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 .
Please note: The examiner handling this application has changed. The new examiner on this case is Kailey Cash (kailey.cash@uspto.gov) in AU1683. Any correspondence relating to the instant application should be directed to this examiner.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-3) in the reply filed on 5/19/2026 is acknowledged.
Claims 1-5 are pending.
Claims 4-5 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 5/19/2026.
Claims 1-3 are being examined on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement (for example, see pages 15-18 of the Specification). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
Figures 1-5 contain color.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Abstract
The abstract of the disclosure is objected to because it contains typos. The abstract currently reads “A FRET based reporter system utilizing the fluorescent semiconductor quantum dots (QDs) and restriction enzymes expressed in cell-free system has the potential to detect multiple analytes in single reaction.” The abstract should read “A FRET based reporter system utilizing [[the]] fluorescent semiconductor quantum dots (QDs) and restriction enzymes expressed in a cell-free system has the potential to detect multiple analytes in a single reaction.”
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Specification
The disclosure is objected to because of the following informalities:
Paragraph [0013] mentions the color drawings and paragraph [0014] contains references to particular colors in the color drawings. Unless a petition is submitted for the acceptance of color drawings, these drawings will be in black and white. Therefore, no references should be made to color drawings or particular colors within the drawings until such petition is filed.
Paragraph [0014] reads “FIG. 1A depicts the general operation oQD reporter” and should read “FIG. 1A depicts the general operation [[oQD]]of a QD reporter”.
Paragraphs [0015, 0031, and 0034-0037] contain references to a non-existent Appendix not included with this disclosure.
Paragraph [0023] reads “exposing a of single-stranded nucleic acid therebetween, thus forming a stem-loop structure” and should read “exposing a loop of single-stranded nucleic acid therebetween, thus forming a stem-loop structure”.
Appropriate correction is required.
The use of the terms "Alexa Fluor" (paragraph [0032]), "PURExpress" (paragraph [0036, 0037]), and "QSY" and "BHQ" (paragraph [0038]), which are trade names or marks used in commerce, have been noted in this application. These 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 terms.
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.
Claim Objections
Claims 1 and 3 are objected to because of the following informalities:
Claim 1, line 4-5 reads “a peptide comprising a polyhisitine sequence” and should read “a peptide comprising a [[polyhisitine]]polyhistidine sequence”. This would be consistent with the specification at paragraph [0026], which teaches that the peptide-PNA comprises a polyhistidine sequence for binding to the quantum dot.
Claim 1, line 6 reads “a sequence complementary the” and should read “a sequence complementary to the”.
Claim 1, line 11-12 reads “a second terminal spacer and quencher configured” and should read “a second terminal spacer and a quencher configured”.
Claim 1, line 13-14 reads “such that the quencher is positioned to quench QD fluorescence bound to the bridge strand” and should read “such that the quencher is positioned to quench QD fluorescence when bound to the bridge strand”.
Claim 3 reads “A system comprising two or more different reporters according to Claim 1, each of which having distinct quantum dots and target sequences” and should read “A system comprising two or more different reporters according to Claim 1, each of which [[having]]have distinct quantum dots and target sequences”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112b - 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 1-3 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 1 is directed to a product (a quantum dot reporter). However, claim 1 also includes a limitation that includes a method step: “wherein cleavage by the restriction endonuclease enzyme of interest causes separation of the quencher from the QD and an increase of QD fluorescence”. As stated in MPEP 2173.05(p):
A single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. See In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303, 1318, 97 USPQ2d 1737, 1748-49 (Fed. Cir. 2011). In Katz, a claim directed to "[a] system with an interface means for providing automated voice messages…to certain of said individual callers, wherein said certain of said individual callers digitally enter data" was determined to be indefinite because the italicized claim limitation is not directed to the system, but rather to actions of the individual callers, which creates confusion as to when direct infringement occurs. Katz, 639 F.3d at 1318, 97 USPQ2d at 1749 (citing IPXL Holdings v. Amazon.com, Inc., 430 F.3d 1377, 1384, 77 USPQ2d 1140, 1145 (Fed. Cir. 2005), in which a system claim that recited "an input means" and required a user to use the input means was found to be indefinite because it was unclear "whether infringement … occurs when one creates a system that allows the user [to use the input means], or whether infringement occurs when the user actually uses the input means."); Ex parte Lyell, 17 USPQ2d 1548 (Bd. Pat. App. & Inter. 1990) (claim directed to an automatic transmission workstand and the method of using it held ambiguous and properly rejected under 35 U.S.C. 112, second paragraph).
Claim 2 depends from claim 1, inherits this deficiency, and is rejected on the same basis.
Claim 3 (also directed to a product, “a system”) contains all of the limitations of claim 1 (“according to Claim 1”) and is rejected on the same basis.
Claim Interpretation
Claim 1 contains the limitation “a nucleic acid bridge strands comprising…a bridge terminal spacer” and “a nucleic acid quencher strand comprising…a second terminal spacer”. No structural limitations are provided for the terminal spacer sequence other than the presence of the sequence in the nucleic acid bridge strand and the nucleic acid quencher strand at a terminal location. Therefore, any sequence that is not part of the recognition sequence for the restriction endonuclease or the sequences that are complementary between the PNA-peptide – bridge strand – quencher strand may be considered a terminal spacer if near the end of the nucleic acid strand.
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.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Urdea (Urdea et al., US 5,118,605 A) in view of Huang (Huang et al., Analytical Chemistry 2011) and Green (Green et al., ACS Nano May 6, 2021).
Claim 1: Urdea teaches a reporter comprising a polynucleotide immobilized to a solid support with complementarity to a bridging polynucleotide with complementarity to the immobilized polynucleotide and complementarity to a labeled polynucleotide (col 4, ln 63 – col 5, ln 29). Urdea teaches that specific binding between the bridging polynucleotide and the labeled polynucleotide creates a DNA duplex that forms a restriction endonuclease site and allows for cleavage of a label for separation from the probe/support complex (col 2, ln 29-43, col 2, ln 64-66, Figure 2B-A(a)). As noted in the claim interpretation section above, the “terminal spacer” is any sequence near the end of the nucleic acid strand that is not part of the restriction endonuclease cut site. As such, Urdea also teaches that the bridging polynucleotide and the label polynucleotide both comprise terminal spacers (see the leftover sequence attached to the digested and removed label in Fig 2B below).
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Urdea teaches that the “label” being used for determination of the presence/absence of the bridging polynucleotide can comprise a fluorescer-quencher pair (col 8, ln 5-22), and that specific binding (and thus cleavage by the restriction endonuclease) results in an increase in fluorescent signal (col 15, ln 61-66).
Urdea does not teach that the solid support is a quantum dot (QD), which acts as the donor in a donor-acceptor FRET partnership, in which the quencher (or label) of the labeled strand is quenching the QD (acting as a quencher strand) when bound to the bridge strand. However, immobilization of DNA substrates containing quenchers to the surface of a QD and subsequent increase in fluorescence upon site-specific cleavage by a restriction endonuclease is known in the art, as taught by Huang.
Huang teaches conjugating dsDNA substrates directly to a solid support, in this case a QD (Abstract, Figure 1). Huang teaches that the dsDNA substrate contains quenchers in a FRET pair with the QD, such that attachment to the QD quenches QD fluorescence and cleavage by a restriction endonuclease of the quencher from the QD results in an increase in QD fluorescence (see Figure 1 below).
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It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the composition (reporter) of Urdea with the QD solid support/quencher system of Huang. One would be motivated to do so given the assertion by Huang that using QDs has “several distinctive advantages over conventional organic labels such as high quantum yields, narrow emission peaks, size-dependent wavelength tenability, and high photo/chemical stability” (Introduction, paragraph 2). Huang also asserts that usage of QDs allows for a high degree of sample multiplexing given that QDs can be “excited with a single excitation light” and have very narrow emission peaks (Introduction, paragraph 2). One would have a reasonable expectation of success given that Urdea teaches that the type of solid support “may be greatly varied” and could include “particles” (col 6, ln 64-68) and Huang teaches successful conjugation of polynucleotide substrates to the surface of QDs and detection of endonuclease cleavage via an increase in fluorescence (Figure 1).
Urdea in view of Huang does not teach that the polynucleotide strand attached to the solid support is PNA, or that this PNA strand is conjugated to the surface of the QD via a peptide comprising a polyhistidine sequence. However, conjugation of a PNA-peptide to the surface of a QD is known in the art, as taught by Green.
Green teaches a peptide-PNA strand comprising a peptide nucleic acid (PNA) comprising a PNA sequence and a peptide comprising a polyhistidine sequence that is effective to bind the peptide-PNA strand to the QD (see the figure below from the Abstract of Green).
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It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the composition (reporter) of Urdea in view of Huang with the peptide-PNA strand as taught by Green. One would be motivated to do so given the assertion by Green that conjugation of ssDNA onto the surface of nanoparticles (such as QDs) is often expensive, inefficient, or challenging (Abstract). The use of the polyhistidine-peptide creates a distinct nanoparticle binding domain that is separate from the DNA binding domain of PNA (Abstract). Additionally, Green asserts that attachment via thiolated DNA and click chemistry (such as that employed by Huang (see Huang – Experimental Section – Preparation of QD-Based Nanoprobes) “resulted in diminished placement precision, stability, or required additional ligand exchange steps, reducing their efficacy in application” (Introduction, paragraph 2). One would be motivated to use PNA rather than DNA as the oligonucleotide attached to the support via the His-peptide linker given the assertion by Green that PNA has “increased chemical and enzymatic stability and demonstrates higher affinity to complementary nucleic acids than DNA” (Introduction, paragraph 4). One would have a reasonable expectation of success given that Green demonstrates successful conjugation of a peptide-PNA strand to the surface of a QD, and demonstrates that said PNA strand can hybridize to complementary DNA (Figure 1b).
Claim 3: As detailed in the rejection of claim 1 above, Urdea in view of Huang and Green teach all of the limitations of the reporter of claim 1. Huang additionally teaches that each reporter can have a different quantum dot and different target sequences for different restriction endonucleases of interest (see Figure 1 of Huang, provided above).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the composition (reporter) of Urdea with the QD solid support/quencher multiplex system of Huang. One would be motivated to do so given the assertion by Huang that employed multiple QDs for different endonucleases enables “high-throughput screening” of endonuclease activity or even potentially endonuclease inhibitors (Conclusions). One would have a reasonable expectation of success given that Huang successfully demonstrates multiplex detection of QD fluorescence of two different QDs and two different restriction endonucleases of interest (see Figure 1 and Figure 3).
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Urdea (Urdea et al., US 5,118,605 A) in view of Huang (Huang et al., Analytical Chemistry 2011) and Green (Green et al., ACS Nano May 6, 2021) as applied to claims 1 and 3 above, and further in view of Díaz (Díaz et al., Methods in Enzymology 2016).
The teachings of Urdea in view of Huang and Green of the elements of the quantum dot reporter of claim 1, from which claim 2 depends, are detailed above.
Urdea in view of Huang and Green do not teach that the quencher is a fluorescent dye. However, use of a fluorescent dye as a quencher in a QD FRET pair is known in the art, as taught by Díaz.
Díaz teaches conjugation of a fluorescent dye labeled substrate to the surface of a quantum dot for the assessment of enzymatic activity via an increase in QD emission (3.5 Spectral Characterization and Figure 11).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the composition (reporter) of Urdea in view of Huang and Green with the fluorescent dye as the quencher partner of the QD in a FRET pair, as taught by Díaz. The use of a fluorescent dye as the quencher (rather than the quenchers as taught by Huang) is a simple substitution of one known element for another with the predictable result of causing quenching of the QD emission. One would have a reasonable expectation of success given that Díaz successfully uses a fluorescent dye as a quencher to monitor enzymatic activity on a substrate conjugated to the surface of a QD.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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