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 .
Preliminary Remark
The examiner of record has been changed to Young J. Kim, of Group Art Unit 1681. All future correspondence should be directed to the undersigned.
Election/Restrictions
Upon reconsideration, the species requirement made by the previous examiner of record is hereby withdrawn.
Claims 1-20 are under prosecution therefore.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Information Disclosure Statement
No IDS has been filed to date of the instant Office communication.
Drawings
The drawings received on February 2, 2023 are acceptable.
Claim Rejections - 35 USC § 112
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 1-20 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 1 is indefinite because the steps of the claim appears to be missing an essential step. For example, claim 1 recites the step of performing a PCR assay in a tube containing at least two fluorescent compounds that have a peak fluorescence excitation and/or emission within a common spectral channel and a sample, but the last step of the claim performs a step of determining a spectral channel signal of each of the at least two fluorescent compounds based on at least two properties of each of the at least two fluorescent compounds, and indicating the presence of a unique testable conditions. But the claim does not recite any steps as to how this relates to the PCR assay and the amplification products generated therein.
For the purpose of prosecution, the at least two proprieties of the fluorescent compounds are utilized to detect the presence of the amplification products of the PCR assay.
Claim 4 is indefinite because the claim is a conditional limitation of, “when six fluorescent compounds … are added to the sample,” and does not actively further limit the parent claim.
Claim 9 is indefinite for reciting dyes which are trademarked, such as JOE, known as 4,5-dichloro-dimethoxy-fluorescein. Usage of a trademark renders the claim indefinite because a product may retain the same tradename while changing its formulation over time (for example, Coke®).
Claim 19 is indefinite because the claim does not make sense. The physical testing conditions are what allows the two fluorescent compounds to be distinguished. So the claim appears to be reciting the physical conditions being applied is based on sensitivity analysis. However, it is unclear what the sensitivity is based on.
Claims 2-20 are indefinite by way of their dependency on claim 1.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description Rejection.
The Federal Circuit reiterated that mere use of the same words in the specification and the claim (an in ipsis verbis test) is not sufficient to establish written description.
The presently claimed method is directed to a method that involves the distinguishing of at least two fluorescent dyes that have a common excitation and/or emission spectral channel, but that which can be distinguishable under on what the specification defines as “physical conditions” (or testable conditions, as claimed).
The claimed method claims that such fluorescent dyes are distinguishable in an amplification reaction based on these physical conditions applied, allowing the method to result in the determination of the presumable targets that are amplified in a PCR reaction (see 112b rejection above).
However, the specification provides no description of what such “physical” conditions that are associated with the fluorescent compounds, nor does the specification provide any description on what conditions are applied in a PCR reaction (or afterwards) which allows such determination to be made.
The specification discloses that various temperatures can be applied as such conditions for determining the distinguishable differences, such as 95oF1. Such a low temperature would result in the fluorescent compounds, presumably attached to a probe (since added to a PCR reaction), being annealed to target as well as other cross-hybridizing targets, rendering that assay unusable.
While the specification provides general conditions that may be utilized to generate a distinguishable emission of the fluorescent compounds, the specification simply does not provide any such compounds that can be utilized in an assay such as PCR so as to provide a specific detection, such as mutation, or a target detection. For example, the specification discloses that pH condition can be utilized for distinguishing among such fluorescent compounds, but none are given. Similarly, photobleaching, electric charge, etc. are also listed as general conditions (see section [0029]), with no specific dyes capable of being used under such conditions and be distinguished from others.
Simply reiterating the assertion of the specification in a claim is not deemed description that applicants were in possession of the claimed method as applicants simply don’t show possession of a single species of at least two fluorescent compounds that have a peak fluorescence excitation and/or emission within a common channel, wherein different unique conditions can be applied to utilize them in a detection assay of targets.
The specification provides no actual examples of such species. The application of matrix calculation is also recited in the claims, but it is theoretically applied and does not show possession that such compounds and unique conditions being applied in the method as claimed.
Applicants are welcomed to provide evidence of using at least two dyes as presently claimed, which are distinguishable based on their unique physical conditions to detect their respective target nucleic acids in a PCR (or after PCR).
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 1-8, 10-12, 18, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chakravorty et al. (Journal of Clinical Microbiology, 2017, vol. 55, pages 183-198).
With regard to claim 1, Chakravorty et al. teach a method comprising:
adding at least two fluorescent compounds, each designed to have a peak fluorescence excitation and/or emission within a common spectral channel (see “[l]arge Stokes-shift fluorophores CF7 (which excites blue and emits yellow … CF9 (which excites blue and emits IR)”, page 185, 2nd paragraph, used in a PCR assay that contains a sample in a tube, see Fig. 3, the probes are target specific, thus “test for a unique testable condition”2);
performing a PCR assay (see Fig. 3);
determining a spectral channel signal of each of the at least two fluorescent compounds based on at least two properties of each of the at least two fluorescent compounds,
wherein the at least two properties of each of the at least two fluorescent compounds comprise at least a property at a physical testing condition and another property at another physical testing condition (the first property is the open/closed configuration of the MB probes; and the second property is based on their melting temperature (see Fig. 3), and
wherein the spectral channel signals of the at least two fluorescent compounds are analyzed to indicate the presence or absence of each of the unique testable conditions (the presence of the target are detected via fluorescence measurements, see Fig. 4).
Therefore, claim 1 is anticipated by Chakravorty et al.
With regard to claims 2 and 3, the unique testable condition is the presence of a known RNA or DNA (via the melting analysis of the target nucleic acids, rrs, inhA, gyrA1, katG, gyrB2, eis2, eis1, gyrA2, gyrB1, and internal control, see Fig. 4).
With regard to claim 4, the claim is a conditional statement, and thus not actively required.
With regard to claim 5, the at least two fluorescent compounds are structurally different (CF7 and CF9).
With regard to claim 6, the at least two properties comprise at least two of a response to a temperature (melting curve, Fig. 4), and measure of fluorescence intensity (see Fig. 4).
With regard to claim 7, the fluorescent compounds are attached to an oligonucleotide probe and added to the tube in a PCR reaction (see 186 bottom paragraph to page 187, 1st paragraph).
With regard to claim 8, the common spectral channel is blue channel (CF7 and CF9 bot excites at blue light wavelength).
With regard to claim 10, the two properties of each of the two fluorescent compounds are unaffected by the presence of others.
With regard to claim 11, the measurement of the fluorescence emission is after the PCR assay has finished (i.e., melting point analysis after PCR, see page 187, 1st paragraph).
With regard to claim 12, the spectral channel signal (i.e., emission) of each of the at least two fluorescent compounds are calculated based on the at least two fluorescence emission measurement of the PCR product at the at least two physical testing conditions (i.e., open/closed configuration of MB probes, temperature, and the emission spectrum of each dye).
With regard to claim 18, the measured fluorescence emission comprises at least a fluorescence intensity at a given temperature, a difference in fluorescence intensity decrease at a peak emission when heating the PCR product from a first temperature to a second temperature (from melting point analysis), or a difference in fluorescence intensity of the PCR product at two or more emission wavelengths.
With regard to claim 20, the peak fluorescence excitation of the at least two fluorescent compounds within the common color spectral channel are the same (i.e., blue light for CF7 and CF9).
Therefore, Chakravorty et al. anticipate the invention as claimed.
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.
Claims 13-17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Chakravorty et al. (Journal of Clinical Microbiology, 2017, vol. 55, pages 183-198) in view of Villa et al. (US 2025/0012722 A1, published January 9, 2025, priority July 30, 2021).
The teachings of Chakravorty et al. have already been discussed above.
While Chakravorty et al. teach that at least two fluorescent dyes of the same excitation spectrum can be utilized to detect two different target nucleic acids via PCR amplification and a subsequent melting point analysis, the artisans do not explicitly teach that the physical testing conditions of the MB probes utilized predetermined based on their sensitivity analysis (claim 19).
Chakravorty et al. do not teach the application of a matrix analysis (claims 13-17).
Villa et al. teach a method of performing multiplexed detection of nucleic acid sequences utilizing at least two fluorescent compounds of overlapping spectra (“multiplexed detection of nucleic acid sequences comprising a thermal cycler … perform a series of thermal cycles with an in vitro nucleic acid amplification reagent containing at least two fluorescence probes combining a quencher and a fluorophore, said fluorescence probe being arranged to each target distinct nucleic acid sequence and said fluorophores emitting in overlapping fluorescence wavelength ranges”, section [0031]).
Villa et al. also teach that the probes, like those of Chakravorty et al., could be MB (molecular beacons, see section [0034]).
Villa et al. also teach that matrix function is applied for determining and distinguishing the fluorescence observed (“analyzer is arranged to determine the value representative of the concentration of each fluorescence probe in a modified state by solving a matrix system based on the fluorescence measurements … of each fluorescence probe … solve one matrix system per group of fluorescence probes”, section [0033]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Chakravorty et al. and Villa et al., thereby arriving at the invention as claimed for the following reasons.
Chakravorty et al., like the instant application, recognize the limitations of detecting multiple targets in a sample, wherein the multiplex capability is limited by the number of different dyes that have different excitation/emission spectra:
“The number of probes that can be distinguished in a single multiplexed homologous amplification assay is limited by the number of fluorophores that can be reliably resolved” (page 185)
The artisans, like the instant application, provide a means of utilizing at least two different fluorescent compounds that have a common excitation and/or emission spectra, wherein the fluorescent compounds are distinguished based on physical testing conditions (probe configuration and temperature).
While Chakravorty et al. do not explicitly teach that such conditions employed were based on a sensitivity analysis, the successful outcome of distinguishable fluorescence observed from the at least two fluorescent compounds at different physical conditions evidence that the artisans had already tested and arrived at a conditions which were optimized. In the alternative, pre-determining the optimal conditions of an assay that provide the maximal sensitivity would also have been well-within the purview of the ordinarily skilled artisan, as such practice would have been conventional.
As to the application of matrix system, without reciting a specific algorithm which is tailored for the assay as claimed, the usage of matrix system and other conventionally adopted computer processes, such as artificial intelligence, neural network, etc., would have been obvious for the generally known motivation of analyzing and processing data, as evidenced by Villa et al.
The courts have deemed that combination of teachings that yield no more than a predictable outcome is likely obvious.
“[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR, at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Conclusion
No claims are allowed.
Claim 9 is free of prior art.
While Chakravorty et al. teach at least two different fluorescent compounds that share a common excitation maximum (i.e., CF7 and CF9), these two fluorescent dyes are distinguishable by the difference in their emission maximum (large Stokes shift). The fluorescent compounds of instant claim 9 do not have this characteristic, and these compounds have not been used in the art to be distinguishable based on the physical conditions they are subjected to.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/YOUNG J KIM/Primary Examiner
Art Unit 1637 October 7, 2026
/YJK/
1 About 35oC.
2 “the term, ‘unique testable condition’ refers to a target that can be identified by fluorescent measurements during and/or after a PCR assay”, section [0026]
Prosecution Insights