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
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 .
Claim Status/Action Summary
This action is in response to the papers filed on April 13, 2026.
Claims 16-18, 27, and 32-33 were canceled by applicant. Claims 35-39 are newly added in the amendment filed April 13, 2026. Claims 1, 2, 6, 7, 19, 21-23, and 25-26, 28-31, and 34-39 are under examination. No other claims are currently pending in the present application.
Any objections and rejections not reiterated below are hereby withdrawn.
Priority
The present application was filed on April 20, 2023 and is a 371 of PCT/US2021/055810, filed on October 20, 2021, which claims the benefit of U.S. Provisional Application No. 63/094,574, filed on October 21, 2020.
Information Disclosure Statement
The information disclosure statement filed April 13, 2026 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed.
In this case, the copy of citation number 25 (the Strell et al. San Antonio Breast Cancer Symposium poster) is not legible.
This reference has not been considered and is lined through on the annotated IDS returned with this action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 is rejected under 35 U.S.C. 112(b) as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: “providing a local cancer tissue sample from each individual among a population of lymph-node negative (N0) patients with stage I or IIA breast cancer”. Claim 1 as presently amended requires a step of “scoring the level of PDGFRb in tertiles of… expression among a population of lymph-node negative (N0) patients with stage I or IIA breast cancer…”, but does not provide for any steps of providing samples and/or measuring the expression among said population.
This is a new grounds of rejection necessitated by the claim amendments.
Claims 1, 2, 6, 7, 16-19, 21-23, and 25-34 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1, as amended, now requires treating a subject with “standard” or “an alternative to standard” radiotherapy conditioned upon the level of PDGFRb expression in a cancer tissue sample relative to expression levels of PDGFRb among a population of lymph-node negative patients with stage I or IIA breast cancer.
The claim term “standard radiotherapy” renders the claim indefinite because “standard” methods are subject to constant change. Furthermore, the specification does not provide any limiting definition of a particular radiotherapy that is “standard”. The specification references exemplary guidelines identified by the tradename “NCCN” Guidelines (see below), and expressly states “it is essential that the NCCN Guidelines also be continuously updated and revised to reflect new data and clinical information that may add to or alter current clinical practice standards (i.e. “standard” therapies). The specification teaches “in some embodiments, the traditional breast cancer therapy (i.e. the “standard” therapy) is defined by the NCCN guidelines as of October 2020… [or] September 2021” (Specification, paragraph 0091). It is noted that i) these guidelines expressly change over time and thus the claim scope as presently written will also change over time and ii) the reference to recommendations made by a particular organization are not limiting definitions, but rather refer to exemplary embodiments of the claims. Accordingly, the claim terms such as “standard” or “traditional” therapy (or other equivalent terminology) do not meaningfully limit the scope of the claimed invention.
Claims 16-19, 21-23, and 25-34 are also indefinite as including the indefinite limitations of the claim(s) upon which they depend.
Claims 19, 21, and 34 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 19, 21, and 34 contain the trademark/trade name “NCCN” and “NCCN Guidelines”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b). See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the guidance issued by the corporation “National Comprehensive Cancer Network, Inc.” and, accordingly, the identification/description is indefinite.
Furthermore, reference to the guidelines issued by an organization do not reasonably apprise the ordinary artisan of the metes and bounds of the claim because said guidelines are subject to change. Indeed, if the claimed method were to be adopted into the NCCN guidelines for treatment of a subset of breast cancers as claimed, then the recited limitations of claims 19, 21, and 34 requiring therapies that are “more aggressive”, “more intense”, “alternative” to, or “at least more than” what would be recommended by the NCCN would become meaningless. Likewise, if the referenced guidelines were to be changed to eliminate or add aspects of the recommended treatment regime, then the claim language would become broader or narrower with time. Therefore, the ordinary artisan would not be reasonably apprised of the metes and bounds of the claims based upon the present claim language.
As presently amended, the claim term “based on the subject’s risk factors excluding PDGFRb levels” is similarly indefinite, because it encompasses any conceivable “risk factor”, including those not yet known, which may include other features which modify responsiveness to radiotherapy.
Applicant is reminded that no new matter may be added to the disclosure.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 6-7, 19, 25, 28, 30, and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Strell et al., “Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ” JNCI J Natl Cancer Inst (2019) 111(9):djy234 pages 983-995 (published February 28, 2019) as evidenced by Gradishar et al., “Breast Cancer, Version 3.2020”, JNCCN-Journal of the National Comprehensive Cancer Network Volume 18, Issue 4 April 2020.
This rejection has been updated as necessitated by the amendments to the claims.
It is noted that Strell et al. has inventors who are inventors on the present application. However, this document was published more than one year prior to the earliest filing date of the present application (October 21, 2020). Therefore, this document qualifies as prior art under 102(a)(1) and the 102(b)(1) exceptions do not apply.
Regarding claims 1-2, 6-7, and 34 Strell et al. teach high PDGFRb expression in stroma and/or epithelia in invasive breast cancer is associated with poor prognosis including increased risk for recurrence (Strell et al., page 983, abstract and page 984, column 2, paragraph 6-page 985, paragraph 5) after treatment comprising breast conserving surgery, radiotherapy, and or hormonal treatment (Strell et al., page 983, column 1-column 2 bridging paragraph). Strell et al. teach treating subjects with high PDGFRb expression with alternatives to standard therapy comprising radiotherapy and standard therapy comprising radiotherapy for subjects without the high PDGFRb expression signature (Strell et al., page 983). Regarding the requirement that the analyzing comprises scoring expression of PDGFRb among a population of node-negative patients with stage I or IIA breast cancer in tertiles, Strell et al. teach that stroma scoring of PDGFRb was performed by dividing the expression levels into four categories (i.e. “tertiles”) “(0= negative, 1= low, 2=moderate, or 3= high) as previously described” (Strell et al., page 984 column 1-column 2 bridging paragraph).
Regarding claim 19, the standard therapies taught by Strell comprising breast conserving surgery, radiotherapy, and or hormonal treatment (Strell et al., page 983, column 1-column 2 bridging paragraph) are therapies in line with the guidelines in the NCCN guidelines at the time of filing (as evidenced by Gradishar et al., whole document, which are/were said guidelines for breast cancer and comprise guidelines for “recurrent/stage IV breast cancer” (i.e. recurrent, invasive breast cancer)) at the time of publication of Gradishar et al. in April 2020.
Regarding claim 25 and 28, Strell et al. teach measuring PDGFRb expression levels by intensity of stroma staining and percent of positive fraction of the tumor stained (Strell et al., figure 1A).
Regarding claim 30, Strell et al. teach analyzing PDGFRb expression as a continuous variable (i.e. metric) in calculating a continuous risk assessment (Strell et al. page 984, column 2, paragraph 4-5).
Response to arguments
The response asserts that Strell et al. only teaches assessing PDGFRb expression in ductal carcinoma in situ (DCIS) (i.e. non-invasive) breast cancer cohorts and fails to teach measuring PDGFRb expression in invasive breast cancer.
This assertion has been thoroughly reviewed and is not persuasive. Strell et al. explicitly teach “Stromal PDGFR expression was analyzed in an IDC (i.e. “invasive ductal carcinoma”) collection… PDGFRb expression remained high in the majority of DCIS and IDC cases” (Strell et al., page 984-985 bridging paragraph and supplementary figure 1). Additionally, Strell et al. teach measuring PDGFRb expression in a population of 289 IDC patients (see figure 1 A, bar chart in right panel).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 6-7, 19, 21-23, 25-26, 28-31, and 34-39 are rejected under 35 U.S.C. 103 as being unpatentable over Strell et al., “Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ” JNCI J Natl Cancer Inst (2019) 111(9):djy234 pages 983-995 (published February 28, 2019) as evidenced by Gradishar et al., “Breast Cancer, Version 3.2020”, JNCCN-Journal of the National Comprehensive Cancer Network Volume 18, Issue 4 April 2020 in view of Paulsson et al., “Prognostic significance of stromal platelet-derived growth factor B-receptor expression in human breast cancer” Am J Pathol. 2009;175(1):334, Borgquist et al., “Oestrogen receptors a and b show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer” J. Clin. Pathol 2008;61:197-202, Weigel et al., “In vitro effects of imatinib mesylate on radiosensitivity and chemosensitivity of breast cancer cells” BMC Cancer 2010, 10:412 and Pasquier et al., “Intensity-modulated radiation therapy with simultaneous integrated boost for locally advanced breast cancer: a prospective study on toxicity and quality of life” Scientific Reports (2019) 9:2759, published February 26, 2019.
This is a new grounds of rejection necessitated by the amendments to the claims and the addition of new claims 35-39.
Regarding claims 1-2, 6-7, and 34, Strell et al. teach high PDGFRb expression in stroma and epithelia in invasive breast cancer is associated with poor prognosis including increased risk for recurrence (Strell et al., page 983, abstract and page 984, column 2, paragraph 6-page 985, paragraph 5) after treatment comprising breast conserving surgery, radiotherapy, and or hormonal treatment (Strell et al., page 983, column 1-column 2 bridging paragraph). In particular, In particular, Strell et al. teach “Stromal PDGFR expression was analyzed in an IDC (i.e. “invasive ductal carcinoma”) collection… PDGFRb expression remained high in the majority of DCIS and IDC cases” (Strell et al., page 984-985 bridging paragraph and supplementary figure 1). Additionally, Strell et al. teach measuring PDGFRb expression in a population of 289 IDC patients (see figure 1 A, bar chart in right panel). Strell et al. further teach treating subjects with high PDGFRb expression with alternatives to standard therapy comprising radiotherapy and standard therapy comprising radiotherapy for subjects without the high PDGFRb expression signature (Strell et al., page 983). Regarding the requirement that the analyzing comprises scoring expression of PDGFRb among a population of node-negative patients with stage I or IIA breast cancer in tertiles, Strell et al. teach that stroma scoring of PDGFRb was performed by dividing the expression levels into four categories (i.e. “tertiles”) “(0= negative, 1= low, 2=moderate, or 3= high) as previously described [by Paulsson et al.]” (Strell et al., page 984 column 1-column 2 bridging paragraph). Paulsson et al. state that the breast cancer patient cohort used for PDGFRb scoring was described [by Borgquist et al.] (Paulsson et al., page 335, column 2, paragraph 2). Borgquist et al. describe “breast cancer samples were obtained from a consecutive series of unselected patients diagnosed with primary invasive breast cancer at the Department of Pathology, Malmö University Hospital, between 1988 and 1992” (Borgquist et al., 198, column 2, paragraph 2) wherein 63% of the population is node negative and 66% of the population is Nottingham Histological Grade 1 or 2. Furthermore, 63% of the population has a tumor size less than 20 mm. (i.e. comprising a population of lymph-node negative patients with stage I(A) or IIA breast cancer).
Regarding claim 19, the standard therapies taught by Strell comprising breast conserving surgery, radiotherapy, and or hormonal treatment (Strell et al., page 983, column 1-column 2 bridging paragraph) are therapies in line with the guidelines in the NCCN guidelines at the time of filing (as evidenced by Gradishar et al., whole document, which are said guidelines for breast cancer and comprise guidelines for “recurrent/stage IV breast cancer” (i.e. recurrent, invasive breast cancer)).
Regarding claims 21-23, Strell et al. teach treating subjects with high PDGFRb expression with alternatives to standard therapy comprising radiotherapy, breast conserving therapy, and or hormonal treatment and standard therapy comprising radiotherapy for subjects without the high PDGFRb expression signature (Strell et al., page 983). Strell et al. further teach PDGFRb overexpression/activation by notch-signaling is a biomarker associated with poor-prognosis given standard treatments. Strell et al. do not teach treating high PDGFRb-expressing breast cancers with “more intense” levels of therapy than that outlined in the “NCCN Guidelines” comprises the specific radiation dosing regimens recited by claim 22 or the specific combination therapies recited by claim 23.
However, Weigel et al. teach methods of treating breast cancer cells wherein a level of active (phosphorylated) PDGFRb is high in the subject (Weigel et al., abstract). Weigel et al. teach methods of treating breast cancer with radiotherapy comprising 50 Gy combined with imatinib (Weigel et al., abstract) (i.e. an alternative/ a more “aggressive therapy” to standard radiotherapy). Weigel et al., further teach that imatinib is an inhibitor of PDGFRb activation that increases the efficacy of standard chemotherapy and radiotherapy (Weigel et al., page 2, column 1). Finally, Weigel et al. teach that PDGFRb expression is prognostic in peritumoral stroma in metastatic (i.e. invasive) breast cancers (Weigel et al., page 10, column 1, paragraph 1).
Similarly, Pasquier et al. teach reduced rates of reoccurrence and mortality in locally advanced breast cancer after treatment with surgical intervention and boosted “standard radiotherapy” (Pasquier et al., abstract) comprising radiation doses of 50 Gy (25 fractions of 2 Gy each with simultaneous integrated boost of 60 Gy in 25 fractions of 2.4 Gy each (Pasquier et al., page 2, paragraph 7).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the standard treatments for breast cancer irrespective of PDGFRb status (i.e. based on risk factors other than PDGFRb) taught by Strell et al., Paulsson et al., Borgquist et al., and Gradishar et al. with the teachings of Weigel et al. comprising combining radiotherapy with imatinib (i.e. a PDGFRb inhibitor) treatment for cancers with high tumor PDGFRb activity and the teachings of Pasquier et al. that intensified radiotherapy improves recurrence and mortality rates in breast cancer.
The ordinary artisan would have been motivated to modify the methods of Strell et al., Paulsson et al., and Borgquist et al. comprising PDGFRb testing in cohorts of patients with invasive breast cancer comprising patients with node-negative stage I or node-negative stage IIA breast cancer with the teachings of Weigel et al. comprising combination breast cancer therapy with radiation and imatinib and the teachings of Pasquier et al. comprising higher “boost” doses of radiation in breast cancer by the teachings of Weigel et al. that PDGFRb inhibitor treatment increases chemosensitivity of breast cancer cells expressing high levels of activated PDGFRb (Weigel et al., abstract).
The ordinary artisan would therefore have had a reasonable expectation that the combination therapy (radiation and imatinib) taught by Weigel et al. would have further increased the efficacy of the radiation-boosted therapies taught by Pasquier et al. in patients exhibiting the prognostic marker (high expression of activated PDGFRb) taught by Weigel et al. and Strell et al. relative to the “standard” therapies taught by Gradishar et al.
Regarding claim 25 and 28, Strell et al. teach measuring PDGFRb expression levels by intensity of stroma staining and percent of positive fraction of the tumor stained (Strell et al., figure 1A)
Regarding claims 26, 29, and 31, the “wherein” clauses defining alternative definitions of “high” and “low” PDGFRb expression consisting of: defining expression levels into tertiles or quintiles, defining “high” expression as among the top 10% of expression levels in an (undefined) population of people, defining “high or low” levels as a function of a fraction of stromal staining and expression levels by multiplying the fraction by the expression levels, or defining “high” or “low” expression only in the area of the tumor with the highest PDGFRb stromal expression, respectively, do not recite active method steps that further limit the claimed methods. Rather, these claims consist of alternative stated definitions for “high” or “low” expression of PDGFRb. Furthermore, each of these criteria for defining relative expression of particular genes (dividing expression levels into quantiles, comparing expression levels in a sub-population of interest to a larger population, integrating “staining” and “expression” measures, and selecting a region of cells of interest in a larger sample are each well-known in the art and would have been obvious alternative definitions of “high” and “low” expression of any particular gene product of interest to those having ordinary skill in the art. For example, as described above, Strell et al. teach defining the expression levels of PDGFRb into four parts; no expression, low expression, intermediate expression, and high expression (i.e. tertiles). Furthermore, Strell et al. teach methods for evaluating PDGFRb expression through combined visual scoring of staining intensity and positive fraction as well as digital analysis of the mean staining intensity multiplied by the positive area fraction (Strell et al., supplementary figure 2).
Regarding claim 30, Strell et al. teach analyzing PDGFRb expression as a continuous variable (i.e. metric) in calculating a continuous risk assessment (Strell et al. page 984, column 2, paragraph 4-5).
Regarding newly added claims 35-38, Strell et al. teach methods for evaluating PDGFRb expression through combined visual scoring of staining intensity and positive fraction as well as digital analysis of the mean staining intensity multiplied by the positive area fraction (Strell et al., supplementary figure 2).
Regarding newly added claim 39, Strell et al. (as evidenced by Paulsson et al. and Borgquist et al.) teach subjects with lymph-node negative stage I or IIA breast cancer. (Strell et al., page 984 column 1-column 2 bridging paragraph ; Paulsson et al., page 335, column 2, paragraph 2 ; Borgquist et al., 198, column 2, paragraph 2).
Response to arguments
The response asserts that Strell et al. only teaches assessing PDGFRb expression in ductal carcinoma in situ (DCIS) (i.e. non-invasive) breast cancer cohorts and fails to teach measuring PDGFRb expression in invasive breast cancer.
This assertion has been thoroughly reviewed and is not persuasive. Strell et al. explicitly teach “Stromal PDGFR expression was analyzed in an IDC (i.e. “invasive ductal carcinoma”) collection… PDGFRb expression remained high in the majority of DCIS and IDC cases” (Strell et al., page 984-985 bridging paragraph and supplementary figure 1). Additionally, Strell et al. teach measuring PDGFRb expression in a population of 289 IDC patients (see figure 1 A, bar chart in right panel).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Sjostrom et al., “Response to Radiotherapy After Breast-Conserving Surgery in Different Breast Cancer Subtypes in the Swedish Breast Cancer Group 91 Radiotherapy Randomized Clinical Trial” J Clin Oncol 35, 28: 3222-3229 (2017).Sjostrom et al. teach the exemplary “SweBCG91RT” cohort referenced in the specification but not required by the claims.
Emdin et al., “SweDCIS: Radiotherapy after sector resection for ductal carcinoma in situ of the breast. Results of a randomized trial in a population offered mammography screening” Acta Oncologica, 2006; 45:536-543.Emdin et al. teach a “SweDCIS” cohort analyzed for response to radiotherapy
Baranowska-Kortylewicz et al., “Effect of Platelet-Derived Growth Factor Receptor-B Inhibition with STI571 on Radioimmunotherapy” Cancer Research 2005; 65(17): 7824-7831. Baranowska-Kortylewicz et al. teach PDGFR-B inhibition in tumor stroma (in colorectal cancer) increased tumor radiosensitivity.
Hortobagyi et al., “Chapter 48: Breast” AJCC Cancer Staging Manual, Eighth Edition, DOI 10.1007/978-3-319-40618-3_48 American College of Surgeons 2017 pg 589-636Hortobagyi et al. teach criteria for staging Invasive (infiltrative) carcinoma of the breast and ductal carcinoma in situ of the breast (i.e. “Stage I or IIA breast cancer”). See, in particular, “Definitions of AJCC TNM” tables on pages 624-625 and “AJCC Anatomic Stage Groups” on page 625.
No claims are allowed.
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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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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