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 .
Claims Status
Claims 1-5, 10, 11, 20-23, 31-33, & 58 filed on 07/28/2025 are pending. Claims 26-28 are withdrawn from consideration as being drawn to a non-elected invention. Claims 3, 10, 22, & 23 are currently under examination directed to the elected species of tumor in claim 3, of 10 particular genes (LRP1, FTL, CKB, ACTG1, HSP90AB1, CTSB, PKM, FN1, ACTB, & EEF1A1) in claim 10, of the particular SEQ ID NOs. (SEQ ID NOS. 9, 10, 13, 14, 19, 20, 21, 22, 27, 28, 37, 38, 41, 42, 49, 50, 57, 58, 61, & 62) in claim 22, and of the method for calculating the cancer progression risk of a subject from claim 23 (see response dated 02/28/2025). The cancellation of claims 6-9, 12-19, 24, 25, 29, 30, & 34-57 without disclaimer, waiver, or prejudice and the addition of new claim 58 in the response dated 07/28/2025 are acknowledged. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 1-5, 10, 11, 20-23, 31-33, & 58 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.
Regarding amended claim 1, the recitations of “treating an aggressive glioblastoma” in line 1, of “whether the subject has aggressive glioblastoma” in line 3, of “the subject has an aggressive glioblastoma” in lines 10-11, and of “to treat the aggressive glioblastoma” in lines 13-14 of the claim is unclear as to what is meant by “aggressive glioblastoma”. The specification teaches that “glioblastoma (GBM) is the most common and aggressive malignancy of the central nervous system” (paragraph [0033] lines 1-2 of the instant specification). Therefore, the guidance in the instant specification is that GBM is aggressive. However, it is unclear if other species of glioblastomas are aggressive or if GBM is the only aggressive form of glioblastoma. How does “aggressive” differentiate between GBM and other glioblastomas?
Regarding claim 23, the recitation of “deriving a cancer progression risk score model” in line 5 of the claim is unclear and, to overcome this rejection, it is suggested to read “calculating a cancer progression risk score model” or “obtaining a cancer progression risk score model”. In addition, the recitation of “carrying our principal component analysis” in lines 16-17 seems to be the result of a typographical error and should read “carrying out principal component analysis”. In addition, the recitation of “wherein the number principal components generated was equal” in line 10 of the claim is unclear and, to overcome this rejection, it is suggested to read “wherein the number of principal components generated is equal”.
Claims 2-5, 10, 11, 20-22, 31-33, & 58 are rejected due to their dependence on claim 1.
Claim Rejections - 35 USC § 101
Claims 1-5, 10, 11, 20, 21, 23, 31-33, & 58 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method determining a glioblastoma progression risk score as high risk progression risk score when the subject has an aggressive glioblastoma through detecting expression levels of genes. This recitation is a natural correlation between expression levels of genes and high risk of glioblastoma progression and aggressive glioblastoma. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites “calculating the glioblastoma progression risk score of the subject” through deriving a cancer progression risk score model (claim 23) which is the recitation of an abstract idea because it encompasses mathematical concepts and calculations. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of detecting expression levels of genes, calculating the cancer progression risk of the subject, and using the glioblastoma progression gene signature to determine the glioblastoma progression risk score of the subject, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
Although the claims recite “administering a glioblastoma therapeutic or modality” to the subject, this step is conditional as it is requires determining the glioblastoma progression risk score of a subject. Accordingly, these generally recited elements are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step of detecting gene expression or calculating the cancer progression risk score. Additionally, the “administering” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
The steps of detecting gene expression are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. In addition, the steps of calculating the cancer progression risk score are generally recited and incorporates the use of mathematical calculations (See MPEP 2106.04(a)(2)(I)(C)). This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Response to Arguments
The response traverses the rejection. The response asserts that the claims are directed to a methos of treating not an abstract idea or law of nature. Specifically, the response asserts the claims are not “directed to” a natural correlation or abstract ideas and, like the claims in Vanda, the claims are directed to a method of treatment of a specific disease (e.g., an aggressive glioblastoma) that, for sake of argument only, applies a natural correlation and as such the claims are patent eligible under step 2A of the USPTO’s subject matter eligibility guidance and there is no need for a step 2B analysis. This argument has been thoroughly reviewed but was not found persuasive. First, it is reiterated that although the claims recite “administering a glioblastoma therapeutic or modality” to the subject, this step is conditional as it is requires determining the glioblastoma progression risk score of a subject. Accordingly, these generally recited elements are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step of detecting gene expression or calculating the cancer progression risk score. Additionally, the “administering” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. Further, the administration of a glioblastoma therapeutic or modality is very broad and encompasses a wide range of possible treatments and therefore are not meaningful constraints on the administration step such that the particular treatment consideration would apply because it is not limited to a particular glioblastoma therapeutic or modality (see example 49 of 2024 Guidance Update on Patent Subject Matter Eligibility).
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 103
Claim(s) 1, 4, 5, 10, 11, 20, 31-33, & 58 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fatai (Fatai & Gamieldien; BMC Cancer, Vol. 18, pages 1-13, April 2018), in view of Davis (Davis; Clinical Journal Oncology Nurse, Vol.20, pages 1-14, October 2016).
Regarding amended claim 1, Fatai teaches a method of assessing the prognostic value of a gene expression signature in glioblastoma patients to discriminate between rapidly-progressing (high risk progression) and slowly-progressing (low risk progression) patients (glioblastoma progression gene signature) through profiling the expression of genes on the Affymetrix HT HG-U133A platform, in which the Affymetrix U133 platform comprises oligonucleotides that measure the gene expression of genes including the five elected genes of HSP90AB1, FTL, CKB, ACTG1, and LRP1 (abstract background paragraph lines 1-4; abstract methods paragraph lines 1-4; pg. 2 paragraph bridging column 1 & 2 lines 1-12; pg. 3 column 2 1st full paragraph lines 14-16; pg. 6 column 2 1st full paragraph lines 1-14). This corresponds with the teachings of the specification of the instant application, which teaches the use of the Affymetrix U133 assay for profiling the expression of genes in glioblastoma patients (paragraph [0161] of the specification of the instant application).
Fatai does not teach administering a glioblastoma therapeutic or modality to the subject to treat the aggressive glioblastoma.
Davis teaches new therapies can be provided to glioblastoma (GBM) patients with recurrent or newly diagnosed GBM, in which patients with newly diagnosed GBM (low risk of progression) are typically treated with a less aggressive approach with maximal safe surgical resection followed by concurrent radiation and a chemotherapy agent whereas in recurrent GBM (high risk of progression) can be further treated with a more aggressive approach of additional surgery with a greater extent of resection, additional radiation, and chemotherapy (administering a glioblastoma therapeutic or modality to treat the aggressive glioblastoma) (abstract background paragraph lines 1-6; pg. 3-4 paragraph bridging pg. 3 & pg. 4 lines 1-5; pg. 4 1st full paragraph lines 1-6; pg. 6 2nd full paragraph lines 1-10; pg. 6 3rd full paragraph lines 1-4; pg. 6-7 paragraph bridging pg. 6 & pg. 7 lines 1-12). Davis also teaches that new therapies developed for recurrent GBM (high risk of progression) and for newly diagnosed GBM (low risk for progression) can provide hope for enhanced survival (abstract background paragraph lines 1-6).
Fatai and Davis are considered to be analogous to the claimed invention because they are all in the same field of analysis of glioblastoma. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring the glioblastoma progression risk score of a subject as taught in Fatai to follow with the administration of a glioblastoma therapeutic or modality as taught in Davis because Davis teaches that doing so provides hope for enhanced survival.
Regarding claims 4 & 5, Fatai teaches the samples were obtained from GMB (glioblastoma) patients (subject is human and is diagnosed with a cancer) (pg. 2 paragraph bridging column 1 & 2 lines 5-7).
Regarding claim 10 & 11, Fatai teaches profiling the expression of genes on the Affymetrix HT HG-U133A platform, in which the Affymetrix U133 platform comprises oligonucleotides that measure the gene expression of genes including all of the genes listed in claims 10 & 11 of the instant application (pg. 2 paragraph bridging column 1 & 2 lines 1-12), corresponding with the teachings of the specification of the instant application, which teaches the use of the Affymetrix U133 assay for profiling the expression of genes in glioblastoma patients (paragraph [0161] of the specification of the instant application).
Regarding claim 20, Fatai teaches using the Cancer Genome Atlas (TCGA) (detecting using an RNAseq method) to obtain the expression profiles of the GBM patients (pg. 2 paragraph bridging column 1 & 2 lines 1-12).
Regarding amended claims 31 & 32, Davis teaches new therapies can be provided to glioblastoma (GBM) patients with recurrent or newly diagnosed GBM, in which patients with newly diagnosed GBM are typically treated with a less aggressive approach with maximal safe surgical resection followed by concurrent radiation and a chemotherapy agent, including chemotherapeutic treatment with TMZ, whereas in recurrent GBM (high risk of progression) can be further treated with a more aggressive approach of additional surgery with a greater extent of resection, additional radiation, and chemotherapy (high-risk (aggressive) recurrent GBM is resistant to original radiation and chemotherapeutic agent treatment), may be further treated with TMZ but other chemotherapeutic agents such as carboplatin may be used, (TMZ chemotherapeutic resistant glioblastoma) (abstract background paragraph lines 1-6; pg. 3-4 paragraph bridging pg. 3 & pg. 4 lines 1-5; pg. 4 1st full paragraph lines 1-6; pg. 6 2nd full paragraph lines 1-10; pg. 6 3rd full paragraph lines 1-4; pg. 6 4th full paragraph lines 1-6; pg. 6-7 paragraph bridging pg. 6 & pg. 7 lines 1-12).
Regarding amended claim 33, Davis teaches the recurrent (more aggressive) GBM (high risk of progression) can be further treated with a more aggressive approach of additional surgery with a greater extent of resection, additional radiation, and chemotherapy compared to treatment with a less aggressive approach with maximal safe surgical resection followed by concurrent radiation and a chemotherapy agent in newly diagnosed GBM (glioblastoma therapeutic or modality is more aggressive than a current glioblastoma therapeutic or modality that the subject is receiving or has received) (abstract background paragraph lines 1-6; pg. 3-4 paragraph bridging pg. 3 & pg. 4 lines 1-5; pg. 4 1st full paragraph lines 1-6; pg. 6 2nd full paragraph lines 1-10; pg. 6 3rd full paragraph lines 1-4; pg. 6 4th full paragraph lines 1-6; pg. 6-7 paragraph bridging pg. 6 & pg. 7 lines 1-12).
Regarding new claim 58, Davis recurrent GBM may be further treated with TMZ but other chemotherapeutic agents such as carboplatin may be used instead as single agents or in regimens (glioblastoma therapeutic or modality is not TMZ) (pg. 6 4th full paragraph lines 1-6).
Claim(s) 2 & 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fatai (Fatai & Gamieldien; BMC Cancer, Vol. 18, pages 1-13, April 2018) and Davis (Davis; Clinical Journal Oncology Nurse, Vol.20, pages 1-14, October 2016), as applied to claims 1, 4, 5, 10, 11, 20, 31-33, & 58 above, and further in view of Liu (Liu et al.; Scientific Reports, Vol. 3, pages 1-10, December 2013).
Regarding amended claim 2, Fatai teaches profiling the expression of genes on the Affymetrix HT HG-U133A platform, in which the Affymetrix U133 platform comprises oligonucleotides that measure the gene expression of genes including the APP and MME genes (pg. 2 paragraph bridging column 1 & 2 lines 1-12), corresponding with the teachings of the specification of the instant application, which teaches the use of the Affymetrix U133 assay for profiling the expression of genes in glioblastoma patients (paragraph [0161] of the specification of the instant application).
Fatai and Davis does not teach detecting a gene mutation in APP, MME, or both in the biological sample.
Liu teaches a methos for analyzing shared genes in pathways linking Alzheimer’s Disease and GBM in which significant genes were identified including cells transfected with the APP mutation in human glioblastoma cell lines (detecting gene mutation in APP) (abstract lines 3-9, pg. 9 column 1 1st full paragraph lines 1-7). Liu also teaches that this method may be used to offer insights into alternative therapeutic strategies (pg. 8 column 2 2nd full paragraph lines 6-8).
Fatai, Davis, and Liu are considered to be analogous to the claimed invention because they are all in the same field of analysis of glioblastoma. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method the method of measuring the glioblastoma progression risk score of a subject in Fatai followed by the administration of a glioblastoma therapeutic or modality in Davis to incorporate the detection of APP mutation as taught in Liu because Liu teaches that doing so would provide a method to offer insights into alternative therapeutic strategies.
Regarding claim 3, Fatai teaches the samples from the GBM patients were obtained from tumor (pg. 2 paragraph bridging column 1 & 2 lines 5-7).
Claim(s) 20 & 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fatai (Fatai & Gamieldien; BMC Cancer, Vol. 18, pages 1-13, April 2018) and Davis (Davis; Clinical Journal Oncology Nurse, Vol.20, pages 1-14, October 2016), as applied to claims 1, 4, 5, 10, 11, 20, 31-33, & 58 above, and further in view of Ming (Ming et al.; Applied Immunohistochemistry & Molecular Morphology, Vol. 26, pages 101-107, February 2018), Wu (Wu et al.; PLOS One, Vol. 11, pages 1-11, February 2016), Koch (Koch et al.; OncoTarget, Vol. 7, pages 73414-73431, September 2016), Huang (Huang et al.; Asian Pacific Journal of Cancer Prevention, Vol. 12, pages 4793-4799, 2012), and Song (Song et al.; Cancer Research, Vol. 69, pages 879-886, February 2009).
The teachings of Fatai and Davis with respect to claim 1 are discussed above.
Regarding claims 20 & 21, Fatai and Davis does not teach measuring the expression levels of the specific genes LRP1, FTL, CKB, ACTG1, & HSP90AB1 in a sample with a PCR method.
Ming teaches measuring the expression of various biomarkers for gliomas including the gene HSP90AB1 through measuring the expression of HSP90AB1 in glioma tumors using quantitative real-time PCR (qPCR) (abstract background paragraph lines 1-4; abstract results paragraph lines 1-9; abstract conclusions paragraph lines 1-2).
Wu teaches measuring the expression of FTL in glioblastoma multiforme (GBM) patients as a biomarker for GBM with quantitative real-time PCR (qPCR) (abstract paragraph lines 2-6; pg. 2-3 paragraph bridging pg. 2 & pg. 3 lines 1-2).
Koch teaches measuring the expression level of CKB as a biomarker for GBM through measuring the expression of CKB in GBM cells using quantitative real-time PCR (qPCR) (pg. 73416 paragraph bridging column 1 & 2 lines 26-29; pg. 73426 paragraph bridging column 1 & 2 lines 8-12).
Huang teaches measuring the expression of ACTG1 as a biomarker for GBM through measuring the expression of ACTG1 in glioma cells using quantitative real-time PCR (qPCR) (pg. 4794 paragraph bridging column 1 & 2 lines 1-3).
Song teaches measuring the expression of mRNA levels of LRP1 as a biomarker for GBM in glioblastoma cells using quantitative real-time PCR (qPCR) (pg. 881 paragraph bridging column 1 & 2 lines 1-2 & 12-15).
Fatai, Davis, Ming, Wu, Koch, Huang, and Song are considered to be analogous to the claimed invention because they are all in the same field of analysis of glioblastoma. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring the cancer progression risk score of a subject taught by Fatai to measure the expression levels of HSP90AB1, FTL, CKB, ACTG1, and LRP1 with qPCR as taught in Ming, Wu, Koch, Huang, and Song, respectively, to arrive at an assay that measures the expression levels of specific genes because Ming, Wu, Koch, Huang, and Song teach that the genes are biomarkers for glioblastoma and teaches that quantitative PCR was able to successfully provide the gene expression levels for each gene.
Claim(s) 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fatai (Fatai & Gamieldien; BMC Cancer, Vol. 18, pages 1-13, April 2018), Davis (Davis; Clinical Journal Oncology Nurse, Vol.20, pages 1-14, October 2016), Ming (Ming et al.; Applied Immunohistochemistry & Molecular Morphology, Vol. 26, pages 101-107, February 2018), Wu (Wu et al.; PLOS One, Vol. 11, pages 1-11, February 2016), Koch (Koch et al.; OncoTarget, Vol. 7, pages 73414-73431, September 2016), Huang (Huang et al.; Asian Pacific Journal of Cancer Prevention, Vol. 12, pages 4793-4799, 2012), and Song (Song et al.; Cancer Research, Vol. 69, pages 879-886, February 2009), as applied to claims 20 & 21 above, and further in view of GenBank Accession Number AB209498 (July 2016).
The teachings of Fatai, Davis, Ming, Wu, Koch, Huang, and Song with respect to claims 1, 20, & 21 are discussed above.
Regarding claim 22, Fatai, Davis, Ming, Wu, Koch, Huang, and Song does not teach a primer comprising SEQ ID NO: 57, however, Song teaches measuring the expression of mRNA levels of LRP1 as a biomarker for GBM in glioblastoma cells using quantitative real-time PCR (qPCR) with sense and antisense primer sequences (pg. 880 column 1 1st full paragraph lines 1-7; pg. 881 paragraph bridging column 1 & 2 lines 1-2 & 12-15). Additionally, GenBank Accession Number AB209498 teaches the nucleic acid sequence of LRP1 which comprises SEQ ID NO. 57 in the instant application (position 9468 to position 9489 from AB209498) and the nucleic acid sequence of SEQ ID NO. 58 in the instant application (position 9619 to position 9601 from AB209498).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Fatai, Davis, Ming, Wu, Koch, Huang, and Song, by constructing additional primers for the measurement of the expression level of LRP1, for example, comprising SEQ ID NOS 57 and/or 58. The routine nature of constructing primers and/or probes for quantitative PCR is illustrated in the prior art cited (see Ming, Wu, Koch, Huang, and Song). Therefore, absent secondary considerations, primers comprising SEQ ID NO: 57 or 58 are considered obvious in view of the prior art cited.
Response to Arguments
The response traverses the rejection. The response asserts that the office action fails to provide an articulated reason to combine the cited art documents. Specifically, the response asserts that the office action merely labels Ming, Wu, Koch, Huang, and Song “analogous” and asserts their teachings “could be” combined with Fatai and it supplies no KSR-compliant rationale linking those disparate studies to the specific reduction-to-practice recited in claims. These arguments have been thoroughly reviewed but were not found persuasive. First, in response to applicant's argument that Fatai, Davis, Ming, Wu, Koch, Huang, and Song is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Fatai, Ming, Wu, Koch, Huang, and Song are not disparate studies and are all in the same field of detection of expression of gene in glioma samples as biomarkers for GBM. Second, the office action did supply a KSR-compliant rationale through the teachings that quantitative PCR of the specific genes of Ming, Wu, Koch, Huang, and Song were able to successfully provide gene expression levels for each gene in glioma tumor samples (see MPEP 2141(III)(G)). Further, as Fatai teaches a method of assessing the prognostic value of a gene expression signature in glioblastoma patients (glioblastoma progression gene signature) through profiling the expression of genes on the Affymetrix HT HG-U133A platform, in which the Affymetrix U133 platform comprises oligonucleotides that measure the gene expression of genes including the five elected genes of HSP90AB1, FTL, CKB, ACTG1, and LRP1, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring the cancer progression risk score of a subject taught by Fatai to measure the expression levels of HSP90AB1, FTL, CKB, ACTG1, and LRP1 with qPCR to incorporate into the cancer progression risk score in Fatai because Ming, Wu, Koch, Huang, and Song that the expression of each of these five specific genes can be measured successfully in glioma tumor samples.
The response also asserts that the office action impermissibly equates analogous art status with articulated rationale. Specifically, the response asserts that the office action has not established a prima facie case of obviousness as the office action has failed to provide clearly articulated rationale that there is motivation to combine the teachings of Ming, Huang, Koch, Song, and Wu with Fatai with any expectation of success. These arguments have been thoroughly reviewed but were not found persuasive as the ability of Ming, Wu, Koch, Huang, and Song in successfully measuring HSP90AB1, FTL, CKB, ACTG1, and LRP1 with qPCR in glioma tumor samples provides a reasonable expectation of success that the method of measuring the cancer progression risk score in glioblastoma tumors through profiling the expression of genes on the Affymetrix HT HG-U133A platform, which comprises oligonucleotides that measure the gene expression of genes including the genes of HSP90AB1, FTL, CKB, ACTG1, and LRP1, as taught in Fatai can be combined the teachings of Ming, Huang, Koch, Song, and Wu and for the reasons set forth above.
The response also asserts that the office action fails to provide a reasonable expectation of success. Specifically, the response asserts that the office action contains no findings, let alone evidence, that addressing the known unpredictability of mixing machine-learning pipelines from Ming with ddPCR primer design from Huang/Koch/Song/Wu so to remedy the deficiencies of Fatai. These arguments have been thoroughly reviewed but were not found persuasive. First, the teachings of machine-learning pipeline from Ming were not relied upon and instead the teachings of Ming relied upon to teach that the expression of the gene HSP90AB1 could be successfully measured in glioma tumors using quantitative real-time PCR (qPCR). Second, these arguments were not found persuasive for the reasons set forth above.
The response also asserts that the office action impermissibly relies on hindsight reasoning or “common sense” without explanation. Specifically, the response asserts that rather than point to a single reference (or a rational combination) that would have led a skilled artisan to the claimed 5-gene panel, the office action reads the claims and then cherry-picks one gene apiece from five unrelated papers and that none of the cited references teaches, suggests, or even mentions measuring LRP1, FTL, CKB, ACTG1, and HSP90AB1 together to calculate a cancer-progression risk score and Fatai omits every one of these genes. These arguments have been thoroughly reviewed but were not found persuasive. First, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Second, Fatai does not omit every one of these genes and in fact teaches profiling the expression of genes on the Affymetrix HT HG-U133A platform, which comprises oligonucleotides that measure the gene expression of genes including the genes of HSP90AB1, FTL, CKB, ACTG1, and LRP1 and Fatai teaches assessing the prognostic value of a gene expression signature in glioblastoma patients (i.e., glioblastoma progression gene signature) through this method of profiling the expression of genes on the Affymetrix HT HG-U133A platform.
The response also asserts that the office action fails to establish a prima facie case of obviousness with respect to claim 22 for at least the same reasons discussed with respect to the 103 rection of claim 21 and that the rejection of claim 22 fails to at least articulate as to why one of ordinary skill in the art would make the combination of references including GenBank Accession Number AB209498. These arguments have been thoroughly reviewed but were not found persuasive. First, Song teaches measuring the expression of mRNA levels of LRP1 as a biomarker for GBM in glioblastoma cells using quantitative real-time PCR (qPCR) with sense and antisense primer sequences and GenBank Accession Number AB209498 teaches the nucleic acid sequence of LRP1 which comprises SEQ ID NO. 57 in the instant application (position 9468 to position 9489 from AB209498) and the nucleic acid sequence of SEQ ID NO. 58 in the instant application (position 9619 to position 9601 from AB209498), therefore it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Fatai, Davis, Ming, Wu, Koch, Huang, and Song, by constructing additional primers for the measurement of the expression level of LRP1, for example, comprising SEQ ID NOS 57 and/or 58 as the routine nature of constructing primers and/or probes for quantitative PCR is illustrated in the prior art cited (see Ming, Wu, Koch, Huang, and Song). Therefore, absent secondary considerations, primers comprising SEQ ID NO: 57 or 58 are considered obvious in view of the prior art cited.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
It is noted, as noted in previous office action dated 03/26/2025, that a method of determining a glioblastoma progression risk score as recited in claim 1 by detecting expression levels of LRP1, FTL, CKB, ACTG1, HSP90AB1, CTSB, PKM, FN1, ACTB, & EEF1A1 with the primers comprising SEQ ID NOS: 9, 10, 13, 14, 19, 20, 21, 22, 27, 28, 37, 38, 41, 42, 49, 50, 57, 58, 61, & 62 is free of the prior art.
Claims 1-5, 10, 11, 20-23, 31-33, & 58 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached on (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682