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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/7/25 has been entered.
Claims 1-16 and 19 are pending.
Claims 1-6 remain withdrawn.
Claims 7 and 19 have been amended by Applicant.
Claims 7-16 and 19 are currently under consideration.
This Office action contains a New Rejection.
Rejections Withdrawn
All previous rejections are withdrawn.
New Rejection
Claim Rejections - 35 USC § 103
Claim(s) 7, 9-16, and 19 is rejected under 35 U.S.C. 103 as obvious over Freeman et al (US 2019/0194124 A1; 6/27/19) in view of de Sousa et al (Tumor Heterogeneity, Pathobiology, 2018, 85: 96-107), Ma et al (Scientific Reports, 2019, 9(20021, 12 pages), Hu et al (OncoTargets and Therapy, 2019, 12: 9849-9860), Diaz et al (BMC Cancer, 2010, 10(188): 1-10), Tièche et al (Neoplasia, 2019, 21(2): 185-196), Hirasawa et al (Br. J. Cancer, 1994, 70: 466-473), and Huang et al (Theranostics, 2017, 7(16): 4013-4028).
Freeman et al demonstrates high ONECUT2 (same as “OC2”) expression correlates with a higher likelihood of progression to lethal disease in prostate cancer (Fig. 1, in particular). Freeman et al further demonstrates inhibiting ONECUT2 or silencing of ONECUT2 results in prostate cancer cell death (Figs. 3 and 7, in particular), inhibition of prostate tumor growth (Fig. 4, in particular), and inhibition of prostate tumor metastasis (Figs. 5 and 15, in particular). Freeman et al further teaches ONECUT2 activates PEG10, a driver of transdifferentiation from adenocarcinoma to neuroendocrine cancer and that an inhibitor of ONECUT2 (CSRM617) downregulates PEG10 mRNA expression (Fig. 16, in particular). Freeman et al further teaches a method of treating a subject with a lung cancer (equivalent to a patient “diagnosed” with lung cancer; see [0078]) that overexpresses ONECUT2 (same as “OC2”) by administering a therapeutically effective amount of a monotherapy with an agent that inhibits the expression of ONECUT2 so as to treat, inhibit, reduce severity of, slow progression, and/or prevent metastases of lung cancer in the subject ([0343], in particular). Freeman et al further teaches said method wherein the lung cancer is NSCLC ([0344], in particular). Freeman et al further teaches said method wherein the administering is intravenously ([0075], in particular). Freeman et al further teaches said method wherein the agent that inhibits the expression of ONECUT2 is an siRNA, shRNA, antisense construct, or a ribozyme ([0021], in particular). Freeman et al does not specifically describe siRNA, shRNA, antisense construct, or a ribozyme as hybridizing to ONECUT2; however, one of skill in the art would readily recognize siRNA, shRNA, antisense construct, or a ribozyme that inhibit expression of a given polynucleotide (such as ONECUT2) function by specifically hybridizing to said polynucleotide. Regarding claim 13, one of skill in the art would recognize signs and symptoms of lung cancer comprise recited signs and symptoms (as acknowledged by the instant specification).
Freeman et al does not specifically describe said method as “inhibiting high-plasticity cell state” in “heterogeneous lung tumors” of the subject, that the tumors “comprise Integrin a2- expressing tumor cells.” Further, Freeman et al does not specifically describe treatment with the agents that inhibit expression of ONECUT2 decrease SLC4A11, TIGIT and/or Integrin a2 levels as compared to prior to treatment (as recited by instant claim 10). However, these deficiencies are made up in the teachings of de Sousa et al, Ma et al, Hu et al, Diaz et al, Tièche et al, Hirasawa et al, and Huang et al.
De Sousa et al teaches lung cancer is a “very heterogenous disease” and “constitutes a group of heterogenous tumors” (page 96, in particular).
Ma et al describes lung cancer as encompassing “a heterogenous group malignancy” (first sentence after abstract, in particular), states lung cancer has a “high level of heterogeneity” (page 8, in particular), and teaches the ability of A549 lung cancer cells to be efficiently transdifferentiated implies a “high level of heterogeneity” of lung tumors comprising A549 lung cancer cells (page 9, in particular). Ma et al further teaches ONECUT2 is overexpressed in lung cancer cells (Figure 1A, in particular) and ONECUT2 overexpressed by A549 NSCLC lung adenocarcinoma cells enhances malignant growth, migration, invasion, and inhesion of the cells in vitro (Figure 2, in particular). Ma et al further teaches overexpression of ONECUT2 in A549 NSCLC lung adenocarcinoma cells promotes tumorigenesis and bone metastasis in vivo (Figure 3, in particular). Ma et al further teaches A549 NSCLC lung adenocarcinoma cells comprise a KRAS mutation (page 3, in particular).
Hu et al teaches ONECUT2 protein is highly expressed in A549 NSCLC lung adenocarcinoma cells (Figure 3, in particular).
Diaz et al teaches HER2 (same as “HER-2”) gene is amplified in A549 NSCLC lung adenocarcinoma cells (right column on page 7, in particular).
Tièche et al teaches A549 NSCLC lung adenocarcinoma cells include subpopulations exhibiting “plasticity” (Figure 3 and Figure 6, in particular).
Hirasawa et al teaches A549 NSCLC lung adenocarcinoma cells of Ma et al express Integrin a2 (Figure 1, in particular).
Huang et al teaches Integrin a2 expression was found to be up-regulated in NSCLC primary tumor clinical samples in ten out of ten datasets (Figure 10, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to treat just any subjects with lung cancer cells overexpressing ONECUT2 protein (including subjects with ONECUT2-overexpressing and Integrin a2- expressing A549 NSCLC cells described by Ma et al as exhibiting “a high level of heterogeneity”) by performing a combined method comprising intravenously administering to the subjects siRNA, shRNA, antisense construct, or a ribozyme that inhibit the expression of ONECUT2 upon hybridizing ONECUT2 polynucleotide because Freeman et al teaches a method of treating a subject with a lung cancer that overexpresses ONECUT2 by intravenously administering a therapeutically effective amount of an agent (such as siRNA, shRNA, antisense construct, or a ribozyme) that inhibits the expression of ONECUT2 so as to treat, inhibit, reduce severity of, slow progression, and/or prevent metastases of lung cancer in the subject, Ma et al and Hu et al teach ONECUT2 and ONECUT2 protein are overexpressed in lung cancer cells, Ma et al teaches ONECUT2 overexpressed by A549 NSCLC lung adenocarcinoma cells enhances malignant growth, migration, invasion, and adhesion of the cells in vitro, Ma et al teaches overexpression of ONECUT2 in A549 NSCLC lung adenocarcinoma cells promotes tumorigenesis and bone metastasis in vivo, and inhibiting pro-metastatic and pro-tumorigenic ONECUT2 using the siRNA, shRNA, antisense construct, or a ribozyme of Freeman et would predictably inhibit such pro-metastatic and pro-tumorigenic events.
In regards to “heterogeneous lung tumors” of subjects, the tumors of the combined method are predictably heterogeneous because lung tumors are taught to be heterogenous (see De Sousa et al and Ma et al).
In regards to “inhibiting high-plasticity cell state” (HPCS), inhibiting the expression of ONECUT2 in subjects of the combined method with ONECUT2-overexpressing lung cancer cells (including ONECUT2-overexpressing and Integrin a2- expressing A549 NSCLC cells described by Ma et al as exhibiting “a high level of heterogeneity”) predictably inhibits HPCS because Freeman et al teaches ONECUT2 activates PEG10, a driver of transdifferentiation from adenocarcinoma to neuroendocrine cancer, and that an inhibitor of ONECUT2 (CSRM617) downregulates PEG10 mRNA expression (Fig. 16, in particular). With the combined method inhibiting activation of PEG10 by inhibiting ONECUT2, HPCS is inhibited by reducing PEG10-driven transdifferentation.
In regards to instant claim 10 encompassing treatment with the agents that inhibit expression of ONECUT2 decrease SLC4A11, TIGIT and/or Integrin a2 levels as compared to prior to treatment, the instant specification acknowledges that treatment with siRNA that specifically hybridizes to ONECUT2 results in a decrease SLC4A11, TIGIT and/or Integrin a2 levels as compared to prior to treatment. Further, the examiner takes the position that a decrease SLC4A11, TIGIT and/or Integrin a2 levels as compared to prior to treatment is not a property having a significance greater than that of the expected property of a predicted therapeutic effect of the combined method. Therefore, recitation that reagents of the combined method have the property of being able to decrease SLC4A11, TIGIT and/or Integrin a2 levels as compared to prior to treatment is not sufficient to rebut obviousness of the combined method that is expected to have the equal or greater property of expected therapeutic benefit. See MPEP 716.02(c). Further, see In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991), where the court held that the fact that another advantage would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 11/7/25, Applicant submitted a declaration by Dr. Tammela and argues an assertion that inhibiting HPCS “does not have ‘greater significance’ than that of ‘the predicted therapeutic effect’ is unsubstantiated and incorrect. Applicant further argues the skilled artisan would not be motivated to modify the methods described in Freeman to specifically inhibit HPCS in heterogenous lung tumors comprising integrin a2-expressing tumor cells with any expectation of success in view of their lack of knowledge as to the very existence of HPCS. Applicant further argues the Office has not provided any reference that explicitly or inherently teaches the existence of HPCS, let alone benefits of specifically inhibiting or targeting HPCS in heterogenous lung tumors because an HPCS cluster (“cluster 5”) in heterogenous lung tumors was first published in 2020 by the declarant.
The declaration, the amendments to the claims, and the arguments found in the Reply of 11/7/25 have been carefully considered, but are not deemed persuasive. The examiner finds argument that inhibiting HPCS “does not have ‘greater significance’ than that of ‘the predicted therapeutic effect’ is unsubstantiated and incorrect persuasive.
In regards to the argument that the skilled artisan would not be motivated to modify the methods described in Freeman to specifically inhibit HPCS in heterogenous lung tumors comprising integrin a2-expressing tumor cells with any expectation of success in view of their lack of knowledge as to the very existence of HPCS, the examiner disagrees. Motivation to perform the combined method is not based on knowledge of the term HPCS. Rationale supporting a rejection under 35 U.S.C. 103 different from applicant’s is permissible. See MPEP 2144. The combined method is based on motivation to treat, inhibit, reduce severity of, slow progression, and/or prevent metastases of lung cancer in just any subjects with lung cancer cells overexpressing ONECUT2 protein (including subjects with ONECUT2-overexpressing and Integrin a2- expressing A549 NSCLC cells described by Ma et al as exhibiting “a high level of heterogeneity”) by inhibiting the expression of ONECUT2 because Freeman et al teaches a method of treating a subject with a lung cancer that overexpresses ONECUT2 by inhibiting the expression of ONECUT2 so as to treat, inhibit, reduce severity of, slow progression, and/or prevent metastases of lung cancer in the subject, Ma et al and Hu et al teach ONECUT2 and ONECUT2 protein are overexpressed in lung cancer cells, Ma et al teaches ONECUT2 overexpressed by A549 NSCLC lung adenocarcinoma cells enhances malignant growth, migration, invasion, and adhesion of the cells in vitro, Ma et al teaches overexpression of ONECUT2 in A549 NSCLC lung adenocarcinoma cells promotes tumorigenesis and bone metastasis in vivo, and inhibiting pro-metastatic and pro-tumorigenic ONECUT2 using an siRNA, shRNA, antisense construct, or a ribozyme of Freeman et would predictably inhibit such pro-metastatic and pro-tumorigenic events. In regards to “inhibiting high-plasticity cell state” (HPCS), inhibiting the expression of ONECUT2 in subjects of the combined method with ONECUT2-overexpressing lung cancer cells (including ONECUT2-overexpressing and Integrin a2- expressing A549 lung cancer cells described by Ma et al as exhibiting “a high level of heterogeneity”) predictably inhibits HPCS because Freeman et al teaches ONECUT2 activates PEG10, a driver of transdifferentiation from adenocarcinoma to neuroendocrine cancer, and that an inhibitor of ONECUT2 (CSRM617) downregulates PEG10 mRNA expression (Fig. 16, in particular). With the combined method inhibiting activation of PEG10 by inhibiting ONECUT2, HPCS is inhibited by reducing PEG10-driven transdifferentation.
In regards to the argument that the Office has not provided any reference that explicitly or inherently teaches the existence of HPCS, let alone benefits of specifically inhibiting or targeting HPCS in heterogenous lung tumors because an HPCS cluster (“cluster 5”) in heterogenous lung tumors was first published in 2020 by the declarant, the existence of HPCS and benefits of specifically inhibiting or targeting HPCS in heterogenous lung tumors are inherent in nature. Further, the claims do not require one to detect “cluster 5” or that tumors of the claimed method express anything other than integrin a2 – a marker Huang et al teaches was found to be up-regulated in NSCLC primary tumor clinical samples in ten out of ten datasets (Figure 10, in particular).
Allowable Subject Matter
Claim 8 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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/SEAN E AEDER/Primary Examiner, Art Unit 1642