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 .
The Amendments and Remarks filed 9/24/26 in response to the Office Action of 6/24/26 are acknowledged and have been entered.
Claims 275-279 have been added by Applicant.
Claims 1-4, 16, 63, 133, 134, 141, 142, and 261-279 are pending.
Claim 262 remains withdrawn.
Claims 1-4, 16, 134, 142, 270, 272, and 273 have been amended by Applicant.
Claims 1-4, 16, 63, 133, 134, 141, 142, 261, and 263-279 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.
The following Office Action contains NEW GROUNDS of rejections Necessitated by Amendments.
Rejections Withdrawn
All previous rejections are withdrawn.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 103
Claims 1-4, 16, 63, 261, 267-270, and 275-279 are rejected under 35 U.S.C. 103(a) as being unpatentable over Jang et al (Entitled: “A radiosensitivity gene signature and PD-L1 status predict clinical outcomes of patients with invasive breast carcinoma in The Cancer Genome Atlas (TCGA) dataset”, Radiotherapy and Oncology, 2017, 124: 403-410) in view of Ghannam et al (Journal of the Egyptian National Cancer Institute, 2016, 28: 39-44).
Jang et al assigned 1045 invasive breast cancer patients as having high expression of PD-L1 or low expression of PD-L1 in tissue samples before any therapy was administered (second full paragraph of the right column on page 407; same as “unirradiated” samples) based on the threshold of median expression of the gene encoding PD-L1 in tumor samples of the patients, wherein at least 73.4% of the patients were estrogen receptor positive (ER+), at least 77.6% of the patients were HER2 negative (HER2-), and the vast majority of the patients were “early” stage 1 or 2 breast cancer (Table 1, in particular). Jang et al teaches 64.9% of radiation sensitive (RS) breast cancer patients have high PD-L1 expression, while 70.7% of radiation resistant (RR) breast cancer patient have low PD-L1 expression (left column on page 405, in particular). Jang et al further concludes radiosensitivity is associated with PD-L1 status (p ˂ 0.001). At the left column on page 405, Jang et al further teaches PD-L1 mRNA (CD274) expression level was significantly higher in invasive breast cancer patients than in radioresistant breast cancer patients (Mann-Whitney test, p ˂ 0.001). Jang et al further teaches the radiosensitive breast cancer patients administered radiation treatment had a lower risk of recurrence in the high PD-L1 expression group (right column on page 405 and Table 3, in particular).
It is further noted that, in response to various arguments found in the Reply of 6/24/26: Jang et al teaches 63% of the radiation sensitive breast cancer patients are ER positive (Table 1, in particular). Further, Jang et al discusses how there is not agreement in the art as to whether ER status is indicative of radiation resistance or radiation sensitive breast cancer (paragraph spanning columns on page 407). In view of Jang et al teaching (i) 63% of the radiation sensitive breast cancer of Jang et al patients are ER positive and (ii) that there is not agreement in the art as to whether ER status is indicative of radiation resistance or radiation sensitive breast cancer (in addition to Jang et al not criticizing, discrediting, or otherwise discouraging administering radiotherapy to breast cancer patients having ER positive status), Jang et al does not “teach away” from administering radiation to ER-positive breast cancer patients.
Jang et al does not specifically teach providing intensified treatment as intensified radiotherapy treatment to the invasive breast cancer patients based on a previous determination that PD-L1 expression is above a threshold level. However, these deficiencies are made up in the teachings of Ghannam et al.
Ghannam et al teaches therapeutically treating pT1 or pT2, pN0-N1 early stage unirradiated breast cancer patients (74% ER-positive) following lumpectomy by administering intensified external radiotherapy with concomitant electron boost to the patients with a BED of 67 Gy or more (page 40, Abstract, and Tabel 2, in particular). Ghannam et al further teaches such a therapy is a widely accepted practice in patients at a higher risk of local recurrence and is known to reduce local recurrence rates (left column on page 40, in particular). As defined by instant claim 1 (which recites “…intensified treatment at:…intensified systemic therapy, as adjuvant therapy following lumpectomy; or mastectomy.”) and the instant specification at [0075] (disclosing radiation therapy as “adjuvant” radiation), the intensified external radiotherapy with concomitant electron boost of Ghannam et al is intensified “systemic” therapy, “as adjuvant therapy” following lumpectomy.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising obtaining a cancer tumor tissue sample obtained by lumpectomy from just any breast cancer patient (including an ER+/HER2- patient of Jang et al that is early stage I or 2; or early stage pT1 or pT2, pN0-N1, unirradiated ER-positive breast cancer patients of Ghannam et al), determining an expression level of PD-L1 protein or mRNA in the sample, determining that the expression level is above the median expression level of PD-L1 to identify the breast cancer patient as having high PD-L1 expression (as taught by Jang et al), and (based on determining that the patient has high PD-L1 expression) administering intensified external radiotherapy with concomitant electron boost of Ghannam et al to the patient identified as having high PD-L1 expression because Jang et al teaches high PD-L1 expression of pre-treatment tumor tissue correlates with sensitivity of breast cancer patients to radiation treatment and Ghannam et al teaches intensified external radiotherapy with concomitant electron boost provide therapeutic benefit to patients with breast cancer. Further, the patient with high PD-L1 expression of the combined method predictably has reduced risk of recurrence from being administered the intensified external radiotherapy with concomitant electron boost because Jang et al teaches radiosensitive breast cancer patients administered radiation treatment had a lower risk of recurrence in a high PD-L1 expression group (right column on page 405 and Table 3, in particular) and Ghannam et al teaches such a therapy is a widely accepted practice in patient at a higher risk of local recurrence and is known to reduce local recurrence rates (left column on page 40, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill 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.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 16, 63, 133-134, 261, 263, 264, 267-270, and 275-279 are rejected under 35 U.S.C. 103 as being unpatentable over Jang et al (Radiotherapy and Oncology, 2017, 124: 403-410) in view of Ghannam et al (Journal of the Egyptian National Cancer Institute, 2016, 28: 39-44) as applied to claims 1-4, 16, 63, 261, 267-270, and 275-279 above, and further in view of Sobral-Leite et al (OncoImmunology, 2018, 7(12)(e1509820) 15 pages; 11/20/25 IDS).
Teachings of Jang et al and Ghannam et al are discussed above.
Jang et al and Ghannam et al do not specifically teach determining a level of PD-L1 positive lymphocytes. However, these deficiencies are made up in the teachings of Sobral-Leite et al.
Sobral-Leite et al teaches a method comprising measuring a stromal area occupied by lymphocytes in a breast cancer tissue sample from a patient, determining the amount of tumor-infiltrating lymphocytes (TILs) in the sample, assessing the proportion of lymphocytes in the sample with positive staining for PD-L1 protein, wherein breast cancer patient with a high proportion of PD-L1 positive TILs (such as above 25% of TILs being positive) are more likely to be a higher tumor grade than patients with a low proportion of PD-L1 positive TILs (Figure 2G, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to characterize the patients of the combined method by performing the combined method with patients with invasive breast cancer wherein the method of Sobral-Leite et al is further performed with the patients (wherein levels of PD-L1 in TILs of Sobral-Leite et al are measured alongside levels of PD-L1 in cancer tissue of the combined method) because the method of Sobral-Leite et al would help determine the tumor grade of the breast cancer patient treated by the combined method. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill 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.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 16, 63, 141, 142, 261, 267-272, and 275-279 are rejected under 35 U.S.C. 103 as being unpatentable over Jang et al (Radiotherapy and Oncology, 2017, 124: 403-410) in view of Ghannam et al (Journal of the Egyptian National Cancer Institute, 2016, 28: 39-44) as applied to claims 1-4, 16, 63, 261, 267-270, and 275-279 above, and further in view of Lischka et al (Clinical Cancer Research, 2020, 26(17): 4606-4615).
Teachings of Jang et al and Ghannam et al are discussed above.
Jang et al and Ghannam et al do not specifically teach determining a level of Ki-67 and/or genomic instability. However, these deficiencies are made up in the teachings of Lischka et al.
Lischka et al teaches determining levels of genomic instability, including low or high, in tumor samples of breast cancer patients (Table 1, in particular), wherein levels of genomic instability predict disease outcome (Abstract, in particular). Lischka et al further teaches method of detecting percentages of tumor cells exhibiting Ki-67 (same as “Ki67”) expression, where tumors were classified as highly proliferating if more than 10% of cells were positive for Ki-67 (left column on page 4607).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to characterize the patients of the combined method by performing the combined method with patients with invasive breast cancer wherein genomic instability and the percentage of cancer cells expression Ki-67 is measured alongside levels of PD-L1 in cancer tissue of the combined method and all patients with high PD-L1 levels, include those with any level of genomic instability and any level of Ki67 expression, are administered the radiotherapy because Jang et al teaches patients with high levels of PD-L1 therapeutically respond to radiotherapy and because the levels of genomic instability and percentages of cancer cells expression Ki-67 would help determine the clinical outcome and proliferation of cancer cells of the breast cancer patient treated by the combined method. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill 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.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 16, 63, 133, 134, 141, 142, 261, 263-272, and 275-279 are rejected under 35 U.S.C. 103 as being unpatentable over Jang et al (Radiotherapy and Oncology, 2017, 124: 403-410) in view of Ghannam et al (Journal of the Egyptian National Cancer Institute, 2016, 28: 39-44) and Sobral-Leite et al (OncoImmunology, 2018, 7(12)(e1509820) 15 pages; 11/20/25 IDS) as applied to claims 1-4, 16, 63, 133-134, 261, 263, 264, 267-270, and 275-279 above, and further in view of Lischka et al (Clinical Cancer Research, 2020, 26(17): 4606-4615).
Teachings of Jang et al, Ghannam et al, and Sobral-Leite et al are discussed above.
Jang et al, Ghannam et al, and Sobral-Leite et al do not specifically teach determining a level of Ki-67 and/or genomic instablity. However, these deficiencies are made up in the teachings of Lischka et al.
Teachings of Lischka et al are discussed above.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to further characterize the patients of the method of Jang et al, Ghannam et al, and Sobral-Leite et al by performing the method of Jang et al, Ghannam et al, and Sobral-Leite et al with patients with invasive breast cancer wherein genomic instability and the percentage of cancer cells expression Ki-67 is measured alongside levels of PD-L1 in cancer tissue of the combined method and all patients with high PD-L1 levels, include those with any level of genomic instability and any level of Ki67 expression, are administered the radiotherapy because Jang et al teaches patients with high levels of PD-L1 therapeutically respond to radiotherapy and because the levels of genomic instability and percentages of cancer cells expression Ki-67 would help determine the clinical outcome and proliferation of cancer cells of the breast cancer patient treated by the combined method. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill 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.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 16, 63, 261, 267-270, and 273-279 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jang et al (Radiotherapy and Oncology, 2017, 124: 403-410) in view of Ghannam et al (Journal of the Egyptian National Cancer Institute, 2016, 28: 39-44) as applied to claims 1-4, 16, 63, 261, 267-270, and 275-279 above, and further in view of Thomas et al (Radiotherapy and Oncology, 1988, 13: 267-276).
Teachings of Jang et al and Ghannam et al are discussed above.
Jang et al and Ghannam et al do not specifically teach methods wherein treatment of Ghannam et al is provided based on the determined expression level of PD-L1 and a determined histological grade. However, these deficiencies are made up in the teachings of Thomas et al.
Thomas et al teaches determining histological grade (HG) of breast cancer tumors and that risk of local recurrence of breast cancer patients treated with radiotherapy is lower with breast tumors with a lower HG, such as HG I, as compared to tumors with HG III (Table III, in particular). Thomas et al further teaches breast cancer patients classified as having a lower risk of local recurrence respond better to doses of radiation higher than 65 Gy, including ˃80 Gy (Table IV, 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 Jang et al and Ghannam et al where tumor HG is measured alongside PD-L1 and the radiotherapy of Ghannam et al is provided based on elevated PD-L1 expression and the determined HG, wherein those patients with HG I are at reduced risk of local recurrence than those patients with an HG III and those patients classified as having a reduced risk of local recurrence respond better to doses of radiation higher than 65 Gy, including ˃80 Gy because Thomas et al teaches risk of local recurrence of breast cancer patients treated with radiotherapy is lower with breast tumors with a lower HG, such as HG I, as compared to tumors with HG III (Table III, in particular) and Thomas et al teaches breast cancer patients classified as having a lower risk of local recurrence respond better to doses of radiation higher than 65 Gy, including ˃80 Gy (Table IV, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine the prior art reference to arrive at the claimed invention. 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
Claims 1-4, 16, 63, 261, 267-270, and 275-279 are rejected under 35 U.S.C. 103(a) as being unpatentable over Jang et al (Entitled: “A radiosensitivity gene signature and PD-L1 status predict clinical outcomes of patients with invasive breast carcinoma in The Cancer Genome Atlas (TCGA) dataset”, Radiotherapy and Oncology, 2017, 124: 403-410) in view of Ghannam et al (Journal of the Egyptian National Cancer Institute, 2016, 28: 39-44) and Fyles et al (NEJM, 2004, 351: 963-970).
Teachings of Jang et al are discussed above.
Jang et al does not specifically teach providing intensified treatment as intensified radiotherapy treatment or intensified systemic therapy as adjuvant therapy following lumpectomy to the invasive breast cancer patients based on a previous determination that PD-L1 expression is above a threshold level. However, these deficiencies are made up in the teachings of Ghannam et al and Fyles et al.
Teachings of Ghannam et al are discussed above.
Fyles et al teaches ER positive breast cancer patients therapeutically benefit from systemically administering the adjuvant tamoxifen in combination with radiation (Abstract and pages 964-965, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method comprising obtaining a pre-operative cancer tumor tissue sample from just any breast cancer patient following lumpectomy (including an ER+/HER2- patient of Jang et al that is early stage I or 2; or early stage pT1 or pT2, pN0-N1, unirradiated ER-positive breast cancer patients of Ghannam et al), determining an expression level of PD-L1 protein or mRNA in the sample, determining that the expression level is above the median expression level of PD-L1 to identify the breast cancer patient as having high PD-L1 expression (as taught by Jang et al), and (based on determining that the patient has high PD-L1 expression) administering intensified external radiotherapy with concomitant electron boost of Ghannam et al to the patient identified as having high PD-L1 expression because Jang et al teaches high PD-L1 expression of pre-treatment tumor tissue correlates with sensitivity of breast cancer patients to radiation treatment and Ghannam et al teaches intensified external radiotherapy with concomitant electron boost provide therapeutic benefit to patients with breast cancer. Further, the patient with high PD-L1 expression of the combined method predictably has reduced risk of recurrence from being administered the intensified external radiotherapy with concomitant electron boost because Jang et al teaches radiosensitive breast cancer patients administered radiation treatment had a lower risk of recurrence in a high PD-L1 expression group (right column on page 405 and Table 3, in particular) and Ghannam et al teaches such a therapy is a widely accepted practice in patient at a higher risk of local recurrence and is known to reduce local recurrence rates (left column on page 40, in particular).
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said combined method wherein estrogen receptor positive breast cancer patients of the combined method administered radiotherapy are further systemically administered tamoxifen because Fyles et al teaches ER positive breast cancer patients therapeutically benefit from systemically administering the adjuvant tamoxifen in combination with radiation (Abstract and pages 964-965, in particular).
This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill 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.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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