DETAILED ACTION
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/21/2026 has been entered.
2. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
3. Claims 79-94 and 99-102 are pending. Claims 1-78 and 95-98 are canceled. Claim 99 has been amended.
4. Claims 79-94 and 99-102 are under examination.
Rejections Withdrawn
5. The rejection of claims 79-94 and 99-102 under 35 U.S.C. 103 as being unpatentable over Gomis et al. (WO 2013/153458A2, pub. date: 10/17/2013, IDS filed on 6/21/2023), in view of Payandeh et al. (Asian Pac J Cancer Prev, 2015, 16(12): 4863-4867) is withdrawn in view of applicant’s persuasive arguments.
New Grounds of Objection and Rejection
Claim Objections
6. Claims 83, 89, 94 and 102 are objected to for reciting “progestogen” which is not considered in the art as an estrogen receptor modulator.
Claim Rejections - 35 USC § 112
7. 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.
8. Claims 79-81, 83-87, 89-92, 94, 99-100 and 102 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for the treatment of a subject having breast cancer which comprises administering to said subject a therapy comprising an estrogen receptor inhibitor (antagonist), does not reasonably provide enablement for a method for the treatment of a subject having breast cancer which comprises administering to said subject a therapy comprising an estrogen receptor agonist. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
''Factors to be considered in determining whether a disclosure would
require undue experimentation have been summarized by the board in Ex
parte Forman. They include (1) the quantity of experimentation necessary,
(2) the amount of direction or guidance presented, (3) the presence or
absence of working examples, (4) the nature of the invention, (5) the state
of the prior art, (6) the relative skill of those in the art, (7) the predictability
or unpredictability of the art, and (8) the breadth of the claims.''
The nature of the invention
Independent claims are drawn to a method for the treatment of a subject having breast cancer which comprises: i) quantifying or determining the c-MAF gene expression level, copy number, amplification, or gain in a tumor sample of said subject and ii) comparing the expression level, copy number, amplification, or gain obtained in i) with a reference value, wherein said subject has a not increased expression level, copy number, amplification, or gain with respect to said reference value, and administering to said subject a therapy comprising an estrogen receptor modulator.
Dependent claims further limit the independent claims, wherein the estrogen receptor modulator is selected from the group consisting of progestogen, estradiol, droloxifene, raloxifiene, lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, LYl17081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]- 2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, and SH646.
The nature of invention is cancer treatment.
The invention is in a class of invention, which the CAFC has characterized as ''the unpredictable arts such as chemistry and biology.'' Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The breadth of the claims
The term “an estrogen receptor modulator” broadly encompasses any agents which can inhibit or enhance the expression, amount and/or activity of an estrogen receptor.
The quantity of experimentation
The quantity of experimentation is extremely large in view of the breadth of the claims and unpredictable nature of cancer treatment.
The state of the prior art and the unpredictability of the art
Saini et al. (Archiv der Pharmazie, 2026, 359:e370206: 1-37) teaches “Selective estrogen receptor modulators (SERMs) are an important class of drugs mainly useful in the treatment of breast cancer as they act as estrogen antagonists in the breast tissue but have an agonistic activity in bone and the cardiovascular system(CVS). ER‐positive breast cancer, driven by estrogen signaling, is the most prevalent subtype worldwide. SERMs remain essential therapeutics, antagonizing estrogen activity in breast tissue while retaining agonist effects in bone and CVS (abstract).” Estrogen itself is not directly responsible for tumor formation; instead, it facilitates the proliferation of ER+ breast cancer cells by binding to ERs and activating downstream signaling pathways that promote cell growth and survival (page 1, column 2).
However, effects of agonists of estrogen receptor on breast cancer treatment are unpredictable, which underscores the criticality of providing workable examples particularly in breast cancer treatment with an estrogen receptor agonist.
Working examples and Guidance in the specification
The instant specification provides no working examples and guidance on treating breast cancer in subjects having a not increased expression level, copy number, amplification, or gain with respect to said reference value with any estrogen receptor agonists including estradiol, and progestogen.
There is no evidence that agonists of estrogen receptor of breast cancer can treat cancer in a subject having a not increased expression level, copy number, amplification, or gain with respect to said reference value.
Level of skill in the art
The level of the skill in the art is deemed to be high
Conclusion
Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of the art, the large quantity of research required to define these unpredictable variables, the lack of working examples and guidance, the negative teachings in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation to perform the full scope of the claimed method.
Claim Rejections - 35 USC § 102
9. 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.
10. Claims 85-88 and 90-93 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hansen et a. (Cancer Research, 1998, 58: 2166-2169), as evidenced by Pavlovic et a. (JNCI J Natl Cancer Inst, September 15, 2015, 107(12):djv256, 1-12)
Hansen et al. teaches that allelic loss, detected as a loss of heterozygosity (LOH) on the long arm of chromosome 16, is an early and frequent event in breast cancer (abstract). Hansen et al. analyzed allelic loss of 16q23.2-24.2 (LOH) in tumor material and matching blood samples of breast cancer patients, and showed that 61% of 168 informative tumors had LOH (abstract). Univariate and multivariate analysis found a highly significant associate between LOH at 16q23.2-24.2 and freedom from distant metastases, disease-free survival and overall survival, respectively (abstract). Hansen et al teaches that allelic loss of 16q23.2-24.2 is an independent marker of good prognosis in primary breast cancer (title).
Regarding claims 85 and 90, Hansen et al. teaches detecting allelic loss of 16q23.2-24.2 (LOH) in tumor material of breast cancer patients and comparing the results between patients or to normal DNA (a reference value) (abstract). Patient with LOH (loss of 16q23.2-24.2) would inherently have a not increased c-MAF expression as compared to patients without LOH (a reference value) because c-MAF is located at 16q23.2, as evidenced by Pavlovic (see abstract). Note that the instant specification discloses that expression level, copy number, amplification, or gain of the c-MAF gene is determined by means of determining the expression level, copy number, amplification, or gain of the locus 16q23 or 16q22-q24 ([0046]).
Hansen further teaches that patients with positive axillary nodes including those with LOH were treated with adjuvant systemic hormone therapy (page 1, column 2, under Patient Material and Table 1). Adjuvants systemic hormone therapy reads on an estrogen receptor modulator.
Regarding claims 86 and 91, Hansen et al. teaches that the patents include postmenopausal and premenopausal patients (table 1).
Regarding claims 87 and 92, Hansen et al. teaches that the breast cancer includes ER+ or ER-.
Regarding claims 88 and 93, adjuvant systemic hormone therapy is understood in the art to inhibit the binding of estrogen to the estrogen receptor.
Claim Rejections - 35 USC § 103
11. 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.
12. Claims 85-94 are under 35 U.S.C. 103 as being unpatentable over Hansen et a. (Cancer Research, 1998, 58:2166-2169), as evidenced by Pavlovic et a. (JNCI J Natl Cancer Inst, September 15, 2015, 107(12):div256 1-12), in view of drug label for tamoxifen citrate (pub. date: Jan, 2010).
The teachings of Hansen et al. have been set forth above as they apply to claims 85-88 and 90-93.
Hansen et al. does not teach treating patients having LOH with tamoxifen.
The drug label for tamoxifen citrate discloses that tamoxifen citrate tablets are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation (page 5). In some tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. Tamoxifen citrate tablets are indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation (page 5). Tamoxifen reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy for breast cancer (page 14).
It would have been prima facie obvious to one of ordinary skill in the art to have treated node-positive breast cancer patients having LOH with tamoxifen in view of the drug label. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Hansen teaches that patients with positive axillary nodes including those with LOH were treated with adjuvant systemic hormone therapy (page 1, column 2, under Patient Material and Table 1), and the drug label for tamoxifen citrate discloses that tamoxifen citrate tablets are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, breast irradiation, and most of the benefit to date has been in the subgroup with four or more positive axillary node, and tamoxifen reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy for breast cancer (page 14).
13. Claims 79-94 and 99-102 are under 35 U.S.C. 103 as being unpatentable over Gomis et al. (US 2014/0057796A1, pub. date: 2/27/2014), in view of drug label for tamoxifen citrate (pub. date: Jan, 2010) and Payandeh et al. (Asian Pac J Cancer Prev, 2015, 16(12): 4863-4867, PTO-892 dated 6/23/2025).
Regarding claims 79, 84-85, 87, 90, 92, 99 and 100, Gomis et al. teaches a method for the diagnosis of metastasis in a subject with ER+ or ER- breast cancer and/or the prognosis of the tendency to develop metastasis in a subject with ER+ or ER-breast cancer which comprises
(i) quantifying the c-MAF gene expression level in a tumor tissue sample of said subject and
(ii) comparing the expression level previously obtained with the expression level of said gene in a control sample,
wherein if the expression levels of said gene are increased with respect to the expression levels of said gene in the control sample, then said subject has a positive diagnosis for metastasis or a greater tendency to develop metastasis, and said subject is susceptible to receive a therapy aiming to prevent an/or treat the metastasis ([0019]-[0025], and [0089]).
Regarding claims 80 and 91, the breast cancer patients in Gomis would necessarily be one of non-postmenopausal and postmenopausal.
Regarding claims 79-80, 84-85, 87, 90-92, 99 and 100, Gomis et al. does not teach that if the expression level or c-MAF gene amplification in the subject is not increased with respect to said reference value, then treat said subject with tamoxifen. However, these deficiencies are made up for in the teachings of the drug label and Payandeh et al.
Regarding claims 79-80, 83-85, 87, 89-92, 94, 99, 100 and 102, the drug label for tamoxifen citrate discloses that tamoxifen citrate tablets are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen adjuvant studies (page 5). Tamoxifen citrate tablets are indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation (page 5). Tamoxifen reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy for breast cancer (page 14).
Regarding claims 84, 87, 92 and 100, Payandeh et al. teaches treating triple negative breast cancer (TNBC) with tamoxifen plus radiation (abstract).
Regarding claims 80, 86 and 91, Payandeh et al. teaches that the age of the patients includes 60-69 (Table 1). These patients would be postmenopausal.
Regarding claim 81, Payandeh teaches that treatment with combination of tamoxifen plus radiation increases the OS and reduces the mortality rate (abstract).
Regarding claims 82, 88, 93, and 101, tamoxifen is known to inhibit the binding of estrogen to estrogen receptor.
Regarding claims 85, 87 and 89, Payandeh et al. teaches that tamoxifen plus radiation can treat patients having bone metastasis (Table 1).
It would have been prima facie obvious to one of ordinary skill in the art to have treated breast cancer patients whose c-MAF expression level or gene amplification is not increased with respect to the reference value with tamoxifen in view of the drug label and Payandeh et al. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because the drug label teaches that tamoxifen can treat node negative, and node positive breast cancer and can reduce the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy for breast cancer (pages 5 and 14), and Payandeh teaches that treatment of triple negative breast cancer patients with combination of tamoxifen plus radiation increases the OS and reduces the mortality rate (abstract).
Conclusion
14. No claims are allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached on Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1643
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