This Office Action supersedes the non-final Office Action mailed on January 7, 2026.
DETAILED ACTIONNotice 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 .
Application Status and Election
Claims 1, 4, 5, 7, 8, 10-14, and 16-20 are pending. Applicant’s election without traverse of group I (claims 1-9 and 15) in the Remarks filed 3/10/26 remains acknowledged. Examiner includes claim 10 in the elected group under consideration, as no longer a search burden. Claims 11-14 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 4, 5, 7, 8, 10, 11, and 13 are amended.
Claims 2, 3, 6, 9, and 15 are canceled.
New claims 16-20 are added.
Examination on the merits commences on claims 1, 4, 5, 7, 8, 10, and 16-20.
Applicant's request for reconsideration of the finality of the rejection of the last Office action is persuasive and, therefore, the finality of that action is withdrawn.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s amendments and arguments have been thoroughly reviewed but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 112(d) - NEW
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.
Claim 19 and 20 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 19 recites, “The method according to claim 1, wherein the substance is:(1) an antisense oligonucleotide having a sequence complementary to a partial contiguous sequence of the MEX3B gene or having a sequence complementary to a partial contiguous sequence of an expression control region of the MEX3B gene and being capable of inhibiting expression of the MEX3B gene, or (2) a nucleic acid having RNAi activity, wherein the nucleic acid having RNAi activity comprises a partial contiguous sequence of a coding or untranslated region of an RNA sequence transcribed from the MEX3B gene or comprises a sequence complementary to the partial contiguous sequence and is capable of inhibiting expression of the MEX3B gene.” Claim 19 is a new claim which recites the same limitations of newly amended claim 1. Therefore, claim 19 is rejected for failing to further limit the subject matter of the claim upon which it depends.
Claim 20 recites, “method according to claim 8, wherein the substance is:(1) an antisense oligonucleotide having a sequence complementary to a partial contiguous sequence of the MEX3B gene or having a sequence complementary to a partial contiguous sequence of an expression control region of the MEX3B gene and being capable of inhibiting expression of the MEX3B gene, or (2) a nucleic acid having RNAi activity, wherein the nucleic acid having RNAi activity comprises a partial contiguous sequence of a coding or untranslated region of an RNA sequence transcribed from the MEX3B gene or comprises a sequence complementary to the partial contiguous sequence and is capable of inhibiting expression of the MEX3B gene.” Claim 20 is a new claim which recites the same limitations of newly amended claim 8. Therefore, claim 20 is rejected for failing to further limit the subject matter of the claim upon which it depends.
Claim Rejections - 35 USC § 103 – NEW
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.
Claim(s) 1 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Fournie of record (Fournie, J., WO 2020070053 A1, published 4/9/20), as applied to claim 1, in view of Yang (Yang, Yan, et al. "The RNA-binding protein Mex3B is a coreceptor of Toll-like receptor 3 in innate antiviral response." Cell research 26.3 (2016): 288-303. (Year: 2016).), and Akiyama (Akiyama, T., JP-WO2018008750-A1) and Huang of record (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 claims 1 and 19, 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 the limitations of canceled claims 2 and 3 incorporated into claim 1, 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.
Fournie does not provide working examples of MEX3b inhibition in the treatment method of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, liver cancer, or non-small cell lung cancer. Fournie also does not directly evidence that MEX3b is specifically associated with the formation of a stress granule. However, Yang teaches MEX3b is known to be associated with the formation of stress granules and Akiyama and Huang teach mechanisms of MEX3b influence in the pathophysiology of various cancers such that a skilled artisan would find it predictable to include MEX3b as a target gene involved in the formation of stress granules for the treatment of lung cancer. Specifically, Yang teaches Mex3B is an RNA-binding protein with two tandem KH domains in its N-terminal region and a C-terminal RING-finger domain and that the adaptor protein 14-3-3 binds to serine 462-phosphorylated Mex3B to stabilize Mex3B and regulates its localization to stress granules (SGs) and processing bodies (PBs) (pg 293 col 1 para 2).
Akiyama teaches treatment of diseases caused by IL-6, IL-13, TNF, G- CSF, CXCL1, CXCL2, or CXCL5 by reducing the expression of MEX3B genes or MEX3B proteins [0010]. Akiyama teaches the functions of MEX3B proteins include binding to various mRNAs such as IL-6, IL-13, TNF, G - CSF,CXCL1,CXCL2 , and / or CXCL5 to control the functions of these mRNAs (i.e., translation into proteins), or functions of regulating the expression of IL-6, IL-13, TNF, G - CSF,CXCL1,CXCL2 , and / or CXCL5 and use of such MEX3B inhibitors for administration in the treatment of diseases related to decreased expression of L-6, IL-13, TNF, G - CSF,CXCL1,CXCL2 , and / or CXCL5 including breast and ovarian cancer [0015].
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).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to include targeting the MEX3b gene as Fournie disclosed in Fournie’s targeting method of genes involved in stress granule formation to treat various cancers. 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 the MEX3b gene would predictably be a gene involved in granule formation because Yang describes MEX3b as involved in granule formation. It would have been predictable that a skilled artisan would be motivated to employ RNAi therapeutics to target the MEX3b gene within Fournie’s method in order to facilitate the treatment of subjects with various cancers such as lung cancer because Akiyama and Huang teach specific mechanisms of MEX3b influence in the pathophysiology of cancer with MEX3b inhibition as a target therapeutic, predictably applied to treat cancers such as lung cancer among others.
Claims 4, 5, 7, 8, 10, 16-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Fournie of record (Fournie, J., WO 2020070053 A1, published 4/9/20), in view of Yang (Yang, Yan, et al. "The RNA-binding protein Mex3B is a coreceptor of Toll-like receptor 3 in innate antiviral response." Cell research 26.3 (2016): 288-303. (Year: 2016).), and Akiyama (Akiyama, T., JP-WO2018008750-A1) and Huang of record (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), as applied to claim 1, in further view of Schoenfeld of record (Schoenfeld, Adam J., and Matthew D. Hellmann. "Acquired resistance to immune checkpoint inhibitors." Cancer cell 37.4 (2020): 443-455).
Regarding claims 4, 5, and 7, the teachings of Fournie, Yan, Akiyama, and Huang, as applied above to claim 1 are incorporated here. Fournie’s method, deemed obvious to target MEX3b inhibition by the §103 rejection above, further teaches the inhibitor of stress granule formation such as MEX3b as protein that is structurally involved in formation of stress granules 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).
Fournie teaches the method applied to lung cancers but is silent as to whether the treated cancer is refractory to an anticancer agent such as in non-small cell lung cancer. 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 predictable target for an anti-cancer strategy which decreases immunotherapy resistance, such as disclosed in Fournie’s method.
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 combination 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 independent claim 8, the limitations of claim 8 as amended are a combination of the limitations of claims 4, 5, and 7, and are obvious given the §103 rationale provided above applied to claims 4, 5, and 7.
Regarding new claim 20 which depends from claim 8, the limitations of claim 20 are a combination of the limitations of claims 4, 5, and 7, and are obvious given the §103 rationale provided above applied to claims 4, 5, and 7.
Regarding independent claim 10, the combination drug substance that reduces expression of an MEX3B gene with an adjunct anti-cancer agent such as an ICI is obvious given the §103 rationale provided above applied to claims 4, 5, and 7.
Regarding claim 16, 17, and 18, Fournie teaches applying this method to a variety of cancers including liver cancer (hepatocellular carcinoma) (pg 30 line 20). Fournie’s method discloses combination MEX3b inhibition with adjuvant immune checkpoint inhibitor (ICI) administration to enhance therapeutic effectiveness. It would have been obvious to the skilled artisan that a predictable target cancer such as the disclosed liver cancer would be a refractory cancer resistant to existing ICI given the method as a combination therapy targeting immune checkpoint proteins for enhanced immune co-therapy.
Response to Arguments
Applicant’s arguments (Remarks pages 6-10) are directed to the withdrawn §§§ 112a, 112d, and 102 rejections of record. Therefore, the arguments are moot.
Conclusion
No claims are allowed.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
