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 .
Remarks
In response to communications sent March 3, 2023, claim(s) 1-13 are pending in this application; of these claims 1 are in independent form.
Response to Amendment
The preliminary amendments filed March 3, 2023 are acknowledged and have been entered into the record.
Priority
The claims are assumed to have the filing date of the priority document, EP20194511.0, which is September 4, 2020. This is because the priority document includes a listing of claims similar to the instant application and the application includes similar content and figures.
Drawings
The drawing(s) filed on March 3, 2023 are accepted by the Examiner.
Specification
The disclosure is objected to because of the following informalities:
The specification uses the terms “principal” and “principle” interchangeably. However, the Examiner’s understanding is that the appropriate term to one of ordinary skill in the art is “principal” as in “principal components analyisis”.
Page 2 line 17 misspells “heterogeneity” as “heterogeneinity”.
Page 2 line 20 misspells “paired” as “paire”.
Page 2 line 23 misspells “method” as “method”.
Appropriate correction is required.
Information Disclosure Statement
The Information Disclosure Statement(s) is/are acknowledged and the references contained therein have been considered by the Examiner. This includes the Information Disclosure Statements(s) filed on: March 3, 2023.
Claim Objections
Claims 1-13 are objected to because of the following informalities: The term “principle” is used in two places in claim 1, whereas Applicant’s specification (and elsewhere in the claims) involves the term “principal” as in principal components analysis. Claims 2-13 are objected to because they depend from claim 1. Appropriate correction is required.
Claim 3 is objected to because of the following informalities: The claim should end in a period instead of a semicolon. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: The phrase “non transitory” omits a hyphen, whereas in claim 13 the hyphen is present. Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are:
"the computer program code means for causing a processor to perform a method..." in claim 13.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an apparatus, does not reasonably provide enablement for the processor performing “scanning” and “measuring” because these steps are typically performed on equipment other than the processor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. While the claimed apparatus comprises a processor and therefore encompasses other possible equipment as elements of the apparatus, the processor itself would not enable one of ordinary skill in the art to scan and measure a sample. This is because the one skilled in computer hardware and programming would require undo experimentation to alter the hardware to become a scanning and measurement device using substantially the processor. In addition, it does not seem to be the intention the inventors to enable changes the processor to take on new capabilities, but instead for the data to be received from a separate scanner. See Figure 4 element 42, which page 11 lines 35-36 describes: “Data 42 may be received from, for example, a scanner or the like.”
Claim 11 is rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, because the claim purports to invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, but fails to recite a combination of elements as required by that statutory provision and thus cannot rely on the specification to provide the structure, material or acts to support the claimed function. As such, the claim recites a function that has no limits and covers every conceivable means for achieving the stated function, while the specification discloses at most only those means known to the inventor. Accordingly, the disclosure is not commensurate with the scope of the claim.
Claim 13 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Page 8 lines 20-21 recites the “program code means”; however, no association between the structure and the function can be found in the specification. Therefore, there is inadequate written description to support the claimed invention.
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.
Claim 13 is 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.
1. Claim 13 recites “… causing a processor to perform a method and/or the signal…” The broadest reasonable interpretation of “and/or” is “or”. Therefore, the claim limitation, under the broadest reasonable interpretation, encompasses “causing a processor to perform… the signal”. However, it is unclear what it means to “perform the signal”.
2. Claim limitation “the computer program code means” invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. Page 8 lines 20-21 recites the “program code means”; however, no association between the structure and the function can be found in the specification. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
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 11 and 12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because claim 11 is software per se (without any structural elements) and claim 12 is a signal per se. For claim 11, the Examiner suggests reciting structure; for claim 12, the examiner suggests using the phrase “non-transitory signal” instead of “signal.”
Note that claim 11 and 12, if amended to fall under a statutory class, might involve a judicial exception to subject matter eligibility. See below for guidance:
Claims 1-13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claim(s) recite(s) mathematics, which is an abstract idea. Claims 5, 9, and 13 also involve mental processes that can be performed in the human mind in combination with the mathematical results. This judicial exception is not integrated into a practical application because the inputs the abstract ideas are necessary pre-solution activity that does not limit the use of the abstract ideas beyond all uses of the abstract ideas. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because application of a general purpose computer to “apply” the judicial exception is recognized in the Alice case as well-understood, routine, and conventional. Regarding claim 3, gathering a biopsy is well-understood, routine, and conventional according to Applicant’s specification at page 1 lines 6-7, which establishes that biopsies are performed by pathologists. As to claim 9, the use of the scanner is well-understood, routine, and conventional because it is being used as a tool to perform an existing process. See TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016). We regarding to gene expression analysis, the measurement is an additional element, but it is not integrated because it is necessary to perform the specific abstract idea without adding additional limitations outside of the abstract idea; in addition, the measurements are well-understood, routine, and conventional because they can be performed with an Affymetrix array or Illumina sequencer, each of which a well-understood, routine, and conventional systems for measurements of gene expression used in industry.
See below for further explanation:
1. A method for estimating heterogeneity of a tumour based on values for two or more genome mutation and/or gene expression related parameters for at least two spatially differentiated areas in a sample, the sample being a tissue sample of a tumour or a liquid sample obtained from a subject having the tumour, and wherein the sample is a single biopsy obtained from said tumour or liquid sample, the method comprising the steps of:
determining a sample heterogeneity score for the heterogeneity of the sample based on variabilities of each measured value for the at least two spatially differentiated areas (this element is mathematics, because the clauses below specify that it is principal components analysis);
estimating the heterogeneity of the tumour by extrapolating the score for the heterogeneity of the sample to the tumour, thereby providing a tumour heterogeneity score, wherein the step of determining the sample heterogeneity score comprises the step of performing a Principal Component Analysis, PCA, for converting the two or more genome mutation and/or gene expression related parameters into principle components, thereby reducing correlations between the two or more genome mutation and/or gene expression related parameters (this element is mathematics, because it is a formulaic combination of statistics determined using principal components analysis),
wherein the step of determining the sample heterogeneity score comprises the steps of:
computing standard deviations for each of the principle components and determining the sample heterogeneity score for the heterogeneity of the sample based on the computed standard deviations (mathematics of computing standard deviations from principal components);
wherein said step of estimating said sample heterogeneity score for the heterogeneity of the sample, comprises any of:
multiplying each of said variabilities of each measured value for the at least two spatially differentiated areas with each other (mathematics of multiplication), and
summing each of said variabilities of each measured value for the at least two spatially differentiated areas (mathematics of addition); and
wherein said method further comprises the step of:
providing a base transformation matrix, M, constructed from samples from different areas of tumours of multiple subjects, wherein the base transformation matrix M is a frozen base (mathematics of matrix multiplication, which includes mathematics of arithmetic operations), and
wherein the heterogeneity score is determined by transforming the parameters of multiple subsamples of a single sample into the space created by the frozen base as a way to represent the molecular constitution of each subsample by a multi-dimensional vector (mathematics of dimension reduction, such as using principal components analysis), and
combining the resulting multi-dimensional vectors by first estimating the variability in each direction and then summarizing or multiplying the multi-dimensional variability vectors into one single score (mathematics common to principal components analysis).
2. The method according to claim 1, wherein the method is a computer implemented method (the additional element of “applying it” on a general purpose computer; while not part of the abstract idea, it is understood by the courts as not integrated into a practical application of the abstract idea and an element that is well-understood, routine, and conventional; see Alice).
3. The method according to claim 1, wherein the method further comprises the step of providing the single biopsy obtained from a subject (the Examiner interprets this claim as providing the actual biological biopsy, which is an additional element; however the biopsy is necessary pre-solution activity to carry out any possible use of the mathematics, and therefore the additional element does not meaningfully limit the mathematics; in addition gathering a biopsy is well-understood, routine, and conventional according to Applicant’s specification at page 1 lines 6-7, which establishes that biopsies are performed by pathologists) and determining the values for two or more genome mutation and/or gene expression related parameters in the single biopsy (the determination is interpreted as a mathematical determination of a parameter by encoding the parameter, calculating, or normalizing the values);
4. A method in accordance with claim 1, wherein the step of performing the PCA comprises:
determining mean values for each of the two or more genome mutation and/or gene expression related parameters based on the measured values (mathematical calculation of a mean);
subtracting each of the measured values by a mean value of its corresponding genome mutation and/or gene expression related parameter (mathematical calculation of subtraction).
5. A method in accordance with claim 1, wherein the method further comprises one or more steps selected from:
deciding a treatment strategy for the subject based at least in part on the tumour heterogeneity score (mental process of a judgement, which is capable of being performed using the human mind contemplating the pre-computed heterogeneity score);
predicting a treatment outcome for the subject based at least in part on the tumour heterogeneity score (mental process of a judgement, which is capable of being performed using the human mind contemplating the pre-computed heterogeneity score);
predicting a survival probability for the subject based at least in part on the tumour heterogeneity score (mental process of a judgement, which is capable of being performed using the human mind contemplating the pre-computed heterogeneity score);
predicting resistance to a therapy (mental process of a judgement, which is capable of being performed using the human mind contemplating the pre-computed heterogeneity score)
deciding on the efficacy of therapy administered prior to the heterogeneity analysis (mental process of a judgement, which is capable of being performed using the human mind contemplating the pre-computed heterogeneity score)
deciding on resistance to therapy administered prior to the heterogeneity analysis (mental process of a judgement, which is capable of being performed using the human mind contemplating the pre-computed heterogeneity score).
6. A method in accordance with claim 1, wherein said gene expression related parameters are gene expression levels of three or more target genes each of one or more cellular signalling pathway selected from the group consisting of ER, AR, HH, PI3K-FOXO, WNT, TGFbeta, NFkB, JAK-STAT1/2, JAK-STAT3, Notch, PR and MAPK-AP1, preferably wherein said gene expression related parameters are cellular signalling pathway activities based on the three or more target genes expression levels for said cellular signalling pathway, more preferably wherein said cellular signalling pathway activity is selected from the group consisting of ER, AR, HH, PI3K-FOXO, WNT, TGFbeta, NFkB, JAK-STAT1/2, JAK-STAT3, Notch, PR and MAPK-AP1 cellular signalling pathway activity (these are limitations to the mathematical calculation that limits the mathematical calculation without taking it outside of the realm of abstract ideas).
7. A method in accordance with claim 1, wherein said step of estimating the heterogeneity of the tumour comprises:
setting an upper bound for the tumour heterogeneity score as the sample heterogeneity score (this is a mathematical upper limit and therefore an abstract idea).
8. An apparatus comprising a processor configured to perform a method in accordance with claim 7 (the additional element of “applying it” on a general purpose computer; while not part of the abstract idea, it is understood by the courts as not integrated into a practical application of the abstract idea and an element that is well-understood, routine, and conventional; see Alice).
9. An apparatus in accordance with claim 8, wherein said processor is further arranged for:
scanning said sample (this is an additional element; however, it is necessary pre-solution activity to carry out the mathematics; according to applicant’s specification, a scanner may be used, see page 11 lines 35-36; however, a scanner is well-understood, routine, and conventional because it is being used as a tool to perform an existing process. See TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016));
identifying, in said sample, an area of interest (a mental process of a judgement, performable in the human mind upon viewing a scanned image);
measuring, for said area of interest, value for the at least two spatially differentiated areas for two or more genome mutation and/or gene expression related parameters (the measurement is an additional element, but it is not integrated because it is necessary to perform the specific abstract idea without adding additional limitations outside of the abstract idea; in addition, the measurements are well-understood, routine, and conventional because they can be performed with an Affymetrix array or Illumina sequencer, each of which a well-understood, routine, and conventional systems for measurements of gene expression used in industry).
10. A non transitory storage medium storing instructions that are executable by a processor to perform a method in accordance with claim 1 (the additional element of “applying it” on a general purpose computer; while not part of the abstract idea, it is understood by the courts as not integrated into a practical application of the abstract idea and an element that is well-understood, routine, and conventional; see Alice).
13. Use of the apparatus according to claim 8, the non-transitory storage medium storing instructions that are executable by a processor, the computer program code means for causing a processor to perform a method and/or the signal representing a tumour heterogeneity score that indicates the heterogeneity of a tumour for diagnosing the subject (mental process of a judgement, which is capable of being performed using the human mind contemplating the pre-computed heterogeneity score), predicting a treatment outcome for the subject (mental process of a judgement, which is capable of being performed using the human mind contemplating the pre-computed heterogeneity score) or predicting an optimal treatment strategy for the subject (mental process of a judgement, which is capable of being performed using the human mind contemplating the pre-computed heterogeneity score), wherein the diagnosing or predicting is based on the tumour heterogeneity score (the input to the mental process as a limitation to the mental process).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-8 and 10-13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by “Yang”. The Yang reference is:
Yang, Zi, and George Michailidis. "Quantifying heterogeneity of expression data based on principal components." Bioinformatics 35.4 (2019): 553-559.
As to claim 1, Yang teaches a method for estimating heterogeneity of a tumour (Yang p. 555 section 2.3 first paragraph: the measurement called α̂ defined on p. 555 column 1 line 25 and called α̂ d for a particular value of d) based on values for two or more genome mutation (this element is claimed in the alternative and does not need to be matched) and/or gene expression related parameters (Yang title “Quantifying heterogeneity of expression data based on principal components”) for at least two spatially differentiated areas in a sample (Yang p. 554 section 2.2 second paragraph: for at least two disease subtypes or subpopulations), the sample being a tissue sample of a tumour or a liquid sample obtained from a subject having the tumour (Yang p. 556: cancer samples as cell lines), and wherein the sample is a single biopsy obtained from said tumour or liquid sample (Yang, p. 557 column 1 lines 13-24: 39 at least one cell line, which, by definition, is typically obtained from a single cancer patient sample), the method comprising the steps of:
determining a sample heterogeneity score for the heterogeneity of the sample (Yang p. 555 section 2.3 first paragraph: the measurement called α̂ defined on p. 555 column 1 line 25 and called α̂ d for a particular value of d) based on variabilities of each measured value (Yang p. 555 column 1 lines 22-32: the score α̂ is based on the loadings from singular vectors; the singular vectors were part of the principle components analysis, according to p. 554 column 1 section 2.1 second paragraph; and the principle components analysis is based on the variabilities of the measured expression data) for the at least two (Yang p. 554 section 2.2 second paragraph: for at least two disease subtypes or subpopulations) spatially differentiated areas (subpopulations are presumed to be in different areas by at least some small distance);
estimating the heterogeneity of the tumour by extrapolating the score for the heterogeneity of the sample to the tumour (Yang p. 555 section 2.3 first paragraph: the measurement called α̂ defined on p. 555 column 1 line 25 and called α̂ d for a particular value of d), thereby providing a tumour heterogeneity score, wherein the step of determining the sample heterogeneity score comprises the step of performing a Principal Component Analysis, PCA (Yang p. 555 column 1 lines 22-32: the score α̂ is based on the loadings from singular vectors; the singular vectors were part of the principle components analysis, according to p. 554 column 1 section 2.1 second paragraph), for converting the two or more genome mutation (this element is claimed in the alternative and does not need to be matched) and/or gene expression related parameters into principle components (Yang title “Quantifying heterogeneity of expression data based on principal components”), thereby reducing correlations between the two or more genome mutation (this element is claimed in the alternative and does not need to be matched) and/or gene expression related parameters (Yang p. 554 column 2 lines 7-10: minimizing sum-of-squared residuals during principal components analysis),
wherein the step of determining the sample heterogeneity score (Yang p. 555 section 2.3 first paragraph: the measurement called α̂) comprises the steps of:
computing standard deviations for each of the principle components (Yang p. 554 section 2.1 first paragraph: computing variances for principal components analysis; standard deviations are at once envisaged from variances)and determining the sample heterogeneity score for the heterogeneity of the sample based on the computed standard deviations (Yang p. 555 section 2.3 first paragraph: the measurement called α̂ defined on p. 555 column 1 line 25 and called α̂ d for a particular value of d);
wherein said step of estimating said sample heterogeneity score for the heterogeneity of the sample, comprises any of:
multiplying each of said variabilities of each measured value for the at least two spatially differentiated areas with each other (Yang p. 555 column 1 line 22-34: the measurement called α̂ and called α̂ d for a particular value of d is based on the loadings which are multiplied), and
summing each of said variabilities of each measured value for the at least two spatially differentiated areas (Yang p. 555 column 1 line 22-34: the measurement called α̂ and called α̂ d for a particular value of d involves a sum); and
wherein said method further comprises the step of:
providing a base transformation matrix, M, constructed from samples from different areas of tumours of multiple subjects (Yang p. 555 column 1 line 22-34: the measurement called α̂ and called α̂ d for a particular value of d is based on the loadings, which are part of the transformation matrix W and the loadings), wherein the base transformation matrix M is a frozen base (Yang p. 555 column 1 line 22-34: the frozen base is d), and
wherein the heterogeneity score is determined by transforming the parameters of multiple subsamples of a single sample into the space created by the frozen base as a way to represent the molecular constitution of each subsample by a multi-dimensional vector (Yang p. 555 column 1 line 22-34: the measurement called α̂ is define formulaically using the principal component space and the base d and involves multiple dimensions d), and
combining the resulting multi-dimensional vectors by first estimating the variability in each direction and then summarizing or multiplying the multi-dimensional variability vectors into one single score (Yang p. 555 column 1 line 22-34: the measurement called α̂ is define formulaically using multiplication of the loadings information).
As to claim 2, Yang teaches the method according to claim 1, wherein the method is a computer implemented method (Yang p. 556 section 3.1 title: “Simulation”).
As to claim 3, Yang teaches the method according to claim 1, wherein the method further comprises the step of providing the single biopsy obtained from a subject (Yang, p. 557 column 1 lines 13-24: 39 at least one cell line, which, by definition, is typically obtained from a single cancer patient sample) and determining the values for two or more genome mutation and/or gene expression related parameters in the single biopsy (Yang title “Quantifying heterogeneity of expression data based on principal components” emphasis added);
As to claim 4, Yang teaches a method in accordance with claim 1, wherein the step of performing the PCA comprises:
determining mean values for each of the two or more genome mutation and/or gene expression related parameters based on the measured values (Yang p. 554 column 2 lines 7-11: computing residuals, which involves determining means);
subtracting each of the measured values by a mean value of its corresponding genome mutation and/or gene expression related parameter (Yang p. 554 column 2 lines 7-11: computing residuals)
As to claim 5, Yang teaches a method in accordance with claim 1, wherein the method further comprises one or more steps selected from:
deciding a treatment strategy for the subject based at least in part on the tumour heterogeneity score (Yang p. 557 column 1 lines 13-24: pre and post treatment effects using the method of Yang, which involves the scores in Table 1);
predicting a treatment outcome for the subject based at least in part on the tumour heterogeneity score (this element is claimed in the alternative and does not need to be mapped);
predicting a survival probability for the subject based at least in part on the tumour heterogeneity score (this element is claimed in the alternative and does not need to be mapped);
predicting resistance to a therapy (this element is claimed in the alternative and does not need to be mapped)
deciding on the efficacy of therapy administered prior to the heterogeneity analysis (this element is claimed in the alternative and does not need to be mapped)
deciding on resistance to therapy administered prior to the heterogeneity analysis (this element is claimed in the alternative and does not need to be mapped).
As to claim 6, Yang teaches a method in accordance with claim 1, wherein said gene expression related parameters are gene expression levels of three or more target genes each of one or more cellular signalling pathway selected from the group consisting of ER, AR, HH, PI3K-FOXO, WNT, TGFbeta, NFkB, JAK-STAT1/2, JAK-STAT3, Notch, PR and MAPK-AP1, preferably wherein said gene expression related parameters are cellular signalling pathway activities based on the three or more target genes expression levels for said cellular signalling pathway, more preferably wherein said cellular signalling pathway activity is selected from the group consisting of ER, AR, HH, PI3K-FOXO, WNT, TGFbeta, NFkB, JAK-STAT1/2, JAK-STAT3, Notch, PR and MAPK-AP1 cellular signalling pathway activity (Yang p. 557 column 1 lines 3-23 suggests that the expression analysis was genome-wide, which would comprise at least three genes as part of a full list of genes; as evidence of the definition of the data used by Yang, see the evidentiary reference: Niepel, Mario, et al. "Analysis of growth factor signaling in genetically diverse breast cancer lines." BMC biology 12.1 (2014): 20).
As to claim 7, Yang teaches a method in accordance with claim 1, wherein said step of estimating the heterogeneity of the tumour comprises:
setting an upper bound for the tumour heterogeneity score as the sample heterogeneity score (Yang p. 555 section 2.3 first paragraph: determining scores for complete heterogeneity or homogeneity).
As to claim 8, Yang teaches an apparatus comprising a processor configured to perform a method in accordance with claim 7 (Yang p. 556 section 3.1 title: “Simulation”; see the mapping of the claims that this claim depends from).
As to claim 10, Yang teaches a non transitory storage medium storing instructions that are executable by a processor to perform a method in accordance with claim 1 (Yang p. 556 section 3.1 title: “Simulation”; see the mapping of the claims that this claim depends from).
As to claim 11, Yang teaches a computer program comprising program code means for causing a processor to perform a method in accordance with claim 1 (Yang p. 556 section 3.1 title: “Simulation”; see the mapping of the claims that this claim depends from).
As to claim 12, Yang teaches a signal representing a tumour heterogeneity score that indicates the heterogeneity of a tumour (Yang p. 555 section 2.3 first paragraph: the measurement called α̂ defined on p. 555 column 1 line 25 and called α̂ d for a particular value of d), wherein the tumour heterogeneity score results from performing a method in accordance with claim 1 (Yang p. 556 section 3.1 title: “Simulation”; see the mapping of the claims that this claim depends from).
As to claim 13, Yang teaches use of the apparatus according to claim 8, the non-transitory storage medium storing instructions that are executable by a processor, the computer program code means for causing a processor to perform a method and/or the signal representing a tumour heterogeneity score that indicates the heterogeneity of a tumour for diagnosing the subject, predicting a treatment outcome for the subject or predicting an optimal treatment strategy for the subject, wherein the diagnosing or predicting is based on the tumour heterogeneity score (Yang p. 557 column 1 lines 13-24: pre and post treatment effects using the method of Yang, which involves the scores in Table 1).
Claim Rejections - 35 USC § 103
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.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over “Yang” in view of “Morrissy”.
The “Yang” reference is: Yang, Zi, and George Michailidis. "Quantifying heterogeneity of expression data based on principal components." Bioinformatics 35.4 (2019): 553-559.
The “Morrissy” references is: Morrissy, A. Sorana, et al. "Spatial heterogeneity in medulloblastoma." Nature genetics 49.5 (2017): 780-788.
As to claim 9, Yang teaches an apparatus in accordance with claim 8, but does not teach wherein said processor is further arranged for:
scanning said sample;
identifying, in said sample, an area of interest;
measuring, for said area of interest, value for the at least two spatially differentiated areas for two or more genome mutation and/or gene expression related parameters.
Nevertheless, Morrissy teaches:
scanning said sample (Morrissy online methods on page 11 of the document in the file wrapper, section “patients and samples”: scanning data from a multi-region biopsy using a bioanalyzer);
identifying, in said sample, an area of interest (Morrissy online methods on page 11 of the document in the file wrapper, section “patients and samples”: identifying a region of interest that is a tumor);
measuring, for said area of interest, value for the at least two spatially differentiated areas for two or more genome mutation and/or gene expression related parameters (Morrissy online methods on page 11 of the document in the file wrapper, section “patients and samples”: using data from spatially separated regions of the tumor for analysis by the bioanalyzer).
Yang and Morrissy are in the same field of bioinformatics. Furthermore, 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 teachings of Yang to include the teachings of Morrissy because “physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor” (See Morrissy’s abstract). There would be a reasonable expectation of success because Yang’s algorithm is ready to input data from separate samples of a common tumor, and Morrissy provides the samples in a spatially separated way.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Niepel, Mario, et al. "Analysis of growth factor signaling in genetically diverse breast cancer lines." BMC biology 12.1 (2014): 20. (Year: 2014)
An evidentiary reference to support terminology and interpretation of the primary reference
Morrissy, A. Sorana, et al. "Spatial heterogeneity in medulloblastoma." Nature genetics 49.5 (2017): 780-788.
US 5945675 A: determining principal components of spectra of a tumor sample
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/JESSE P FRUMKIN/ Primary Examiner, Art Unit 1685 June 25, 2026
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