DETAILED ACTION
Preliminary Amendment filed on 01/09/2024 is acknowledged. Claims 1-2, 5-18, 20-21, 23 and 25 are pending in the application and are considered on merits.
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 .
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 1-2, 5, 14-15, 20-21 and 25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stefko et al. (Optical Express, 2018) (Stefko).
Regarding claim 1, Stefko teaches a method of operating an imaging system for imaging a biological target (abstract), the imaging system comprising a fluorescence microscope, a light source, an imaging device, a processor, a probe reagent, and a chemical buffer (Fig. 1, page 3), the method comprising:
acquiring, by the imaging device and the fluorescence microscope, a first
image of the biological target at a first time (Fig. 1, page 3);
determining, by the processor, a first value of an image acquisition metric
of the first image (Fig. 1, page 3);
(C) determining, by the processor, a first difference between the first value of
the image acquisition metric and a predetermined value of the image acquisition metric (Fig. 1, page 3);
(D) adjusting, by the processor, one or more physical parameters of the
imaging system based on the first difference, wherein the one or more physical parameters of the imaging system comprise one or more of: an illumination characteristic of the light source, concentration of the probe reagent, and concentration of the chemical buffer (Fig. 1, page 3); and
(E) repeating steps A to D for a second image acquired at a second time
subsequent to the first time (Fig. 1, page 3).
Regarding claim 2, Stefko teaches that “A transition from one state to another during a given time interval is a random event and occurs with a probability that depends only on the rate coefficient ascribed to that transition. In general, the rate coefficients can depend on a number of sample-specific factors, such as a fluorophore’s local environment and its chemical structure. At least one rate coefficient between fluorescence emitting and non-emitting states is proportional to the irradiance (power-per-area) integrated across the fluorophore’s absorption cross section” (page 2).
Thus, Štefko teaches determining a metric based on the density of active emitters detected in fluorescence images. The emitters switch between emitting and non-emitting states via stochastic transitions, producing stochastic fluorescent events whose distribution within the image is used to estimate emitter density. Accordingly, the image acquisition metric is based on a stochastic fluorescent events distribution as recited in claim 2.
Regarding claim 5, Stefko teaches that wherein adjusting the illumination power of the light source comprises:
sending an instruction, from the processor to the light source, to change the illumination characteristic (Fig. 1, page 3).
Regarding claim 14, Štefko discloses a feedback controller that determines an adjustment to illumination power based on the difference between a measured emitter density and a set point (page 3). Štefko further teaches the use of proportional-integral controllers, which include a proportional term that is proportional to the difference (error signal) (Eq. 6) (page 11). Accordingly, Štefko teaches that wherein adjusting, by the processor, one or more physical parameters based on the first difference comprises determining one or more physical parameter control metrics that are proportional to the first difference.
Regarding claim 15, Štefko teaches a proportional–integral controller for adjusting illumination power based on the difference between measured emitter density and a set point (Eq. 6, page 11). A proportional–integral controller includes an integral term corresponding to an accumulation of the error signal over time, i.e., an integral of the difference and preceding differences (Eq. 6). Accordingly, Štefko teaches wherein adjusting, by the processor, one or more physical parameters based on the first difference further comprises determining one or more physical parameter control metrics that are an integral of the first difference and any preceding differences.
Regarding claim 20, Stefko teaches repeating steps A to D for an nth image acquired at an nth time subsequent to the n-1th time (Fig. 1, page 3).
Regarding claim 21, Štefko is in the field of localization microscopy (PALM/STORM), where:
many individual images are acquired
fluorescent emitter locations are determined per frame
a final super-resolution image is reconstructed from multiple frames.
This is inherent to localization microscopy and explicitly discussed in the paper’s context.
Accordingly, Stefko teaches forming, by the processor, a reconstructed image of the biological target using the first image, second image ... n-1th image and nth image; or
selecting, by the processor, one of the first image, second image ... n-1th image and nth image.
Regarding claim 25, Stefko discloses an imaging system for imaging a biological target (abstract), the imaging system comprising:
a fluorescence microscope (Fig. 1, page 3);
an imaging device optically coupled to the fluorescence microscope, wherein the imaging device is configured to acquire a first image of the biological target using the fluorescence microscope at a first time and a second image of the biological target using the fluorescence microscope at a second time at a second time subsequent to the first time (page 3);
a light source (page 3);
a chemical buffer (inherent);
a probe reagent (inherent); and
a processor configured to:
determine a first value of an image acquisition metric of the first image;
determine a first difference between the first value of the image acquisition metric and a predetermined value of the image acquisition metric;
(C) adjust one or more physical parameters based on the first difference (page 3),
wherein the one or more physical parameters comprise one or more of: an illumination characteristic of the light source, concentration of the probe reagent, and concentration of the chemical buffer (page 3); and
(D) repeat steps A to C for the second image (page 3).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 6-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stefko et al. (Optical Express, 2018) (Stefko) in view of Cox et al. (The International Journal of Biochemistry & Cell Biology, 2013, IDS) (Cox).
Regarding claim 6, Stefko does not specifically teach that wherein adjusting the concentration of the probe reagent comprises:
sending an instruction, from the processor to a microfluidic device, to increase or decrease the concentration of the probe reagent.
However, Cox teaches that “The blinking rate of organic fluorophores is tuned by the laser intensity, the concentration of the reducing agent and the pH of the embedding medium.” (page 1674, par 1). Thus, it would have been obvious to one of ordinary skill in the art to adjust the concentration of the probe reagent comprises:
sending an instruction, from the processor to a microfluidic device, to increase or decrease the concentration of the probe reagent, in order to further tune the blinking rate.
Regarding claim 7, Stefko does not specifically teach that wherein adjusting the concentration of the chemical buffer comprises:
sending an instruction, from the processor to a microfluidic device, to increase or decrease the concentration of the chemical buffer.
However, Cox teaches that “The blinking rate of organic fluorophores is tuned by the laser intensity, the concentration of the reducing agent and the pH of the embedding medium.” (page 1674, par 1). Thus, it would have been obvious to one of ordinary skill in the art to adjust the concentration of the chemical buffer comprises:
sending an instruction, from the processor to a microfluidic device, to increase or decrease the concentration of the chemical buffer (pH), in order to further tune the blinking rate.
Regarding claim 18, Stefko and Cox fairly suggest to one of ordinary skill in the art to adjust at least two of the one or more physical parameters; or each of the one or more physical parameters, in order to further tune the blinking rate.
Claim(s) 8-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stefko et al. (Optical Express, 2018) (Stefko) in view of Kleppe et al. (US 9,726,877, IDS (Klippe)
Regarding claim 8, Stefko does not specifically teach obtaining, using a temperature sensor, a first temperature of the biological target at the first time; and
determining, by the processor, a first difference between the first temperature and a predetermined temperature.
However, Klippe teaches that “Obviously, it is also possible to adjust the blinking rate of the molecules by way of interaction. Depending on the molecule, this may involve different physical parameters, in particular temperature, wavelength of the illumination radiation acting as excitation radiation, intensity of the illumination radiation acting as excitation radiation, etc” (col. 6, line 22-27).
Thus, it would have been obvious to one of ordinary skill in the art to obtain, using a temperature sensor, a first temperature of the biological target at the first time; and
determine, by the processor, a first difference between the first temperature and a predetermined temperature, in order to control the blinking rate of the molecule.
Regarding claim 9-10, auto focus is obvious for a person skilled in the art of imaging. It would have been obvious to one of ordinary skill in the art to adjust a distance between an objective lens of fluorescence microscope and a mechanical platform, and
adjust the distance between the objective lens of the fluorescence microscope and the biological target comprises:
sending an instruction, from the processor to the mechanical platform, to electromechanically change the mechanical platform location, in order to auto focus the image.
Regarding claim 11-13, as has been discussed regarding claim 8 above, it would have been obvious to one of ordinary skill in the art to adjust the biological target temperature, in order to in order to control the blinking rate of the molecule.
wherein adjusting the biological target temperature comprises:
sending an instruction, from the processor to a heating and/or cooling device located adjacent to a chamber containing the biological target, to provide heating or cooling to the chamber.
Or
sending an instruction, from the processor to a heating and/or cooling device located adjacent to a tube that connects to a chamber containing the biological target, to provide heating or cooling to the tube; and
sending an instruction, from the processor to a microfluidic device, to circulate the chemical buffer through the chamber and the tube.
Claim(s) 16-17 and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stefko et al. (Optical Express, 2018) (Stefko).
Regarding claim 16, Štefko teaches a proportional–integral controller that adjusts illumination based on an error signal (page 11). It would have been obvious to include a derivative term corresponding to the rate of change of the error signal, as derivative control is a well-known component of PID control systems used to improve stability and response characteristics.
Regarding claim 17, Štefko teaches adjusting illumination using a proportional–integral controller based on an error signal (page 11). It would have been obvious to employ a proportional–integral–derivative (PID) controller, which includes an additional derivative term corresponding to the rate of change of the error, as PID control is a well-known and commonly used extension of PI control for improving system response and stability.
Regarding claim 23, outputting the reconstructed image to a display and/or storing the reconstructed image in a memory; or
outputting the selected image to a display and/or storing the selected image in a memory is conventional.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./Primary Examiner, Art Unit 1797
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