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 .
Election/Restriction
Applicant's election with traverse of Group II (claims 20 and 21) in the reply filed on 05/01/2026 is acknowledged. Applicant’s arguments have been fully considered but are not persuasive for reasons set forth in the Restriction Requirement and in view of applicant’s amendments and cancelled claims. Furthermore, Applicant has not submitted any evidence showing the inventions to be obvious variants or clearly admitting on the record that this is the case.
Applicant's election with traverse of Species A (claim 7) in the reply filed on 05/01/2026, is acknowledged. Applicant’s arguments have been fully considered but are not persuasive for reasons set forth in the Restriction Requirement and in view of applicant’s amendments and cancelled claims. Furthermore, Applicant has not submitted any evidence showing the inventions to be obvious variants or clearly admitting on the record that this is the case.
Accordingly, claim(s) 1-4, 7-9, 11, 12, 14, 17, 24, 29, 28, 29, 32-34 is/are hereby withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. The requirement is still deemed proper and is therefore made FINAL.
Status of Claims
Claims 20, 21, and newly added claims 37-51 are under examination.
Claims 28 and 29 are withdrawn.
Claims 1-4, 7-9, 11, 12, 14, 17, 22-27 and 30-36 are cancelled.
Priority
This application includes a claim of priority under 35 U.S.C. §119(e) to U.S. provisional patent application No. 62/905,980, filed September 25, 2019.
Information Disclosure Statement
The two (2) information disclosure statement (IDS) documents submitted are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS document(s) has/have been fully considered by the examiner.
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 20, 21, and 37-51 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and ‘as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355).
Guidance: Step 1.
Under the broadest reasonable interpretation, the claimed invention (claim 20 being representative) is directed to a method for profiling a tumor microenvironment and therefore falls within one of the four statutory categories.
A. Guidance Step 2A, Prong 1
The Revised Guidance instructs us first to determine whether any judicial exception to patent eligibility is recited in the claim. The Revised Guidance identifies three judicially-excepted groupings identified by the courts as abstract ideas: (1) mathematical concepts, (2) certain methods of organizing human behavior such as fundamental economic practices, and (3) mental processes. In this case, the following steps encompass an abstract idea for the reasons set forth below:
performing complex spatial analysis on the IMC image of the tumor sample by a process comprising: identifying one or more phenotypic clusters of cells relative to an index cell in the tumor sample based on the IMC image, wherein each phenotypic cluster comprises two or more neighboring cells of a same phenotype; and
measuring a marker intensity of each phenotypic cluster of cells from the IMC image.
Mental Processes
With regards to said performing, this step is recited at a high level of generality (without any technological details directed to how it is performed) and does not explicitly require a computer. In addition, scientists routinely perform complex analysis and/or clustering of data. As such, this step encompasses a mental process of observing data, performing analysis, and making a judgement. MPEP 2106.04(a)(2), section III.
With regards to measuring, this step is recited at a high level of generality (without any technological details or rules directed to how it is performed) and does not explicitly require a computer. In addition, scientists routinely perform measurements or estimations of intensities in images. As such, this step encompasses a mental process of observing data, performing analysis, and making a judgement. MPEP 2106.04(a)(2), section III.
It is important to note that a claim to “collecting information, analyzing it, and displaying certain results of the collection and analysis,” where the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016). [Step 2A, Prong 1: YES].
Mathematical Concept
With regards to performing complex spatial analysis (by identifying clusters), a review of the specification teaches performing Z-score calculations to achieve this function [0011]. Accordingly, when read in light of the specification, this step also encompasses a mathematical concept of manipulating information through mathematical correlations or calculations. MPEP 2106.04(a)(2) Section I. It is important to note that a mathematical concept need not be expressed in mathematical symbols, because “[w]ords used in a claim operating on data to solve a problem can serve the same purpose as a formula.” In re Grams, 888 F.2d 835, 837 and n.1, 12 USPQ2d 1824, 1826 and n.1 (Fed. Cir. 1989). See, e.g., SAP America, Inc. v. InvestPic, LLC, 898 F.3d 1161, 1163, 127 USPQ2d 1597, 1599 (Fed. Cir. 2018) (holding that claims to a ‘‘series of mathematical calculations based on selected information’’ are directed to abstract ideas). See also Digitech Image Techs., LLC v. Electronics for Imaging, Inc., 758 F.3d 1344, 1350, 111 USPQ2d 1717, 1721 (Fed. Cir. 2014)[Step 2A, Prong 1: YES].
B. Guidance Step 2A, Prong 2
Having made that determination, under the 2019 Guidance, the examiner next determines whether there are additional elements beyond the recited abstract idea(s) that integrate them into a practical application. In this case, the additional steps/elements that are not part of the abstract idea are as follows:
performing imaging mass cytometry (IMC) on a tumor sample from a subject in need thereof, thereby obtaining imaging mass cytometry data to generate an IMC image of the tumor sample;
With regards to performing imaging mass cytometry, this step is recited at a high level of generality and results in gathering data for use by the abstract idea. Accordingly, this step amounts to insignificant extra-solution activity and is not indicative of an integration into a practical application. See MPEP 2106.05(g). In summary, the claimed invention does not provide any objective evidence of an improvement to the technology, nor does the specification explain the details of an unconventional technical solution expressed in the claim, or identify technical improvements realized by the claim over the prior art. See MPEP 2106.04(d)(1) and MPEP 2106.05(a). Therefore, even when viewed in combination, these additional steps/elements do not integrate the recited judicial exception into a practical application. [Step 2A, Prong 2: NO].
C. Guidance Step 2B:
This part of the eligibility analysis evaluates whether the claim as a whole amount to significantly more than the recited exception i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. See MPEP 2106.05.
As discussed above, the non-abstract steps/elements amount to nothing more than insignificant extra-solution activity. Moreover, Chang et al. (Cytometry Part A, 2017, 91A, pp. 160-169) teaches methods and systems for performing imaging mass cytometry (IMC) to analyze cells from tissue samples [Abstract]. Therefore, even upon reconsideration, there is nothing unconventional with regards to the above non-abstract elements/steps. See MPEP 2106.05(d)(Part II). Thus, the independent claim(s) as a whole do not amount to significantly more than the exception itself. Therefore, the claim(s) is/are not patent eligible. [Step 2B: NO].
Dependent Claims
Dependent claims 21, and 37-51, have also been considered under the two-part analysis but do not include additional steps/elements appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception(s) for the following reasons. Regarding claims 221, and 37-51, these claims further limit the specificity of the abstract idea or the nature of the data being used and therefore are not patent eligible for reasons set forth above (Step 2A, prong 1). Therefore, the claims as a whole are not patent eligible.
Claim rejections - 35 USC § 112, 2nd Paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 20, 21, 37-51 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. Claims that depend directly or indirectly from claim(s) 20 are also rejected due to said dependency.
Claim 20 recites “performing complex spatial analysis on the IMC image of the tumor sample by a process comprising: identifying one or more phenotypic clusters of cells relative to an index cell in the tumor sample based on the IMC image, wherein each phenotypic cluster comprises two or more neighboring cells of a same phenotype; and measuring a marker intensity…”. In this case, it is unclear as to the metes and bounds of “complex spatial analysis”, as merely identifying clusters and measuring markers different functions that have nothing to do with “complex spatial analysis, per se. A review of the specification does not provide any limiting definition or example that would serve to clarify the scope. As a result, it is also unclear what computational techniques are included or excluded by “complex spatial analysis” such that one of ordinary skill in the art would know how to avoid infringement. Clarification is requested via amendment.
Claim 20 recites the terms “phenotypic clusters” and an “index cell”. It is unclear as to the metes and bounds of these terms such that the artisan would recognize what limiting effect is intended. In other words, what are the observable characteristics associated with “phenotypic clusters” and an “index cell” (e.g. size, shape, structure, physiological function, etc.) such that that artisan would know how to avoid infringement. A review of the specification does not provide any limiting definition that would serve to clarify the scope. As such, these limitations appear to be nothing more than highly stylized language or hollow field-of-use limitations. Clarification is requested via amendment.
Claim 20 recites “measuring a marker intensity of each…cluster of cells.” In this case, there are not previous steps that introduce or require the use of markers or marker intensities and such intensities are not inherently part of the IMC image as claimed. While the artisan would recognize that IMC does make use of cells labelled with antibodies or probes and scanned by lasers, for example, no such limitations are being claimed and it is improper to import narrowing limitations from the specification into the claims. MPEP 2111.01. Accordingly, there is lack of antecedent basis for “a marker intensity”, as claimed. Clarification is requested via amendment.
Claim 42 recites “identifying a first, tumor-core-immune-desert zone which comprises a phenotypic cluster whose centroid distance to the index cell is no less than a first threshold or the farthest in all clusters…”. It is unclear as to the metes and bounds of a “tumor-core-immune-desert zone” such that the artisan would recognize what limiting effect is intended. A review of the specification does not provide any limiting definition that would serve to clarify the scope. Clarification is requested via amendment.
Claim 43 recites “first threshold is 40 pm, 41 pm, 42 pm, 43pm,…”. It is unclear what metric is intended by the term “pm”. A review of the specification does not provide any limiting definition that would serve to clarify the scope. Clarification is requested via amendment.
Claim 49 recites “…markers according to Table 2.” The claim is indefinite because it refers to tables and/or figures in the specification. In this case, the genes associated with the recited tables can be readily incorporated into the claim, therefore reference to the specification is improper. See MPEP 2173.05(s), which states: “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993).” Accordingly, correction is requested via amendment.
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.
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 20, 21, 37-41, 47-51 are rejected under 35 U.S.C. 103 as being unpatentable over Sarachan et al. (US20170091527; Pub. Date: 04/04/2017) in view of Chang et al. (Cytometry Part A, 2017, 91A, pp. 160-169).
Regarding claim(s) 20, Sarachan teaches methods for determining heterogeneity of cell populations in a biological sample. In particular, Sarachan teaches generating (i.e. receiving) image data of a biological sample comprising a plurality of cells, wherein the image data is representative of expression of a plurality of biomarkers and wherein samples include tumor samples [ref. claim 1; ¶0027; ¶0028, ¶0047, ¶0053; Figure 15]. Sarachan does not specifically teach performing imaging mass cytometry (IMC), as claimed.
However, Chang teaches methods and systems for performing imaging mass cytometry (IMC) to analyze cells from tissue samples [Abstract]. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Sarachan by performing IMC, as taught by Chang, since Sarachan teaches using any suitable imaging modalities that include an imager for detecting fluorescent or light microscopy signals and converting them to data for downstream processing [0028]. The rationale would have been the predictable use of prior art elements according to their established functions. KSR, 550, U.S. at 417.
Sarachan teaches performing spatial analysis of the image data to assess how cells are different from their neighbors, identify clusters using distance thresholds, and determine spatial heterogeneity metrics [0035, 0036, 0038, 0039; ref. claims 3-6]. Sarachan does not specifically teach identifying phenotypic clusters “relative to an index cell” in the tumor sample, as claimed. However, Sarachan makes obvious this feature since they their spatial analysis process includes identifying a “selected cell” (i.e. index) and count clusters [Figure 4] or, alternatively, using clustering algorithms to divide the cells in an image into a set of “groups” that are more similar to each when compared to features of cells in other groups (i.e. indexes) [0038].
Sarachan teaches measuring a marker intensity of clusters of cells (i.e. phenotypic cluster of cells) [0004, 0033, 0041, 0042]; processing images to identify biomarker expression levels (i.e. intensity levels) [ref. claim 1]; and providing intensity values and cell profiles [0033], which broadly reads on measuring marker intensity given the breadth of what is claimed. Alternatively, Chang teaches software for mapping data for each cell directly onto the tissue sections to determine marker intensity, intensity statistics within compartments, morphology parameters such as size and shape, spatial correlates, and contextual parameters such as epithelium versus stroma [page 163-64, “Data Analysis and Quatitation”]. Therefore, in the later case, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Sarachan by measuring marker intensity, since Sarachan suggests at a minimum suggests such limitations, as discussed above, and since Chang explicitly teaches methods for determining marker intensity. The rationale would have been the predictable use of prior art elements according to their established functions. KSR, 550, U.S. at 417.
Regarding dependent claims 22, 37-51, the combination of Sarachan and Chang teach or suggest all aspects of these claims for the following reasons.
Regarding claim(s) 21, Sarachan teaches a plurality of different tissue samples include colorectal cancer [0054].
Regarding claim(s) 37, 38, 39, Sarachan teaches clusters that include cancer cells and proteins, small molecules, or antigens (i.e. cells associated with immunity) [0028, 0054, 0066]. Chang additionally teaches using functional markers and antibody conjugates against intracellular markers can be used for IMC [page 161, 162].
Regarding claim(s) 40, 41, Sarachan teaches spatial analysis that includes determining distances between all cells of the particular type within the sample (or FOV), e.g. by using Euclidean distances, normalized distaces, or Euclidean Minimum Spanning Tree (EMST) to connect the centroids of cells of a given type [0043, 0064, 0065] and calculating metrics for each cell including each cells centroid x and y location and cell areas [0054].
Regarding claim(s) 47, Sarachan does not specifically teach that two or more neighboring cells comprise 5-10, 11-15, 16-20, 21-25, or 26-30 neighboring cells, each being adjacent to at least one other cell in the cluster, and the process of complex spatial analysis identifies 2-4, 5-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, or 46-50 different phenotypic clusters of cells in the tumor sample, as claimed. However, the number of cells in a cluster or how many are identified is nothing more than a design choice that does not change the function of the claimed process steps, as claimed, and Applicant has not disclosed that this particular feature provides an advantage, is used for a particular purpose, or solves a stated problem. Moreover, Sarachan clearly teaches determining multiple clusters in samples wherein a plurality of adjacent to each other [ref. claim 4; 0039-0042; and Figure 4]. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the method of Sarachan as claimed because such a modification would have been considered a mere design consideration which fails to patentably distinguish over the teachings of Sarachan.
Regarding claim(s) 48, Sarachan teaches identifying the closest neighboring cells in a cluster [0042]. Regarding claim(s) 49, Sarachan teaches measuring a marker intensity of clusters of cells (i.e. phenotypic cluster of cells) [0004, 0033, 0041, 0042]. Regarding claim(s) 50, Sarachan teaches calculating survival curves [0053; Figure 12]. Regarding claim(s) 51, Sarachan teaches administering treatment decisions based on the outputs [0034], e.g. based on molecular and/or spatial heterogeneity, a caregiver may make determinations as to appropriate drug treatments.
Cited Prior Art
The following prior art made of record and not presently relied upon is considered pertinent to applicant' s disclosure.
Gerdtsson et al. (Converg. Sci. Phys. Oncol., 2018, 4, pp. 1-11) teaches methods of protein detection on circulating tumor cells from liquid biopsies using imaging mass cytometry, including using liquid biopsies from a metastatic prostatecancer cell, HLA-DR and CD14 were selected for monocytes identification along with CD3, CD8. See entire.
Takahiro et al. (WO 2017087847) teaches image cytometry methods and immunohistochemical (IHC) techniques that enable the sequential evaluation of biomarkers in tissue section. The methods involve high-throughput multiplexed, quantitative IHC imaging, sequential IHC with iterative labeling, digital scanning, image coregistration and merging, and subsequent stripping of sections. Tumor samples include breast cancer and immune cell phenotypes including CD8 can be discerned and classified based on expression characteristics of immune cell phenotypes. See entire.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PABLO S WHALEY whose telephone number is (571)272-4425. The examiner can normally be reached between 1pm-9pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Anita Coope can be reached at 571-270-3614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PABLO S WHALEY/Primary Examiner, Art Unit 3619
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