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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 11/03/2025 is acknowledged. Claims 4-6 were cancelled. Claims 1,7-10 and 15 were amended. Claim 17 is new. Claims 1,2,7-12 and 15-17 are pending and under examination.
Response to Arguments
Applicant’s arguments and amendments, see page 5, filed 11/03/2025, with respect to the objections to claim 1 have been fully considered and are persuasive due to the amendments to claim 1 which recite the full name rather than just the acronym. The objection to claim 1 has been withdrawn.
Applicant’s arguments and amendments, see pages 5-6, filed 11/03/2025, with respect to the 35 U.S.C. 112(b) rejection of claims 1,2,4-12,15 and 16 have been fully considered and are persuasive due to the amendments to the claims correcting the antecedent basis issues, clarifying the subject matter of the claim as being an in vitro method of identifying a protein kinase inhibitor, wherein the protein kinase inhibitor is suitable to be used in precision cancer therapy. Therefore, the 35 U.S.C. 112(b) rejection of claims 1,2,4-12,15 and 16 has been withdrawn.
Applicant’s arguments and amendments, see page 6, filed 11/03/2025, with respect to the 35 U.S.C. 112(d) rejection of claims 7-10 have been fully considered and are persuasive due to the amendments to claims 7-10 which recite “said one or more protein kinase inhibitor(s)” which clarify that the one or more protein kinase inhibitors are those as recited in claim 1 (B-Raf kinase inhibitors, VEGFR2 inhibitors, PLK inhibitors, and combinations thereof) and are not broader in scope. Therefore, the 35 U.S.C. 112(d) rejection of claims 7-10 has been withdrawn.
Applicant’s arguments and amendments, see pages 12-14, filed 11/03/2025, with respect to the nonstatutory double patenting rejection of claims 1,2,7-10 and 12 over claims 1-9 of Patent 12,295,955 in view of Hitti et al., McDermott et al. and Khabar, claim 11 over claims 1-9 of Patent 12,295,955 in view of Hitti et al., McDermott et al., Khabar and WO961, and claims 15 and 16 over claims 1-9 of Patent 12,295,955 in view of Hitti et al., McDermott et al., Khabar and Walerych et al. have been fully considered and are persuasive due to applicants argument that the ‘955 patent claims require determining whether said one or more targeted therapy compounds reduce the levels of phosphorylated TTP in said treated sample to determine whether said one or more targeted therapy compounds are effective for treating said patient and that the claims of ‘955 Patent require that a reduction in the level of phosphorylated TTP after treatment indicates that one or more targeted therapy compound(s) is/are effective for treatment the patient, in contrast to the instant claims which require that the cancer cells or tissue of a cancer patient be transfected with the recited expression vector having diminished levels of TTP and/or elevated levels of HuR compared to normal cells, and one skilled in the art would recognize that the tumor cells of ‘955 have reduced levels of TTP after treating the test compounds whereas the instant recited cancer cells have reduced TTP level before treatment with the protein kinase inhibitors. Applicant argues even using the combination of cited references, the skilled artisan still fails to arrive at the claimed invention because there is no reason to modify the tumor cells of the ‘955 Patent to those having diminished levels of TTP, and doing so would render the claimed method of ‘955 Patent inoperable. Therefore, the rejections have been withdrawn.
The following rejections and/or objections are either modified or newly applied and necessitated by amendment. They constitute the complete set presently being applied to the instant application.
Claim Objections
Claim 10 is objected to because of the following informalities: line 2 recites “one or more protein kinase inhibitor is inhibitor(s) is/are” and therefore recites “inhibitor is” twice. The examiner suggests removing the first instance of “inhibitor is” so that the claim reads “one or more protein kinase inhibitor(s) is/are”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
Written Description Rejection
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.
Claims 1,2,7-12 and 15-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention of claims 1,2,7-12 and 15-17 is directed to an in vitro method for identifying a protein kinase inhibitor for normalizing post-transcriptional regulation, wherein said one or more protein kinase inhibitor(s) is (are) selected from the group consisting of a B-raf kinase inhibitor, VEGFR2 inhibitor, polo-like kinase inhibitor and combinations thereof, in a genus of cancer cells having diminished levels of TTP and/or elevated levels of HuR compared to normal cells, and wherein the genus of cancers of the cancer patient is characterized by one of the following: underexpression of TTP and overexpression of HuR, underexpression of TTP and overexpression of PLK-1, overexpression of HuR and overexpression of PLK-1, underexpression of TTP and overexpression of PLK-1 in cancer cells compared to expression in non-cancerous cells. While claims 2,15 and 16 recite “wherein the precision cancer therapy is breast cancer therapy”, these claims do not recite that the cancer cells or tissue of a cancer patient that are being tested are breast cancer cells and that the cancer of the cancer patient is breast cancer. These claims only limit the intended use of the precision cancer therapy to be breast cancer therapy rather than limiting that the recited identifying method occurs in breast cancer cells or tissues.
The instant specification provides support that the cancers cells or tissues that are transfected with the expression vector and being tested to identify a specific kinase inhibitor are breast cancer cells. Example 1, page 29 shows that breast cancer cell lines are used, and pages 30-31 of Example 1 show that Selleckchem Kinase Inhibitor Library that includes 378 pharmacologically active inhibitors of a number of protein kinases were used in the experiments. Example 1 pages 31-32 shows that the reporter constructs were transfected into the MDA-MB-231 breast cancer cells, and the cells were treated with each member of the protein kinase inhibitors library and then a luciferase reaction was performed and reporter activities were measured by chemiluminescence. Example 1 shows only 3 of the protein kinase inhibitors were confirmed to be involved in ARE-dependent mRNA regulation in the later stages of screening, and these potent protein kinase inhibitors were AZ628, Regorafenib and Volasertib and their substrates are Raf, VEGFR2 and PLK-1 respectively (page 32, and Fig. 8B).
Example 2 shows breast cancer cells exhibit moderate to higher expression of PLK-1 compared to a normal cell line, and the triple negative breast cancer subtype is characterized by higher expression of PLK-1 compared to other types of breast cancer (page 33).
Example 3 shows the PLK-1 inhibitor volasertib significantly reduces the expression of all ARE-containing cancer genes including SLC2A1, uPA, uPAR, CXCR4, MMP13, PDL1 and HuR which are known to be upregulated in cancer and bearing ARE sequence in their mRNA (Example 3 page 34 and Fig 11).
Example 4 also shows MDA-MB-231 breast cancer cells treated with PK inhibitors, and results showed that the PK inhibitor, volasertib inhibits invasion, migration, and proliferation of breast cancer cells (pages 35-36 and Fig 10B and C), and that Volasertib and Regorafenib led to reduction in the ARE-containing mRNA, uPA in most of the breast cancer cell lines (page 36 and Fig 5B). Example 4 discloses the PLK-1 kinase is over-expressed in breast cancer cells lines (page 36).
Example 5 shows PLK-1 inhibition using volasertib in breast cancer cells increased TPP expression and reduced HuR expression (page 37). Also shown, however is that other PLK-1 inhibitors including rigosertib, HMN-214, GSK461364, Ro3280 and NMS-P937 did not reduce ARE-reporter activity (page 38).
Page 39 again discloses that triple negative breast cancer cells express significantly higher levels of PLK-1 mRNA and protein compared to HER negative cancer and normal breast cancer cells, but that the effect of PLK-1 inhibition is consistent among different types of breast cancer as shown by volasertib on MDA-MB-231, MCF7, and SKBR3 cell lines which show increasing expression of TTP and decreasing HuR level.
Example 6 pertains to post-transcriptional control as a universal platform for kinase inhibitor drug screening. Example 6, page 40 shows that the inventor tested a protein kinase library comprising about 400 protein kinase inhibitors in a cellular model of triple-negative breast cancer using MDA-MB-231 cells and were able to identify several groups of protein kinase inhibitors showing an effect in MDA-MB-231 cells which pave the way for targeting a cancer such as triple negative breast cancer, with high precision.
Regarding the genus of cancer cells or tissue of a cancer patient and the cancer of the cancer patient, there are hundreds of types of cancer, including origin in the body or metastatic types. There are even sub-species of cancer depending on the tissue or organ. In addition, claim 1 recites the cancer cells or tissue of the cancer patent have diminished levels of TTP and/or elevated levels of HuR compared to normal cells, and now recites wherein the genus of cancers of the cancer patient is characterized by one of the following: underexpression of TTP and overexpression of HuR, underexpression of TTP and overexpression of PLK-1, overexpression of HuR and overexpression of PLK-1, underexpression of TTP and overexpression of PLK-1 in cancer cells compared to expression in non-cancerous cells. Therefore, the claims recite the method and conditions for a large genus of cancer cells or tissues and cancers of a cancer patient. The claims read on the screening method for solid tumors, hematological tumors, leukemias, lymphomas, breast, colon, prostate or liver tumors, and metastatic tumors with the recited conditions regarding the levels of TTP, HuR, and PLK-1 in the cancer cells. Page 11 defines the term “cancer” as comprising all types of cancers, including carcinomas, sarcomas, lymphomas, germ cell tumors, and blastomas, as well as breast cancer, including triple-negative breast cancer.
As shown above, the examples only pertain to assays in breast cancer cell lines, therefore breast cancer and breast cancer cells are the only species of cancer that has sufficient written description for the recited screening method and regarding the conditions recited of diminished levels of TTP and/or elevated levels of HuR compared to normal cells and wherein the genus of cancers of the cancer patient is characterized by one of the following: underexpression of TTP and overexpression of HuR, underexpression of TTP and overexpression of PLK-1, overexpression of HuR and overexpression of PLK-1, underexpression of TTP and overexpression of PLK-1 in cancer cells compared to expression in non-cancerous cells. A “representative number of species” means that the species which are adequately described are representative of the entire genus. The specification does not describe any other species within the genus of cancer cells, tissues and cancers for the recited method with the conditions recited regarding the levels of TTP, HuR, or PLK-1. As breast cancer is the only species of cancer that is adequately described, breast cancer is not representative of the entire cancer genus.
Regarding the state of the art, McDermott et al. (Journal of Clinical Oncology, Vol. 27, Published 20 November 2009, pages 5650-5657) teach that two fundamental principles that underlie the concept of personalized cancer therapy are that significant genomic heterogeneity exists among tumors, even those derived from the same tissue of origin, and that these differences can play an important role in determining the likelihood of a clinical response to treatment with particular agents (Column 2 page 5650).
McDermott et al. teach genomic heterogeneity can involve differences in the spectrum of coding sequence mutations, as well as focal gene amplifications, deletions or translocations, as well as epigenetic changes in the expression profile of a tumor cell (Column 2 page 5650). McDermott et al. teach that genomic analysis of numerous human tumors has revealed widespread mutations, amplifications, translocations involving the genes encoding various kinases, many of which promote increased activation of downstream effectors involved in regulating proliferation and survival of the cancer cell and many tumors expressing these activated kinases have dependency on these kinases for their sustained viability (Columns 1,2 page 5651). McDermott et al. also teach that while kinase inhibitors including imatinib, erlotinib, and lapatinib (tyrosine kinase inhibitors) have shown clinical success and prompted and explosion in the development of additional kinase inhibitors for cancer therapy, this also comes with the realization that these agents are generally effective for a relatively small subset of treatment patients, often defined by a common genomic denominator present within the tumor cells, thereby showing the importance of identifying genomically defined patient subpopulations before treatment with kinase inhibitors to optimize clinical outcomes (Column 2 page 5651).
Zhang et al. (Front. Oncol. Vol 11, 07 May 2021, pages 1-8), teach a comparison of normal tissues to that of different cancers for mRNA expression of TTP, and found mRNA expression of TTP is significantly lower in adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, and colon adenocarcinoma, and expression level is always associated with clinicopathological features, overall survival rate, and patient prognosis (Page 2, left column, and Figure 1, page 3). However, Zhang et al. also teaches that TTP levels are higher in certain cancers compared to normal cells, including in GBM (Glioblastoma multiforme), KIRC (Kidney renal clear cell carcinoma), LAML (Acute Myeloid Leukemia) and PAAD (Ovarian serous cystadenocarcinoma), which shows the unpredictability that a genus of cancer cells or tissues would have diminished levels of TTP and/or elevated levels HuR compared to normal cells.
Therefore, the state of the art does not teach that all types of cancer cells or tissues have diminished levels of TTP and/or elevated levels of HuR compared to normal cells, or that a B-Raf kinase inhibitor, VEGFR2 inhibitor or polo-like kinase inhibitor or combination thereof identified by the method could be used as targeted cancer therapy for a genus of cancers.
When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. (emphasis added). See Enzo Biochem., 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). See also MPEP §2163.
Therefore, there is lack of written description within the cancer genus having diminished levels of TTP and/or elevated levels of HuR compared to normal cells, and wherein the genus of cancers of the cancer patient is characterized by one of the following: underexpression of TTP and overexpression of HuR, underexpression of TTP and overexpression of PLK-1, overexpression of HuR and overexpression of PLK-1, underexpression of TTP and overexpression of PLK-1 in cancer cells compared to expression in non-cancerous cells. The specification only provides written support that the assay can be used for breast cancer cells/tissues.
In conclusion, the disclosure of the identifying method in one species of cancer cells (breast cancer cells) with the recited conditions regarding the levels/expression of TTP, HuR and PLK-1, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Response to Arguments
Applicant's arguments and amendments, filed 11/03/2025, have been fully considered and are partially persuasive, and therefore the written description rejection has been partially withdrawn with regard to the claims previously reading on a precision cancer therapy method rather than a screening method, due to the amendments to the claims clarifying that the method is an in vitro method of identifying a protein kinase inhibitor for normalizing post-transcriptional regulation as well as the amendment stating “wherein said protein kinase inhibitor is suitable to be used in precision cancer therapy” which clarifies that the claims are directed to a screening method and not a therapeutic method. However, the written description rejection remains for the recited method encompassing a large genus of cancer cells or tissues and cancers of the patient.
Applicant argues on page 7 of response that claim 1 has been amended to recite an in vitro method of identifying and not a method of administering the compound, and claim 1 has been amended to define the cancer to be characterized by one of the following: underexpression of TTP and overexpression of HuR, underexpression of TTP and overexpression of PLK-1, overexpression of HuR and overexpression of PLK-1, underexpression of TTP and overexpression of PLK-1 in cancer cells compared to expression in non-cancerous cells. Applicant cites Moba, B.V. v. Diamond Automation Inc and Pozen Inc. v. Par Pharm. Inc.
While the amendments to the claims to clarify that the method is an in vitro method of identifying and not a therapeutic method are persuasive, the argument and amendments regarding the genus of cancer cells or tissue of a cancer patient and the cancer of the cancer patient is not found persuasive. The instant claims encompass the recited method in a large genus of cancer cells or tissue of a cancer patient wherein said cancer cells or tissue have diminished levels of TTP and/or elevated levels of HuR compared to normal cells, which are being transfected with the expression vector and the B-Raf kinase inhibitor, VEGFR2 inhibitors, polo-like kinase inhibitor and combinations thereof are being tested on, and now wherein the cancer of the cancer patient is characterized by one of the following: underexpression of TTP and overexpression of HuR, underexpression of TTP and overexpression of PLK-1, overexpression of HuR and overexpression of PLK-1, underexpression of TTP and overexpression of PLK-1 in cancer cells compared to expression in non-cancerous cells. Regarding Applicant citing Moba, B.V. v. Diamond Automation Inc and Pozen Inc. v. Par Pharm. Inc., this is not found persuasive because applicant has not pointed to any support in the specification or prior art that provides written description support for the recited method occurring in other species of cancers cells or tissues and that have the recited conditions regarding the levels and expression of TTP, HuR, and PLK-1. Based on the guidance provided in the specification and knowledge in the state of the art, one of ordinary skill in the art would not be able to determine what other types of cancer cells or tissues have diminished levels of TTP and/or elevated levels of HuR and wherein the cancer of the cancer patient is characterized by underexpression of TTP and overexpression of HuR, underexpression of TTP and overexpression of PLK-1, overexpression of HuR and overexpression of PLK-1, underexpression of TTP and overexpression of PLK-1 in cancer cells compared to expression in non-cancerous cells and are used in the method to identify the recited protein kinase inhibitors.
Applicant argues on pages 7-8 that the specification teaches in Example 1 a model for highly invasive breast carcinoma, namely MDA-MB-231 cells and with these cells a screening method in accordance with the claimed invention was performed, resulting in identification of various suitable protein kinase inhibitors shown in Figure 2, and Example 3 describes the action of several protein kinase inhibitors as identified in Example 1 on the MDA-MB-231 cells and results are shown in Figure 3. Example 4 shows the action of selected protein kinase inhibitors on the invasion, migration and proliferation of the breast cancer cells with results shown in Figure 10, making it clear that in this cancer model, identification of suitable protein kinase inhibitors results in a number of inhibitors that can then successfully and precisely be used in the treatment of such cancer. Applicant argues that one skilled in the art would have no doubt that the same method of identifying (the screening method) can be applied to other types of cancer and cancer models characterized by the features recited in amended claim 1 and therefore that Applicant has met the test for sufficient written description given the specification and currently amended claims.
This is not found persuasive. While the examiner agrees that the specification provides written support for the method wherein the cancer cells are breast cancer cells with the recited conditions of levels/expression of TTP, HuR, and PLK-1, which is stated in the written description rejection, and applicant argues that the examples pertain to breast cancer cells, this argument does not provide support for the method using other types of cancer cells and cancers of the cancer patient with the recited conditions. Applicant has not pointed to any support in the specification or prior art that provides written description support for the recited method occurring in other species of cancers cells or tissues and that have the recited conditions regarding the levels and expression of TTP, HuR, and PLK-1.
For these reasons, the written description rejection is maintained for the recited method occurring in a large genus of cancer cells or tissues with the recited conditions.
Claim Rejections - 35 USC § 103- Maintained Rejections
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1,2,7-10,12 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Hitti et al. (Cancer Res., Vol. 76, Published 15 July 2016, pages 4068-4078), McDermott et al. (Journal of Clinical Oncology, Vol. 27, Published 20 November 2009, pages 5650-5657) and Khabar (WIREs RNA, Published January 2017, Vol. 8, pages 1-16).
Regarding claims 1,2 and 17, Hitti et al. teach that AU-rich elements (ARE) act as key cis-acting factors in posttranscriptional control of gene expression and abnormalities involving this pathway can occur in several diseases including cancer (Intro. page 4068). Hitti et al. teach that a growing body of evidence has linked aberrantly elevated and prolonged expression of ARE-encoding mRNAs to cancer, such as EGF, estrogen receptor, COX-2, VEGF, MMP1, CXCR4, and uPA (page 4068). Hitti et al. teach ARE-mRNAs are regulated by trans-acting RNA-binding proteins, notably tristetraprolin (TTP) and human antigen R (HuR), which have antagonistic activities with regard to ARE-mRNA regulation; TTP destabilizes the mRNA and represses protein translation and HuR is an mRNA stability and translation promoting factor (Intro. page 4068).
Hitti et al. teach a systematic analysis of ARE-mRNA expression in invasive breast cancer and across different types of cancer, and found an ARE-mRNA cluster that is enriched in a mitotic cell cycle, highly correlated with RNA-binding proteins, and correlated with the clinical outcome of patients (Intro, page 4069). Hitti et al teach that tumor breast lines MDA-MB-231, and MCF-7 are grown (Col. 1, page 4069). Hitti et al. also teach ARE reporter constructs comprising the RPS30 promoter-linked reporter expression vector containing the ARE’s and the annealed DNA were cloned in the 3’UTR of the RPS30-SGFP vector, and that the use of the RPS30 promoter with SGFP, allows for selective posttranscriptional effects (Col. 2, page 4069). Hitti et al. teach that the AREs of the 11-gene cluster and their context sequences were cloned in the 3’UTR of fluorescent reporter assays (page 4074, Fig 5A) and used an HEK293 cell line, and found that seven of the ARE’s caused a reduction in the reporter activity demonstrating functional and active ARE’s (page 4074, Fig 5B). Hitti et al. teach their study expanded cancer ARE-mRNAs to nearly 200 ARE-mRNAs that correlate negatively with TTP and positively with HuR expression, and led to the identification of 11 ARE-mRNAs, and that ARE-mRNA expression is over-represented in multiple cancer types, and in these same types of tumors TTP deficiency is observed and is linked to nearly half of the over-expressed ARE-mRNAs in breast cancer as assessed here (Discussion, page 4078).
Regarding claims 7,9 and 12, Hitti et al. teach the mRNAs for CENPA, PRCA and TOP2A demonstrated a 25% reduction in reporter fluorescence and regarding claims 8 and 12, the IL8 ARE caused 52% reduction in reporter expression (page 4074).
Additionally, McDermott et al. teach that selective kinase inhibitors have emerged as an important class of anticancer agents, and that there is a substantial effort underway to identify additional therapeutically relevant kinase targets and to develop and test inhibitors of those proteins in a variety of human malignancies (Abstract). McDermott et al. teach that efforts are being made to stratify patients before treatment with kinase inhibitors based on specific genomic biomarkers, with the goal of optimizing clinical outcomes through the effective personalization of treatment, and with advances in understanding of the relationship between tumor genotypes and cancer cell sensitivity to kinase inhibition, and improved technologies for rapidly genotyping tumor biopsies for relevant lesions, the implementation of personalized cancer care with this exciting new class of inhibitors is now becoming a reality (Abstract). McDermott et al. teach that a large body of evidence supports an important and widespread causative role for many of the more than 500 kinases encoded by the human genome in tumorigenesis, and that the members of this group of kinases mediate the transduction of a wide array of extracellular signals that promote proliferation, migration and survival of cancer cells, thereby contributing several aspects of the malignant phenotype (page 5651, left column). McDermott et al. teach genomic analysis of numerous tumors has revealed widespread mutations/amplifications/translocations involving the genes encoding various kinases, many of which have been shown to promote increased activation of downstream effectors involved in regulating proliferation and survival of the cancer cell, and therefore many tumors expressing such activated kinases exhibit strict dependency on, or addition to these kinases for their sustained viability (page 5651). Additionally, McDermott et al. teach the use of large panels of human cancer-derived cell lines has revealed genotype-correlated sensitivities that have been observed clinically can often be faithfully recapitulated in cell culture, and that the genomic features that play a role in the cell autonomous response to selective kinase inhibitions in patients, seem to be largely preserved in cancer cells lines as demonstrated by recent large scale analysis of lung cancer, breast cancer, and melanoma specimens and established cell lines (page 5653).
McDermott et al. also teach that while kinase inhibitors including imatinib, erlotinib, and lapatinib (tyrosine kinase inhibitors) have shown clinical success and prompted an explosion in the development of additional kinase inhibitors for cancer therapy, that these agents are generally effective for a relatively small subset of treatment patients, often defined by a common genomic denominator present within the tumor cells, thereby showing the importance of identifying genomically defined patient subpopulations before treatment with kinase inhibitors to optimize clinical outcomes (Column 2 page 5651). McDermott et al. teach other oncogenic kinases as therapeutic targets for cancer and the therapeutic agents being developed in Table 1 on page 5651, which includes BRAF kinase associated with melanoma and colon cancer and the therapeutic agents being SB-590885, PLX-4720, RAF265 and XL281, and the Polo-like kinases associated with breast, lung, lymphoma and colon cancer and the therapeutic agents being BI2536 and GSK461364 (PLK-1 inhibitors).
Finally, McDermott et al. concludes the success of several kinase-targeted cancer therapies has prompted an explosion in further efforts to develop additional kinase-directed antitumor agents, and the importance of underlying tumor genotypes as determinants of cancer cell sensitivity to these treatments, pointing to the likely broad importance of personalizing treatments with these agents by matching individual patients with the appropriate drug on the bases of drug-sensitizing genomic biomarkers (Conclusion, page 5657).
Hitti et al. and McDermott et al. do not teach the relationship between protein kinase inhibitors which are B-Raf kinase inhibitors, VEGFR2 inhibitors, polo-like kinase inhibitors and AU-rich elements (AREs).
However, before the effective filing date, Khabar teaches that AU-rich elements play a major role in the posttranscriptional regulation of many genes involved in cancer processes (Abstract). Khabar teaches that ARE-RBPs can be subjected to a number of modifications that affect their function, such as phosphorylation in response to signals or cellular changes, and several signaling pathways such as mitogen-activated protein kinase and PI3 kinase pathways, control ARE and RBP interactions (Column 1, page 3). Khabar teaches that in the case of phosphorylation, several kinases have been shown to mediate the process including protein kinase C, AMP-activated protein kinase, mitogen activated kinases 1 and 4, checkpoint kinase 2, Janus Kinase 3, SRC and ABl-1 tyrosine kinases (Column 1, page 3). Khabar teaches that under-expression or loss of the activity of mRNA decay-promoting proteins such as TPP or SFP3L will lead to overexpression of cancer ARE genes, and overexpression or increased activity of mRNA stability promoting proteins such as HuR is seen in cancer states (Column 2 page 3). Khabar teaches that TTP controls HuR mRNA, so the TTP-HuR axis is reversed in cancer because of TTP deficiency and HuR overexpression and that this aberrant TTP-HuR axis in cancer cells can occur as a result of changes in the phosphorylation status of each RBP (Column 1, page 4).
Khabar teaches phosphorylated TTP becomes inactive and has reduced affinity toward ARE’s and thus increased levels of ARE-mRNAs including huR mRNA are observed in tumor cells (Column 1, page 4). Table 1 page 7 shows gene products coded by ARE-mRNAs that participate in the hallmarks of cancer and their interactions, and include PLK3 (polo-like kinase 3) involved in proliferation of cancer and TTP. Khabar teaches that since there are many kinases in which their activities are altered in cancer, they can affect the phosphorylation status of HuR and thus participate in aberrant TTP-HuR axis, however HuR phosphorylation is complex and dependent on the kinase and the phosphorylation site on HuR (Column 1, page 4). Finally, Khabar teaches that “Further work is required to find and assess kinase inhibitors or other small molecule drugs that override the various abnormalities encountered in cancer because of ARE dysregulation” (Conclusion page 14).
Therefore, it would be obvious to one of ordinary skill in the art before the effective filing date in view of the teaching of Khabar to combine the ARE reporter construct of Hitti et al. in an assay in breast cancer cells or tissue for identifying a B-Raf or polo-like kinase inhibitor for normalizing post-transcriptional regulation suitable for use in precision cancer therapy as taught by McDermott et al. One of ordinary skill in the art would have been motivated to use the ARE reporter construct of Hitti et al. in an assay in breast cancer cells to identify the suitability of a B-Raf or polo-like kinase inhibitor for normalizing post-transcriptional regulation, as Khabar teaches that ARE-RBPs can be subjected to a number of modifications that affect their function, such as phosphorylation by kinases that mediate the process and that phosphorylated TTP becomes inactive and has reduced affinity toward ARE’s and thus increased levels of ARE-mRNAs including huR mRNA are observed in tumor cells (Column 1, page 40) and teaches gene products coded by ARE-mRNAs that participate in the hallmarks of cancer and their interactions, and include PLK3 (polo-like kinase 3) involved in proliferation of cancer and TTP. One of ordinary skill in the art would have been motivated to provide a PLK-1 inhibitor to be tested and used in the method of Hitti et al. McDermott et al. and Khabar because McDermott et al. teach other oncogenic kinases as therapeutic targets for cancer and the therapeutic agents being developed which includes the Polo-like kinases associated with breast, lung, lymphoma and colon cancer and the therapeutic agents being BI2536 and GSK461364 (PLK-1 inhibitors) (Table 1 on page 5651).
Accordingly, the limitations of claims 1,2 and 17 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would be obvious to one of ordinary skill in the art at the time of the effective filing date that the precision breast cancer therapy of administering a B-raf or polo-like kinase inhibitor as taught by McDermott et al., would result in a breast cancer-related gene being post-transcriptionally normalized, and would result in reduction of expression of a mRNA comprising AU-rich element. One of ordinary skill in the art would be motivated to post-transcriptionally normalize a breast cancer-related gene, as Hitti et al. teach ARE-mRNA expression is over-represented in multiple cancer types, and in these same types of tumors TTP deficiency is observed and is linked to nearly half of the over-expressed ARE-mRNAs in breast cancer. The “wherein” clause in claim 7 would be a functional limitation resulting from the assay made obvious by McDermott et al., Hitti et al. and Khabar. Hitti et al. teach that ARE-mRNA expression is over-represented in multiple cancer types adding to the significance of the ARE-mediated post-transcriptional control in cancer (page 4078). The “wherein” clause in claims 7 and 9 would be a functional limitation resulting from the assay made obvious by McDermott et al., Hitti et al. and Khabar to try to reduce ARE-mRNA expression. Regarding claim 12, Hitti et al. teach the mRNAs for CENPA, PRCA and TOP2A demonstrated a 25% reduction in reporter fluorescence and the IL8 ARE caused 52% reduction in reporter expression (page 4074).
It would be obvious to one of ordinary skill in the art at the time of the effective filing date that the precision breast cancer therapy of administering a protein kinase inhibitor (B-raf or polo-like kinase) as taught by McDermott et al., would result in a gene encoding a proinflammatory cytokine being post-transcriptionally normalized with a reasonable expectation of success. One of ordinary skill in the art would have expected this result, as Hitti et al. teach that ARE’s are fundamental to the transient expression of genes that regulate critical cellular functions such as cell proliferation, apoptosis, cytokine response and cellular motility (page 4068) and IL8 ARE caused 52% reduction in reporter expression (page 4074). The limitation in claim 8 is a ‘wherein’ clause that is considered a functional limitation when one of ordinary skill in the art carries out the method involving a gene encoding a proinflammatory cytokine as taught by McDermott. Combining the teachings of McDermott et al. and Hitti et al. and Khabar would result in the functional limitation of claim 8.
It would be obvious to one of ordinary skill in the art at the time of the effective filing date that the protein kinase inhibitor (B-raf or polo-like kinase) is selected from inhibitors of kinases of which kinase activity is aberrant in cancer, as McDermott et al. teach genomic analysis of numerous tumors has revealed widespread mutations/amplifications/translocations involving the genes encoding various kinases, many of which have been shown to promote increased activation of downstream effectors involved in regulating proliferation and survival of the cancer cell, and therefore many tumors expressing such activated kinases exhibit strict dependency on, or addition to these kinases for their sustained viability (page 5651). Table 1 of McDermott et al. shows many oncogenic kinases as therapeutic targets in cancer, along with their corresponding alterations and tumor types that they are found in (page 5651). Khabar teaches that since there are many kinases in which their activities are altered in cancer, they can affect the phosphorylation status of HuR and thus participate in aberrant TTP-HuR axis, however HuR phosphorylation is complex and dependent on the kinase and the phosphorylation site on HuR (Column 1, page 4). Since protein kinases, including B-raf and polo-like kinases as taught by Khabar and McDermott et al. can have aberrant kinase activity in breast cancer, combining the teachings of McDermott et al. and Hitti et al. and Khabar would make obvious the limitation of claim 10.
Therefore, the invention as a whole would have been prima facie obvious at the time of the effective filing date.
Response to Arguments
Applicant's arguments, see pages 8-9, filed 11/03/2025 have been fully considered but they are not persuasive.
Applicant cites In re Zurko, stating when the prior art references fail to teach or suggest every limitation of the claims, an invention is not obvious. Applicant argues Hitti et al., McDermott et al. and Khabar do not disclose or suggest the recited method, and that the mere fact that the prior art could have been modified or applied in some manner to yield applicant’s invention does not make the modification or application obvious unless “there was an apparent reason to combine the known elements in the fashion claimed” by applicant, KSR International Co. v. Teleflex Inc. Applicant argues an invention is not “proved obvious merely by demonstrating that each of its elements was, independently, known in the (purported) prior art”. Id. Applicant argues on page 9 that Hitti et al. and McDermott et al. do not teach or suggest a relationship between protein kinase inhibitors and AU-rich elements and their suitability for precision cancer therapy of a cancer characterized by one of the following: underexpression of TTP and overexpression of HuR, underexpression of TTP and overexpression of PLK-1, overexpression of HuR and overexpression of PLK-1, underexpression of TTP and overexpression of PLK-1 in cancer cells compared to expression in non-cancerous cells. Applicant argues that the teaching of Khabar that PLK3 is one of a number of ARE-genes does not provide any motivation for one skilled in the art to combine the cited references to arrive at the method recited in the instant claims. Applicant cites Karsten Mfg. Corp. v Cleveland Golf Corp. and In re Dembiczak, and that the cited references do not provide any clear and particular teaching, suggestion, or motivation that would have led a skilled artisan to select these reference and combine in a way to arrive at the claimed invention.
This is not found persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981): In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Circ. 1986). Both Hitti et al. and Khabar et al. teach the correlation between diminished levels or underexpression of TTP and elevated levels or overexpression of HuR, AREs, and cancer. (Hitti et al. teach ARE-mRNAs are regulated by trans-acting RNA-binding proteins, notably tristetraprolin (TTP) and human antigen R (HuR), which have antagonistic activities with regard to ARE-mRNA regulation; TTP destabilizes the mRNA and represses protein translation and HuR is an mRNA stability and translation promoting factor (Intro. page 4068). Khabar teaches that under-expression or loss of the activity of mRNA decay-promoting proteins such as TPP or SFP3L will lead to overexpression of cancer ARE genes, and overexpression or increased activity of mRNA stability promoting proteins such as HuR is seen in cancer states (Column 2 page 3)). McDermott et al. teaches oncogenic kinases as therapeutic targets for cancer and the therapeutic agents being developed in Table 1 on page 5651, which includes BRAF kinase associated with melanoma and colon cancer and the therapeutic agents being SB-590885, PLX-4720, RAF265 and XL281, and the Polo-like kinases associated with breast, lung, lymphoma and colon cancer and the therapeutic agents being BI2536 and GSK461364 and Khabar teach gene products coded by ARE-mRNAs that participate in the hallmarks of cancer and their interactions, and include PLK3 (polo-like kinase 3) involved in proliferation of cancer and TTP (Table 1 page 7). Khabar provides a link between polo-like kinase 3 and its involvement in cancer and TTP and cancer ARE genes (under-expression or loss of the activity of mRNA decay-promoting proteins such as TPP or SFP3L will lead to overexpression of cancer ARE genes, and overexpression or increased activity of mRNA stability promoting proteins such as HuR is seen in cancer states).
The examiner maintains that the provided references are all relevant art, with the combination teaching the instant claimed limitations and motivations for combining. In response to applicant’s argument that the teaching of Khabar that PLK3 is one of a number of ARE-genes does not provide any motivation for one skilled in the art to combine the cited references to arrive at the method recited in the instant claims, absent a demonstration of an unexpected effect of the instantly claimed polo-like kinase (PLK) inhibitors, it would have been obvious to select any of the ARE genes taught, including PLK3 which was shown to be involved in proliferation of cancer and TTP.
“Disclosure of a multitude of effective combinations does not render any particular formulation less obvious.” Merck & Co. v. Biocraft Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). Note MPEP 2123.
In response to Applicants argument that the cited references do not provide any clear and particular teaching, suggestion, or motivation that would have led a skilled artisan to select these reference and combine in a way to arrive at the claimed invention, the obviousness rejection of the Non-final office action dated 06/04/2025 at page 17 states that Hitti et al. teach that aberrantly elevated and prolonged expression of ARE-encoding mRNAs are linked to cancer, and that ARE-mRNAs are regulated by TTP and HuR which have antagonistic activities, and tested ARE reporter constructs of the same structure as the instant claims in breast cancer cells and found ARE’s that caused reduction in the reporter activity, and identified ARE-mRNAs that correlate negatively with TTP and positively with HuR expression. The non-final office action also states that McDermott et al. teaches oncogenic kinases as therapeutic targets for cancers and therapeutic agents being developed, and targets include B-raf kinase and Polo-like kinases and further efforts to develop kinase-directed antitumor agents and personalized treatments with the agents by matching individual patients with the appropriate drug based on drug-sensitizing genomic biomarkers (page 19 of non-final) which provides a motivation to identify B-raf kinase and Polo-like kinase inhibitors to treat the cancer and provide personalized therapy. The non-final office action states Khabar provides a link between ARE-mRNAs, cancer, TPP and HuR levels, and various kinases that mediate the process of phosphorylation of ARE-RBPs, and includes polo-like kinase 3 involved in proliferation of cancer and TTP, as a gene product coded by ARE-mRNAs that participate in hallmarks of cancer and their interactions (office action pages 20-21). Khabar also provides similar motivation that “Further work is required to find and assess kinase inhibitors or other small molecule drugs that override the various abnormalities encountered in cancer because of ARE dysregulation”. As seen by the comments above, the office action has provided sufficient links and teachings of each of the references and motivations as to why it is obvious to combine them to arrive at the instant invention.
Therefore, the examiner maintains that Hitti et al., McDermott et al. and Khabar in combination teach the instant claim limitations and motivation for combining the references and the rejection of claims 1,2,7-10 and 12 remains.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Hitti et al., McDermott et al., and Khabar as applied to claims 1,2,7-10,12 and 17 above, and further in view of WO2009155961, hereinafter “WO961”, Published 30 Dec 2009.
The teachings of Hitti et al. McDermott et al. and Khabar as application to claims 1,2,7-10,12 and 17 are described above.
While Hitti et al. teach that the promoter comprises a modified promoter of the human RPS30 gene, Hitti et al., McDermott et al. and Khabar do not teach that the promoter has the nucleic acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4.
However, before the effective filing date, WO961 recites an expression vector comprising a promoter region comprising a non-inducible constitutively active ribosomal protein gene promoter, an operably linked reporter, and a 3’ UTR (Claim 1), wherein the promoter is RPS30 (Claims 2,3), and wherein the 3’UTR contains AU-rich elements (Claim 8). WO961 teaches the human modified ribosomal protein S30 promoter region of SEQ ID NO: 3 which has a 100% match to SEQ ID NO: 3 in the instant claim 11. See alignment below wherein Qy is instant SEQ ID NO: 3 and Db is SEQ ID NO: 3 of WO961.
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778
571
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have used the RPS30 promoter of SEQ ID NO: 3 of WO961 in the expression vector of Hitti et al. with a reasonable expectation of success, as both WO961 and Hitti et al. teach the same expression vector with the RPS30 promoter. One of ordinary skill in the art would be motivated to use the human modified ribosomal protein S30 promoter region of SEQ ID NO: 3, as WO961 teaches that the expression vector comprising RPS30 are highly suitable for a number of applications, particularly for selective post-transcriptional assessment, and that RPS30 was rendered to moderate expression (page 6).
Therefore, the invention as a whole would have been prima facie obvious at the time of the effective filing date.
Response to Arguments
Applicant's arguments, see page 10, filed 11/03/2025 have been fully considered but they are not persuasive.
Applicant argues the deficiencies of Hitti et al., McDermott et al. and Khabar are discussed above, and that WO961 does not teach or suggest an in vitro method of identifying a protein kinase inhibitor, specifically, a B-Raf kinase inhibitor, VEGFR2 inhibitor or polo-like kinase inhibitor for normalizing post-transcriptional regulation which is suitable to be used in precision cancer therapy by using ARE reporter constructs in cancer cells or tissues having diminished levels of TTP and/or elevated levels of HuR compared to normal cells, and wherein the cancer is characterized by one of the following: underexpression of TTP and overexpression of HuR, underexpression of TTP and overexpression of PLK-1, overexpression of HuR and overexpression of PLK-1, underexpression of TTP and overexpression of PLK-1 in cancer cells compared to expression in non-cancerous cells. Therefore WO961 does not cure the deficiencies of Hitti et al., McDermott et al. and Khabar and does not make the claimed invention obvious.
This is not found persuasive. The examiner’s arguments regarding the combination of Hitti et al, McDermott et al. and Khabar is explained in the response to the rejection of claims 1,2,7-10, and 12 above. WO 961 was not cited to teach or suggest the entire method stated above in Applicant’s argument. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981): In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Circ. 1986). WO 961 is cited for teaching the claimed limitations of the sequence of the RPS30 gene promoter in claim 11 and is analogous art because both WO961 and Hitti et al. teach the same expression vector with the RPS30 promoter, and WO961 teaches that the expression vector comprising RPS30 is highly suitable for selective post-transcriptional assessment, and that RPS30 was rendered to moderate expression. The examiner maintains that Hitti et al., McDermott et al. and Khabar and WO961 in combination teach the instant claim limitations and motivation for combining the references and the rejection of claim 11 remains.
Claims 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Hitti et al., McDermott et al., and Khabar as applied to claims 1,2,7-10,12 and 17 above, and further in view of Walerych et al. (Carcinogenesis, Vol. 33, No. 11, pp. 2007-2017, 2012).
The teachings of Hitti et al. McDermott et al. and Khabar as application to claims 1,2,7-10,12 and 17 are described above.
Hitti et al. McDermott et al. and Khabar do not teach wherein the breast cancer is a metastatic tumor, or wherein the metastatic tumor is hormone negative, microsatellite instability high or low, or p53 mutant cancer.
However, before the effective filing date, Walerych et al. teach TP53 mutations are exceptionally frequent and a key driving factor in triple negative breast cancer which is the most aggressive breast cancer subgroup and whose management is a clinical challenge, and the majority of TP53 mutations result in the substitution of single amino acids in the central region of the p53 protein, generating a spectrum of variants (‘mutant p53s’) and lose the normal p53 oncosuppressive functions and acquire oncogenic properties by gain-of-function mechanisms (Abstract). Walerych et al. teach the majority of breast cancer patient deaths are associated with metastasis and mutant p53 has been reported to boost the metastatic potential of breast cancer cells (page 2012, left column). Walerych et al. teach it would be important to improve the reliability of p53 mutation as the prognostic marker, and that different studies have shown this can be achieved by combining the analysis of PT53 mutational status with the assessment of other factors relevant for either mutant p53 stability or pro-oncogenic functions, and an examples of these are Polo-like kinase 1 (page 2012, bottom right, page 2014, top left). Regarding mutant p53 as a potential target of therapy for breast cancer, Walerych et al. teach the potential for blocking its upstream activators, and results in several models have suggested candidates such as the signaling pathway components EGFR, TGFBR1, Ras-activated kinases, and the Polo-like kinase family members 1 and 2 for pharmacological inhibition in breast cancer (page 2014, right column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to combine the teachings of Hitti et al., McDermott et al, Khabar and Walerych et al. with a reasonable expectation of success in order to provide a method for identifying a polo-like kinase inhibitor for precision cancer therapy of metastatic p53 mutant breast cancer. One of ordinary skill in the art would have been motivated to do so because Walerych et al. teach TP53 mutations are frequent and a key driving factor in triple negative breast cancer which is the most aggressive breast cancer subgroup and whose management is a clinical challenge, and the majority of breast cancer patient deaths are associated with metastasis and mutant p53 has been reporter to boost the metastatic potential of breast cancer cells, and the importance to improve the reliability of p53 mutation as the prognostic marker. Walerych et al. teach different studies have shown this can be achieved by combining the analysis of PT53 mutational status with the assessment of other factors relevant for either mutant p53 stability or pro-oncogenic functions which include Polo-like kinase 1 and the potential for Ras-activated kinases and the Polo-like kinase family members 1 and 2 for pharmacological inhibition in breast cancer.
Accordingly, the limitations of claims 15 and 16 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments, see page 11, filed 11/03/2025 have been fully considered but they are not persuasive.
Applicant argues the deficiencies of Hitti et al., McDermott et al. and Khabar are discussed above, and that Walerych et al. do not teach or suggest an in vitro method of identifying a protein kinase inhibitor, specifically, a B-Raf kinase inhibitor, VEGFR2 inhibitor or polo-like kinase inhibitor for normalizing post-transcriptional regulation which is suitable to be used in precision cancer therapy by using ARE reporter constructs in cancer cells or tissues having diminished levels of TTP and/or elevated levels of HuR compared to normal cells, and wherein the cancer is characterized by one of the following: underexpression of TTP and overexpression of HuR, underexpression of TTP and overexpression of PLK-1, overexpression of HuR and overexpression of PLK-1, underexpression of TTP and overexpression of PLK-1 in cancer cells compared to expression in non-cancerous cells. Therefore Walerych et al. fails to cure the deficiencies of Hitti et al., McDermott et al. and Khabar and does not make the claimed invention obvious.
This is not found persuasive. The examiner’s arguments regarding the combination of Hitti et al, McDermott et al. and Khabar is explained in the response to the rejection of claims 1,2,7-10, and 12 above. Walerych et al. was not cited to teach or suggest the entire method stated above in Applicant’s argument. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981): In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Circ. 1986). Walerych et al. was cited because it teaches that the majority of breast cancer patient deaths are associated with metastasis and mutant p53 has been reported to boost the metastatic potential of breast cancer cells (page 2012, left column) and the importance of improving the reliability of p53 mutation as the prognostic marker, and that different studies have shown this can be achieved by combining the analysis of PT53 mutational status with the assessment of other factors relevant for either mutant p53 stability or pro-oncogenic functions, and an examples of these are Polo-like kinase 1 (page 2012, bottom right, page 2014, top left). Regarding mutant p53 as a potential target of therapy for breast cancer, Walerych et al. teach the potential for blocking its upstream activators, and results in several models have suggested candidates such as the signaling pathway components EGFR, TGFBR1, Ras-activated kinases, and the Polo-like kinase family members 1 and 2 for pharmacological inhibition in breast cancer (page 2014, right column).
Therefore, Walerych et al. is relevant art and the examiner maintains that Hitti et al., McDermott et al. and Khabar and Walerych et al. in combination teach the instant claim limitations and motivation for combining the references and the rejection of claims 15 and 16 remains.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1,2,7-12 and 15-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3,6-10,14,20 and 22-26 of copending Application No. 16/007,146 in view of Hitti et al. (Cancer Res., Vol. 76, Published 15 July 2016, pages 4068-4078) and Khabar (WIREs RNA, Published January 2017, Vol. 8, pages 1-16).
Claims 1-3,6-10,14,20 and 22-26 of Application 16/007,146 recite a method of treating cancer in a patient, wherein said cancer is characterized by under-expression of TTP and overexpression of HuR and overexpression of PLK-1, in cancer cells compared to expression in non-cancerous cells and wherein said cancer is triple-negative breast cancer; said method comprising administering an effective dose of a protein kinase inhibitor to a patient in need thereof having said cancer, wherein TTP expression is increased and/or HuR expression is decreased by administering said protein kinase inhibitor which is a B-raf kinase inhibitor, VEGFR2 inhibitor, or polo-like kinase inhibitor, and wherein the protein kinase inhibitor is co-administered with an interferon and co-administered with a checkpoint inhibitor, and further detecting expression of at least one cancer related gene selected from IL-8, uPAR, SLC2A1, CXCR4, and wherein IL-8, uPAR, SLC2A1, CXCR4 are post-transcriptionally controlled by administering said protein kinase inhibitor. Claim 2 recites determining the level of TTP, HuR and PLK-1 in a tumor sample and administering a therapeutically effective amount of said protein kinase inhibitor to the patient if there is reduced expression of TTP and increased expression of HuR and increased expression of PLK-1 in the tumor sample. Claims 6-10 recite specific protein kinase inhibitors and polo-like kinase 1 inhibitors Claim 22 recites the method of treating triple-negative breast cancer in a patient.
Instant claims 1,2,7-12 and 15-17 recite a method of identifying a protein kinase inhibitor comprising transfecting cancer cells or a tissue of a cancer patient with an expression vector, wherein the cancer cells or tissue of a cancer patient comprise cells having diminished levels of TTP and/or elevated levels of HuR compared to normal cells, providing one or more protein kinase inhibitor(s) to be tested selected from the group consisting of B-Raf kinase inhibitors, VEGFR2 inhibitors, and polo-like kinase inhibitors, and combinations thereof which are the same kinase inhibitors recited in application 16/007,146; incubating the cells or tissues with said one or more protein kinase inhibitors; determining a normalizing effect of said one or more protein kinase inhibitors on post-transcriptional regulation by determining reporter activity, wherein a reduction in reporter activity indicates that said one or more protein kinase inhibitors are suitable for targeted cancer therapy, and include the same condition wherein the cancer has underexpression of TTP and overexpression of HuR and overexpression of PLK-1 compared to expression in non-cancer cells as recited in claim 1 of 16/007,146.
Application 16/007,146 does not recite identifying a protein kinase inhibitor comprising transfecting cancer cells or tissue of a cancer patient with an expression vector recited in the instant claims that comprise a 3’ UTR containing an AU-rich element.
The teachings of Hitti et al. and Khabar are described in the 103 rejection above.
It would be obvious to one of ordinary skill in the art before the effective filing date to modify claims 1-3,6-10,14,20 and 22-26 of Application 16/007,146 in view of the teaching of Hitti et al. and Khabar to arrive at the instant claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to use the ARE reporter construct of Hitti et al. in an assay in breast cancer cells to identify the suitability of a B-Raf or polo-like kinase inhibitor as targeted cancer therapy, as Khabar teaches that ARE-RBPs can be subjected to a number of modifications that affect their function, such as phosphorylation by kinases that mediate the process and that phosphorylated TTP becomes inactive and has reduced affinity toward ARE’s and thus increased levels of ARE-mRNAs including huR mRNA are observed in tumor cells (Column 1, page 40) and teaches gene products coded by ARE-mRNAs that participate in the hallmarks of cancer and their interactions, and include PLK3 (polo-like kinase 3) involved in proliferation of cancer and TTP.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments, see page 11, filed 11/03/2025, have been fully considered but are not persuasive. Applicant notes that because this is a provisional rejection, Applicant will take an appropriate action once claims have been indicated as being otherwise allowable.
No arguments were provided pertaining to the obviousness type double patenting
rejection. It is noted that the instant application and copending application 16/007,146 have the same patent term filing date (06/13/2018). The examiner directs Applicants attention to MPEP 804: If both applications are filed on the same day, the provisional nonstatutory double patenting rejection made in each of the applications should be maintained until applicant overcomes the rejections by either filing a reply showing that the claims subject to the provisional nonstatutory double patenting rejections are patentably distinct or filing a terminal disclaimer in each of the pending applications.
If both applications are entitled to the benefit of the same U.S. nonprovisional application under 35 U.S.C. 120, 121, or 365(c), and (B)(2) above does not apply, then the provisional nonstatutory double patenting rejection made in each of the applications should be maintained until applicant overcomes the rejections by either filing a reply showing that the claims subject to the provisional nonstatutory double patenting rejections are patentably distinct or filing a terminal disclaimer in each of the pending applications.
Therefore the rejection is maintained.
Conclusion
Claims 1,2,7-12 and 15-17 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636