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 .
Claim Status and Formal matters
The instant action is in response to papers filed 7/17/2026 and 8/3/2026.
When providing claim amendments applicant should only provide the marked-up copy of the claims.
Claims 1, 2, 7, 9, 10, 11-13, 20 have been amended.
Claims 21-28 have been added by amendment.
Newly submitted claims 22, 23, 26 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons nucleic acid target molecules are different than protein, polypeptide, antibody or antigens, as nucleic acids comprise nucleotides while proteins comprise nucleic acids.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 22, 23, 26 withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Applicant’s election without traverse of group I, claims 1-13 and 20 in the reply filed on 3/21/2026 is acknowledged.
Claims 14-19 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 3/21/2026.
Claims 1, 2, 7, 9, 10, 11-13, 20-21, 24-25, 27-28 are being examined.
Priority
The instant application was filed 08/13/2024 and claims priority from provisional application 63532606 , filed 08/14/2023.
Claim Objections
Claims 1, 2, 7, 9, 10, 11-13, 20-21, 24-25, 27-28 are objected to because of the following informalities:
Claim 1 has been amended to recite, ”a method.” Claims are more clear and concise when the preamble of the claim sets for the intended outcome of the method.
Appropriate correction is required.
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 10-13 and 20-21, 24-25, 27-28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental step or abstract idea without significantly more. The claim(s) recite(s) the abstract idea or mental step of analyzing the change information to detect the target and/or analyzing the change information to detect the targe. These judicial exception are not integrated into a practical application because if there is no steps depend from or otherwise integrate the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no specific steps or reagents which would provide for significantly more.
Claim analysis
The instant claim 10 is directed a method for detecting the presence of a target molecule of interest in a sample, comprising the steps of: (a) providing the sample to a chamber; and (b) performing the method of claim 1 on the sample by providing at least a first indicator molecule by (1) allowing the indicator molecule to bind to a first region of a target molecule; (2) exciting the indicator molecule to emit a detectable signal; and (3) producing output when a change is detected in a pixel or group of pixels within an array of the TCPA; thereby detecting the presence of the target molecule in the sample. The thereby detecting the presence of the target molecule in the sample is a mental step or abstract idea.
Claim 11 requires method for detecting the presence of a target molecule of interest having a plurality of regions in a sample, comprising the steps of: (a) providing the sample to a chamber; (b) performing the method of claim 1 on the sample by providing at least a first indicator molecule by (1) allowing the indicator molecule to bind to a first region of a target molecule; and providing at least a second indicator molecule that can bind to the first region but having a different binding moiety and a different detectable moiety; (2) exciting the indicator molecule to emit a detectable signal; and (3) producing output when a change is detected in a pixel or group of pixels within an array of the TCPA; (4) removing the detectable moiety; and (c) performing step (b) with a different region of a target molecule; thereby detecting the plurality of regions of the target molecule in the sample.” The thereby detecting the presence of the target molecule in the sample is a mental step or abstract idea.
Claim 20 is drawn to A method for using an artificial intelligence system to sequence a target nucleic acid, comprising the steps of (a) training the system with target nucleic acids of known sequence, primary sequence features, methylation or other epigenetic modifications, or secondary structures in order to obtain a model; and (b) performing the method of claim 12 on a target nucleic acid, wherein the detected changes in step (b)(3) are compared to the training model obtained in step (a); and (c) reporting a primary sequence feature, methylation or other epigenetic modification, or secondary structure of the target nucleic acid.. The detected changes are characterized by the training model obtained in step (a) is a mental step or abstract idea.
Claim 10 steps (a)-(b) (1), (2), and (3) can be considered positive active steps.
Claim 11 steps (a)-(b) (1), (2), (3), (4) (c) can be considered positive active steps.
Claims 20-21, 24-25, 27-28 depend directly or indirectly from claim 11 and thus have the same active
Dependent claims set forth further limitations to about the sample and outcome of data analysis.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea or mental step.
Claims 10-11 require detecting the presence of the target molecule in the sample is a mental step or abstract idea.
Claim 20 depends from claim 11 via claim 12 and requires detected changes are characterized by the training model obtained in step (a) is a mental step or abstract idea. This is also a mental step
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as there are no steps which specifically depend from or otherwise integrate the judicial exceptions.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, the steps provide no limitations which are specific and provide for significantly more.
The active steps of the claims are routine and conventional over the teachings of over Eid ((Science (2009) volume 323, pages 133-138), Bhan (J. Am. Chem. Soc. 2021, 143, 16630−16640), and Wang (US 20140263961 A1)
Response to Arguments
The response traverses the rejection in view of the amendment.
Claim Rejections - 35 USC § 112
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, 2, 7, 9, 10, 11-13, 201, 24-25, 27-28 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.
As set forth in In re Alonso 88 USPQ2d 1849 (Fed. Cir. 2008), at 1851:
The written description requirement of 35 U.S.C. § 112, ¶ 1, is straightforward: “The specification shall contain a written description of the invention ….” To satisfy this requirement, the specification must describe the invention in sufficient detail so “that one skilled in the art can clearly conclude that the inventor invented the claimed invention as of the filing date sought.” Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997); see also LizardTech, Inc. v. Earth Res. Mapping, Inc., 424 F.3d 1336, 1345 [76 USPQ2d 1724] (Fed. Cir. 2005); Eiselstein v. Frank, 52 F.3d 1035, 1039 [34 USPQ2d 1467] (Fed. Cir. 1995).
Alonso at 1852:
A genus can be described by disclosing: (1) a representative number of species in that genus; or (2) its “relevant identifying characteristics,” such as “complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.” Enzo, 323 F.3d at 964.
In applying the test as set forth in Alonso, it is noted that applicant is claiming Independent claim 1 is drawn to A method comprising using an event-based
temporal contrast pixel array (TCPA) to detect a change in the emission of an indicator molecule that is bound to a target molecule of interest, wherein the indicator molecule comprises a detectable moiety and a binding moiety that is capable of binding to a region of the target molecule, and wherein the pixels of the array independently produce output when a change in the emission of the indicator molecule is detected
.Thus the claim encompass anything which can be considered an event based temporal contrast pixel array. This is an enormous genus as the specification provides no definition or standard what is required of a TCPA.
Further the claims encompass anything which can be considered target molecule. This is enormous genus as the specification does provide a limiting definition or standard of what is encompassed by a target molecule. Filser (Horizons, The Swiss Research Magazine, 6/9/2018) pages 1-) teaches, “His original ‘Generated Data Base’, GDB-11, held 26.4 million molecules. GDB-17 has 166 billion entries and is unsurprisingly the world’s biggest database for small molecules.” Thus this encompasses an enormous genus.
The claims encompass any indicator molecule which can bind by any means to the target molecule and comprises anything which can be considered a detectable moiety. This is an enormous genus as the specification provides no definition or standard what is required of an indicator molecule or binding or detectable moiety.
The teachings of the specification are limited to biological polymers-nucleic acids and proteins. Thus the specification and claims do not provide a representative number of species or structures and relevant characteristics to provide adequate written description for the genus encompassed by the claims.
Response to Arguments
The response begins traversing the rejection in view of the teachings of Posch. This argument has been thoroughly reviewed but is not considered persuasive as Posh provides an example at best a single species of what is encompassed by a TCPA. Posch does not demonstrate possession of the genus encompassed by the claims or the use of a TCPA for the detection of any target molecule.
The response asserts target molecules, binding moiety and detectable moiety have written description in view of the teachings of 0019-0021 and 0028-0037. This argument has been thoroughly reviewed but is not considered persuasive as the cited paragraphs merely provide preferred embodiments and do no limit the claim. Thus the claim lacks adequate written description.
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, 2, 7, 9, 10, 11-13, 20-21, 24-25, 27-28 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 has been amended to recite, “event based temporal contrast pixel array.” The recitation of “event based” suggests there is non-event based. The specification and claims provide no standard to differentiate event based from non-event based. Further the metes and bounds are unclear as the TCPA appears to be a device and thus it is unclear how event based changes the structure of the TCPA. Thus the metes and bounds are unclear.
Claim 1 has been amended to recite, “using an event-based temporal contrast pixel array (TCPA) to detect a change in the emission of an indicator molecule that is bound to a target molecule of interest, wherein the indicator molecule comprises a detectable moiety and a binding moiety that is capable of binding specifically to a region of the target molecule, and wherein the pixels of the array independently produce output when a change in the emission of the indicator molecule is detected.” The metes and bounds of the claim are vague, unclear, and incomplete as to what is required of TCPA, and how it is being used. The response asserts “using” is an active step, however it is unclear what is being used, how it is being used, or what is being performed by the method.
Claim 7 has been amended to recite, “wherein the detection is performed with a continuous flow of indicator molecules.” The claim is confusing and unclear how this limits the single active step of using of the independent claim. The claim is confusing and unclear as to how a continuous flow of indicator molecules relates to the using or the TCPA.
Claim 10 is indefinite because it lacks a positive active step relating back to the preamble. The preamble recites a method for detecting the presence of a target
molecule of interest in a sample , however the last positive active step is drawn to producing output when a change is detected in a pixel or group of pixels within an array of the TCPA . Therefore it is unclear as to whether the method is drawn to detecting the presence of a target molecule of interest in a sample or producing output when a change is detected in a pixel or group of pixels within an array of the TCPA.
Further the recitation of “producing output when a change is detected in a pixel or group of pixels within an array of the TCPA” is vague unclear and incomplete. Review and searching of the specification did not provide antecedent basis for “producing output.” Thus it is unclear how or what is required of producing output requires, encompasses, or excludes.
Claim 11 is indefinite because it lacks a positive active step relating back to the preamble. The preamble recites a method for detecting the presence of a target molecule of interest having a plurality of regions in a sample, however the last positive active step is drawn to (c) performing step (b) with a different region of a target molecule. Therefore it is unclear as to whether the method is drawn to detecting the presence of a target molecule of interest having a plurality of regions in a sample or (c) performing step (b) with a different region of a target molecule. Thus the metes and bounds are unclear what is being done.
Further the recitation of “producing output when a change is detected in a pixel or group of pixels within an array of the TCPA” is vague unclear and incomplete. Review and searching of the specification did not provide antecedent basis for “producing output.” Thus it is unclear how or what is required of producing output requires, encompasses, or excludes.
Claim 12 recites, “A method for sequencing a nucleic acid in real time, comprising performing the method of claim 11 on a sample having unamplified nucleic acids as target molecules to detect a nucleotide sequence.” The metes and bounds are unclear how performing the steps of claim 11 which is to detecting a target nucleic acid molecule. Amending the claim to provide steps which would allow for sequencing would address this rejection.
Claim 13 recites, “wherein the changes reported in step (b)(3) further indicate primary sequence features, methylation or other epigenetic modifications, or secondary structures.” The recitation is confusing and unclear as it is unclear how the detected changes indicate primary sequence features, methylation or other epigenetic modifications, or secondary structures as the claim provides no specific steps. Further it is confusing and unclear as it relates to step (b)(3) which is “(3) producing output when a change is detected in a pixel or group of pixels within an array of the TCPA.” This recitation is confusing , unclear and appears to be incomplete.
Claim 20 recites, “A method for using an artificial intelligence system to sequence a target nucleic acid, comprising the steps of (a) training the system with target nucleic acids of known sequence, primary sequence features, methylation or other epigenetic modifications, or secondary structures in order to obtain a model; and (b) performing the method of claim 12 on a target nucleic acid, wherein the detected changes in step (b)(3) are compared to the training model obtained in step (a); and (c) reporting a primary sequence feature, methylation or other epigenetic modification, or secondary structure of the target nucleic acid..” The recitation of “producing output when a change is detected in a pixel or group of pixels within an array of the TCPA” is vague unclear and incomplete. Review and searching of the specification did not provide antecedent basis for “producing output.” Thus it is unclear how or what is required of producing output requires, encompasses, or excludes.. Further step (a) appears to be vague , unclear and incomplete how the training is performed.
Response to Arguments
The response traverses the rejection in view of the amendments. These arguments are not persuasive as the amendment has introduced new issues.
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(s) 1, 2, 7, 9, 10, 11-13, 201, 24-25, 27-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Eid ((Science (2009) volume 323, pages 133-138), Bhan (J. Am. Chem. Soc. 2021, 143, 16630−16640), and Wang (US 20140263961 A1)
The claims are encompass detection nucleic acids by temporal contrast pixel array. The specification does not provide a definition or standard of what is required of event based temporal contrast pixel array. The art of record exemplifies use of event based temporal detection of nucleic acid sequences by pixel analysis was known, as exemplified below. Further the art exemplifies An imaging device has an array with pixels that can image an aspect of an object. In addition, pixels in the array can be used to perform motion detection or edge detection. A first and a second pixel can integrate light non-concurrently, and then their outputs may be compared. A difference in their outputs may indicate an edge in an imaging operation, and motion in a motion detection operation. The motion detection operation may be performed without needing the imaging device to have an additional modulated LED light source, and to spend the power to drive that source.
With regards to claim 1, 10-13 Eid teaches real time sequencing of single polymerase molecules (title)
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Bhan teaches, “we introduce TdT-based Untemplated Recording of Temporal Local Environmental Signals (TURTLES), a polymerase-based molecular recording system that achieves high time resolution in vitro by utilizing post-translational control to change the bases incorporated. First, we describe methods to characterize DNA sequences synthesized by TdT and show that cation concentrations can be encoded in populations of TdT-synthesized DNA using an approach that analyzes the average composition of several bases added at similar times on the same or parallel strands of DNA. We next developed an algorithm to accurately estimate the times of signal changes and show that temporal information can be accurately recovered by using estimates of DNA synthesis rates to map DNA sequences to real time. We also describe an expanded TURTLES system that uses an engineered, allosterically modulated TdT to expand the generalizability and tunability of the system. By inserting an exogenous sensing domain, we show that TURTLES can be adapted to the arbitrary signals of interest. When they are taken together, these results establish the feasibility of DNA synthesis-based encoding systems and demonstrate a recording of cationic environmental signals with minutes resolution for enhanced applications in DNA data storage and DNA recording.” (16631, bottom 1st column-top 2nd column).
Wang teaches, “[0008] In one embodiment, an imaging device has an array with pixels that can image an aspect of an object. In addition, pixels in the array can be used to perform motion detection or edge detection. A first and a second pixel can integrate light non-concurrently, and then their outputs may be compared. A difference in their outputs may indicate an edge in an imaging operation, and motion in a motion detection operation. [0009] An advantage over the prior art is that the motion detection operation may be performed without needing the imaging device to have an additional modulated LED light source, and to spend the power to drive that source. Moreover, motion detection may be performed in a single frame, which does not tax the frame rate.”
Thus it would have been prima facie obvious to one of ordinary skill in the art to use incorporation of nucleotides as indicators for specifically detecting nucleic acid sequences. The artisan would be motivated as Eid teaches it allows for real time sequencing. The artisan would further be motivated as Bhan teaches, “DNA is an attractive medium for both long-term data storage and for in vitro recording of molecular events due to its high information density and long-term stability. Molecular recording strategies write information into DNA by altering existing DNA sequences5 or adding new sequences. “ The artisan would have a reasonable expectation of success as the artisan is merely using known technology.
With regards to claim 2, Eid teaches the detection of intensity (Fig 1 and Fig 2)
With regards to claim 3, Eid teaches the use of waveguide nanostructure arrays (133, abstract) Eid teaches “For the observation of incorporation events, we used a nanophotonic structure, the zero-mode waveguide (ZMW), which can reduce the volume of observation by more than three orders of magnitude relative to confocal fluorescence microscopy (20). This level of confinement enables single-fluorophore detection despite the relatively high labeled dNTP concentrations—between 0.1 and 10 mM—required by DNA polymerase for fast, accurate, and processive synthesis. This range produces average molecular occupancies between ~0.01 and 1 molecules for a ZMW 100 nm in diameter (20, 23), compared with ~3 to 300 molecules for total internal reflection microscopy.”
Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims that waveguides use evanescent fields. The artisan would be motivated to use waveguides using evanescent fields as Eid teaches, “This range produces average molecular occupancies between ~0.01 and 1 molecules for a ZMW 100 nm in diameter (20, 23), compared with ~3 to 300 molecules for total internal reflection microscopy.” The artisan would have a reasonable expectation of success as the artisan is merely using known correlation.
With regards to claim 4, Eid and Bhan teach a nucleic acid is the target (titles, figures)
With regards to claim 6, Eid teaches real time. (tile)
With regards to claim 7, Eid teaches, “The average DNA synthesis rate for 740 single-molecule reads was 4.7 T 1.7 bases/s.” Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims incorporation of nucleotides at the recited rate would require a continuous flow of indicators to allow for incorporation.
With regards to claim 9, Bhan and Eid teach incorporation of nucleotides.
Bhan teaches, “In Silico Simulations of Recording Faster and Higher Numbers of Input Signal Changes. Using the average dNTP incorporation rate from experiments, and the amount of output signal in the control conditions, we simulated additional experiments in silico. Each simulated experiment had at least 6 signal changes (instances of a single signal change from 0 → 1 or 1 → 0), where each condition was randomly chosen to be 0 or 1. All nucleotides that were added during the 0 or 1 condition had the signal associated with these control conditions. More specifically, to account for the experimental variability in signals within a given control condition, nucleotide signals were sampled from a normal distribution determined by the experimental variability of nucleotide signals within the control conditions. We calculated the variability in two ways, corresponding to the two representative curves in Figure S12A,C. In the first, the variability was calculated across the first 100 nucleotides, in which there were at least 2000 recordings of all base numbers. In the second, the variability was calculated across the first 50 nucleotides, in which there were at least 60000 recordings of all base numbers. Using the output signal of the simulated nucleotides, we used the algorithm we developed from Glaser et al. for decoding binary concentrations.13 The accuracy corresponds to the percentage of conditions correctly classified as 0 or 1 over the duration of the entire recording experiment.” It is routine to use computers to store and analyze large data sets by use an algorithm to further examine feature of the data obtained.
With regards to claims 21, 25, Eid and Bhan teach a nucleic acid is the target (titles, figures)
With regards to claims 24, 27 and 28, Eid teaches:
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Thus Eid teaches asynchronously detection.
Response to Arguments
The response traverses the rejection asserting, “Wang detected the edges and the motion of objects using an array that reported continuously from each pixel in the array. However, Wang did not describe an event-based TCPA as recited in the claims as amended. Neither Bhan nor Eid remedy this deficiency to suggest the invention of claim 1.” This argument has been thoroughly reviewed but is not considered persuasive as the specification does not provide a limiting definition of TCPA. Thus the teachings of the art at least render obvious the limitations of the claims.
Claim(s) 1, 2, 7, 9, 10, 11-13, 201, 24-25, 27-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Eid ((Science (2009) volume 323, pages 133-138), Bhan (J. Am. Chem. Soc. 2021, 143, 16630−16640), Wang (US 20140263961 A1), POSCH et al., "Sensitivity and Uniformity of a 0.18pm CMOS Temporal Contrast Pixel Array," International Symposium on Circuits and Systems (IEEE) on May 15, 2011 at page 1572) and Liao (Journal of Semiconductors (2021) 42, 013105)
This rejection is provided in view of the amendment and arguments to provide compact prosecution as to what the response asserts is the invention.
The claims are encompass detection nucleic acids by temporal contrast pixel array. The specification does not provide a definition or standard of what is required of event based temporal contrast pixel array. The art of record exemplifies use of event based temporal detection of nucleic acid sequences by pixel analysis was known, as exemplified below. Further the art exemplifies An imaging device has an array with pixels that can image an aspect of an object. In addition, pixels in the array can be used to perform motion detection or edge detection. A first and a second pixel can integrate light non-concurrently, and then their outputs may be compared. A difference in their outputs may indicate an edge in an imaging operation, and motion in a motion detection operation. The motion detection operation may be performed without needing the imaging device to have an additional modulated LED light source, and to spend the power to drive that source.
With regards to claim 1, 10-13 Eid teaches real time sequencing of single polymerase molecules (title)
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Bhan teaches, “we introduce TdT-based Untemplated Recording of Temporal Local Environmental Signals (TURTLES), a polymerase-based molecular recording system that achieves high time resolution in vitro by utilizing post-translational control to change the bases incorporated. First, we describe methods to characterize DNA sequences synthesized by TdT and show that cation concentrations can be encoded in populations of TdT-synthesized DNA using an approach that analyzes the average composition of several bases added at similar times on the same or parallel strands of DNA. We next developed an algorithm to accurately estimate the times of signal changes and show that temporal information can be accurately recovered by using estimates of DNA synthesis rates to map DNA sequences to real time. We also describe an expanded TURTLES system that uses an engineered, allosterically modulated TdT to expand the generalizability and tunability of the system. By inserting an exogenous sensing domain, we show that TURTLES can be adapted to the arbitrary signals of interest. When they are taken together, these results establish the feasibility of DNA synthesis-based encoding systems and demonstrate a recording of cationic environmental signals with minutes resolution for enhanced applications in DNA data storage and DNA recording.” (16631, bottom 1st column-top 2nd column).
Wang teaches, “[0008] In one embodiment, an imaging device has an array with pixels that can image an aspect of an object. In addition, pixels in the array can be used to perform motion detection or edge detection. A first and a second pixel can integrate light non-concurrently, and then their outputs may be compared. A difference in their outputs may indicate an edge in an imaging operation, and motion in a motion detection operation. [0009] An advantage over the prior art is that the motion detection operation may be performed without needing the imaging device to have an additional modulated LED light source, and to spend the power to drive that source. Moreover, motion detection may be performed in a single frame, which does not tax the frame rate.”
Thus it would have been prima facie obvious to one of ordinary skill in the art to use incorporation of nucleotides as indicators for specifically detecting nucleic acid sequences. The artisan would be motivated as Eid teaches it allows for real time sequencing. The artisan would further be motivated as Bhan teaches, “DNA is an attractive medium for both long-term data storage and for in vitro recording of molecular events due to its high information density and long-term stability. Molecular recording strategies write information into DNA by altering existing DNA sequences5 or adding new sequences. “ The artisan would have a reasonable expectation of success as the artisan is merely using known technology.
Liao teaches, “. Neuromorphic electronic systems are much more energy efficient, which consume ten thousand times less power than digital systems, and are much more resistant to component degradation and failure than traditional digit al systems.” (page 1, 1st column). Liao teaches traditional sensor are data intensive and delay sensitive. (page 1, 2nd column, bottom to page 2) Liao teaches, “Posch and co-workers developed the ATIS[47, 48], which incorporates the “where” and “what” system. As shown in Fig. 3(a), this ATIS sensor consists of an event-based change detector (CD) that detects changes in the event stream and an exposure measurement (EM) unit based on pulse width modulation (PWM) that gains event-based intensity values. An EM is executed when it is triggered by a change detec tion. As a result, two types of asynchronous address-event representation (AER) events, encoding change and exposure information, are generated and transmitted separately (Fig. 3(b)). From a biological retina point of view, the CD unit (similar to DVS pixel) works as a magno-cellular structure (“where” system), while the additional EM unit represents biolo gical parvo-cellular structure (“what” system). Fig. 3(c) dis play an example of change detection events recorded dur ing a short time window and associated gray-level updates at the corresponding pixel positions. For the first time, the development of ATIS showed the possibility to obtain static and dynamic image information in parallel. The duality opens up a large number of new pro cessing capabilities, because many conventional machine vision algorithms do not work with asynchronous event streams. “
Posch teaches TCPA.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use the Neuromorphic electronic systems or TCPA of Liao and Posch in the methods of Eid and Bhan. The artisan would be motivated as Liao teaches Neuromorphic electronic systems and TCPA are more energy efficient and provide for shorter delays. Further Liao teaches TCPA allows for asynchronous detection. The artisan would have a reasonable expectation of success as the artisan is merely applying a known sensor to a known method.
With regards to claim 2, Eid teaches the detection of intensity (Fig 1 and Fig 2)
With regards to claim 3, Eid teaches the use of waveguide nanostructure arrays (133, abstract) Eid teaches “For the observation of incorporation events, we used a nanophotonic structure, the zero-mode waveguide (ZMW), which can reduce the volume of observation by more than three orders of magnitude relative to confocal fluorescence microscopy (20). This level of confinement enables single-fluorophore detection despite the relatively high labeled dNTP concentrations—between 0.1 and 10 mM—required by DNA polymerase for fast, accurate, and processive synthesis. This range produces average molecular occupancies between ~0.01 and 1 molecules for a ZMW 100 nm in diameter (20, 23), compared with ~3 to 300 molecules for total internal reflection microscopy.”
Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims that waveguides use evanescent fields. The artisan would be motivated to use waveguides using evanescent fields as Eid teaches, “This range produces average molecular occupancies between ~0.01 and 1 molecules for a ZMW 100 nm in diameter (20, 23), compared with ~3 to 300 molecules for total internal reflection microscopy.” The artisan would have a reasonable expectation of success as the artisan is merely using known correlation.
With regards to claim 4, Eid and Bhan teach a nucleic acid is the target (titles, figures)
With regards to claim 6, Eid teaches real time. (tile)
With regards to claim 7, Eid teaches, “The average DNA synthesis rate for 740 single-molecule reads was 4.7 T 1.7 bases/s.” Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims incorporation of nucleotides at the recited rate would require a continuous flow of indicators to allow for incorporation.
With regards to claim 9, Bhan and Eid teach incorporation of nucleotides.
Bhan teaches, “In Silico Simulations of Recording Faster and Higher Numbers of Input Signal Changes. Using the average dNTP incorporation rate from experiments, and the amount of output signal in the control conditions, we simulated additional experiments in silico. Each simulated experiment had at least 6 signal changes (instances of a single signal change from 0 → 1 or 1 → 0), where each condition was randomly chosen to be 0 or 1. All nucleotides that were added during the 0 or 1 condition had the signal associated with these control conditions. More specifically, to account for the experimental variability in signals within a given control condition, nucleotide signals were sampled from a normal distribution determined by the experimental variability of nucleotide signals within the control conditions. We calculated the variability in two ways, corresponding to the two representative curves in Figure S12A,C. In the first, the variability was calculated across the first 100 nucleotides, in which there were at least 2000 recordings of all base numbers. In the second, the variability was calculated across the first 50 nucleotides, in which there were at least 60000 recordings of all base numbers. Using the output signal of the simulated nucleotides, we used the algorithm we developed from Glaser et al. for decoding binary concentrations.13 The accuracy corresponds to the percentage of conditions correctly classified as 0 or 1 over the duration of the entire recording experiment.” It is routine to use computers to store and analyze large data sets by use an algorithm to further examine feature of the data obtained.
With regards to claims 21, 25, Eid and Bhan teach a nucleic acid is the target (titles, figures)
With regards to claims 24, 27 and 28, Eid teaches:
PNG
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779
556
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Greyscale
Thus Eid teaches asynchronously detection.
Response to Arguments
The response traverses the rejection asserting, “Wang detected the edges and the motion of objects using an array that reported continuously from each pixel in the array. However, Wang did not describe an event-based TCPA as recited in the claims as amended. Neither Bhan nor Eid remedy this deficiency to suggest the invention of claim 1.” This argument has been thoroughly reviewed but is not considered persuasive as the specification does not provide a limiting definition of TCPA. Thus the teachings of the art at least render obvious the limitations of the claims.
Summary
No claims are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Steven Pohnert/ Primary Examiner, Art Unit 1683
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