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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/13/26 has been entered.
Claims 1-21 are pending.
Claims 1, 14, 18, and 21 have been amended by Applicant.
Claims 1-21 are currently under consideration.
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 comprise: (i) 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, EREG, HB-EGF, and TGF-a) are below cut offs and indicate a shorter “progression-free survival” from EGFR-directed therapeutics, and (ii) methods of administering an EGFR-directed therapeutic when percentages of tumor cells expressing known efficacy biomarkers (AREG and EREG in combination with either HB-EGF or TGF-a) are above cut offs and indicate longer “progression-free survival” from EGFR-directed therapeutics.
Yoshida et al teaches colorectal cancer patients with wild-type KRAS treated with anti-EGFR antibody predictably exhibit greater therapeutic benefit (significantly higher “disease control rate”, a “better response”, and “longer progression-free survival”) when tumors of the patients exhibit immunoreactivity to greater than two of AR (same as AREG), HB-EGF, TGF-a, and EREG biomarker proteins than patients with immunoreactivity to zero or one of AR, HB-EGF, TGF-a, and EREG (Abstract and right paragraph on page 374, 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” for determining response to anti-EGFR therapy in the method of Yoshida et al 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; 30% of tumor cells of a sample stain for HB-EGF; and 30% of tumor cells of a sample stain for TGF-a) 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 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 in combination with HB-EGF or TGF-a) 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 greater 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 than patients with immunoreactivity to zero or one of AR, HB-EGF, TGF-a, and EREG (Abstract, in particular) and providing a treatment option that does not include anti-EGFR antibody treatment provides another therapeutic option for patients that do not respond as well to anti-EGFR antibody treatment. An embodiment of the claims encompassed by the combined method is when AREG, HB-EGF, TGF-a, and EREG biomarker proteins are all below cut-offs (indicative of poor response to EGFR-directed therapeutics and worse progression-free survival from EGFR-directed therapeutics based on Yoshida) and a therapeutic course that does not include an EGFR-directed therapeutic is administered due to lack of responsiveness to EGFR-directed therapeutics.
In particular regards to claim 3: In addition to performing said combined method wherein the cut-offs used to determine positivity or negativity include “30% of tumor cells of a sample stained for AREG” and “30% of tumor cells of a sample stained for EREG” for determining response to anti-EGFR therapy (as taught by Yoshida et al), one would have been motivated, with a reasonable expectation of success, to optimize the combined method by performing said method wherein just any combination of cut-offs are used to determine positivity or negativity of each biomarker used to correlate with therapeutic response (including: (1) 20% of tumor cells of a sample stained for AREG and 30% of tumor cells of a sample stained for EREG in combination with HB-EGF or TGF-a cutoffs; (2) 30% of tumor cells of a sample stained for AREG and 20% of tumor cells of a sample stained for EREG in combination with HB-EGF or TGF-a cutoffs; 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 combination with HB-EGF or TGF-a cutoffs) 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 (including AREG and EREG in combination with HB-EGF or TGF-a) 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 (AREG, EREG, HB-EGF, and TGF-a) that correlate with response to therapy 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, EREG, HB-EGF, and TGF-a 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 particular regards to claims 14 and 18, reciting when either AREG or EREG is high or when both markers are low, an embodiment of the claims encompassed by the combined method is when both markers are high in combination with HB-EGF or TGF-a (an indication response to EGFR-directed therapeutics is increased based on Yoshida) and an EGFR-directed therapeutic is administered.
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 8/13/26, Applicant argues cited references do not teach positive cut offs associated with improvement and negative cut offs associated with worsening, in at least one overall survival and progression-free survival after treatment with an EGFR-directed therapeutic agent. Applicant further argues Yoshida et al does not teach administration of an anti-EGFR antibody when biomarker measurements are above their cut offs and administration of a treatment "that does not include the anti-EGFR antibody treatment (such as irinotecan chemotherapy of Yoshida et al)" when they are not positive. Applicant further argues Yoshida et al is a retrospective study and did not use AREG and EREG results to determine whether an EGFR-directed agent would be administered. Applicant further argues Yoshida’s 30% staining criterion that retrospectively identified groups having different outcomes after anti-EGFR treatment does not disclose using AREG- and EREG-specific cut offs having the recited clinical-outcome relationships to select treatment and/or to make the treatment-exclusion decision required by claims. Applicant further argues Yoshida does not identify the 30% AREG staining criterion as a cut off associated with worsening in overall survival or progression-free survival after EGFR-directed therapy. Applicant further argues the Office's contentions that values below the common 30% criterion indicate a "negative/poor response" and that values above the criterion indicate a "positive/good response" does not establish marker-specific relationships. Applicant further argues Yoshida does not disclose administering a therapy that excludes an EGFR-directed therapeutic agent, such as irinotecan as an alternative to cetuximab or panitumumab. Applicant further argues Yi does not disclose selecting a treatment that excludes an EGFR-directed therapeutic agent when AREG+ and EREG+ tumor-cell percentages are each blow marker-specific cut offs associated with worsening in overall survival and/or progression-free survival after EGFR-directed treatment. Applicant further argues Buffet does not disclose using marker-specific AREG and EREG clinical-response cut offs to determine whether an EGFR-directed therapeutic agent should be excluded from administered treatment. Applicant further argues the cited combination does not provide a teaching or reasoned basis for using AREG and EREG determinations to make a treatment-selection decision required by claim 1. Citing claims 14 and 18, Applicant further indicates Yoshida does not teach a treatment when either AREG or EREG is high or when both markers are low. Applicant further argues Yoshida does not disclose administering EGFR-directed therapy based on satisfaction of recited marker-specific positive cut offs associated with improvement in overall survival or progression-free survival as required by claim 1 and that the presence of patients who were positive for both AREG and EREG does not disclose the claimed marker-specific positive-response cut offs or their use in recited treatment selection. Applicant further argues Yi’s single-marker ER classification and Buffet’s assay-variable study provide no reason to replace Yoshida’s “greater than two of four ligands” criterion with a method in which AREG and EREG are used independently in treatment selection and the recited positive and negative marker-specific cut offs are used to determine treatment administered. Applicant further agues a lack of motivation to modify Yoshida’s “greater than two of four ligand” and the combination of Yi, Buffet, and Yoshida does not disclose or suggest a treatment-selection rule recited by claims 14 and 18, in which either AREG HIGH or EREG HIGH requires administration of EGFR-directed therapy and both RAEG LOW and EREG LOW require administration of a treatment that excludes an EGFR-directed therapeutic agent. Applicant further indicates a “30% AREG cut off” and a “30% EREG cut off” are not different. Applicant further argues Yoshida does not disclose separate AREG-specific and EREG-specific cut offs associated with worsening in overall survival or progression-free survival after EGFR-directed treatment. Applicant further argues Yi et al does not define staining below 9% as negative nor use such a cut off to direct patients away from endocrine therapy. Applicant further argues Yi does not disclose separate positive and negative cut offs for each of two EGFR ligands, a claimed “either-high/both-low” treatment-selection recitation, or selection of a treatment that excludes EGFR-directed therapeutic agent. Applicant further argues Yi does not provide a distinct positive and negative cut off framework attributed to it by the Office and cannot cure Yoshida’s failure to disclosed claimed marker-specific AREG/EREG treatment-selection relationships. Applicant further argues Yi's ER-negative, ER-positive 1%-9%, and ER-positive at least 10% breast-cancer categories do not disclose clinical relationships for AREG or EREG and do not concern response to an EGFR-directed therapeutic agent. Applicant further argues that Buffet does not correlate alternative AREG-specific or EREG-specific cut offs with response to EGFR-directed therapy. Applicant further argues conclusions of Buffet do not provide support for a reasonable expectation that routine adjustment of staining cut offs would produce AREG-specific and EREG-specific cut offs having the recited clinical-outcome relationships and the claimed treatment-selection method. Applicant further argues Buffet does not supply a required relationship between marker-specific cut off values and claimed treatment decision. Applicant further argues Buffet does not teach or suggest using AREG-specific and EREG-specific response thresholds to determine whether administered treatment includes an EGFR-directed therapeutic agent. Applicant further argues Buffet does not associate any AREG or EREG cut off with improvement or worsening in overall survival or progression-free survival after EGFR-directed treatment. Applicant further argues cited references do not identify recited variable-result relationships now recited in amended claims. Applicant further agues no cited reference discloses AREG-specific and EREG-specific cut offs associated with worsening in overall survival or progression-free survival after EGFR-directed treatment. Applicant further agues no cited reference discloses both positive and negative cut offs for each marker, respectively associated with improvement and worsening in overall survival or progression-free survival after ERFR-directed treatment. Applicant further argues Yoshida does not treat either AREG or EREG as independently controlling. Applicant further argues neither Yi nor Buffet disclose the claimed treatment-selection methodology or clinical-outcome relationships. Applicant further indicates it has not been shown why a skilled artisan would have selected recited marker-specific cut offs and treatment decisions required by claims as amended. Applicant further argues the combination lacks AREG-specific and EREG-specific cut offs associated with worsening in overall survival and/or progression-free survival and the corresponding treatment step of claim 1. Applicant further argues the combination lacks positive and negative marker-specific clinical-response cut offs, and associated treatment-selection relationships, required by claims 14 and 18.
The amendments to the claims and the arguments found in the Reply of 8/13/26 have been carefully considered, but are not deemed persuasive. In regards to the following 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)):
Yoshida et al does not teach administration of an anti-EGFR antibody when biomarker measurements are above their cut offs and administration of a treatment "that does not include the anti-EGFR antibody treatment (such as irinotecan chemotherapy of Yoshida et al)" when they are not positive.
Yoshida et al is a retrospective study and did not use AREG and EREG results to determine whether an EGFR-directed agent would be administered.
Yoshida’s 30% staining criterion that retrospectively identified groups having different outcomes after anti-EGFR treatment does not disclose using AREG- and EREG-specific cut offs having the recited clinical-outcome relationships to select treatment and/or to make the treatment-exclusion decision required by claims.
Yoshida does not identify the 30% AREG staining criterion as a cut off associated with worsening in overall survival or progression-free survival after EGFR-directed therapy.
Yoshida does not disclose administering a therapy that excludes an EGFR-directed therapeutic agent, such as irinotecan as an alternative to cetuximab or panitumumab.
Yi does not disclose selecting a treatment that excludes an EGFR-directed therapeutic agent when AREG+ and EREG+ tumor-cell percentages are each blow marker-specific cut offs associated with worsening in overall survival and/or progression-free survival after EGFR-directed treatment.
Buffet does not disclose using marker-specific AREG and EREG clinical-response cut offs to determine whether an EGFR-directed therapeutic agent should be excluded from administered treatment.
Yoshida does not teach a treatment when either AREG or EREG is high or when both markers are low.
Yoshida does not disclose administering EGFR-directed therapy based on satisfaction of recited marker-specific positive cut offs associated with improvement in overall survival or progression-free survival as required by claim 1.
Yi’s single-marker ER classification and Buffet’s assay-variable study provide no reason to replace Yoshida’s “greater than two of four ligands” criterion with a method in which AREG and EREG are used independently in treatment selection and the recited positive and negative marker-specific cut offs are used to determine treatment administered.
Yoshida does not disclose separate AREG-specific and EREG-specific cut offs associated with worsening in overall survival or progression-free survival after EGFR-directed treatment.
Yi et al does not define staining below 9% as negative nor use such a cut off to direct patients away from endocrine therapy.
Yi does not disclose separate positive and negative cut offs for each of two EGFR ligands, a claimed “either-high/both-low” treatment-selection recitation, or selection of a treatment that excludes EGFR-directed therapeutic agent.
Yi does not provide a distinct positive and negative cut off framework attributed to it by the Office.
Yi's ER-negative, ER-positive 1%-9%, and ER-positive at least 10% breast-cancer categories do not disclose clinical relationships for AREG or EREG and do not concern response to an EGFR-directed therapeutic agent.
Buffet does not correlate alternative AREG-specific or EREG-specific cut offs with response to EGFR-directed therapy.
Conclusions of Buffet do not provide support for a reasonable expectation that routine adjustment of staining cut offs would produce AREG-specific and EREG-specific cut offs having the recited clinical-outcome relationships and the claimed treatment-selection method.
Buffet does not supply a required relationship between marker-specific cut off values and claimed treatment decision.
Buffet does not teach or suggest using AREG-specific and EREG-specific response thresholds to determine whether administered treatment includes an EGFR-directed therapeutic agent.
Buffet does not associate any AREG or EREG cut off with improvement or worsening in overall survival or progression-free survival after EGFR-directed treatment.
Yoshida does not treat either AREG or EREG as independently controlling.
Neither Yi nor Buffet disclose the claimed treatment-selection methodology or clinical-outcome relationships.
In regards to the argument that cited references do not teach positive cut offs associated with improvement and negative cut offs associated with worsening in at least one overall survival and progression-free survival after treatment with an EGFR-directed therapeutic agent, the examiner disagrees. Yoshida teaches “positive” cut offs for AREG (30% tumor cells AREG+) and EREG (30% tumor cells EREG+) in addition to positive cut offs for HB-EGF and TGF-a, which correlate with a significantly higher “disease control rate”, a “better response”, and “longer progression-free survival” when levels of two or more of the biomarkers are above cut offs, as compared to AREG-/EREG-/HB-EGF-/TGFa- tumors (Abstract and right paragraph on page 374, in particular). Yoshida further teaches “negative” cut offs for AREG (30% tumor cells AREG+), EREG (30% tumor cells EREG+), HB-EGF (30% tumor cells HG-EGF+), and TGF-a (30% tumor cells TGF-a+), below which result in significantly lower disease control rate, worse “response, and shorter progression-free survival to an EGFR-directed therapeutic than AREG+/EREG+ tumors (Abstract and right paragraph on page 374, in particular). Further, the combined method comprises optimizing said cut offs, for the reasons stated above, and is not limited to using said cut offs.
In regards to the argument the Office's contentions that values below the common 30% criterion indicate a "negative/poor response" and that values above the criterion indicate a "positive/good response" does not establish marker-specific relationships, the examiner maintains Yoshida teaches “positive” cut offs for AREG (30% tumor cells AREG+), EREG (30% tumor cells EREG+), HB-EGF (30% tumor cells are HB-EGF+), and TGF-a (30% tumor cells are TGF-a+). Two or more biomarkers above cut offs correlates with significantly higher “disease control rate”, a “better response”, and “longer progression-free survival” when treated with an EGFR-directed therapeutic as compared to AREG-/EREG-/HB-EGF-/TGFa- tumors treated with an EGFR-directed therapeutic (Abstract and right paragraph on page 374, in particular). Yoshida further teaches “negative” cut offs for AREG (30% tumor cells AREG+), EREG (30% tumor cells EREG+), HB-EGF (30% tumor cells HG-EGF+), and TGF-a (30% tumor cells TGF-a+), below which result in significantly lower “disease control rate”, a “better response”, and “longer progression-free survival” to treatment with an EGFR-directed therapeutic than AREG+/EREG+ tumors in combination with either HB-EGF+ or TGF-a+ treated with an EGFR-directed therapeutic (Abstract and right paragraph on page 374, in particular). Further, the combined method comprises optimizing said cut offs, for the reasons stated above, and is not limited to using said cut offs.
In regard to the arguments the cited combination does not provide a teaching or reasoned basis for using AREG and EREG determinations to make a treatment-selection decision required by claim 1 and the combination lacks AREG-specific and EREG-specific cut offs associated with worsening in overall survival and/or progression-free survival and the corresponding treatment step of claim 1, the examiner disagrees. Yoshida et al correlates expression of AREG, HB-EGF, TGF-a, and EREG with response to EGFR-directed therapeutics. An embodiment of claim 1 encompassed by the combined method is when AREG, HB-EGF, TGF-a, and EREG biomarker proteins are all below cut-offs of Yoshida (cut offs of Yoshida: 30% tumor cells AREG+, 30% tumor cells EREG+, 30% tumor cells HG-EGF+, and 30% tumor cells TGF-a+) indicative of poor response to EGFR-directed therapeutics and worse progression-free survival from EGFR-directed therapeutics based on Yoshida and a therapeutic course that does not include an EGFR-directed therapeutic is administered due to lack of responsiveness to EGFR-directed therapeutics. Further, the combined method comprises optimizing said cut offs, for the reasons stated above, and is not limited to using said cut offs.
In regards to the argument the presence of patients who were positive for both AREG and EREG does not disclose the claimed marker-specific positive-response cut offs or their use in recited treatment selection, it is not the Office’s position that the claimed marker-specific positive-response cut offs or their use in recited treatment selection is rendered obvious solely based on the presence of patients who were positive for both AREG and EREG.
In regards to a lack of motivation to modify Yoshida’s “greater than two of four ligand”, the examiner disagrees and takes the position that the combined method comprises detecting all four biomarkers and is encompassed by a “greater than two of four” assay. Further, the combined method has additional benefits not limited to Yoshida’s teachings. These include: providing a treatment option that does not include anti-EGFR antibody treatment provides another therapeutic option for patients that do not respond as well to anti-EGFR antibody treatment; and optimizing the method of Yoshida by varying cut-offs are used to determine positivity or negativity of biomarker that correlate with therapeutic response.
In regard to the arguments the combination of Yi, Buffet, and Yoshida does not disclose or suggest a treatment-selection rule recited by claims 14 and 18 in which either AREG HIGH or EREG HIGH requires administration of EGFR-directed therapy and both RAEG LOW and EREG LOW require administration of a treatment that excludes an EGFR-directed therapeutic agent, Yi et al cannot cure Yoshida’s failure to disclosed claimed marker-specific AREG/EREG treatment-selection relationships, and the combination lacks positive and negative marker-specific clinical-response cut offs and associated treatment-selection relationships required by claims 14 and 18, an embodiment of claims 14 and 18 encompassed by the combined method is when AREG and EREG markers are high in combination with either HB-EGF or TGF-a (indicative of response to EGFR-directed therapeutics is increased and results in longer “progression-free survival” based on Yoshida) and an EGFR-directed therapeutic is administered.
In regards to the argument a “30% AREG cut off” and a “30% EREG cut off” are not different, the cut-offs “30% of tumor cells of a sample stain for AREG” and “30% of tumor cells of a sample stain for EREG” of Yoshida et al for determining response to anti-EGFR therapy are different. Further, the combined method comprises optimizing said cut offs, for the reasons stated above, and is not limited to using said cut offs.
In regards to the argument that cited references do not identify recited variable-result relationships now recited in amended claims, cited references render obvious optimizing cut offs that correlate with treatment response. Yi et al demonstrates optimizing cut-offs for biomarkers correlating with treatment efficacy. 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 in combination with HB-EGF or TGF-a) 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).
In regard to the arguments cited no reference discloses AREG-specific and EREG-specific cut offs associated with worsening in overall survival or progression-free survival after EGFR-directed treatment, no cited reference discloses both positive and negative cut offs for each marker associated with improvement and worsening in overall survival or progression-free survival after ERFR-directed treatment, and it has not been shown why a skilled artisan would have selected recited marker-specific cut offs and treatment decisions required by claims as amended, Yoshida et al teaches 30% AREG+, 30% EREG+, 30% HB-EGF+, and 30% TGF-a+ as “negative” cut offs used to indicate (when below cut offs) a worse response (including shorter “progression-free survival”) to EGFR-directed therapeutics (Abstract and right paragraph on page 374, in particular). Further, Yoshida teaches 30% AREG+, 30% EREG+, 30% HB-EGF+, and 30% TGF-a+ as “positive” cut offs used to indicate (when more then two, including AREG and EREG in combination with HB-EGF or TGF-a, are above cut offs) a better response (including lunger “progression free survival”) to EGFR-directed therapeutics (Abstract and right paragraph on page 374, in particular). Again, the combined method comprises optimizing said cut offs, for the reasons stated above, and is not limited to using said cut offs.
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 8/13/26, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 7-12, and 14-21 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 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 8/13/26, Applicant repeats arguments addressed above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN E AEDER whose telephone number is (571)272-8787. The examiner can normally be reached M-F 9am-6pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SEAN E AEDER/ Primary Examiner, Art Unit 1642
Prosecution Insights