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 .
Applicant's response filed 10/17/2025 has been fully considered. The following rejections
and/or objections are either reiterated or newly applied.
Status of Claims
Claims 1, 2, and 4-20 pending and examined on the merits.
Claim 3 canceled.
Priority
The instant application filed on 9/15/2021 is a 371 national stage entry of PCT/US20/22048 having an international filing date of 3/11/2020, and claims the benefit of priority to U.S. Provisional Patent Application No. 62/819,375 filed on 3/15/2019... Thus, the effective filing date of the claims is 9/15/2019.
The applicant is reminded that amendments to the claims and specification must comply with 35 U.S.C. § 120 and 37 C.F.R. § 1.121 to maintain priority to an earlier-filed application. Claim amendments may impact the effective filing date if new subject matter is introduced that lacks support in the originally filed disclosure. If an amendment adds limitations that were not adequately described in the parent application, the claim may no longer be entitled to the priority date of the earlier filing.
Claim Objections
The objections to claims 6 and 9 are withdrawn in view of Applicant's claim amendments.
Withdrawn Rejections
35 USC § 112(b)
The rejection of claim 3 under 35 USC 112(b) withdrawn because the claim has been canceled.
The rejection of claims 6 and 8 under 35 USC 112(b) withdrawn in view of Applicant's claim amendments.
The rejection of claims 1-20 under 35 USC 112(b) withdrawn in view of Applicant's claim amendments and arguments. Specifically, Applicant's amendments to claims 1, 16, and 20 render clear the metes and bounds of "contiguous" (Remarks 10/17/2025 Pages 1-3). Likewise, although the following limitation rejection seems to be argued under the response to 35 USC 112(a) on page 4 (Remarks 10/17/2025), "the screen definition identifies" wells, is now clear as well given the context provided on page 4, notably that the term "identifies" in this limitation is not an action, but a definition of "the screen definition" itself.
35 USC § 101
35 USC § 102
The rejection of claims [1] under 35 U.S.C. 102 is withdrawn in view of Applicant's claim
amendments.
35 USC § 103
The rejection of claims [1] under 35 U.S.C. 103 withdrawn in view of Applicant's claim amendments.
Double Patenting
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-15 and 20 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Regarding claims 1 and 20, "the screen comprises a cell-based assay that is run on a temporarily contiguous basis using a plurality of multi-well plates" is not enabled by the computer system disclosed. The computer system has no disclosed parts or features that are enabled for physical sample manipulation. To further prosecution, the limitation is interpreted as "the screen comprises obtaining measurements from a cell-based assay that is run using a plurality of multi-well plates".
Response to Arguments under 35 USC § 112
Applicant’s arguments filed 10/17/2025 are fully considered but they are not persuasive.
Applicant asserts that the amendments to claims 1 and 20 remedy the enablement rejection (Remarks 10/17/2025 Page 3). The examiner notes that the limitation starting at line 21, indicating that data regarding well contents is the topic, as opposed to "an aliquot of cells". However, the distinction between how Examiner interpreted the limitation and how it is amended is incongruent. Specifically, the interpretation is specifically calling out that there is a measurement (or data) obtained from an assay. The amended limitation still reads as "a cell-based assay that was obtained using…", i.e. the assay, not measurements or data, was obtained. Although Applicant argues that "no actual physical manipulation is being claimed as part of the computer system functionality", this is not reflected in the amended claim language because "an assay" is a wet lab procedure with physical manipulation steps. Therefore, the limitation is either not enabled to perform the steps of an assay, or the act of a computer system "obtaining" an assay (i.e. a wet lab procedure with physical manipulation steps) is nonsensical.
Therefore, the rejection of claims 1 and 20 maintained. Claims 2-15 depend from independent claim 1; therefore, their rejection is likewise maintained. Examiner notes that while the amendments to claims 5 and 7 do enable those specific limitations pointed out in the rejection, their rejection is maintained due to dependency on claim 1.
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of a mental process, a mathematical concept, organizing human activity, or a law of nature or natural phenomenon without significantly more. In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 1: “evaluating an effect of one or more perturbations on cells of a first cell type” provides an evaluation (evaluating an effect) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“forming a variability model based, at least in part, on all or a portion of a variance across the first plurality of control vectors” provides a mathematical relationship (forming a variability model) that is considered a mathematical concept, which is an abstract idea.
“the variability model is formed based on a variance across control vectors obtained from control wells that are spatially distributed across multiple multi-well plates to account for plate-to-plate variability, wherein the variability model is trained on control perturbations that are selected to have similar magnitudes of effects on non-disease related cellular features as the data perturbations have on disease related cellular features, and wherein the variability model normalizes for technical batch effects between multi-well plates while preserving biological effects of the perturbations” provides a mathematical calculation (forming/training a model involves many mathematical calculations, but specifically: normalizing, standardizing, or centering features embedded in the model as described in para.0034 of the instant specification, "the feature values embedded into the variability model are normalized, standardized, and/or centered based on feature measurements from a separate set of control states (e.g., that is specific to the multi-well plate from which the test state was located). The method then includes evaluating (108) one or more screening conditions (e.g., the effect of a perturbation and/or candidate therapeutic compound on a cellular context) within the mathematical space defined by the trained variability model"; and executing dimensionality reduction for components of the model as described on para.0061 "the variability model is a plurality of dimension reduction components") that is considered a mathematical concept, which is an abstract idea.
“embedding each data vector in the plurality of data vectors by applying the variability model” to obtain a set of values provides a mathematical calculation (calculating values with a model - "embedding data" interpreted as inputting data to the model) that is considered a mathematical concept, which is an abstract idea.
“using the set of variability model values and the corresponding data perturbation label of each data well in the plurality of data wells to resolve an effect of at least one data perturbation in the plurality of data perturbations on the first cell type” provides an evaluation (determining and effect) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“comparison of large experiments run over an extended period of time by creating a mathematical space in which variation within multi-dimensional phenotypic data is represented by a series of control experiments, thereby decoupling significance of individual phenotypes from test assays themselves such that the mathematical space can be recreated later without having to re-run all test assays again, enabling comparable statistical tests to be performed across different experiments” provides a comparison (comparing experimental data involves assessing similarities or differences between items) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claims 2-5: Depends on claim 1 which recites limitations that equate to an abstract idea.
Claim 6: “computing a first measure of central tendency for each respective feature in the plurality of features across each corresponding normalization vector in the plurality of normalization features vectors thereby forming a first plurality of measures of central tendency” provides a mathematical calculation (computing a first measure, computing is calculating) that is considered a mathematical concept, which is an abstract idea.
“subtracting a measured value for the respective feature by the first measure of central tendency corresponding to the respective feature and dividing the measured value for the respective feature by a standard deviation in measurement of the respective feature across the plurality of normalization vectors” provides a mathematical calculation (subtracting and dividing) that is considered a mathematical concept, which is an abstract idea.
Claim 7: Depends on claim 6 which recites limitations that equate to an abstract idea.
Claim 8: “computing a second measure of central tendency for each respective dimension reduction component in the plurality of dimension reduction components across each corresponding dimension reduction normalization vector in the plurality of dimension reduction normalization vectors thereby forming a plurality of second measures of central tendency” provides a mathematical calculation (computing a second measure, computing is calculating) that is considered a mathematical concept, which is an abstract idea.
“subtracting a measured value for the respective dimension reduction component by the second measure of central tendency corresponding to the respective dimension reduction component across the plurality of dimension reduction normalization vectors” provides a mathematical calculation (subtracting) that is considered a mathematical concept, which is an abstract idea.
Claims 9 and 17: “pruning the plurality of features by removing from the plurality of features each feature in the plurality of features that fails to satisfy a complexity threshold across the first plurality of control vectors” provides an evaluation (pruning features based on a threshold) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 10: “the plurality of dimension reduction components account for at least ninety percent of the variance of the plurality of features across the first plurality of control vectors” provides a mathematical calculation (accounting a sum of variance) that is considered a mathematical concept, which is an abstract idea.
Claim 11: “the plurality of dimension reduction components account for at least ninety-nine percent of the variance of the plurality of features across the first plurality of control vectors” provides a mathematical calculation (accounting a sum of variance) that is considered a mathematical concept, which is an abstract idea.
Claims 12 and 19: “applying principal component analysis to the plurality of features across the first plurality of control vectors” provides a mathematical calculation (applying PCA necessitates calculations) that is considered a mathematical concept, which is an abstract idea.
Claim 13: “transforms in accordance with a feature transform lookup table, of the measurement of the respective feature in the respective control well” and “a transform, selected from among a set of transforms in accordance with the feature transform lookup table, of the measurement of the respective feature in the respective data well” provides an evaluation (determining a transform from a lookup table) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 14: Depends on claim 1 which recites limitations that equate to an abstract idea.
Claim 15: Depends on claim 1 which recites limitations that equate to an abstract idea.
Claims 16 and 20: “evaluating an effect of one or more perturbations on cells of a first cell type” provides an evaluation (evaluating an effect) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“the screen definition identifies a first plurality of control wells and a plurality of data wells in the plurality of multi-well plates” provides an evaluation (identifying wells) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“forming a variability model based, at least in part, on all or a portion of a variance across the first plurality of control vectors” provides a mathematical relationship (forming a variability model) that is considered a mathematical concept, which is an abstract idea.
“the variability model is formed based on a variance across control vectors obtained from control wells that are spatially distributed across multiple multi-well plates to account for plate-to-plate variability, wherein the variability model is trained on control perturbations that are selected to have similar magnitudes of effects on non-disease related cellular features as the data perturbations have on disease related cellular features, and wherein the variability model normalizes for technical batch effects between multi-well plates while preserving biological effects of the perturbations” provides a mathematical calculation (forming/training a model involves many mathematical calculations, but specifically: normalizing, standardizing, or centering features embedded in the model as described in para.0034 of the instant specification, "the feature values embedded into the variability model are normalized, standardized, and/or centered based on feature measurements from a separate set of control states (e.g., that is specific to the multi-well plate from which the test state was located). The method then includes evaluating (108) one or more screening conditions (e.g., the effect of a perturbation and/or candidate therapeutic compound on a cellular context) within the mathematical space defined by the trained variability model"; and executing dimensionality reduction for components of the model as described on para.0061 "the variability model is a plurality of dimension reduction components") that is considered a mathematical concept, which is an abstract idea.
“embedding each data vector in the plurality of data vectors onto the variability model” to obtain a set of values provides a mathematical calculation (calculating values with a model - "embedding data" interpreted as inputting data to the model) that is considered a mathematical concept, which is an abstract idea.
“using the set of variability model values and the corresponding data perturbation label of each data well in the plurality of data wells to resolve an effect of at least one data perturbation in the plurality of data perturbations on the first cell type” provides an evaluation (determining and effect) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“comparison of large experiments run over an extended period of time by creating a mathematical space in which variation within multi-dimensional phenotypic data is represented by a series of control experiments, thereby decoupling significance of individual phenotypes from test assays themselves such that the mathematical space can be recreated later without having to re-run all test assays again, enabling comparable statistical tests to be performed across different experiments” provides a comparison (comparing experimental data involves assessing similarities or differences between items) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 18: “a different feature in the plurality of features arises as a result of a convolution or a series convolutions and pooling operators run against native pixel values in the corresponding plurality of native pixel values of the corresponding two-dimensional pixelated image” provides a mathematical calculation (running mixing operators on imaging data) that is considered a mathematical concept, which is an abstract idea.
These recitations are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d
1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or are mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. Additionally, while claims 1-15 and 20 recite performing some aspects of the analysis on “A computer system for evaluating an effect of one or more perturbations on cells of a first cell type, the computer system comprising: [] programs including instructions” and “A non-transitory computer readable storage medium and one or more computer programs embedded therein for evaluating an effect of one or more perturbations on cells of a first cell type, the one or more computer programs comprising instructions which, when executed by a computer system, cause the computer system to perform a method”, there are no additional limitations that indicate that this requires anything other than carrying out the recited mental processes or mathematical concepts in a generic computer environment. Merely reciting that a mental process is being performed in a generic computer environment does not preclude the steps from being performed practically in the human mind or with pen and paper as claimed. If a claim limitation, under its broadest reasonable interpretation, covers performance of the limitation in the mind but for the recitation of generic computer components, then it falls within the “Mental processes” grouping of abstract ideas. As such, claims 1-20 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exceptions listed above are not integrated into a practical application because the claims do not recite an additional element or elements that reflects an improvement to technology. Specifically, the claims recite the following additional elements:
Claims 1 and 20: “the screen comprises a cell-based assay that was obtained using a plurality of multi-well plates which were run contiguously with one another” provides insignificant extra-solution activities (obtaining data is a pre-solution activity involving data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
“each respective control well in the first plurality of control wells is labeled with a control perturbation label corresponding to a control perturbation in a first plurality of control perturbations that is independently included in the respective control well” and “each respective data well in the plurality of data wells is labeled with a data perturbation label corresponding to a data perturbation in a plurality of data perturbations that is independently included in the respective data well” provides insignificant extra-solution activities (labeling wells is a pre-solution activity involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
“data indicates a presence of cells of the first cell type in each control well in the first plurality of control wells and in each data well in the plurality of data wells” provides insignificant extra-solution activities (obtaining locations is a pre-solution activity involving data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
“obtaining a first plurality of control vectors”, “obtaining a first plurality of data vectors”, and “obtaining a set of variability model values for each data vector in the plurality of data vectors” provides insignificant extra-solution activities (obtaining vector data and variability model values are a pre-solution activities involving data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 5: “each respective control well in the second plurality of control wells is labeled with a control perturbation label corresponding to a control perturbation in a second plurality of control perturbations that is independently included in the respective control well and the second plurality of control wells collectively represents each control perturbation in the second plurality of control perturbations” provides insignificant extra-solution activities (labeling wells is a pre-solution activity involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
“obtaining a plurality of normalization vectors” provides insignificant extra-solution activities (obtaining vector data is a pre-solution activity involving data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
“use the plurality of normalization vectors to normalize a set of data wells in the plurality of data wells that are in the respective multi-well plate prior to the obtaining the screen definition for the screen” provides insignificant extra-solution activities (normalizing data is a pre-solution activity involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 7: “obtaining a plurality of dimension reduction normalization vectors” provides insignificant extra-solution activities (obtaining vector data is a pre-solution activity involving data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
“using the plurality of dimension reduction normalization vectors to standardize the set of data wells in the plurality of data wells that are in the respective multi-well plate prior to the computing” provides insignificant extra-solution activities (normalizing data is a pre-solution activity involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 16: “the screen comprises a cell-based assay that was obtained using a plurality of multi-well plates which were run contiguously with one another” provides insignificant extra-solution activities (running samples is a pre-solution activity involving sample manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
“each respective control well in the first plurality of control wells is labeled with a control perturbation label corresponding to a control perturbation in a first plurality of control perturbations that is independently included in the respective control well” and “each respective data well in the plurality of data wells is labeled with a data perturbation label corresponding to a data perturbation in a plurality of data perturbations that is independently included in the respective data well” provides insignificant extra-solution activities (labeling wells is a pre-solution activity involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
“data indicates a presence of cells of the first cell type in each control well in the first plurality of control wells and in each data well in the plurality of data wells” provides insignificant extra-solution activities (adding cells to wells is a pre-solution activity involving sample manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
“obtaining a first plurality of control vectors”, “obtaining a first plurality of data vectors”, and “obtaining a set of variability model values for each data vector in the plurality of data vectors” provides insignificant extra-solution activities (obtaining vector data and variability model values are a pre-solution activities involving data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 18: “imaging a corresponding well” provides insignificant extra-solution activities (imaging to collect data and running mixing operators on imaging data are a pre-solution activities involving data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
The steps for obtaining data, well locations, and images; labeling well and normalizing data; and adding cells to wells and executing sample runs are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application because they are pre- and post-solution activities involving data gathering, data manipulation, and sample manipulation steps (see MPEP 2106.04(d)(2)). Furthermore, the limitations regarding implementing program instructions do not indicate that they require anything other than mere instructions to implement the abstract idea in a generic way or in a generic computing environment. As such, this limitation equates to mere instructions to implement the abstract idea on a generic computer that the courts have stated does not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. Therefore, claims 1-20 are directed to an abstract idea (Step 2A, Prong 2: NO).
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). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application, or equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment.
As discussed above, there are no additional elements to indicate that the claimed “computer system comprising: one or more processors; a memory; and one or more programs, wherein the one or more programs are stored in the memory and are configured to be executed by the one or more processors, the one or more programs including instructions” nor “computer programs comprising instructions which, when executed by a computer system, cause the computer system to perform a method” requires anything other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. MPEP 2106.05(f) discloses that mere instructions to apply the judicial exception cannot provide an inventive concept to the claims. Additionally, the limitations for obtaining data, well locations, and images; labeling well and normalizing data; and adding cells to wells and executing sample runs are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application. Furthermore, no inventive concept is claimed by these limitations as they are demonstrated by the application’s specification to be well-understood, routine, and conventional: para.0003 “High throughput screening (HTS) is a process used in pharmaceutical drug discovery to test large compound libraries containing thousands to millions of compounds for various biological effects. HTS typically uses robotics, such as liquid handlers and automated imaging devices, to conduct tens of thousands to tens of millions of assays, e.g., biochemical, genetic, and/or phenotypical, on the large compound libraries in multi-well plates, e.g., 96-well, 384-well, 1536-well, or 3456-well plates. In this fashion, lead-compounds that provide a desired biochemical, genetic, or phenotypic effect can be quickly identified from the large compound libraries, for further testing and development towards the goal of discovering a new pharmaceutical agent for disease treatment. For a review of basic HTS methodologies see, for example, Wildey et al., 2017, “Chapter Five—High-Throughput Screening,” Annual Reports in Medicinal Chemistry, Academic Press, 50:149-95, which is hereby incorporated by reference.” Ling et al. (US- 20010044129) reinforces the assertion that no inventive concept is claimed by these limitations as they are well-understood, routine, and conventional: para.0009 "Laser scanning fluorescent microscopy, as a chemical imaging technique, has been routinely used for in vitro sample analysis for many years." Finally, Bray et al. (Bray MA, Carpenter A; Imaging Platform, Broad Institute of MIT and Harvard. Advanced Assay Development Guidelines for Image-Based High Content Screening and Analysis. 2017 Jul 8. In: Markossian S, Grossman A, Baskir H, et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK126174/) also reinforces the assertion that no inventive concept is claimed by these limitations as they are well-understood, routine, and conventional: Page 2 paragraph 5 "Unfortunately, this practice renders the assay susceptible to the well-known problem of plate-based edge effects, which lead to over- or under-estimation of cellular responses when normalizing by the control wells."
The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-20 are not patent eligible.
Response to Arguments under 35 USC § 101
Applicant’s arguments filed 10/17/2025 are fully considered but they are not persuasive.
Applicant asserts that the amendments to claims 1, 16, and 20 now recite patent eligible subject matter in the form of a practical application, specifically citing an improvement to the functioning and capabilities of automated high-throughput screening systems by allowing experiments to be compared across time without re-running controls (Remarks 10/17/2025 Page 5-6). The Examiner has indicated above that these amendments provide mathematical concepts and mental processes which are both abstract ideas. Additionally, the additional elements remain insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application. Furthermore, no inventive concept is claimed by this amendment as parameter adjustments are well-understood, routine, and conventional, as indicated above.
Applicant also asserts that the recent decision in application 16/319,040) by the Mr. Squires renders the judicial exceptions recited throughout the claims (indicated above) as no longer being directed to abstract ideas because they are "an improvement to other technology or technical field" and therefore are patent eligible. Examiner again notes that the additional elements remain insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application. Furthermore, no inventive concept is claimed by this amendment as parameter adjustments are well-understood, routine, and conventional, as indicated above.
The Examiner also notes that MPEP 2106(I) states that if the claims are directed to a judicial exception, the second part of the Mayo test is to determine whether the claim recites additional elements that amount to significantly more than the judicial exception. Id. citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966). In the “search for an ‘inventive concept’” (the second part of the Alice/Mayo test), the additional elements identified do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception because the steps for obtaining data, well locations, and images; labeling well and normalizing data; and adding cells to wells and executing sample runs (pre- and post-solution activities involving data gathering, data manipulation, and sample manipulation steps) are all well-understood, routine, and conventional techniques that are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application. Therefore, combining insignificant extra-solution activities with any of the identified judicial exceptions would not result in patent eligible subject matter because integrating well-understood, routine, and conventional techniques does not yield “significantly more” to a mental process, a mathematical concept, organizing human activity, or a law of nature or natural phenomenon.
Therefore, the rejection of claims 1-20 is maintained. All other claims depend from these independent claims; therefore, their rejection is likewise maintained.
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.
Claims 1-9, 13, 15-17, 19, and 20 rejected under 35 U.S.C. 103 as being unpatentable over Cohen et al. (US-20170292961) in view of Becker et al. (Becker, A.-K.; Erfle, H.; Gunkel, M.; Beil, N.; Kaderali, L.; Starkuviene, V. Comparison of Cell Arrays and Multi-Well Plates in Microscopy-Based Screening. High-Throughput 2018, 7, 13. https://doi.org/10.3390/ht7020013), and Mhaskar et al. (Mhaskar et al. Modeling and control of batch processes. London, UK: Springer, 2015).
Regarding claims 1, 16, and 20, Cohen teaches evaluating an effect of one or more perturbations on cells (Para.0346 "Methods of the invention may be used to evaluate the effects of compounds on neurons.").
Cohen provides for obtaining measurements from a cell-based assay that is run on subsets of samples (Para.0283 "The subsets are exposed to stimuli and detectable signals are recorded.").
Cohen provides for identifying a first plurality of controls (Para.0108 "In certain embodiments, control cells are obtained from healthy individuals, i.e., without using genome editing on cells taken from the subject.").
Cohen provides for labeling control and sample wells with the performed perturbation (Para.0016 "Libraries of numerous agents are applied to comprehensively identify and characterize their effects on electrical or chemical communication between cells. In addition, cluster or subsets within the array can also include cells from various organs to characterize an agent's impact over a wide variety of cells. Compounds may be screened in combination with other drug agents to construct interference profiles").
Cohen provides for obtaining the location of the first cell type in each control well in the first plurality of control wells and in each sample well in the plurality of sample wells (Para.0281 "After experimentation, the overlying medium can be analyzed for overall metabolism of the test material and the individual cell types can be processed for the quantification of associated test material to evaluate possible organ-specific bioaccumulation, evaluation of cell viability for cytotoxicity, and evaluation of efficacy.").
Cohen also provides for obtaining measurements from control and sample subsets (Para.0283 "The subsets are exposed to stimuli and detectable signals are recorded.").
Cohen does not explicitly teach running assays using multiple multi-well plates, building a variability model based on variance across control sample measurements, obtaining a set of variability values for each measurement data set, nor using the model to determine an effect of a perturbation on cell type. Cohen also does not explicitly teach measuring variability between multiple multi-well plates or comparing this variability.
However, Becker teaches running assays using multiple multi-well plates (Page 2 paragraph 2 "One of the major drawbacks of multi-well plates is that only middle scale of samples (24, 96 or 384 samples) can be analysed in one experiment. Plates with 1536- and 3456-wells are suitable to intact-cell-based screening only to a limited exten[t] due to difficulties in cultivating cells and handling small amounts of the liquids in such formats. As a result, many plates need to be used when performing genome-scale screens.").
Becker also provides building a variability model based on variance across control sample measurements (Page 11 Discussion, paragraph 2 "achieve the same standard error for arrays as for multi-well plates, we would need replicates, where Var.sub.a and Var.sub.w denote the variances of the data of the cell arrays and multi-well plates, respectively and n.sub.w is the number of replicates used for of multi-well plates. Therefore, the multiplication factor is the quotient of the variances. As the variance was constantly higher on the cell arrays in the cell cycle progression assay, more replicates are recommended.")
Becker provides obtaining a set of variability values for each measurement data set and using the model to determine an effect of a perturbation on cell type (Page 5 section 2.8 "We used one-way analysis of variance (ANOVA) to test for statistical differences between means of different groups, taking unequal variances into account (oneway.test from R stats package)").
Becker also suggests that multiple multi-well plate measurement variability is a potential issue (page 2 paragraph 2 "This increases time and costs of the experiment, and the variability of measurements due to between-plate-effects"), and that comparing standard errors is a way to describe how robust mean values of phenotypes are (i.e. repeatability of a biological effect) (page 11 last paragraph "To address this question, we compared standard errors on both platforms. The standard error is a measure of precision of the estimator of a mean, hence here describes how robust the mean values of the phenotypes on the two platforms are").
Becker nor Cohen teach or suggest training a model on control perturbations for addressing variability of batch-effects.
However, Mhaskar teaches training neural network models on measurements of perturbed batch processes in order to control for between batch variability (Page 29 paragraph 2 "In [20, 21], neural networks are used to identify a dynamic model. One of the most commonly studied approaches in the literature is the application of latent variable methods and in particular principal component analysis (PCA). In these approaches, the correlation between subsequent measurements is employed to describe the evolution of the process [22–25]. As with more traditional trajectory tracking approaches, the drawback of all trajectory tracking approaches is that the relationship between the controlled variable and quality may change. The solution is to apply direct quality control" and page 224 section 11.5.1 "Next, perturbations (e.g., by PRBS) are made to the inputs over some duration of time. These inputs and the corresponding outputs form a contiguous block of data. The appropriate Hankel matrices for a given subspace identification algorithm can be readily formed from this contiguous block of data in the manner presented in the preliminary section. In contrast to continuous processes, batch processes, by their very definition, do not possess meaningful steady-state conditions around which to identify a model. Instead, the objective is to develop a model for the transient dynamic behavior of the process. To achieve this, the entire range of dynamic behavior for which a model is desired must be present in the training data. This can be partially accomplished by using data from the complete duration of a batch. However, owing to the variation in initial conditions, it is unlikely that any single batch (even with experimental augmentation) would cover the range of operating conditions necessary to build a reliable, general model. This motivates the need to include multiple batches in the training data. However, since each batch is independent of the batches before or after it, this results in a database with multiple contiguous blocks of data rather than one single contiguous block. One approach would be to build separate Hankel matrices for each of these blocks and then modify the chosen subspace identification algorithm to incorporate the multiple batches").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Cohen as taught by Becker for reducing variability between samples by having a larger number of cells in each well compared to other methods (Page 1 Abstract "The measurements of cell cycle progression were less variable in multi-well plates. The result can largely be attributed to higher cell numbers resulting in less data variability when dealing with the assay generating phenotypic cell subpopulations."). One skilled in the art would have a reasonable expectation of success because both approaches are using a cell-based assay.
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Cohen and Becker as taught by Mhaskar in order to improve batch-like processes by controlling variability (page 27 section 1.1 Motivation "Competitive economic conditions have compelled the manufacturing industries in most industrialized countries to pursue improved economic margins through the production of low volume, higher-value-added specialty chemicals and materials, such as advanced alloys, polymers, herbicides, insecticides, pharmaceuticals, and biochemicals, that are manufactured predominantly in batch processes. Moreover, startups and shutdowns (that are batch-like processes) are an integral constituent of almost every process operation. The operation of these processes, however, has to grapple with several challenges, such as the lack of online sensors for measuring critical process variables, the finite duration of the process operation, the presence of significant nonlinear dynamics (due to a predominantly transient operation), and rejecting raw material variability. Modeling and control of these batch and batch-like processes are therefore essential to ensure their safe and reliable function, and to guarantee that they produce consistent and high-quality products or, in the case of startup operation, transit smoothly to continuous operation. Batch process operation, however, differs from operation around equilibrium points, both in the model identification aspects and in the control design. Motivated by the above, this book presents batch-specific modeling and control approaches along with their application to nonlinear process systems"). One skilled in the art would have a reasonable expectation of success because both methods are utilizing batch or batch-like processes with a need for controlling batch-to-batch variability.
Regarding claim 2, Cohen teaches subsets of control and sample wells that are distinct (Para.0283 "The plurality of subsets is exposed to an agent, or a combination of agents. The subsets are exposed to stimuli and detectable signals are recorded. Evaluation of the two signals allows for characterization of the agent on the various subsets, allowing for a comprehensive analysis of the agent. It should be appreciated that this example is only demonstrative; other combinations of agents, subsets, measurement parameters, etc. can be employed.").
Regarding claim 3, Cohen teaches the first and second plurality of control wells consists of between 200 and 1500 control wells (Para.0252 "In some embodiments of the invention, a cell or a cell subset is contained within a well or a multi-well plate or substrate. The multi-well plate or substrate may contain 96, 384, 1536, or 3456 wells").
Regarding claim 4, Becker teaches each control perturbation in the first plurality of control perturbations is a different siRNA (Pages 9-10, last and first paragraph, respectively "One well/siRNA was coated and 25 images/well acquired (Table S6). Collectively, 75 images from one plate were used to assess the RNAi-mediated changes. Higher cell numbers were imaged in this set-up: nearly 2500 cells/well/siRNA/replica were collected."
Regarding claim 5, the locating of cell aliquots, control, and sample wells, and labeling or identifying them as such is taught by Cohen above. Cohen also teaches normalizing a set of sample wells (Para.0219 "For individual cells, the sub-cellular details of action potential propagation can be represented by the timing at which an interpolated action potential crosses a threshold at each pixel in the image. Identifying the wavefront propagation may be aided by first processing the data to remove noise, normalize signals, improve SNR, other pre-processing steps, or combinations thereof").
Regarding claim 6, Cohen teaches computing a measure of central tendency (Para.0234 "In certain embodiments, the imaging methods are applied to obtain a signature mean probability of spike for cells from a subject and may also be used to obtain a signature from a control line of cells such as a wild-type control").
Cohen also teaches applying a measure of central tendency involving division by standard deviation, interpreted here as being a z-score (Para.0271 "Methods of the invention may incorporat