the target sequence comprises an RNA sequence in EBER small RNA.
Aloisi teaches using in situ hybridization to determine the presence of EBV-encoded small nuclear mRNAs (EBERs) that are expressed during the latent phase of EBV infection (p. 6, last paragraph).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pierce and Aloisi to arrive at the instantly claimed invention. The modification would have entailed selecting the EBER small RNA of Aloisi as the target nucleic acid in the method of Pierce. One would have been motivated by a desire to determine whether a subject was suffering from EBV (Epstein-Barr virus) infection. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al., (US PGPub 2011/0288148. On IDS dated 09/18/2024) in view of Yoshii et al. (In situ localization of ribosomal RNAs is a reliable reference for hybridizable RNA in tissue sections. 1995. Journal of Histochemistry & Cytochemistry. 43(3): 321-327).
Regarding claim 14, the teachings of Pierce as they relate to claim 1 are stated in the 102 rejection above in this office action and are incorporated herein.
Pierce teaches target nucleic acids may include rRNA (para 90), but does not teach the target sequence comprises an RNA sequence in 28S rRNA.
Yoshii teaches in situ localization of 28s rRNA (p.1, Abstract). Yoshii states that in situ localization of ribosomal RNAs as can be used to evaluate levels of hybridizable RNAs in tissue sections (p. 1, Abstract).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pierce and Yoshii to arrive at the instantly claimed invention. The modification would have entailed selecting the 28s rRNA of Yoshii as the target nucleic acid in the method of Pierce. One would have been motivated by a desire to have a control or reference target nucleic acid to determine hybridizability of a tissue section. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al., (US PGPub 2011/0288148. On IDS dated 09/18/2024) in view of Huang et al. (WO 2019/071262).
Regarding claim 15, the teachings of Pierce as they relate to claim 1 are stated in the 102 rejection above in this office action and are incorporated herein.
Pierce does not teach denaturation of the test sample with an aqueous solution mixture containing 80 volume% of formamide after the hybridizing.
Huang teaches methods for in situ detection of DNA and RNA, the methods comprising denaturing DNA or RNA by contacting the cells with 80% formamide (para 104).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pierce and Huang to arrive at the instantly claimed invention. The modification would have entailed using the denaturing solution of 80% formamide as taught in Huang as the denaturant in the method of Pierce. Varying formamide concentration for denaturation of different molecules is well-known and conventional in the art. One would have been motivated to adjust denaturant parameters to be appropriate for the specifics of the nucleic acid being targeted, the oligonucleotide probe, and the sample. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claims 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al., (US PGPub 2011/0288148. On IDS dated 09/18/2024) in view of Kononen et al. (US PGPub 2006/0166253).
Regarding claim 18, the teachings of Pierce as they relate to claims 1 and 4 are stated in the 102 rejection above in this office action and are incorporated herein.
Pierce teaches denaturing using an ultrastringent wash comprising 75% formamide (para 75).
Pierce does not teach the target sequence comprises an RNA sequence in any one of human HER2 protein mRNA, Satb2 protein mRNA and EBER small RNA.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pierce and Kononen to arrive at the instantly claimed invention. The modification would have entailed selecting HER2 mRNA of Kononen as the target nucleic acid in the method of Pierce. One would have been motivated to select HER2 to assay expression in breast cancer samples. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 19, Pierce teaches chemical denaturants such as organic cosolvents, or urea (para 75).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Pierce et al., (US PGPub 2011/0288148. On IDS dated 09/18/2024) in view of Kononen et al. (US PGPub 2006/0166253) as applied to claims 18 and 19 above, and further in view of Yoshii et al. (In situ localization of ribosomal RNAs is a reliable reference for hybridizable RNA in tissue sections. 1995. Journal of Histochemistry & Cytochemistry. 43(3): 321-327)..
Regarding claim 20, the elements of claims 18 and 19 as required by claim 20 are rendered obvious above.
Neither Pierce nor Kononen teach the target sequence comprises an RNA sequence in 28S rRNA.
Yoshii teaches in situ localization of 28s rRNA (p.1, Abstract). Yoshii states that in situ localization of ribosomal RNAs as can be used to evaluate levels of hybridizable RNAs in tissue sections (p. 1, Abstract).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Pierce and Kononen with Yoshii to arrive at the instantly claimed invention. The modification would have entailed selecting the 28s rRNA of Yoshii as an additional target nucleic acid in the method of Pierce. One would have been motivated by a desire to have a control or reference target nucleic acid to determine hybridizability of a breast cancer tissue section. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA GRAY whose telephone number is (571)272-0116. The examiner can normally be reached Monday-Friday 8-5 with second Fridays off.
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/JESSICA GRAY/Examiner, Art Unit 1682 /JOSEPH G. DAUNER/ Primary Examiner, Art Unit 1682