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 .
Status of Claims/Application
The claims filed on 02/05/2024 is acknowledged. No preliminary amendment was submitted. Claims 1 – 20 are pending in the instant application, and are examined on the merits herein.
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e)
or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The instant application,
filed on 11/16/2023, claims domestic benefit to U.S. provisional application no.
63/425,790, filed on 11/16/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted in the instant application
on 07/23/2024, 08/27/2024, and 02/07/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification Objection
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
A hyperlink is provided in the instant specification (pg. 13, line 14, [0063]). Appropriate correction is required.
The disclosure is objected to because it refers to (Figure 4A-H) (pg. 18, line 12, [0080]), which are not provided. Appropriate correction is required.
Claim Objections
Claims 5 is objected to because of the following informalities:
Claim 5 recites a list of cancers. It needs an “and” before the last cancer listed.
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 18 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 18 states “A method of inhibiting the interaction between an RGS2 protein and a Galpha protein in a cell comprising administering the cell to an RGS2 inhibitor in an amount capable of non- covalently interacting with the RGS2 protein.” It is not clear how the cell could be administered to an RGS2 inhibitor. So, for examination purposes, the claim is being interpreted as “ administering an RGS2 inhibitor to the cell”. Appropriate correction is required.
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 – 20 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 a certain set of inhibitors listed in Table 1, pg. 14 – 15, and provides support for their activity against renal cancer, and leukemia [0082], and for their ability to inhibit RGS2-Galpha-q interaction ([0064] – [0068]), does not reasonably provide enablement for any and all RGS2 inhibitors for their anticancer activity, or for their ability to inhibit RGS2-Galpha-q interaction. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
Claim 1 is drawn to a method of treating a subject with cancer, comprising administering to the subject an RGS2 inhibitor in an amount therapeutically effective to treat the cancer. The dependent claims 2 – 12 recite the preferred binding region on the RGS2 protein for the inhibitor using the pharmacophore model, structures of a select group of 10 compounds as RGS2 inhibitors, or their mode of administration to a subject with various types of cancer to treat the cancer. Claim 13 is drawn to a pharmaceutical composition comprising an RGS2 inhibitor in an amount effective to inhibit the interaction between an RGS2 protein and a Galpha protein in a cell of a cancer of a subject. The dependent claims 14 – 17 recite the Galpha protein is a Galpha-q protein, the preferred binding region on the RGS2 protein for the inhibitor using the pharmacophore model, the structures of a select group of 10 compounds as RGS2 inhibitors, or the mode of administration of the pharmaceutical composition. Claim 18 is drawn to a method of inhibiting the interaction between an RGS2 protein and Galpha protein in a cell comprising of administering an RGS2 inhibitor to the cell in an amount capable of non-covalently interacting with the RGS2 protein. The dependent claims 19, and 20 recite the preferred binding region on the RGS2 protein for the inhibitor using the pharmacophore model, or the structures of a select group of 10 compounds as RGS2 inhibitors.
The breadth of the claims
As Claim 1 recites an RGS2 inhibitor could be administered to a subject to treat cancer, in its broadest reasonable interpretation, any and all RGS2 inhibitors could be administered to treat cancer, and inhibition of RGS2 protein would result in the treatment of cancer. As Claim 13 recites a pharmaceutical composition comprising an RGS2 inhibitor to inhibit the interaction between an RGS2 protein and a Galpha protein in a cell of a cancer of a subject, in its broadest reasonable interpretation, a pharmaceutical composition comprising any and all RGS2 inhibitors would inhibit the RGS2 protein and Galpha protein interaction. As Claim 18 recites an RGS2 inhibitor could be administered to a cell to inhibit the interaction between an RGS2 protein and Galpha protein by non-covalently interacting with the RGS2 protein, in its broadest reasonable interpretation, any and all RGS2 inhibitors having non-covalent interactions with RGS2 protein would inhibit the RGS2 protein and Galpha protein interaction.
The amount or direction provided by the inventor / the existence of working examples
The specification in Example 1 ([0041] – [0077]) provides the methodology in determining the small species of RGS2 inhibitors using pharmacophore model and docking, followed by the RGS2 inhibition and selectivity assays, and the anticancer activity of the group of compounds. The specification ([0067] – [0071]) is about RGS2 inhibition and selectivity assays, and states that 10 compounds in Table 1 inhibited RGS2-Galpha-q interaction with moderate to high potency. Several studies have reported the over expression of RGS2 in different cancers especially metastatic ones. If RGS2 truly played a role in cancer development and/or metastasis then inhibitors of its function should have anticancer activities. Nine inhibitors were submitted to the National Cancer Institute NCI-60 program for anti-cancer screening. All inhibitors submitted inhibited the growth of several cancer cell lines with varying potency. In addition, the ability of AJ-3 to inhibit the migration of the LNCaP prostate cancer cell line was tested. AJ-3 inhibited the migration of LNCaP cells at concentrations as low as 1 µM but more potently at 2 µM and higher concentrations [0073]. The specification discloses in Example 2 that both the shRGS2 knockdown cancer cells (cells with reduced expression of RGS2) and the RGS2 inhibitor (AJ-3) treated cancer cells exhibited a reduction in metastatic potential [0082]. The specification [0085] discloses that every RGS2 inhibitor showed some amount of inhibitory effect against at least two types of cancer, namely renal cancer and leukemia. Composition AJ1 (Table 1) exhibited cytotoxic effect against all aforementioned cancers (leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer [0083]) except prostate, ovarian, and colon cancer. Compositions AJ3, AJ4, AJ8, AJ9, and AJ10 (Table 1) have all shown strong cytotoxic effect against the full list of cancers.
The state of the prior art / the level of predictability in the art
McNabb et al (Emerging Roles of Regulator of G Protein Signaling 2 in (Patho) physiology, Mol. Pharmacol. 98: 751 – 760, December 2020)
McNabb teaches in the section on RGS2 as a Potential Cancer Target (pg. 756, col. 1, para. 2) differing outcomes in the up and down regulation of RGS2 – RGS2 as a tumor suppressor in breast, prostate, and acute myeloid leukemia, repression of RGS2 has been proposed to be associated with other less common cancer types such as bladder cancer, ovarian cancer, and colorectal cancer, low RGS2 mRNA and protein levels have been associated with poor survival in stage II and III colorectal cancer, whereas upregulation of RGS2 is related to poor survival in patients with lung adenocarcinoma, and overexpression of RGS2 may promote cancer progression is demonstrated by mantle cell lymphoma.
McNabb is a review that provides an update of the current knowledge of RGS2 function as it relates to molecular mechanisms of regulation as well as its potential role
in regulating a number of physiologic systems and pathologies, including cardiovascular disease and central nervous system disorders, as well as various forms of cancer (Abstract). McNabb teaches in the section on RGS2 as a Potential Cancer Target (pg. 756, col. 1, para. 2) differing outcomes in the up and down regulation of RGS2. RGS2 is downregulated in breast cancer cells and human tumor samples, and overexpression of RGS2 can inhibit MCF-7 breast cancer cell growth, and the role of RGS2 as a breast cancer tumor suppressor warrants further investigation. However, the role of RGS2 in
prostate cancer is complex and may depend on the stage of cancer progression (pg. 756, col. 2, para. 1). Apart from breast and prostate cancer, RGS2 has also been proposed as a tumor suppressor in acute myeloid leukemia (AML) (pg. 756, col. 2, para. 2). Repression of RGS2 has been proposed to be associated with other less common cancer types such as bladder cancer, ovarian cancer, and colorectal cancer (pg. 756, col. 2, para. 3). For instance, upregulation of RGS2 is related to poor survival in patients with lung adenocarcinoma. In contrast, downregulation of RGS2 is associated with increased invasion and metastasis of human non-small cell lung cancer cells caused by loss of
Mediator Complex Subunit 1. These studies emphasize that RGS2 may play different roles depending on the cancer subtype, even in the same tissue (pg. 757, col. 1, para. 2). The mechanisms by which RGS2 may alter proliferation, migration, or invasion of cancer cells are currently unknown. Increased knowledge of all of these concepts will enhance our understanding of the diverse phenotypes related to RGS2 in different cancer types (pg. 757, col. 1, para. 3).
McNabb summarizes the role of RGS2 protein in cancer - the mechanisms by which RGS2 may alter proliferation, migration, or invasion of cancer cells are currently unknown. The teachings of McNabb demonstrate that inhibition of RGS2 might not be the only mode of treatment of cancer, and that inhibition might have an opposite effect too.
Deng et al (ZHX3 promotes the progression of urothelial carcinoma of the bladder via repressing of RGS2 and is a novel substrate of TRIM21, Cancer Science. 2021;112:1758–1771).
Deng teaches that zinc finger and homeobox 3 (ZHX3) represses RGS2 expression in urothelial carcinoma of the bladder (UCB) cells (pg. 1763, col. 2). Deng further teaches that RGS2 can accelerate the intrinsic GTPase activity of Gα proteins and interfere with G protein-coupled receptor (GPCR) signaling pathway transduction. In the human genome, RGS2 is considered the most potent negative regulator of Gqα and attenuates Gqα-, Giα-, and Gsα-mediated pathways. To date, as the most potent negative regulator of Gqα, RGS2 has been reported to act as a tumor suppressor in certain human cancers, such as breast, prostate, ovarian, and bladder cancers.
The teachings of Deng demonstrate that inhibition of RGS2 and its interaction with Galpha protein might not lead to the treatment of cancer of certain types.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed in detail above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a subject or an individual with any of the several cancers listed in claims 5 and 6, except for renal cancer and leukemia would have been treated by the claimed method of administering an RGS2 inhibitor, except for the small species of 10 compounds in Table 1 as the mechanism by which RGS2 acts in various cancer types and the stages of cancer is not well understood. Therefore, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to develop a method to determine when inhibition of RGS2 by any RGS2 inhibitor would be an appropriate mode of action in the treatment of the cancer in a subject. Similarly, one of ordinary skill in the art would have to participate in undue experimentation to determine any and all compounds, or a pharmaceutical composition comprising them that would interact with RGS2 protein to inhibit RGS2 – Galpha protein interactions other than the ten compounds in Table 1.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention, and is only enabled to use the invention with the ten compounds disclosed for two cancer types, namely renal cancer and leukemia, and is only enabled to use the invention as a method, or a pharmaceutical composition with the ten compounds disclosed as the inhibitors of RGS2 – Galpha protein interactions. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Claims 1 – 12, 15, 18, and 19 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claims 1 – 12 are drawn to a method of treating a subject with cancer, comprising administering to the subject an RGS2 inhibitor in an amount therapeutically effective to treat the cancer, wherein the RGS2 inhibitor non-covalently interacts with turn-183 of human RGS2 defined by a first asparagine at residue 183 ("N183"), a second asparagine at residue 184 ("N184"), and a serine at residue 185 ("S185"), wherein N183 and N184 interact with a positively charged pharmacophore site and S185 interacts with a hydrogen-bond donor pharmacophore site, structures of a select group of 10 compounds as RGS2 inhibitors, or their mode of administration to a subject with various types of cancer to treat the cancer. Claim 15 is drawn to a pharmaceutical composition comprising an RGS2 inhibitor in an amount effective to inhibit the interaction between an RGS2 protein and a Galpha protein in a cell of a cancer of a subject, wherein the Galpha protein is a Galpha-q protein, wherein the RGS2 inhibitor non-covalently interacts with turn-183 of human RGS2 defined by a first asparagine at residue 183 ("N183"), a second asparagine at residue 184 ("N184"), and a serine at residue 185 ("S185"), wherein N183 and N184 interact with a positively charged pharmacophore site and S185 interacts with a hydrogen-bond donor pharmacophore site, and their administration to a subject via oral, injection, or combinations thereof. Claim 19 is drawn to a method of inhibiting the interaction between an RGS2 protein and a Galpha protein in a cell comprising administering to the cell an RGS2 inhibitor in an amount capable of non-covalently interacting with the RGS2 protein, wherein the RGS2 inhibitor non-covalently interacts with turn-183 of human RGS2 defined by a first asparagine at residue 183 ("N183"), a second asparagine at residue 184 ("N184"), and a serine at residue 185 ("S185"), wherein N183 and N184 interact with a positively charged pharmacophore site and S185 interacts with a hydrogen-bond donor pharmacophore site.
The instant claims recite that an RGS2 inhibitor non-covalently interacts with turn-183 of human RGS2 defined by a first asparagine residue 183 (“N183”), a second asparagine residue 184 (“N184”), and serine at residue 185 (“S185”), wherein N183 and N184 interact with a positively charged pharmacophore site and S185 interacts with a hydrogen-bond donor pharmacophore site. The disclosure, however, does not identify a representative number of species within the RGS2 inhibitor genus to perform the claimed function of non-covalent interactions with the recited amino acid residues of the RGS2 protein with the pharmacophore site on the inhibitor, nor does the disclosure provide a structure-function relationship which would allow one of ordinary skill in the art to identify which structural moieties in the pharmacophore site of the RGS2 inhibitor species to perform the claimed function of non-covalently interacting with the specific amino acids of the RGS2 protein.
MPEP 2173.05(g) states that "A claim term is functional when it recites a feature 'by what it does rather than by what it is" and that "Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph."
The specification discloses a process by which compounds with simultaneous high binding affinity and selectivity to RGS2 that would perform an inhibitory function on the RGS2-Galpha-q protein-protein interaction were determined in Example 1 [0041]. The specification [0066] in Table 1, on pages 14 – 15 discloses compounds that act as RGS2 inhibitors, that are shown to have the pharmacophore site that would bind to the RGS2 protein. The specification also discloses that not all retrieved hits based on the pharmacophore model inhibited RGS2 function because matching molecules, despite having the groups required for inhibition, also have other functional groups that may cause them to bind different from expected [0064]. Therefore, Applicant has not sufficiently shown that any RGS2 inhibitor will perform the binding function. Accordingly, in view of the instant disclosure, one of ordinary skill in the art would be unable to envisage the necessary structure or the full genus of compounds that would have high binding affinity and selectivity to RGS2 that would perform an inhibitory function on the RGS2-Galpha-q protein-protein interaction.
McNabb et al (Emerging Roles of Regulator of G Protein Signaling 2 in (Patho) physiology, Mol. Pharmacol. 98: 751 – 760, December 2020).
McNabb teaches in the section on RGS2 as a Potential Cancer Target (pg. 756, col. 1, para. 2) differing outcomes in the up and down regulation of RGS2. McNabb summarizes the role of RGS2 protein in cancer - the mechanisms by which RGS2 may alter proliferation, migration, or invasion of cancer cells are currently unknown. Increased knowledge of all of these concepts will enhance our understanding of the diverse phenotypes related to RGS2 in different cancer types (pg. 757, col. 1, para. 3).
Deng et al (ZHX3 promotes the progression of urothelial carcinoma of the bladder via repressing of RGS2 and is a novel substrate of TRIM21, Cancer Science. 2021;112:1758–1771).
Deng teaches that zinc finger and homeobox 3 (ZHX3) represses RGS2 expression in urothelial carcinoma of the bladder (UCB) cells (pg. 1763, col. 2). Deng teaches that Knockdown of RGS2 restores the migration and invasion capacities of UCB cells with
ZHX3 knockdown (pg. 1763, col. 2), and ZHX3 could activate RhoA by repressing RGS2, and promotes UCB cell aggressiveness through the RGS2-RhoA pathway (pg. 1764, col. 1-2). Deng teaches in the clinical significance of ZHX3 and RGS2 in human patients with UCB that both low ZHX3 and high RGS2 expression had the best survival rate, and patients with high ZHX3 and low RGS2 expression had the worst prognosis (pg. 1767, col. 1). Deng further teaches that RGS2 can accelerate the intrinsic GTPase activity of Gα proteins and interfere with G protein-coupled receptor (GPCR) signaling pathway transduction. In the human genome, RGS2 is considered the most potent negative regulator of Gqα and attenuates Gqα-, Giα-, and Gsα-mediated pathways. To date, as the most potent negative regulator of Gqα, RGS2 has been reported to act as a tumor suppressor in certain human cancers, such as breast, prostate, ovarian, and bladder cancers.
Horvath (“Pharmacophore-based virtual screening”, Jurgen Bajorath (ed.), Chemoinformatics and Computational Chemical Biology, Methods in Molecular Biology, vol. 672, DOI 10.1007/978-1-60761-839-3_11, © Springer Science+Business Media, LLC 2011, pg. 268 – 298).
Horvath teaches the limitations of pharmacophore-based virtual screening as “The main problem with pharmacophore typing scheme is, however, that the complex site–ligand interaction mechanisms cannot be rigorously understood in terms of some six or so functional group types. There is a universal consensus among all the flagging schemes – pKa-based or not – on the issue that a carboxylate group (acceptor, anion) is pharmacophorically different, and thus not interchangeable with the hydrophobe –CF3. Yet, it is also well known that the Cyclooxygenase II binding site easily accommodates –CF3 groups in a carboxylate binding pocket. This is an example of the fundamental limitation of the pharmacophore concept, which, all its successes notwithstanding, represents an extremely sketchy and poor model of binding interactions. Also, the protonation state of a bound ligand may be, due to the influence of the binding pocket, different from the most populated state in solution. This effect cannot be taken into account by pure ligand-based approaches and is extremely difficult to model even if the structure of the binding pocket is known.” (pg. 275, para. 3).
Elsaka et al ((2026) Pharmacophore modeling: advances and pitfalls. Front. Mol. Biosci. 12:1760982).
Elsaka, a recent review on pharmacophore modeling, not a prior art to the instant application, talks about the pitfalls as both ligand-based and structure-based pharmacophore models offer valuable insights for hit identification, yet they are constrained by assumptions about molecular conformation and feature alignment (pg. 6, col. 1, para. 4), and structure-based pharmacophore models, while partially addressing the limitations of ligand-based approaches, are also susceptible to bias. Conformational restrictions inherent in the model can lead to binding mode bias, as the pharmacophore is constructed based on a specific co-crystallized ligand. However, many ligands may interact with the protein in alternative binding modes, which the model may not fully capture. Furthermore, chance continues to play a significant role in pharmacophore modeling (pg. 6, col. 2, para. 4).
Accordingly, the skilled artisan would be unable to envisage the structure of an inhibitor that would non-covalently interact with specific site of the RGS2 protein to further inhibit its interaction with Galpha protein given the current state of the pharmacophore-based screening methods, and to know that such inhibition will lead to the treatment of cancer in a subject. Therefore, it is not evident by the disclosure or the prior art, that the Applicant was in possession of a representative number of species of RGS2 inhibitor for performing non-covalent interactions with the specific binding site with the pharmacophore model claimed. Furthermore, as discussed above, there is no disclosed or art recognized correlation between structure and function which would allow for the predictable identification of RGS2 inhibitor to perform non-covalent interactions with turn-183 of human RGS2 that would lead to the treatment of cancer in a subject. Therefore, the instant claims do not meet the written description requirement under 35 USC 112(a).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 8, and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cho et al (RGS2-mediated translational control mediates cancer cell dormancy and tumor relapse, J Clin Invest. 2021;131(1):e136779).
Cho teaches that slow-cycling/dormant cancer cells (SCCs) have pivotal roles in driving cancer relapse and drug resistance. A mechanistic explanation for cancer cell dormancy and therapeutic strategies targeting SCCs are necessary to improve patient prognosis, but are limited because of technical challenges to obtaining SCCs. By applying proliferation-sensitive dyes and chemotherapeutics to non–small cell lung cancer (NSCLC) cell lines and patient-derived xenografts, Cho identified a distinct SCC subpopulation that resembled SCCs in patient tumors. These SCCs displayed major dormancy-like phenotypes and high survival capacity under hostile microenvironments through transcriptional upregulation of regulator of G protein signaling 2 (RGS2). Database analysis revealed RGS2 as a biomarker of retarded proliferation and poor prognosis in NSCLC. Cho showed that RGS2 caused prolonged translational arrest in SCCs through persistent eukaryotic initiation factor 2 (eIF2α) phosphorylation via proteasome-mediated degradation of activating transcription factor 4 (ATF4). Translational activation through RGS2 antagonism or the use of phosphodiesterase 5 inhibitors, including sildenafil (Viagra), promoted ER stress–induced apoptosis in SCCs in vitro and in vivo under stressed conditions, such as those induced by chemotherapy.
Cho teaches that RGS2 ablation by injection with a liposome-encapsulated
siRNA significantly suppressed the outgrowth of residual xenograft tumors by inducing apoptosis, as evidenced by IHC analysis of cleaved caspase-3 levels in the tumors (Figure 8, B and C). The siRNA-mediated RGS2 ablation also suppressed H460/PcR-mediated xenograft tumor growth (Figure 8D and Supplemental Figure 17A) (pg. 9, col. 2, para. 4). Cho teaches that the siRNA formulation for in vivo delivery using in vivo-jetPEI (Polyplus-Transfection SA) was prepared according to the manufacturer’s instructions. Briefly, 5 μg of siRNAs diluted in a sterile 5% glucose solution were complexed with in vivo-jetPEI at a ratio of 0.12 μL of in vivo-jetPEI per 1 μg of siRNAs. Formulated siRNAs were injected intratumorally twice a week (pg. 18, col. 2, para. 3).
Claims 13, 14, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Beladiya et al (Acute and 28-days subacute toxicity studies of Gαq-RGS2 signaling inhibitor, Laboratory Animal Research (2021) 37:17).
Beladiya teaches the synthetic compound Gαq-RGS2 signaling inhibitor,
(1-(5-chloro-2-hydroxyphenyl)-3-(4-(trifluoromethyl) phenyl)-1 H-1,2,4-triazol-5(4 H)-one) is a triazolone ring containing compound, and that the triazolone ring bearing compounds are emerging class of therapeutic target in the drug development. Recently, novel chemical entity containing triazolone ring, Ganetespib has been identified and extensively studied the anticancer activity of Ganetespib in the animals. In which
Ganetespib showed the anticancer activity in both in-vitro and in-vivo preclinical studies (pg. 1, col. 2, para. 2). Beladiya further teaches that the Gαq-RGS2 signaling inhibitor has demonstrated Gαq signaling inhibitor activity by acting at the intersection of RGS2 and G-αq proteins, resulting in attenuated the Gαq signaling which reduced calcium
fluxes and reduced muscle contraction (pg. 2, col. 1, para. 1). Beladiya teaches that single oral administration of Gαq-RGS2 signaling inhibitor up to dose of 2000 mg/kg in mice and repeated administration of Gαq-RGS2 signaling inhibitor at higher dose 100 mg/kg for 28 days in the rats is safe (Abstract).
Conclusion
Claims 1 – 20 are rejected. No claims are allowed.
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/JANAKI ANANTH MAHADEVAN/Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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