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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/15/26 has been entered.
Claims 270-274 have been added by Applicant.
Claims 1-4, 16, 63, 133, 134, 141, 142, 261-274 are pending.
Claim 262 remains withdrawn.
Claim 142 has been amended by Applicant.
Claims 1-4, 16, 63, 133, 134, 141, 261, 263-274 are currently under consideration.
This Office Action contains New Rejections Necessitated by Amendments.
Rejection Withdrawn
The rejection under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 1-4, 16, 63, 261, and 267-269 remain rejected and claim 270 is rejected under 35 U.S.C. 103(a) as being unpatentable over Jang et al (Radiotherapy and Oncology, 2017, 124: 403-410) in view of Würschmidt et al (Radiation Oncology, 2008, 3(28): 1-9).
Jang et al assigned 1045 invasive breast cancer patients as having high expression of PD-L1 or low expression of PD-L1 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+) and at least 77.6% of the patients were HER2 negative (HER2-) (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).
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 Würschmidt et al.
Würschmidt et al teaches breast cancer patients benefit from being administered radiation treatments with a mean BED of 168.5 Gy with an α/β assumed to be 3 Gy (Abstract and right column on page 2, in particular). Radiation treatments of Würschmidt et al include partial breast radiotherapy (Table 2, in particular). Würschmidt et al further teaches radiation treatments may be applied with brachytherapy or external (same as “systemic”) beam radiation (right column on page 5, 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 cancer tissue sample from just any invasive breast cancer patient (including an ER+/HER2- patient of Jang 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) and then administering just any radiation treatment of Würschmidt et al to the patient identified as having high PD-L1 expression because Jang et al teaches high PD-L1 expression correlates with sensitivity of breast cancer patients to radiation treatment and Würschmidt et al teaches radiation treatment that 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 radiation treatment 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). 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.
Response to Arguments
In the Reply of 6/15/26, Applicant argues Jang does not teach an expression level of PD-L1 is associated with responsiveness to radiotherapy. Applicant further argues the Office has not articulated why high PD-L1 expression would direct the skilled artisan to administer a recited intensified radiation therapy. Applicant further argues a lack of motivation to administer intensified radiotherapy to a radiosensitive patient because one would be motived to administer a low dose, and not a high dose, of radiotherapy to a radiosensitive patient to avoid side effect of intensified radiotherapy.
The amendments to the claims and the arguments found in the Reply of 6/15/26 have been carefully considered, but are not deemed persuasive. In regards to the argument that Jang does not teach an expression level of PD-L1 is associated with responsiveness to radiotherapy, the examiner disagrees. Jang teaches “PD-L1-high” (as opposed to “PD-L1-low”) as an expression level of PD-L1 that is associated with radiosensitive (“RS”) patients that are responsive to radiotherapy. See left column on page 405 of Jang:
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In regards to the argument that the Office has not articulated why high PD-L1 expression would direct the skilled artisan to administer a recited intensified radiation therapy, the examiner disagrees. As stated above, 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 tissue sample from just any invasive breast cancer patient (including an ER+/HER2- patient of Jang 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) and then administering just any radiation treatment of Würschmidt et al to the patient identified as having high PD-L1 expression because Jang et al teaches high PD-L1 expression correlates with sensitivity of breast cancer patients to radiation treatment and Würschmidt et al teaches radiation treatment that 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 radiation treatment 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). 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.
In regards to the argument of a lack of motivation to administer intensified radiotherapy to a radiosensitive patient because one would be motived to administer a low dose, and not a high dose, of radiotherapy to a radiosensitive patient to avoid side effect of intensified radiotherapy, the examiner disagrees. Jang et al does not teach radiation doses, while Würschmidt et al teaches radiation treatments that provide therapeutic benefit to patients with breast cancer. Further, one would not expect the radiation treatment of Würschmidt et al to result in particularly poor side effects because Würschmidt et al teaches side effects of the radiation treatment of Würschmidt et al resulted in “normal tissue toxicity” and included mild to moderate acute side effects with no grad 3 or 4 toxicity; no grade 3 or 4 late effects were observed, and no grade 3 or 4 plexopathy was observed by Würschmidt et al (right column on page 5 and Results portion of Abstract, in particular).
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 16, 63, 133-134, 261, 263, 264, and 267-269 remain and claim 270 is rejected under 35 U.S.C. 103 as being unpatentable over Jang et al (Radiotherapy and Oncology, 2017, 124: 403-410) in view of Würschmidt et al (Radiation Oncology, 2008, 3(28): 1-9) as applied to claims 1-4, 16, 63, 261, and 267-270 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 Würschmidt et al are discussed above.
Jang et al and Würschmidt 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.
Response to Arguments
In the Reply of 6/15/26, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 16, 63, 141, 142, 261, and 267-269 remain rejected and claims 270 and 272 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 Würschmidt et al (Radiation Oncology, 2008, 3(28): 1-9) as applied to claims 1-4, 16, 63, 261, and 267-270 above, and further in view of Lischka et al (Clinical Cancer Research, 2020, 26(17): 4606-4615).
Teachings of Jang et al and Würschmidt et al are discussed above.
Jang et al and Würschmidt 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.
Response to Arguments
In the Reply of 6/15/26, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 16, 63, 133, 134, 141, 142, 261, and 263-269 remain rejected and claims 270-272 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 Würschmidt et al (Radiation Oncology, 2008, 3(28): 1-9) 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, and 267-270 above, and further in view of Lischka et al (Clinical Cancer Research, 2020, 26(17): 4606-4615).
Teachings of Jang et al, Würschmidt et al, and Sobral-Leite et al are discussed above.
Jang et al, Würschmidt 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, Würschmidt et al, and Sobral-Leite et al by performing the method of Jang et al, Würschmidt 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.
Response to Arguments
In the Reply of 6/15/26, Applicant repeats arguments addressed above.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 103
Claim 270 is rejected under 35 U.S.C. 103(a) as being unpatentable over Choi et al (American Journal of Clinical Oncology, 2018, 41(11): 1049-1057) in view of Jang et al (Radiotherapy and Oncology, 2017, 124: 403-410) and Würschmidt et al (Radiation Oncology, 2008, 3(28): 1-9).
Choi et al teaches a method comprising obtaining tissue samples of tumors from breast cancer patients (TNBC patients, including those with invasive breast cancer), determining expression levels of PD-L1 protein in tumor cells and TILs of the samples wherein the samples are “PD-L1 positive” when ≥5% of tumor cells or TILs exhibit at least moderate expression and ˃70% is considered strong PD-L1 staining, and determining the expression levels of PD-L1 are above threshold levels, wherein expression levels of PD-L1 in tissue sample of tumors from cancer patients above threshold levels indicates the cancer patients have a high chance of systemic cancer recurrence (Figure 2 and Table 2, in particular). Choi et al further teaches such systemic cancer recurrence is indicative of need for intensive systemic therapy (see “Especially strong PD-L1 expression status was related to distant metastasis-dominant recurrence pattern which needs for intensive systemic therapy.” at Abstract and right column on page 1054, in particular). Choi et al further teaches high and low PD-L1 expression does not correlate with histological grade (right column on page 1052, in particular). Choi et al further teaches high histological grade correlates with SUVmax uptake and (right column on page 1052, in particular) and that while intensified systemic therapy may be particularly important in tumors with strong PD-L1 expression, and aggressive therapy including both (intensified systemic therapy & optimal locoregional treatment) may be needed for tumors with high SUVmax uptake (first two paragraphs of right column on page 1054, in particular).
Choi et al does not specifically demonstrate administering intensive/intensified systemic radiotherapy therapy to a patient. However, these deficiencies are made-up in the teachings of Jang et al and Würschmidt et al.
Jang et al teaches elevated PD-L1 expression in breast tumors correlates with sensitivity to radiation treatment (Abstract, in particular).
Würschmidt et al teaches breast cancer patients benefit from being administered radiation treatments with a mean BED of 168.5 Gy with an α/β assumed to be 3 Gy (Abstract and right column on page 2, in particular). Radiation treatments of Würschmidt et al include partial breast radiotherapy (Table 2, in particular). Würschmidt et al further teaches radiation treatments may be applied with brachytherapy or external beam radiation (right column on page 5, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method providing therapeutic benefit to just any patient with breast cancer (including TNBC patients; including those with invasive breast cancer; including those with histological grade I or II and less than 10% of tumor cells having Ki67 expression) by determining the histological grade of the tumor as a surrogate for “high SUVmax uptake” when performing the method of Choi et al comprising obtaining tissue samples of tumors from breast cancer patients (including TNBC patients, including invasive breast cancer patients), determining expression levels of PD-L1 protein in tumor cells and TILs of the samples wherein the samples are “PD-L1 positive” when ≥5% of tumor cells or TILs exhibit at least moderate expression and ˃70% is considered strong PD-L1 staining, determining the expression levels of PD-L1 are above threshold levels, and administering an intensive/intensified systemic therapy to the patients with expression levels of PD-L1 in tissue sample of tumors above threshold levels and administering intensive/intensified systemic therapy with optimal locoregional treatment when the tumors exhibit a high histological grade because Choi et al teaches intensified systemic therapy may be particularly important in tumors with strong PD-L1 expression, and aggressive therapy including both (intensified systemic therapy & optimal locoregional treatment) may be needed for tumors with high SUVmax uptake (first two paragraphs of right column on page 1054, in particular).
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the method rendered obvious by Choi et al wherein the breast cancer patients administered the intensified systemic therapy are administered radiation treatments of Würschmidt et al (with a mean BED of 168.5 Gy with an α/β of 3 Gy) because Jang et al teaches elevated PD-L1 expression in breast tumors correlates with sensitivity to radiation treatments and the radiation treatments of Würschmidt et al (with a mean BED of 168.5 Gy with an α/β assumed to be 3 Gy) therapeutically treat breast cancer patients. 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 references to arrive at the claimed invention.
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
Claim(s) 1-4, 16, 63, 261, 267-270, 273, and 274 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 Würschmidt et al (Radiation Oncology, 2008, 3(28): 1-9) as applied to claims 1-4, 16, 63, 261, and 267-270 above, and further in view of Thomas et al (Radiotherapy and Oncology, 1988, 13: 267-276).
Teachings of Jang et al and Würschmidt et al are discussed above.
Jang et al and Würschmidt et al do not specifically teach methods wherein radiation treatment of Würschmidt 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 Würschmidt et al where tumor HG is measured alongside PD-L1 and the radiotherapy of Würschmidt 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.
Conclusion
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/SEAN E AEDER/Primary Examiner, Art Unit 1642
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