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
This application is a 371 PCT of JP2021/017019 filed 4/28/21.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed on 10/26/22.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
This application is currently being prosecuted with an effective filing date of 4/28/2021, because a certified English translation of the foreign application has not been provided.
Election/Restrictions
Claims 1-15 are pending. Applicant’s election without traverse of group I (claims 1-9 and 15) in the Remarks filed 3/10/26 is acknowledged. Applicant elects the species of “pancreatic cancer” and “a substance that reduces the expression of an MEX3B gene.” Claims 10-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Examiner notes that the Remarks filed 3/10/26 required clarification of the species election and attorney of record Dan Thomson Reg #43189 confirmed the species election in a phone correspondence on 3/25/26 to be “pancreatic cancer” and “a substance that reduces the expression of an MEX3B gene.” However, after further consideration the election of species for cancer treated is withdrawn.
Examination on the merits commences on claims 1-9, and 15.
Claim Objections
Claim 5 is objected to because it recites, “The prophylactic or therapeutic method agent according to claim 1.” However the word “agent” appears to be a typographical error, given all other claims are drawn to a “prophylactic or therapeutic method” and not “agent”.
Claim 8 is objected to because it recites “in combination with the substance that reduces expression of an MEX3B gene or an MEX3B protein or the substance inhibiting an MEX3B protein according to claim I.”, such that claim 8 is not in proper dependent form because it only requires the substance that reduces expression of claim 1 and not the method steps. Additionally, “claim I” appears to be a typographical error which should be replaced with “claim 1”.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 8 and 9 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8 recites, “in combination with the substance that reduces expression of an MEX3B gene or an MEX3B protein or the substance inhibiting an MEX3B protein according to claim I.”, such that claim 8 is not in proper dependent form because it only requires the substance that reduces expression of claim 1 and not the method steps of claim 1.” Therefore, claim 8 is rejected for failing to include all the limitations of the claim upon which it depends.
Claim 9 is also rejected under 35 USC 112 (d) by virtue of dependency on claim 8 without remedying the above issue.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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.
Claim 1-9, and 15 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 therapeutic treatment method for at least one cancer selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, and liver cancer, does not reasonably enable a prophylactic method of preventing said cancers. 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.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of claims
The claims are drawn to a method of a prophylactic or therapeutic method for at least one cancer selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, and liver cancer, the prophylactic or therapeutic method, comprising: administering, to a subject, a substance that reduces expression of an MEX3B gene.
Guidance from the Specification
National Cancer institute defines prophylaxis as preventing disease (pg 1, NCI, https://www.cancer.gov/publications/dictionaries/cancer-terms/def/prophylaxis, retrieved 3/30/26, printed as pages 1/1 to 1/1, 2026). Guidance from the specification is short with no working examples of cancer prophylaxis, i.e. preventing cancer disease.
The Specification teaches, in Examples 1 and 2 (Figures 1 and 2), MEX3b gaper antisense oligonucleotides induced growth inhibition of pancreatic cancer cells [0080]. The Specification teaches, in Example 3 and Figure 3, MEX3b gaper antisense oligonucleotides induced growth inhibition of non-small cell lung cancer cells [0085]. The Specification teaches, in Example 4 and Figure 4, MEX3b gaper antisense oligonucleotide induced growth inhibition of cholangiocarcinoma [0087]. The Specification teaches, in Example 5 and Figure 5, MEX3b gaper antisense oligonucleotides in combination with immune checkpoint inhibitors causing growth inhibition of colorectal cancer cells [0090]. The Specification teaches, in Example 6 and Figure 6, MEX3b gaper antisense oligonucleotides in combination with pyrimidine antimetabolite causing growth inhibition of pancreatic cancer cells [0093]. The Specification teaches, in Example 7 and Figure 7, MEX3b gaper antisense oligonucleotide induced growth inhibition of pancreatic cells [0095].
State of the Art
A thorough search of the related art demonstrates the genus of “cancer prophylaxis” is broad and diverse. At the time of the effective filing date, there were no known substances that completely prevented a subject from acquiring these diseases by using a substance embraced by the claimed method. The skilled artisan would look to the specification for teaching of prophylactic agents and would not find teaching for the making and using these types of agents. The observation of ameliorating or limiting cancer cell growth is not considered preventing the subject form cancer because the subject already has cancer and the disease is reduced, not prevented. Furthermore, other than contemplating making the agents and administering a genus of prophylactic agents and the working example showing that cancer cells are reduced in subjects at given time point, the specification of the application does not disclose how to use the claimed invention without an undue amount of experimentation. See Penny et. al., on the significant challenges of cancer prevention (abstract, pg 8837 col 1 para 1).
Taking this into consideration, the lack of related examples in the specification, the lack of knowledge in the art how to completely prevent cancer, and the large genus of prophylaxis recited in the claims, it is the conclusion that undue experimentation would be required to use the described invention with the entire genus of cancer prophylaxis.
Dependent claims
Claim 2-9, and 15 depend from claim 1 and do not further limit cancer prophylaxis, and therefore lack enablement for the reason outlined above for claim 1.
Claim Rejections - 35 USC § 112(a) – Written Description
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.
Claim(s) 1, 3-9, and 15 is/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.A3.(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.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
The claims are drawn to an “anticancer agent” as well as the elected species of “gene expression inhibitors.” The specification has not adequately described the entire genus of “anticancer agents” and “gene expression inhibitors” for the following reasons.
Size and Breadth of the Genus
The claims are drawn to anticancer agents and gene expression inhibitors. However, the claimed language does not sufficiently limit the structure of the gene expression inhibitors or anticancer agents, and therefore could encompass any means, directly or indirectly, for targeting a MEX3b gene as an anticancer agent or in combination with other anticancer agents in the treatment of a subject with a cancer. The genus of “anticancer agents” and “gene expression inhibitors” is extensive and diverse.
Species disclosed in the Specification
The Specification teaches, in Examples 1 and 2 (Figures 1 and 2), MEX3b gaper antisense oligonucleotides induced growth inhibition of pancreatic cancer cells [0080]. The Specification teaches, in Example 3 and Figure 3, MEX3b gaper antisense oligonucleotides induced growth inhibition of non-small cell lung cancer cells [0085]. The Specification teaches, in Example 4 and Figure 4, MEX3b gaper antisense oligonucleotide induced growth inhibition of cholangiocarcinoma [0087]. The Specification teaches, in Example 5 and Figure 5, MEX3b gaper antisense oligonucleotides in combination with immune checkpoint inhibitors causing growth inhibition of colorectal cancer cells [0090]. The Specification teaches, in Example 6 and Figure 6, MEX3b gaper antisense oligonucleotides in combination with pyrimidine antimetabolite causing growth inhibition of pancreatic cancer cells [0093]. The Specification teaches, in Example 7 and Figure 7, MEX3b gaper antisense oligonucleotide induced growth inhibition of pancreatic cells [0095].
Specification [0059-0061] further teaches anticancer agents include immune checkpoint inhibitors and a pyrimidine. The specification teaches examples of immune checkpoint inhibitors include agents that inhibits the function of an immune checkpoint molecule (e.g., binding between immune checkpoint molecules, such as binding between a receptor and its ligand). Examples of the immune checkpoint molecule include receptors, such as PD-1 and CTLA4, and ligands, such as PD-L1, PD-L2, and CD80/86. The immune checkpoint inhibitor include a substance (e.g., an antibody, an aptamer) that selectively (preferably specifically) binds to such an immune checkpoint molecule. Specific examples of the immune checkpoint inhibitor described include anti-PD-1 antibodies, anti-CTLA4 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, and anti-CD80/86 antibodies. The specification [0060] also teaches pyrimidine antimetabolites such as an agent that inhibits in vivo synthesis of nucleic acid or an agent that can be converted into an agent that inhibits in vivo synthesis of nucleic acid. Specific examples of the pyrimidine antimetabolite include gemcitabine (abbreviated as Gem), cytarabine, capecitabine, TS-1 (registered trademark), tegafur-gimeracil-oteracil potassium (S-1), tegafur-uracil, and fluorouracil.
Although the Specification includes in the Examples reduced pancreatic cancer cell growth from MEX3b gapmers, no other nucleic acid inhibitor of MEX3b gene, such as the claimed RNAi or miRNA (claim 4), was demonstrated to reduce MEX3b expression in any cancer, either alone or in combination with another anticancer agent.
Species Disclosed in the Art
The genus of “anticancer agents” as described in claims 4, 5, 6, 8, 9, and 15 is broad and diverse in the art. Anticancer agents are classified by their mechanism of action into several key categories: alkylating agents damage DNA to prevent cell reproduction, antimetabolites mimic essential nutrients to starve cancer cells, antitumor antibiotics interfere with DNA replication, plant alkaloids or mitotic inhibitors disrupt cell division, topoisomerase inhibitors prevent DNA repair, hormonal therapies block hormones that fuel tumor growth, and targeted therapies or immunotherapies specifically attack molecular targets or boost the immune system.
Regarding anticancer agents which can target cancer, Fournie et. al., teaches administering to the subject with cancer a therapeutically effective amount at least one inhibitor of stress granule formation that reduces the expression of an immune checkpoint protein, wherein said administration enhances the proliferation, migration, persistence and/or activity of cytotoxic T lymphocytes (CTLs) in the subject (pg 3 line 20). Fournie teaches inhibiting stress granule formation by inhibitors of related genes including MEX3b as protein that is structurally involved in formation of stress granules (pg 16 line 10; Fournie (Fournie, J., WO 2020070053 A1, published 4/9/20)).
The genus of “gene expression inhibitor” is broad and diverse in the art and includes anticancer agents. Other types of gene expression inhibitors include small molecules that block transcription factors, epigenetic modulators, RNA-based interference (siRNA/miRNA) that degrades messenger RNA, antisense oligonucleotides that disrupt translation, and engineered nucleases (like CRISPR/Cas) that silence DNA, all acting to reduce protein production. Furthermore, gene expression inhibitors can be single stranded or double stranded, DNA or RNA, modified with 2’, 5’, and 3’ modifications. Single stranded gene expression inhibitors may have a double stranded region, and double stranded gene expression inhibitors may have a single stranded region. Some gene expression inhibitors include structural genes, genes containing control and termination regions, self-replicating systems such as viral or plasmid DNA, single-stranded and double-stranded siRNA and other RNA interference reagents (RNAi or iRNA agents), shRNA, antisense oligos. Nucleotide, ribozyme, microRNA, microRNA mimetic, supermir, aptamer, antimir, antagomir, Ul adapter, triplex-forming gene expression inhibitor, G-quadruplex gene expression inhibitor, RNA activator, immunostimulatory oligo, and decor gene expression inhibitors, among others.
Regarding gene expression inhibitors as anticancer agents of MEX3b, Huang et. al., teaches knockdown of MEX3B by shRNA in melanoma cell lines (Supplementary Fig. S4A and S4B) significantly increased the tumor apoptosis induced by autologous tumor-infiltrating lymphocytes TILs (pg 3371 col 1 para 1, Supplementary Fig. S4C and S4D; Huang, Lu, et al. "The RNA-binding protein MEX3B mediates resistance to cancer immunotherapy by downregulating HLA-A expression." Clinical Cancer Research 24.14 (2018): 3366-3376.).
Regarding nucleic acid gene expression inhibitors as gene modulators, Wang teaches that the ability to predict nucleic acid hybridization (i.e., via “rational design”) is generally limited to the use of unmodified nucleic acids, and that many broadly employed chemical modifications to DNA and RNA have not been included in predictive models (pg. 2, para. 1 and pg. 14, para. 1; Wang et al., 2022, PLOS ONE, 17(5), e0268575). Wang teaches thermodynamic models of hybridization for nucleic acid molecules with phosphorothioate linkages, where each linkage modification decreases duplex stability (pg. 13, para. 4) Wang teaches that backbone and sugar ring modifications, in conjunctions with nucleotide sequence, would likely require a combinatorially large (and synthetically intractable) set of duplexes to fully characterize (pg. 13, para. 3). Therefore, it is unpredictable that nucleic acid hybridization without a rational design incorporating thermodynamics, phosphorothioate linkages or backbone/sugar ring modifications would successfully promote nucleic acid binding and predictable gene expression inhibition.
As the prior art establishes, there is substantial variation within the genus of anticancer agents and gene expression inhibitors. Applicant fails to adequately describe a sufficient variety of species to reflect the variation within the genus. Furthermore, the description of a representative number of species from the specification is not representative of the entire genus. Given the lack of guidance in the art and specification regarding common structural characteristics shared by members of the genus of “anticancer agents” and “gene expression inhibitor” and lack of predictability of undefined modifications, secondary structure, or function, the specification disclosure is not sufficient to show that the Applicant was in possession of the claimed “anticancer agent” and “gene expression inhibitor” at the time the invention was filed.
Dependent claims
Claim 2 further limits the substance which reduces MEX3b gene expression as an antisense oligonucleotide such as in the Specification working examples, therefore claim 2 is not included in the Written Description rejection. Examiner notes that “anticancer agent” is not a limitation of claim 1 or 2.
Although claim 6, 9, and 15 further limit the anticancer agent to immune checkpoint inhibitors and pyrimidine antimetabolite, these claims do not resolve issues related to the broad genus of inhibitors of MEX3b gene expression and therefore still lack adequate written description for the reasons outlined for claim 1. Although claim 3 further limits the substance which reduces MEX3b gene expression as having RNAi activity or an miRNA, working Examples in the Specification are limited to only MEX3b gapmers therefore claim 3 still lacks adequate written description for the reason outlined above for claim 1.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-3, 5, 6, 8, 9, and 15 is/are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Fournie (Fournie, J., WO 2020070053 A1, published 4/9/20).
Regarding claim 1, Fournie teaches enhanced treatment of a subject with cancer by administering a therapeutically effective amount at least one inhibitor of stress granule formation where the administration enhances the proliferation, migration, persistence and/or activity of cytotoxic T lymphocytes (CTLs) in the subject (pg 30 line 2). Fournie teaches inhibiting stress granule formation by inhibitors of related genes including MEX3b as protein that is structurally involved in formation of stress granules (pg 16 line 10 and pg 33 line 2). Fournie teaches the term "inhibitor of expression" refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene including siRNA, an antisense oligonucleotide or a ribozyme, among others, for preventing protein translation of the target gene (pg 16 line 23). Fournie teaches applying this method to a variety of cancers including liver cancers (hepatocellular carcinoma), lung cancers, and melanoma (pg 30 line 20).
Regarding claims 2 and 3, Fournie teaches inhibiting stress granule formation by inhibitors of related genes including MEX3b as protein that is structurally involved in formation of stress granules (pg 16 line 10 and pg 33 line 2). Fournie teaches the term "inhibitor of expression" refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene including siRNA, an antisense oligonucleotide or a ribozyme, among others, for preventing protein translation of the target gene (pg 16 line 23). Examiner is interpreting an antisense oligonucleotide or siRNA inhibitor of expression of MEX3b as having a sequence complementary to a partial contiguous sequence of the MEX3B gene.
Regarding claim 5, Fournie further teaches the inhibitor of stress granule formation is administered to the patient in combination with at least one immune checkpoint inhibitor, such as an antagonist of PDL1 or PD-1 (pg 33 line 15), i.e. an anticancer agent other than the substance that reduces expression of an MEX3B gene or an MEX3B protein or the substance inhibiting an MEX3B protein.
Regarding claim 6, Fournie further teaches the above applied to claims 1 and 5, i.e. the inhibitor of stress granule formation is administered to the patient in combination with at least one immune checkpoint inhibitor, such as an antagonist of PDL1 or PD-1 (pg 33 line 15).
Regarding claim 8, Fournie teaches the above applied to claims 1 and 5, i.e. the inhibitor of stress granule formation including MEX3b as protein that is structurally involved in formation of stress granules (pg 16 line 10 and pg 33 line 2) is administered to the patient with lung cancer (pg 30 line 20) in combination with at least one immune checkpoint inhibitor, such as an antagonist of PDL1 or PD-1 (pg 33 line 15).
Regarding claim 9 and 15, Fournie teaches the above applied to claims 1 and 5, i.e. the inhibitor of stress granule formation including MEX3b as protein that is structurally involved in formation of stress granules (pg 16 line 10 and pg 33 line 2) is administered to the patient with lung cancer (pg 30 line 20) in combination with at least one immune checkpoint inhibitor, such as an antagonist of PDL1 or PD-1 (pg 33 line 15).
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.
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 7 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Fournie (Fournie, J., WO 2020070053 A1, published 4/9/20), as applied to claim 1, in view of Huang (Huang, Lu, et al. "The RNA-binding protein MEX3B mediates resistance to cancer immunotherapy by downregulating HLA-A expression." Clinical Cancer Research 24.14 (2018): 3366-3376) and Schoenfeld (Schoenfeld, Adam J., and Matthew D. Hellmann. "Acquired resistance to immune checkpoint inhibitors." Cancer cell 37.4 (2020): 443-455).
Regarding claim 7, the teachings of Fournie as applied above are incorporated here. Although Fournie teaches applying the MEX3b inhibition cancer therapeutic method to a variety of cancers including liver cancers (hepatocellular carcinoma), lung cancers, and melanoma (pg 30 line 20), Fournie does not specify treating non-small cell lung cancer specifically.
However, Schoenfeld teaches non-small cell lung cancer (NSCLC) is refractory to immunotherapy such as the immune checkpoint inhibitor nivolumab and where NSCLC is specifically associated with acquired resistance to immunotherapies (Table 1, Figure 1, page 443 col 1 para 1), making non-small cell lung cancer a target for an anti-cancer strategy which decreases immunotherapy resistance. As an example, Schoenfeld teaches PDL-1 immunotherapy blockade where just one of six patients with non-small cell lung cancer (NSCLC) experienced response in a single target lesion (pg 443 col 1 para 1) and that certain lung cancer patients in particular demonstrate high acquired resistance (~80%) to ICI immunotherapy (pg 446 para 2).
Huang teaches MEX3B mediates resistance to cancer immunotherapy by binding to the 30 UTR of HLA-A to destabilize the HLA-A mRNA and thus downregulate HLA-A expression on the surface of tumor cells, thereby making the tumor cells unable to be recognized and killed by T cells (abstract). Huang teaches higher MEX3B expression is correlated with worse response to anti–PD-1 immunotherapy (pg 3375 col 1 para 2). Huang teaches knockdown of MEX3B by shRNA in melanoma cell lines (Supplementary Fig. S4A and S4B) significantly increased the tumor apoptosis induced by autologous tumor-infiltrating lymphocytes TILs (pg 3371 col 1 para 1, Supplementary Fig. S4C and S4D).
Therefore, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have altered Fournie’s method, enhancing lung cancer treatment by combining PDL1 checkpoint inhibitors with inhibitors of genes including MEX3b that reduce stress granule formation, to also include that MEX3b inhibition to further target non-small cell lung cancer (NSCLC). It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that inhibiting MEX3b gene expression would further enhance the anticancer combination methodology of Fournie because Huang teaches; 1)MEX3b mediates resistance to cancer immunotherapy; 2) MEX3B overexpression correlates with worse anti-PD-1 immunotherapy outcomes; and 3) knockdown of MEX3b with shRNA demonstrated improved autologous T-cell antitumor activity. It would have been predictable that Fournie’s modified method would be effective specifically in non-small cell lung cancer because Schoenfeld teaches non-small cell lung cancer (NSCLC) is refractory to immunotherapy such as the immune checkpoint inhibitor nivolumab and where NSCLC is specifically associated with acquired resistance to immunotherapies. Therefore, the skilled artisan would be motivated to enhance the immunotherapy effectiveness in NSCLC by inhibiting expression of MEX3b to overcome the resistance of NSCLC to immune checkpoint immunotherapy and enhance overall anticancer efficacy.
Regarding claim 4, Fournie is silent as to whether the treated cancer is refractory to an anticancer agent. However, as described above, applied to claim 7, Schoenfeld teaches non-small cell lung cancer (NSCLC) is refractory to immunotherapy such as the immune checkpoint inhibitor nivolumab and where NSCLC is specifically associated with acquired resistance to immunotherapies (Table 1, Figure 1, page 443 col 1 para 1), making non-small cell lung cancer a target for an anti-cancer strategy which decreases immunotherapy resistance.
Therefore, It would have been obvious to one skilled in the art before the effective filing date of the claimed invention that Fournie’s modified method of treating non-small cell lung cancer (NSCLC), as deemed obvious in the §103 rejection above applied to claim 7, would have included a cancer refractory to an immune checkpoint inhibiting anticancer agent because Schoenfeld teaches non-small cell lung cancer (NSCLC) is refractory to immunotherapy such as the immune checkpoint inhibitor nivolumab and where NSCLC is specifically associated with acquired resistance to immunotherapies. Thus, it would have been predictable that the NSCLC treated was a cancer refractory to an immune checkpoint inhibitor (ICI) immunotherapy. The skilled artisan would be motivated to enhance the immunotherapy effectiveness in an ICI refractory NSCLC by inhibiting expression of MEX3b to overcome the resistance of NSCLC to immune checkpoint immunotherapy and enhance overall anticancer efficacy.
Conclusion
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN CHARLES MCKILLOP whose telephone number is (703)756-1089. The examiner can normally be reached Mon-Fri 8:30-5:30.
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 on (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.
/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637