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 1-7, 10-14, 26, 30, 31, & 40-42 filed on 05/05/2026 are pending. Claim 33 is withdrawn from consideration as being drawn to a non-elected invention. Claims 1, 3, 5, 7, 31, & 41 are currently under examination directed to the elected species of (i) ANLN, ESR1, PGR, & SLC39A6 and (ii) SFRS1, DNAJC6, FBXO5, DCK, & TMPO in claims 1, 3, 5, 14, & 31, of 8 housekeeping genes of ACTB, MRPL19, PSMC4, RPLP0, SF3A1, GUSB, PUM1, & TFRC in claim 7, of all (i)-(iv) in claim 31, and of abemaciclib in claim 41 (see response dated 10/28/2025). 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Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.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 10-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 10, the recitation of “when the average log2 gene expression of E2F signature genes is greater than or equal to 9.392 or is greater than or equal to 9.4462” in lines 2-3 of the claim is unclear how this value is calculated and how to determine what expression levels of the elected genes are encompassed by this recitation. In addition, claim 10 contains the trademark/trade name NanoString nCounter. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a form of analysis and, accordingly, the identification/description is indefinite.
Regarding claim 11, the recitation of “when the average log2 gene expression measures less than or equal to 8.4068 or measures less than or equal to 8.4332” in lines 2-3 of the claim is unclear how this value is calculated and how to determine what expression levels of the RB1 gene are encompassed by this recitation. In addition, claim 11 contains the trademark/trade name NanoString nCounter. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a form of analysis and, accordingly, the identification/description is indefinite.
Regarding claim 12, the recitation of “when the average log2 gene expression measures greater than or equal to 8.264 or measures greater than or equal to 7.9596” in lines 2-3 of the claim is unclear how this value is calculated and how to determine what expression levels of the CCNE1 gene are encompassed by this recitation. In addition, claim 12 contains the trademark/trade name NanoString nCounter. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a form of analysis and, accordingly, the identification/description is indefinite.
Regarding claim 13, the recitation of “classifies the sample as luminal when gene expression of the at least four genes is closer to a luminal reference centroid than a non-luminal reference centroid, or as non-luminal otherwise” in lines 2-3 of the claim is unclear. How does the nearest luminal or non-luminal reference centroid classify a sample as luminal or non-luminal? Does all four genes of the at least four genes closer to a luminal reference centroid classify a sample as luminal or all four genes of the at least four genes closer to a non-luminal centroid classify a sample as non-luminal? Only some of the at least four genes closer to a luminal reference centroid classify a sample as luminal or only some of the at least four genes closer to a non-luminal reference centroid classify a sample as non-luminal?
Regarding claim 14, the recitations numerical values in the claim, for example the recitation of “of -0.436597966 and -0.171060579 for ANLN… 0.060331049 and 0.318978765 for UBE2C” in a)-f) of the claim is unclear what the values mean and how are the used in the luminal vs. non-luminal module?
Response to Arguments
The response traverses the rejection. The response asserts that claim 13 is allegedly unclear for lack of clarity of the relationship between the nearest centroid and the sample being luminal or non-luminal and that claim 13 has been amended to recite “when gene expression of the at least four genes is closer to a luminal reference centroid than a non-luminal reference centroid, or as non-luminal otherwise, wherein the luminal reference centroid is derived from measured gene expression of the said at least four genes from a plurality of samples known of luminal phenotype and the non-luminal reference centroid is derived from gene expression of said at least four genes from a plurality of samples known to be of non-luminal phenotype” which applicant believes that this amendment address the rejection. This argument has been thoroughly reviewed but was not found persuasive as this amendment to the claim is unclear. How does the nearest luminal or non-luminal reference centroid classify a sample as luminal or non-luminal? Does all four genes of the at least four genes closer to a luminal reference centroid classify a sample as luminal or all four genes of the at least four genes closer to a non-luminal centroid classify a sample as non-luminal? Only some of the at least four genes closer to a luminal reference centroid classify a sample as luminal or only some of the at least four genes closer to a non-luminal reference centroid classify a sample as non-luminal?
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) 1-5, 13, 14, 26, 31, 40, & 41 is/are rejected under 35 U.S.C. 103 as being unpatentable over Garrido-Castro (Garrido-Castro & Goel; Curr Breast Cancer Rep, Vol. 9, pages 26-33, February 2017), as cited in the IDS dated 03/24/2023, in view of Miller (Miller et al.; Cancer Discover, Vol. 1, pages 338-351, September 2011), as cited in the IDS dated 03/24/2023, as evidenced by Parker (Parker et al.; Journal of Clinical Oncology Vol. 27, pages 1160-1167, February 2009), as cited on the IDS dated 10/24/2023.
Regarding amended claim 1, it is noted that the specification of the instant application teaches that the luminal vs. non-luminal classification may be made according to the PAM50 nearest centroid as disclosed in Parker (Parker et al., J Clin Oncol, 2009, Vol. 27, pages 1160-1167) (paragraph [37] of the instant specification).
Garrido-Castro teaches a method for determining potential biomarkers for sensitivity or resistance to CDK4/6 inhibitors in which the biomarkers comprise measuring a luminal pattern of gene expression as assessed by the PAM50 gene set (abstract purpose of review lines 1-5; pg. 30 1st column 1st full paragraph lines 1-12), in which the PAM50 gene set encompasses the genes of ANLN, ESRL, PGR, and SLC39A6, as evidenced by Parker (abstract purpose lines 1-3; pg. 1164-1165 paragraph bridging pg. 1164 & 1165 lines 1-12; pg. 1166 column 1 1st full paragraph lines 1-6; Supplemental Table 5 of Parker), (measuring gene expression of a luminal vs. non-luminal module comprising at least four genes of ANLN, ESR1, PGR, & SLC39A6), measuring E2F transcription factor activity and expression of E2F target genes (measuring gene expression of a E2F module), measuring expression of RB1 (measuring gene expression of a RB1 module), and measuring expression of CCNE1 (measuring gene expression of CCNE1 module) to predict resistance or sensitivity to CDK4/6 inhibitors in patients with breast cancer (making a prediction of whether the subject will be resistant or sensitive to CDK inhibitor treated based on the sample gene expression profiles of modules (i)-(iv)) (abstract summary lines 1-6; pg. 27 column 2 1st full paragraph lines 13-20; pg. 28 column 2 1st full paragraph lines 9-13; pg. 30 column 2 3rd full paragraph lines 1-18; pg. 31 column 1 2nd full paragraph lines 1-11). Garrido-Castro also teaches that breast cancer with a luminal gene expression pattern might show sensitivity to CDK4/6 inhibitors (resistant to CDK inhibitor if the sample is classified as non-luminal), unconstrained E2F transcription factor activity (high E2F expression) classifies a sample as resistant to CDK4/6 inhibitors (resistant to CDK inhibitor if sample is classified as having high E2F expression), loss of RB1 classifies the sample as resistant to CDK4/6 inhibitors (resistant to CDK inhibitor if sample is classified as having low RB1 expression), and hyperactivity of CCNE1 (high CCNE1 expression) classifies the sample as resistant to CDK4/6 inhibitors (resistant to CDK inhibitors if sample is classified as having high CCNE1 expression) (pg. 30 1st column 1st full paragraph lines 1-12; pg. 30 column 2 3rd full paragraph lines 1-18; pg. 31 column 1 2nd full paragraph lines 1-11).
Garrido-Castro does not teach that the E2F module comprises measuring the gene expression of E2F signature group of DCK, DNAJC9, FBXO5, SFRS1, and TMPO genes.
Miller teaches a E2F activation gene signature that correlates with a lesser response to treatment in breast cancer patients in which this E2F gene signature comprises measuring the expression of DCK, DNAJC9, FBXO5, SFRS1, and TMPO genes (E2F module comprising at least five genes selected from the E2F signature of DCK, DNAJC9, FBXO5, SFRS1, and TMPO) (abstract lines 1-15; pg. 343 column 2 1st full paragraph lines 1-12; Fig. S7B). In addition, Miller teaches that this method is important is supporting further development of ER downregulators and CDK4 inhibitors for the treatment of antiestrogen-resistant breast cancers (abstract significance lines 1-6).
Garrido-Castro and Miller are considered to be analogous to the claimed invention because they are all in the same field of determining response to treatment in breast cancer patients with expression of E2F genes. 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 E2F transcription factor activity and expression of E2F target genes to determine resistance or sensitivity to CDK4/6 inhibitors in breast cancer patients in Garrido-Castro to incorporate measuring an E2F gene signature comprising the expression of DCK, DNAJC9, FBXO5, SFRS1, and TMPO as taught in Miller because Miller teaches that doing so would provide a method that is important in supporting further development of CDK4 inhibitors for the treatment of antiestrogen-resistant breast cancer.
Regarding amended claim 2, Garrido-Castro teaches measuring a luminal pattern of gene expression as assessed by the PAM50 gene set (pg. 30 1st column 1st full paragraph lines 1-12), in which the PAM50 gene set encompasses the genes of ANLN, ESRL, PGR, and SLC39A6, as evidenced by Parker (abstract purpose lines 1-3; pg. 1164-1165 paragraph bridging pg. 1164 & 1165 lines 1-12; pg. 1166 column 1 1st full paragraph lines 1-6; Supplemental Table 5 of Parker), (measuring gene expression of a luminal vs. non-luminal module comprising genes of ANLN, ESR1, PGR, & SLC39A6).
Regarding amended claim 3, Garrido-Castro teaches measuring a luminal pattern of gene expression as assessed by the PAM50 gene set (pg. 30 1st column 1st full paragraph lines 1-12), in which the PAM50 gene set encompasses the all of the genes listed in claim 3, as evidenced by Parker (abstract purpose lines 1-3; pg. 1164-1165 paragraph bridging pg. 1164 & 1165 lines 1-12; pg. 1166 column 1 1st full paragraph lines 1-6; Supplemental Table 5 of Parker), (measuring gene expression of a luminal vs. non-luminal module comprising genes of claim 3 lines 2-6).
Regarding amended claim 4, Miller teaches measuring a E2F activation gene signature in which this E2F gene signature comprises measuring the expression of DCK, DNAJC9, FBXO5, SFRS1, and TMPO genes (E2F module comprising at least five genes of DCK, DNAJC9, FBXO5, SFRS1, and TMPO) (abstract lines 1-15; pg. 343 column 2 1st full paragraph lines 1-12; Fig. S7B).
Regarding amended claim 5, Miller teaches measuring a E2F activation gene signature in which this E2F gene signature comprises measuring the expression of all of the genes listed in claim 5 (E2F module comprising genes of claim 5 lines 2-4) (abstract lines 1-15; pg. 343 column 2 1st full paragraph lines 1-12; Fig. S7B).
Regarding amended claim 13, it is noted that the specification of the instant application teaches that the luminal vs. non-luminal classification may be made according to the PAM50 nearest centroid as disclosed in Parker (Parker et al., J Clin Oncol, 2009, Vol. 27, pages 1160-1167) (paragraph [37] of the instant specification).
Garrido-Castro teaches measuring a luminal pattern of gene expression as assessed by the PAM50 gene set (abstract purpose of review lines 1-5; pg. 30 1st column 1st full paragraph lines 1-12), in which the PAM50 gene set encompasses centroid-based prediction methods comprising classifying the sample on classification of the nearest centroid (the luminal vs. non-luminal module classifies the sample as luminal vs. non-luminal on the basis of the nearest centroid), as evidenced by Parker (abstract purpose lines 1-3; pg. 1161 column 2 5th full paragraph lines 1-9; pg. 1164-1165 paragraph bridging pg. 1164 & 1165 lines 1-12; pg. 1166 column 1 1st full paragraph lines 1-6; Supplemental Table 5 of Parker).
Regarding amended claim 14, as discussed above the recitations numerical values in the claim, for example the recitation of “of -0.436597966 and -0.171060579 for ANLN… 0.060331049 and 0.318978765 for UBE2C” in a)-f) of the claim is unclear what the values mean and how are the used in the luminal vs. non-luminal module? Therefore, for the purposes of this rejection it is interpreted that claim 14 require measuring the expression of the elected genes of ANLN, ESR1, PGR, and SLC39A6 (a) for classifying a sample as luminal vs. non-luminal.
Garrido-Castro teaches measuring a luminal pattern of gene expression as assessed by the PAM50 gene set (pg. 30 1st column 1st full paragraph lines 1-12), in which the PAM50 gene set encompasses the genes of ANLN, ESRL, PGR, and SLC39A6, as evidenced by Parker (abstract purpose lines 1-3; pg. 1164-1165 paragraph bridging pg. 1164 & 1165 lines 1-12; pg. 1166 column 1 1st full paragraph lines 1-6; Supplemental Table 5 of Parker), (measuring gene expression of a luminal vs. non-luminal module of (a) comprising genes of ANLN, ESR1, PGR, & SLC39A6).
Regarding amended claim 26, Garrido-Castro teaches a method for determining potential biomarkers for sensitivity or resistance to CDK4/6 inhibitors in which determining sensitivity to CDK4/6 inhibitors identifies useful clinical markers for potential candidates for CDK4/6 inhibitor therapy (administering a therapeutically effective amount of a CDK inhibitor if subject is predicted to be sensitive to CDK inhibitor therapy) (pg. 29-30 paragraph bridging pg. 29 & pg. 30 lines 20-25).
Regarding amended claim 31, it is noted that the specification of the instant application teaches that the luminal vs. non-luminal classification may be made according to the PAM50 nearest centroid as disclosed in Parker (Parker et al., J Clin Oncol, 2009, Vol. 27, pages 1160-1167) (paragraph [37] of the instant specification).
Garrido-Castro teaches a method for determining potential biomarkers for sensitivity or resistance to CDK4/6 inhibitors in which the biomarkers comprise measuring a luminal pattern of gene expression as assessed by the PAM50 gene set (abstract purpose of review lines 1-5; pg. 30 1st column 1st full paragraph lines 1-12), in which the PAM50 gene set encompasses the genes of ANLN, ESRL, PGR, and SLC39A6, as evidenced by Parker (abstract purpose lines 1-3; pg. 1164-1165 paragraph bridging pg. 1164 & 1165 lines 1-12; pg. 1166 column 1 1st full paragraph lines 1-6; Supplemental Table 5 of Parker), (measuring gene expression of a luminal vs. non-luminal module comprising at least four genes of ANLN, ESR1, PGR, & SLC39A6), measuring E2F transcription factor activity and expression of E2F target genes (measuring gene expression of a E2F module), measuring expression of RB1 (measuring gene expression of a RB1 module), and measuring expression of CCNE1 (measuring gene expression of CCNE1 module) to predict resistance or sensitivity to CDK4/6 inhibitors in patients with breast cancer (making a prediction of whether the subject will be resistant or sensitive to CDK inhibitor treated based on the sample gene expression profiles of modules (i)-(iv)) (abstract summary lines 1-6; pg. 27 column 2 1st full paragraph lines 13-20; pg. 28 column 2 1st full paragraph lines 9-13; pg. 30 column 2 3rd full paragraph lines 1-18; pg. 31 column 1 2nd full paragraph lines 1-11). Garrido-Castro also teaches that breast cancer with a luminal gene expression pattern might show sensitivity to CDK4/6 inhibitors (resistant to CDK inhibitor if the sample is classified as non-luminal), unconstrained E2F transcription factor activity (high E2F expression) classifies a sample as resistant to CDK4/6 inhibitors (resistant to CDK inhibitor if sample is classified as having high E2F expression), loss of RB1 classifies the sample as resistant to CDK4/6 inhibitors (resistant to CDK inhibitor if sample is classified as having low RB1 expression), and hyperactivity of CCNE1 (high CCNE1 expression) classifies the sample as resistant to CDK4/6 inhibitors (resistant to CDK inhibitors if sample is classified as having high CCNE1 expression) (pg. 30 1st column 1st full paragraph lines 1-12; pg. 30 column 2 3rd full paragraph lines 1-18; pg. 31 column 1 2nd full paragraph lines 1-11).
Garrido-Castro does not teach that the E2F module comprises measuring the gene expression of E2F signature group of DCK, DNAJC9, FBXO5, SFRS1, and TMPO genes.
Miller teaches a E2F activation gene signature that correlates with a lesser response to treatment in breast cancer patients in which this E2F gene signature comprises measuring the expression of DCK, DNAJC9, FBXO5, SFRS1, and TMPO genes (E2F module comprising at least five genes of DCK, DNAJC9, FBXO5, SFRS1, and TMPO) (abstract lines 1-15; pg. 343 column 2 1st full paragraph lines 1-12; Fig. S7B). In addition, Miller teaches that this method is important is supporting further development of ER downregulators and CDK4 inhibitors for the treatment of antiestrogen-resistant breast cancers (abstract significance lines 1-6).
Garrido-Castro and Miller are considered to be analogous to the claimed invention because they are all in the same field of determining response to treatment in breast cancer patients with expression of E2F genes. 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 E2F transcription factor activity and expression of E2F target genes to determine resistance or sensitivity to CDK4/6 inhibitors in breast cancer patients in Garrido-Castro to incorporate measuring an E2F gene signature comprising the expression of DCK, DNAJC9, FBXO5, SFRS1, and TMPO as taught in Miller because Miller teaches that doing so would provide a method that is important in supporting further development of CDK4 inhibitors for the treatment of antiestrogen-resistant breast cancer.
Regarding claims amended 40 & 41, Garrido-Castro teaches CDK4/6 inhibitors including abemaciclib (CDK inhibitor administered to the subject is CDK4/6 inhibitor of abemaciclib) (pg. 26-27 paragraph bridging pg. 26 & pg. 27 lines 1-17; pg. 29-30 paragraph bridging pg. 29 & pg. 30 lines 20-25).
Claim(s) 6 & 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Garrido-Castro (Garrido-Castro & Goel; Curr Breast Cancer Rep, Vol. 9, pages 26-33, February 2017), as cited in the IDS dated 03/24/2023, and Miller (Miller et al.; Cancer Discover, Vol. 1, pages 338-351, September 2011), as cited in the IDS dated 03/24/2023, as evidenced by Parker (Parker et al.; Journal of Clinical Oncology Vol. 27, pages 1160-1167, February 2009), as cited on the IDS dated 10/24/2023 as applied to claims 1-5, 13, 14, 26, 31, 40, & 41 above, and further in view of Perou (United States Patent Application Publication US 2019/0264290 A1).
The teachings of Garrido-Castro and Miller with respect to claim 1 is discussed above.
Regarding amended claims 6 & 7, Garrido-Castro & Miller does not teach measuring the expression of at least 8 housekeeping genes.
Perou teaches a method of predicting outcome or response to therapy of a subject diagnosed with or suspected of having breast cancer through measuring a gene expression profile comprising normalizing gene expression values to a set of housekeeping genes comprising ACTB, MRPL19, PSMC4, RPLP0, SF3A1, GUSB, PUM1, and TFRC (measuring the gene expression of at least 8 housekeeping genes comprising ACTB, MRPL19, PSMC4, RPLP0, SF3A1, GUSB, PUM1, and TFRC) (abstract lines 1-18; pg. 53 claim 6 lines 1-2; pg. 53 claim 7 lines 1-3). In addition, Perou teaches that expression profiling of breast cancer is important in identifying biologically and clinically different molecular subtypes that may require different treatment approaches (paragraph [0022] lines 1-3).
Garrido-Castro, Miller, and Perou are considered to be analogous to the claimed invention because they are all in the same field of measuring expression of genes in breast cancer patients to asses response to therapy. 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 a gene expression profile comprising modules (i)-(iv) to determine resistance or sensitivity to CDK4/6 inhibitors in breast cancer patients in Garrido-Castro to incorporate measuring a set of housekeeping genes comprising ACTB, MRPL19, PSMC4, RPLP0, SF3A1, GUSB, PUM1, and TFRC as taught in Perou because Perou teaches that doing so would provide a method that is important in identifying biologically and clinically different molecular subtypes that may require different treatment approaches.
Claim(s) 10-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Garrido-Castro (Garrido-Castro & Goel; Curr Breast Cancer Rep, Vol. 9, pages 26-33, February 2017), as cited in the IDS dated 03/24/2023, and Miller (Miller et al.; Cancer Discover, Vol. 1, pages 338-351, September 2011), as cited in the IDS dated 03/24/2023, as evidenced by Parker (Parker et al.; Journal of Clinical Oncology Vol. 27, pages 1160-1167, February 2009), as cited on the IDS dated 10/24/2023 as applied to claims 1-5, 13, 14, 26, 31, 40, & 41 above, and further in view of Picornell (Picornell et al.; BMC Genomics, Vol. 20, pages 1-11, June 2019).
The teachings of Garrido-Castro and Miller with respect to claim 1 is discussed above.
Regarding amended claim 10, as discussed above, the recitation of “when the average log2 gene expression of E2F signature genes is greater than or equal to 9.392 or is greater than or equal to 9.4462” in lines 2-3 of the claim is unclear how this value is calculated and how to determine what expression levels of the elected genes are encompassed by this recitation. Further, the claim does not define how to calculate these average log2 gene expression values. Garrido-Castro teaches measuring E2F transcription factor activity and expression of E2F target genes (measuring gene expression of a E2F module). Therefore, the average log2 gene expression is taken to be inherent to the genes themselves (average log2 gene expression of E2F signature genes is greater than or equal to 9.392 or is greater than or equal to 9.4462) (pg. 30 column 2 3rd full paragraph lines 1-18).
Garrido-Castro and Miller does not teach wherein the gene expression level is of E2F signature genes is measured using NanoString nCounter analysis of RNA-seq analysis.
Picornell teaches analysis of gene expression in breast cancer samples with both digital multiplexed gene expression platform of a NanoString nCounter and through RNA-seq platforms (abstract background lines 1-6; abstract results lines 1-9; pg. 2 column 1 1st full paragraph lines 1-10; pg. 2 column 1 2nd full paragraph lines 1-10; pg. 2 column 1 3rd full paragraph lines 1-15; pg. 2 paragraph bridging column 1 & 2 lines 1-8 & 17-21). In addition, Picornell teaches that the digital multiplexed platform of the NanoString nCounter enabled for quick and cost effective analysis of gene expression in breast cancer samples and RNA-seq enabled analysis of whole genome expression patterns in breast cancer samples (abstract conclusions lines 1-4).
Garrido-Castro, Miller, and Picornell are considered to be analogous to the claimed invention because they are all in the same field of measuring expression of genes in breast cancer patients. 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 a gene expression level of E2F signature genes in breast cancer patients in Garrido-Castro to incorporate analysis of gene expression in breast cancer samples with both digital multiplexed gene expression platform of a NanoString nCounter and through RNA-seq platforms as taught in Picornell because Picornell teaches that doing so would provide a method enables for quick and cost effective analysis of gene expression in breast cancer samples with the digital multiplexed platform of the NanoString nCounter and enables analysis of whole genome expression patterns in breast cancer samples with RNA-seq.
Regarding amended claim 11, as discussed above, the recitation of “when the average log2 gene expression measures less than or equal to 8.4068 or measures less than or equal to 8.4332” in lines 2-3 of the claim is unclear how this value is calculated and how to determine what expression levels of the RB1 gene are encompassed by this recitation. Further, the claim does not define how to calculate these average log2 gene expression values. Garrido-Castro teaches measuring expression of RB1 (measuring gene expression of a RB1 module). Therefore, the average log2 gene expression is taken to be inherent to the genes themselves (average log2 gene expression measures less than or equal to 8.4068 or measures less than or equal to 8.4332) (pg. 30 column 2 3rd full paragraph lines 1-18).
Garrido-Castro and Miller does not teach wherein the gene expression level is of RB1 is measured using NanoString nCounter analysis of RNA-seq analysis.
Picornell teaches analysis of gene expression in breast cancer samples with both digital multiplexed gene expression platform of a NanoString nCounter and through RNA-seq platforms (abstract background lines 1-6; abstract results lines 1-9; pg. 2 column 1 1st full paragraph lines 1-10; pg. 2 column 1 2nd full paragraph lines 1-10; pg. 2 column 1 3rd full paragraph lines 1-15; pg. 2 paragraph bridging column 1 & 2 lines 1-8 & 17-21). In addition, Picornell teaches that the digital multiplexed platform of the NanoString nCounter enabled for quick and cost effective analysis of gene expression in breast cancer samples and RNA-seq enabled analysis of whole genome expression patterns in breast cancer samples (abstract conclusions lines 1-4).
Garrido-Castro, Miller, and Picornell are considered to be analogous to the claimed invention because they are all in the same field of measuring expression of genes in breast cancer patients. 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 a gene expression level of RB1 in breast cancer patients in Garrido-Castro to incorporate analysis of gene expression in breast cancer samples with both digital multiplexed gene expression platform of a NanoString nCounter and through RNA-seq platforms as taught in Picornell because Picornell teaches that doing so would provide a method enables for quick and cost effective analysis of gene expression in breast cancer samples with the digital multiplexed platform of the NanoString nCounter and enables analysis of whole genome expression patterns in breast cancer samples with RNA-seq.
Regarding amended claim 12, as discussed above, the recitation of “when the average log2 gene expression measures greater than or equal to 8.264 or measures greater than or equal to 7.9596” in lines 2-3 of the claim is unclear how this value is calculated and how to determine what expression levels of the CCN1E gene are encompassed by this recitation. Further, the claim does not define how to calculi these average log2 gene expression values. Garrido-Castro teaches measuring expression of CCNE1 (measuring gene expression of CCNE1 module). Therefore, the average log2 gene expression is taken to be inherent to the genes themselves (average log2 gene expression measures greater than or equal to 8.264 or measures greater than or equal to 7.9596) (pg. 31 column 1 2nd full paragraph lines 1-11).
Garrido-Castro and Miller does not teach wherein the gene expression level is of CCNE1 is measured using NanoString nCounter analysis of RNA-seq analysis.
Picornell teaches analysis of gene expression in breast cancer samples with both digital multiplexed gene expression platform of a NanoString nCounter and through RNA-seq platforms (abstract background lines 1-6; abstract results lines 1-9; pg. 2 column 1 1st full paragraph lines 1-10; pg. 2 column 1 2nd full paragraph lines 1-10; pg. 2 column 1 3rd full paragraph lines 1-15; pg. 2 paragraph bridging column 1 & 2 lines 1-8 & 17-21). In addition, Picornell teaches that the digital multiplexed platform of the NanoString nCounter enabled for quick and cost effective analysis of gene expression in breast cancer samples and RNA-seq enabled analysis of whole genome expression patterns in breast cancer samples (abstract conclusions lines 1-4).
Garrido-Castro, Miller, and Picornell are considered to be analogous to the claimed invention because they are all in the same field of measuring expression of genes in breast cancer patients. 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 a gene expression level of CCNE1 in breast cancer patients in Garrido-Castro to incorporate analysis of gene expression in breast cancer samples with both digital multiplexed gene expression platform of a NanoString nCounter and through RNA-seq platforms as taught in Picornell because Picornell teaches that doing so would provide a method enables for quick and cost effective analysis of gene expression in breast cancer samples with the digital multiplexed platform of the NanoString nCounter and enables analysis of whole genome expression patterns in breast cancer samples with RNA-seq.
Claim(s) 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Garrido-Castro (Garrido-Castro & Goel; Curr Breast Cancer Rep, Vol. 9, pages 26-33, February 2017), as cited in the IDS dated 03/24/2023, and Miller (Miller et al.; Cancer Discover, Vol. 1, pages 338-351, September 2011), as cited in the IDS dated 03/24/2023, as evidenced by Parker (Parker et al.; Journal of Clinical Oncology Vol. 27, pages 1160-1167, February 2009), as cited on the IDS dated 10/24/2023 as applied to claims 1-5, 13, 14, 26, 31, 40, & 41 above, and further in view of Buzdar (Buzdar; Semin Oncol, Vol. 28, pages 291-304, June 2001).
The teachings of Garrido-Castro and Miller with respect to claim 1 is discussed above.
Regarding amended claim 30, Garrido-Castro teaches administering a combination of CDK4/6 inhibitors with endocrine therapy when predicting resistance or sensitivity to CDK4/6 inhibitors (pg. 29 column 1 1st full paragraph lines 1-6; pg. 31 column 2 2nd full paragraph lines 1-5).
Garrido-Castro & Miller does not teach administering endocrine therapy in the absence of any CDK4/6 inhibitor.
Buzdar teaches a method of administering treating patients with breast cancer with endocrine therapy (abstract lines 1-10; pg. 292 column 2 2nd full paragraph lines 1-6). In addition, Buzdar teaches endocrine therapy offers an effective treatment in breast cancer patients (pg. 301 column 2 1st full paragraph lines 1-2).
Garrido-Castro, Miller, and Buzdar are considered to be analogous to the claimed invention because they are all in the same field of assessing response to therapy in breast cancer patients. 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 a gene expression profile comprising modules (i)-(iv) to determine resistance or sensitivity to CDK4/6 inhibitors in breast cancer patients and administering a combination of CDK4/6 inhibitors with endocrine therapy when predicting resistance to CDK4/6 inhibitors in Garrido-Castro to incorporate administering endocrine therapy in the absence of a CDK4/6 inhibitor as taught in Buzdar because Buzdar teaches that doing so would provide an effective treatment in patients with breast cancer.
Claim(s) 42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Garrido-Castro (Garrido-Castro & Goel; Curr Breast Cancer Rep, Vol. 9, pages 26-33, February 2017), as cited in the IDS dated 03/24/2023, and Miller (Miller et al.; Cancer Discover, Vol. 1, pages 338-351, September 2011), as cited in the IDS dated 03/24/2023, as evidenced by Parker (Parker et al.; Journal of Clinical Oncology Vol. 27, pages 1160-1167, February 2009), as cited on the IDS dated 10/24/2023 as applied to claims 1-5, 13, 14, 26, 31, 40, & 41 above, and further in view of Raspé (Raspé et al.; EMBO Molecule Medicine, Vol. 9, pages 1052-1066, May 2017).
The teachings of Garrido-Castro and Miller with respect to claim 1 is discussed above.
Regarding amended claim 42, Garrido-Castro does not teach that the total number of genes used in the method is not more than 50.
Raspé teaches a method of measuring a 11 gene expression signature in breast cancer samples to identify breast cancer tumors that were unlikely to respond to CDK4/6 inhibitors (a method for predicting whether a human subject having breast cancer will be resistant to therapy with CDK inhibitor wherein the total number of genes used in the method is not more than 50) (abstract lines 1-18; pg. 1053 paragraph bridging column 1 & 2 lines 5-18). In addition, Raspé teaches that this 11 gene signature correctly identifies sensitivity to treatment with CDK inhibitor in breast cancer samples and may be used for improving treatment selection for patients (pg. 1053 paragraph bridging column 1 & 2 lines 5-18; pg. 1062 column 2 1st full paragraph lines 1-10).
Garrido-Castro, Miller, and Raspé are considered to be analogous to the claimed invention because they are all in the same field of assessing response to therapy in breast cancer patients. 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 a gene expression profile comprising modules (i)-(iv) to determine resistance or sensitivity to CDK4/6 inhibitors in breast cancer patients in Garrido-Castro to incorporate measuring a 11 gene expression signature (total number of genes is not more than 50) in breast cancer samples to identify breast cancer tumors that were unlikely to respond to CDK4/6 inhibitors as taught in Raspé because Raspé teaches that doing so would provide a method to correctly identify sensitivity to treatment with CDK inhibitor in breast cancer samples and a method that may be used for improving treatment selection for patients.
Response to Arguments
The response traverses the rejection. The response asserts that with respect to a luminal pattern of gene expression, Garrido-Castro only mentions RB1 and CCNE1 and neither teaches nor suggests measuring at least four genes selected from the group listed in (a)(i) of claim 1. The response also asserts that Parker cited as teaching measuring gene expression of a luminal vs. non-luminal modules comprising at least four genes of ANLN, ESR1, PGR, and SLC39A6 in supplemental table 5, that supplemental table 5 of Parker includes over 1900 genes and does not provide any suggestion of selecting these four genes from the large list of possibilities. Specifically, the response asserts that these genes are included in different classifiers of risk, as illustrated by Parker Fig. A2, in which, for example, ANLN and ESR1 are part of the “basal-like” classifier, PGR is part of the “Luminal B” classifier, and SLC39A6 is part of the “Luminal A” classifier, and therefore there is nothing in Parker, alone or in combination with Garrido-Castro, that would motivate one of ordinary skill in the art to select a luminal vs. non-luminal module comprising at least four genes selected from the list in (a)(i) as recited in amended claim 1. This argument has been thoroughly reviewed but was not found persuasive. First, claim 1 as currently amended is a comprising “open” claim and recites “the method comprising … a luminal vs. non-luminal module comprising at least four genes selected from the group…” therefore comprising measuring the gene expression at least the four elected genes of ANLN, ESR1, PGR, and SLC39A6, and open to measuring gene expression in more genes (at least four genes, i.e., four or more genes). Further, Garrido-Castro teaches a method for determining potential biomarkers for sensitivity or resistance to CDK4/6 inhibitors in which the biomarkers comprising measuring a luminal pattern of gene expression as assessed by the PAM50 gene set (abstract purpose of review lines 1-5; pg. 30 1st column 1st full paragraph lines 1-12), in which the PAM50 gene set encompasses the genes of ANLN, ESRL, PGR, and SLC39A6, as evidenced by Parker (abstract purpose lines 1-3; pg. 1164-1165 paragraph bridging pg. 1164 & 1165 lines 1-12; pg. 1166 column 1 1st full paragraph lines 1-6; Supplemental Table 5 of Parker), (measuring gene expression of a luminal vs. non-luminal module comprising at least four genes of ANLN, ESR1, PGR, & SLC39A6). Further, Fig. A2 of Parker narrows down the potential list of biomarkers for measuring a luminal pattern of gene expression to 50 genes from supplemental table 5 of Parker that includes over 1900 genes, in which Fig. A2 of Parker teaches measuring expression of ANLN, ESR1, PGR, & SLC39A6 to classify luminal vs. non-luminal (measuring gene expression of a luminal vs. non-luminal module comprising at least four genes of ANLN, ESR1, PGR, & SLC39A6) (Fig. A2 of Parker). Second, claim 1 as currently amended, does not exclude measuring gene expression of genes included in different classifiers of risk and further, measuring genes with different classifiers of risk enables detection of luminal vs. non-luminal as recited in amended claim 1.
The response also asserts that there is nothing to prompt a person or ordinary skill in the art to combine the teachings of Garrido-Castro and Miller, and in particular, there is nothing to prompt a person of ordinary skill in the art to isolate a specific sub-section of five markers of E2F activity from Miller, and combine this selection with the teachings of Garrido-Castro, much less with the four specific modules in present claim 1. Further, the response asserts that nothing in the combination of references would motivate a person of ordinary skill in the art to first select these four modules and from the various genes discussed, and second to choose to combine them together in a single method as in Applicant’s claim 1 as Garrido-Castro (alone or in combination with Miller and Parker) contains no teaching or suggestion about how these specific four modules could be utilized together to arrive at a sensitive method of predicting CDK response in a human subject. Further, the response asserts that one or ordinary skill in the art would not have been motivated to combine the teachings of Garrido-Castro, Miller, and Parker to arrive at methos of claim 1 with a reasonable expectation of success. This argument has been thoroughly reviewed but was not found persuasive. First, Garrido-Castro teaches these specific four modules in determining sensitivity or resistance to CDK inhibitors as discussed above in section 7 comprising measuring E2F transcription factor activity and expression of E2F target genes (measuring gene expression of a E2F module). Garrido-Castro does not teach that the E2F module comprises measuring the gene expression of E2F signature group of DCK, DNAJC9, FBXO5, SFRS1, and TMPO genes. Further, Miller teaches a E2F activation gene signature that correlates with a lesser response to treatment in breast cancer patients in which this E2F gene signature comprises measuring the expression of DCK, DNAJC9, FBXO5, SFRS1, and TMPO genes (E2F module comprising at least five genes selected from the E2F signature of DCK, DNAJC9, FBXO5, SFRS1, and TMPO) (abstract lines 1-15; pg. 343 column 2 1st full paragraph lines 1-12; Fig. S7B). In addition, Miller teaches that this method is important is supporting further development of ER downregulators and CDK4 inhibitors for the treatment of antiestrogen-resistant breast cancers (abstract significance lines 1-6). Therefore, Garrido-Castro and Miller are considered to be analogous to the claimed invention because they are all in the same field of determining response to treatment in breast cancer patients with expression of E2F genes. 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 E2F transcription factor activity and expression of E2F target genes to determine resistance or sensitivity to CDK4/6 inhibitors in breast cancer patients in Garrido-Castro to incorporate measuring an E2F gene signature comprising the expression of DCK, DNAJC9, FBXO5, SFRS1, and TMPO as taught in Miller because Miller teaches that doing so would provide a method that is important in supporting further development of CDK4 inhibitors for the treatment of antiestrogen-resistant breast cancer. Therefore, a person of ordinary skill in the art would have been motivated to combine the teachings of Garrido-Castro with the teachings of Miller as described above and Miller teaches that doing so would provide a method that is important in supporting further development of CDK4 inhibitors for the treatment of antiestrogen-resistant breast cancer and further with a reasonable expectation of success as Garrido-Castro and Miller are in the same field of determining response to treatment in breast cancer patients with measuring expression of E2F genes.
The response also asserts that independent claim 31, which defines a computer-implemented method closely related to the method of claim 1, is also non-obvious for the same reasons outlined above and further that thus the Office has not established a prima facie case of obviousness of pending claims 1-5, 10-14, 26, 31, 40, & 41. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
The response also asserts that claims 6 & 7 depend from independent claim 1, which is not obvious over the combination of Garrido-Castro, Miller, and Parker as discussed above and that Perou does not remedy the deficiencies of Garrido-Castro, Miller, and Parker. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
The response also asserts that claim 30 depend from independent claim 1, which is not obvious over the combination of Garrido-Castro, Miller, and Parker as discussed above and that Buzdar does not remedy the deficiencies of Garrido-Castro, Miller, and Parker. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
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
Claims 1-7, 10-14, 26, 30, 31, & 40-42 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.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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