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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-6 and 13-18, in the reply filed on July 20th, 2026 is acknowledged.
Applicant’s election without traverse of species (1) Connexin 43 mRNA and (2) Palbociclib in the reply filed on July 20th, 2026 is acknowledged.
Claims 7-12 and 19 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 20th, 2026.
Priority
The instant application claims priority to 371 National Stage Application PCT/EP2022/070350, filed July 20th, 2022, and foreign application EP21382657.1, filed July 20th, 2021, under 35 U.S.C. 119(a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The priority date of July 20th, 2021 is acknowledged.
Information Disclosure Statement
The information disclosure statement is not filed, failing to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. Copies non patent literature are provided but are not considered due to the missing IDS.
Claims Status
The claims listing filed on July 20th, 2026 is pending. Claims 7-12 and 19 are withdrawn from further consideration for the reasons set forth in the restriction requirement, 37 CFR 1.142(b). Claims 1-6 and 13-18 are being examined on the merits in this office action.
Claim Rejections - 35 USC § 112
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 1-6 and 13-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating breast, colon, and lung cancer characterized by the presence of functional RB, does not reasonably provide enablement for the method of treating all cancers characterized by the presence of functional RB. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 1’s breadth encompasses treating all cancers characterized by the presence of functional retinoblastoma gene comprising administering a therapeutic amount of Connexin 43 with a CDK4/6 inhibitor. The nature of the invention is therapeutic; based upon targeting CDK4/6-cyclin complex dysregulation in the cell cycle and connexin 43 downregulation in tumor cells. However, the prior art does not support that Cx43 upregulation helps treat all the claimed cancers, such as glioma tumors. Oligodendroglioma and glioblastoma are cancers characterized by the presence of functional RB because they are present in the dependent claims.
(Sánchez, O. F., Rodríguez, A. V., Velasco-España, J. M., Murillo, L. C., Sutachan, J. J., & Albarracin, S. L. (2020). Role of Connexins 30, 36, and 43 in Brain Tumors, Neurodegenerative Diseases, and Neuroprotection. Cells, 9(4), 846.)
Sánchez et al introduce that gliomas are the most common type of brain cancer and have been histologically divided into four types: diffuse astrocytoma, oligoastrocytoma, oligodendroglioma, and glioblastoma. Glioblastomas (GBMs) are considered the most aggressive, hardest to treat, and with the poorest prognosis [pg 9 pgh 4 line 1]. While some studies report that an increase in Cx43 levels could inhibit tumor capacities, other studies have suggested that Cx43 can increase the migration of some glioma tumors based on the cell type, despite blocking their proliferation [pg 10 pgh 2]. Thus, the prior art does not support that inducing Cx43 overexpression translates into the treatment of glioma tumors such as oligodendroglioma and oligoastrocytoma.
Furthermore, the current state of the art also does not support this conjecture. (Pridham, K.J., Shah, F., Hutchings, K.R. et al. Connexin 43 confers chemoresistance through activating PI3K. Oncogenesis 11, 2 (2022)). Pridham et al. share that the gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to chemotherapy [Abstract line 1]. They report that Cx43, but not other connexins, is highly expressed in a subpopulation of glioblastoma and Cx43 mRNA levels strongly correlate with poor prognosis and chemoresistance in this population, making Cx43 the prime therapeutic target among all connexins. Depleting Cx43 or treating cells with αCT1–a Cx43 peptide inhibitor that sensitizes glioblastoma to the chemotherapy temozolomide–inactivates phosphatidylinositol-3 kinase (PI3K), whereas overexpression of Cx43 activates this signaling.
The level of one of ordinary skill in the art allows them to deduce that a method comprising connexin 43 cannot be used to treat all cancers characterized by the presence of functional RB. This is not predictable as cancers are differentiated by tumor location, patient population, prognosis, stage, cell type, and gene expression. The inventors provide direction by demonstrating that Connexin 43 induced proliferation arrest and increases the efficacy of CDK4/6 inhibitors in the RB positive MCF7 breast cancer cell line [pg 8 and Fig 1 and 3]. The inventors additionally show the increased efficacy of CDK4/6 inhibitors in A375 melanoma and HT29 colon adenocarcinoma cells when combined with Cx43 [pg 9 line 27 and Fig 5]. However, the cell lines reduced to practice by the applicant are not representative of the entire genus of cancer claimed. To overcome the state of the art’s teachings, the inventor would have to test cell lines representing other cancer subtypes, such as oligodendroglioma and oligoastrocytoma, constituting undue experimentation.
Therefore, the applicant, while enabled for the scope of treating cancers representative of breast, lung, and colon cancers characterized by the presence of functional RB, are not enabled for the complete scope of treating all cancers characterized by the presence of functional RB comprising Connexin 43 and a CDK4/6 inhibitor.
Claims 2-4 do not limit the genus of cancers characterized by the presence of functional RB claimed and are therefore rejected for failing to fulfill the enablement requirement.
Regarding claim 5, Sánchez and Pridham teach that Cx43 overexpression results in poor prognosis in some glioma tumors. Sánchez and Pridham do not evidence that glioma tumors are also characterized by CDK4/6 hyperactivity (Bronner, S. M., Merrick, K. A., Murray, J., Salphati, L., Moffat, J. G., Pang, J., Sneeringer, C. J., Dompe, N., Cyr, P., Purkey, H., Boenig, G. L., Li, J., Kolesnikov, A., Larouche-Gauthier, R., Lai, K. W., Shen, X., Aubert-Nicol, S., Chen, Y. C., Cheong, J., Crawford, J. J., … Heffron, T. P. (2019). Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma. Bioorganic & medicinal chemistry letters, 29(16), 2294–2301).
Bronner et al. evidence that glioblastoma is characterized by a high frequency of CDKN2A/CCND2/CDK4/CDK6 pathway dysregulation, making dual inhibition of CDK4 and CDK6 an attractive therapeutic approach for this disease [Abstract line 2]. Thus, the applicant is not enabled for the complete scope of a method of treating cancers characterized by the presence of functional RB and CDK4/6 hyperactivity because glioma tumors are encompassed in the scope and not predictably treatable as demonstrated by the art.
Regarding claim 6, Sánchez and Pridham teach that Cx43 overexpression results in poor prognosis in some glioma tumors. Thus, the applicant is not enabled for the complete scope of a method of treating oligodendroglioma and oligoastrocytoma based on the contents of the disclosure and state of the art.
Claim 13 does not limit the genus of cancers characterized by the presence of functional RB claimed and therefore is rejected for failing to fulfill the enablement requirement (see claim 1 rejection).
Regarding claim 14, Sánchez and Pridham teach that Cx43 overexpression results in poor prognosis in some glioma tumors. Sánchez and Pridham do not evidence that glioma tumors are also characterized by CDK4/6 hyperactivity.
Bronner et al. evidence that glioblastoma is characterized by a high frequency of CDKN2A/CCND2/CDK4/CDK6 pathway dysregulation, making dual inhibition of CDK4 and CDK6 an attractive therapeutic approach for this disease [Abstract line 2]. Thus, the applicant is not enabled for the complete scope of a method of treating cancers characterized by the presence of functional RB.
Claims 15-18 do not limit the genus of cancers characterized by the presence of functional RB claimed and therefore are rejected for failing to fulfill the enablement requirement (see claim 1 rejection).
Claims 1-5 and 13-18 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. While the applicant does have support for a representative number of species reduced in practice for a method of treating breast cancer, melanoma, lung cancer, colon, squamous cell lung cancer, pancreatic neuroendocrine tumor, oligodendroglioma and oligoastrocytoma, they do not have support for a method of treating all cancers characterized by the presence of functional retinoblastoma gene (RB).
Claims 1 and 13 recite “characterized by the presence of functional retinoblastoma gene (RB)” and “cancer is positive for retinoblastoma protein,” respectively, However, the specification does not support that the complete genus is able to be treated by connexin 43 and CDK4/6 inhibitors.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus [MPEP 2163 ii)].
The inventors provide direction by demonstrating that Connexin 43 induced proliferation arrest and increases the efficacy of CDK4/6 inhibitors in the RB positive MCF7 breast cancer cell line [pg 8 and Fig 1 and 3]. The applicant additionally shows the increased efficacy of CDK4/6 inhibitors in A375 melanoma and HT29 colon adenocarcinoma cells [pg 9 line 27 and Fig 5]. However, the cell lines reduced to practice by the applicant are not representative of the entire genus of cancer claimed. Nor, would one of ordinary skill in the art be able to attest to the complete genus’s ability to be treated by Connexin 43 and a CDK 4/6 inhibitor due to the differences of gene dysregulation, tumor location, cell types, prognosis, and patient populations in cancer subtypes. Furthermore, the applicant does not disclose relevant, functional characteristics besides the presence of a functional Rb protein shared between the representative cancer species necessary, or unnecessary for the efficacy of Connexin 43 and CDK4/6 inhibitors. Thus, while the applicant has support for the specific breast, colon, and lung cancer reduced to practice, they do not have support for the complete genus of treatment of cancers characterized by the presence of a functional retinoblastoma gene.
Claims 2-4 do not limit the genus of cancers characterized by the presence of functional RB claimed and are therefore rejected for failing to fulfill the written requirement.
Regarding claim 5, the breast cancer, colon adenocarcinoma, and melanoma cell line reduced to practice by the applicant are not representative of the complete genus of cancers characterized by functional RB and hyperactive CDK4/6 because each cancer subtype is differentiated by tumor location, patient population, prognosis, stage, cell type, and gene expression. One of ordinary skill in the art would not find it predictable that the same method of treatment can be applied to each cancer species. Thus, claim 5 does not comply with the written description requirement.
Regarding claim 6, the breast cancer, colon adenocarcinoma, and melanoma cell line reduced to practice by the applicant are not representative of the complete genus of cancers characterized by functional RB and hyperactive CDK4/6 because cancers such as oligodendroglioma and oligoastrocytoma differ by tumor location, patient population, prognosis, stage, gene expression, and cell type. One of ordinary skills in the art would not find it predictable that the same method of treatment can be applied to those cancer species. Thus, claim 6 does not comply with the written description requirement.
Claim 13 does not limit the genus of cancers characterized by the presence of functional RB claimed and therefore is rejected for failing to fulfill the written description requirement (see claim 1 rejection).
Regarding claim 14, the breast cancer, colon adenocarcinoma, and melanoma cell line reduced to practice by the applicant are not representative of the complete genus of cancers characterized by functional RB and hyperactive CDK4/6 because each cancer subtype is differentiated by tumor location, patient population, prognosis, stage, cell type, and gene expression. One of ordinary skill in the art would not find it predictable that the same method of treatment can be applied to each cancer species. Thus, claim 14 does not comply with the written description requirement.
Claims 15-18 do not limit the genus of cancers characterized by the presence of functional RB claimed and therefore are rejected for failing to fulfill the written description requirement (see claim 1 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-6 and 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (US20120045501A1) and Gadsden et al. (Gadsden, N. J., Fulcher, C. D., Li, D., Shrivastava, N., Thomas, C., Segall, J. E., Prystowsky, M. B., Schlecht, N. F., Gavathiotis, E., & Ow, T. J. (2021). Palbociclib Renders Human Papilloma Virus-Negative Head and Neck Squamous Cell Carcinoma Vulnerable to the Senolytic Agent Navitoclax. Molecular cancer research : MCR, 19(5), 862–873).
Huang et al. claim a method for inhibiting the proliferation of tumor cells in a mammal, comprising contacting the tumor cells with a nucleic acid encoding connexin 43 (cx43) in an amount sufficient to effectively reduce the expression of bc1-2; and an effective concentration of a chemotherapeutic drug [claims 1-3]. Huang et al. teach that the “administration of a connexin nucleic acid enhances the sensitivity of certain target cells, i.e., glioblastoma cells, to chemotherapeutic agents, e.g., etoposide, paclitaxel, and doxorubicin, such that sub-optimal levels of the drugs induces apoptosis in the cells” [0012]. Huang et al. first demonstrated that the over-expression of cx43 enhanced the sensitivity of U251 cells to the cytotoxic agent VP16 [0172]. Then, to determine if cx43 over-expression sensitizes these cells to the cytotoxic effects of other chemotherapeutic agents with different mechanisms of cytotoxicity, Tax and doxorubicin were tested. Both had enhanced cytotoxic effects, and were not specific to the cell’s clonal variation [Table 1 and 0173]. Thus, Huang et al. teaches the potential for using cx43 to enhance the effect of various chemotherapeutics, however not specific to CDK 4/6 inhibitors. The method is applied to tumors cells from carcinoma, sarcoma, lymphoma, leukemia, or melanoma is specifically claimed [claim 5]. Though Huang et al. does not specifically evidence that these tumor cells are characterized by the presence of a retinoblastoma gene (RB), the instant dependent claims comprise of breast cancer, melanoma, lung cancer, and colon cancer as cancers characterized by RB which are carcinomas or melanomas. Thus, Huang et al. teaches a method of treating cancer comprising administering a therapeutic amount of Connexin 43 nucleic acid and a chemotherapeutic agent. Huang et al. does not teach that the therapeutic agent is a CDK4/6 inhibitor.
Gadsden et al. evaluated the efficacy of combining palbociclib and navitoclax in human papillomavirus (HPV)-negative (−) head and neck squamous cell carcinoma (HNSCC) using three HPV- HNSCC cell lines and three HPV+ HNSCC cell lines [Abstract line 4]. Treatment drove reduced expression of phosphorylated Rb (p-Rb) and phenotypic evidence of senescence in all HPV- cell lines, while HPV+ cell lines did not display a consistent response by Rb or p-Rb and did not exhibit morphologic changes of senescence in response to palbociclib. Gadsden et al. also teach:
Loss of normal cell cycle regulation is a hallmark of HNSCC. With human papillomavirus positive (HPV+) disease, the viral oncoproteins E6 and E7 produced by HPV lead to the functional inactivation of the p53 and Rb tumor suppressor proteins, respectively. This disruption allows unchecked progression of the cell cycle, even while the CDKN2A gene, which encodes the p16INK4A (p16) cell cycle inhibitor, remains intact. In HPV-negative (HPV-) disease, loss or inactivation of CDKN2A/p16 is an early and common event in HNSCC tumorigenesis, with disruption of this gene occurring in 58% of cases. P16 is immediately upstream of cyclin dependent kinase 4 and 6 (CDK4/6). Loss of functional p16 allows CDK4/6 to complex with D-type cyclins in order to phosphorylate and inactivate Rb, leading to release of E2F and subsequent progression through the G1 checkpoint to the S phase of the cell cycle. Loss of regulation of this critical checkpoint leads to cell cycle dysregulation and unchecked cell proliferation [pg 862 Introduction pgh 2].
This means that CDK4/6 inhibitors have efficacy in HPV- diseases, characterized by an active functional Rb protein, due to the unchecked cell proliferation being caused by CDK4/6-cyclin complex dysregulation. Thus, Gadsden teaches the use of a treatment with a CDK 4/6 inhibitor in a cancer characterized by the presence of functional RB.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine prior art elements of a therapeutic amount of Connexin 43 and CDK4/6 inhibitor palbociclib and senolytic agent navitoclax according to known methods to yield predictable results of connexin 43 enhancing the cytotoxic effects of the chemotherapeutic agent palbociclib [MPEP § 2143.01(A)]. This is because one of ordinary skill in the art would have recognized Gadsden’s teaching of a CDK4/6 inhibitor and navitoclax’s efficacy in treating HPV- HNSCC, characterized by active functional RB and Huang’s teaching of cx43 nucleic acid’s efficacy at enhancing the effect of all chemotherapeutics Huang et al. tested.
Regarding claims 2 and 3, the CDK 4/6 inhibitor taught by Gadsden is palbociclib.
Regarding claim 4, Gadsden et al. teaches the increased efficacy of treatment when palbociclib is combined with senolytic agent navitoclax.
Regarding claim 5, Gadsden et al. teaches that in HPV- HNSCC, loss or inactivation of CDKN2A/p16 is an early and common event, allowing loss of regulation at the critical checkpoint when CDK4/6 complexes with D-type cyclins in order to phosphorylate and inactivate Rb, leading to release of E2F and subsequent progression through the G1 checkpoint to the S phase of the cell cycle [pg 862 Introduction pgh 2]. Thus, HPV- HNSCC is characterized by hyperactivity of CDK4/6. Therefore, prior to the effective filing date, it was obvious to combine a therapeutic amount of Connexin 43 and palbociclib to yield the predictable result of cx43 enhancing palbociclib in a cancer further characterized by hyperactivity of CDK4/6 because Gadsden et al. further teach that HPV- HNSCC is characterized by hyperactivity of CDK4/6.
Regarding claim 6, Huang et al. claim a method for inhibiting the proliferation of tumor cells from carcinoma, sarcoma, lymphoma, leukemia, or melanoma in a mammal, comprising a nucleic acid encoding connexin [claims 1-3 and 5] Huang et al. specify that the therapeutic of the invention is administered to a human patient to prevent progression to brain, breast, colon, prostate, lung, or skin cancer [0085]. Thus, one of ordinary skill in the art would find it obvious to administer cx43 and a CDK 4/6 inhibitor to treat melanoma, breast cancer, lung cancer, colon cancer, or squamous cell lung cancer if the cancer is characterized by the presences of functional RB because Huang et al. teaches that cx43 can be administered to such cancers and that cx43 increases the therapeutic effect of the chemotherapeutic agent it is administered with and Gadsden et al. teach that CDK4/6 inhibitors are effective against cancers with functional RB.
Regarding claim 13, Huang et al. claim a method for inhibiting the proliferation of tumor cells comprising a nucleic acid encoding connexin 43 (cx43) and an effective concentration of a chemotherapeutic drug [claims 1-3]. Huang et al. teach that the “administration of a connexin nucleic acid enhances the sensitivity of certain target cells, i.e., glioblastoma cells, to chemotherapeutic agents, e.g., etoposide, paclitaxel, and doxorubicin, such that sub-optimal levels of the drugs induces apoptosis in the cells” [0012]. Huang et al. first demonstrated that the over-expression of cx43 enhanced the sensitivity of U251 cells to the cytotoxic agent VP16 [0172]. Then, to determine if cx43 over-expression sensitizes these cells to the cytotoxic effects of other chemotherapeutic agents with different mechanisms of cytotoxicity, Tax and doxorubicin were tested. Both had enhanced cytotoxic effects and were not specific to the cell’s clonal variation [Table 1 and 0173]. Thus, Huang et al. teaches the potential for using cx43 to enhance the effect of various chemotherapeutics, however not specific to CDK 4/6 inhibitors. The method is applied to tumors cells from carcinoma, sarcoma, lymphoma, leukemia, or melanoma is specifically claimed [claim 5]. Though Huang et al. does not specifically evidence that these tumor cells are characterized by the presence of a retinoblastoma gene (RB), the instant dependent claims comprise of breast cancer, melanoma, lung cancer, and colon cancer as cancers characterized by RB which are carcinomas or melanomas. Thus, Huang et al. teaches combination drug product of Connexin 43 nucleic acid and a chemotherapeutic agent. Huang et al. does not teach that the therapeutic agent is a CDK4/6 inhibitor.
Gadsden et al. evaluated the efficacy of combining palbociclib and navitoclax in human papillomavirus (HPV)-negative (−) head and neck squamous cell carcinoma (HNSCC) using three HPV- HNSCC cell lines and three HPV+ HNSCC cell lines [Abstract line 4]. Treatment drove reduced expression of phosphorylated Rb (p-Rb) and phenotypic evidence of senescence in all HPV- cell lines, while HPV+ cell lines did not display a consistent response by Rb or p-Rb and did not exhibit morphologic changes of senescence in response to palbociclib. Gadsden et al. also teach:
Loss of normal cell cycle regulation is a hallmark of HNSCC. With human papillomavirus positive (HPV+) disease, the viral oncoproteins E6 and E7 produced by HPV lead to the functional inactivation of the p53 and Rb tumor suppressor proteins, respectively. This disruption allows unchecked progression of the cell cycle, even while the CDKN2A gene, which encodes the p16INK4A (p16) cell cycle inhibitor, remains intact. In HPV-negative (HPV-) disease, loss or inactivation of CDKN2A/p16 is an early and common event in HNSCC tumorigenesis, with disruption of this gene occurring in 58% of cases. P16 is immediately upstream of cyclin dependent kinase 4 and 6 (CDK4/6). Loss of functional p16 allows CDK4/6 to complex with D-type cyclins in order to phosphorylate and inactivate Rb, leading to release of E2F and subsequent progression through the G1 checkpoint to the S phase of the cell cycle. Loss of regulation of this critical checkpoint leads to cell cycle dysregulation and unchecked cell proliferation [pg 862 Introduction pgh 2].
This means that CDK4/6 inhibitors have efficacy in HPV- diseases, characterized by an active functional Rb protein, due to the unchecked cell proliferation being caused by CDK4/6-cyclin complex dysregulation. Thus, Gadsden teaches the use of a drug product with a CDK 4/6 inhibitor in a cancer characterized by the presence of functional RB.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine prior art elements of Connexin 43 and a CDK4/6 inhibitor palbociclib according to known methods to yield predictable results of connexin 43 enhancing the cytotoxic effects of the chemotherapeutic agent palbociclib [MPEP § 2143.01(A)]. This is because one of ordinary skill in the art would have recognized Gadsden’s teaching of a CDK4/6 inhibitor’s efficacy in treating HPV- HNSCC, characterized by active functional RB and Huang’s teaching of cx43 nucleic acid’s efficacy at enhancing the effect of all chemotherapeutics Huang et al. tested.
Regarding claim 14, Gadsden et al. teaches that in HPV- HNSCC, loss or inactivation of CDKN2A/p16 is an early and common event, allowing loss of regulation at the critical checkpoint when CDK4/6 complexes with D-type cyclins in order to phosphorylate and inactivate Rb, leading to release of E2F and subsequent progression through the G1 checkpoint to the S phase of the cell cycle [pg 862 Introduction pgh 2]. Thus, HPV- HNSCC is characterized by hyperactivity of CDK4/6. Therefore, prior to the effective filing date, it was obvious to use a combination drug product of Connexin 43 and palbociclib to yield the predictable result of cx43 enhancing palbociclib in a cancer further characterized by hyperactivity of CDK4/6 because Gadsden et al. further teach that HPV- HNSCC is characterized by hyperactivity of CDK4/6.
Regarding claim 15, Gadsden et al. specify that the pharmaceutical composition of their invention comprise a therapeutically effective amount of a therapeutic, and a pharmaceutically acceptable carrier [0116]. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Thus, Gadsden teaches connexin 43 being administered using a delivery vehicle, and one of ordinary skill in the art would find it obvious to do so for a reasonable expectation and being successful at treating cancer.
Regarding claims 16 and 17, Gadsden et al. state that an important aspect of the present invention is a method for introducing connexin proteins and/or selected genes [0034]. The expression of natural or synthetic nucleic acids is typically achieved by operably linking a nucleic acid of interest (e.g., one encoding a connexin) to a promoter and incorporating the construct into an expression vector [0035]. The expression vector typically comprises a prokaryotic replicon covalently linked to an expression cassette that contains all the elements required for the expression of exogenous connexin protein in eukaryotic cells. A typical expression cassette contains a promoter linked to the DNA sequence encoding the selected connexin protein and signals required for efficient polyadenylation of the transcript [0036]. While Gadsden does not explicitly state that the DNA encodes mRNA before encoding the selected connexin protein, one of ordinary skill in the art knows that DNA first encodes mRNA (transcription), which in turn encodes a protein (translation). Thus, Gadsden teaches connexin 43 being administered using an expression vector, wherein the expression vector encodes Connexin 43 mRNA. One of ordinary skill in the art would find it obvious to take Gadsden’s taught expression vector for a reasonable expectation of success at treating cancer.
Regarding claim 18, Gadsden et al, teaches the increased efficacy of treatment when palbociclib is combined with senolytic agent navitoclax.
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 1-6 and 13-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18248101 in view of Gadsden et al. (Gadsden, N. J., Fulcher, C. D., Li, D., Shrivastava, N., Thomas, C., Segall, J. E., Prystowsky, M. B., Schlecht, N. F., Gavathiotis, E., & Ow, T. J. (2021). Palbociclib Renders Human Papilloma Virus-Negative Head and Neck Squamous Cell Carcinoma Vulnerable to the Senolytic Agent Navitoclax. Molecular cancer research : MCR, 19(5), 862–873).
Regarding claim 1, ‘101 claims a method of treating cancer in a subject in need thereof, wherein the cancer is characterized by the activation of a mitogen-activated protein kinase (MAPK) selected from the group consisting of. BRAF, RAS, MEK, and ERK, comprising administering to the subject in need thereof a therapeutically effective amount of Connexin 43, wherein the cancer is melanoma, colon cancer, lung cancer, or breast cancer [claims 1-5]. While ‘101 does not specifically claim cancers characterized by the presence of functional RB, the instant dependent claims also comprise of melanoma, colon cancer, lung cancer, or breast cancer, evidencing that there is an overlap between cancers characterized by the activation of a mitogen-activated protein kinase (MAPK) and cancers characterized by the presence of functional RB. ‘101 does not teach the method further comprising a CDK 4/6 inhibitor.
Gadsden et al. evaluated the efficacy of combining palbociclib and navitoclax in human papillomavirus (HPV)-negative (−) head and neck squamous cell carcinoma (HNSCC) using three HPV- HNSCC cell lines and three HPV+ HNSCC cell lines [Abstract line 4]. Treatment drove reduced expression of phosphorylated Rb (p-Rb) and phenotypic evidence of senescence in all HPV- cell lines, while HPV+ cell lines did not display a consistent response by Rb or p-Rb and did not exhibit morphologic changes of senescence in response to palbociclib. Gadsden et al. also teach:
Loss of normal cell cycle regulation is a hallmark of HNSCC. With human papillomavirus positive (HPV+) disease, the viral oncoproteins E6 and E7 produced by HPV lead to the functional inactivation of the p53 and Rb tumor suppressor proteins, respectively. This disruption allows unchecked progression of the cell cycle, even while the CDKN2A gene, which encodes the p16INK4A (p16) cell cycle inhibitor, remains intact. In HPV-negative (HPV-) disease, loss or inactivation of CDKN2A/p16 is an early and common event in HNSCC tumorigenesis, with disruption of this gene occurring in 58% of cases. P16 is immediately upstream of cyclin dependent kinase 4 and 6 (CDK4/6). Loss of functional p16 allows CDK4/6 to complex with D-type cyclins in order to phosphorylate and inactivate Rb, leading to release of E2F and subsequent progression through the G1 checkpoint to the S phase of the cell cycle. Loss of regulation of this critical checkpoint leads to cell cycle dysregulation and unchecked cell proliferation [pg 862 Introduction pgh 2].
This means that CDK4/6 inhibitors have efficacy in HPV- diseases, characterized by an active functional Rb protein, due to the unchecked cell proliferation being caused by CDK4/6-cyclin complex dysregulation. Thus, Gadsden teaches the use of a treatment with a CDK 4/6 inhibitor in a cancer characterized by the presence of functional RB.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to claim a method of treating cancer comprising administering a therapeutic amount of Connexin 43 before, after or simultaneously to administering a treatment with a CDK4/6 inhibitor, wherein the cancer is characterized by the presence of functional retinoblastoma gene (RB) because one of ordinary skill in the art would have recognized Gadsden’s teaching of a CDK4/6 inhibitor’s efficacy in treating HPV- HNSCC, characterized by active functional RB and that it can be combined with Connexin 43 for the same purpose of treating cancer.
Regarding claim 2, ‘101 does not claim that the method further comprises abemaciclib, palbociclib, or ribociclib. Gadsden teaches using palbociclib. Thus, it was obvious, prior to the effective filing date, to claim a method wherein CDK4/6 inhibitor is selected from: Abemaciclib, Palbociclib, Ribociclib.
Regarding claim 3, ‘101 does not claim that the method further comprises palbociclib. Gadsden teaches using palbociclib. Thus, it was obvious, prior to the effective filing date, to claim a method wherein CDK4/6 inhibitor is palbociclib.
Regarding claim 4, ‘101 claims the method of claim 1, wherein Connexin 43 is administered to the subject before, after, or simultaneously to a treatment with a senolytic agent [claim 7]. Thus, it was obvious, prior to the effective filing date, to claim the method of claim 1 further comprising before, after or simultaneously to administering Connexin 43, administering a treatment with a senolytic agent.
Regarding claim 5, ‘101 does not claim that a method of treating cancer is further characterized by hyperactivity of CDK4 and CDK6. Gadsden et al. teaches that in HPV- HNSCC, loss or inactivation of CDKN2A/p16 is an early and common event, allowing loss of regulation at the critical checkpoint when CDK4/6 complexes with D-type cyclins in order to phosphorylate and inactivate Rb, leading to release of E2F and subsequent progression through the G1 checkpoint to the S phase of the cell cycle [pg 862 Introduction pgh 2]. Thus, HPV- HNSCC is characterized by hyperactivity of CDK4/6. Therefore, prior to the effective filing date, it was obvious to claim a method of treating cancer characterized by the presence of functional RB and hyperactivity of CDK4 and CDK6 comprising a therapeutic amount of Connexin 43 and CDK 4/6 inhibitor because it would yield the predictable result of both elements treating cancer.
Regarding claim 6, ‘101 further claims the method of claim 1, wherein the cancer is melanoma, colon cancer, lung cancer, or breast cancer [claim 3].
Regarding claim 13, ‘101 claims method of treating cancer in a subject in need thereof, wherein the cancer is characterized by the activation of a mitogen-activated protein kinase (MAPK) selected from the group consisting of. BRAF, RAS, MEK, and ERK, comprising administering to the subject in need thereof a therapeutically effective amount of Connexin 43, wherein the cancer is melanoma, colon cancer, lung cancer, or breast cancer [claims 1-5]. While ‘101 does not specifically claims cancers characterized by the presence of functional RB, the instant dependent claims also comprise of melanoma, colon cancer, lung cancer, or breast cancer, evidencing that there is an overlap between cancers characterized by the activation of a mitogen-activated protein kinase (MAPK) and cancers characterized by the presence of functional RB, ‘101 does not teach the method further comprising a CDK 4/6 inhibitor.
Gadsden et al. evaluated the efficacy of combining palbociclib and navitoclax in human papillomavirus (HPV)-negative (−) head and neck squamous cell carcinoma (HNSCC) using three HPV- HNSCC cell lines and three HPV+ HNSCC cell lines [Abstract line 4]. Treatment drove reduced expression of phosphorylated Rb (p-Rb) and phenotypic evidence of senescence in all HPV- cell lines, while HPV+ cell lines did not display a consistent response by Rb or p-Rb and did not exhibit morphologic changes of senescence in response to palbociclib. Gadsden et al. also teach:
Loss of normal cell cycle regulation is a hallmark of HNSCC. With human papillomavirus positive (HPV+) disease, the viral oncoproteins E6 and E7 produced by HPV lead to the functional inactivation of the p53 and Rb tumor suppressor proteins, respectively. This disruption allows unchecked progression of the cell cycle, even while the CDKN2A gene, which encodes the p16INK4A (p16) cell cycle inhibitor, remains intact. In HPV-negative (HPV-) disease, loss or inactivation of CDKN2A/p16 is an early and common event in HNSCC tumorigenesis, with disruption of this gene occurring in 58% of cases. P16 is immediately upstream of cyclin dependent kinase 4 and 6 (CDK4/6). Loss of functional p16 allows CDK4/6 to complex with D-type cyclins in order to phosphorylate and inactivate Rb, leading to release of E2F and subsequent progression through the G1 checkpoint to the S phase of the cell cycle. Loss of regulation of this critical checkpoint leads to cell cycle dysregulation and unchecked cell proliferation [pg 862 Introduction pgh 2].
This means that CDK4/6 inhibitors have efficacy in HPV- diseases, characterized by an active functional Rb protein, due to the unchecked cell proliferation being caused by CDK4/6-cyclin complex dysregulation. Thus, Gadsden teaches the use of a treatment with a CDK 4/6 inhibitor in a cancer characterized by the presence of functional RB.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to claim a method of treating cancer comprising administering a therapeutic amount of a combination drug product comprising Connexin 43 and a CDK4/6 inhibitor, wherein the cancer is characterized by the presence of functional retinoblastoma gene (RB) because one of ordinary skill in the art would have recognized Gadsden’s teaching of a CDK4/6 inhibitor’s efficacy in treating HPV- HNSCC, characterized by active functional RB and that it can be combined with Connexin 43 for the same purpose of treating cancer.
Regarding claim 14, ‘101 does not claim that a method of treating cancer is further characterized by hyperactivity of CDK4 and CDK6. Gadsden et al. teaches that in HPV- HNSCC, loss or inactivation of CDKN2A/p16 is an early and common event, allowing loss of regulation at the critical checkpoint when CDK4/6 complexes with D-type cyclins in order to phosphorylate and inactivate Rb, leading to release of E2F and subsequent progression through the G1 checkpoint to the S phase of the cell cycle [pg 862 Introduction pgh 2]. Thus, HPV- HNSCC is characterized by hyperactivity of CDK4/6. Therefore, prior to the effective filing date, it was obvious to claim a method of treating cancer characterized by the presence of functional RB and hyperactivity of CDK4 and CDK6 comprising a combination drug product of Connexin 43 and CDK 4/6 inhibitor because it would yield the predictable result of both elements treating cancer.
Regarding claim 15, ‘101 claims a method of treating in cancer in a subject in need thereof, wherein the cancer is characterized by the activation of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK, comprising administering to the subject in need thereof a pharmaceutical composition of connexin 43 and an inhibitor of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK., wherein connexin 43 is administered by using a delivery vehicle [claim 8, 12-13, and 15]. Thus, it was obvious to claim the method according to claim 13, wherein the Connexin 43 is administered by using a delivery vehicle.
Regarding claims 16, ‘101 claims a method of treating in cancer in a subject in need thereof, wherein the cancer is characterized by the activation of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK, comprising administering to the subject in need thereof a pharmaceutical composition of connexin 43 and an inhibitor of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK., wherein connexin 43 is administered by nanoparticle, an extracellular vesicle, or an expression vector which encodes Connexin 43 [claim 8, 12-13, and 15-16]. Thus, it was obvious to claim the method according to claim 15, wherein the delivery vehicle is a nanoparticle, a vesicle, an extracellular vesicle, an expression vector or a molecule of DNA or RNA.
Regarding claim 17, ‘101 claims a method of treating in cancer in a subject in need thereof, wherein the cancer is characterized by the activation of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK, comprising administering to the subject in need thereof a pharmaceutical composition of connexin 43 and an inhibitor of a mitogen-activated protein kinase (MAPK) selected from the group consisting of: BRAF, RAS, MEK, and ERK., wherein connexin 43 is administered by nanoparticle, an extracellular vesicle, or an expression vector which encodes Connexin 43 [claim 8, 12-13, and 15-16]. Thus, it was obvious to claim the method according to claim 15, wherein the delivery vehicle is a nanoparticle, a vesicle, an extracellular vesicle, an expression vector or a molecule of DNA or RNA. Thus, it was obvious to claim the method according to claim 16, wherein the expression vector encodes Connexin 43 mRNA which in turn is translated into Connexin 43 protein.
Regarding claim 18, ‘101 claims the method of claim 1, wherein Connexin 43 is administered to the subject before, after, or simultaneously to a treatment with a navitoclax [claim 1, 7 and 15]. Thus, it was obvious, prior to the effective filing date, to claim the method further comprising before, after or simultaneously to administering Connexin 43, administering a treatment with a navitoclax.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-6 and 13-18 are rejected under 35 U.S.C. 112(a). Claims 1-6 and 13-18 are rejected under 35 U.S.C. 103. Claims 1-6 and 13-18 are provisionally rejected on the ground of nonstatutory double patenting.
Correspondence
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/SACHI JAUHARI/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
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