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 .
Restriction Election
Applicant’s election of Group I, Claims 26-34 and 36-45 in the reply filed on 11 August 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 35 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11 August 2025.
Claim Status
Claims 26-45 are currently pending and under exam herein.
Claims 26-34 and 36-45 are currently under exam herein.
It is noted that the instant Application has been assigned to a new Examiner in Group Art Unit 1687.
Priority
This application is the U.S. National Phase Application filed under 35 U.S.C. § 371 claiming benefit to International Patent Application No. PCT/EP2020/052054, filed on January 28, 2020, which is entitled to priority of GB Application No. 1905111.9, filed April 10, 2019, which is in turn entitled to priority of U.S. Provisional Patent Application No. 62/797,437, filed January 28, 2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statements filed 12 July 2022 are in compliance with the provisions of 37 CFR 1.97 and have therefore been considered. A signed copy of the IDS documents are included with this Office Action.
Drawings
The Drawings filed 23 July 2021 have been accepted.
Specification
Note: All references to the Specification herein pertain to the PG publication: US20220093251.
Claim Objections
Claim 31 is objected to because of the following informalities: Claim 31 recites, “Claim 31 recites, “wherein the n cancer risk groups comprise a group associated with no cancer diagnosis and one or more groups, for example1, 2 or 3 groups associated with increasing risk of cancer diagnosis, severity of cancer or chance of cancer progression”, wherein there is no space between the word “example” and “1”. Appropriate correction is requested.
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.
Claims 26-27, 29-34 and 37-45 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for providing a prognosis or diagnosis for prostate cancer based on expression status of genes, does not reasonably provide enablement for doing so for any and all cancers, as currently claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use or make the invention commensurate in scope with these claims. The instant Specification is directed solely to prostate cancer (PC) and the use of biomarkers for the diagnosis of PC (abstract). The Specification discloses methods for assessment of the progression of prostate cancer using algorithm based assessments to generated scores and use for prediction of prostate cancer status [0022]. The Specification fails to include teachings for any other type of cancer and therefore the instant claims reciting “a method of providing a cancer diagnosis or prognosis based on the expression status of a plurality of genes” (claim 26) and further steps directed to “patient expression profiles” and “patient expression profiles associated with cancer risk groups” and “selection of a subset of one or more genes from the plurality of genes in the patient expression profiles” (claim 26) do not include the specific recitation of “prostate cancer” and said steps are therefore directed to the broad class of any and all cancers. Claim 27 is directed to “ a method of classifying prostate cancer or a method of identifying a test subject with a poor prognosis for cancer” which broadly includes any and all cancers wherein the claim in the alternative reads only on “a method of identifying a test subject with a poor prognosis for cancer”.
Claim 28 and 36 specifically include prostate cancer genes and or recitations of prostate cancer and are therefore not included in the above rejection.
This is a scope of enablement rejection.
Claim Rejections - 35 USC § 112(b)-Indefiniteness
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.
Claim 26 and those claims dependent therefrom (27-34 and 36-45), recite, “applying a cumulative link model to the patient expression profiles to select a subset of one or more genes from the plurality of genes in the patient expression profile that are significantly associated with the n cancer risk groups” wherein the step is unclear with respect to the recitation of “to select a subset” as no step of “selecting” is actually claimed. As such, clarification is requested with respect to an active step recited in the claim of making a selection of the subset. Clarification is requested.
Claim 26 and those claims dependent therefrom (27-34 and 36-45), recite, “applying a cumulative link model to the patient expression profiles to select a subset of one or more genes from the plurality of genes in the patient expression profile that are significantly associated with the n cancer risk groups” wherein the recitation of “patient profile” is unclear. The claim is directed to providing patient profiles and counting risk groups from profiles. However, selection of a subset of genes in the patient expression profile that are significantly associated with cancer raises confusion with respect to which profile is intended herein. Clarification through clear claim language is requested.
Claim 27 and those claims dependent therefore (28, 34, 36-40) recite, “providing a test subject expression profile comprising the expression status of a subset of one or more genes selected by a method according to claim 1 in a sample obtained from the test subject…”, wherein the claim is unclear as pertains to the recitation of “claim 1” because claim 1 herein has been cancelled. It is assumed, for examination purposes, that the claim depends from claim 26. Further, if the claim does depend from claim 26, the claim is unclear with respect to “providing a test subject expression profile comprising the expression status of a subset…selected according to eh method of claim 1 (26)” because no selection of any expression status is performed in claim 26. Therefore, clarification is requested through clearer claim language.
Claim 27 and those claims dependent therefore (28, 34, 36-40) recite, “inputting the test subject expression profile to a constrained continuation ratio logistic regression model comprising the n modifier coefficients and gene regression coefficients generated using a method according to claim 26”, wherein it is unclear as by which method of claim 26 is intended herein. Claim 26 optionally includes “wherein the regression model generates gene regression coefficients associated with each of the selected subset of genes based on the plurality of patient expression profiles” without any steps by which this occurs. Further, it is suggested that is this it he method step intended as limited in claim 27 that the claim be amended to recite, “gene regression coefficients generated using the method according to claim 26”. Clarification is requested.
Claim 28 recites, “ (a) the subset of one or more genes is a plurality of the 37 genes in table 3 and the gene regression coefficients comprise the 37 gene regression coefficients in table 8; (b) the subset of one or more genes is a plurality of the 33 genes in table 4 and the gene regression coefficients comprise the 33 gene regression coefficients in table 9; (c) the subset of one or more genes is a plurality of the 29 genes in table 5 and the gene regression coefficients comprise the 29 gene regression coefficients in table 10; or (d) the subset of one or more genes is a plurality of the 25 genes in table 6 and the gene regression coefficients comprise the 25 gene regression coefficients in table 11”, wherein the recitation of tables in the claim is unclear. MPEP 2173.05(s): “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) (citations omitted).”
Claim 30 recites, “Table 2” and claim 34 recites, “Table 3” and are also subject to the above rejection as pertains to the recitation of “tables” in the claim.
Claim 28 recites, “Cp1, Cp2, Cp3” wherein said recitation is unclear as to the meaning of “Cp” or the intended limitation in the claim. It is unclear if Cp1 corresponds to (a), for example and Cp2 to (b) etc. Clarification is requested. It is further suggested that the term be spelled out the first time it appears in the claim.
Claim 28 recites, “wherein the model generates four risk scores (PUR-1, PUR-2, PUR-3 and PUR-4), wherein the risk scores indicate the likelihood of non-cancerous tissue (PUR-1), low-risk of cancer or cancer progression (PUR-2), intermediate-risk of cancer or cancer progression (PUR-3) and high-risk of cancer or cancer progression (PUR-4) in the test subject”, wherein the recitation of PUR is not defined in the claim. Clarification is requested through clearer claim language.
Claim 31 recites, “wherein the n cancer risk groups comprise a group associated with no cancer diagnosis and one or more groups, for example1, 2 or 3 groups associated with increasing risk of cancer diagnosis, severity of cancer or chance of cancer progression”, wherein the recitation of “for example 1, 2, or 3 groups: renders the claim unclear with respect to the metes and bounds of the claim. It is not clear if 1 or 2 or 3 or all are included herein as the claim language is exemplary. As such, said recitation does not limit the instant claim. Clarification is requested.
Claim 33 recites, “wherein n=4 and wherein the 4 cancer risk groups are the D'Amico risk groups or are equivalent to the D'Amico risk groups (i.e. no evidence of cancer, low-risk of cancer or cancer progression, intermediate-risk of cancer or cancer progression and high-risk of cancer or cancer progression)”. It is unclear if the parenthetical recitation is intended to limit the instant claim but defining the groups as “no evidence of cancer, low-risk of cancer or cancer progression, intermediate-risk of cancer or cancer progression and high-risk of cancer or cancer progression”. As such, said steps are not limiting herein as the scope is unclear. Clarification through clearer claim language is requested.
Claims 36-38 and 40 recite, “wherein the method can be used” which renders the claims indefinite with respect to what extent the language limits the claim scope herein. For example, claim 36 directed to the method that can be used to predict includes no such step of any actual prediction and therefore the recitations are intended herein. This is true for claim 37 reciting that the method can be used to determine whether a patient should be biopsied; claims 38 wherein the method can be used to predict disease; and further claim 40 wherein the method can be used to predict. As such, said steps at not limiting herein.
Claim 41 recites, “wherein determining the expression status of the one or more genes comprises extracting RNA from the biological sample”. There is lack of sufficient antecedent basis in the claim for the recitation of “biological sample” as only “sample is recited in claim 26 from which said claim depends. Clarification is requested.
Claim 43 recites, “wherein determining the expression status of the one or more genes comprises the step of quantifying the expression status of the RNA transcript or cDNA molecule and wherein the expression status of the RNA or cDNA is quantified using any one or more of the following techniques: microarray analysis, real-time quantitative PCR, DNA sequencing, RNA sequencing, Northern blot analysis, in situ hybridisation and/or detection and quantification of a binding molecule”, wherein there is lack of antecedent basis in the claim for “the RNA transcript or cDNA molecule” as no RNA or cDNA is recited in claim 26 from which said claim depends. Clarification is requested.
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 26-34 and 36-45 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
The instant rejection reflects the framework as outlined in the MPEP at 2106.04:
Framework with which to Evaluate Subject Matter Eligibility:
(1) Are the claims directed to a process, machine, manufacture or composition of matter;
(2A) Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
(2B) If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1 Analysis: Are claims directed to process, machine, manufacture/composition of matter
With respect to step (1): yes, the claims are directed to a method of providing a cancer diagnosis or prognosis.
Step 2A, Prong 1 Analysis: Do claims recite abstract idea
With respect to step (2A)(1), the claims recite abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts, (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the (2A)(1) evaluation, the claims are found herein to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and in conjunction with mathematical concepts (in particular mathematical relationships and formulas).
The claim steps to abstract ideas are as follows:
Claim 26: (b) counting the number (n) of different cancer risk groups to which the patient expression profiles belong…; (c)applying a cumulative link model to the patient expression profiles to select a subset of one or more genes from the plurality of genes in the patient expression profile that are significantly associated with the n cancer risk groups; inputting the expression values of the selected subset of one or more genes to a constrained continuation ratio logistic regression model comprising n modifier coefficients such that the model generates n risk scores for each patient expression profile… optionally wherein the regression model generates gene regression coefficients associated with each of the selected subset of genes based on the plurality of patient expression profiles, which include operations herein to “counting” and application of models (cumulative link and continuation ratio logistic regression) which are steps that are directed to mathematical operations. The Specification discloses cumulative link beginning at [0279] wherein said model is described as one that includes ordinal data in a proportional odds model. Further to the ratio logistic regression, said operation is a mathematical operations as described in the Specification at least beginning at [0281].
Claim 27: (b) inputting the test subject expression profile to a constrained continuation ratio logistic regression model comprising the n modifier coefficients and gene regression coefficients generated using a method according to claim 26, thereby generating n risk scores…; (c) classifying the cancer of the test subject or determining whether the test subject has a poor prognosis based on the value of a risk score associated with a poor prognosis cancer risk group for the test subject expression profile, wherein the higher the risk score associated with a poor prognosis cancer risk group, the worse the predicted outcome wherein said steps are further limited to mathematical operations and are abstract.
Dependent claim 28 further limits the constrained continuation ratio logistic regression model; claim 31 further limits the group numbers; claim 32 further limits the definition of the risk score; claim 33 further limits the risk groups.
Claims 36-38 and 40 are not further limiting to the instant claims as indicated in the above 112b rejection. However, for purposes of compact prosecution, assuming that the claims are directed to active steps of “predicting” etc., said claim further limit the mathematical operations herein and are also abstract.
Claim 44 further limits claim 26 to include steps of “comparing” which are mental operations wherein one can mentally asses one group of data as compared to another, as no further claim steps are required beyond said BRI.
Hence, the claims explicitly recite numerous elements that, individually and in combination, constitute abstract ideas.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined herein to each cover performance either in the mind (calculations by hand or pen and paper) and performance by mathematical operation and thus, under the BRI, one could simply, for example, perform said operation with pen and paper, or, alternatively with the aid of a generic computer as a tool to perform said calculations. These recitations are similar to the concepts of collecting information, analyzing it and providing certain results from the collection and analysis (Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations (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 with pen and paper, and can include mathematical concepts.
Further, see MPEP § 2106.04(a)(2), subsection III. The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation (see, e.g., Benson, 409 U.S. at 67, 65, 175 USPQ at 674-75, 674: noting that the claimed "conversion of [binary-coded decimal] numerals to pure binary numerals can be done mentally," i.e., "as a person would do it by head and hand."); Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1139, 120 USPQ2d 1473, 1474 (Fed. Cir. 2016): holding that claims to a mental process of "translating a functional description of a logic circuit into a hardware component description of the logic circuit" are directed to an abstract idea, because the claims "read on an individual performing the claimed steps mentally or with pencil and paper"). Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, "[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person’s mind" (see Versata Dev. Group v. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015); Mortgage Grader, Inc. v. First Choice Loan Servs. Inc., 811 F.3d 1314, 1324, 117 USPQ2d 1693, 1699 (Fed. Cir. 2016): holding that computer-implemented method for "anonymous loan shopping" was an abstract idea because it could be "performed by humans without a computer").
Step 2A, Prong 2 Analysis: Integration to a Practical Application
Because the claims do recite judicial exceptions, direction under (2A)(2) provides that the claims must be examined further to determine whether they integrate the abstract ideas into a practical application (MPEP 2106.04(d). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim is said to fail to integrate the abstract idea into a practical application (MPEP 2106.04(d).III).
With respect to the instant recitations, the claims recite the following additional elements:
Claim 26: providing a plurality of patient expression profiles each comprising the expression status of the plurality of genes in at least one sample obtained from each patient, which are operations that have basis in routine laboratory operations and serve to present the data for computations in the abstract idea.
Claims 27: providing a test subject expression profile comprising the expression status of a subset of one or more genes selected by a method according to claim [1] in a sample obtained from the test subject, which are operations that are routine laboratory operations and serve to get the data for computations in the abstract idea.
Claims 29-30, 34, 39, 41-43 and 45 further limit the types of “data” (plurality of gene numbers; number of gene subsets; type of patient; type of sample; and method of gene expression analysis) wherein each of said limiting steps further serves to gather the data for computations in the abstract idea using routine laboratory methods.
Further with respect to the additional elements in the instant claims, those steps directed to data gathering perform functions of collecting the data needed to carry out the abstract idea. Data gathering does not impose any meaningful limitation on the abstract idea, or on how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application. (MPEP 2106.05(g).
The courts have recognized the following laboratory techniques as insignificant extra-solution activity. See further, the MPEP at 2106.05(d)II.): determining the level of a biomarker in blood by any means (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)); 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)).
Step 2B Analysis: Do Claims Provide an Inventive Concept
The claims are lastly evaluated using the (2B) analysis, wherein it is determined that because the claims recite abstract ideas, and do not integrate that abstract ideas into a practical application, the claims also lack a specific inventive concept. Applicant is reminded that the judicial exception alone cannot provide the inventive concept or the practical application and that the identification of whether the additional elements amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they provide significantly more than the judicial exception. (MPEP 2106.05.A i-vi).
With respect to the instant claims, the additional elements of data gathering described above do not rise to the level of significantly more than the judicial exception. As directed in the Berkheimer memorandum of 19 April 2018 and set forth in the MPEP, determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the instant Specification provides that gene expression profiles are derived from known methods such as in [0015]; [0021]; [0155] providing that routine laboratory steps as disclosed herein are directed to are data gathering elements as in 2A, prong 2 and that under the assessment herein under 2B encompass steps that are well-understood and conventional in the art.
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (see MPEP 2106.05(d)II.): determining the level of a biomarker in blood by any means (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)); 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)).
The dependent claims have been analyzed with respect to step 2B and none of these claims provide a specific inventive concept, as they all fail to rise to the level of significantly more than the identified judicial exception.
For these reasons, the claims, when the limitations are considered individually and as a whole, are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
1. Claims 26-34 and 36-45 are rejected under 35 U.S.C. 103 as being unpatentable over McKiernan et al. (JAMA Oncol. (2016) Vol. 2:882-889; IDS reference) in view of Chen et al. (Computer Methods and Programs in Biomedicine (2012) Vol. 108:1070-1077; IDS reference) and in further view of Archer et al. (Stat. Med. (2012) Vol. 31:1464-1474: IDS reference).
Claim 26 is directed to:
A method of providing a cancer diagnosis or prognosis based on the expression status of a plurality of genes comprising:
(a) providing a plurality of patient expression profiles each comprising the expression status of the plurality of genes in at least one sample obtained from each patient, wherein each of the patient expression profiles is associated with one or more cancer risk groups, wherein each cancer risk group is associated with a different cancer prognosis or cancer diagnosis, optionally wherein each patient expression profile is normalised relative to (i) the expression status of one or more normalising genes in the same patient sample, (ii) an average expression status of one or more normalising genes in a reference population and/or (iii) the status of one or more control- probes;
(b) counting the number (n) of different cancer risk groups to which the patient expression profiles belong, optionally wherein at least one cancer risk group is associated with an absence of cancer;
(c) applying a cumulative link model to the patient expression profiles to select a subset of one or more genes from the plurality of genes in the patient expression profile that are significantly associated with the n cancer risk groups; and
(d) inputting the expression values of the selected subset of one or more genes to a constrained continuation ratio logistic regression model comprising n modifier coefficients such that the model generates n risk scores for each patient expression profile, wherein for each patient expression profile, a risk score is provided for each of the n cancer risk groups and wherein each of the n risk scores for a given patient expression profile is associated with the likelihood of membership to the corresponding cancer risk group, optionally wherein the regression model generates gene regression coefficients associated with each of the selected subset of genes based on the plurality of patient expression profiles.
With respect to claim 26, the prior art to McKiernan et al. discloses provision of patient gene expression profiles using urine exosome gene expression assays from 449 patients (abstract; and page 883-methods) . Said assay outcomes were compared with PSA levels and a prognostic score validated in 1064 patients (page 884). McKiernan et al. include AUC evaluation for discrimination into disease groups or benign (abstract). As such, McKiernan et al. disclose getting expression data associated with cancer risk and determining scores of prognosis therein.
McKiernan et al. do not specifically disclose application of a cumulative link model and input into a constrained continuation ratio logistic regression model to provide risk scores per se. However the prior art to Chen et al. disclose the use of statistical operations that include classifications of cancer state from microarray expression data that include using ordinal response model (cumulative link models) and ordinal regression for feature selection of cancer stage classifiers (page 1071).
Chen et al. do not specifically disclose continuation ratio model. However, Chen et al. do utilize regression modeling. Further to regression modeling, the prior art to Archer et al. disclose that continuation ratio models for ordinal response data is useful in high-dimensional data (abstract).
As such, it would have been prima facie obvious to one or ordinary skill in the art before the effective filing date of the claimed invention to have utilized the specific gene expression profiles from McKiernan et al. in prostate cancer with the statistical analysis techniques as disclosed by Chen et al. and Archer et al. because, as Chen et al. explain, cancer stage is on an ordinal scale and using a strict ordinal classifier to predict stave is more accurate than traditional non-ordinal classifiers (abstract). Further, Chen et al. demonstrate the applicability to prostate cancer (page 1074-1075). In addition. Archer et al. include use with ordinal data use of regression in gene expression microarray data for aid in selecting between pathologies of disease (abstract), particularly prostate cancer (page 6-7).
Claim 27 is directed to:
A method of classifying prostate cancer in a test subject or identifying a test subject with a poor prognosis for cancer comprising:
(a) providing a test subject expression profile comprising the expression status of a subset of one or more genes selected by a method according to claim 1 in a sample obtained from the test subject, optionally wherein the test subject expression profile is normalised relative to (i) the expression status of one or more normalising genes in the test subject sample, (ii) an average expression status of one or more normalising genes in a reference population, and/or (iii) the status of one or more control-probes;
(b) inputting the test subject expression profile to a constrained continuation ratio logistic regression model comprising the n modifier coefficients and gene regression coefficients generated using a method according to claim 26, thereby generating n risk scores, wherein each of the n risk scores for a given test subject expression profile is associated with the likelihood of membership to the corresponding cancer risk group, wherein the n modifier coefficients and corresponding gene regression coefficients are generated by applying the regression model to patient expression profiles comprising the expression status of the same subset of one or more genes; and
(c) classifying the cancer of the test subject or determining whether the test subject has a poor prognosis based on the value of a risk score associated with a poor prognosis cancer risk group for the test subject expression profile, wherein the higher the risk score associated with a poor prognosis cancer risk group, the worse the predicted outcome.
With respect to claim 27 (assuming herein that claim 27 does depend on claim 26-see above 112b rejection), the prior art to McKiernan et al. discloses provision of patient gene expression profiles using urine exosome gene expression assays from 449 patients (abstract; and page 883-methods) . Said assay outcomes were compared with PSA levels and a prognostic score validated in 1064 patients (page 884). McKiernan et al. include AUC evaluation for discrimination into disease groups or benign (abstract). As such, McKiernan et al. disclose getting expression data associated with cancer risk and determining scores of prognosis therein.
McKiernan et al. do not specifically disclose application of a cumulative link model and input into a constrained continuation ratio logistic regression model to provide risk scores per se. However the prior art to Chen et al. disclose the use of statistical operations that include classifications of cancer state from microarray expression data that include using ordinal response model (cumulative link models) and ordinal regression for feature selection of cancer stage classifiers (page 1071).
Chen et al. do not specifically disclose continuation ratio model. However, Chen et al. do utilize regression modeling. Further to regression modeling, the prior art to Archer et al. disclose that continuation ratio models for ordinal response data is useful in high-dimensional data (abstract).
As such, it would have been prima facie obvious to one or ordinary skill in the art before the effective filing date of the claimed invention to have utilized the specific gene expression profiles from McKiernan et al. in prostate cancer with the statistical analysis techniques as disclosed by Chen et al. and Archer et al. because, as Chen et al. explain, cancer stage is on an ordinal scale and using a strict ordinal classifier to predict stave is more accurate than traditional non-ordinal classifiers (abstract). Further, Chen et al. demonstrate the applicability to prostate cancer (page 1074-1075). In addition. Archer et al. include use with ordinal data use of regression in gene expression microarray data for aid in selecting between pathologies of disease (abstract), particularly prostate cancer (page 6-7).
With respect to claim 28, the prior art to McKiernan et al. discloses at least the genes PCA3, ERG (and SPDEF) to derived an exosome expression score. Said genes exist as “one” or more from Table 3. PCA3 and/or ERG are in Table 3, 4, 5, and 6.
With respect to claim 29, both Chen et al. disclose genes in an expression profile that include microarray profiles including at least any number of “p” genes (p. 1071; p. 1075-prostate data).
With respect to claim 30, the prior art to McKiernan et al. discloses at least the genes PCA3, ERG (and SPDEF) to derived an exosome expression score. Said genes exist as “one” or more from Table 3. PCA3 and/or ERG are in Table 3, 4, 5, and 6.
With respect to claim 31, the prior art to McKiernan et al. include AUC evaluation for discrimination into disease groups or benign (abstract).
With respect to claim 32, McKiernan et al. disclose that higher score (Gleason>/=7) indicates higher probability of disease-abstract).
With respect to claim 33, McKiernan et al. disclose equivalent ratings that include “benign” or high risk (abstract).
With respect to claim 34, the prior art to McKiernan et al. include two from the Table 3 genes (ERG and PCA3; p. 883).
With respect to claims 36-38 and 40, the “use” of the instant invention is obvious over the prior art of record wherein said operations do not limit the claim steps herein (see above 112b rejection).
With respect to claim 39, a “patient” being under active surveillance is prima facie obvious given the recitations herein to predict stage of prostate cancer as made obvious by McKiernan et al. in view of Chen et al. and archer et al. One would be motivated to actively monitor a patient over time for any increase risk in prostate cancer, as motived by the art to McKiernan et al. disclosing monitoring over time (page 886).
With respect to claim 41, McKiernan et al. disclose expression status from RNA extraction (page. 883).
With respect to claim 42, McKiernan et al. disclose that RNA is extracted from EVs (p. 883).
With respect to claim 43, McKiernan et al. disclose quantification of gene expression using RT-PCR (p. 883).
With respect to claim 44, McKiernan et al. disclose using standards for expression status at p. 883.
With respect to claim 45, McKiernan et al. disclose urine samples (p. 883).
Prior Art Made of Record
The following prior art made of record and not relied upon is considered pertinent to applicant’s disclosure:
1. 20200263255 to Luca et al. directed to classification of prostate cancers by identification of aggressive versus indolent cancers (same assignee as in the instant invention).
2. Archer et al. (Cancer Informatics (2014) Vol. 13:187-195) disclosing classification of samples as normal to pre-malignant to malignant or by stage using ordinal response modeling.
3. Chen et al. (Biomedicine Hub (2017) Vol. 2:15 pages) disclosing a qualitative review of gene expression profiling in tissue-based prostate cancer research.
4. Klein et al. (European Urology (2014) Vol. 66:550-560) disclosing a 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling.
5. Knezevic et al. (BMC Genomics (2013) Vol. 14:12 pages) disclosing the Oncotype Dx® prostate cancer assay (a multi-gene RT-PCR expression assay).
6. Larkin et al. (British Journal of Cancer (2012) Vol. 106:157-165) disclosing seven putative markers of PCs progression.
7. Tsang et al. (Expert Review of Molecular Diagnostics (2017) Vol. 17:95-103) disclosing NanoString digital color-coded barcode technology.
Conclusion
No claims are allowed.
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