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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/8/26 has been entered.
Claims 1, 36-40, 48, 50, 53, 56, 64, 71, 73, 75, 76, 78, 81, 85, 88-90, 92, 94, 95, 98, and 100 are pending.
Claims 1, 36, 37, 39, 48, 85, 88, 89, 92, 95, 98, and 100 have been amended by Applicant.
Claims 1, 36-40, 48, 50, 53, 56, 64, 71, 73, 75, 76, 78, 81, 85, 88-90, 92, 94, 95, 98, and 100 are currently under consideration.
This Office Action contains New Rejections Necessitated by Amendments.
Rejections Withdrawn
All previous rejections are withdrawn.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 103
Claims 1, 37-40, 48, 50, 53, 56, 64, 71, 73, 75, 76, 78, 81, 85, 88-90, 92, 94, 95, 98, and 100 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hanash et al (WO 2018/148600 A1; 8/16/18) in view of Yang et al (Cancer, 2018, 124(2): 262-270), Borgia et al (US 9753037; 9/5/17; 9/8/26 IDS), Cohen et al (WO 2017173428; 10/5/17; 9/8/26 IDS), Ding et al (Thoracic Cancer, 2018, 1413-1420), Sin et al (Clin Cancer Res, 2014, 20(2_Supp) PR08, Abstract), Etzioni et al (Nature Reviews, 2003, 3: internet pages 1-10), and Mercer (Immunol Ser, 1990, 53: 39-54).
Hanash et al teaches a method of determining the risk of a subject for harboring lung cancer comprising measuring the levels of markers CEA, CA125, CYFRA21-1, and Pro-SFTPB, or reporter molecules bound thereto in a biological subject obtained from a subject ([0040]-[0041], in particular). Hanash et al further teaches said method wherein the marker diacetylspermine (DAS) is also measured ([0010], in particular). Hanash et al further teaches said method wherein combined level of a panel comprising the markers CEA, CA125, CYFRA21-1, and Pro-SFTPB classifies the subject as being at risk for harboring lung cancer when the combined level is elevated in the subject relative to a healthy subject that does not have lung cancer ([0033], in particular). Hanash et al further teaches said method wherein concentrations of the markers are measured/determined in a blood, plasma, or sample and at substantial the same time and compared to the prediction of a statistical model ([0046], in particular). Hanash et al further teaches said method wherein an alternate diagnostic test for that is an assay is administered for a subject assigned as having lung cancer ([0028], in particular). Hanash et al further teaches said method wherein the lung cancer is diagnosed at or before the borderline resectable stage, or at the resectable stage ([0033], in particular). Hanash et al further teaches said method wherein the amounts of the markers are detected using a solid bead ([0028], in particular). Hanash et al further teaches said method wherein the reporter molecules provide a detectable signal detectable by UV-visible spectroscopy ([0046], in particular). Hanash et al further teaches said method wherein the method further comprises comparing the amount of the markers with a cut-off value comprising an AUC (95% CI) of at least 0.83 ([0047], in particular). Hanash et al further teaches said method that comprises generating a risk categorization table wherein a sample is obtained, the panel is measured, amounts of the biomarkers are determined, biomarker scores are summed to obtain a composite score for each subject, quantifying an increased risk for the presence of lung cancer for the subject as a risk score, wherein the composite score is matched to a risk category of a grouping of stratified subject populations, wherein each risk category comprises a multiplier indicating increased likelihood of having the lung cancer correlated to a range of composite scores as compared to use of a single threshold value, wherein the multiplier is determined from positive predictive scores of retrospective samples; and administering a computerized tomography (CT) scan or other imagine modality to the subject with a quantified increased risk for the presence of lung cancer based on both biomarker levels and imaging results ([0072], in particular). Hanash et al further teaches said method wherein the subject is 50 years or older and has a history of smoking tobacco ([0072], in particular). Hanash et al further teaches said method wherein a subject identified as having risk of lung cancer is administered a lung cancer therapy comprising chemotherapy, radiation, and/or surgery of instant claim 98 ([0033], in particular). Hanash et al further teaches said method wherein the subject is human ([0067], in particular).
Hanash et al does not specifically teach a method of distinguishing benign from malignant pulmonary nodules in a subject previously diagnosed with indeterminate pulmonary nodules and treating malignant pulmonary nodules. However, these deficiencies are made up in the teachings of Yang et al, Borgia et al, Cohen et al, Ding et al, Sin et al, Etzioni et al and Mercer.
Yang et al teaches using blood biomarkers, including elevated CYFRA21-1, to differentiate benign from malignant lung cancer in indeterminate pulmonary nodules (see page 265 and nodule model discussed at Abstract and Patient Selection at right column on page 263).
Borgia et al teaches elevated CA125 levels in plasma differentiate benign nodules from malignant lung cancer nodules in patients with indeterminate nodules with a p value of 0.001 (Table 3 and lines 12-24 of column 9, in particular). Borgia et al further teaches recited CYFRA21-1 differentiated benign nodules from malignant lung cancer nodules, but not with a p value as significant as that with CA125 (Table 3, in particular).
Cohen et al teaches levels of CEA and CYFRA (same as “CYFRA 21-1”) in biological samples, including serum and plasma, differentiate between benign nodules from malignant lung cancer nodules in patients with radiographically apparent pulmonary nodules ([0017], in particular). Cohen et al further teaches mir-21 and miR-210 as lung cancer biomarkers ([0111], in particular).
Ding et al teaches elevated levels of CEA in serum of a patient indicates a pulmonary with a nodule indicates the nodule is a malignant lung cancer nodule (Table 3 and paragraph spanning pages 1414-1415, in particular).
Sin et al teaches a study examining levels of Pro-SFTPB in blood from 2,485 subjects, including 113 subjects later diagnosed as lung cancer, and teaches elevated Pro-SFTPB in blood as a biomarker of lung cancer and teaches pro-SFTB as being “associated with early stage lung cancer, suggesting its potential utility in predicting early stage NSCLC tumors” (Results and Conclusions, in particular).
Etzioni et al teaches motivation for early detection of tumor markers in order to detect tumors before they spread and become incurable (page 1 and Table 1, in particular). Etzioni et al further teaches that the power of combining multiple tumor markers for diagnosis to improve specificity and sensitivity has been known in the art (Box 2, in particular). Mercer teaches that the use of multiple markers to create a panel of tumor markers for diagnosis in order to improve sensitivity and specificity is known (page 39, in particular). Mercer teaches the use of multiple markers for cancer diagnosis is known and provides significant gains in sensitivity for diagnosis (page 43, in particular). Therefore, methods using multiple markers gain the advantages of early diagnosis, increased sensitivity and increased specificity of diagnosis.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising the method of Hanash et al of determining the risk of a patient for harboring lung cancer comprising detecting concentration levels of CEA, CA125, CYFRA21-1, and Pro-SFTPB wherein the sample (blood, plasma, or serum) from just any patient that has been previously diagnosed with indeterminate pulmonary nodules and that is suspected of having lung cancer (including a patient of Hanash et al with tobacco smoking history 50 years or older) wherein when the combined concentration levels of biomarkers CEA, CA125, CYFRA21-1, and Pro-SFTPB is elevated in the patient relative to a healthy subject the patient is classified as having malignant lung cancer pulmonary nodules and administered a therapeutically effective amount of any one or more lung cancer therapy of Hanash et al because Birse et al, Yang et al, Borgia et al, Cohen et al, and Sin et al teach elevated levels of said biomarkers in blood samples from subjects with nodules indicate the subjects have lung cancer and lung cancer patients benefit from such therapies. This is an example of combining prior art elements according to known methods (combining known biomarkers of malignant lung cancer in patients with nodules) to yield predictable results (classify pulmonary nodules as malignant lung cancer nodules based on the biomarkers). See MPEP 2143.
Regarding the recited sensitives/specificities and/or AUC as compared to a control recited by claim 85, the combined method has those sensitivities/specificities and/or AUC as compared to a control, depending on particular samples from particular patients used to determine the sensitivities/specificities and depending on particular control. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1, 36-40, 48, 50, 53, 56, 64, 71, 73, 75, 76, 78, 81, 85, 88-90, 92, 94, 95, 98, and 100 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hanash et al (WO 2018/148600 A1; 8/16/18) in view of Yang et al (Cancer, 2018, 124(2): 262-270), Borgia et al (US 9753037; 9/5/17; 9/8/26 IDS), Cohen et al (WO 2017173428; 10/5/17; 9/8/26 IDS), Ding et al (Thoracic Cancer, 2018, 1413-1420), Sin et al (Clin Cancer Res, 2014, 20(2_Supp) PR08, Abstract), Etzioni et al (Nature Reviews, 2003, 3: internet pages 1-10), and Mercer (Immunol Ser, 1990, 53: 39-54), as applied to claims 1, 37-40, 48, 50, 53, 56, 64, 71, 73, 75, 76, 78, 81, 85, 88-90, 92, 94, 95, 98, and 100 above, and further in view of Shen et al (BMC Cancer, 2011, 11(374): 1-9).
Teachings of Hanash et al, Yang et al, Borgia et al, Cohen et al, Ding et al, Sin et al, Etzioni et al, and Mercer are discussed above.
Hanash et al, Yang et al, Borgia et al, Cohen et al, Ding et al, Sin et al, Etzioni et al, and Mercer do not specifically teach measuring levels of miR-210 and miR-21. However, these deficiencies are made up in the teachings of Shen et al.
Shen et al teaches miR-21 levels and miR-210 levels are increased in plasma samples from patients with malignant lung cancer pulmonary nodules as compared to samples from subjects with benign pulmonary nodules (Abstract, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein levels of miR-210 and miR-21 are detected by the other biomarkers of the combined method used to differentiate the presence of malignant lung cancer pulmonary nodules from benign pulmonary nodules because Shen et al teaches miR-21 levels and miR-210 levels are increased in plasma samples from patients with malignant lung cancer pulmonary nodules as compared to samples from subjects with benign pulmonary nodules (Abstract, in particular). Such a combination is merely a “predictable use of prior art elements according to their established functions.”…” (see page 14 of Appeal No 2012008274). Further, in another non-precedential decision involving analogous claims that the BPAI found obvious, the BPAI acknowledges Mercer teaches that “the use of multiple markers for cancer diagnosis provides significant gains in sensitivity for diagnosis” provides a reason to have use a combination of known markers and that Mercer teaches it was known in the art that utilizing more than one marker for diagnostic detection increases sensitivity (see Appeal 2018-008269). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Double Patenting
Claims 1, 36-40, 48, 50, 53, 56, 64, 71, 73, 75, 76, 78, 81, 85, 88-90, 92, 94, 95, 98, and 100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12405274 B2 in view of Hanash et al (WO 2018/148600 A1; 8/16/18) in view of Yang et al (Cancer, 2018, 124(2): 262-270), Borgia et al (US 9753037; 9/5/17; 9/8/26 IDS), Cohen et al (WO 2017173428; 10/5/17; 9/8/26 IDS), Ding et al (Thoracic Cancer, 2018, 1413-1420), Sin et al (Clin Cancer Res, 2014, 20(2_Supp) PR08, Abstract), Etzioni et al (Nature Reviews, 2003, 3: internet pages 1-10), Mercer (Immunol Ser, 1990, 53: 39-54), and Shen et al (BMC Cancer, 2011, 11(374): 1-9).
The patent claims and the instant claims are both directed to classifying lung cancer status based on biomarkers CEA, CA125, CYFRA21-1, and PRO-SFTPB. The patent claims differ from the instant claims in in that the instant claims recite a method wherein a subject has pulmonary nodules and the method distinguishes benign from malignant pulmonary nodules in a subject previously diagnosed with indeterminate pulmonary nodules and treating malignant pulmonary nodules. Further, the instant claims recite addition miR markers not recited by patent claims. However, these deficiencies are made up in the teachings of Yang et al, Borgia et al, Cohen et al, Ding et al, Sin et al, Etzioni et al, Mercer, and Shen et al.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising the method of the patent claims wherein the sample (blood, plasma, or serum) is from just any patient that has been previously diagnosed with indeterminate pulmonary nodules and that is suspected of having lung cancer (including a patient of Hanash et al with tobacco smoking history 50 years or older) wherein when the combined concentration levels of biomarkers CEA, CA125, CYFRA21-1, and Pro-SFTPB is elevated in the patient relative to a healthy subject the patient is classified as having malignant lung cancer pulmonary nodules and administered a therapeutically effective amount of any one or more lung cancer therapy of Hanash et al because Birse et al, Yang et al, Borgia et al, Cohen et al, and Sin et al teach elevated levels of said biomarkers in blood samples from subjects with nodules indicate the subjects have lung cancer and lung cancer patients benefit from such therapies.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein levels of miR-210 and miR-21 are detected by the other biomarkers of the combined method used to differentiate the presence of malignant lung cancer pulmonary nodules from benign pulmonary nodules because Shen et al teaches miR-21 levels and miR-210 levels are increased in plasma samples from patients with malignant lung cancer pulmonary nodules as compared to samples from subjects with benign pulmonary nodules (Abstract, in particular).
Double Patenting
Claims 1, 36-40, 48, 50, 53, 56, 64, 71, 73, 75, 76, 78, 81, 85, 88-90, 92, 94, 95, 98, and 100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12504430 B2 in view of Hanash et al (WO 2018/148600 A1; 8/16/18) in view of Yang et al (Cancer, 2018, 124(2): 262-270), Borgia et al (US 9753037; 9/5/17; 9/8/26 IDS), Cohen et al (WO 2017173428; 10/5/17; 9/8/26 IDS), Ding et al (Thoracic Cancer, 2018, 1413-1420), Sin et al (Clin Cancer Res, 2014, 20(2_Supp) PR08, Abstract), Etzioni et al (Nature Reviews, 2003, 3: internet pages 1-10), Mercer (Immunol Ser, 1990, 53: 39-54), and Shen et al (BMC Cancer, 2011, 11(374): 1-9).
The patent claims and the instant claims are both directed to classifying lung cancer status based on biomarkers CEA, CA125, CYFRA21-1, and PRO-SFTPB. The patent claims differ from the instant claims in in that the instant claims recite a method wherein a subject has pulmonary nodules and the method distinguishes benign from malignant pulmonary nodules in a subject previously diagnosed with indeterminate pulmonary nodules and treating malignant pulmonary nodules. Further, the instant claims recite addition miR markers not recited by patent claims. However, these deficiencies are made up in the teachings of Yang et al, Borgia et al, Cohen et al, Ding et al, Sin et al, Etzioni et al, Mercer, and Shen et al.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising the method of the patent claims comprising the method of Hanash et al wherein the sample (blood, plasma, or serum) is from just any patient that has been previously diagnosed with indeterminate pulmonary nodules and that is suspected of having lung cancer (including a patient of Hanash et al with tobacco smoking history 50 years or older) wherein when the combined concentration levels of biomarkers CEA, CA125, CYFRA21-1, and Pro-SFTPB is elevated in the patient relative to a healthy subject the patient is classified as having malignant lung cancer pulmonary nodules and administered a therapeutically effective amount of any one or more lung cancer therapy of Hanash et al because Birse et al, Yang et al, Borgia et al, Cohen et al, and Sin et al teach elevated levels of said biomarkers in blood samples from subjects with nodules indicate the subjects have lung cancer and lung cancer patients benefit from such therapies.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein levels of miR-210 and miR-21 are detected by the other biomarkers of the combined method used to differentiate the presence of malignant lung cancer pulmonary nodules from benign pulmonary nodules because Shen et al teaches miR-21 levels and miR-210 levels are increased in plasma samples from patients with malignant lung cancer pulmonary nodules as compared to samples from subjects with benign pulmonary nodules (Abstract, in particular).
Double Patenting
Claims 1, 36-40, 48, 50, 53, 56, 64, 71, 73, 75, 76, 78, 81, 85, 88-90, 92, 94, 95, 98, and 100 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-8, 10, 13, 16, 24-30, 46, 47, and 49 of copending Application No. 19/206866 in view of Hanash et al (WO 2018/148600 A1; 8/16/18) in view of Yang et al (Cancer, 2018, 124(2): 262-270), Borgia et al (US 9753037; 9/5/17; 9/8/26 IDS), Cohen et al (WO 2017173428; 10/5/17; 9/8/26 IDS), Ding et al (Thoracic Cancer, 2018, 1413-1420), Sin et al (Clin Cancer Res, 2014, 20(2_Supp) PR08, Abstract), Etzioni et al (Nature Reviews, 2003, 3: internet pages 1-10), Mercer (Immunol Ser, 1990, 53: 39-54), and Shen et al (BMC Cancer, 2011, 11(374): 1-9).
The copending claims and the instant claims are both directed to classifying lung cancer status based on biomarkers CEA, CA125, CYFRA21-1, and PRO-SFTPB. The copending claims differ from the instant claims in in that the instant claims recite a method wherein a subject has pulmonary nodules and the method distinguishes benign from malignant pulmonary nodules in a subject previously diagnosed with indeterminate pulmonary nodules and treating malignant pulmonary nodules. Further, the instant claims recite addition miR markers not recited by copending claims. However, these deficiencies are made up in the teachings of Yang et al, Borgia et al, Cohen et al, Ding et al, Sin et al, Etzioni et al, Mercer, and Shen et al.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising the copending method comprising the method of Hanash et al wherein the sample (blood, plasma, or serum) is from just any patient that has been previously diagnosed with indeterminate pulmonary nodules and that is suspected of having lung cancer (including a patient of Hanash et al with tobacco smoking history 50 years or older) wherein when the combined concentration levels of biomarkers CEA, CA125, CYFRA21-1, and Pro-SFTPB is elevated in the patient relative to a healthy subject the patient is classified as having malignant lung cancer pulmonary nodules and administered a therapeutically effective amount of any one or more lung cancer therapy of Hanash et al because Birse et al, Yang et al, Borgia et al, Cohen et al, and Sin et al teach elevated levels of said biomarkers in blood samples from subjects with nodules indicate the subjects have lung cancer and lung cancer patients benefit from such therapies.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined wherein levels of miR-210 and miR-21 are detected by the other biomarkers of the combined method used to differentiate the presence of malignant lung cancer pulmonary nodules from benign pulmonary nodules because Shen et al teaches miR-21 levels and miR-210 levels are increased in plasma samples from patients with malignant lung cancer pulmonary nodules as compared to samples from subjects with benign pulmonary nodules (Abstract, in particular).
This is a provisional nonstatutory double patenting rejection.
Conclusion
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