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 1-2, 5-6, 8-9, 11-17, and 22-24 are pending and examined herein.
Claims 3-4, 7, 10, and 18-21 are canceled.
Priority
As detailed on the 10 November 2020 filing receipt, the application claims priority as early as 27 April 2018. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date.
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 1-2, 5-6, 8-9, 11-17, and 22-24 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 individually and in combination, are directed to a judicial exception at Step 2A, Prong 2, and the additional elements of the claims, considered individually and in combination, do not provide significantly more at Step 2B than the abstract idea of identifying a disease signature in a patient.
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 a method (claims 1-2, 5-6, 8-9, 11-17, and 22-23), which falls within one of the categories of statutory subject matter. [Step 1: Yes]
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 the independent claims include "processing the signal intensities… to calculate concentrations" which comprises "log transforming" which is a verbal description of a mathematical process; “feeding” data as “features or inputs” into a machine learning model, where inputting data into a model is part of using a mathematical concept; "determining the particle phenotypes using a dynamic fluorescence thresholding algorithm" where using an algorithm is a verbal description of a mathematical process; and "using these concentrations… as the inputs for machine learning algorithms" where using a machine learning algorithm is a description of a mathematical concept. The claims recite determining particle phenotypes using an algorithm, where using an algorithm is interpreted as math. The claims recite using concentrations as inputs for a model, which may include "at least one of an individual/bagged/boosted decision tree algorithm, linear/quadratic/cubic/Gaussian support vector machine algorithm, logistic regression, linear/quadratic/subspace discriminant analysis, or k-nearest neighbors algorithm," where at least some of the recite list are interpreted as mathematical concepts. The model is then used to "generate probability scores," where generating a score is interpreted as a mathematical concept. The "generating… a patient-specific probability score that determines a probability of the patient having the clinically significant prostate cancer" is determining a probability and thus a mathematical concept. 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)).
Steps of evaluating, analyzing or organizing information recited in the independent claims include: “identifying a disease signature” in the sample, where identification of a disease based on the data is interpreted as data evaluation and thus a mental process; "processing the signal intensities" which comprises "binning" where binning is organization of data; determining if the score exceeds a threshold, which is a data comparison step practically performed mentally; and “recommending a prostate biopsy,” where a recommendation is interpreted as conveying information, which is a step practically performed by the human mind or with pen and paper. Alternatively, the recommendation may be considered organizing human activity, where a recommendation is an interaction between people (MPEP 2106.04(a)(2)(II)).
Additional abstract ideas recited in the dependent claims include log transforming signal intensities (claim 2), where log transforming is a mathematical concept; binning particles (claim 2), where binning is interpreted as a mental data sorting step; comparing concentration data (claim 2), where comparison can be practically performed by the human mind; determining ROC area (claim 2), which can be interpreted as a mental or mathematical step; selecting a combination of biomarkers (claim 2), which is a mental step as the human mind can practically perform a selection; log transforming (claim 5), where log transforming is a mathematical concept; binning (claim 5), where binning is interpreted as a mental data sorting step; log transforming (claim 6), where log transforming is a mathematical concept; binning (claim 6), where binning is interpreted as a mental data sorting step; additional information regarding ROIs (claim 8); fitting a kernel density estimation function (claim 9), where fitting a model is a mathematical step; identifying fluorescence values based on region in a graph (claim 8), where identification on a graph is performable in the human mind; calculating slopes (claim 9), calculating intensity values (claim 9), determining biomarker positivity status (claim 9), binning particles (claim 9), and determining particle phenotypes (claim 9), where binning and determination are mental steps and calculations are mathematical steps; a boosted decision tree algorithm (claim 11), the XGBoost algorithm (claim 12), additional information about said algorithm (claim 13), and additional information about the probability score (claim 14), which are descriptions of mathematical steps; and additional information about the patients (claim 16), where data is abstract.
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 Prong One: 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 recite elements in addition to the abstract ideas which 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)).
Independent claims 1 and 24 recite additional elements that are not abstract ideas: “providing a sample comprising extracellular vesicles,” "incubating a sample from the patient," "subjecting the sample to microflow cytometry," and "obtaining signal intensities." Claim 15 recites additional information about the biomarkers. Claim 17 recites additional information about the source of the sample. Claims 22-23 recite additional information about the probes. Claim 24 also recites providing a biopsy.
These steps related to providing a sample, incubating the sample, subjecting the sample to microflow cytometry, and obtaining signal intensities are interpreted as data gathering steps necessary for the mathematical operations conducted on the signal intensities to diagnose the patient based on the sample. Therefore, these steps are considered insignificant extra-solution activity and do not integrate the abstract ideas into a practical application at this step (MPEP 2106.05(g)).
Providing a biopsy when a score is considered to by a general application of the abstract ideas as the biopsy is not changed based on the signal processing steps (MPEP 2106.05(f)).
Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are directed to that abstract idea. [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). The steps reciting “providing a sample,” "incubating," and "cytometry" are insufficient to amount to significantly more than the abstract idea because they are necessary data gathering steps for performing steps directed to the abstract ideas (MPEP 2106.05(g)).
Ateya (Analytical and Bioanalytical Chemistry 391: 1485-1498, 2008; cited previously on the 20 November 2023 PTO-892 form) teaches a review of microflow cytometry including applications to disease diagnosis. Shao (Chemical Reviews 118: 1917-1950, 2018; previously cited on the 26 March 2025 PTO-892 form) teaches analysis of extracellular vesicles, including using small particle flow cytometry (pg. 1926, Table 3) and measuring fluorescence (pg. 1927, Figure 12). Shao teaches EVs are found in "biological fluids including blood" and "urine" (pg. 1921, col. 2, last paragraph to pg. 1922, col. 1, first paragraph). The recited incubation of a sample to bind biomarkers is considered conventional relating to hybridizing a gene probe (MPEP 2106.05(d)(II)). Shao also teaches biopsy for prostate cancer diagnosis and its using EVs as a complement to current tests, which include biopsies, and other cancer screening using tissue biopsy (pg. 1938, Sections 7.1.4 and 7.1.5).
Additionally, the specification discloses flow cytometric analysis is well-understood, routine, and conventional based on the methods explained in [3] and [40-44] and references therein, including commercially-available probes for the disclosed biomarkers (pg. 8, paragraph [41]). The remaining steps are all directed to abstract ideas and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05). [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.
Response to the 05 June 2026 Applicant Remarks
Applicant remarks state the instant claims recite “an improvement to microflow cytometry technology by addressing signal variability inherent in the instrumentation” provided by the dynamic fluorescent thresholding algorithm (pg. 9-10). More specifically, applicant remarks state this is a technical solution to a concrete problem because steps of fitting a kernel density estimation function, identifying fluorescence differences, and calculating intensity values that separate markers using the disclosed equation demonstrate the algorithm provides an improvement in cancer diagnosis.
At Step 2A Prong Two, claims determined to recite a judicial exception are further examined to determine whether they recite elements in addition to the abstract ideas which integrate the judicial exceptions into a practical application (MPEP 2106.04(d)), such as when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. Here, the algorithmic steps, determined to be part of the judicial exception at Step 2A Prong One, are asserted to provide the improvement. However, only elements in addition to the abstract ideas can provide the improvement. Therefore, one must focus on the elements in addition to the abstract ideas: providing the sample with certain biomarkers from certain sample types, incubating the sample, performing flow cytometry, obtaining signal intensities, and providing a biopsy. Given the alleged improvement lies in the algorithmic steps as disclosed in the instant remarks, most of these steps are data collecting steps to perform the algorithmic steps and thus insignificant extra-solution activity (MPEP 2106.05(g)). The biopsy step is not materially changed based on the dynamic fluorescence thresholding algorithm and thus is interpreted as instructions to apply the abstract idea (MPEP 2106.05(f)).
Applicant remarks state providing a biopsy as recited in claim 24 is an “affirmative treatment step” (pg. 11, second paragraph). However, providing a biopsy is not interpreted as a treatment, which is understood to be removal of tissue for further diagnostic testing. Prostate cancer, the condition being diagnosed by the algorithmic steps, is not being treated, and thus a particular treatment under MPEP 2106.05(d)(2) is not recited.
Therefore, the rejection under 35 USC 101 is maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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