DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the papers filed March 5, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Claims 1-2, 3-6, 15-17, and 31-33 are currently pending.
Claims 17 and 31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on November 10, 2025.
Nucleotide and/or Amino Acid Sequence Disclosures
3. 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. It is noted that Figures 1B, 1C, and 3A-F each contain nucleic acid sequences without the required sequence identifiers.
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.
Response To Arguments-Sequence Rules
4. In response to the alleged deficiencies of the sequences exemplified in the drawings, Applicant respectfully points out that FIGs. 1-3 show targeted MUC5AC mRNA sequences consistent with shortened versions (for illustrative purposes, only) of sequences found in Tables 8a, 8b, and 8d.
This Application is still not in compliance with the Sequence Rules. The figures show probes, wherein there are portions of the probes that comprise sequences of 10 or more nucleotides. These sequences should be in the Sequence Listing and Applicants are required to identify sequences present in the Sequence Listing when they appear in the drawings. Sequence identifiers for the sequences must appear either in the drawings or in the Brief Description of the Drawings. Figure 1B is shown below. The sequences with arrows should be in the Sequence Listing and the drawings must be amended to recite their SEQ ID NOs: or the Brief Description of Figure 1B must be amended to recite their SEQ ID NOs:.
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Additionally Figures 1C has the same issue and should be corrected accordingly. It is noted that the Brief Description of Figure 3 states that it contains SEQ ID NOs: 344-353. However Figure 3 has 6 subparts (Figures 3A-3F) and it is not clear which sequences are shown in each of Figures 3A-3F.
Claim Rejections - 35 USC § 103
5. 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.
Claims 1-2, 5-6, 15-16, and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Luo (US 2013/0023433 Pub 1/24/2013).
Regarding Claim 1, Figure 3 in Luo illustrates an indirect labeling approach in which label probes are hybridized to capture probes hybridized to a target nucleic acid.
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The target molecule captures the label probe through the capture probe. In each capture probe, there is at least one section, T, complementary to a section on the target molecule, and another section, L, complementary to a section on the label probe. The T and L sections are connected by a section C (para 0771). Luo further teaches that other capture probe configurations can readily be employed. Additional exemplary capture probe configurations that can be adapted to the practice of the present invention are illustrated in FIG. 19 (para 0775). In particular Fig 19G is shown below:
[AltContent: textbox (T2)][AltContent: textbox (L2)][AltContent: arrow][AltContent: textbox (L1)][AltContent: arrow][AltContent: arrow][AltContent: arrow][AltContent: textbox (T1)][AltContent: textbox (Label probe)][AltContent: textbox (Target)][AltContent: arrow][AltContent: arrow][AltContent: textbox (C)][AltContent: arrow]
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FIG. 19 G is shown above. Luo teaches that the solid horizontal line represents the target nucleic acid, and the dashed horizontal line is a label probe (para 0523). Thus Luo teaches a pair of nucleic acid probes for detecting a polynucleotide analyte, comprising: i. a first nucleic acid probe comprising: a) a first probe binding arm (section L) that is complementary to a first probe target region of a bridge probe (label probe); and b) a first polynucleotide analyte binding arm (section T) that is complementary to a first analyte target region of a polynucleotide analyte (target), and ii. a second nucleic acid probe comprising: a) a second probe binding arm (section L) that is complementary to a second probe target region of the bridge probe (label probe); wherein the first probe target region is located downstream of the second probe target region on the bridge probe, and b) a second polynucleotide analyte binding arm that is complementary to a second analyte target region of the polynucleotide analyte, wherein the second analyte target region is located downstream of the first analyte target region on the polynucleotide analyte, wherein binding of the first polynucleotide analyte binding arm to the first analyte target region and binding of the second polynucleotide analyte binding arm to the second analyte target region permit binding of the first probe binding arm to the first bridge probe target region and binding of the second probe binding arm to the second bridge probe target region, thereby detecting the polynucleotide analyte, wherein the first probe binding arm is downstream of the first analyte binding arm and the second analyte binding arm is downstream of the second probe binding arm.
Luo teaches that section L of the capture probe is complementary to a section on the label probe (para 0771). Luo teaches that L sections can be 13-15 nucleotides in length (para 0775). Thus Luo teaches a pair of nucleic acid probes wherein the probe binding arm in the first and/or second nucleic acid probes consists of 13-15 nucleotides. Luo does not teach a pair of nucleic acid probes wherein the probe binding arm in the first and/or second nucleic acid probes consists of 9 or 10 nucleotides (claim 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pair of nucleic acid probes of Luo so that the probe binding arm in the first and/or second nucleic acid probes consists of 9 or 10 nucleotides. The claim would have been obvious because it is common practice for a person skilled in the art to try different lengths for the probe binding arms. If this leads to the anticipated success, it is like the product not of innovation but of ordinary skill and common sese. Further to have determined the optimum length of the probe binding arm would have been obvious to one of ordinary skill in the art and well within the skill of the art. As discussed in MPEP 2144.05(b), “(w)here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 105 USPQ 233, 235 (CCPA 1955).
Regarding Claim 2 Luo teaches that section T of the capture probe is complementary to a section on the target nucleic acid molecule (para 0771). Luo teaches that T sections can be 20-30 nucleotides in length (para 0775). Thus Luo teaches a pair of nucleic acid probes wherein the polynucleotide analyte binding arm (section T) consists of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides.
Regarding Claim 4 Luo teaches that section L of the capture probe is complementary to a section on the label probe (para 0771). Luo teaches that the capture and label probes are specific for a target gene of interest (para 0771). Thus Luo teaches a pair of nucleic acid probes wherein the probe binding arm (section L) in the first and/or second nucleic acid probes comprises an identification portion for binding to a unique bridge probe (the label probe).
Regarding Claims 5 and 6 Luo teaches that section C of the capture probe connects the T and L sections (para 0771). Luo teaches that C sections can be 0-10 nucleotides in length (para 0775). Thus Luo teaches a pair of nucleic acid probes wherein the first and second nucleic acid probes comprise a linker (section C) positioned between the probe binding arm (section L) and the polynucleotide analyte binding arm (section T). Luo teaches that the linker (section C) consists of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleobases.
Regarding Claim 15 Luo teaches a probe system comprising a pair of non-naturally occurring nucleic acid probes of claim 1. Herein a “probe system” has been broadly interpreted as a collection of reagents (see Fig 19G).
Regarding Claim 16 Luo teaches a probe system further comprising a bridge probe (label probe) (see Fig 19G).
Regarding Claim 32 Luo teaches that the label probes contain signal generating particles (SGPs) (para 0770). Luo teaches that signal generating particles are labels (para 0511). Luo teaches that a label is a moiety that facilitates detection of a molecule. Common labels in the context of the present invention include fluorescent, luminescent, light-scattering, and/or colorimetric labels (para 0584). Thus Luo teaches a bridge probe (label probe) that is a readout probe that is coupled or conjugated to a fluorescent label.
Regarding Claim 33 Luo illustrates a indirect labeling approach, wherein the label probe is hybridized or connected to an amplifier molecule, which provides many more attachment locations for label probes. The structure and attachment method of the amplifier can take many forms. FIG. 8 Panel A (produced below) shows multiple singly-labeled label probes bind to the amplifier (paras 0512, 0785). Luo further teaches that although a specific capture approach (indirect labeling with capture probe pairs) has been used to illustrate the labeling and amplification schemes in FIG 9, it is important to note that any other probe capture approaches, direct or indirect, described in previous sections can be used in combination with the labeling and amplification schemes described in these sections (para 0788).
[AltContent: textbox (amplifier)][AltContent: textbox (Label probe)][AltContent: arrow][AltContent: arrow]
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Thus Luo teaches a pair of nucleic acid probes wherein the bridge probe (amplifier probe) is detected via hybridization to a readout probe (label probe) that is conjugated to a label.
Response To Arguments 35 USC 103
6. The response states that the present disclosure relates to a circular format which exhibits behavior contrary to conventional nucleic acid hybridization expectations and therefore would not have been predictable to a person skilled in the art. The response states several pairing schemes were screened, including circular, cruciform, double 'C', and double 'Z' (Fig. 3), and it was found that the circular construct produces the brightest on-target signal.
The response states that Luo et al describes a dual probe strategy for a multiplex branched-chain DNA assay. Luo increases detectability through amplification and cooperative binding. On the other hand, the Applicant's application achieves specificity through cooperative binding alone.
This argument has been fully considered but is not persuasive. It is not relevant that Luo increases detectability in a way that it is different from than Applicants. The claims are drawn to a product and it is the structure of the product that is being examined for patentability.
The response argues that Luo et al does not teach or suggest the claimed probe architecture. Neither does Luo et al disclose the strand assignments, orientation constraints, or performance characteristics as shown in the specification. Luo et al does not compare the performance between different formats for the purpose of detecting polynucleotide analytes in a cell or tissue (in particular fluorescence in-situ hybridization). Neither does Luo et al demonstrate the superior performance of the circular format over other formats for the purpose of detecting polynucleotide analytes in a cell or tissue (in particular fluorescence in-situ hybridization).
These arguments have been fully considered but are not persuasive. Applicants are reminded the prior art that is cited in a 102/103 is only required to teach what is actually being claimed. Luo is not required to teach information that is present only in the specification. Applicants are reminded that where the “claimed” and prior art products are identical or substantially identical in structure or composition a prima facie case of either anticipation or obviousness has been established. In the instant case it is maintained that Luo teaches the claimed probe structure, the only difference being the length of the probe binding arms.
The Applicants argue that a skilled person would have no reasonable expectation that the circular format would outperform alternative configurations, which could only have been confirmed through experimental screening.
This argument has been fully considered but is not persuasive. This argument is not germane. There is no requirement for Luo to teach which structure is best for the rejection to be proper.
Applicants argue that Luo does not teach or suggest that the probe binding arm consists of 9 or 10 nucleotides. They argue that a person skilled in the art would have been faced with multiple options of modifying the nucleic acid probe pairs. These include shortening, maintaining and/or lengthening the probe binding arms/polynucleotide analyte binding arms. The skilled person would not have any motivation to shorten the length of the probe binding arm to 9 or 10 nucleotides. They argue that Luo provides no teaching, suggestion, or motivation to shorten such arms from its preferred 13-15 nucleotides, nor does it indicate that shortening would confer any technical benefit. In the absence of such teaching, the modification asserted by the Office would only have been derived by hindsight.
This argument has been fully considered but is not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case Luo teaches the same basic probe structure, the only difference being the length of the probe binding arm. It is maintained that it would have obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pair of nucleic acid probes of Luo so that the probe binding arm in the first and/or second nucleic acid probes consists of 9 or 10 nucleotides. The claim would have been obvious because it is common practice for a person skilled in the art to try different lengths for the probe binding arms. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. Further to have determined the optimum length of the probe binding arm would have been obvious to one of ordinary skill in the art and well within the skill of the art. As discussed in MPEP 2144.05(b), “(w)here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 105 USPQ 233, 235 (CCPA 1955).
They further argue that reducing the binding arm length to 9-10 nucleotides, when combined with the probe architecture maintains signal intensity and virtually eliminates non-specific background. Accordingly, the claimed length represents a non-predictable technical effect rather than routine optimization. They argue that the skilled person would not have expected that shortening the probe binding arm to 9 or 10 nucleotides would lead to any advantageous effect as shown in the present application. Hence, claim 3, which has been incorporated into claim 1, is non-obvious over Luo et al. The prior art provides no reasonable expectation that shortening the arms to 9 or 10 nucleotides would virtually eliminate non-specific background signal.
This argument has been fully considered but is not persuasive. Applicants appear to be arguing that the it was unexpected that shortening the arms to 9 or 10 nucleotides would virtually eliminate non-specific background signal. While non-obviousness can be shown by presenting evidence of secondary considerations (such as unexpected results), Applicants have not met this burden. There are no direct comparisons between the claimed invention and the closest prior art (Luo). Even if differences in non-specific background signal exist between probes which have probe binding arms of 9/10 in comparison to longer or shorter arm lengths, the Applicants would need to establish that the unexpected result is actually unexpected and of statistical and practical significance. See MPEP 716.02(a). The rejections are maintained.
7. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached at 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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