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
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Specification
On page 4 of applicant’s specification applicant refers to an objective and embodiments of the invention in reference to claims 1-15 which have been canceled.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1. Claims 16, 17, 19-32 and 35 are rejected under 35 USC 103 as being unpatentable over Vogelsang et al. (“Make Them Blink: Probes for Super-Resolution Microscopy,” ChemPhysChem 2010, 11, 2475-2490) (cited by applicant)
Vogelsang et al. teaches fluorescence microscopy that involves the use of fluorescent emitters in
two distinct states, a bright and a dark state for purposes of fluorescence localization of single molecules. (Abstract and bottom of left-hand column on page 2475)
The method uses a light source and detector and detects single-molecule localization. (last sentence, right-hand column, page 2475.
Vogelsang et al. does not teach automatically adjusting a composition of a fluid in the sample reservoir to optimize the one or more parameters during the localization or imaging of the light-emitting molecules; however, it would have been obvious to one of ordinary skill in the art to adjust at least the concentration or types of target molecules in the sample fluid for purposes of optimizing detection of target molecules of interest.
I.) As noted above, Vogelsang et al. renders all the limitations of claim 16 obvious.
Therefore, Vogelsang et al. renders clam 16 obvious.
II.) Regarding applicant’s claim 17, as noted above Vogelsang et al. renders clam 16 obvious from which claim 17 depends.
Claim 17 recites that at least one of the parameters is determined by analyzing a time trace of the detected light comprising a plurality of time points from at least one region in the sample.
In Fig. 6 Vogelsang et al. teaches detecting light at a plurality of time points from a region of a sample.
Therefore, Vogelsang et al. renders claim 17 obvious.
III.) Regarding applicant’s claim 19, as noted above Vogelsang et al. renders clam 16 obvious from which claim 19 depends.
Claim 19 recites that the one or more parameters comprise a blinking parameter of the light-emitting molecules.
Vogelsang et al. teaches using blinking to detect targets of interests. (paragraph bridging pages 2482-2493)
Therefore, Vogelsang et al. renders claim 19 obvious.
IV.) Regarding applicant’s claim 20, as noted above Vogelsang et al. renders clam 19 obvious from which claim 20 depends.
Claim 20 recites that the blinking parameter is a blinking rate, an on/off time or brightness ratio, a transition rate between molecular states of the light-emitting molecules or an average time spent by the light-emitting molecule in the bright state or the dark state.
Vogelsang et al. teaches off-times in Table 2 which renders blinking rate obvious.
Therefore, Vogelsang et al. renders claim 20 obvious.
V.) Regarding applicant’s claim 21, as noted above Vogelsang et al. renders clam 16 obvious from which claim 21 depends.
Claim 21 recites that the parameters are optimized, such that an average number of the light-emitting molecules in the bright state in a diffraction limited volume in the sample equals 0,5 to 2.
As noted above, it would have been obvious to one of ordinary skill in the art to adjust at least the concentration or types of target molecules in the sample fluid for purposes of optimizing detection of target molecules of interest.
Adjusting the concentration of target molecules to any desired about, including 0.5 to 2 would have been obvious to one of ordinary skill in the art.
Therefore, Vogelsang et al. renders claim 21 obvious.
VI.) Regarding applicant’s claim 22, as noted above Vogelsang et al. renders clam 21 obvious from which claim 22 depends.
Claim 22 recites that the parameters are optimized such that the average number of the light-emitting molecules in the bright state in the diffraction limited volume in the sample equals 1.
As noted above, it would have been obvious to one of ordinary skill in the art to adjust at least the concentration or types of target molecules in the sample fluid for purposes of optimizing detection of target molecules of interest.
Adjusting the concentration of target molecules to any desired about, including 1 would have been obvious to one of ordinary skill in the art.
Therefore, Vogelsang et al. renders claim 22 obvious.
VII.) Regarding applicant’s claim 23, as noted above Vogelsang et al. renders clam 16 obvious from which claim 23 depends.
Claim 23 recites that the method comprises a plurality of localization steps, wherein in each localization step, a location of a single light-emitting molecule is determined, and wherein the optimization of the one or more parameters depends on a duration of the localization steps.
Vogelsang et al. teaches single molecule localization based on confining molecules spatially. (“Introduction” left-hand column, page 2475)
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to use a plurality of localizing steps in Vogelsang et al. for purposes of identifying different target molecules in different areas of a sample.
Therefore, Vogelsang et al. renders claim 23 obvious.
VIII.) Regarding applicant’s claim 24, as noted above Vogelsang et al. renders clam 23 obvious from which claim 24 depends.
Claim 24 recites that the one or more parameters are optimized, such that at least 30% of the light-emitting molecules stay in the bright state for a time period equal to the combined duration of the localization steps.
In Vogelsang et al. it would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to keep a desired number target molecules in a bright state during a the localizing steps, including 30% of the target molecules for purposes of quantifying the target molecules.
Therefore, Vogelsang et al. renders claim 24 obvious.
IX.) Regarding applicant’s claim 25, as noted above Vogelsang et al. renders clam 16 obvious from which claim 25 depends.
Claim 25 recites a plurality of tracking steps, wherein in each tracking step, the position of a moving molecule is recorded, and wherein a trajectory is recorded, wherein the optimization of the one or more parameters depends on a duration of the tracking steps and/or a desired length of the recorded trajectory.
Vogelsang et al does not teach a plurality of tracking steps, wherein in each tracking step, the position of a moving molecule is recorded, and wherein a trajectory is recorded, wherein the optimization of the one or more parameters depends on a duration of the tracking steps and/or a desired length of the recorded trajectory.
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to include a plurality of tracking steps wherein in each tracking step, the position of a moving molecule is recorded, and wherein a trajectory is recorded, wherein the optimization of the one or more parameters depends on a duration of the tracking steps and/or a desired length of the recorded trajectory, for purposes of identifying/tracking molecules so as not to misidentify a molecule that has merely moved spatially as a different molecule.
Therefore, Vogelsang et al. renders claim 25 obvious.
X.) Regarding applicant’s claim 26, as noted above Vogelsang et al. renders clam 25 obvious from which claim 26 depends.
Claim 26 recites that the one or more parameters are optimized, such that at least 30% of the light-emitting molecules stay in the bright state for a time period equal to the desired length of the trajectory.
In Vogelsang et al. it would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to keep a desired number target molecules in a bright state for a period of time equal to the length of trajectory for purposes of keeping track of the target molecules, including 30% of the target molecules.
Therefore, Vogelsang et al. renders claim 26 obvious.
XI.) Regarding applicant’s claim 27, as noted above Vogelsang et al. renders clam 16 obvious from which claim 27 depends.
Claim 27 recites that at least one of the parameters comprises or is an emission lifetime of the light-emitting molecules.
Vogelsang et al. teaches that the dynamics of the switching process, that is, the lifetime of the OFF-state limits the acquisition time. (“Super-Resolution Microscopy by Targeted Readout” on page 2476)
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to optimize emission lifetime of the light-emitting molecules for purposes of providing a sufficient acquisition time for detecting the same.
Therefore, Vogelsang et al. renders claim 27 obvious.
XII.) Regarding applicant’s claim 28, as noted above Vogelsang et al. renders clam 16 obvious from which claim 28 depends.
Claim 28 recites the fluid comprises at least one oxidizing agent and/or at least one reducing agent, wherein a concentration of the oxidizing agent and/or the reducing agent in the fluid or a ratio between the oxidizing agent and the reducing agent in the fluid is automatically adjusted to optimize the one or more parameters.
Vogelsang et al. teaches organic fluorophores exploiting a generic dark state that is switched by photoinduced redox-reactions using a reducing and oxidizing system. (left-hand column, page 2476)
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to use at least one oxidizing agent and/or at least one reducing agent, wherein a concentration of the oxidizing agent and/or the reducing agent in the fluid or a ratio between the oxidizing agent and the reducing agent in the fluid is automatically adjusted to optimize the one or more parameters based on Vogelsang et al teaches using a reducing and oxidizing system to switch between dark and bright states.
Therefore, Vogelsang et al. renders claim 28 obvious.
XIII.) Regarding applicant’s claim 29, as noted above Vogelsang et al. renders clam 16 obvious from which claim 29 depends.
Claim 29 recites that the fluid comprises an oxygen scavenging agent and/or a triplet state quencher, wherein a concentration of the oxygen scavenging agent or the triplet state quencher in the fluid is automatically adjusted to optimize the one or more parameters.
Vogelsang et al. teaches Since the triplet state is considered to be part of the main bleaching pathway, the number of possible switching processes is limited. kT can be controlled by the concentration of triplet quenchers such as oxygen yielding OFF-times up to the millisecond range under oxygen depleted conditions. (left-hand column, page 2479)
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to use an amount of the triplet state quencher to optimize the one or more parameters such as OFF-time for detecting target molecules.
Therefore, Vogelsang et al. renders claim 29 obvious.
XIV.) Regarding applicant’s claim 30, as noted above Vogelsang et al. renders clam 16 obvious from which claim 30 depends.
Claim 30 recites a first fluid component is provided from a first reservoir and a second fluid component is provided from a second fluid reservoir, wherein the composition of the fluid is adjusted by controlling a flow rate of the first fluid component and/or the second fluid component.
Vogelsang et al. necessarily provides samples from a supply course.
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to modify Vogelsang et al. to include a first fluid component including target molecules in a first reservoir and a second fluid component for diluting the first fluid component in a second fluid reservoir, wherein the composition of the fluid is adjusted by controlling a flow rate of the first fluid component and/or the second fluid component, for purposes of controlling the amount of target molecules that are subject to the fluorescence microscopy.
Therefore, Vogelsang et al. renders claim 30 obvious.
XV.) Regarding applicant’s claim 31, as noted above Vogelsang et al. renders clam 16 obvious from which claim 31 depends.
Claim 31 recites that a light intensity of activation light illuminating the sample is adjusted to further optimize the one or more parameters during the localization or imaging of the light-emitting molecules, wherein the activation light is adapted to promote a transition of the light-emitting molecules to the bright state.
In Vogelsang et al. it would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to adjust the light intensity of activation light illuminating the sample to further optimize the one or more parameters during the localization or imaging of the light-emitting molecules, wherein the activation light is adapted to promote a transition of the light-emitting molecules to the bright state.
Therefore, Vogelsang et al. renders claim 31 obvious.
XVI.) Regarding applicant’s claim 32, as noted above Vogelsang et al. renders clam 16 obvious from which claim 32 depends.
Claim 32 recites that an optimized composition of the fluid and/or an optimized light intensity of activation light illuminating the sample is determined by an artificial intelligence module to achieve an optimal value of the one or more parameters using an artificial intelligence algorithm which has been trained on a training data set comprising measured values of at least one of the parameters and corresponding compositions of the fluid and/or light intensity values.
Vogelsang et al. teaches optimizing the resolution, the probability for a successful localization has to be increased, which can be done in two ways: 1) By using reversibly switchable emitters, the localization could be repeated, if it was discarded. 2) The ratio of the lifetime of the fluorescent state (ON-time) to the lifetime of the non-fluorescent state (OFF-time) has to be decreased, resulting in an increased probability of localizing exactly one single emitter within a diffraction limited area. (right-hand column, page 2477).
Vogelsang et al. does not teach that an optimized composition of the fluid and/or an optimized light intensity of activation light illuminating the sample is determined by an artificial intelligence module to achieve an optimal value of the one or more parameters using an artificial intelligence algorithm which has been trained on a training data set comprising measured values of at least one of the parameters and corresponding compositions of the fluid and/or light intensity values.
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to provide a processor programmed to optimize light intensity of activation light illuminating the sample for purposes of automating the optimization. Such programmed processor is deemed equivalent to an artificial intelligence module inasmuch as both would include similar programming to achieve the same optimization result.
Therefore, Vogelsang et al. renders claim 32 obvious.
XVII.) Regarding applicant’s claim 35, as noted above Vogelsang et al. renders clam 16 obvious from which claim 35 depends.
Claim 35 recites a non-transitory computer-readable medium for storing computer instructions for localizing and/or imaging light-emitting molecules in a sample that, when executed by one or more processors associated with a microscope causes the one or more processors to perform a method according to claim 16.
Vogelsang et al. does not teach non-transitory computer-readable medium for storing computer instructions for localizing and/or imaging light-emitting molecules in a sample that, when executed by one or more processors associated with a microscope causes the one or more processors to perform a method according to claim 16.
It would have been obvious to one of ordinary skill in the art to modify Vogelsang et al. with a non-transitory computer-readable medium for storing computer instructions for localizing and/or imaging light-emitting molecules in a sample that, when executed by one or more processors associated with a microscope causes the one or more processors to perform a method according to claim 16, since automating a manual activity is not sufficient to distinguish over the prior art. (See MPEP 2144.04(III)).
Therefore, Vogelsang et al. renders claim 35 obvious.
2. Claim 18 stands rejected under 35 USC 103 as being unpatentable over Vogelsang et al. as applied to claim 16 above and further in view of International Patent Application Publication No. WO2020198750 to Pertsinidis. (cited by applicant)
I.) Regarding applicant’s claim 18, as noted above Vogelsang et al renders claim 16 obvious from which claim 18 depends.
Claim 18 recites that at least one of the parameters is determined by analyzing the arrival times of photons emitted by the light emitting molecules from at least one location in the sample.
Vogelsang et al. does not teach that at least one of the parameters is determined by analyzing the arrival times of photons emitted by the light emitting molecules from at least one location in the sample.
Pertsinidis teaches detecting target molecules using fluorescence. In paragraph [0086] Pertsinidis teaches that single fluorescence photons are detected with avalanche photo-diode (APD) detectors.
In paragraph [0151] Pertsinidis teaches that rigger pulses were sent to the photon-counting electronics to mark each raster line, and in paragraph [0152} that implementations may extract the arrival time of each photon from the PicoHarp 300 data that include photon-counting.
It would have been obvious to one of ordinary skill in the art to modify Vogelsang et al. to analyzing the arrival times of photons emitted by the light emitting molecules from at least one location in the sample, in view of Pertsinidis teaching monitoring photon trigger pulses and arrival time.
Therefore, Vogelsang in view of Pertsinidis renders claim 18 obvious.
3. Claims 33 and 34 are rejected under 35 USC 103 as being obvious over Vogelsang et al.
As noted above, Vogelsang et al teaches fluorescence microscopy that involves the use of fluorescent emitters in two distinct states, a bright and a dark state for purposes of fluorescence localization of single molecules. (Abstract and bottom of left-hand column on page 2475)
The method uses a light source and detector and detects single-molecule localization. (last sentence, right-hand column, page 2475.
Vogelsang et al. does not teach automatically adjusting a composition of a fluid in the sample reservoir to optimize the one or more parameters during the localization or imaging of the light-emitting molecules; however, it would have been obvious to one of ordinary skill in the art to adjust at least the concentration or types of target molecules in the sample fluid for purposes of optimizing detection of target molecules of interest.
Vogelsang et al. necessarily uses a fluidic device that provides a controlled amount of sample in the areas where target molecules are detected.
As noted above, Vogelsang et al. teaches that the dynamics of the switching process, that is, the lifetime of the OFF-state limits the acquisition time. (“Super-Resolution Microscopy by Targeted Readout” on page 2476)
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to provide Vogelsang et al. with a controller that is configured to determine a current value of the one or more parameters based on the detected light and control the fluidic device to adjust a composition of the fluid in the sample reservoir to optimize the one or more parameters during the localization or imaging of the light-emitting molecules, including diluting the sample to adjust the population of target molecules that are to be detected.
I.) As noted above, Vogelsang et al. renders all the limitations of claim 33 obvious.
Therefore, Vogelsang et al. renders clam 33 obvious.
II.) Regarding applicant’s claim 34, as noted above, Vogelsang et al. renders claim 33 obvious from which claim 34 depends.
Claim 34 recites that the control device is further configured to control a light intensity of activation light illuminating the sample to further optimize the one or more parameters during the localization or imaging of the light-emitting molecules, wherein the activation light is adapted to promote a transition of the light-emitting molecules to the bright state.
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to configure the control in Vogelsang et al. to control a light intensity of activation light illuminating the sample to further optimize the one or more parameters during the localization or imaging of the light-emitting molecules, wherein the activation light is adapted to promote a transition of the light-emitting molecules to the bright state, for purposes of optimizing detection of target molecules.
Therefore, Vogelsang renders claim 34 obvious.
Conclusion
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/MICHAEL STANLEY GZYBOWSKI/Examiner, Art Unit 1798
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