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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 16 February 2026 has been entered.
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.
Withdrawn Objections and Rejections
The rejections under 35 USC 112(b) are withdrawn in view of amendment removing the unclear “such as” language and clarifying which sample is being subjected to microflow cytometry.
The following objections and rejections constitute the complete set of objections and rejections applied to the instant claims.
Claim Interpretation
Claim 1 recites recommending a biopsy when the probability score exceeds a threshold. The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met (MPEP 211.04(II)). Therefore, there is a circumstance in which the score does not exceed the threshold and therefore the biopsy is not recommended. Amendment to recite determining the score exceeds the threshold then recommending the biopsy where the score exceeds the threshold may obviate this interpretation.
Similarly, claim 14 recites “providing a prostate biopsy to the patient when the patient-specific probability score exceeds a predetermined threshold,” and there is a circumstance in which the score does not exceed the threshold and therefore the biopsy is not provided. Amendment to recite determining the score exceeds the threshold then providing the biopsy where the score exceeds the threshold may obviate this interpretation.
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, 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))?
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 when a score is exceeded.
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 exceeded is a non-limiting step because providing the biopsy is contingent on a score exceeding the threshold as explained in the Claims Interpretation section above.
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)), while providing a biopsy is not required in all circumstances due to being a contingent limitation. 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)). Additionally, the specification shows 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 16 February 2026 Applicant Remarks
Applicant remarks state the amendment reciting recommending a prostate biopsy for patients having a probability score exceeding a threshold integrates the abstract ideas into a practical application at Step 2A Prong Two of 101 analysis because it recites a particular treatment (procedure) for a particular population, and thus overcomes the rejection in view of MPEP 2106.04(d)(2) (remarks: pg. 10, last paragraph). This argument is not persuasive because recommending a treatment is not treatment, procedure, or intervention. A recommendation is an abstract step, and the biopsy is not required to be performed as active step as it is in claim 24.
Applicant asserts Example 43 is analogous to the instant claims (pg. 12, fourth paragraph). This is unpersuasive because Example 43 recites administering a treatment. The assertion that recommending can be interpreted the same as performing is unpersuasive as being tied to a procedure is not the same as performing the procedure. For similar reasons, applicant asserts analogy to Example 49 (pg. 13, second paragraph), which recites administering eye drops. Example 46, which recites monitoring a signal and automatically operating a gate are regarded as additional elements imposing meaningful limitations on the abstract ideas, whereas the instant claims’ recommendation is another abstract idea. Example 46 is indicated as reciting “the ‘particular treatment or prophylaxis’ consideration ‘requires the claim to affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition’” (pg. 13, last paragraph), but for reasons explained above effecting a treatment is an additional element whereas recommending a treatment is not. This passage in Example 46 can be found further explained in MPEP 2106.04(d)(2), which goes on to state that if the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. The recited treatment is not actually provided by way of the recommendation and thus cannot integrate a judicial exception under the "treatment or prophylaxis" consideration.
Applicant remarks assert the claims recite an improvement to the field of microflow cytometry for disease diagnosis in the form of processing steps (pg. 14, third paragraph), particularly the dynamic fluorescence thresholding algorithm (pg. 15, second paragraph). However, these are also abstract steps, and the improvement must be realized by elements in addition to the abstract ideas (MPEP 2106.04(d)). Disease diagnosis is not a technical field being improved, and the additional element steps of obtaining signal intensities using flow cytometry from biomarkers bound to extracellular vesicles are conventional, meaning they do not provide an improvement nor provide significantly more than the abstract steps (MPEP 2106.05).
Applicant remarks assert analogy to Rapid Litigation Management v. CellzDirect, Inc., 827 F.3d 1042, 119 USPQ2d 1370 (Fed. Cir. 2016), where the court found that a claimed process for
preserving hepatocytes was eligible as an improvement to technology because the claim achieved
a new and improved way for preserving hepatocyte cells for later use (pg. 15, last paragraph). This decision is not considered analogous to the instant claims because the improvement was directed to elements in addition to the abstract ideas – physical steps for preservation of cells – that provide the improvement and not an improvement in the abstract idea itself (MPEP 2106.05(a)(II). Here, the alleged improvement lies in the data processing and algorithmic steps, which are not realized by an element in addition the abstract ideas.
Therefore, for the reasons explained above, the rejection of claims 1-2, 5-6, 8-9, 11-17, and 22-24 under 35 USC 101 is maintained.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia M. Wise can be reached at (571) 272-2249. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Robert J. Kallal/Examiner, Art Unit 1685