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 .
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, 6-7, 9, 12-27, 134-135, and 171-173 are pending.
Claims 4-5, 8, 10-11 28-133, and 136-170 are canceled.
Claims 1, 3, 20, 23-25, and 171-173 are objected to.
Claims 1-3, 6-7, 9, 12-27, 134-135, 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, 6-7, 9, 12-27, 134-135, and 171-173 are afforded the effective filing date of the Jun 24 2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed on Aug 25 2022, Nov 16 2022, and Nov 20 2025 are in compliance with the provisions of 37 CFR 1.97 and have therefore been considered. Signed copies of the IDS documents are included with this Office Action.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: “420” in FIG. 4; “3001”, “3002”, “3003”, “3004”, and “3005” in FIG. 30A-E.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(4) because:
reference character “512” has been used to designate both generating a single-analyte data set in FIG 5A and [0099] of the specification as published, and obtaining a process metric from the single-analyte data set in FIG. 5B and [0100] of the specification as published. It is suggested to change “512” to “513” in FIG. 5B and [0100] of the specification as published;
reference character “516” has been used to designate both generating “Modify cycle based upon the process metric” in FIG 5A and [0099] of the specification as published, and “Determine a next cycle of the iterative process based upon the process metric” in FIG. 5B and [0100] of the specification as published.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
The claims are objected to for the following informalities:
Claim 1 is objected to for not beginning the method step in line 2 on a new line separate from the preamble and separating the “wherein” clauses on the 4th and 5th lines. 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)). Claims 171-173 are similarly objected to.
Claim 3 is objected to for reciting “ii.”, “iii.”, “iv.”, etc., to delineate the group of unforced determinant criterion. According to MPEP 608.01(m), “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995)”. The applicant may consider an amendment to replace “ii.”, “iii.”, “iv.”, etc., with “ii)”, “iii)” and “iv)”, respectively. It is also noted that the list of the group begins with “ii” rather than “i" and should be renumbered accordingly. Claims 23-25 are similarly objected to.
Claim 20 recites “iterative process”, which should be amended to recite “iterative detection process” to maintain consistent claim language.
Claim 23 repetitively recites the same user input categories in i. and ii., as well as iii. and iv. One of each of the duplicate entries should be deleted and the categories should be renumbered.
Claim 23 recites “viii. information identifying of a characterization”, where it is assumed that “of” should be deleted.
Claim 24 recites “wherein the determinant criterion comprises feedback selected from the groups”, which should be amended to recite “wherein the determinant criterion comprises system feedback selected from the group[[s]]”.
In claim 25, line 2, “groups” should be amended to recite “group”.
Claim Interpretation
Claim Terminology
In claims 1 and 171-173, the recitations of “controlling” the recited processes do not limit the scope of the claim. As stated in the MPEP 2111.02(II), a preamble generally is not limiting when the claim body describes a structurally complete invention such that deletion of the preamble phrase does not affect the structure or steps of the claimed invention. Consequently, “preamble language merely extolling benefits or features of the claimed invention does not limit the claim scope without clear reliance on those benefits or features as patentably significant.” The preamble of claims 1 and 171-173 merely states an intended use of the method and it does not affect the steps of the claim because none of the steps recite an actual single-molecule/single-analyte process or its detection or control.
Claim Rejections - 35 USC § 112
35 U.S.C. 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.
Claims 6-7, 9, 12, 19, 27, and 134-135 are 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.
Claim 6 recites “wherein the fixed number of cycles, the maximum number of cycles, or the minimum number of cycles is determined after completing a first cycle of the at least two cycles”. It is unclear whether the wherein clause is intended to require determining the fixed number of cycles, the maximum number of cycles, or the minimum number of cycles within the metes and bounds of the claimed invention, or if it is only further limiting the determinant criterion such that the actual determination of the criterion is not required within the metes and bounds of the invention. As set forth in MPEP 2111.04.I, “wherein” clauses raise the question as to the limiting effect of the language in a claim. As the claims do not previously recite an active determination of the criterion, the metes and bounds of the claims are unclear. For compact examination, it is assumed that the determination is not required to be performed. The rejection may be overcome by clarifying what steps are required to be performed. Claims 7 and 9 are similarly rejected for the determination of the fixed number of cycles, the maximum number of cycles, or the minimum number of cycles, and claim 12 are similarly rejected for the determination of the threshold value.
Claim 19 recites “wherein the obtaining a final characterization of the single analyte”. There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of obtaining a final characterization of the single analyte in the claims. Therefore, it is not clear what claim 19 is attempting to further limit. For compact examination, it is assumed that claim should actively recite that the method further comprises obtaining a final characterization of the single analyte. The rejection may be overcome by clarifying the antecedent basis of the limitation.
Claim 27 recites “resuming the single-analyte process”. There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of a single-analyte process. It is noted that claim 1 recites “an iterative detection process for detecting a polypeptide at single-molecule resolution”, and it is assumed that this is the process which claim 27 intends to refer to resuming. The rejection may be overcome by clarifying the antecedent basis of the limitation.
Claim 134 recites “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 134 intends to limit. The rejection may be overcome by clarifying the antecedent basis of the limitation. Claim 135 is rejected based on its dependency from claim 134.
Claim 135 recites “wherein the single analyte comprises a nucleic acid, a lipid, a polypeptide, a polysaccharide, a metabolite, a cofactor, or a combination thereof”. However, claim 1 is already limited to a polypeptide. It is therefore not clear claim 135 intends to replace the polypeptide (which “the single analyte” of claim 135 is assumed to intend to refer to, as discussed in the above 35 USC 112(b) rejection) of claim 1 with one of the other options recited in the claim, which would not be proper under 35 USC 112(d), or if the claim intends to recite an additional single analyte to the polypeptide of claim 1. For compact examination, it is assumed that an additional single analyte of the list is included in the method of claim 1. The rejection may be overcome by clarifying the scope of the claim.
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, 6-7, 9, 12-27, 134-135, 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.
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… and 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;
b) implementing an action on the detection system based upon the uncertainty metric; and
c) updating the data set after implementing the action on the detection system.
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;
b) implementing an action on a single-analyte system based upon the process metric, wherein the single-analyte system comprises a detection system that is configured to obtain a physical measurement of the single analyte at single-analyte resolution; and
c) updating the single-analyte data set after implementing the action on the single-analyte system.
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 based upon a single-analyte data set; and
b) implementing an action on a single-analyte system that alters a source of uncertainty based upon the process metric, wherein the single-analyte system comprises a detection system that is configured to obtain a physical measurement of the single analyte at single-analyte resolution; and
c) updating the single-analyte data set after implementing the action on the single-analyte system.
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;
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 a physical measurement at single-analyte resolution of each single analyte of the plurality of single analytes; and
c) updating the single-analyte data set after implementing the action on the single-analyte system.
Dependent claims 2-3, 6-7, 9, 12-25, 27, and 134-135 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, 6-7, 9, and 12-20 further limit the determinant criterion to an unforced determinant criterion; claims 21-24 further limit the determinant criterion to a forced determinant criterion; claim 25 further limits the action to being selected from the group of i. pausing the iterative detection process, ii. altering a sequence of steps for the iterative detection process, iii. identifying a next step of a sequence of steps for the iterative detection process; claim 27 further limits the method to resuming the single-analyte process before step c); and claims 134-135 further limit 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, 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:
Dependent claim 25: iv. performing a related process on the polypeptide; and
v. performing a related process on a second polypeptide.
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 25 provides optional steps iv. and v. which are not required to be performed, and claim 26 further limits an optional step in claim 25 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.
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; claim 171 includes single-analyte system which comprises a detection system that is configured to obtain a physical measurement of the single analyte at single-analyte resolution; claim 173 includes a detection system that is configured to obtain a physical measurement of the single analyte at single-analyte resolution; and claim 174 includes a single-analyte system which comprises a detection system that is configured to obtain a 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 in claims 25-26 which recite additional elements are not required to be performed, 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 steps in claims 25-26 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)). Data gathering and outputting do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting 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 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.
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; newly cited).
Claim 171 discloses a method for controlling 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; b) implementing an action on a single-analyte system based upon the process metric, wherein the single-analyte system comprises a detection system that is configured to obtain a physical measurement of the single analyte at single-analyte resolution; and c) updating the single-analyte data set after implementing the action on the single-analyte system.
Claim 172 discloses a method for controlling the processes of 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 based upon a single-analyte data set; and b) implementing an action on a single-analyte system that alters a source of uncertainty based upon the process metric, wherein the single-analyte system comprises a detection system that is configured to obtain a physical measurement of the single analyte at single-analyte resolution; and c) updating the single-analyte data set after implementing the action on the single-analyte system.
Claim 173 discloses a method for controlling the processes of 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; 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 a physical measurement at single-analyte resolution of each single analyte of the plurality of single analytes; and c) updating the single-analyte data set after implementing the action on the single-analyte system.
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 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 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).
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].
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.
Claims 1-3, 6-7, 9, 12-27, and 134-135 are rejected under 35 U.S.C. 103 as being unpatentable over Kain et al. (US 2010/0138,162; newly cited) in view of Alfaro (Nature Methods, Jun 7 2021, 18(6), pp.604-617; newly cited).
Claim 1 discloses a method for controlling an iterative detection process 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, and 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; b) implementing an action on the detection system based upon the uncertainty metric; and c) updating the data set after implementing the action on the detection system.
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 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]). 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).
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, 6-7, 9, 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: ii. a fixed number of the cycles; iii. a maximum number of the cycles; iv. a minimum number of the cycles; v. the uncertainty metric traversing a threshold value; vi. a categorized value of the uncertainty metric changing from a first categorized value to a second categorized value; vii. a trend in the uncertainty metric; and viii. a pattern in the uncertainty metric. Claims 6-7 and 9 further limit the fixed number of cycles, the maximum number of cycles, or the minimum number of cycles in claim 3, ii.-iv. Claims 12-13 further limit the threshold value of claim 3, v. Claims 15-16 further limit the categorized value of the uncertainty metric in claim 3, vi. Claims 17-18 further limit the trend and pattern or claim 3, vii. and viii. Claim 20 further adds performing the iterative process until two or more determinant criteria have been achieved.
Kain teaches that sequencing continues until the quality of data derived from sequencing degrades due to cumulative loss of yield or until a predetermined number of cycles have been completed (i.e., a fixed or maximum number of cycles, ii. and iii. of claim 3) [0030]. Kain also teaches determining whether a cycle is an initial cycle and performing specific actions based on that determination (i.e., a minimum number of cycles, iv. of claim 3) [0061]. 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.-viii. of claim 3 because they describe unacceptable or undesirable limits of parameters (i.e., a threshold value in v.; changes from an acceptable to an unacceptable or undesirable categorized value in vi.) and changes in parameters over time (i.e., a trend in vii.; a pattern in viii.).
Regarding claims 6-7 and 9, Kain teaches that the logic determines whether the current cycle is the initial sequencing cycle and then determining whether to continue or to repeat the current cycle [0061-0062], which reads on determining the fixed number of cycles, the maximum number of cycles, or the minimum number of cycles after the first cycle in claims 6 and 9. Kain teaches continuing the sequencing until a predetermined number of cycles (i.e., a default value in claim 7) has been completed [0030; 0064]. Kain also teaches that the protocols may alternatively be based on user interaction (i.e., a user-defined value in claim 7) [0032].
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 claims 1-3 as described above. Claim 19 further adds obtaining a final characterization of the single analyte comprises identifying the single analyte, determining a physical property of the single analyte, determining an interaction of the single analyte, determining a structure of the single analyte, or a combination thereof.
Kain teaches a process of sequencing molecules (abstract; entire document is relevant), which reads on identifying the single analyte and determining a physical property and structure of the single analyte because the sequence of the molecule conveys its identity, as well as a physical property and structure of the single analyte. Kain also teaches a sequence of the molecule as it interacts with a pore [0027].
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 discontinue the iterative detection process; iii. an instruction to alter a sequence of steps of the iterative detection process; iv. an instruction to alter a sequence of steps of the iterative detection process; v. information identifying a trend in the uncertainty metric; vi. information identifying a pattern in the uncertainty metric; vii. information identifying a categorized value of the uncertainty metric; and viii. information identifying of a characterization of the polypeptide. Claim 24 further adds that the feedback is selected from the groups 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 25-27, Kain in view of Alfaro teaches claim 1 as described above. Claim 25 further adds the action is selected from the groups consisting of: i. pausing the iterative detection process; ii. altering a sequence of steps for the iterative detection process; iii. identifying a next step of a sequence of steps for the iterative detection process; iv. performing a related process on the polypeptide; and v. performing a related process on a second polypeptide. 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 single-analyte process.
Regarding claim 25, Kain teaches that samples may be paused [0045] or interrupted [0032] during sequencing (i.e., i.). 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 (i.e., ii.-iii.) [0061], which also reads on performing a related process on the molecule in iv. 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 as in v. Alfaro teaches single-molecule protein sequencing (abstract).
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 134-135, 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. Claim 135 adds that the single analyte comprises a nucleic acid, a lipid, a polypeptide, a polysaccharide, a metabolite, a cofactor, or a combination thereof.
Kain teaches that the sample can be isolated from a biological source (i.e., claim 134) [0055]. 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-molecules in claim 135) [0005; 0059]. As the metes and bounds of claim 135 are not clear as described in the above 35 USC 112(b) rejection, it is considered than Kain fairly teaches the limitations of the claim.
Conclusion
No claims are allowed.
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/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685
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