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 .
Priority
The application is a 371 PCT of KR2021/020161 filed 12/29/2021. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements filed 6/28/2023 and 12/11/2024 have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 16 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 16 recites “the anticancer agent” and depends from cl aim 14. There is insufficient antecedent basis for this limitation in the claim.
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 1-3, 5-16 and 19-21 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states 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 applicant was in possession of the claimed genus. “Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
Claim 1, 13-14, and 19 is directed to a method of inhibiting metastasis/method of co-administration for preventing or treating cancer/method of enhancing anticancer drug sensitivity/ method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition comprising a p53 activator, a mothers against decapentaplegic homolog 4 (SMAD4) inhibitor, and an extracellular signal-regulated kinase (ERK) inhibitor. Possession of these claims requires the possession of the genus of cancer that can be inhibited, prevented, or treated with the claimed composition.
The current specification, as filed, discloses that ‘the present inventors confirmed that a three-combination of activation of p53 and inhibition of SMAD4 and ERK signaling pathways may induce a change to a phenotype with enhanced responsiveness while studying, in order to
enhance the responsiveness to a chemotherapeutic agent by removing both stem cell properties and heterogeneity acquired by EMT from metastatic and resistant cancer cells, and then completed the present invention’ [pg. 2, line 21 – pg. 3, line 2]. The specification teaches that ‘According to the present invention, a combination of a p53 activator, a SMAD4 inhibitor and an ERK inhibitor enables a mesenchymal cell phenotype to return to an epithelial cell phenotype, and also enables the ability of cancer cells to metastasize to be inhibited by overcoming the high variability and drug resistance of 20 the cancer cells, and thus may be widely used in the field of cancer treatment’ [pg. 4, lines 16-20]. The specification teaches that the target cancer of the present invention is preferably cancer in which epithelial-to-mesenchymal transition (EMT) has progressed, more preferably cancer with wild-type p53, much more preferably at least one selected from the group consisting of lung cancer, colon cancer, pancreatic cancer, liver cancer, thyroid cancer and breast cancer with wild-type p53, and even more preferably lung cancer with wild-type p53 [pg. 7, lines 10-13]. The specification provides working examples using lung cancer cells. The specification does not disclose any other cancer cell type or cancers, or a representative number of cancers, that can be prevented or inhibited by the claimed genes.
Thorlacius (Thorlacius et al. European Journal of Cancer Vol. 31A, No. 11, pp. 1856--1861, 1995) teaches that abnormal p53 protein staining was observed in only 33.7% of breast carcinomas, indicating that a majority of the analyzed cancers lacked detectable p53 expression (see entire paper). Therefore, persons of ordinary skill in the art understood that p53 expression was not a universal characteristic of cancer cells. Schutte (Schutte et al. Cancer Research 56. 2527-2530. June 1, 1996 )surveyed multiple tumor types and reported homozygous deletions and inactivating mutations of DPC4 (i.e., SMAD4) in several cancers, further establishing that many cancers do not retain normal SMAD4 (see entire paper). Kiyokawa (Kiyokawa et al. Cancer Research 54, 3645-3650, July 15, 1994) report that ERK expression levels vary across 76 human tumor tissues and cell lines, with significant heterogeneity among tumor types, indicating that ERK expression is not uniform across cancers and instead depends on tissue and tumor context (see entire paper). Taken together, the prior are teaches that not all cancer typer express or has functional p53, SMAD4, or ERK suggesting that activation or inhibition of these protein may be useful in inhibiting metastasis or treating cancer.
Therefore, considering the extremely large variation in the genus of cancers; the failure of the specification to describe or provide predictability for preventing or treating all cancers; and the lack of predictability provided by the art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing.
The additional dependent claims do not further limit the genus of cancers so as to resolve the issues above, and are therefore not sufficiently described for at least the reasons above.
Claims 1-16 and 19-21 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states 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 applicant was in possession of the claimed genus. “Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
The claim recites a method of inhibiting metastasis/preventing or treating cancer/enhancing anticancer drug sensitivity/method for treating cancer comprising administering a composition comprising a “p53 activator,” a “SMAD4 inhibitor,” and an “ERK inhibitor.” Each of these limitations is defined purely by functional result and encompasses broad, structurally and mechanistically diverse classes of agents. Possession of these claims also requires the possession of the genus of all activators of p53, SMAD4 inhibitors, and ERK inhibitor that can be used together for inhibiting metastasis/preventing or treating cancer/enhancing anticancer drug sensitivity/method for treating cancer.
The specification teaches that ‘In the present invention, the p53 activator is not limited thereto, but may be at least one selected from the group consisting of Nutlin-3a, RO6839921, NSC 146109 hydrochloride, RITA, Tenovin-1, HLl373, WR 0165, Idasanutlin, and YH 239-EE. Preferably, the p53 activator may be Nutlin-3a. In addition, the SMAD4 inhibitor may be at least one selected from the group consisting of siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, compounds, and antibodies that target SMAD4 gene or protein, and a signaling pathway of SMAD4, and vectors expressing thereof. In addition, the ERK inhibitor may be at least one selected from the group consisting of siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, compounds, and antibodies that target ERK gene or protein, and a signaling pathway of ERK, and vectors expressing thereof [pg. 7, line 16 – pg. 8, line 2]. The specification only provides working examples using Nutlin-3a for p53 activation, shRNA (shS4, SEQ ID NO: 1) for SMAD4 inhibition, and U0126 as a EMT inhibitor.
With respect to p53 activation, the art predating the filing date demonstrates that p53 is not activated by a single class of compounds or mechanism, but instead is regulated through multiple distinct upstream stress-response pathways, including DNA damage signaling, oncogene-induced ARF/MDM2 regulation, hypoxic stress, and ribosomal stress pathways, each involving different molecular intermediates and post-translational mechanisms. [See Levine (Levine et al. Cell 1997, 88:323–331) (p53 activation occurs in response to diverse stresses including DNA damage, oncogene activation, and hypoxia via multiple regulatory pathways)]. Accordingly, “p53 activator” encompasses a vast and structurally unrelated genus of molecules and biological interventions without a unifying structural feature or common mechanism.
Similarly, SMAD4 loss is known in the art to occur through multiple independent mechanisms including homozygous deletion, truncating mutation, and pathway inactivation in specific tumor types. Hahn (Hahn et al. Science 1996, 271:350–353), report frequent homozygous deletion and mutation of DPC4 (SMAD4) in pancreatic cancer, establishing that SMAD4 status varies across tumor types and is not universally expressed or uniformly targetable by a single inhibitory strategy. Thus, a “SMAD4 inhibitor” spans genetically, epigenetically, and pharmacologically distinct modalities without structural correlation.
ERK signaling likewise represents a ubiquitous MAPK cascade present in normal and malignant cells, with activity dependent on upstream pathway context rather than a single molecular entity. Hoshino (Hoshino et al. Oncogene 1999, 18:813–822), demonstrate that ERK pathway activation varies significantly among tumor types, with constitutive activation present only in subsets of cancers. Accordingly, an “ERK inhibitor” encompasses multiple mechanistically distinct inhibitors acting at RAF, MEK, or ERK levels, without a single structural or functional genus definition.
Although the specification may disclose isolated examples of agents within each category, it fails to demonstrate possession of the full scope of combinations of all p53 activators, all SMAD4 inhibitors, and all ERK inhibitors as required by the claim. The disclosure does not provide representative species or structural features common to the full genus of each functional limitation, nor does it establish that the inventors were in possession of the claimed broad therapeutic combination across cancer types. Accordingly, the written description requirement is not satisfied.
Claims 1-16 and 19-21 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 methods for inhibiting lung cancer metastasis and treating and preventing lung cancer with Nutlin-3a for p53 activation, shRNA (shS4, SEQ ID NO: 1) for SMAD4 inhibition, and U0126 as a EMT inhibitor, does not reasonably provide enablement for the prevention and treatment of all cancers and metastasis by using any a p53 activator, a mothers against decapentaplegic homolog 4 (SMAD4) inhibitor, and an extracellular signal-regulated kinase (ERK) inhibitor.. 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.
Nature of the Invention
The claim requires identification and administration of a composition comprising three independently broad functional classes: (i) a “p53 activator,” (ii) a “SMAD4 inhibitor,” and (iii) an “ERK inhibitor,” for inhibiting metastasis/preventing or treating cancer/enhancing anticancer drug sensitivity. Each limitation encompasses structurally diverse and mechanistically unrelated species, and the combination effect is highly context-dependent across tumor types. Enablement of the claims turns on whether one of ordinary skill in the art could prevent or treat all cancers or metastasis using any claimed inhibitors and activator without undue experimentation.
State of the Art
Levine (Levine et al. Cell 1997, 88:323–331) teaches that p53 activation is mediated by multiple distinct stress-response pathways involving DNA damage sensors (e.g., ATM/ATR), oncogene signaling via ARF-mediated MDM2 inhibition, and ribosomal stress pathways, each producing activation through different molecular intermediates. Because these pathways are mechanistically unrelated, there is no predictable structure–function relationship permitting a skilled artisan to identify which “p53 activator” species will function in combination with SMAD4 and ERK pathway modulation across cancer types without extensive empirical screening.
SMAD4 function is likewise altered in cancer through heterogeneous mechanisms including gene deletion and mutation, as shown in Hahn (Hahn et al. Science 1996, 271:350–353). Consequently, “SMAD4 inhibition” may require fundamentally different modalities (gene knockdown, dominant negative constructs, or pharmacologic suppression depending on context), none of which are predictably interchangeable across tumor types or compatible with p53 and ERK modulation without testing.
Hoshino (Hoshino et al., Oncogene 1999, 18:813–822) teaches that ERK pathway inhibition is also context-dependent, as constitutive ERK activation occurs only in subsets of tumors, and pathway dependence varies widely. Thus, identifying an “ERK inhibitor” that produces metastasis inhibition in combination with p53 activation and SMAD4 inhibition requires unpredictable optimization across multiple signaling networks.
Breadth of the claims
The claims of the instant specification recites a method for inhibiting metastasis/preventing or treating cancer/enhancing anticancer drug sensitivity in a subject in need thereof comprising administering a p53 activator, a mothers against decapentaplegic homolog 4 (SMAD4) inhibitor, and an extracellular signal-regulated kinase (ERK) inhibitor. This recitation broadly encompass any and all forms of cancer, activators, and inhibitors.
Guidance of the Specification
The specification teaches that ‘In the present invention, the p53 activator is not limited thereto, but may be at least one selected from the group consisting of Nutlin-3a, RO6839921, NSC 146109 hydrochloride, RITA, Tenovin-1, HLl373, WR 0165, Idasanutlin, and YH 239-EE. Preferably, the p53 activator may be Nutlin-3a. In addition, the SMAD4 inhibitor may be at least one selected from the group consisting of siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, compounds, and antibodies that target SMAD4 gene or protein, and a signaling pathway of SMAD4, and vectors expressing thereof. In addition, the ERK inhibitor may be at least one selected from the group consisting of siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, compounds, and antibodies that target ERK gene or protein, and a signaling pathway of ERK, and vectors expressing thereof [pg. 7, line 16 – pg. 8, line 2]. The specification only provides working examples using Nutlin-3a for p53 activation, shRNA (shS4, SEQ ID NO: 1) for SMAD4 inhibition, and U0126 as a EMT inhibitor.
Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. To practice the invention as broadly claimed, it would be necessary for one of ordinary skill in the art to systematically test every combination of inhibitors and activators against every cancer known at all cancer stages to determine which combination is capable of preventing all cancer types. Given the vast number of possible species within each claimed genus and the lack of guidance as to which combinations are operative, a person of ordinary skill would be required to perform extensive, iterative screening across multiple cancer types, drug classes, dosing regimens, and signaling contexts.
Accordingly, practicing the invention as broadly claimed would require a massive amount of highly unpredictable experimentation.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue experimentation would be required to make and use the invention as claimed.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 8, 19 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Rolf (EP 3 560 516 A1, 10/30/2019) in view of Kang (Kang et al. PNAS. 2005. vol. 102, no. 39, 13909–13914) and (Song et al. Am J Transl Res 2019;11(7):3932-3944).
Regarding claim 1, 4-6, 19 and 21 Rolf teaches a pharmaceutical composition comprising an ERK inhibitor in combination with another drug for the treatment of cancer including metastatic cancer [abstract]. Rolf teaches that metastatic cancer like melanoma with brain metastases can be treated with a combination drug comprising an ERK inhibitor thereby increasing survival and improve treatment [0022]. Rolf teaches that the combination drug can be used to treat breast, lung, colon, pancreatic, and hepatocellular carcinoma (regarding claim 4) [0062].
Rolf does not teach that administering a p53 activator or Smad4 inhibitor in a method of inhibiting metastasis.
Kang provides functional evidence for a switch of the Smad pathway, from tumor-suppressor to prometastatic, in the development of breast cancer bone metastasis [abstract]. Kang teaches that RNA interference-mediated depletion of Smad4 inhibited bone metastasis in this mouse xenograft model [pg. 13914, col. 1, para 2]. Kang teaches the administration of cell lines comprising Smad4 knockdown (shRNA) to mice (regarding claim 6) [pg. 13913, col. 2, para 2].
Song teaches that loss of E-cadherin is able to induce EMT process, which is associated with cancer stem cells and drug resistance in human cancer and restoring E-cadherin could be a useful strategy for reversal of EMT and overcoming drug resistance [abstract]. Song teaches that Nutlin-3 is a small molecule regulator of p53 [Table 1]. Song teaches that Nutlin-3 increases E-cadherin, inhibits migration and invasion, suppresses EMT [Table 1]. Song teaches that nutlin-3 exhibited antimetastatic properties on hepatocellular carcinoma (HCC) cell lines by inhibiting Smad-mediated EMT [pg. 3938, col. 1, para 2].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition of Rolf to contain a Smad4 shRNA and Nutlin-3 (regarding claim 5) in addition to the ERK inhibitor for the treatment of metastatic cancer such as HCC and breast cancer. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success that the combined composition would have success in treating metastatic cancer since each element is individually known to aid in treating metastatic cancer.
Regarding claim 2, a limitation of the cancer components does not distinguish the method of metastasis inhibition as taught above. However, song teaches that HCC treatment includes reversing EMT. Therefore, would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention that HHC has progressed epithelial-to-mesenchymal transition (EMT).
Regarding claim 3, a limitation of the cancer components does not distinguish the method of metastasis inhibition as taught above. However, Song teaches that nutlin-3, a p53 regulator, exhibited antimetastatic properties on hepatocellular carcinoma (HCC) cell lines by inhibiting Smad-mediated EMT. Therefore, would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention that HCC comprises a wild type p53.
Regarding claim 4, Rolf teaches that the combination drug can be used to treat breast, lung, colon, pancreatic, and hepatocellular carcinoma [0062].
Regarding claim 8, Rolf teaches that the ERK inhibitor is a compound [0048].
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Rolf (EP 3 560 516 A1, 10/30/2019) in view of Kang (Kang et al. PNAS. 2005. vol. 102, no. 39, 13909–13914) and (Song et al. Am J Transl Res 2019;11(7):3932-3944) as applied to claims 1 and 6 and further in view of Thastrup (US20030082564 A1).
The teachings of Rolf, Kang, and Song are discussed above as applied to claims 1 and 6 and similarly apply to claim 7.
Rolf, Kang, and Song do not teach that wherein the SMAD4 inhibitor is a shRNA of the nucleotide set forth in SEQ ID NO: 1.
Thastrup teaches method that can be used as a screening program for identifying a compound that modulates a component and is capable of treating a disease related to the function of the component [abstract]. Thastrup teaches Pprobes for detection of Smad4 [0301]. Thastrup teaches a Smad4-EGFP fusion (SEQ ID NO:76 &77) [0305]. SEQ ID NO: 76 is 100% identical to SEQ ID NO: 1.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to use SEQ ID NO: 1 of Thastrup as the shRNA Smad4 inhibitor. One of ordinary skill would be motivated to do so with a reasonable expectations of success given Thastrup’s teaching that SEQ ID NO: 76, which is 100% identical to SEQ ID NO: 1, encodes for Smad4.
Claims 9, 11-13, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Rolf (EP 3 560 516 A1, 10/30/2019) in view of Kang (Kang et al. PNAS. 2005. vol. 102, no. 39, 13909–13914) and (Song et al. Am J Transl Res 2019;11(7):3932-3944) as applied to claims 1 and 8 and further in view of Schaus (US20200039996A1, published 2/6/2020).
The teachings of Rolf, Kang, and Song are discussed above as applied to claims 1 and 8 and similarly apply to claim 9, and 11-13.
Rolf, Kang, and Song do not teach that the ERK inhibitor is U0126. Rolf, Kang, and Song do not teach the composition for use in an anticancer adjuvant.
Schaus teach compositions, methods and kits for treatment of cancer, e.g. hepatocellular carcinoma (HCC) by using inhibitors of late SV40 factor (LSF) [astract; 0009]. Schaus teach that LSF activates cell survival-regulating pathways, such as MEK/ERK, a LSF inhibitor disclosed herein can be used alone or in combination with chemotherapeutic agents, and that diseases or disorders associated with LSF-induced MEK/ERK activation can be contemplated for treatment with a LSF inhibitor as disclosed herein alone or in combination with inhibitors of MEK/ERK pathway such as PD98059 and U0126, thereby teaching that U1026 is an inhibitor of the MEK/ERK pathway [0243]. Schaur teaches administering the pharmaceutical composition comprising therapeutic agents after surgery (i.e., an anticancer adjuvant).
Regarding claims 9 and 20, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to substitute the ERK inhibitor in the pharmaceutical composition as taught and suggested by Rolf, Kang, and Song with U0126 and administer the composition comprising the therapeutic agents after surgery. This modification would about to a simple substitution of one known ERK inhibitor for another, and an alternative administration method One of ordinary skill would have a reasonable expectation of success because both Rolf and Schaus teach that an ERK inhibitor can be used for cancer treatment and teach compositions for treating HCC metastasis.
Regarding claim 11-13, while Rolf teach that the components of the pharmaceutical composition are administered simultaneously, separately or sequentially [0065], Rolf does not teach additionally administering doxorubicin. Schaus teach that doxorubicin is a chemotherapeutic agents that can be used in combination with other anti-cancer compounds [0243]. Therefore, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to additionally administer doxorubicin with the pharmaceutical composition as taught and suggested by Rolf, Kang, and Song. One of ordinary skill would be motivated to make this modification with a reasonable of success given Schaus disclosure that doxorubicin is a chemotherapeutic agents that can be used in combination with other anti-cancer compounds.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Rolf (EP 3 560 516 A1, 10/30/2019) in view of Kang (Kang et al. PNAS. 2005. vol. 102, no. 39, 13909–13914) and (Song et al. Am J Transl Res 2019;11(7):3932-3944) as applied to claim 1 and further in view of Wu (Wu et al. Oncology Reports 36: 1325-1332, 2016).
The teachings of Rolf, Kang, and Song are discussed above as applied to claim 1 and similarly apply to claim 10.
While Song teaches that nutlin-3, a p53 regulator, increases E-cadherin, decreases the levels of Smad2, inhibits migration and invasion, and suppresses EMT [Table 1]; Rolf, Kang, and Song do not teach that the p53 activator, the SMAD4 inhibitor, and the ERK inhibitor restore a mesenchymal cell phenotype to an epithelial cell phenotype by epithelial-to-mesenchymal transition (EMT) of cancer cells.
Wu teaches that nutlin-3 reverses EMT in gemcitabine‑resistant (GR) hepatocellular carcinoma (HCC) through the regulation of Smad2 expression.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention that the pharmaceutical compositions as taught and suggested by Rolf, Kang, and Song which comprises a Smad4 shRNA, Nutlin-3, and a ERK inhibitor would be capable of restoring a mesenchymal cell phenotype to an epithelial cell phenotype by epithelial-to-mesenchymal transition (EMT) of cancer cells given Wu’s disclosure that nutlin-3 reverses EMT.
Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Rolf (EP 3 560 516 A1, 10/30/2019) in view of Kang (Kang et al. PNAS. 2005. vol. 102, no. 39, 13909–13914) and (Song et al. Am J Transl Res 2019;11(7):3932-3944) as applied to claim 1 and further in view of Park (US 2017/0369887 A1)
The teachings of Rolf, Kang, and Song are discussed above as applied to claim 1 and similarly apply to claims 14-16.
Rolf, Kang, and Song do not teach a method of enhancing anticancer drug sensitivity.
Park teaches pharmaceutical compositions for inhibiting breast cancer proliferation and metastasis more effectively and provides for an adjuvant for restoring drug sensitivity of anticancer agent-resistant breast cancer more effectively [0039]. Park teaches a correlation of inhibition of metastasis and drug sensitivity by teaching that an inhibitor for the expression or activity of PRKD1 can be used for inhibiting metastasis and restoring of the drug sensitivity. Therefore, 27. It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention that the pharmaceutical compositions as taught and suggested by Rolf, Kang, and Song which comprises a Smad4 shRNA, Nutlin-3, and a ERK inhibitor would be capable of restoring/enhancing anticancer drug sensitivity given the teachings of Park.
Regarding claim 15, the teachings of Rolf, Kang, Song, and Wu are discussed above as applied to claim 10.
Regarding claim 16, the teachings of Rolf, Kang, Song, and Schaus are discussed above as applied to claim 12.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
Prosecution Insights