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 without traverse of the invention of Group 1 (methods of detecting) in the reply filed on 06/16/2026 is acknowledged.
Claim 26 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (i.e.: non elected product claims), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/16/2026.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies (identified as I. and II. below) and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See Table 1 on page 25 of the specification as filed.
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 sequence identifiers, 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.
II. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. See the sequences in Figure 1A and the brief description of Figure 1A on page 4 of the specification as filed.
Required response – Applicant must provide:
Replacement and annotated 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 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.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 9, 10, 12 and 15 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.
Claims 9, 10 and 12 are unclear because the claims depend from cancelled claim 8 (i.e.: claim 8 has been cancelled, claim 9 depends from claim 8, and claims 10 and 12 each depend from claim 9), and thus the intended limitations of the rejected claims are unclear.
Claim 15 is rejected because the claim contains a plurality of trademarks/trade names (each identified in the claim with the superscript TM notation). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe particular dyes and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 2, 3, 6, 13, 15, 16, 18-22 and 25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bill et al (2018).
Bill et al teaches methods for detecting mutations in exon 12 of the NPM1 gene in a sample. Relevant to claim 1, Bill et al teaches (e.g.: p.1758 - Absolute quantification by ddPCR; supplemental page 2 - Absolute quantification of ABL1 and mutated NPM1 copies using ddPCR; Supplemental Table 2) ddPCR (relevant to claim 6) comprising amplification of cDNA using primers that produce an extension product of exon 12 of NPM1 and duplex detection of labeled probes directed to a wild type and a mutant sequence (Type A or Type D; relevant to claims 2 and 16) of exon 12 of NPM1 where the probes are labeled with a fluorophore (FAM or HEX) (relevant to claim 15) and a dark quencher (BHQ1) and include locked nucleic acids, and detection of the fluorescent label to detected the target nucleic acid.
Relevant to claim 3, where Bill et al teaches amplification of NPM1 cDNA with primers, and detection using probes, the methods include amplicons (i.e.: extension products) that have a part of SEQ ID NO: 1, 2 and 4 (i.e.: products that hybridize to ‘probe wild type’, ‘probe mutation type A’ or ‘probe mutation type D’).
Relevant to claims 18-20, Bill et al teaches the detection of absolute copies of targets, and teaches the detection of complementary DNA (cDNA) synthesized from RNA isolated from pre-transplant bone marrow or peripheral blood. It is noted that the ranges recited in the rejected claims encompass any amount of copies; for example claim 18 requires “at least 100 copies” (i.e. > 100) or “less than 100 copies” (i.e.: < 100). Based on this breadth of the claims, the methods of Bill et al meets the limitations of the claims. Furthermore it is noted that Bill et al has a threshold of detection of a 0.01% mutated NPM1/ABL1 (e.g.: p.1762 – right col), and included samples with at least 1000 ABL1 copies per well (e.g.: p.1758 - Absolute quantification by ddPCR).
Relevant to claim 21, 22 and 25, Bill et al teaches the use of the method in the detection of measurable residual disease in subjects treated for acute myeloid leukemia (e.g.: p.1757 – Abstract).
Claim Rejections - 35 USC § 103
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(s) 1-4, 6 13, 15, 16-22 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bill et al (2018) in view of Szankasi et al (2008) and Parkin et al (2019).
Bill et al teaches methods of detecting NPM1 wild type and mutant sequences in a ddPCR reaction using primers to amplify a target sequence and probes labeled with fluorophores and quenchers to detect the target sequences, as applied to the rejection of claims 1, 2, 6, 13, 15, 16, 18-22 and 25 above.
Bill et al does not teach amplification using primers that comprise SEQ ID NO: 5 and 6 (as encompassed by claim 4), or a probe that is SEQ ID NO: 22 (as encompassed by claim 17). However the relevant sequence elements of the NPM1 gene sequence, and the design of detection probes, were known in the prior art.
Relevant to the rejection of claim 4, Szankasi et al teaches methods for the detection of NPM1 mutations, including the amplification of the NPM1 gene from genomic DNA, and teaches the relevant genomic DNA sequence including exon 12 (Figure 1). The locus of the prior art includes the sequence of SEQ ID NO: 5 and the reverser complement of SEQ ID NO: 6
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Further relevant to the rejection of claim 4, and to the rejection of claim 17, Parkin teaches the detection of target nucleic acid sequences using labeled wild type and mutant probes in a digital doplet PCR reaction (e.g.: Fig 1), and exemplifies the detection of the TCTG (i.e.: mutant type A) insertion in NPM1 (e.g.: Figure 3). Parkin teaches that probes with chemically altered nucleotides such as locked nucleic acids (LNA) that have an increased affinity for complementary DNA bases and can be incorporated into ASO probes at or near the position of the variant of interest (e.g.: p.241). Parkin teaches that probes and primers may be designed using sequence information form databases and various software packages for analyzing sequences and choosing primers and probes (e.g.: p.241 – Materials; p.242 – Methods).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used the sequence and design methods known in the art to design primers and probes for the detection of NPM1 mutations. Where Szankasi et al provides a disclosure of the NPM1 gene locus, and exemplifies the detection of NPM1 mutations in genomic DNA, the skilled artisan would be motivated to adapt the methods of Bill et al to the detection of mutations in the samples of Szankasi et al based on the expressed teachings of Bill et al that such methods are sensitive and specific for the detection of known NPM1 mutations. The prior art teaches that primers and probes can be designed with established software; the prior teaches the sequence elements of the NPM1 locus relevant to the claimed primer and probes; and the prior art teaches a probe comprising the sequence elements of a claimed probe (i.e.: the ‘probe wild type’ of Bill et al in Supplementary Table 2 comprises the entirety of SEQ ID NO: 22, relevant to claim 17). The particular sequences used in the claimed methods are obvious a the result of routine optimization and design choice using the methods of the prior art. For example, Parkin teaches (e.g.: p. 243) methods to effectively design LNA probes. Where the prior art demonstrates the use of different primers and probes, and a person of ordinary skill has good reason to pursue the known options within his or her technical grasp for optimization of relevant reagents, if this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense to provide routine optimization.
Claim(s) 1, 2, 6, 7, 13, 15, 16, 18-22 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bill et al (2018) in view of Chou et al (2007).
Bill et al teaches methods of detecting NPM1 wild type and mutant sequences in a ddPCR reaction using primers to amplify a target sequence and probes labeled with fluorophores and quenchers to detect the target sequences, as applied to the rejection of claims 1, 2, 6, 13, 15, 16, 18-22 and 25 above.
Further relevant to instantly rejected claim 7, Bill et al teaches the analysis of positive control cDNA from the NPM1 mutated cell line OCI-AML3 and negative control cDNA from the NPM1 wild type cell line KASUMI-1 (e.g.: Supplementary Methods).
Bill et al does not explicitly teach a nucleic acid vector comprising all or part of NPM1, or recording results, but such elements in the analysis of NPM1 mutations were known in the prior art.
Chou et al teaches quantitative PCR for the quantitative detection of NPM1 mutations. Relevant to the instant rejection of claim 7, Chou et al teaches using cloned plasmids containing either WT or mutant NPM1 sequences to generate standard curves (e.g.: p.1000m left col) and demonstrates the display of results in a graph (e.g.: Figure 2) which is a recording of the results of the assay.
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used a vector comprising a control sequence, as taught by Chou et al, in the methods of detection taught by Bill et al. Using the control constructs of Chou et al would be the simple substitution of one known element for another with predictable results. It would have further been obvious to record the results of any analysis, where the skilled artisan would recognize that recording results would allow the results to be shared, or allow the results to be compared with results from another assay performed at a later time point.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
Prosecution Insights