DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's amendment and remarks filed on 08/12/2026 are acknowledged.
Claims 1-13 and 21-26 are pending.
3. Applicant’s election of the invention of Group I in the reply filed on 08/12/2026 is acknowledged. Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Applicant’s amendment has rendered the election moot. Presently pending claims read on inventions identified as Groups I, IV and V in the Restriction Requirement dated 06/17/2026.
In the interest of compact prosecution, the restriction requirement among Groups I, IV and V is withdrawn, and all presently pending claims are fully examined for patentability under 37 CFR § 1.104.
In view of the withdrawal of the restriction requirement as to the rejoined inventions, Applicant is advised that if claims directed to any of the rejoined inventions are presented in a continuation or divisional application, such claims may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
4. The claims are objected to because of the following apparent typographical errors:
“dacarbayine” in claim 23,
“thiptepa” in claim 23,
“capazitaxel” in claim 23,
“epirubicine” in claim 23, and
“consisiting” in claim 25.
Appropriate corrections or clarifications are required.
5. 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.
6. Claims 1-13 and 21-26 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.
(i) Claim 1 is indefinite as being in improper Markush format in the recitation of a group “comprised” of GATA3 and p53. The Office recommends the use of the phrase "selected from the group consisting of ..." with the use of the conjunction "and" rather than "or" in listing the species. See MPEP 803.02.
(ii) Claims 1-2, 4, 6-13 and 21-26 are indefinite in the recitations of “good” prognosis and “poor” prognosis, because “good” and “poor” are relative terms not specifically defined by the claims.
(iii) Claim 1 is further indefinite in the recitation of the method steps of “establishing the statistical significance of the biomarker expression level for patient prognosis” and “assigning to the patient a good prognosis or a poor prognosis based on the biomarker expression level,” because it is unknown how the “establishing” or “assigning” is performed.
(iv) Claim 1 is further indefinite in the recitation of “hormone-targeted” antineoplastic drug, because it is unknown which hormone the drug is targeted to.
(v) Claim 2 is indefinite because it is incompatible with claim 1 on which it depends. Claim 1 recites a step of “assigning to the patient a good prognosis or a poor prognosis,” which is distinct from a “likelihood” or a good or poor prognosis recited in claim 2.
(vi) Claims 6, 8, 9 and 13 are indefinite in the use of the term “particularly,” because it is unclear whether or not the particular embodiments constitute claim limitations.
(vii) Claim 7 is indefinite in the recitations of “GATA3 threshold” and “p53 threshold,” because the value of the respective thresholds is unknown.
(viii) Claims 8 and 9 are indefinite in the recitation of a “healthy tissue” sample as a negative control sample, because the identity of the tissue is unknown.
(ix) Claims 10 and 13 are indefinite in the recitation of “obtaining information about” the expression level of the biomarkers, because it is unknown what type of information about the expression level is being obtained. Claims 10 and 13 depend on claim 1 which recites a step of “determining” the expression level of the biomarkers, so it is unclear how claims 10 and 13 limit the scope of claim 1.
(x) Claims 10-13 are indefinite, because the meaning of the phrase “ex vivo lymph node metastasis” is unknown.
(xi) Claim 13 is indefinite in the recitation of the phrase “even 51pm,” because it is unclear how the term “even” limits the scope of the claim.
(xii) Claims 2-13 and 21-26 are indefinite, because they encompass the indefinite limitations of the claim(s) on which they depend.
In view of the above, a person of ordinary skill in the art cannot unequivocally interpret the metes and bounds of the claims so as to understand how to avoid infringement. Applicant is reminded that any amendment must point to a basis in the specification so as not to add New Matter. See MPEP 714.02 and 2163.06.
7. 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 of this title, 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.
8. Claims 1-3, 5-13 and 21-26 are rejected under 35 U.S.C. 103 as being unpatentable over Knudsen (US Patent No. 10392667) in view of Calvo et al. (2013; cited on IDS).
Instant claims 1 and 2 are directed to a method for treating a breast cancer patient comprising:
determining expression level of GATA3 and/or p53 in a lymph node metastasis sample from the patient, and
administering a hormone-targeted antineoplastic drug if the patient has a higher GATA3 expression and/or a lower p53 expression, or
administering a non-hormone-targeted antineoplastic drug if the patient has a lower GATA3 expression and/or a higher p53 expression.
Knudsen teaches a method for treating a breast cancer patient comprising:
quantifying GATA3 expression in a tumor sample from the patient, and
administering fulvestrant to the patient if the GATA3 expression is above a cutoff level (e.g. claim 1).
Fulvestrant is a hormone-targeted antineoplastic drug recited in instant claims 25-26.
While Knudsen does not specifically exemplify determining GATA3 expression in a lymph node metastasis sample, a person of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated, and have an expectation of success, to use such a sample, at least because the molecular phenotype of lymph node metastasis cells is not perfectly concordant with that of primary tumor cells.
For example, Calvo found that in some cases, GATA3-positive primary tumor cells lose GATA3 expression in matched lymph node samples, and GATA3-negative cells may acquire GATA3 expression upon metastasizing to lymph nodes (e.g. p. 6, second full paragraph). A skilled artisan would reasonably infer that since lymph node tumor cells have already acquired metastatic properties, they are likely to be more predictive of tumor aggressiveness, survival prognosis and treatment outcomes.
Claims 3 and 5 are included in the rejection, because practicing the same method leads to the same outcomes. Limitations of claims 6 and 7 are taught e.g. by Knudsen in claim 1. Claims 8 and 9 are included, because finding optimal threshold levels is routine in the art. Claims 10-13 are included, because they recite methods routinely used in the art for determining expression levels of genes or proteins. Claims 21-24 are included, because they recite standard-of-care breast cancer therapies.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
9. Claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Knudsen (US Patent No. 10392667) and Calvo et al. (2013) as applied to claim 1 above, and further in view of Kitamura et al. (2019).
Instant claim 1 is obvious in view of the combined teachings of Knudsen and Calvo, as articulated in section 8 above.
Instant claim 4 differs from the above teachings in relying on expression levels of both GATA3 and p53.
Kitamura teaches that ductal carcinoma in situ (DCIS) of the breast is heterogeneous in terms of the risk of progression to invasive ductal carcinoma (the Abstract). To treat DCIS appropriately for its progression risk, Kitamura performed gene and protein expression profiling on both primary tumors and metastatic tumors in lymph nodes (p. 93), and classified individual DCIS by their profile of genomic changes into 2 risk groups, the combination of TP53 and GATA3 expression levels contributing the most to the discrimination between the groups (e.g. the Abstract).
This would have provided both the motivation and the expectation of success to those of ordinary skill in the art before the effective filing date of the claimed invention to use expression levels of both GATA3 and p53 in selecting the treatment appropriate for the progression risk.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
10. The following prior art is cited of record but not presently relied upon teaches various aspects of the claimed invention:
US Pat. Pub. No. 20140004542
Albergaria et al. Expression of FOXA1 and GATA-3 in Breast Cancer: The Prognostic Significance in Hormone Receptor-Negative Tumors. Breast Cancer Research, vol. 11 No. 3, pp. 1-15 (2009).
Arun et al. Correlation of Bcl-2 and p53 expression in primary breast tumors and corresponding metastatic lymph nodes. Cancer (2003) Vol. 98, No. 12, pp. 2554-2559.
Aziz et al. Relationship of p53 expression with clinicopathological variables and disease outcome: a prospective study on 315 consecutive breast carcinoma patients. Malaysian J Pathol. 2001; 23(2) : 65 - 71.
Chow et al. (2005) “Study of COX-2, Ki67, and p53 expression to predict effectiveness of 5-flurouracil, epirubicin and cyclophosphamide with celecoxib treatment in breast cancer patients”, Biomedicine and Pharmacotherapy, vol. 59, pp. S298-S301.
Gonzalez-Angulo et al. (2004) p53 expression as a prognostic marker in inflammatory breast cancer. Clin Cancer Res 10(18 Pt 1): 6215-21.
Gulbahce et al. (2013) Significance of GATA-3 expression in outcomes of patients with breast cancer who received systemic chemotherapy and/or hormonal therapy and clinicopathologic features of GATA-3-positive tumors. Human pathology 44, 2427-2431.
Guo et al. (2017) Prognostic and clinicopathological value of GATA binding protein 3 in breast cancer: A systematic review and meta-analysis. PLOS ONE 12(4): e0174843, p. 1-12.
Kai et al. (2006) p53 expression status is a significant molecular marker in predicting the time to endocrine therapy failure in recurrent breast cancer: a cohort study. Int J Clin Oncol 11(6): 426-33.
Lin et al. Notch3 inhibits epithelial-mesenchymal transition in breast cancer via a novel mechanism, upregulation of GATA-3 expression. Oncogenesis, (2018) Vol. 7, No. 8, Article No.: 59, p. 1-15.
Liu J, et al. (2016) GATA3 mRNA expression, but not mutation, associates with longer progression-free survival in ER-positive breast cancer patients treated with first-line tamoxifen for recurrent disease. Cancer Lett 376(1): 104-109.
McCleskey et al., GATA3 expression in advanced breast cancer: prognostic value and organ-specific relapse. Am J Clin Pathol. Nov. 2015; 144(5): 756-63.
Miettinen et al. GATA 3 – A Multispecific But Potentially Useful Marker In Surgical Pathology – A Systematic Analysis Of 2500 Epithelial And Non-Epithelial Tumors. Am J Surg Pathol. 2014 Jan;38(1):13–22.
Miller et al. An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 2005; 102(38): 13550-13555.
Redondo et al. ( 2003) Expression of bax and p53 Proteins in the Tumorigenesis and Progression of Breast Carcinomas. Tumor Biology 24: 23-31.
Rolland et al. (2007) p53 positive Bcl-2 negative phenotype is an independent marker of prognosis in breast cancer. Int J Cancer 120(6): 1311-7.
Sjöström-Mattson et al. (2009) The expression of p53, bcl-2, bax, fas and fasL in the primary tumour and lymph node metastases of breast cancer. Acta Oncologica, 48:8, 1137-1143.
Thakkar et al. (2015) High Expression of Three-Gene Signature Improves Prediction of Relapse-Free Survival in Estrogen Receptor-Positive and Node-Positive Breast Tumors. Biomarker Insights, Vol.10, p. 103-112.
Tiezzi et al.. HER-2, p53, p21 and hormonal receptors proteins expression as predictive factors of response and prognosis in locally advanced breast cancer treated with neoadjuvant docetaxel plus epirubicin combination. BMC Cancer. 2007; 7:36, p. 1-10.
Yoon et al.. Higher levels of GATA3 predict better survival in women with breast cancer. Human pathology. 2010; 41(12): 1794-801.
11. Conclusion: no claim is allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILIA I OUSPENSKI whose telephone number is (571)272-2920. The examiner can normally be reached 9 AM - 5:30 PM.
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/ILIA I OUSPENSKI/ Primary Examiner, Art Unit 1644
