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 .
Claims 1-16 and 18-21 are pending. Claims 1-11 and 18-21 are being examined on the merits. Claims 12-16 are withdrawn.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-11 and 18-21) in the reply filed on November 14, 2025 is acknowledged.
Claims 12-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 14, 2025.
The requirement is still deemed proper and is therefore made FINAL.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statement submitted January 23, 2026 has been considered.
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 and the required response to this Office Action are as follows:
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. Specifically, sequence identifiers are missing for the sequences in each of Fig. 2A, 2B, 2C, 3A, 3B and 3C.
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.
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is incomplete. See item 1) a) or 1) b) above. Specifically, the incorporation by reference paragraph describes the size of the ASCII text file in kilobytes. However, the size of the file must be described in bytes, not kilobytes.
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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. Specifically, hyperlinks appear, at least, at p. 5, l. 30; p. 24, l. 20; p. 29, l. 11; p. 30, l. 28; and p. 31, in each of ll. 9, 22 and 31.
The use of the terms for various nucleic acid assay reagents and kits, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Specifically, the following trade names or marks appear in the specification: mirVana (p. 3), Tween (p. 20), Triton (p. 20), Taqman (pp. 14, 23, 24), FAM (pp. 25, 26, 36 (twice), 37, 39), TAMRA (p. 25).
The disclosure is objected to because of the following informalities:
Regarding Figs. 2 and 3, the specification provides a description of these figures on p. 2.
However, Figs. 2 and 3 each comprise 3 views (2A-2C, and 3A-3C), and the specification does not describe the various views of each of Figs. 2 and 3 individually.
Appropriate correction is required.
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.
Claims 1, 7, 10 and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kutyavin (US Patent App. Pub. No. 2010/0304442 A1).
Regarding independent claim 1, Kutyavin teaches …
A method for detecting or amplifying a RNA target nucleotide in a sample performed in a one-step approach combining the reverse transcription and subsequent polymerase chain reaction in a single tube and buffer, wherein the method comprises: (Fig. 1; paras. 6, 8-9, 20, 24, 55-56, 83, 112, 115; claims 1, 10-11, 14);
a. carrying-out a retro-transcription reaction by using a bivalent primer that acts as a forward primer for the conservative step of retro-transcription of the RNA target nucleotide and forms a first strand cDNA product from the said RNA target nucleotide (Fig. 1; paras. 6, 8-9, 20, 24, 55-56, 83, 112, 115; claims 1, 10-11, 14);
and b. carrying-out a polymerase chain reaction by using a forward primer that hybridizes with the first strand cDNA product which is then extended to form a second cDNA strand product (Fig. 1; paras. 6, 8-9, 20, 24, 55-56, 83, 112, 115; claims 1, 10-11, 14);
wherein then the bivalent primer then continues the amplification reaction over the second strand product acting as a reverse primer for the polymerase chain reaction (Fig. 1; paras. 6, 8-9, 20, 24, 55-56, 83, 112, 115; claims 1, 10-11, 14);
wherein the bivalent primer comprises a first sequence of a given base length complementary to one primer portion of the RNA target nucleotide that serves directly as the template upon which the primer can anneal and to one primer portion of the second strand or cDNA product that serves directly as the template upon which the primer can anneal (Fig. 1; paras. 6, 8-9, 20, 24, 55-56, 83, 112, 115; claims 1, 10-11, 14);
and a second sequence of a given base length provided adjacent to the side of 3' terminus of said first sequence which is non-complementary with the cDNA products and allows end-tagging the amplicon(s) obtained (Fig. 1; paras. 6, 8-9, 20, 24, 55-56, 83, 112, 115; claims 1, 10-11, 14).
Regarding dependent claim 7, Kutyavin additionally teaches that the forward primer has a structure comprising a first sequence of a given base length complementary to one primer portion of the first cDNA product that serves directly as the template upon which the primer can anneal; and a second sequence of a given base length provided upstream of said first sequence which is non-complementary with the cDNA products and allows end-tagging the amplicon(s) obtained (Fig. 1; paras. 6, 8-9, 20, 24, 55-56, 83, 112, 115; claims 1, 10-11, 14).
Regarding dependent claim 10, Kutyavin additionally teaches analyzing the results of the amplified products, and determining the presence or absence of the RNA target nucleotide in the biological sample (Fig. 1; paras. 8, 18, 26, 27).
Regarding dependent claim 18, Kutyavin additionally teaches that the sample is a human biological sample (paras. 3, 30, 36).
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.
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 2-3, 6, 8-9 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Kutyavin (US Patent App. Pub. No. 2010/0304442 A1) in view of Busk (A tool for design of primers for microRNA-specific quantitative RT-qPCR, BMC Bioinformatics, 15:29, 1-9, 2014), as evidenced by Thermo Fisher Scientific (Pfu DNA Polymerase, native, 2016).
Regarding dependent claims 2 and 9, Kutyavin additionally teaches that the RNA target nucleotide is between 18 to 25 nucleotides in length (paras. 35-36), wherein the DNA polymerase used for carrying-out the polymerase chain reaction possesses a 3'-5' exonuclease activity (paras. 76-77: native polymerases, including Pfu, are useful for the method; Thermo Fisher Scientific, 2nd col., para. 1: Pfu has 3’ to 5’ exonuclease activity).
Regarding the probe, Kutyavin additionally teaches that the detection probe is sufficiently complementary to the cDNA products to hybridize under the selected reaction conditions and is used for detecting the amplified PCR products (e.g., para. 92), and additionally suggests that the detection probe is from 13 to 21 nucleotides, and optionally about 17 to about 21 nucleotides, in length (para. 97, 98: 12-18 or 20-24 nucleotides in length).
Kutyavin additionally suggests the limitation requiring that the probe complementarity overlaps in one, two or three nucleotides with the primer portion of the cDNA product that serves directly, or by virtue of its complement, as the template upon which the bivalent primer or the forward primer anneal. That is, given the lengths of primers and probe, discussed above, and given how short the template is (e.g., the miRNA in Fig. 1), the ordinary artisan would understand that the primers and probes would have to overlap such that each primer/probe is long enough to anneal specifically to the target. The ordinary artisan would have optimized the assay to arrive at the particular level of overlap.
Regarding dependent claim 3, Kutyavin additionally teaches that the RNA target nucleotide is a miRNA (paras. 1-4, 36).
Regarding dependent claims 6 and 21, Kutyavin additionally teaches or suggests that the second sequence is between 9 and 31 nucleotides, and optionally 16 to 24 nucleotides, long, and that the first sequence is between 4 and 8 oligonucleotides long. That is, in Fig. 1A, the reverse primer has a second sequence that is 14 nucleotides in length, and a first sequence that is 10 nucleotides in length.
Regarding dependent claim 8, Kutyavin additionally teaches or suggests that the second sequence (of the forward primer) is between 9 and 31 nucleotides long, and that the first sequence is between 4 and 8 oligonucleotides long. That is, in Fig. 1A, the forward primer has a second sequence that is 15 nucleotides in length, and a first sequence that is 12 nucleotides in length.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Kutyavin method to arrive at the instant primer and probe sequences. The ordinary artisan would have been motivated to optimize the assay design through routine experimentation to customize the assay as desired. The ordinary artisan would have had an expectation of success as the design and modification of oligonucleotides used for the amplification and detection of miRNA is known in the art, as taught in Busk (e.g., Abstract, Implementation section). Optimization within prior art conditions or through routine experimentation is obvious in the absence of a showing of unexpected results. MPEP 2144(II)(A).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Kutyavin (US Patent App. Pub. No. 2010/0304442 A1) as applied to claim 1 above, and further in view of Liu1 (US Patent App. Pub. No. 2016/0265031 A1).
Regarding dependent claim 5, Liu additionally teaches isolating or purifying the amplified products using the end-tag sequences of the amplicon(s) obtained to isolate (Fig. 1; paras. 6, 29).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Kutyavin method to incorporate an isolation/purification step using the end-tag sequences of the amplicons. The ordinary artisan would have been motivated to do so with the expectation that adding the isolation/purification step would result in the advantage of a product that would be useful in downstream applications, e.g., library preparation steps for next-generation sequencing. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid assays is well-known in the art.
Claims 4, 11 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Kutyavin (US Patent App. Pub. No. 2010/0304442 A1) in view of Liu (US Patent App. Pub. No. 2016/0265031 A1) and Busk (A tool for design of primers for microRNA-specific quantitative RT-qPCR, BMC Bioinformatics, 15:29, 1-9, 2014), as evidenced by Thermo Fisher Scientific (Pfu DNA Polymerase, native, 2016).
Regarding independent claim 4 and dependent claim 11, Kutyavin teaches …
A method for isolating or purifying amplified products of a RNA target nucleotide of between 18 to 25 nucleotides in length, in a sample performed in a one-step approach combining the reverse transcription and subsequent polymerase chain reaction in a single tube and buffer, wherein the method comprises: (Fig. 1; paras. 6, 8-9, 20, 24, 35-36, 55-56, 83, 112, 115; claims 1, 10-11, 14);
a. carrying-out a retro-transcription reaction by using a bivalent primer that acts as a forward primer for the conservative step of retro-transcription of the RNA target nucleotide and forms a first strand cDNA product from the said RNA target nucleotide (Fig. 1; paras. 6, 8-9, 20, 24, 55-56, 83, 112, 115; claims 1, 10-11, 14);
b. carrying-out a polymerase chain reaction by using a forward primer that hybridizes with the first strand cDNA product which is then extended to form a second cDNA strand product; wherein then the bivalent primer then continues the amplification reaction over the second strand product acting as a reverse primer for the polymerase chain reaction (Fig. 1; paras. 6, 8-9, 20, 24, 55-56, 83, 112, 115; claims 1, 10-11, 14);
wherein the DNA polymerase used for carrying-out the polymerase chain reaction possesses a 3'-5' exonuclease activity (paras. 76-77: native polymerases, including Pfu, are useful for the method; Thermo Fisher Scientific, 2nd col., para. 1: Pfu has 3’ to 5’ exonuclease activity);
Regarding the probe, Kutyavin additionally teaches that the detection probe is sufficiently complementary to the cDNA products to hybridize under the selected reaction conditions and is used for detecting the amplified PCR products (e.g., para. 92), and additionally suggests that the detection probe is from 13 to 21 nucleotides in length (para. 97, 98: 12-18 or 20-24 nucleotides in length).
Kutyavin additionally suggests the limitation requiring that the probe complementarity overlaps in one, two or three nucleotides with the primer portion of the cDNA product that serves directly, or by virtue of its complement, as the template upon which the bivalent primer or the forward primer anneal. That is, given the lengths of primers and probe, discussed above, and given how short the template is (e.g., the miRNA in Fig. 1), the ordinary artisan would understand that the primers and probes would have to overlap such that each primer/probe is long enough to anneal specifically to the target. The ordinary artisan would have optimized the assay to arrive at the particular level of overlap
Liu teaches isolating or purifying the amplified products (Fig. 1; paras. 6, 29).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Kutyavin method to arrive at the instant primer and probe sequences. The ordinary artisan would have been motivated to optimize the assay design through routine experimentation to customize the assay as desired. The ordinary artisan would have had an expectation of success as the design and modification of oligonucleotides used for the amplification and detection of miRNA is known in the art, as taught in Busk (e.g., Abstract, Implementation section). Optimization within prior art conditions or through routine experimentation is obvious in the absence of a showing of unexpected results. MPEP 2144(II)(A).
It would have been additionally obvious to further modify the Kutyavin method to incorporate an isolation/purification step using the end-tag sequences of the amplicons. The ordinary artisan would have been motivated to do so with the expectation that adding the isolation/purification step would result in the advantage of a product that would be useful in downstream applications, e.g., library preparation steps for next-generation sequencing. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid assays is well-known in the art.
Regarding dependent claims 19 and 20, Kutyavin additionally teaches that the RNA target nucleotide is a miRNA (paras. 1-4, 36), as recited in claim 19, and that the sample is a human biological sample (paras. 3, 30, 36), as recited in claim 20.
Conclusion
Claims 1-11 and 18-21 are being examined, and are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN GREENE whose telephone number is (571)272-3240. The examiner can normally be reached M-Th 7:30-5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CAROLYN L GREENE/Examiner, Art Unit 1681
1 Liu was cited in the Information Disclosure Statement submitted January 23, 2026.