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 .
Detailed Action
The Amendments and Remarks filed 5/26/26 in response to the Office Action of 4/9/26 are acknowledged and have been entered.
Claims 1-21 are pending.
Claims 1, 5, 6, 13, 14, 16, 18, and 21 have been amended by Applicant.
Claims 1-21 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 1-4, 7-12, and 14-20 remain rejected under 35 U.S.C. 103(a) as being unpatentable over Yoshida et al (J Cancer Res Clin Oncol, 2013, 139: 367-378; 3/20/23 IDS) in view of Yi et al (Annals of Oncology, 2014, 26: 1004-1011) and Buffet et al (Acta Gastro-Enterologica Belgica, 2008, LXX1, 213-218).
The pending claims are drawn to methods of treating patients with tumors by administering an alternative therapy that does not include an EGFR-directed therapeutic when percentages of tumor cells expressing known efficacy biomarkers (AREG and EREG) indicative of response to EGFR-directed therapeutics are decreased below cut offs and methods of administering an EGFR-directed therapeutic when percentages of tumor cells expressing known efficacy biomarkers (AREG and EREG) indicative of response to EGFR-directed therapeutics are above cut offs.
Yoshida et al teaches colorectal cancer patients with wild-type KRAS treated with anti-EGFR antibody predictably exhibit therapeutic benefit when tumors of the patients exhibit immunoreactivity to greater than two of AR (same as AREG), HB-EGF, TGF-a, and EREG biomarker proteins (Abstract, in particular). Yoshida et al further teaches a method comprising histochemically staining samples of wild-type KRAS colorectal tumor patients (lacking KRAS mutations that confer resistance to EGFR monoclonal antibody therapy) for human AREG (same as “amphiregulin” or “AR”) protein; histochemically staining samples of the colorectal tumor patients for human EREG protein; quantitating percentages of tumor cells in the samples stained for AREG and comparing the percentages to a cut-off of 30% (that is both a “positive” and “negative” cut-off) wherein samples are determined to be AREG+ when greater than 30% of tumor cells of a sample stain for AREG; and quantitating percentages of tumor cells in the samples stained for EREG and comparing the percentages to a cut-off of 30% wherein samples are determined to be EREG+ when greater than 30% of tumor cells of a sample stain for EREG (page 369, in particular). The cut offs of Yoshida et al are associated with both a “negative response” and “positive response” to the anti-EGFR antibody, wherein below the cut-offs indicates a negative/poor response to anti-EGFR antibody and above the cut-offs indicates a positive/good response to anti-EGFR antibody. On page 369, Yoshida et al teaches the samples of Yoshida et al stained for AREG or EREG are consecutive sections that are either stained with a primary antibody to AREG or EREG and then a biotinylated 2ndary antibody and then with avidin-biotin HRP (i.e., samples/sections stained for AREG are not the same samples/sections stained for EREG). Patients of the method of Yoshida et al are administered cetuximab or panitumumab (right column on page 368, in particular). The patients of Yoshida et al are further administered chemotherapy (Table 1 and right column on page 368, in particular). Further, 16/26 patients of Yoshida et al are administered the chemotherapeutic irinotecan (Table 1, in particular). Patients of Yoshida et al include those that are determined to be AREG+ (same as “AREG HIGH”) and EREG+ (same as “EREG HIGH”) and are administered an EGFR-directed therapeutic monoclonal antibody (see patient Nos 1, 2, 6, 8, 9, 14, and 16 of Table 1, in particular).
While the cut-offs “30% of tumor cells of a sample stain for AREG” and “30% of tumor cells of a sample stain for EREG” are different (“30% of tumor cells of a sample stain for AREG” is not the same as “30% of tumor cells of a sample stain for EREG”), Yoshida et al does not specifically refer to the cut-offs used by Yoshida et al (30% of tumor cells of a sample stain for AREG; 30% of tumor cells of a sample stain for EREG) as “being different” or methods wherein a therapy that does not include an EGFR-directed therapeutic agent is administered if percentages of AREG+ and EREG+ tumor cells are less than cut-offs referred to as being different pre-determined cut offs. However, these deficiencies are made up in the teachings of Yi et al and Buffet et al.
Yi et al teaches using various cut offs (1%-9%; 10%) of expression percentage for cells expressing a biomarker (ER) for a therapeutic treatment (chemotherapy and endocrine therapy) to determine which cut off better responded to the therapeutic treatment and identified those patients with ≥10% of cells expressing ER responded better to the therapeutic treatment than ER negative patients and those with 1%-9% of cells expressing ER (Abstract, in particular). The cut offs of Yi et al are associated with both a “negative response” and “positive response” to the therapeutic treatment of Yi et al, wherein below negative cut-offs (1%-9% of cells expressing ER) indicates a negative/poor response to the therapeutic treatment and above the cut-offs (≥10% of cells expressing ER) indicates a positive/good response to the therapeutic treatment.
The abstract of Buffet et al teaches different cell expression % cut offs (1%; 10%) using different antibodies (2-18C9; 31G7; 111.6) that each specifically bind the same biomarker (EGFR) result in different “positive” staining results depending on the antibody used. With a 1% cut-off, 2-18C9 stained 86% of cell samples as positive, the 31G7 antibody 77%, and the 116. 52%. With a 10% cut-off, 2-18C9 stained 77% of cell samples as positive, the 31G7 antibody 61%, and the 116. 30%. The Abstract concludes that different antibodies to the same biomarker stain different percentages of cells in a sample and a “correct cut-off” value for a positive result is important and can be different depending upon antibody.
In particular regards to claims 1, 2, 4, and 7-12: 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 Yoshida et al of identifying colorectal cancer patients with wild-type KRAS (lacking KRAS mutations that confer resistance to EGFR monoclonal antibody therapy) that predictably exhibit therapeutic benefit from treatment with anti-EGFR antibody based on tumors of the patients exhibiting immunoreactivity above cut-offs of greater than two of AR (same as AREG), HB-EGF, TGF-a, and EREG biomarker proteins (Abstract, in particular) by performing a method comprising histochemically staining tumor samples from the patients for the biomarker proteins (as taught by Yoshida et al), quantitating the percentages of the cells expressing biomarkers protein in the samples and comparing the percentages to pre-determined cut-offs for each biomarker protein to determine positivity or negativity (as taught by Yoshida et al), and administering an anti-EGFR antibody treatment of Yoshida et al (such as cetuximab) to the patients when cells positive for two or more biomarker proteins (such as AREG and EREG) are greater than the corresponding cut-offs of Yoshida et al and administer a therapeutic treatment that does not include the anti-EGFR antibody treatment (such as irinotecan chemotherapy of Yoshida et al) when cells are not positive for two of the biomarker proteins (such as when none of the biomarker proteins are above the cut-offs) because Yoshida et al teaches colorectal cancer patients with wild-type KRAS treated with anti-EGFR antibody predictably exhibit therapeutic benefit when tumors of the patients are determined to be positive for two of said biomarker proteins (Abstract, in particular).
In particular regards to claim 3: In addition to performing said combined method wherein the cut-offs used to determine positivity or negativity are “30% of tumor cells of a sample stained for AREG” and “30% of tumor cells of a sample stained for EREG” (as taught by Yoshida et al), one would have been motivated, with a reasonable expectation of success, to optimize a combined method by performing said method wherein just any combination of cut-offs are used to determine positivity or negativity of a biomarker (including: (1) 20% of tumor cells of a sample stained for AREG and 30% of tumor cells of a sample stained for EREG; (2) 30% of tumor cells of a sample stained for AREG and 20% of tumor cells of a sample stained for EREG; or (3) including 50% of tumor cells of a sample stained for AREG and 50% of tumor cells of a sample stained for EREG) in order to optimize the best cut-offs to determine positivity and negativity that correlate with efficacy to anti-EGFR therapy and to optimize due to differences in specifically chosen anti-AREG and anti-EREG antibodies of the method (from any available anti-AREG and anti-EREG antibodies) used to immunohistochemically detecting AREG and EREG because (1) Yi et al demonstrates optimizing cut-offs for biomarkers correlating with treatment efficacy and (2) Buffet concludes that different antibodies to the same biomarker stain different percentages of cells in a sample and a “correct cut-off” value for a positive result is important and can be different depending upon antibody. Cut-offs to determine immunohistochemistry positivity of biomarkers (AREG and EREG) detected by antibodies that correlate with treatment efficacy are clearly result-effective variables because it was known in the prior art that cut-offs are optimized for biomarkers correlating with treatment efficacy (see Yi et al) and different antibodies to the same biomarker stain different percentages of cells in a sample and a “correct cut-off” value for a positive result is known to be important and can be different depending upon antibody Buffet et al). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143.
In particular regards to instant claims 18-20 (which amended claims require “comparing” percentages of biomarker-positive tumor cells to a positive cut off and a negative cut off, wherein the positive cut off and negative cut off for a given biomarker are different) and claims 14-17 (which recite “positive cutoff” and “ negative cutoff” of a given biomarker that differ): One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to optimize the combined method wherein, different cut-offs are assayed to determine positivity (above which EGFR-directed therapy is indicated) and negativity (below which, therapy other than EGFR-directed is indicated) for each biomarker (EREG and AREG), wherein the cut-offs to determine positivity are above those used to determine negativity for each biomarker because Yi et al teaches using various cut offs (1%-9%; 10%) of expression percentage for cells expressing a biomarker (ER) for a therapeutic treatment (chemotherapy and endocrine therapy) to determine which cut off for determining positivity or negativity better correlates with therapeutic response and identified those patients with ≥10% of cells expressing ER responded better to the therapeutic treatment than ER negative patients and those with 1%-9% of cells expressing ER (Abstract, in particular). Again, cut-offs to determine immunohistochemistry positivity and negativity of biomarkers (AREG and EREG of Yoshida et al) detected by antibodies that correlate with treatment efficacy are clearly result-effective variables because it was known in the prior art that cut-offs are optimized for biomarkers correlating positivity and negativity with treatment efficacy (see Yi et al). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/26/26, Applicant argues Yoshida et al teaches different staining measurements and does not teach different marker-specific cut offs. Applicant further argues Yi et al is far removed from Yoshida's colorectal cancer/anti-EGFR treatment disclosures, Yi et al does not address AREG, EREG, or EGFR-directed therapy, and Yi et al does not teach developing marker-specific negative-response cut offs for two different EGFR ligands and using those cut offs to select a therapy that excludes an EGFR-directed therapeutic agent. Applicant concludes Yi et al provides no reason to depart from Yoshida's four-ligand 30% positivity strategy and arrive at Applicant's AREG/EREG-specific negative-response therapy-selection method. Applicant further argues Buffet et al does not teach using marker-specific AREG and EREG negative-response cut-offs to select a therapy that excludes an EGFR-directed therapeutic agent. Applicant further argues the combination of cited references does not teach marker-specific AREG/EREG cut offs used to select a non-EGFR-directed therapeutic course. Applicant further indicates cited art does not teach or suggest AREG-specific and EREG-specific negative response cut offs as a result-effective variable for deciding whether to administer a therapy that excludes an EGFR-directed therapeutic agent. Applicant further indicates the claims are non-obvious and that one would not be motivated to optimize a method using cut offs for a biomarker by using just any combination of cut-offs to determine positivity or negativity of a biomarker because the cut offs are not mere laboratory preferences but rather influence clinical stratification and treatment selection. Applicant further argues the rejection is based on impermissible hindsight because the rejection starts with Applicant’s AREG/EREG negative-response method and then searches the art for general teachings about IHC thresholds and antibody-dependent staining variability and the cited references would not have led a person of ordinary skill to select the claimed variables, assign them the claimed clinical meaning, or use them to make the claimed treatment decision. In particular to claims 14, 16, and 18, Applicant argues cited references do not teach a “dual-threshold-therapy-selection method.”
The amendments to the claims and the arguments found in the Reply of 5/26/26 have been carefully considered, but are not deemed persuasive. In regards to the argument Yoshida et al does not teach different marker-specific cut offs, the examiner disagrees. 30% of tumor cells of a sample stained for AREG and 30% of tumor cells of a sample stained for EREG (as taught by Yoshida et al) are different cut-offs.
In regards to the argument Yi et al is far removed from Yoshida's colorectal cancer/anti-EGFR treatment disclosures, Yi et al does not address AREG, EREG, or EGFR-directed therapy, and Yi et al does not teach developing marker-specific negative-response cut offs for two different EGFR ligands and using those cut offs to select a therapy that excludes an EGFR-directed therapeutic agent, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In regards to the argument Yi et al provides no reason to depart from Yoshida's four-ligand 30% positivity strategy and arrive at Applicant's AREG/EREG-specific negative-response therapy-selection method, the examiner disagrees. Yi et al illustrates optimizing a therapeutic method by determining cut-offs (both positive and negative cut offs) of biomarkers that correlate with a therapeutic response. Specifically, Yi et al teaches using various cut offs (1%-9%; 10%) of expression percentage for cells expressing a biomarker (ER) for a therapeutic treatment (chemotherapy and endocrine therapy) to determine which cut off better responded to the therapeutic treatment and identified those patients with ≥10% of cells expressing ER (above a “positive cut off” of ≥10% of cells expressing ER) responded better to the therapeutic treatment than ER negative patients and those with no ER expression and those with 1%-9% of cells expressing ER (below a “negative cut off” of 9%). One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to optimize a method rendered obvious by Yoshida et al, wherein different cut-offs are assayed to determine positivity (above which EGFR-directed therapy is indicated) and negativity (below which, therapy other than EGFR-directed is indicated) for each biomarker (EREG and AREG), wherein the cut-offs to determine positivity are above those used to determine negativity for each biomarker because Yi et al teaches using various cut offs (1%-9%; 10%) of expression percentage for cells expressing a biomarker (ER) for a therapeutic treatment (chemotherapy and endocrine therapy) to determine which cut off for determining positivity or negativity better correlates with therapeutic response and identified those patients with ≥10% of cells expressing ER responded better to the therapeutic treatment than ER negative patients and those with 1%-9% of cells expressing ER (Abstract, in particular). Again, cut-offs to determine immunohistochemistry positivity and negativity of biomarkers detected by antibodies that correlate with treatment efficacy are clearly result-effective variables because it was known in the prior art that cut-offs are optimized for biomarkers correlating positivity and negativity with treatment efficacy (see Yi et al). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143.
In regards to the argument Buffet et al does not teach using marker-specific AREG and EREG negative-response cut-offs to select a therapy that excludes an EGFR-directed therapeutic agent, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In regards to the argument that the combination of cited references does not teach marker-specific AREG/EREG cut offs used to select a non-EGFR-directed therapeutic course, Yoshida et al teaches marker-specific AREG/EREG cut offs used to select a non-EGFR-directed therapeutic course: “30% of tumor cells of a sample stain for AREG” and “30% of tumor cells of a sample stain for EREG.” Further, 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 Yoshida et al of identifying colorectal cancer patients with wild-type KRAS (lacking KRAS mutations that confer resistance to EGFR monoclonal antibody therapy) that predictably exhibit therapeutic benefit from treatment with anti-EGFR antibody based on tumors of the patients exhibiting immunoreactivity above cut-offs of greater than two of AR (same as AREG), HB-EGF, TGF-a, and EREG biomarker proteins (Abstract, in particular) by performing a method comprising histochemically staining tumor samples from the patients for the biomarker proteins (as taught by Yoshida et al), quantitating the percentages of the cells expressing biomarkers protein in the samples and comparing the percentages to pre-determined cut-offs for each biomarker protein to determine positivity or negativity (as taught by Yoshida et al), and administering an anti-EGFR antibody treatment of Yoshida et al (such as cetuximab) to the patients when cells positive for two or more biomarker proteins (such as AREG and EREG) are greater than the corresponding cut-offs of Yoshida et al and administer a therapeutic treatment that does not include the anti-EGFR antibody treatment (such as irinotecan chemotherapy of Yoshida et al) when cells are not positive for two of the biomarker proteins (such as when none of the biomarker proteins are above the cut-offs) because Yoshida et al teaches colorectal cancer patients with wild-type KRAS treated with anti-EGFR antibody predictably exhibit therapeutic benefit when tumors of the patients are determined to be positive for two of said biomarker proteins (Abstract, in particular).
In regards to the indication cited art does not teach or suggest AREG-specific and EREG-specific negative response cut offs as a result-effective variable for deciding whether to administer a therapy that excludes an EGFR-directed therapeutic agent, the examiner maintains cut-offs to determine immunohistochemistry positivity and negativity of biomarkers (AREG and EREG of Yoshida et al) detected by antibodies that correlate with treatment efficacy are clearly result-effective variables because it was known in the prior art that cut-offs are optimized for biomarkers correlating positivity and negativity with treatment efficacy (see Yi et al).
In regards to the indication the claims are non-obvious and that one would not be motivated to optimize a method using cut offs for a biomarker by using just any combination of cut-offs to determine positivity or negativity of a biomarker because the cut offs are not mere laboratory preferences but rather influence clinical stratification and treatment selection, the examiner maintains one would have been motivated, with a reasonable expectation of success, to optimize a combined method of the cited references by performing said method wherein just any combination of cut-offs are used to determine positivity or negativity of a biomarker (including: (1) 20% of tumor cells of a sample stained for AREG and 30% of tumor cells of a sample stained for EREG; (2) 30% of tumor cells of a sample stained for AREG and 20% of tumor cells of a sample stained for EREG; or (3) including 50% of tumor cells of a sample stained for AREG and 50% of tumor cells of a sample stained for EREG) in order to optimize the best cut-offs to determine positivity and negativity that correlate with efficacy to anti-EGFR therapy and to optimize due to differences in specifically chosen anti-AREG and anti-EREG antibodies of the method (from any available anti-AREG and anti-EREG antibodies) used to immunohistochemically detecting AREG and EREG because (1) Yi et al demonstrates optimizing cut-offs for biomarkers correlating with treatment efficacy and (2) Buffet concludes that different antibodies to the same biomarker stain different percentages of cells in a sample and a “correct cut-off” value for a positive result is important and can be different depending upon antibody. Cut-offs to determine immunohistochemistry positivity of biomarkers (AREG and EREG) detected by antibodies that correlate with treatment efficacy are clearly result-effective variables because it was known in the prior art that cut-offs are optimized for biomarkers correlating with treatment efficacy (see Yi et al) and different antibodies to the same biomarker stain different percentages of cells in a sample and a “correct cut-off” value for a positive result is known to be important and can be different depending upon antibody Buffet et al). Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to optimize the combined method wherein, different cut-offs are assayed to determine positivity (above which EGFR-directed therapy is indicated) and negativity (below which, therapy other than EGFR-directed is indicated) for each biomarker (EREG and AREG), wherein the cut-offs to determine positivity are above those used to determine negativity for each biomarker because Yi et al teaches using various cut offs (1%-9%; 10%) of expression percentage for cells expressing a biomarker (ER) for a therapeutic treatment (chemotherapy and endocrine therapy) to determine which cut off for determining positivity or negativity better correlates with therapeutic response and identified those patients with ≥10% of cells expressing ER responded better to the therapeutic treatment than ER negative patients and those with 1%-9% of cells expressing ER (Abstract, in particular). Again, cut-offs to determine immunohistochemistry positivity and negativity of biomarkers (AREG and EREG of Yoshida et al) detected by antibodies that correlate with treatment efficacy are clearly result-effective variables because it was known in the prior art that cut-offs are optimized for biomarkers correlating positivity and negativity with treatment efficacy (see Yi et al). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143.
In regards to the argument that the rejection is based on impermissible hindsight because the rejection starts with Applicant’s AREG/EREG negative-response method and then searches the art for general teachings about IHC thresholds and antibody-dependent staining variability and the cited references would not have led a person of ordinary skill to select the claimed variables, assign them the claimed clinical meaning, or use them to make the claimed treatment decision, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the rejection does not start with Applicant’s AREG/EREG negative-response method. Rather, the rejection starts with teachings of Yoshida et al that elevated percentages of tumor cells expressing AREG and EREG correlate with responsiveness to EGFR-directed therapeutic treatment to reject claimed methods of treating patients with tumors by (i) administering an alternative therapy that does not include an EGFR-directed therapeutic when percentages of tumor cells expressing known biomarkers (AREG and EREG) indicative of response to EGFR-directed therapeutics are decreased below cut offs and (ii) administering an EGFR-directed therapeutic when percentages of tumor cells expressing known biomarkers (AREG and EREG) indicative of response to EGFR-directed therapeutics are above cut offs.
In regards to the argument cited references do not teach a “dual-threshold-therapy-selection method,” Yi et al teaches using various cut offs (1%-9%; 10%) of expression percentage for cells expressing a biomarker (ER) for a therapeutic treatment (chemotherapy and endocrine therapy) to determine which cut off better responded to the therapeutic treatment and identified those patients with ≥10% of cells expressing ER responded better to the therapeutic treatment than ER negative patients and those with 1%-9% of cells expressing ER (Abstract, in particular). The cut offs of Yi et al are associated with both a “negative response” and “positive response” to the therapeutic treatment of Yi et al, wherein below negative cut-offs (1%-9% of cells expressing ER) indicates a negative/poor response to the therapeutic treatment and above the cut-offs (≥10% of cells expressing ER) indicates a positive/good response to the therapeutic treatment. As stated above, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to optimize the combined method wherein, different cut-offs are assayed to determine positivity (above which EGFR-directed therapy is indicated) and negativity (below which, therapy other than EGFR-directed is indicated) for each biomarker (EREG and AREG), wherein the cut-offs to determine positivity are above those used to determine negativity for each biomarker because Yi et al teaches using various cut offs (1%-9%; 10%) of expression percentage for cells expressing a biomarker (ER) for a therapeutic treatment (chemotherapy and endocrine therapy) to determine which cut off for determining positivity or negativity better correlates with therapeutic response and identified those patients with ≥10% of cells expressing ER responded better to the therapeutic treatment than ER negative patients and those with 1%-9% of cells expressing ER (Abstract, in particular). Again, cut-offs to determine immunohistochemistry positivity and negativity of biomarkers (AREG and EREG of Yoshida et al) detected by antibodies that correlate with treatment efficacy are clearly result-effective variables because it was known in the prior art that cut-offs are optimized for biomarkers correlating positivity and negativity with treatment efficacy (see Yi et al). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143.
Claim Rejections - 35 USC § 103
Claim(s) 1-20 remain rejected under 35 U.S.C. 103 as being unpatentable over Yoshida et al (J Cancer Res Clin Oncol, 2013, 139: 367-378; 3/20/23 IDS) in view of Yi et al (Annals of Oncology, 2014, 26: 1004-1011) and Buffet et al (Acta Gastro-Enterologica Belgica, 2008, LXX1, 213-218) as applied to claims 1-4, 7-12, and 14-20 above, and further in view of Salem et al (Oncotarget, 2017, 8(49): 86356-86368) and Mahmoud et al (Eur J Mass Spect, 2013, 19: 17-28).
Teachings of Yoshida et al, Yi et al, and Buffet et al are discussed above.
Yoshida et al, Yi et al, and Buffet et al do not specify whether tumor samples are left-sided or right-sided tumor samples or that samples of the combined method are formalin-fixed paraffin-embedded (FFPE). However, these deficiencies are made up in the teachings of Salem et al and Mahmoud et al.
Salem et al teaches performing immunohistochemistry on FFPE colorectal tumor samples from left colon tumors and right colon tumors from subjects with colorectal cancer (see Tumor Characteristics on page 86357 and Multiplatform testing on page 86364, in particular).
Mahmoud et al teaches methods of performing immunohistochemistry to detect AREG and EREG in FFPE tissue samples (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 of determining whether a patient will respond to EGFR-directed therapeutic agents of Yoshida et al, Yi et al, and Buffet et al wherein just any samples of wild-type KRAS colorectal tumor patients are histochemically stained for the biomarkers, including left-sided or right-sided FFPE tumor samples, for human AREG (same as “amphiregulin” or “AR”) protein and EREG because Salem et al identifies FFPE right-side and left-side colorectal tumor samples as tumor samples for performing immunohistochemistry, and Mahmoud et al teaches methods of performing immunohistochemistry to detect AREG and EREG in FFPE tissue samples. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/26/26, Applicant repeats arguments addressed above and argues against Salem et al and Mahmoud et al individually.
The amendments to the claims and the arguments found in the Reply of 5/26/26 have been carefully considered, but are not deemed persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 7-12, and 14-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yoshida et al (J Cancer Res Clin Oncol, 2013, 139: 367-378; 3/20/23 IDS) in view of Yi et al (Annals of Oncology, 2014, 26: 1004-1011) and Buffet et al (Acta Gastro-Enterologica Belgica, 2008, LXX1, 213-218) as applied to claims 1-4, 7-12, and 14-20 above, and further in view of Wanram et al (J Med Assoc Thai, 2016, 99(Suppl. 1): S67-S75).
Teachings of Yoshida et al, Yi et al, and Buffet et al are discussed above.
Yoshida et al, Yi et al, and Buffet et al do not specifically teach using an “automated” method to quantitate the percentages of AREG+ tumor cells and EREG+ tumors cells in the immunohistochemically stained samples. However, these deficiencies are made up in the teachings of Wanram et al.
Wanram et al teaches performing automated immunohistochemistry to detect the percentage of tumor cells expressing a marker comprising generating digital images of samples and using automated image analysis to determine percentages of cells expressing a marker (pages S68-S69 and Figure 2, in particular). Wanram et al teaches such automated immunohistochemistry provides internally consistent results (sentence spanning columns of S71, in particular), provide precision in ranges of staining that appear weak to the eye, and provide pathologists with support for visual scoring (paragraph spanning S67-S68, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method Yoshida et al, Yi et al, and Buffet et al wherein an automated method is used to generate digital images of the samples and quantitate the percentage of AREG+ tumor cells and EREG+ tumor cells in the immunohistochemically stained samples because Wanram et al teaches performing automated immunohistochemistry that generates digital images of samples and quantitates the percentage of tumor cells expressing a marker (S68-S69 and Figure 2, in particular) and that such automated immunohistochemistry provides internally consistent results (sentence spanning columns of S71, in particular), provides precision in ranges of staining that appear weak to the eye, and provides pathologists with support for visual scoring (paragraph spanning S67-S68, in particular). As compared to pathologists determining the percentages, as done by Yoshida et al, such automation provides additional support the method uses unbiased results. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 5/26/26, Applicant repeats arguments addressed above. Applicant further argues Wanram does not teach a therapy-selection method required by independent claims 1, 14, and 18. Applicant further argues Wanram is directed to automated IHC scoring of MHC class I and Tapasin expression in cervical cancer and not AREG/EREG-based treatment selection in colorectal cancer.
The amendments to the claims and the arguments found in the Reply of 5/26/26 have been carefully considered, but are not deemed persuasive. In response to applicant's arguments that Wanram does not teach a therapy-selection method required by independent claims 1, 14, and 18 and Wanram is directed to automated IHC scoring of MHC class I and Tapasin expression in cervical cancer and not AREG/EREG-based treatment selection in colorectal cancer, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
THIS ACTION IS MADE FINAL. 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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/SEAN E AEDER/ Primary Examiner, Art Unit 1642
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