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 .
Priority
This application filed 03/17/2023 is a National Stage entry of PCT/CN2021/114636, with an International Filing Date of 08/26/2021, and claims foreign priority to Chinese Application 202010982860.5, filed 09/18/2020. The claims are therefore examined as filed on 09/18/2020, the effective filing date. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further review of the priority application(s).
Claim Status
Claims 1-9 are pending.
Claims 1-4 and 8-9 are objected to.
Claims 1-9 are examined.
Claims 1-9 are rejected.
Information Disclosure Statement
The Information Disclosure Statements are in compliance with the provisions of 37 CFR 1.97. Accordingly, all references have been considered.
Drawings
The drawings are objected to because Fig 1 contains blurry and illegible text, and unclear images. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1-4 and 8-9 are objected to because of the following informalities:
Claim 1 (line 15) should read “S1: constructing a space and spectral calibration matrix A as [[a]] prior information” (incorrectly placed article)
Claim 1 (line 8) and claim 4 (line 5) should both read “wherein the spatial modulation module adopts a spatial random phase modulator…” (missing article)
Claim 2 should read “the spatial and spectral calibration matrix A is obtained through experimental calibration or ray tracing and wave optics calculation, or through deep learning training, and the spatial and spectral calibration matrix A is constructed by the light intensity distribution…” (missing conjunction)
Claim 3 should read “what the area array detector detects is a polychromatic fluorescence two-dimensional intensity measurement matrix based on point spread function, Gaussian spot or Airy disk.” (missing article)
Claim 8 should read “wherein, in the step S0, the excitation light source is an LED or laser.” (missing article)
Claim 9 should read “the projection lens sets includes: a large-aperture and short-focus compound lens, or a high numerical aperture objective lens, or a projection objective lens, or a microlens array.” (missing articles)
Appropriate correction is required.
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 1-9 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.
The phrase “thereby realizing efficient nucleic acid detection and gene sequencing” at the end of claim 1 is unclear, as it appears to be an intended result, and it is unclear what component or combination of components are necessary to achieve the efficiency. Further, “efficient” is a relative term which renders the claim indefinite, as it is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what would need to be achieved to satisfy the claim limitation of “realizing efficient nucleic acid detection and gene sequencing.” Therefore the claim is indefinite due to lack of clarity.
Claim 7 similarly recites “finding the optimal solution of the signal through min| |X| subject to Y=AX it can quickly recover the spatial and spectral intensity information of the target signal” – this is also unclear as “quickly” also appears to be an intended result, and a relative term not defined by the claim or specification. Therefore this claim is also indefinite due to lack of clarity.
Dependent claims 2-6 and 8-9 do not resolve the above issues, and are therefore also indefinite due to lack of clarity.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of mental processes and mathematical concepts, without significantly more.
The MPEP at MPEP 2106 sets forth steps for identifying eligible subject matter:
(1) Are the claims directed to a process, machine, manufacture or composition of matter?
(2A)(1) Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea?
(2A)(2) Do the claims recite additional elements that integrate the judicial exception into a practical application?
(2B) If the claims recite a judicial exception and do not integrate the judicial exception, do the claims recite additional elements that provide an inventive concept and amount to significantly more than the judicial exception?
With regard to step (1) (Are the claims directed to a process, machine, manufacture or composition of matter?): Yes. The claims are directed to one of the statutory classes. The claims are directed to a process (method).
With regard to step (2A)(1) (Do the claims recite a judicially recognized exception?): Yes. The claims recite the abstract ideas of processing data using mental steps and mathematical concepts. Claims that recite nothing more than abstract ideas, natural phenomena, or laws of nature are not eligible for patent protection (see MPEP 2106.04).
Abstract ideas include mathematical concepts, (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (including procedures for collecting, observing, evaluating, and organizing information (See MPEP 2106.04(a)(2)). In particular, these abstract ideas include but are not limited to:
Performing a correlation calculation between the calibration matrix A and the measurement matrix Y through a correlation imaging algorithm, solving Y=AX, and reconstructing a target signal X (mental process/mathematical concept; the human mind is capable of solving the equation Y=AX and calculating correlation between data, and performing a calculation is a mathematical process; claim 1)
Dependent claims 2 and 7 further limit the abstract ideas recited in the independent claims, and do not change their characterization as abstract ideas.
Therefore, the claims recite elements that constitute one or more judicial exceptions.
With regard to step (2A)(2) (Do the claims recite additional elements that integrate the judicial exception into a practical application?): No. The claims recite the additional element of a sequencing device composed of a combination of optical imaging elements, including a excitation light source, projection lens sets and multi-channel filter sets, spatial random phase modulator or liquid crystal spatial light modulator or DMD or a dispersive element, and array detector composed of a microchannel plate-based image intensifier and a high-speed CMOS camera, or a two-dimensional array of photomultiplier tubes/avalanche diodes, or a highly sensitive area array CMOS or CCD camera. Claims 3-6 and 8-9 further define these elements. The claims also recite the additional elements of labeling a target nucleic acid sequence with fluorescent probes and using the imaging system and array detector to collect fluorescent signals.
While the claims recite the additional element of receiving data from the optical system, such steps that only amount to necessary data gathering and outputting are insignificant extrasolution activities that do not add a meaningful limitation to the claims (see MPEP 2106.05(g)). Similarly, the additional element of the sequencing device, as it is broadly defined and may be composed of several combinations of listed components, merely indicates a field of use or technological environment in which to apply a judicial exception (see MPEP 2106.05(h)). As a result, the judicial exception is not integrated into a practical application. Because the claims do not recite any additional elements that integrate the judicial exception into a practical application, the claims as a whole are directed to an abstract idea.
With regard to step (2B) (Do the claims recite additional elements that provide an inventive concept and amount to significantly more than the judicial exception?): No.
The claims recite an abstract idea with additional elements; however, these additional elements are non-particular instructions to apply the abstract idea by linking it to a field of use or extrasolution activity (see MPEP 2106.05(f-h)). Non-particular instructions to gather or produce data do not provide an inventive concept, and are also considered well-understood, routine and conventional activities (see MPEP 2106.05(d), which indicates that limitations such as “Receiving or transmitting data over a network” from Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362, or “Storing and retrieving information in memory” from Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93,) are recognized as conventional activities). Further, the listed components of the sequencing device are all individually known, routine and conventional elements of optical systems (see SKINNER, KIM, OTUBOAH, ALMORO and WANG, cited on the 892 form). The claims therefore do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As a result, the claims as a whole do not provide an inventive concept.
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.
Claim Rejection
Claims 1-5 and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over
SKINNER 2019 “Generalized Stochastic Super-Resolution Sequencing” (US 20190276886 A1), in view of OTUBOAH 2019 “Design of a reduced objective Lens fluorescence dPCR Gene chip detection system with high-throughput and large field of view”, KIM 2018 “Optical System for Multi-Channel Real-Time PCR Detection”, ALMORO 2011 “Enhanced wavefront reconstruction by random phase modulation with a phase diffuser”, and WANG 2019 “Multicolor fluorescent imaging by space constrained computational spectral imaging.”
Claim Interpretation and Scope and Contents of Prior Art
Claim 1 recites a nucleic acid detection and gene sequencing method using a nucleic acid detection and gene sequencing device that includes an excitation light source module, which is a single-channel excitation light source or multiple- channel excitation light sources according to the requirements of single or multiple target fluorescent labeling of nucleic acid samples; an imaging module, including projection lens sets and multi-channel filter sets; and a spatial modulation module, or a spatial coding module, or a dispersive element, wherein the spatial modulation module adopts spatial random phase modulator to realize random modulation of the light field to obtain a speckle image of the fluorescence signal, and the spatial coding module adopts liquid crystal spatial light modulator or DMD to construct a specific two-dimensional encoding matrix; and an area array detector, which adopts a single photon camera composed of a microchannel plate-based image intensifier and a high-speed CMOS camera, or a two-dimensional array of photomultiplier tubes/avalanche diodes, or a highly sensitive area array CMOS or CCD camera.
With respect to these limitations, SKINNER teaches sequencing methods and systems that includes a excitation light source in the form of a laser [0032], an imaging system that includes an objective lens [029], various filters [0031], and a CCD camera [0031, 36], where the sequencer detects the intensity of the signal in each of the four channels (ACGT), the fluorescence of the dye is manifested as an increase in signal corresponding to the base that has been incorporated, and where the imaging system can image multiple channels at the same time [077]. OTUBOAH similarly teaches a fluorescence dPCR gene chip detection system that includes an excitation light source in the form of an LED (Abstract, pg 1072 par 3) and an imaging module including an objective lens, a mirror to reflect the beam, and an emission filter and fluorescence filter for multiple channels (pg 1072 par 3, pg 1073 par 3-4). KIM also teaches an optical system for multi-channel real-time PCR detection (Abstract), comprising an excitation light source module in the form of an LED, a collimating lens to focus on the fluorescence target, an emission filter, a dichroic beam splitter to differentiate the light from the white LED and the exited light from the fluorescent material, a hyperspectral band pass filter, and CMOS photo sensor as an area array detector (pg 1, Fig 1).
Neither SKINNER, OTUBOAH or KIM specifically teach a spatial modulation module, or a spatial coding module, or a dispersive element. However, ALMORO teaches methods for using random phase modulation with a phase diffuser to obtain a speckle image (Abstract, Fig 2-3, pg 253 col 2) which can be applied to any optical system. Various combinations of existing optical systems, such as those described, could produce the claimed device, depending on what is required.
Claim 1 also recites the limitations of S1: constructing a space and spectral calibration matrix A as a prior information; S2: labeling a target nucleic acid sequence with fluorescent probes to prepare a nucleic acid chip with a spatial distribution, and exciting the nucleic acid chip with the light source to emit multicolor fluorescent signals, and sequentially modulating, encoding and collecting the multicolor fluorescent signals with the imaging module and the area array detector, and thus obtaining a fluorescence two-dimensional intensity measurement matrix Y; and S3: performing correlation calculation between the calibration matrix A and the measurement matrix Y through a correlation imaging algorithm, solving Y=AX, and reconstructing a target signal X, that is, the fluorescence molecular spatial, spectral and intensity distribution information of the labeled target nucleic acid sequence, thereby realizing efficient nucleic acid detection and gene sequencing.
With respect to this limitations, SKINNER teaches labeling a target nucleic acid sequence with fluorescent probes for sequencing that are excited by the light source and detected by the CCD camera [032, 36, 39-40], and OTUBOAH specifically teaches that is system is used in PCR involving labeling a target nucleic acid sequence with fluorescent probes to prepare a nucleic acid chip with a spatial distribution and encoding/collecting the signals with the CMOS camera (pg 1072, Fig 3), but neither specifically teach constructing a calibration matrix or calculating the correlation between the calibration matrix and the measurement matrix. However, WANG teaches using fluorescence microscopy to generate an intensity measurement matrix representing the fluorescence signal and a space and spectral calibration matrix and solving Y=AX to reconstruct a target signal (pg 2-3).
Claim 2 recites the limitation wherein the spatial and spectral calibration matrix A is obtained through experimental calibration or ray tracing and wave optics calculation, or through deep learning training, the spatial and spectral calibration matrix A is constructed by the light intensity distribution of point light sources with different spatial positions and different wavelengths on the calibrating surface being imaged by the imaging module on the area array detector. With respect to this limitation, WANG teaches determining the spectral positions of the corresponding wavelength in the spectral image relative to the image position in the spatial image and registering paired images to estimate the lateral spatial shift of different wavelengths using cross-correlation (pg 4).
Claim 4 recites the limitation wherein the imaging module comprises projection lens sets, multi-channel filter sets and a spatial modulation module, and wherein the spatial modulation module adopts spatial random phase modulator to realize random modulation of the light field to obtain a speckle image of the fluorescence signal, and what the area array detector detects is a polychromatic fluorescence two-dimensional intensity measurement matrix based on the speckle image.
With respect to this limitation, ALMORO teaches methods for using random phase modulation with a phase diffuser to obtain a speckle image and an array detector in the form of a sCMOS camera to detect the polychromatic fluorescence intensity measurement matrix (Abstract, Fig 2-3, pg 253 col 2) which can be applied to the optical systems of KIM, OTUBOAH or WANG.
Claim 5 recites the limitation wherein the imaging module comprises projection lens sets, multi-channel filter sets and a spatial coding module, wherein the spatial coding module adopts liquid crystal spatial light modulator or DMD to construct a specific two-dimensional encoding matrix, and what the area array detector detects is the encoded polychromatic fluorescence two-dimensional intensity measurement matrix. With respect to this limitation, ALMORO also teaches using a DMD to construct the matrix (pg 2-3).
Claim 6 recites the limitation wherein the imaging module comprises projection lens sets, multi-channel filter sets and a dispersive element, wherein the dispersive element splits the spectral dispersion of the polychromatic fluorescent signal, and what the area array detector detects is a polychromatic fluorescence two-dimensional intensity measurement matrix based on spectral signals. With respect to this limitation, WANG teaches using a prism as a dispersive element to split the spectral dispersion, so the detector (sCMOS camera) detects the measurement matrix based on spectral signals (pg 2 par 4-5, pg 4).
Claim 7 recites the limitation wherein the correlation imaging algorithm is selected from any one of following four kinds, where one is the compressed sensing algorithm: combining with the matrix mapping theory and the optical correlation imaging algorithm, finding the optimal solution of the signal through min| |X| subject to Y=AX it can quickly recover the spatial and spectral intensity information of the target signal. With respect to this limitation, teaches using the compressed sensing algorithm and solving Y = AX (WANG pg 3).
Claim 8 recites the limitation wherein the excitation light source is LED or laser. With respect to this limitation, both KIM (pg 1, Fig 1) and OTUBOAH (Abstract, pg 1072 par 3) teaches that the excitation light source is an LED, and SKINNER teaches that its excitation light source is a laser or assembly of multiple lasers [0032].
Claim 9 recites the limitation wherein the projection lens sets includes: large-aperture and short-focus compound lens, or high numerical aperture objective lens, or projection objective lens, or microlens array. With respect to this limitation, OTUBOAH teaches that the projection lens is a high numerical aperture objective lens (pg 1077).
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in fluorescence optical systems would have been motivated to combine the teachings of SKINNER, OTUBOAH, KIM, ALMORO, and WANG, in order to achieve the claimed invention, because many different combinations of spectral imaging components, including different light sources, lenses, filters, and signal modulators/dispersive elements can be used to achieve efficient sequencing or PCR by controlling and measuring the fluorescent signal. Further, one of ordinary skill would be motivated to use random phase modulation to obtain a speckle image as this can be used to reduce noise in image reconstruction (ALOMORO pg 253 col 2), and would further be motivated to solve Y=AX to reconstruct a target signal as this is a known method and equation of signal reconstruction. A person of ordinary skill would reasonably expect success from combining these teachings, as SKINNER, OTUBOAH, KIM, ALMORO, and WANG all teach methods and systems for fluorescence signal measurement and processing, such that the various components of each can be combined in multiple ways. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Claim Rejection
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over
SKINNER in view of OTUBOAH, KIM 2018 “Optical System for Multi-Channel Real-Time PCR Detection”, ALMORO, and WANG as applied to claims 1-5 and 7-9 above, and further in view of ZHANG 2007 “Gaussian approximations of fluorescence microscope point-spread function models.”
Claim Interpretation and Scope and Contents of Prior Art
SKINNER in view of OTUBOAH, KIM, ALMORO, and WANG teach the limitations of claims 1-5 and 7-9 above.
Claim 3 recites the limitation wherein, in the step S2, the imaging module comprises projection lens sets and multi-channel filter sets, and what the area array detector detects is polychromatic fluorescence two-dimensional intensity measurement matrix based on point spread function, Gaussian spot or Airy disk.
SKINNER in view of KIM, OTUBOAH, WANG, and ALMORO teach projection lens sets and multi-channel filter sets, but do not teach that the polychromatic fluorescence two-dimensional intensity measurement matrix based on point spread function, Gaussian spot or Airy disk. However, ZHANG teaches Gaussian approximations of fluorescence microscope point-spread function models (Abstract).
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in fluorescence optical systems would have been motivated to combine the teachings of SKINNER, OTUBOAH, KIM, ALMORO, WANG, and ZHANG in order to achieve the claimed invention, because approximative PSFs and particularly separable Gaussian approximations are widely preferred in practical microscopic applications requiring fast data processing (pg 1819 col 1). A person of ordinary skill would reasonably expect success from combining these teachings, as SKINNER in view of OTUBOAH, KIM, ALMORO, WANG, and ZHANG all teach methods and systems for fluorescence signal processing, and the processing methods of ZHANG can be applied to the fluorescence signals in the other systems. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY C LEVERETT whose telephone number is (571)272-5494. The examiner can normally be reached 8:00am - 5:00pm M-Th.
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/MARY C LEVERETT/Examiner, Art Unit 1687
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