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 .
Status of the Claims
Claims 21-24 were withdrawn following the 09 September 2025 restriction requirement and 10 November 2025 response. However, the method of claim 1 also recites the standards of claim 21 in dependent claim 18, and generates an algorithm, termed the predictor function, in claims 10-18. Furthermore, claim 24 recites a computer readable medium performing the sizing steps of independent claim 1 and its dependent claims. Therefore, upon further consideration of the claims, the restriction requirement is withdrawn.
In view of 35 USC 121, a patent issuing on an application with respect to which a requirement for restriction under this section has been made, or on an application filed as a result of such a requirement, shall not be used as a reference either in the Patent and Trademark Office or in the courts against a divisional application or against the original application or any patent issued on either of them, if the divisional application is filed before the issuance of the patent on the other application. Therefore, a divisional claim may be subject to double patenting.
Claims 1-24 are pending and examined herein.
No claims are canceled.
Priority
As detailed on the date filing receipt, the application claims priority as early 24 March 2022 as found on provision application 63/323,314. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date.
Information Disclosure Statement
An information disclosure statement (IDS) was filed on 17 October 2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the references are being considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informality: the “enumerating” step is not indented the same as the other steps and the phrase “using results of enumerating” is missing articles. Appropriate correction is required.
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.
Claim 24 is rejected under 35 USC § 101 because the claimed invention is directed to non-statutory subject matter. Claim 24 recites a computer-readable medium, which is not, in all embodiments within a broadest reasonable interpretation, interpreted as belonging to any statutory category at Step 1 of the 101 analysis. The specification discloses “the computer-readable medium may be transitory or non-transitory” (pg. 6, paragraph [27]), where a transitory computer-readable medium and thus transitory propagating signals, which are not proper patentable subject matter because it does not fit within any of the four statutory categories of invention (In re Nuijten, Federal. Circuit, 2006). Amendment to recite “A non-transitory computer-readable medium” may overcome this rejection.
Claims 1-24 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements both individually and in combination, do not amount to significantly more than the abstract idea of predicting a length characteristic of nucleic acid fragments.
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
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 (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The claims are directed to methods (claims 1-23) and a computer-readable medium (claim 24), which falls within one of the categories of statutory subject matter. [Step 1: claims 1-23: Yes; claim 24: No]
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 (MPEP 2106.04(a-c))?
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
Mathematical concepts recited in claims 1, 21, and 24 include enumerating target-defined subsets of the partitions and predicting at least one characteristic of the population of nucleic acid fragments using results of enumerating. The enumerating is interpreted as a verbal description of a mathematical concept which may be as simple as counting or determining ratios, which is supported in light of the specification (pg. 19, paragraph [77]). The predicting is also interpreted as a mathematical step, where the predicting is disclosed as using the results of the enumerating steps as inputs for a predicting algorithm (pg. 19, paragraph [79]), which is further disclosed as generated by logistic regression (pg. 27, Subsection D). A mathematical relationship may be expressed in words and there is no particular word or set of words that indicates a claim recites a mathematical calculation (MPEP 2106.04(a)(2)). These claims may also take the form of mental processes as enumerating and predicting a length characteristic describe observation and evaluation steps which are practically performed by the human mind.
Claims 2-18 and 22-23 recite further limitations on the predicting step, which is a mathematical concept, such as predicting length (claim 2), classifying length (claim 3), predicting a percentage meeting a criterion (claim 4) such as threshold length (claim 5), confidence interval (claim 6), measures of central tendency (claims 7-8), confidence interval of the median (claim 9), and further details of the predictor function (claims 10-18) and generating the size prediction algorithm (claims 22-23), where the predictor function is disclosed as “any function that provides an output value for a dependent variable, based on one or more input values for one or more independent variables, where the output value represents a prediction from the one or more input values,” having variables, coefficients, and constants(pg. 9, paragraph [41]), having a mathematical form (pg. 10, paragraph [42]), and fitting the function results in a linear regression model (pg. 10, paragraph [43]) or logistic regression model (pg. 10-11, paragraph [44]), and as such the claims are interpreted as directed to a mathematical concept.
Claims 19-20 recite additional information about the targets, including their lengths (claim 19) and separation from each other in the genome (claim 20). Selection of the lengths of the targets and their distance is performed by the human mind.
Hence, the claims explicitly recite numerous elements that, individually and in combination,
constitute abstract ideas. The claims must therefore be examined further to determine whether they
integrate that abstract idea into a practical application (MPEP 2106.04(d)). [Step 2A: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Because the claims 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)).
Claims 1 and 21 recite forming partitions of the sample, performing amplification reactions, and collecting amplification data, where the amplification data collection is derived from fluorescence. These steps are data collection steps required to perform the enumerating and predicting using the prediction algorithm. Clam 21 also recites providing a standard and measuring the length of the standards. Therefore, they are considered to be insignificant extra-solution activity, which does not integrate the abstract ideas into a practical application (MPEP 2106.05(g)).
Claim 24 recites a computer-readable medium. This is interpreted as invoking a computer to perform the abstract steps of enumerating target subsets and predicting at least one length characteristic, which does not integrate the abstract ideas into a practical application (MPEP 2016.05(f)).
None of the dependent claims recite any additional non-abstract elements; they are all directed
to further aspects of the information being analyzed, the manner in which that analysis is performed, or
the mathematical operations performed on the information. [Step 2A Prong Two: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself. Step 2B of 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05).
Claim 1 and 21 recites forming partitions of the sample, performing amplification reactions, and collecting amplification data, where the amplification data collection is derived from fluorescence.
Claim 21 further recites providing a standard and measuring the length of the standards.
Claim 24 recites a computer-readable medium.
Regarding claim 1, Basu (SLAS Technology 22(4): 369-386, 2017; newly cited) teaches digital assay in which the sample is partitioned (pg. 369, col. 1, first paragraph), amplified (pg. 370, col. 1, last paragraph), and data is collected on the amplification results by “spectrophotometry, fluorimetry, or nonoptical methods. For example, fluorescence intensity emitted from a probe may be used to quantify the concentration of DNA” (pg. 370, col. 1, last paragraph). Using such a method, it is taught “approximate distribution of nucleotide sequence lengths could be digitally quantified by counting the number of amplified species resulting from each probe” (pg. 381, col. 2, last paragraph).
Regarding claim 21, the further limitations of providing and measuring a standard are taught by Basu as quantitation of standards by commercial sources (pg. 381, col. 2, first paragraph), where quantitation is interpreted as measuring the standards which are commercially provided.
Regarding claim 24, the recitation of a computer in the form of a computer-readable medium to perform the abstract limitations amounts to no more than mere instructions to apply the exception using a generic computer component (MPEP 2106.05(f)). Furthermore, saving instructions to perform steps is considered a conventional computer activity (Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93; MPEP 2106.05(d)(II)).
Therefore, the recited additional elements, alone or in combination with the judicial exceptions, do not appear to provide an inventive concept. [Step 2B: No]
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole,
are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not
constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as
being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 and 24
Claims 1 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Basu (SLAS Technology 22(4): 369-386, 2017; newly cited).
Claim 1 recites forming partitions each containing a portion of the sample, wherein each target of
at least two targets is present in only a fraction of the nucleic acid fragments.
Basu teaches a “digital assay is one in which the sample is partitioned into many small containers such that each partition contains a discrete number of biological entities” (abstract), with a discrete number of entities including two.
Claim 1 recites performing amplification reactions for each of the at least two targets in the partitions and collecting amplification data for the at least two targets from the partitions.
Basu teaches fluorescence data generation following amplification (pg. 375, Fig. 6, caption).
Claim 1 recite enumerating target-defined subsets of the partitions using the amplification data.
Basu teaches enumeration of signal in the partitions (pg. 370, Fig. 1, right column) and a ratio of purification of two targets (pg. 371, Fig. 2).
Claim 1 recites predicting at least one length characteristic of the population of nucleic acid
fragments using results of enumerating.
Basu teaches targeting different lengths such that “the approximate distribution of nucleotide sequence lengths could be digitally quantified by counting the number of amplified species resulting from each probe” (pg. 381, col. 2, last paragraph).
Claim 24 recites a computer-readable medium for predicting the length of fragments using values obtained by, or derived from, enumerating target-defined subsets of partitions in a digital amplification assay for at least two targets, the partitions containing each of the at least two targets at partial occupancy, each of the at least two targets being provided by the population of nucleic acid fragments.
This claim is interpreted as storing the steps of claim 1 on a computer-readable medium. Basu teaches a computational environment as “computations performed in logic circuits” (pg. 396, col. 2, second paragraph) and digital measurements (Fig. 1).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2-4, 7, 19, and 21
Claims 2-4, 7, 19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Basu as applied to claims 1 and 24 in the 35 USC 102 rejection above and further in view of Didelot (Molecular Diagnostics and Genetics 59(5): 815-812, 2013; newly cited).
Claim 2 recites predicting includes predicting whether the population of nucleic acid fragments meets one or more predefined size criteria.
Didelot teaches measurements meeting the expectations from a distribution (pg. 818, col. 2, fourth paragraph), where an expectation is interpreted as a predetermined criterion.
Claim 3 recites predicting includes classifying a length of the population with respect to a threshold size.
Didelot teaches thresholds of quality based on fragment amplification (pg. 821, col. 1, first paragraph).
Claim 4 recites predicting includes predicting a value for a percentage of the population of nucleic acid fragments that meets one or more predefined size criteria.
Didelot teaches a percentage of expected amplifiable DNA for a given nucleotide length (pg. 822, Table 1).
Claim 7 recites predicting includes predicting a mean, median, quartile, and/or quintile length of the population of nucleic acid fragments.
Didelot teaches the mean lengths of the fragments (pg. 818, col. 2, second paragraph).
Claim 19 recites the at least two targets include a first target and a second target, and wherein the second target is at least 50 nucleotides longer than the first target.
Didelot teaches fragments of 170 bp, 230 bp, 290 bp, 370 bp, and 570 bp (Fig. 2) and thus fragments which are at least 50 bp different in length.
Claim 21 teaches the method steps of claim 1 as taught by Basu as well as providing standards for targets with different fragmentations and generating a predictor based on the measurements.
Didelot teaches commercially available standards (pg. 381, col. 2, first paragraph) and predicting quality by virtue of fragmentation (pg. 816, col. 1, second paragraph), evidenced by amplifiable fragments matching the prediction (pg. 818, col. 2, fourth paragraph).
Combining Basu and Didelot
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the teachings of Didelot, which teaches quantitative assessment of DNA by ddPCR, with the teachings of Basu because Didelot teaches analysis of different target lengths to analyze fragmentation and integrity of DNA (abstract), and Basu teaches partitioning as a means of quantifying nucleic acids (abstract) including determining fragment lengths (pg. 381, col. 2, last paragraph). The teachings of the prior art are both drawn to the shared field of endeavor of quantification of nucleic acids using digital assays, and their combination would be expected to succeed. Therefore, the invention is prima facie obvious.
Claims 5-6, and 10
Claims 5-6, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Basu, as applied to claims 1 and 24 in the above 35 USC 102 rejection, and in view of Didelot as applied to claims 2-4, 7, 19, and 21 above, and further in view of Alcaide (Scientific Reports 10(12564): 10 pgs., 2020; newly cited).
Claim 5 recites the value for the percentage represents a percentage of the population of nucleic acid fragments having a predefined relationship to a threshold length.
Didelot teaches determining a percentage of expected amplifiable DNA for a given nucleotide length (pg. 822, Table 1) but not necessarily whether they reach a threshold length.
Alcaide teaches a relating a length distribution of cfDNA, whether the lengths are considered to be fragment sizes, having low fragment lengths (or high fragmentation) versus a normal size (pg. 3, first paragraph), where being normal is interpreted as a threshold.
Claim 6 recites predicting includes predicting a confidence interval of the value for the percentage.
Basu teaches confidence intervals in partitioning statistics (pg. 372, col. 1, second paragraph).
Claim 10 recites enumerating includes obtaining two or more enumeration values, and wherein predicting includes combining the two or more enumeration values, or values derived therefrom, as input values for independent variables of a predictor function, to generate an output value representing a length characteristic of the at least one length characteristic.
Alcaide teaches a ratio between short and medium fragments which are combined in a ratio (pg. 2, last paragraph), where these are interpreted as enumeration values which are combined. The average ratio results in information about the fragment lengths (Fig. 2).
Combining Basu, Didelot, and Alcaide
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the teachings of Alcaide, which include determining a size distribution of cfDNA based on ddPCR, because Alcaide teaches measuring multiple fragments against a normal (pg. 3, first paragraph) and a ratio of fragment occurrence (pg. 2, last paragraph), which together teach interpretation of fragment lengths, which can be considered a metric of integrity similar to that of Basu and Didelot. The teachings of the prior art are drawn to the shared field of endeavor of quantification of nucleic acids using digital assays, and their combination would be expected to succeed. Therefore, the invention is prima facie obvious.
Claims 8-9
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Basu as applied to claims 1 and 24 in the 35 USC 102 rejection above, and in view of Didelot as applied to claims 2-4, 7, 19, and 21 above, and further in view of Quinn (Experimental Design and Data Analysis for Biologist, Cambridge Press: New York, 552 pgs., 2002; newly cited).
Claim 8 recites predicting includes predicting a median length of nucleic fragments in the population.
Didelot teaches the mean lengths of the fragments (pg. 818, col. 2, second paragraph) but not the median.
Quinn teaches common metrics of the center of a distribution, including both the mean and median as common population parameters and sampling statistics (pg. 16, Table 2.1).
Claim 9 recites predicting includes predicting a confidence interval of the median length.
Quinn teaches both the median as described above and confidence intervals as a range of values that may include the parameter (pg. 15, col. 1, bullet 2), also a common metric (pg. 16, Table 2.1).
Combining Basu, Didelot, and Quinn
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the teachings of Quinn, which include common methods of parameterization of biological data, with the teachings of Basu and Didelot because they teach mean and confidence interval, but Quinn teaches the benefit of using the median as an unbiased estimator of the population mean for a normal distribution and being resistant to outliers compared to the mean (pg. 15, Section 2.2.1). Therefore, it would be obvious to also use the median as a metric of central tendency in evaluating the fragment lengths. The teachings of the applied prior art are directed to measurement of biological data and thus the invention is prima facie obvious.
Claims Free of the Prior Art
Claims 11-18, 20, and 22-23 teach further aspects of the algorithmic steps for determining fragment lengths based on the ratio of amplified fragments in a partitioned assay. Applied prior art, such as Basu for partitioned analysis of DNA fragments, Didelot for determining lengths, and Alcaide for interpreting a ratio of different fragment lengths, do not teach the required limitations such as their linear combination, predicting based on partition count, or determining linkage between fragments. Therefore, the claims are considered free of the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert J Kallal whose telephone number is (571)272-6252. The examiner can normally be reached Monday through Friday 8 AM - 4 PM EST.
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/R.J.K./Examiner, Art Unit 1685
/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685