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 11/20/25 in response to the Office Action of 6/20/25 are acknowledged and have been entered.
Claims 263-269 have been added by Applicant.
Claims 1-4, 16, 63, 133, 134, 141, 142, and 261-269 are pending.
Claim 262 remains withdrawn.
Claims 1-4, 16, 63, 133, 134, and 141 have been amended by Applicant.
Claims 1-4, 16, 63, 133, 134, 141, 142, 261, and 263-269 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Rejections Withdrawn
All previous rejections are withdrawn.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, and 267-269 are 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 breast cancer patients have high PD-L1 expression, while 70.7% of radiation resistant 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). Jang et al further teaches PD-L1 (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.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 16, 63, 133-134, 261, 263, 264, and 267-269 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 267-269 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.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 16, 63, 141, 142, 261, and 267-269 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 267-269 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 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 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, and 263-269 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) 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 267-269 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 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 § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 16, 63, 133, 134, 141, 142, 261, and 263-269 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
Claim 1 recites a method of determining an expressions level of PD-L1 protein or mRNA in a breast cancer tumor tissue sample from an estrogen receptor positive tumor of a patient is above a threshold level and then providing intensified treatment to the patient. Descriptions of methods of determining an expressions level of PD-L1 protein or mRNA in a breast cancer tumor tissue sample from an “estrogen receptor positive” tumor of a patient is above a threshold level and then providing intensified treatment to the patient are not found in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventors, at the time the invention was filed, had possession of the claimed invention.
Claim 16 recites a method of analyzing a cancer tissue sample from a subject who has invasive breast cancer that is estrogen receptor positive and administering intensified treatment to the patient upon determining that the cancer tissue sample has high level of PD-L1. Descriptions of methods of analyzing a cancer tissue sample from a subject who has invasive breast cancer “that is estrogen receptor positive” and administering intensified treatment to the patient upon determining that the cancer tissue sample has high level of PD-L1 are not found in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventors, at the time the invention was filed, had possession of the claimed invention.
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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/SEAN E AEDER/Primary Examiner, Art Unit 1642