DETAILED ACTION
Applicant’s response, filed Jun 29 2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
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 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.
Claim Status
Claims 1-3, 12-24, 26-27, 134, and 171-173 are pending.
Claims 4-11, 25, 28-133, and 135-170 are canceled.
Claims 1 and 171-173 are objected to.
Claims 1-3, 12-24, 26-27, 134, and 171-173 are rejected.
Priority
The instant Application claims domestic benefit to US provisional application 63214297, filed Jun 24 2021. Accordingly, each of claims 1-3, 12-24, 26-27, 134, and 171-173 are afforded the effective filing date of the Jun 24 2021.
Drawings
The replacement drawing sheets submitted Jun 29 2026 are accepted and the outstanding objections from the previous Office Action are withdrawn in view of those amendments as well as those to the specification submitted Jun 29 2026.
Specification
The amendments to the specification submitted Jun 29 2026 are accepted.
Claim Objections
The outstanding objections to the claims are withdrawn in view of the amendments submitted herein.
The claims are objected to because of the following informalities. The instant objection is newly stated and is necessitated by claim amendment.
In claim 1, second limitation, “wherein” should be added before “the physical measurement of the polypeptide…”.
Claims 171-173 recite, in the final limitation, a plurality of steps: “updating… and obtaining…”. As set forth in 37 CFR 1.75, where a claim sets forth a plurality of steps, each step of the claim should be separated by a line indentation (see MPEP 608.01(i)).
Claim Interpretation
The interpretation regarding the term “controlling” in the previous Office Action is no longer applied to the claims, because the term “controlling” has been removed from amended claims 1 and 171-173.
Claim 27 recites “The method of claim 1, further comprising, after step b) and before step c) resuming the iterative detection process”. Under the broadest reasonable interpretation, the claim is assumed to require resuming the iterative detection process after the iterative detection process has been paused in claim 1. It is noted that neither claim 1 nor claim 27 requires pausing the iterative detection process, because “pausing” is one of an option of actions that can be taken. Therefore, the limitation of claim 27 is not required to be performed unless the iterative detection process has been paused.
Claim Rejections- 35 USC § 112
The outstanding rejections to the claims are withdrawn in view of the amendments submitted herein.
35 USC § 112(b)
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.
Claim 19 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. The instant rejection is newly stated and is necessitated by claim amendment.
Claim 19 recites “determining a structure of the single analyte”. There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of a single-analyte. It is noted that claim 1 recites “a polypeptide at single-molecule resolution”, and it is assumed that this polypeptide at single-molecule resolution is what claim 19 intends to limit. The rejection may be overcome by clarifying the antecedent basis of the limitation.
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 1-3, 12-24, 26-27, 134, and 171-173 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. Any newly recited portions are necessitated by claim amendment.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Framework with which to Evaluate Subject Matter Eligibility:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1
With respect to Step 1: yes, the claims are directed to methods, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) are as follows:
Independent claim 1: performing an iterative detection process in a detection system until a determinant criterion has been achieved, wherein… the iterative detection process comprises at least two cycles, each cycle comprising the steps of:
a) determining an uncertainty metric for the polypeptide based upon a data set acquired from the detection system, wherein the uncertainty metric represents a statistical measure of variability of the physical measurement;
b) implementing an action on the detection system based upon the uncertainty metric, wherein the action comprises pausing the iterative detection process…, altering a sequence of steps of the iterative detection process, or identifying a next step of a sequence of steps of the iterative detection process;
c) updating the data set after implementing the action on the detection system; and
the determinant criterion is achieved based on the uncertainty metric.
Independent claim 171: performing an iterative process until a determinant criterion has been achieved, wherein the iterative process comprises at least two cycles, each cycle comprising the steps of:
a) combining data from a single-analyte data set comprising data from more than one data source to determine a process metric for a single analyte and an uncertainty metric for the single analyte, wherein: the uncertainty metric represents a statistical measure of variability of a physical measurement for the single analyte;
b) implementing an action on a single-analyte system based upon the process metric and the uncertainty metric… wherein the action comprises pausing the iterative process, altering a sequence of steps of the iterative process, or identifying a next step of a sequence of steps of the iterative process; and
c) updating the single-analyte data set after implementing the action on the single-analyte system… wherein the determinant criterion is achieved based on at least the uncertainty metric.
Independent claim 172: performing an iterative process until a determinant criterion has been achieved, wherein the iterative process comprises at least two cycles, each cycle comprising the steps of:
a) determining a process metric for a single analyte and an uncertainty metric for the single analyte based upon a single-analyte data set, wherein: the uncertainty metric represents a statistical measure of variability of a physical measurement for the single analyte;
b) implementing an action on a single-analyte system that alters a source of uncertainty based upon the process metric and the uncertainty metric, wherein the action comprises pausing the iterative process, altering a sequence of steps of the iterative process, or identifying a next step of a sequence of steps of the iterative process; and
c) updating the single-analyte data set after implementing the action on the single-analyte system… wherein the determinant criterion is achieved based on at least the uncertainty metric.
Independent claim 173: performing an iterative process until a completion criterion has been achieved, wherein the iterative process comprises at least two cycles, each cycle comprising the steps of:
a) determining a curated uncertainty metric for a plurality of single analytes based upon a single-analyte data set, wherein: the curated uncertainty metric represents a statistical measure of variability of each respective physical measurement in a plurality of physical measurements;
b) implementing an action on a single-analyte system based upon the curated uncertainty metric, wherein the action comprises pausing the iterative process, altering a sequence of steps of the iterative process, or identifying a next step of a sequence of steps of the iterative process; and
c) updating the single-analyte data set after implementing the action on the single-analyte system… wherein the determinant criterion is achieved based on at least the uncertainty metric.
Dependent claims 2-3, 12-18, 20-24, 27, and 134 recite further steps that limit the judicial exceptions in independent claim 1 and, as such, also are directed to those abstract ideas. For example, claims 2-3, 12-18, and 20 further limit the determinant criterion to an unforced determinant criterion and further limit the threshold value used for the unforced determinant criterion; claims 21-24 further limit the determinant criterion to a forced determinant criterion; claim 27 further limits the method to resuming the iterative detection process before step c); and claim 134 further limits the type of sample being analyzed.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation because the method only requires a user to manually update a data set after implementing an action based upon an uncertainty metric. Without further detail as to the methodology involved in “performing” an iterative process, “combining” data, “determining” an uncertainty or process metric, and “updating” a dataset, under the BRI, one may simply, for example, use pen and paper to perform an iterative process of combining data from a single-analyte data set, determining a process or uncertainty metric from a single-analyte data set, implementing an action that pauses, alters, or identifies steps involved in the iterative detection process such as, for example, determining a process or uncertainty metric, and updating the single-analyte data set after implementing the action. The interpretation of “an iterative detection process” and “an iterative process” as a mental process is supported by the instant specification at least at [0074], which discloses that “the term “iterative process” refers to a cyclical procedure in which each cycle (e.g., iteration) of the procedure includes one or more shared sub-procedures or steps”, and because the steps which are claimed to comprise each cycle of the iterative process also recite mental processes. The interpretation of “implementing an action” as a mental process is supported in the instant specification as published at least at [0075], which discloses that “an action includes a physical operation, mechanical operation, signal transmission operation, energy transduction operation, computational operation, algorithmic operation, logical operation, or a combination thereof”, and clearly embodies purely computation steps performed in a computer which may be part of the detection system, as supported by the instant specification as published at least at [0274]. Determining a process metric and its trend further include embodiments which require mathematical techniques as the only supported embodiments, as is disclosed in the specification as published at: [0071-0072; 0111; 0133].
Therefore, claims 1 and 171-173 and those claims dependent therefrom recite an abstract idea [Step 2A, Prong 1: YES; See MPEP § 2106.04].
Step 2A, Prong Two
Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two, provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III).
Additional elements, Step 2A, Prong Two
With respect to the instant recitations, the claims recite the following additional elements:
Independent claim 1: performing an iterative detection process in a detection system until a determinant criterion has been achieved, wherein: the detection system is configured to obtain a physical measurement of the polypeptide at single-polypeptide resolution, the physical measurement of the polypeptide measures a property, characteristic, behavior, interaction, or identity of the polypeptide;
b) implementing an action on the detection system based upon the uncertainty metric and the uncertainty metric, wherein the action comprises… performing a related process on the polypeptide, or performing a related process on a second polypeptide; and
wherein: the iterative detection process further comprises, between at least a first cycle and a second cycle in the at least two cycles, obtaining an updated physical measurement of the polypeptide based on the updated data set.
Dependent claim 19: wherein obtaining the updated physical measurement of the polypeptide further comprises determining a structure of the single analyte.
Dependent claim 26: wherein the pausing the iterative detection process further comprises an action selected from the group consisting of reconfiguring the detection system, recalibrating the detection system, repairing the detection system, transmitting an instruction or information to a second detection system, adding a second polypeptide to the detection system, stabilizing the polypeptide in the detection system, refreshing a computer-implemented algorithm, updating a computer-implemented algorithm, receiving a user input, and a combination thereof.
It is noted that claim 26 further limits an optional step in claim 1 which is not required to be performed. Therefore, even though these limitations recite additional elements, their performance is not required and will not be considered in the remainder of the analysis.
Independent claims 171-172: wherein the physical measurement of the single analyte measures a property, characteristic, behavior, interaction, or identity of the single analyte; and
b) implementing an action on a single-analyte system based upon the process metric and the uncertainty metric, wherein… the action comprises… performing a related process on the single analyte, or performing a related process on a second single analyte; and
c)… obtaining an updated physical measurement of the single analyte based on the updated single-analyte data set.
Independent claim 173: wherein each respective physical measurement in the plurality of physical measurements measures a property, characteristic, behavior, interaction, or identity of a respective single analyte in the plurality of single analytes;
b) implementing an action on a single-analyte system based upon the process metric and the uncertainty metric, wherein… the action comprises… performing a related process on the single analyte, or performing a related process on a second single analyte; and
c)… obtaining an updated physical measurement on each single analyte in the plurality of the single analytes based on the updated single-analyte data set.
The claims also include non-abstract computing elements. For example, independent claim 1 includes a detection system configured to obtain a physical measurement of the polypeptide at single-polypeptide resolution; claims 171-172 include a single-analyte system which comprises a detection system that is configured to obtain the physical measurement of the single analyte at single-analyte resolution; and claim 173 includes a single-analyte system which comprises a detection system that is configured to obtain the physical measurement at single analyte resolution of each single analyte of the plurality of single analytes.
Considerations under Step 2A, Prong Two
With respect to Step 2A, Prong Two, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to data gathering, such as “performing an iterative detection process” using a detection system configured to obtain a physical measurement of the polypeptide at single-polypeptide resolution and “obtaining” an updated physical measurement in claims 1 and 171-173 and determining a structure in claim 19, perform functions of collecting the data needed to carry out the judicial exceptions. Data gathering does not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
Those steps in claims 1 and 171-173 directed to “implementing an action on the detection system based upon the uncertainty metric and the uncertainty metric, wherein the action comprises… performing a related process on the polypeptide, or performing a related process on a second polypeptide” which recite additional elements are not required to be performed because the actions which are recited are selected from a list. As some of the options in the list are considered to recite judicial exceptions, as discussed above, the performance of the steps which are considered to recite additional elements are not required to be performed in the scope of the method, and therefore cannot provide a practical application when they are not performed. It is noted that even if they were required to be performed, these steps appear to merely recite “apply it” steps to step a) of determining an uncertainty metric and data gathering steps to step c) of updating the data set after implementing the action, and would therefore not provide a practical application. The actions of “performing a related process on the polypeptide, or performing a related process on a second polypeptide” merely recite the idea of a solution or outcome in a very general manner and therefore do not provide a practical application (MPEP 2106.05(f)). Claim 26 is similarly not be required to be performed unless pausing the iterative detection process in claim 1 was performed. Insignificant extra-solution activity does not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Insignificant extra-solution activity steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
Further steps directed to additional non-abstract elements of the detection system do not describe any specific computational steps by which the “computer parts” perform or carry out the judicial exceptions, nor do they provide any details of how specific structures of the computer, such as the computer-readable recording media, are used to implement these functions. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, and therefore the claim does not integrate that judicial exceptions into a practical application. The courts have weighed in and consistently maintained that when, for example, a memory, display, processor, machine, etc.… are recited so generically (i.e., no details are provided) that they represent no more than mere instructions to apply the judicial exception on a computer, and these limitations may be viewed as nothing more than generally linking the use of the judicial exception to the technological environment of a computer (MPEP 2106.05(f)).
The specification discloses systems and methods for improved detecting, characterizing, or manipulating molecules in bulk or for detecting, characterizing, or manipulating analytes other than molecules such as biological cells, organelles, tissues, or the like at [0004], but does not provide a clear explanation for how the additional elements provide these improvements. Therefore, the additional elements do not clearly improve the functioning of a computer, or comprise an improvement to any other technical field. Further, the additional elements do not clearly affect a particular treatment; they do not clearly require or set forth a particular machine; they do not clearly effect a transformation of matter; nor do they clearly provide a nonconventional or unconventional step (MPEP2106.04(d)).
Thus, none of the claims recite additional elements which would integrate a judicial exception into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Step 2B (MPEP 2106.05.A i-vi)
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represents other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the prior art to Alfaro et al. (Nature Methods, Jun 7 2021, 18(6), pp.604-617; newly cited) discloses that a single-analyte system which comprises a detection system that is configured to obtain a physical measurement of the single analyte/polypeptide at single-analyte resolution, where the sequence of the protein is considered to read on a property, characteristic, identity, as in claims 1 and 171-173, or a structure as in claim 19, is a data gathering element that is routine, well-understood and conventional in the art. Said portions of the prior art are, for example, Figure 1 which indicates industry adoption and the establishment of certain technologies. As such, the claims simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception (MPEP2106.05(d)). The data gathering steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception (MPEP2106.05(g)&(h)).
With respect to claims 1 and 171-173 and those claims dependent therefrom, the computer-related elements or the general purpose computer do not rise to the level of significantly more than the judicial exception. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, which the courts have found to not provide significantly more when recited in a claim with a judicial exception (Alice Corp., 573 U.S. at 225-26, 110 USPQ2d at 1984; see MPEP 2106.05(A)). The specification as published also notes that computer processors and systems, as example, are commercially available or widely used at [0066; 0293]. The additional elements are set forth at such a high level of generality that they can be met by a general purpose computer. Therefore, the computer components constitute no more than a general link to a technological environment, which is insufficient to constitute an inventive concept that would render the claims significantly more than the judicial exceptions (see MPEP 2106.05(b)I-III).
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself [Step 2B: NO; See MPEP § 2106.05].
Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
Response to Applicant Arguments
At p. 14-16, section I., Applicant submits that the claimed method improves a technical field because it reduces uncertainty and improves confidence in single-analyte systems by controlling actions performed by a detection system. Applicant submits that the claims are not directed to a judicial exception at Step 2A, Prong 2, because the claim as a whole integrates the judicial exceptions into a practical application by improving the conventional processes for single-analyte analysis by using an iterative process that obtains and monitors the physical measurements of the single analyte to control and regulate the selection of steps to be performed within the process. Applicant submits that the claims recite a particular way of achieving improved outcomes in single-analyte processes by requiring the detection system to obtain the physical measurements and use the iterative approach to monitor and refine the hygiene and efficacy of the process. Applicant points to Ex parte Desjardins as a reminder to consider whether the claims as a whole reflect the improvement discussed in the specification.
It is respectfully submitted that this is not persuasive. Applicant’s arguments are not entirely commensurate with the scope of the claims because, first, the claims recite no limitations regarding “to monitor and refine the hygiene and efficacy of the process” as submitted by Applicant, and several of the potential actions performed by the detection system in claims 1 and 171-173 recite judicial exceptions. The iterative detection process itself is not strictly limited to the additional element of obtaining a physical measurement, but also involves the judicial exceptions of determining an uncertainty metric and updating the data set. Thus, those actions performed at step b) directed to pausing, altering a sequence of steps, or identifying a next step of a sequence of steps of the iterative detection process encompass actions which are judicial exceptions. Therefore, potential actions performed in the iterative detection process recite judicial exceptions, and cannot provide a practical application, even if they provide the supposed improvement in the claims. The improvement at Step 2A, Prong 2, must flow from the additional elements or be in the additional elements themselves.
The courts have made clear that a judicial exception is not eligible subject matter (Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)) if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, it is the additional elements (if any) in the claim that must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B. If there are no additional elements in the claim, then it cannot be eligible.
Ultimately, the claims are directed to a judicial exception of analyzing single-analyte data to determine an uncertainty metric, implement an action which reads on additional or modified data analysis, and update the data set after obtaining another physical measurement. The steps of obtaining the physical measurements merely function in the claims as a whole as data gathering steps to the recited judicial exceptions. Therefore, the claims have been considered as a whole to determine if the reflect the improvement discussed in the specification and are found not to. If the claims were amended to clearly limit the actions performed to being additional elements rather than judicial exceptions, and/or if the claims were amended to explain how the uncertainty metric is incorporated to produce a specific action which provides an improvement in the actual single-analyte detection process of obtaining a physical measurement, the claims may be directed to a practical application at Step 2A, Prong 2.
At p. 16-17, Section II., Applicant submits that the claimed method imposes additional meaningful limits on any judicial exception by implementing actions on the detection system and obtaining updated measurements for the polypeptide. Applicant submits that the claim does not preempt all uses of mental processes or mathematical concepts, but reflect other meaningful limitations which transform the claim.
It is respectfully submitted that this is not persuasive. As discussed above, the list of possible actions performed in the independent claims include actions which do not obviously recite additional elements. Therefore, those actions which do recite additional elements are not required to be performed. Even if those actions which recite additional elements were required to be performed, the actions are still so generally recited (performing a related process on the peptide or on a second polypeptide) that it is not apparent how those actions would result in the improvements argued by Applicant. The claims fail to link or describe how any of the actions recited in step b) affect the subsequent obtaining of an updated physical measurement after the first cycle. Therefore, the claims do not reflect the supposed improvements argued by Applicant or described in the specification.
While preemption is the concern underlying the judicial exceptions, it is not a standalone test for determining eligibility (Rapid Litig. Mgmt. v. CellzDirect, Inc., 827 F.3d 1042, 1052, 119 USPQ2d 1370, 1376 (Fed. Cir. 2016)). It is necessary to evaluate eligibility using the Alice/Mayo test, because while a preemptive claim may be ineligible, the absence of complete preemption does not demonstrate that a claim is eligible (Diamond v. Diehr, 450 U.S. 175, 191-92 n.14, 209 USPQ 1, 10-11 n.14 (1981); “We rejected in Flook the argument that because all possible uses of the mathematical formula were not pre-empted, the claim should be eligible for patent protection”; see MPEP 2106.04).
At p. 17-18, Section III., Applicant submits that the claimed method is similar to Example 45 because the instant claims do not merely determine an uncertainty metric but instead require obtaining a physical measurement used to obtain the uncertainty metric and further uses the uncertainty metric to control the detection system by implementing a particular action.
It is respectfully submitted that this is not persuasive. The instant claims are not analogous to those in Example 45 because, as described above, the instant claims do not require the performance of an action which only recites an additional element and they do not clearly describe how any of the recited actions affect the performance of the detection system to provide an improved measurement. Claims 2 and 4 of Example 45 recite limitations which distinctly describe actions that are performed in response to specific scenarios that result in a practical application (example in claim 2: “send control signals to the injection molding apparatus once the polyurethane has reached a target percentage, the control signals instructing the apparatus to open the mold and eject the molded polyurethane from the mold”). Such limitations are absent in the instant claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 171-173 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Kain et al. (US 2010/0138,162; previously cited). The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Claim 171 discloses a method for a single-analyte process, the method comprising:
performing an iterative process until a determinant criterion has been achieved, wherein the iterative process comprises at least two cycles, each cycle comprising the steps of:
a) combining data from a single-analyte data set comprising data from more than one data source to determine a process metric for a single analyte and an uncertainty metric for the single analyte, wherein:
the uncertainty metric represents a statistical measure of variability of a physical measurement for the single analyte, and wherein
the physical measurement of the single analyte measures a property, characteristic, behavior, interaction, or identity of the single analyte;
b) implementing an action on a single-analyte system based upon the process metric and the uncertainty metric, wherein:
the single-analyte system comprises a detection system that is configured to obtain the physical measurement of the single analyte at single-analyte resolution; and wherein
the action comprises pausing the iterative process, altering a sequence of steps of the iterative process, identifying a next step of a sequence of steps of the iterative process, performing a related process on the single analyte, or performing a related process on a second single analyte; and
c) updating the single-analyte data set after implementing the action on the single-analyte system and obtaining an updated physical measurement of the single analyte based on the updated single-analyte data set, wherein the determinant criterion is achieved based on at least the uncertainty metric.
Claim 172 discloses a method for a single-analyte process, the method comprising:
performing an iterative process until a determinant criterion has been achieved, wherein the iterative process comprises at least two cycles, each cycle comprising the steps of:
a) determining a process metric for a single analyte and an uncertainty metric for the single analyte based upon a single-analyte data set, wherein:
the uncertainty metric represents a statistical measure of variability of a physical measurement for the single analyte, and wherein the physical measurement of the single analyte measures a property,
characteristic, behavior, interaction, or identity of the single analyte; and
b) implementing an action on a single-analyte system that alters a source of uncertainty based upon the process metric and the uncertainty metric, wherein:
the single-analyte system comprises a detection system that is configured to obtain the physical measurement of the single analyte at single-analyte resolution, and wherein
the action comprises pausing the iterative process, altering a sequence of steps of the iterative process, identifying a next step of a sequence of steps of the iterative process, performing a related process on the single analyte, or performing a related process on a second single analyte; and
c) updating the single-analyte data set after implementing the action on the single-analyte system and obtaining an updated physical measurement of the single analyte based on the updated single-analyte data set, wherein the determinant criterion is achieved based on at least the uncertainty metric.
Claim 173 discloses a method for a single-analyte process, the method comprising:
performing an iterative process until a completion criterion has been achieved, wherein the iterative process comprises at least two cycles, each cycle comprising the steps of:
a) determining a curated uncertainty metric for a plurality of single analytes based upon a single-analyte data set, wherein:
the curated uncertainty metric represents a statistical measure of variability of each respective physical measurement in a plurality of physical measurements, and
wherein each respective physical measurement in the plurality of physical measurements measures a property, characteristic, behavior, interaction, or identity of a respective single analyte in the plurality of single analytes;
b) implementing an action on a single-analyte system based upon the curated uncertainty metric, wherein:
the single-analyte system comprises a detection system that is configured to obtain the physical measurement at single-analyte resolution of each single analyte of the plurality of single analytes, and wherein
the action comprises pausing the iterative process, altering a sequence of steps of the iterative process, identifying a next step of a sequence of steps of the iterative process, performing a related process on a first single analyte in the plurality of single analytes, or performing a related process on a second single analyte in the plurality of single analytes; and
c) updating the single-analyte data set after implementing the action on the single-analyte system and obtaining an updated physical measurement of each single analyte in the plurality of single analytes based on the updated single-analyte data set, wherein the completion criterion is achieved based on at least the curated uncertainty metric.
Regarding claims 171-173, Kain discloses a technique for sequencing nucleic acids in an automated or semi-automated manner, where sample arrays of a multitude of nucleic acid sites are processed in multiple cycles (i.e., an iterative process) to add nucleotides to the material to be sequenced and detect the nucleotides added to sites (i.e., a detection system configured to obtain a physical measurement) (abstract). Kain teaches that genetic sequencing consists of determining the order of nucleotides for a nucleic acid [0003], which reads on obtaining a physical measurement that measures a property, characteristic, or identity of a single analyte as instantly claimed. Kain teaches that multiple parameters, or process parameters, of the system are monitored to enable diagnosis (i.e., a) a process metric as in claims 171 -172; a curated uncertainty metric as in claim 173) and correction of problems as they occur during sequencing (i.e., each cycle comprises steps a)-c)) of the samples and that quality control routines are run during sequencing to determine quality of samples (i.e., b) implementing an action), and quality of the data collected (i.e., c) updating the data set) (abstract; see also [0006-0008; 0031; 0057]).
Kain teaches a number of embodiments involving evaluating parameters of the sequencing system, including a base addition quality control routine that evaluates parameters of the sequencing system to determine whether changes should be made to the system operating settings (i.e., b) altering a sequence of steps; identifying a next step) or whether sequencing could or should continue (i.e., b) pausing) under the same or different conditions (i.e., b) performing a related process) [0062]. Kain teaches another parameter examined is whether too few sites are detectable, where if the detected number of such sites is low or lower than desired, this may be indicated by a count of the number of sites or by determining that a number of “dark” pixels or “dark” circuits (e.g., pixels or circuits not apparently indicative of the presence of a site) is above a ceiling [0071], which reads on the uncertainty metric representing a statistical measure of variability of the physical measurement as instantly claimed. Kain also teaches determining whether operating parameters are within the acceptable ranges [0078], which reads on the uncertainty metric representing a statistical measure of variability of the physical measurement as instantly claimed. Kain also teaches that several parameters may be used to help monitor imaging and sequencing operations, including sample site parameters (e.g., site quality, distribution, shape, number, and so forth) [0085; see also 0049], which reads on the uncertainty metric representing a statistical measure of variability of the physical measurement as instantly claimed. Kain also teaches that feedback may include noise in the data [0039], which reads on the uncertainty metric representing a statistical measure of variability of the physical measurement as instantly claimed.
Regarding step b), Kain teaches that samples may be paused [0045] or interrupted [0032] during sequencing. Kain teaches determining whether the current cycle is the initial sequencing cycle and whether to continue the sequencing or cause steps to be re-performed [0061], which also reads on performing a related process on the molecule because a re-performed step is a related process. Kain teaches analyzing an array with a population of different reaction sites of multiple biopolymers [0059], which reads on performing a related process on a second molecule.
Kain teaches that sequencing operations may be interrupted by the sequencer based upon the occurrence of certain predetermined events, and can then perform the processing steps again after adjusting certain operating conditions, such as if an image of a particular cycle is analyzed in real time and shows a low signal for that channel, the image can be re-exposed using a longer exposure time, or have a particular chemical treatment repeated [0046; see also 0057; 0062; 0067; 0077], which reads on obtaining an updated physical measurement of the single analyte based on the updated data set as instantly claimed.
Kain teaches that the techniques are based upon analysis of nucleotide sequences in samples supported on a substrate, and typically containing a multitude of individual sites such as in a nucleic acid array (i.e., single-analyte process) [0005; 0059]. Kain teaches that the system control/operator interface of the sequencer may permit human operators to interface with the system to regulate operation or initiate and interrupt sequencing (i.e., a determinant criterion), but that an automated system may have multiple different protocols stored for carrying out different orders of certain steps which may be pre-loaded in the system with pre-set protocols (i.e., a determinant criterion) [0032] (see also teachings for the sequencer interrupting sequencing operations based upon certain predetermined events at [0046], which also reads on a determinant criterion). As Kain teaches that parameters and events are evaluated to determine whether to continue the sequencing operations [0046; 0062], it is considered that Kain fairly teaches a determinant criterion achieved based on the uncertainty metric as instantly claimed.
Kain teaches that a single species of biopolymer, such as a nucleic acid, is attached or otherwise coupled to each individual reaction site of an array and that the array taken as a whole will typically include a plurality of different biopolymers attached at or coupled to a plurality of different sites (i.e., a single-analyte data set comprising data from more than one data source as in claim 171) [0059]. Kain also teaches that process parameters may be combined to determine when the sequencing system is operating properly, when sequencing can proceed, or when one or more such parameters is out of a normal range to the extent that sequencing should not proceed (i.e., combining data to determine a process metric for a single analyte as in claim 171) [0069].
Response to Applicant Arguments
At p. 18-19, Applicant submits that Kain fails to teach or suggest obtaining physical measurements at single-analyte resolution, determining uncertainty measurements using such physical measurements at single-analyte resolution, or an iterative process that includes updating physical measurements of single-analytes using an updated data set.
It is respectfully submitted that this is not persuasive. As set forth in the above rejection, it is considered the Kain teaches each of the limitations which Applicant has submitted are not taught by Kain. As Applicant has provided no reasoning or evidence for why they consider Kain to not teach these limitations, because the limitations are addressed in the above rejection, and because Kain is considered to teach every limitation of claims 171-173, the rejection is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
A. Claims 1-3, 12-24, 26-27, and 134 are rejected under 35 U.S.C. 103 as being unpatentable over Kain et al. (US 2010/0138,162; previously cited) in view of Alfaro (Nature Methods, Jun 7 2021, 18(6), pp.604-617; previously cited). The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Claim 1 discloses a method for detecting a polypeptide at single-molecule resolution, the method comprising:
performing an iterative detection process in a detection system until a determinant criterion has been achieved, wherein:
the detection system is configured to obtain a physical measurement of the polypeptide at single-polypeptide resolution, the physical measurement of the polypeptide measures a property, characteristic, behavior, interaction, or identity of the polypeptide, and
the iterative detection process comprises at least two cycles, each cycle comprising the steps of:
a) determining an uncertainty metric for the polypeptide based upon a data set acquired from the detection system, wherein the uncertainty metric represents a statistical measure of variability of the physical measurement;
b) implementing an action on the detection system based upon the uncertainty metric, wherein the action comprises pausing the iterative detection process, altering a sequence of steps of the iterative detection process, identifying a next step of a sequence of steps of the iterative detection process, performing a related process on the polypeptide, or performing a related process on a second polypeptide; and
c) updating the data set after implementing the action on the detection system, wherein:
the iterative detection process further comprises, between at least a first cycle and a second cycle in the at least two cycles, obtaining an updated physical measurement of the polypeptide based on the updated data set, and
the determinant criterion is achieved based on the uncertainty metric.
Kain discloses a technique for sequencing nucleic acids in an automated or semi-automated manner, where sample arrays of a multitude of nucleic acid sites are processed in multiple cycles (i.e., an iterative detection process) to add nucleotides to the material to be sequenced and detect the nucleotides added to sites (i.e., a detection system configured to obtain a physical measurement) (abstract). Kain teaches that genetic sequencing consists of determining the order of nucleotides for a nucleic acid [0003], which reads on obtaining a physical measurement that measures a property, characteristic, or identity as instantly claimed. Kain teaches that multiple parameters, or process parameters, of the system are monitored to enable diagnosis (i.e., a) determining an uncertainty metric) and correction of problems as they occur during sequencing (i.e., each cycle comprises steps a)-c)) of the samples and that quality control routines are run during sequencing to determine quality of samples (i.e., b) implementing an action), and quality of the data collected (i.e., c) updating the data set) (abstract; see also [0006-0008; 0031; 0057]).
Regarding step b), Kain teaches that samples may be paused [0045] or interrupted [0032] during sequencing. Kain teaches determining whether the current cycle is the initial sequencing cycle and whether to continue the sequencing or cause steps to be re-performed [0061], which also reads on performing a related process on the molecule because a re-performed step is a related process. Kain teaches analyzing an array with a population of different reaction sites of multiple biopolymers [0059], which reads on performing a related process on a second molecule. Alfaro teaches single-molecule protein sequencing (abstract).
Kain teaches a number of embodiments involving evaluating parameters of the sequencing system, including a base addition quality control routine that evaluates parameters of the sequencing system to determine whether changes should be made to the system operating settings (i.e., b) altering a sequence of steps; identifying a next step) or whether sequencing could or should continue (i.e., b) pausing) under the same or different conditions (i.e., b) performing a related process) [0062]. Kain teaches another parameter examined is whether too few sites are detectable, where if the detected number of such sites is low or lower than desired, this may be indicated by a count of the number of sites or by determining that a number of “dark” pixels or “dark” circuits (e.g., pixels or circuits not apparently indicative of the presence of a site) is above a ceiling [0071], which reads on the uncertainty metric representing a statistical measure of variability of the physical measurement as instantly claimed. Kain also teaches determining whether operating parameters are within the acceptable ranges [0078], which reads on the uncertainty metric representing a statistical measure of variability of the physical measurement as instantly claimed. Kain also teaches that several parameters may be used to help monitor imaging and sequencing operations, including sample site parameters (e.g., site quality, distribution, shape, number, and so forth) [0085; see also 0049], which reads on the uncertainty metric representing a statistical measure of variability of the physical measurement as instantly claimed. Kain also teaches that feedback may include noise in the data [0039], which reads on the uncertainty metric representing a statistical measure of variability of the physical measurement as instantly claimed.
Kain teaches that sequencing operations may be interrupted by the sequencer based upon the occurrence of certain predetermined events, and can then perform the processing steps again after adjusting certain operating conditions, such as if an image of a particular cycle is analyzed in real time and shows a low signal for that channel, the image can be re-exposed using a longer exposure time, or have a particular chemical treatment repeated [0046; see also 0057; 0062; 0067; 0077], which reads on obtaining an updated physical measurement of the molecule based on the updated data set as instantly claimed.
Kain teaches that the techniques are based upon analysis of nucleotide sequences in samples supported on a substrate, and typically containing a multitude of individual sites such as in a nucleic acid array (i.e., single-molecule resolution) [0005; 0059]. Kain teaches that the system control/operator interface of the sequencer may permit human operators to interface with the system to regulate operation or initiate and interrupt sequencing (i.e., a determinant criterion), but that an automated system may have multiple different protocols stored for carrying out different orders of certain steps which may be pre-loaded in the system with pre-set protocols (i.e., a determinant criterion) [0032] (see also teachings for the sequencer interrupting sequencing operations based upon certain predetermined events at [0046], which also reads on a determinant criterion). As Kain teaches that parameters and events are evaluated to determine whether to continue the sequencing operations [0046; 0062], it is considered that Kain fairly teaches a determinant criterion achieved based on the uncertainty metric as instantly claimed.
Although Kain teaches that their methods may be used for any desired sequencing not limited to DNA and RNA sequencing [0005], Kain does not explicitly teach an iterative detection process for detecting a polypeptide at single-molecule resolution.
However, the prior art to Alfaro discloses methods for single-molecule protein (i.e., polypeptide) sequencing (abstract; entire document is relevant).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, Kain and Alfaro because both references disclose methods for single-molecule detection. The motivation to apply the methods of Kain to the single-molecule protein sequencing as taught by Alfaro would have been to apply process control techniques that provide for more highly automated or higher quality sequencing, permitting higher throughput and ultimately reduced sequence costs, as taught by Kain [0005], to the known field of single-molecule protein sequencing, as taught by Alfaro (abstract). The basic technique of applying process control as taught by Kain to single-molecule protein sequencing would have yielded no more than the predictable outcome of controlling said sequencing process which one of ordinary skill would have expected to achieve with this common tool of the trade, and was therefore an obvious expedient.
Regarding claim 2, Kain in view of Alfaro teaches claim 1 as described above. Claim 2 further adds that the determinant criterion is an unforced determinant criterion.
Kain teaches that an automated system may have multiple different protocols stored for carrying out different orders of certain steps which may be pre-loaded in the system with pre-set protocols (i.e., an unforced determinant criterion) [0032] (see also teachings for the sequencer interrupting sequencing operations based upon certain predetermined events at [0046], which also reads on a determinant criterion).
Regarding claims 3, 12-18, and 20, Kain in view of Alfaro teaches claims 1-2 as described above. Claim 3 further adds that the unforced determinant criterion is selected from the group consisting of: i) the uncertainty metric traversing a threshold value; ii) a categorized value of the uncertainty metric changing from a first categorized value to a second categorized value; iii) a trend in the uncertainty metric; and iv) a pattern in the uncertainty metric. Claims 12-13 further limit the threshold value of claim 3 to being determined based upon a preliminary data set or a default value or a user-defined value. Claim 14 further limits the first categorized value or the second categorized value is a member of a binary pair group. Claims 15-16 further limit the categorized value of the uncertainty metric in claim 3 to the categorized value of a first uncertainty metric changing and the categorized value of a second uncertainty metric changing or the categorized value of a first uncertainty metric changing and the categorized value of a second uncertainty metric not changing. Claims 17-18 further limit the trend and pattern of claim 3 to an increasing, decreasing, or neutral trend for the uncertainty metric over at least two of the cycles or a converging, diverging, oscillatory, or static pattern for the uncertainty metric. Claim 20 further adds performing the iterative detection process until two or more determinant criteria have been achieved.
Kain teaches that predetermined events can include, without limitation, unacceptable environmental factors such as undesirable temperature, humidity, vibrations or stray light; inadequate reagent delivery or hybridization; unacceptable changes in sample temperature; unacceptable sample site number/quality/distribution; decayed signal-to-noise ratio; insufficient image data; and so forth [0046], which each read on i)-iv) of claim 3 because they describe unacceptable or undesirable limits of parameters (i.e., a threshold value in i); changes from an acceptable to an unacceptable or undesirable categorized value in ii)) and changes in parameters over time (i.e., a trend in iii); a pattern in iv)).
Regarding claims 12-13, Kain teaches that the failure to add a base may be indicated by a single intensity in the image data that is below a desired threshold, where an indicator for a low yield base coupling may, as indicated above, be a signal intensity that is lower than expected, similar to the test for no base having been added[0083]. Kain teaches that the expected intensity can be a particular threshold level that remains unchanged for all cycles (i.e., a default value as in claim 13) [0083]. Kain teaches that, alternatively, the threshold level can be reduced at each cycle in accordance with an acceptable loss of yield at each step or in accordance with an empirically determined loss of yield determined from the signal detected from one or more previous cycles (i.e., based upon a preliminary data set as in claim 12), as described for example in regard to signal-to-noise (S/N) ratio [0083].
Regarding claims 14-16, at least the changes from an acceptable to an unacceptable or undesirable parameter at [0046] reads on a binary pair group (claim 14), a category of a first and second uncertainty metric changing because Kain teaches multiple acceptable/unacceptable parameters (claim 15), and a category of a first uncertainty metric changing but not a category of a second metric changing because Kain does not limit the method to requiring at least two changes (claim 16). Kain also teaches that parameters may be combined to determine when the sequencing system is operating properly, when sequencing can proceed, or when one or more such parameters is out of a normal range to the extent that sequencing should not proceed [0069], which also teaches claims 16-17.
Regarding claims 17-18, at least the decayed signal-to-noise ratio at [0046] reads on at least a decreasing uncertainty metric (claim 17) and a diverging uncertainty metric (claim 18).
Regarding claim 20, Kain teaches that a number of individual system parameters are monitored and regulated during sequencing, and that in addition to these ongoing and regular checks, unusual process developments may be detected, and in cases where the system determines that continuing the sequencing process would not result in data being collected for each cycle, the system can make an automated decision to end the sequencing run or to flush reagents through the flow cell to preserve the sample and enter a safe state that preserves the sample until data collection can be resumed [0068-0069], which reads on two or more determinant criteria as instantly claimed.
Regarding claim 19, Kain in view of Alfaro teaches claim 1 as described above. Claim 19 further adds obtaining the updated physical measurement of the polypeptide further comprises determining a structure of the single analyte.
The claim is interpreted to require determining a structure of the polypeptide, which Kain does not teach.
However, Alfaro teaches methods that determine the properties of folded proteins to determine their structure fingerprint (Fig. 1), as well as other methods to determine structures or structural changes (p. 610, col. 1, par. 1 and 3).
Regarding claims 21-24, Kain in view of Alfaro teaches claim 1 as described above. Claim 21 further adds that the determinant criterion comprises a forced determinant criterion, Claim 22 further adds that the forced determinant criterion comprises a user input or a system feedback. Claim 23 further adds that the user input comprises an input selected from the group consisting of: i) an instruction to discontinue the iterative detection process; ii) an instruction to alter a sequence of steps of the iterative detection process; iii) information identifying a trend in the uncertainty metric; iv) information identifying a pattern in the uncertainty metric; v) information identifying a categorized value of the uncertainty metric; and vi) information identifying a characterization of the polypeptide. Claim 24 further adds that the system feedback is selected from the group consisting of: i) a reagent level or rate of consumption; ii) an addressable hardware failure mode; iii) a non-addressable hardware failure mode; iv) a software failure mode; v) an environmental condition; and vi) an unexpected external condition.
Regarding claims 21-22, Kain teaches that the system control/operator interface may also permit human operators to interface with the system to regulate operation, initiate and interrupt sequencing, and any other interactions that may be desired with the system hardware or software (i.e., a user input as in claim 22) [0032]. Kain teaches that process parameters may be used for sophisticated quality and process control, for example, as part of a feedback loop that can change instrument operation parameters during the course of a sequencing run (i.e., system feedback) [0031; 0039]. Both of the above indicated teachings of Kain therefore read on a forced determinant criterion as recited in claim 21.
Regarding claim 23, Kain teaches that human operators may interface with the system to regulate operation (i.e., alter a sequence of steps as in iii.-iv), initiate (i.e., alter a sequence of steps as in iii.-iv) and interrupt (i.e., discontinue as in i.-ii.) sequencing, and any other interactions that may be desired with the system hardware or software [0032]. Kain teaches that predetermined events can include, without limitation, unacceptable environmental factors such as undesirable temperature, humidity, vibrations or stray light; inadequate reagent delivery or hybridization; unacceptable changes in sample temperature; unacceptable sample site number/quality/distribution; decayed signal-to-noise ratio; insufficient image data; and so forth [0046], which each read on v.-vii. because they describe unacceptable or undesirable limits of parameters (changes from an acceptable to an unacceptable or undesirable categorized value in vii.) and changes in parameters over time (i.e., a trend in v.; a pattern in vi.). Kain teaches that the system also examines qualities of the sample (i.e., information identifying a characterization of the molecule as in viii.) [0073]. Although Kain does not teach a user inputting the values which read on v.-viii., it would have been obvious for a user to input those values as Kain already teaches both the values and user input. Alfaro teaches single-molecule protein sequencing (abstract).
Regarding claim 24, Kain teaches that the feedback may include feedback regarding preparation of a substrate for processing, status in any of the processing steps, ability of the sample to be removed, an indication (e.g. a warning, a positive feedback that conditions are acceptable, etc.) regarding processing conditions (e.g. site density, environmental conditions such as temperature (i.e., v.), availability of reagents (i.e., i.), noise in the data, etc.), estimated time to complete sequencing and/or any sub-step for sequencing, and/or any other information relating to the system [0039]. Kain teaches detection of failure of the laser module, then the instrument can flush the sample with a “holding buffer” to preserve the sample until the error in the laser can be corrected [0052], which reads on both an addressable and non-addressable hardware failure mode as in ii. and iii., because the hardware failure of the laser may or may not be able to be addressed but the instrument remains paused until otherwise indicated. Kain teaches that various environmental parameters may be monitored to provide input as to how external factors may be affecting sequencing operations, including, without limitation, humidity, external power sources, temperature, vibration, and so forth (i.e., vi.) [0085].
Regarding claims 26-27, Kain in view of Alfaro teaches claim 1 as described above. Claim 26 further adds that pausing the iterative detection process further comprises an action selected from the group consisting of reconfiguring the detection system, recalibrating the detection system, repairing the detection system, transmitting an instruction or information to a second detection system, adding a second polypeptide to the detection system, stabilizing the polypeptide in the detection system, refreshing a computer- implemented algorithm, updating a computer-implemented algorithm, receiving a user input, and a combination thereof. Claim 27 further adds after step b) and before step c) resuming the iterative detection process.
Regarding claim 26, Kain teaches at least placing the sample in a storage state to stabilize the biopolymer (i.e., stabilizing the polypeptide in the detection system) [0045].
Regarding claim 27, Kain teaches that samples may be paused [0045] or interrupted [0032] during sequencing, and resuming data collection after interruption [0067].
Regarding claims 134, Kain in view of Alfaro teaches claim 1 as described above. Claim 134 further adds that the single analyte is derived from a biological sample.
Kain teaches that the sample can be isolated from a biological source [0055].
Response to Applicant Arguments
At p. 19-21, Applicant submits that a prima facie case of obviousness does not exist because Kain does not teach or suggest obtaining a physical measurement of a polypeptide at single-polypeptide resolution. Applicant submits that the process parameters relied upon in Kain are, at most, system-level or run-quality metrics and do not constitute physical measurements of an individual peptide or measurements of the property, characteristic, behavior, interaction, or identity of the polypeptide itself at single polypeptide resolution. Applicant submits that because Kain does not teach obtaining a physical measurement of a polypeptide at single-polypeptide resolution, Kain also does not teach or suggest the claimed uncertainty metric. Applicant further submits that Kain does not teach an iterative detection process to obtain an updated physical measurement using the updated data set. Applicant submits that Alfaro does not remedy these deficiencies because, even though Alfaro may disclose protein sequencing generally, neither Alfaro nor Kain, alone or in combination, teach the controlling an iterative single-polypeptide detection process by calculating a statistical uncertainty metric for a physical measurement of the polypeptide, using that metric to control the detection system to reduce uncertainty, and then acquiring an updated physical measurement after the control action. Applicant further submits that Alfaro does not disclose the system-level or run-quality metrics relied upon from Kain for sequencing quality control and therefore does not provide teaching, suggestion, or motivation to modify Kain, and the rejection fails to establish a prima facie case of obviousness.
It is respectfully submitted that this is not persuasive. The above rejection acknowledges that while Kain teaches physical measurement of a single-analyte at single-analyte resolution, Kain does not teach that the single-analyte is a polypeptide. However, Kain is not relied upon for teaching obtaining a physical measurement of a polypeptide at single-polypeptide resolution. Alfaro is relied upon for teaching polypeptide sequencing and it is considered that one of ordinary skill in the art would be motivated and think it obvious to combine these references. As set forth in MPEP 2145.IV., one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. As the above rejection sets forth (A) the relevant teachings of the prior art relied upon, preferably with reference to the relevant column or page number(s) and line number(s) where appropriate, (B) the difference or differences in the claim over the applied reference(s), (C) the proposed modification of the applied reference(s) necessary to arrive at the claimed subject matter, and (D) an explanation as to why the claimed invention would have been obvious to one of ordinary skill in the art at the relevant time, as is outlined in MPEP 2142 as sufficient to establish a prima facie case of obviousness, and as Applicant has not directly addressed the combination of the references and why they would not be obvious, it is considered that the rejection is correct and is maintained herein.
Regarding the process parameters taught by Kain, the above rejection describes various disclosure by Kain that integrate parameters or data obtained from the physical measurements of the single analyte to make decisions about the next steps of the sequencing operations. Therefore, Applicant’s arguments regarding Kain not teaching the uncertainty metric as instantly claimed are not convincing. Further, as Kain in view of Alfaro are considered to teach obtaining a physical measurement of a polypeptide at single-polypeptide resolution, and Kain teaches an uncertainty metric as instantly claimed, Applicant’s arguments that Kain does not teach an uncertainty metric are also not convincing. It is considered that one or ordinary skill in the art would recognize that the parameters and events which Kain examines to determine sequencing quality for a given cycle would also be applicable to polypeptide sequencing, and could function similarly during such a process to improve polypeptide sequencing quality.
Further, Kain is considered to teach the new limitation of an iterative detection process to obtain an updated physical measurement using the updated data set as set forth in the above rejection. Kain at least teaches examining parameters or events of the data produced from a sequencing cycle, which read on uncertainty metrics as instantly claimed, to determine whether to continue or essentially recapture the data for the given cycle [0046; see also 0057; 0062; 0067; 0077], which reads on obtaining an updated physical measurement of the molecule based on the updated data set as instantly claimed.
Conclusion
No claims are allowed.
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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/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685
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