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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12 May 2026 has been entered.
Claims 1, 31, and 60 have undergone amendments. Claim 56 is cancelled. Claims 63-67 are newly added. Thus, Claims 1, 7, 11, 13, 14, 22, 23, 25, 27, 29, 31, 32, 35, 53-55, and 57-67, submitted 12 May 2026, represent all claims currently under consideration.
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.
Information Disclosure Statement
One Information Disclosure Statement (IDS), submitted on 12 May 2026, is acknowledged and has been considered.
Response to Arguments
The 35 U.S.C. § 112(a) rejection of Claims 1, 7, 11, 13, 14, 22, 23, 27, 29, 32, 35, 55-59, 61, and 62 is maintained. While Applicant has overcome the rejection for the prevention of cancer, the rejection is still maintained as the claims are still directed to the treatment of any form of solid tumor. Not all solid tumors are sensitive to inhibition of TLR2, as the prior art cited in the previous rejection states, as well as the art Applicant has included in the rebuttal to the 35 U.S.C. § 103 and non-statutory double patenting rejections demonstrates.
The 35 U.S.C. § 103 rejection of Claims 1, 7, 11, 13, 14, 22, 23, 27, 29, 32, 35, 55-59, 61, and 62 over Bartlett in view of Jackson 2012, as well as over Jackson 2019 in view of Jackson 2012 are each withdrawn. Applicant argues that at the time of filing, there were contradictory teachings to the assertions in both Jackson references regarding cancer treatments with TLR2 agonists, with evidence demonstrating that agonism can promote cancer growth. Further, both Jackson references contain no data demonstrating efficacy in treating cancer. The Examiner finds these arguments to be persuasive.
The provisional non-statutory patenting rejection of Claims 1, 7, 11, 13-14, 22-23, 27, 29, 32, 35, 55-59, and 61-62 over Claims 1, 4, 16, and 18-20 of co-pending Application No. 18/931,434 (Amended Claims of 30 October 2024) (‘434) is maintained. Applicant argues that at the time of filing of the examined application, there was clear evidence that TLR2 agonism, while being able to stimulate the innate immune system, was unable to treat cancer. The Examiner does not find this argument to be persuasive. The claim at issue which results in this being obvious is the limitation of “treating and/or preventing a disease or condition associated with the TLR2 receptor”. The cancers which are to be treated using the compounds of the examined application are associated with the TLR2 receptor. Thus, the co-pending application necessarily encompasses the methods of the examined application.
Claim Objections
Claim 64 is objected to because of the following informalities: The Examiner believes that “hepatoma/cholongio” should read “hepatoma/cholangiocarcinoma”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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, 7, 11, 13-14, 22-23, 25, 27, 29, 31, 32, 35, 53-55, 57-59, and 61-67 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 the treatment or minimization of progression of certain types of solid tumor wherein TLR2 is downregulated or dysregulated, it does not reasonably provide enablement for treatment of all forms of cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed towards a method of treating cancer comprising administering to a patient in need a therapeutically effective amount of a compound of Formula (I). The compounds of Formula (I) are TLR2 agonists. Thus, the claims are directed to a method which can be used for the treatment of any cancer, by agonizing TLR2 using the compounds of the invention.
The state of the prior art and the predictability or unpredictability of the art:
Pahlavanneshan (Journal of Immunology Research, 2021 May 22; 2021:9912188) provides a review of toll-like receptors (TLRs) in cancer and current treatment strategies targeting these receptors. TLRs are expressed in a variety of immune cell types involved in tumor immunity, and there is data on the pharmacological targeting of TLR using agonist molecules that boost antitumor immune responses. A recent body of research also points to the systemic administration of TLR antagonists (Abstract). These receptors are expressed on a variety of cells, including innate immune system cells such as macrophages, neutrophils, dendritic cells, natural killer cells, and mast cells, as well as the adaptive immune system (T and B lymphocytes), stromal cells, and different types of tumor cells (Introduction). These immune cells are found throughout the tumor microenvironment, and play key roles in cancer immunity. For example, macrophages can function as tumor-protective M1 or tumor-promoting M2 subtypes. TLR3 activation can revert M2 to M1. Various types of TLR agonists are being developed including natural microbial components or synthetic compounds and being used in anti-cancer therapy. These agents are considered immune-stimulating factors which enhance TLR signaling and activate an innate immune response which results in long-lasting adaptive immunity. These molecules can stimulate cytotoxic lymphocytes, NK cells, and dendritic cells, and can also be used as vaccine adjuvants to increase the immune response. TLR2 agonists such as Pam3Cys have been used for bladder cancer. Although current studies have shown the proof of concept for the application of TLR-targeted drugs for cancer treatment, given the variations in tumor immunophenotypes, it is likely that cancer type and microenvironment condition among other factors may affect the clinical outcome of TLR-targeting immunotherapies. These differences need to be addressed especially when preclinical animal experiments are conducted. Rolfo (Precision Oncology, 7: 26, 2023) provides a review of TLR agonists that are being evaluated clinically as new therapies for solid tumors. TLR agonists have the potential to convert “cold tumors” to “hot tumors”, making TLRs potential targets for cancer therapies (Abstract). As a family, TLRs have been implicated in both cancer progression and suppression, with the effects of individual receptors varying by tumor histology. The anti-tumor effects of TLRs are mediated by the secretion of pro-inflammatory cytokines and the induction of tumor cell death, while their pro-tumor effects include facilitating cancer cell proliferation, survival, and metastasis, as well as immunosuppression. TLRs can also stimulate regulatory T-cells, which further contribute to the creation of a tumor-permissive immune environment. The antithetical effects of TLRs have been attributed to variations in the response and expression of individual receptors by tumor cells and cells in the tumor microenvironment. As a consequence, it is not possible to regard all TLRs and tumor types as equal; rather, it is necessary to parse out the role of a particular TLR in a given treatment setting, as some patients may derive greater clinical benefit from a TLR antagonist and others from a TLR agonist (Role of TLRs in cancer). Given the conflicting roles of different TLRs and of the same TLR in different tumor types, novel clinical study designs, namely adaptive designs, may be of value in effectively evaluating the efficacy and safety of novel TLR agonists (Conclusions). Yamakazi (PLoS ONE, 2011, 6:(4):e18833) (cited by Applicant in response) reported that subcutaneous or intraperitoneal administration of the TLR2 agonist Pam2CysSK4 and MALP2 have no anti-tumor activity and IL-10 and Tregs. Maruyama (2015, 457:445e450) (cited by Applicant in response) reported that intravenous administration of Pam2CysSK4 promotes myeloid derived suppressor cells. Kim (Nature, 2009, 47:102-106) (cited by Applicant in response) suggested that endogenous TLR2/6 agonists derived from cancer cells may enhance cancer metastasis. Finally, Liu (International Immunopharmacology, 2018, 59: 375-383) (cited by Applicant in response) performed a study which suggested that TLR2 stimulation may promote colorectal cancer cell growth via PI3K/Akt and NFkB signaling. In view of these teachings, not all cancers can be successfully treated in this manner, as the prior art indicates that each cancer has specific tumor microenvironments with differing expression patterns of TLRs and presence of the cells within the tumor itself, and there is currently no known treatment that can be used to treat all forms of cancer.
The relative skill of those in the art:
The artisan would generally have an advanced degree related to the treatment or study of various cancers; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to use the claimed compounds to treat all forms of cancer, as not all forms of cancer are sensitive to treatment by modulating the innate immune system, specifically, through agonizing TLR2. Further, there is yet to be evidence of a therapeutic which can be used as a cancer panacea.
The amount of direction or guidance presented and the presence or absence of working examples:
The specification provides experimental data demonstrating the efficacy of the compounds of the invention in the treatment of certain cancers. Example 1 (Page 112) demonstrates that compound A101 has in vivo efficacy in xenograft mouse models of colon carcinoma (MC38 cells), melanoma (B16F10 cells), and breast cancer (4T1.2 cells). Example 2 (Page 115) demonstrates compound A108 is effective in treatment of a murine model of colon carcinoma (MC38 cells). Example 3 (Page 115) demonstrates that compound A108 is effective in treatment of a murine model of fibroblastoma (WEHI164 cells). Examples 4 and 5 (Page 116) show efficacy of compound A108 in reducing lung metastasis in murine models of colon and lung cancer. Example 6 (Page 116) provides data showing efficacy of other compounds of the invention in murine models of colon cancer. The specification does not provide data demonstrating efficacy in the treatment of all forms of cancer.
The quantity of experimentation necessary:
Considering the state of the art as described above, in particular with regards to the lack of a panacea for the treatment of cancer due to the heterogenous nature of the disease, and the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims.
Claim Rejections - 35 USC § 112(b)
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 31 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. The claim is indefinite because the transitional phrases “comprising” and “consisting of” each differently define the scope of a claim with respect to what unrecited additional components or steps, if any, are excluded from the scope of the claim. The transitional term “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or methods steps. The transitional phrase “consisting of” excludes any element, step, or ingredient not specified within the claim. The use of both of these phrases renders the claim indefinite because it is unclear if any additional, unrecited elements are included in the definition of the moiety A (See MPEP § 2111.03 I, II). There is no description of what other structures can be included in this partial structure, causing the metes and bounds of the claim to be undefined, and therefore, indefinite. The Examiner suggests removing “comprising” to overcome this rejection.
Claim 64 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 64 is indefinite because the claim lists several plural forms of cancer, such as “seminomas” and “bone tumors”. It is unclear if the patient must have more than one of these tumors in order for the method to be practiced as the claim also includes several singular forms of cancer (“small round cell tumor” for example). The Examiner suggests placing all cancers/tumors in the singular form to overcome this rejection.
Claim 65 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 65 is indefinite because the claim is written as treating “colon cancer, fibroblastoma, breast cancer, and lung cancer in a subject” (emphasis added). It is unclear if the patient must have all four forms of these cancer for the method to be practiced, or if the cancer is one selected from this group. The Examiner suggests replacing “and” with “or” to overcome this rejection.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 7, 11, 13-14, 22-23, 25, 27, 29, 31, 32, 35, 53-55, 57-59, and 60-67, provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 16, and 18-20 of copending Application No. 18/931,434 (Amended Claims of 30 October 2024) (‘434) (reference application).
Claim 1 of ‘434 is directed to a compound of Formula (VII)
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56
524
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wherein A has the structure
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435
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; Y is
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; n is 10 to 100, m is 1, 2, 3, or 4; each g is independently 10-18; p is 2, 3, or 4; q is null or 1; one of R1 and R2 is hydrogen and the other is H, CH2OH, CH2CH2OH, CH(CH3)OH, CH2OPO(OH)2, CH2C(=O)NH2, CH2CH2C(=O)OH, and CH2C(=O)OR8, wherein any of the alkyl hydrogens can be replaced with halogen; R6 and R7 are independently selected from H, straight or branched C1-C4 alkyl, and -C(=O)CH3; R8 is H or straight or branched C1-C6 alkyl; R9 and R10 are independently selected from -NH-, -O-, and bond; z is 1 or 2; X is S or S(=O); wherein when q is 1, R3 is -NH2 or -OH; wherein when q is 0, R3 is H; L is null or consists of 1 to 10 units wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula
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wherein R4 is H and R5 is the side chain or second hydrogen of the amino acid. Claim 4 claims the compound of claim 1 wherein A is Pam2Cys
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. Claim 16 claims the compound of Claim 1 wherein the compound is the R diastereomer around the following chiral center
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and/or the L-diastereomer of the compound around the following chiral center
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and/or the L-diastereomer around the following
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. Claim 18 claims the compound of Claim 1 that is
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, which is identical to the compound claimed in the examined application. Claim 19 claims a composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient. Claim 20 claims a method of treating a subject by raising an innate immune response in a subject, and/or preventing a disease caused by an infectious agent in a subject and/or treating or preventing a disease or condition associated with the TLR2 receptor comprising administering a therapeutically effective amount of a compound of Claim 1. The method of treating cancer in the examined application raises an innate immune response, and is used to treat a disease which is associated with the TLR2 receptor.
Regarding Claim 60, ‘434 does not disclose a kit comprising a compound of Formula (I) and instructions for its use in a method of treating or minimizing progression of a solid tumor in a subject. However, it would be obvious to one of ordinary skill in the art to combine a compound of Formula (I) with instructions for use as the artisan would recognize that these compounds function as TLR2 agonists, which as described previously, encompasses the treatment of cancers which are associated with the TLR2 receptor. The artisan would be motivated to combine the compounds with instructions for ease of use for the practitioner to ensure that the therapeutic is delivered properly.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1, 7, 11, 13-14, 22-23, 25, 27, 29, 31, 32, 35, 53-55, 57-59, and 60-67 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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/P.M.R./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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