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/Restrictions
Claims 2 and 13-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/29/2026.
Applicant’s election without traverse of claims 1 and 3-12 in the reply filed on 1/29/2026 is acknowledged.
Priority
This application filed 11/12/2021 is a National Stage entry of PCT/EP2020/062925, with an International Filing Date of 05/08/2020, and claims foreign priority to European Application 19174032.3, filed 05/13/2019. The claims are therefore examined as filed on 05/13/2019, the effective filing date. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further review of the priority application(s).
Claim Status
Claims 1-15 are pending.
Claim 8 is objected to.
Claims 2 and 13-15 are withdrawn.
Claims 1 and 3-12 are directed to the elected invention.
Claims 1 and 3-12 are examined.
Claims 1 and 3-12 are rejected.
Information Disclosure Statement
The Information Disclosure Statements are in compliance with the provisions of 37 CFR 1.97. Accordingly, all references have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see pg 29). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 8 is objected to because of the following informalities:
The optional steps of claim 8 should all be the same tense verbs instead of a mix of verbs and nouns, since these are additional steps comprising the method. For example claim 8 should read “providing… and/or predicting… and/or determining a prognosis…and/or developing a drug or assay” etc.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 3-6 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 3 and 5 have limitations that refer to “the risk score.” There is insufficient antecedent basis for this limitation in the claim. These claims both depend from claim 1, which does not contain any reference to a risk score. Therefore these claims are indefinite due to lack of clarity.
Claim 6 is unclear with regards to the limitation “wherein the cellular signaling pathways comprise the TGF-β pathway and one or more of the PI3K-FOXO pathway, and the Notch pathway, preferably the PI3K-FOXO pathway and at least the PI3K-FOXO pathway”. Based on the wording of this claim, it is unclear which pathways are required and which are optional. Therefore this claim is indefinite due to lack of clarity.
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, 3-10 and 12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of mental processes and mathematical concepts, without significantly more.
Claim 11 is rejected under 35 U.S.C. 101 as it is not directed to any statutory category.
The MPEP at MPEP 2106 sets forth steps for identifying eligible subject matter:
(1) Are the claims directed to a process, machine, manufacture or composition of matter?
(2A)(1) Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea?
(2A)(2) Do the claims recite additional elements that integrate the judicial exception into a practical application?
(2B) If the claims recite a judicial exception and do not integrate the judicial exception, do the claims recite additional elements that provide an inventive concept and amount to significantly more than the judicial exception?
With regard to step (1) (Are the claims directed to a process, machine, manufacture or composition of matter?): Claims 1, and 3-12 are directed to statutory classes. Claims 1 and 3-8 are directed to a process (computer implemented method performed by a digital processing device), claim 9 is directed to a machine product (apparatus comprising a digital processor), claim 10 is also directed to a machine product (non-transitory storage medium with executable instructions) and claim 12 is directed to a kit comprising components and the apparatus of claim 9).
Claim 11 is not directed to a statutory class. Claim 11 is directed to a computer program, or software. A product claim to a software program that does not also contain at least one structural limitation (such as a "means plus function" limitation) has no physical or tangible form, and thus does not fall within any statutory category (see MPEP 2106.03).
The following analyses apply only to those claims determined to be statutory categories.
With regard to step (2A)(1) (Do the claims recite a judicially recognized exception?): Yes. The claims recite the abstract ideas of processing data using mental steps and mathematical concepts. Claims that recite nothing more than abstract ideas, natural phenomena, or laws of nature are not eligible for patent protection (see MPEP 2106.04).
Abstract ideas include mathematical concepts, (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (including procedures for collecting, observing, evaluating, and organizing information (See MPEP 2106.04(a)(2)). In particular, these abstract ideas include but are not limited to:
Determining an airway abnormality factor based on a combination of activities of cellular signaling pathways (mental process; the human mind is capable of assigning a value based on data; claim 1, 9-12)
Determining the abnormality factor and the risk score based on evaluating a calibrated mathematical model (mental process/mathematical process; the human mind is capable of determining a value based on a mathematical model, and using a mathematical model to determine a value is equivalent to performing a calculation; claim 3)
Inferring activities of cell signaling pathways by determining an activity level of a cellular signaling pathway associated transcription factor element based on evaluating a calibrated mathematical model (mental process/mathematical process; the human mind is capable of determining a value based on a mathematical model and data, and using a mathematical model to determine a value is equivalent to performing a calculation; claim 4)
Determining an airway abnormality factor based on the combination of activities of the cellular signaling pathways and translating the airway abnormality factor into the risk score and/or determining a signaling pathway abnormality factor based on activity of the pathway and determining the airways abnormality factor based on a combination of signaling pathway abnormality factors (mental process/mathematical concept; the human mind is capable of determining factors based on data or by combining factors into new values, determining values from data or combining values into new values is a mathematical process; claim 5)
Making predictions/prognoses based on data (mental process; the human mind is capable of making predictions or prognoses based on data; claim 8)
Dependent claims 6-7 further limit the abstract ideas recited in the independent claims, and do not change their characterization as abstract ideas.
Therefore, the claims recite elements that constitute one or more judicial exceptions.
With regard to step (2A)(2) (Do the claims recite additional elements that integrate the judicial exception into a practical application?): No. Claims 1 and its dependents recite the additional element that the method is “computer-implemented” and claim 4 recites the additional element of receiving expression levels (data) for the method. Claim 9 recites the additional element of an apparatus comprising a digital processor, claim 10 recites the additional element of a non-transitory storage medium with executable instructions, and claim 12 recites the additional element of a kit comprising components for determining expression levels (gathering data to be used in an analysis) and the apparatus of claim 9.
While the claims recite the additional element of receiving or gathering data, such steps that only amount to necessary data gathering , without any technical details of how the data is obtained that integrate the judicial exception, are insignificant extrasolution activities that do not add a meaningful limitation to the claims (see MPEP 2106.05(g)). As a result, the judicial exception is not integrated into a practical application. Similarly, the additional element of a kit for gathering data in claim 12 merely indicates a field of use or technological environment in which to apply a judicial exception (see MPEP 2106.05(h)), and also does not integrate the claims into a practical application. In addition, while the claims recite additional elements related to the use of computers, they do not provide any specific details by which the computer, apparatus, processors, or storage medium performs or carries out the judicial exception listed in step (2A)(1), nor do they provide any details of how specific structures of the computer are used to implement these functions. The judicial exception is therefore not integrated into a practical application because the generically recited computer elements do not add a meaningful limitation to the abstract idea, as they amount to simply implementing the abstract idea on a computer (see MPEP 2106.05(f)). Because the claims do not recite any additional elements that integrate the judicial exception into a practical application, the claims as a whole are directed to an abstract idea.
With regard to step (2B) (Do the claims recite additional elements that provide an inventive concept and amount to significantly more than the judicial exception?): No. The claims recite an abstract idea with additional elements; however, these additional elements are general computer elements added to abstract ideas, and non-particular instructions to apply the abstract idea by linking it to a field of use or extrasolution activity (see MPEP 2106.05(f-h)). General computer elements used to perform an abstract idea do not provide an inventive concept, and similarly, non-particular instructions and means to gather data do not provide an inventive concept. Non-particular instructions to gather data, using computers or conventional laboratory techniques, are also considered well-understood, routine and conventional activities (see MPEP 2106.05(d), which indicates that limitations such as “Receiving or transmitting data over a network” from Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362, and “Storing and retrieving information in memory” from Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, “Determining the level of a biomarker in blood by any means” from Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017) and “Detecting DNA or enzymes in a sample” , Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017) are recognized as conventional activities). The claims therefore do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As a result, the claims as a whole do not provide an inventive concept.
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.
Claim Rejection
Claims 1 and 3-12 are rejected under 35 U.S.C. 103 as being unpatentable over VAN OOIJEN 2016 “Superior Bioinformatics Process For Identifying At Risk Subject Populations” (US 20160117439 A1) in view of PAZHOUHANDEH 2017 “Comparative Network Analysis of Patients with Non-Small Cell Lung Cancer and Smokers for Representing Potential Therapeutic Targets.”
Claim Interpretation and Scope and Contents of Prior Art
Claim 1 recites a computer implemented method for determining whether a subject has abnormal airway epithelium, performed by a digital processing device, wherein the determining comprises: determining an airway abnormality factor indicating whether the subject has abnormal airway epithelium based on a combination of activities of cellular signaling pathways in an epithelial cell sample derived from an airway of the subject.
With respect to this limitation, VAN OOIJEN recites a computer implemented method and systems for determining a risk score (Abstract), in which a subject is at risk of cancers that include the epithelial airway cancers esophageal adenocarcinoma and squamous cell carcinoma [0369], and the risk is determined from a multi-pathway score (synonymous with an abnormality score, as indicated by pg 8-9 of the specification) determined based on a combination of activities of cellular signaling pathways (Abstract) in a cell sample from the subject [0021, 25, 45].
Claim 1 also recites the limitation wherein the cellular signaling pathways comprise two or more cellular signaling pathways selected from the group consisting of a TGF-β pathway, a PI3K-FOXO pathway, and a Notch pathway, wherein the determining of the signaling pathway abnormality factor is further based on a reference activity of the respective cellular signaling pathway, wherein the reference activity reflects activity of the respective cellular signaling pathway found in airway epithelium of healthy subjects.
With respect to this limitation, VAN OOIJEN teaches that the cellular signaling pathways comprise two or more pathways including the TGF-β pathway, PI3K pathway, and Wnt pathway (Abstract), where the PI3K pathway can include the PI3K-FOXO pathway [0513] and the Wnt pathway can include Notch target genes (indicated on pg 15-16 of the present invention specification) including CD44, EPHB3, SOX9 [032]. VAN OOIJEN does not teach that the risk score/abnormality factor is based on a reference activity of the respective cellular signaling pathway of healthy subjects, but rather teaches comparing cell signaling pathway activity levels to the activity levels determinative of the occurrence of a clinical event/cancer [046-47].
However, PAZHOUHANDEH teaches comparing the cellular signaling pathways of non-small cell lung cancer patients and smokers to healthy control samples (pg 10 par 3-4) and determining abnormality associated with pathway patterns (pg 3 par 2-3). PAZHOUHANDEH also teaches NOTCH signaling is also associated with non-small cell lung cancer and can interact with Wnt and TGF-β pathways driving cancer development (pg 9). Based on the teachings of both prior art references, it would be obvious to one of ordinary skill in the art that a risk score/abnormality factor can be determined by comparing a subject’s cellular activity to either activity levels associated with a clinical event/cancer or the absence of these to determine whether the subject is exhibiting normal vs activity related to a specific cancer. Further, it would be obvious that any condition, including airway epithelial abnormality, can be analyzed when cellular pathways relating to the condition are known.
This rejection is also applied to claims 9-11 which recite an apparatus containing a digital processor, a non-transitory computer storage medium with instructions, and a computer program, respectively, for performing the limitations of claim 1, as VAN OOIJEN also teaches these as part of its methods/systems (Abstract).
Claim 3 recites the limitation herein the airway abnormality factor and the risk score, respectively, is determined based on evaluating a calibrated mathematical model relating the activities of the cellular signaling pathways in the epithelial cell sample to the airway abnormality factor and the risk score, respectively. With respect to this limitation, VAN OOIJEN teaches that the risk score/abnormality factor is determined based on evaluating a calibrated mathematical model which is used to calculate pathway activity levels [0021-23].
Claim 4 recites the limitation wherein the activities of the cellular signaling pathways in the epithelial cell sample is inferred or inferable by a method comprising: receiving expression levels of one and preferably three or more target genes of each of the respective cellular signaling pathway, determining an activity level of a cellular signaling pathway associated transcription factor (TF) element, the cellular signaling pathway associated TF element controlling transcription of the one and preferably three or more target genes, the determining being based on evaluating a calibrated mathematical pathway model relating expression levels of the target gene(s) to the activity level of the respective cellular signaling pathway, and inferring the activity of the respective cellular signaling pathway based on the determined activity level of the cellular signaling pathway associated TF element.
With respect to this limitation, VAN OOIJEN teaches determining activities of the signaling pathways by receiving data on the expression levels of at least three pathway target genes derived from the sample, and calculating an activity level of the cellular signaling pathway associated transcription factor element by evaluating a calibrated mathematical pathway model which defines an activity level of the transcription factor element of the cellular signaling pathway [0021-23], where the transcription factor element controls transcription and expression of the genes [0024].
Claim 5 recites the limitation of determining a signaling pathway abnormality factor for each of the respective cellular signaling pathways based on the activity of the respective cellular signaling pathway in the epithelial cell sample and determining the airway abnormality factor based on a combination of the determined cellular signaling pathway abnormality factors. With respect to this limitation, VAN OOIJEN teaches determining a risk score using a calibrated Multi-Pathway Score model which combines the calculated cell signaling activities into a MPS score which can be /used to calculate a risk score [0025] (the multi-pathway score is interpreted as equivalent to an abnormality score).
Claim 6 recites the limitation wherein the cellular signaling pathways comprise the TGF-β pathway and one or more of the PI3K-FOXO pathway, and the Notch pathway, preferably the PI3K-FOXO pathway and at least the PI3K-FOXO pathway. With respect to this limitation, VAN OOIJEN teaches the cellular signaling pathways comprise the TGF-β pathway and one or more other pathways that include the PI3K pathway and Wnt pathway (Abstract), where the PI3K pathway can include the PI3K-FOXO pathway [0513].
Claim 7 recites the limitation wherein the three or more TGF-β target genes are selected from the group consisting of:ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, JUNB, PDGFB, PTHLH, SERPINEl, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, VEGFA, more preferably, from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45B, ID1, IL 11, JUNB, SERPINEl, PDGFB, SKIL, SMAD7, SNAI2, and VEGFA, most preferably, from the group consisting of: ANGPTL4, CDC42EP3, ID1, IL11,JUNB, SERPINEl, SKIL, and SMAD7, or wherein the three or more TGF-β target genes are selected from the group consisting of: CDC42EP3, GADD45B, HMGA2, ID1, JUNB, OVAL 1, VEGFA, SGK1,and/or the three or more PI3K-FOXO target genes are selected from the group consisting of: AGRP, BCL2L11, BCL6, BNIP3, BTG1, CAT, CAV1, CCND1, CCND2, CCNG2, CDKNIA, CDKN1B, ESR1, FASLG, FBXO32, GADD45A, INSR, MXIl, NOS3, PCK1, POMC, PPA.
With respect to this limitation, VAN OOIJEN teaches that the TGF-β target genes are selected from the group consisting of least 3 genes from the above claimed list [030] and also teaches that the PI3K-FOXO target genes are selected from the group consisting of least 3 genes from the above claimed list [031].
Claim 8 recites the limitation wherein the method further comprises one of several optional steps including predicting cancer risk and effectiveness of treatment, and making decisions relating to monitoring and treatment. With respect to this limitation, VAN OOIJEN teaches providing a prediction that the subject will experience a negative clinical event, which can include disease progression, development of metastasis and cancer, and where the cancer can be breast, prostate, lung, glioma or colon cancer [017, 0382] and further providing cancer prognosis and/or prediction, and prediction of drug efficacy [0420-421].
Claim 12 recites a kit for determining an airway abnormality factor indicating whether a subject has abnormal airway epithelium or a risk score that indicates a risk that a subject having abnormal airway epithelium will develop an airway cancer, the kit comprising: components for determining the expression levels of at least three target genes of a TGF-3 cellular signaling pathway, at least three target genes of a PI3K-FOXO cellular signaling pathway, at least three target genes of a Notch cellular signaling pathway, and the apparatus of claim 9.
With respect to this limitation, VAN OOIJEN teaches kits for measuring expression levels of at least three or more TGF-β cellular signaling pathway target genes, at least three PI3K signaling target genes, and at least three target genes of a notch cellular signaling pathway [055-68]; (pg 15-16 of the present specification indicates several notch pathway genes, which include at least CD44, EPHB3, SOX9 that are included in the kits of the prior art [032]).
PAZHOUHANDEH also teaches measuring gene expression in signaling target genes of the notch pathway, and that NOTCH signaling is also associated with non-small cell lung cancer and can interact with Wnt and TGF-β pathways driving cancer development (pg 9), such that it would be obvious to one of ordinary skill in the art to include notch pathway genes in a kit indicating abnormal airway epithelium/cancer.
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in cancer-related sell signaling analysis would have been motivated to combine the teachings of VAN OOIJEN with the teachings of PAZHOUHANDEH in order to achieve the claimed invention, because comparing the cellular signaling pathways of subjects to healthy control samples allows for determining abnormality that may be associated with pathway patterns indicative of cancer or the development of cancer (pg 3 par 2-3, 8), and because NOTCH signaling is also associated with non-small cell lung cancer/abnormal airway epithelium and can interact with Wnt and TGF-β pathways driving cancer development (pg 9). A person of ordinary skill would reasonably expect success from combining these teachings, as both VAN OOIJEN and PAZHOUHANDEH teach methods of cellular signaling pathway analysis relating to cancers, and it would be obvious to one of ordinary skill that a risk score/abnormality factor can be determined by comparing a subject’s cellular activity to either activity levels associated with a clinical event/cancer or the absence of these to determine whether the subject is exhibiting normal vs activity related to a specific cancer, where any cancer-related condition, including airway epithelial abnormality, can be analyzed when cellular pathways relating to the condition are known. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY C LEVERETT whose telephone number is (571)272-5494. The examiner can normally be reached 8:00am - 5:00pm M-Th.
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/MARY C LEVERETT/Examiner, Art Unit 1687