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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/4/2025 has been entered.
Claim Status and Formal Matters
This action is in response to papers filed 8/4/2025.
Claims 8, 14, 19 have been amended.
Claims 1-7, 11, 15-18 and 20 have been canceled.
Applicant’s election without traverse of PGR and IRS-1, increases expression relative to control, mifepristone and RNA in the reply filed on 5/14/2024 is acknowledged.
Claim 19 has been amended to depend from claim 8 and thus is rejoined.
Claim 14-16, 18.20-21 are withdrawn as the listed tables do not recite the elected gene combination.
Claim 9-10, 12-16, 18, 21 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/24/2024.
Claims 8 and 19 are being examined.
Priority
The instant application was filed 01/12/2021 and is a divisional of 15945901 , filed 04/05/2018 ,which claims priority from provisional application 62481966 , filed 04/05/2017 and claims priority from provisional application 62500694 , filed 05/03/2017.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. It is noted the examiner has not compared the IDS submitted to the references in the specification.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 8, 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 8 recites, “in a cell of a biological sample from a patient that is higher than an expression level of the one or more genes in a control sample comprising non-cancerous tissue.” The recitation of “a patient that is higher than the expression level” is confusing and unclear.
Further the claim recites, “therapeutically effective amount of progesterone receptor agonist.” The specification teaches, “A "therapeutically effective" concentration or amount as used herein is an amount that25 provide some improvement or benefit to the subject. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. Likewise, the term "preventing," as used herein, is not intended as an absolute term. Instead, prevention refers to 30 delay of onset, reduced frequency of symptoms, or reduced severity of symptoms associated with a disorder. Prevention therefore refers to a broad range of prophylactic measures that will be understood by those in the art. In some circumstances, the frequency and severity of symptoms is reduced to non-pathological levels. In some circumstances, the symptoms of an individual receiving the compositions of the invention are only 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or 1% as frequent or severe as symptoms experienced by an untreated individual with the disorder. Therapeutically effective concentrations and amounts may be determined for each application herein empirically by testing the compounds in known in vitro and in vivo systems, such as those described herein, dosages for humans or other animals may then be extrapolated therefrom. “ The metes and bounds are unclear as the claim encompasses healthy patients or subjects. Thus it is unclear what a “therapeutically effective amount of progesterone receptor agonist” encompasses or requires for healthy patients.
Response to Arguments
This is a new ground of rejection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 8 and 19 are is/are rejected under 35 U.S.C. 103 as being unpatentable over Porter (Cancer Lett. 2013 September 28; 338(2): 239–248.), Cui (Oncogene (2003) 22, 6937–6941) , Hung (JOURNAL OF CELLULAR PHYSIOLOGY 198:197–208 (2004)) and Land (US2012/0082659)
Claim 8 recites, “determining an expression sample level of one or more genes in a cell of a biological sample from a patient that is higher than an expression level of the one or more genes in a control sample comprising non-cancerous tissue, wherein the one or more genes comprises progesterone receptor gene (PGR) and insulin receptor substrate 1 (IRS-1); and administering a therapeutically effective amount of a progesterone receptor (PR) antagonist to the patient after determining the expression level of the one or more genes.” Thus the broadest reasonable interpretation is the claim requires determining increased expression of IRS1, PGR, and any additional genes and treating a therapeutically effective of PR antagonist if IRS1, PGR or any other gene detected has increased expression relative to any non-cancerous tissue.
The specification dos not provide a limiting definition of determining. The specification teaches determining of gene expression by microarray analysis (page 19). Thus the broadest reasonable interpretation of determining is reading a report.
With regards to claim 8, Porter teaches, “Three tumor-specific tissue microarrays (TMAs) were constructed from paraffin-embedded blocks of breast tumors with varying grade and diagnosis by the Translational Genomics Research Institute TMA core facility (Phoenix, AZ) as previously described [25,26]. All tumor cases were histologically reviewed for tumor type, grade, and for expression of estrogen and progesterone receptors. There were three tissue microarrays with 216, 246, or 231 tissue samples that were spotted in triplicate or duplicate. Control tissues were included to represent normal tissue counterparts. Sections (5 lm) were sequentially cut and stained with antibodies specific for IRS1, IRS2, tyrosine phosphorylated (pY 641) STAT6, and STAT6 using a BondMax TMA autostainer (Vision Biosystems, Inc.). Endogenous
peroxidase activity was quenched by incubating slides in 3% hydrogen peroxide for 10
minutes at 25 °C. Slide blocking was done with background Sniper from Biocare and slides were counterstained with hematoxylin. The stained slides were evaluated by a pathologist and scored for staining intensity where 0 = negative, 1 = weak, 2 = moderate, and 3 = strong. Tests for pairwise correlations, using the Kendall's tau rank correlation test, were calculated using the cor.test function in the R statistical package as described by Whitsett et al. [2,28 ]” (2.6) Porter teaches, “We found that normal breast epithelium expressed low levels of IRS1, IRS2, STAT6, and pSTAT6 (Fig. 1). Normal breast undergoing lactational changes was also positive for IRS1, STAT6, and pSTAT6, but did not express IRS2. In contrast, localized tumors such as ductal carcinoma in situ (DCIS) showed high levels of IRS1 and pSTAT6 (Fig. 1).” (3.1)(page 4)
Cui teaches, “We found that insulin receptor substrate-2 (IRS-2) levels were markedly induced by progesterone and the synthetic progestin R5020 in MCF-7 and other progesterone receptor (PR) positive breast cancer cell lines, whereas IRS-1 and the IGF-I receptor were not induced.The antiprogestin RU486 blocked the R5020 effect on IRS-2 expression.Ectopic expression of either PR-A or PR-B in C4-12 breast cancer cells (estrogen receptor and PR negative) showed that progestin upregulation of IRS-2 was mediated specifically by PR-B.”
Cui and Porter implicate PGR and IRS1 expression in breast cancer. Cui teaches, “To better define the role of progesterone and the two PR isoforms on IRS-2in breast cancer cells, we established the expression of either PR isoform by stably transfecting PR-A or PR-B cDNA into C4-12 cells, a specifically selected MCF-7 cell subline that does not have detectable ER or PR (Oesterreich et al., 2001). In PR-B-transfected C4-12cells, IRS-2, but not IRS-1 or IGF-IR, was upregulated significantly by R5020 (Figure 2a), while PR-B by itself had no ligand independent induction of IRS-2expression. In addition, the antiprogestin RU486 completely blocked the IRS-2 upregulation by R5020 in the C4-12/PR-B cells.”
Further, Hung teaches, “ Expression of estrogen-dependent genes such as insulin receptor substrate 1 (IRS-1), cyclin D1,and PgR was inhibited by kaempferol.” (page 198, 2nd column, 1st full paragraph).
While Hung, Porter and Cui suggest the role of PGR and IRS1 expression in breast cancer and following treatment with PGR antagonist, they do not teach treating with kaempferol.
However, Land teaches, “[0075] Also disclosed are methods of treating, inhibiting, and/or reducing a cancer comprising administering to the subject one or more, two or more, three or more, four or more, or five or more agents that enhance the activity of one or more CRG's in combination with one or more, two or more, three or more, four or more, or five or more agents…..” Later in 0075 Land teaches kaempferol and mifepristone. Land teaches breast cancer. (0015).
Therefore it would have been prima facie obvious to one of skill in the art prior to the effective filing date of the claims to substitute and effective amount of mifepristone for kaempferol or treat with kaempferol in addition to mifepristone in cells known to have increased levels of IRS1, PGR or any other gene relative to non-cancerous tissue. The artisan would be motivated to treat with effective amounts of mifepristone, kaempferol, or combinations and examine gene expression in cancerous and non-cancerous samples before and after treatment to examine markers known to have a role in breast cancer. The artisan would have a reasonable expectation of success as the artisan is merely substituting one treatment for cancer for another or treating with multiple treatment for cancer as suggested by Land.
Response to Arguments’
The response traverses the rejection in view of the amendment. This is a new grounds of rejection and the combined prior art renders the claims obvious.
Summary
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/ Primary Examiner, Art Unit 1683