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 .
DETAILED ACTION
Status of claims
The amendment filed on Dec. 2, 2025 is acknowledged. Claims 2-13, 15-16, 19-20, 22-26, 34-49, and 51 have been canceled and claims 29 and 31-33 have been withdrawn. Claims 1, 14, 17-18, 21, 27-28, 30, 50, and 52-55 are under examination in the instant office action.
Applicants' arguments, filed on Dec. 2, 2025, have been fully considered but they are moot in view of new ground of rejections which are necessitated by newly added limitation. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied in view of amendments. They constitute the complete set presently being applied to the instant application.
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.
Claims 1, 14, 17-18, 21, 27-28, 30, 50, and 52-55 are 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 pre-AIA the applicant regards as the invention.
Claim 1 as amended recites “the treatment comprises sensitizing tumor cells expressing SIK3 to a cell-mediated immune response, wherein the sensitizing comprises inhibiting SIK3”. However, the preamble only recites “[A] method for the therapeutic treatment of a solid tumor in a subject”, but does not require that the solid tumor has tumor cells expressing SIK3. Because not all solid tumors appear to have SIK3-expressing tumor cells, there is insufficient antecedent basis for “tumor cells expressing SIK3”.
Amending claim 1 to recite “A method for the therapeutic treatment of a salt-inducible kinase 3 (SIK3)-expressing solid tumor” in the preamble might obviate the rejection, provided there is support in the disclosure for such an amendment.
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.
Claims 1, 14, 17-18, 21, 27-28, 30, 50, and 52-55 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2018/193084.
WO 2018/193084 teaches methods of sensitizing cells involved with a proliferative disorder against the cytotoxic effect of certain pro-inflammatory signaling pathways, and/or to kill such cells and/or methods for treating proliferative diseases, using a SIK3 inhibitor together with ligands or agonists of such signaling pathways wherein the proliferative diseases is a solid tumor such as pancreatic cancer, breast cancer, melanoma, ovarian cancer, esophageal cancer, sarcomoa and colorectal cancer, and non-small cell lung cancer and the SIK3 inhibitor is dastinib (
PNG
media_image1.png
150
427
media_image1.png
Greyscale
) or a compound for the following structure (B3):
PNG
media_image2.png
101
295
media_image2.png
Greyscale
(abstract, [62], [63], [10], [315], 216], [217], p48, Table A3, p49, Table A4, and claim 40). WO 2018/193084 further teaches the SIK3 inhibitor inhibits SIK3 in the cell involved with the tumor cells ([66]).
WO 2018/193084 also teaches the method further comprises administering an agent that is capable of increasing TNFRl-signalling (and/or TNFR2- signaling) of, and/or increasing the amount of TNF exposed to cells involved with the proliferative disorder in the subject, wherein such agent is preferably chimeric antigen receptor (CAR) T cells which are immune cells displaying engineered receptors that graft an arbitrary specificity (e.g., to a tumor cell) onto an immune effector cell (e.g., a T cell) ([0145]-[0151]). WO 2018/193084 further discloses that these T cells, which can then recognize the subject's cancer cells, are reintroduced into the subject, leading to exposure of TNF produced by the CAR T cells to the tumor cells and hence killing of such cells, in particular such cells that are sensitized to such TNF-mediate cytotoxicity after administration of a SIK3 inhibitor to the subject ([0151]). This reads on sequential administration.
Also, WO 2018/193084 discloses that dastinib and the compound B3 inhibits additional kinase such as ABL1 and SRC ([486] and p100, Table 4).
In addition, WO 2018/193084 teaches that the subject involved in the treatment methods of the invention may have a plasma concentration of TNF greater than about 2 pg/mL or greater than about 5 pg/mL (e.g., the cells involved with the proliferative disorder are one present in a subject having a plasma concentration of TNF greater than about 2 pg/mL or 5 pg/mL) ([121]-[122]).
As to the limitations, “inhibiting DDR2 or LCK in claims 17-18 and 55, those are intended results of claimed method. The prior art teaches administering the same kinase inhibitor, dasatinib to the same patient as claimed, thus such intended results necessarily occur. It should be noted that products of identical chemical composition cannot have mutually exclusive properties and a chemical composition and its properties are inseparable. In addition, it is generally well settled in the courts that a mechanistic property of a chemical compound, or combination of chemical compounds, when administered under identical conditions, is necessarily present, despite the fact that such a property may not have been readily apparent to, or recognized by, one of ordinary skill in the art. “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Also see In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
As such, the instant claims are anticipated by WO 2018/193084.
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 of this title, 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 14, 17-18, 21, 27-28, 50, and 52-55 are rejected under 35 U.S.C. 103 as being unpatentable over US 8680103 (hereafter, Lajeunesse) and Hekim et al. (Cancer Immunol Res. 2017 Feb;5(2):157-169, cited in the IDS filed on 4/2/2021) in view of US 2017/0281766 (hereafter, WILTZIUS) in further view of Sundberg et al. (PNAS, 111 (4): 12468-12473, 2014).
Lajeunesse teaches that the compound of formula (IV):
PNG
media_image3.png
136
323
media_image3.png
Greyscale
('N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-m- ethyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, also known as dasatinib) is an inhibitor of SRC/ABL kinase and is useful in the treatment of oncological disorders which are selected from a chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), ovarian cancer, melanoma, mastocytosis, germ cell tumors, acute myelogenous leukemia (AML), pediatric sarcomas, breast cancer, colorectal cancer, pancreatic cancer, and prostate cancer such as non-small cell lung cancer (NSCLC) and colorectal cancer (abstract, col 1, lines 63-67 and col 26, line 32-42). Lajeunesse further teaches that the compound may be delivered orally, such as in the form of tablets, capsules, granules, powders (col 31, lines54-56). Lajeunesse discloses the compound of formula IV may be administered in a dose of 15-200 mg twice a day, or 30-100 mg twice a day (col 34, lines 6-12). Lajeunesse further discloses the compound is administered in conjunction with at least one anti-neoplastic agent (col 28, lines 13-15).
Lajeunesse discloses the use of the compound for treating protein tyrosine kinase-associated disorders which includes cancers where Lck or other Src-family kinases such as Src are activated or overexpressed, such as colon carcinoma and thymoma, and cancers where Src-family kinase activity facilitates tumor growth or survival (col 27, lines 22-50). As to claim 55, Lajeunesse discloses that the compounds inhibit protein tyrosine kinases, especially Src-family kinases such as Lck (col. 26, line 65-col. 27, lines 5).
Hekim et al. teach that dasatinib is able to slow down the tumor growth of various solid tumor models, which is associated with the favorable blood/tumor T-cell immunomodulation (abstract). Hekim et al. further teaches that the effects on tumor growth and on the immune system were studied in four different syngeneic mouse models (B16.OVA melanoma, 1956 sarcoma, MC38 colon, and 4T1 breast carcinoma), wherein in all cases mice treated daily with dasatinib, there were a significant decrease in tumor growth (abstract). Hekim et al. suggest synergistic combinatorial therapies with other immunomodulatory drugs or targeted small-molecule oncokinase inhibitors (abstract). Hekim et al. teach that dasatinib is a broadly specific BCR/ABL and SRC-family tyrosine kinase inhibitor (TKI) (abstract), Thus, the treatment involves inhibiting one or more key kinases as recited in claim 14.
Lajeunesse or Hekim does not specifically teach CAR-T cells directed against a tumor antigen.
WILTZIUS teaches chimeric antigen receptor (CAR)-T cells which comprise binding domains capable of interacting with a particular tumor antigen, allow T cells to target and kill cancer cells that express the particular tumor antigen and a method of treating a cancer in a subject in need thereof comprise administering the CAR T cells (abstract, [0004], and [0247]). WILTZIUS further teaches that the cancer may also include solid or non-solid tumors ([0252]). WILTZIUS further teaches that the CAR-T cells may be administered in conjunction with any number of chemotherapeutic agents wherein the additional therapeutic agent includes dasatinib ([0256] and [0259) and the chemotherapeutic agent is administered at the same time or within one week after the administration of the engineered cell or nucleic acid (sequential administration) ([0257]). As to claim 52, WILTZIUS teaches that immune cells are genetically engineered to express antigen receptors (CARs) or T cell receptors (TCRs) which specifically target and kill cancer cells ([006]).
Sundberg et al. teaches inhibition of salt-inducible kinases (SIKs) as therapeutic strategy to enhancing immunoregulatory functions of dendritic cells (title). Sundberg specifically disclose dasatinib as inhibitor of SIKs including SIK3 (abstract and p12470, col 2, para 3-p12471, col 1, para 1). Sundberg et al. further teaches that elevated serum IL-10 levels mediated by SIK inhibition could modulate the chemotherapeutic activity of dasatinib given that T-cell–mediated immune responses targeting tumor antigens are a critical component of dasatinib’s mode-of-action, therefore, combining dasatinib or related kinase inhibitors with an IL-10 neutralizing strategy might be a rational approach to enhance the chemotherapeutic activity of these compounds (p12472, col 2, para 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select dasatinib as a chemotherapeutic agent in combination with CAR T cells as taught by WILTZIUS for treating a SIK3-expressing solid tumor because of the following reasons. As stated above, WILTZIUS already teach and suggest co-administrating CAR-T cells directed against a tumor antigen with a chemotherapeutic agent including dasatinib. Also, dasatinib was taught to be useful for treating the same cancer as evidenced by Lajeunesse. In addition, Hekim et al. teach that dasatinib is able to slow down the tumor growth of various solid tumor models, which is associated with the favorable blood/tumor T-cell immunomodulation and suggest synergistic combinatorial therapies of dasatinib with other immunomodulatory drugs. Further, it was known in the art that dasatinib is an inhibitor of SIKs including SIK3 and T-cell–mediated immune responses targeting tumor antigens are a critical component of dasatinib’s mode-of-action as evidenced by Sundberg et al. Thus, the skilled artisan would have been motivated to use the combination of dasatinib with the CAR-T cells as taught and suggested by WILTZIUS in the treatment of solid tumor having SIK3-expressing tumor cells and associated with the favorable blood/tumor T-cell immunomodulation taught and suggested by Hekim et al. The skilled artisan would have reasonably expected that the SIK3-expressing tumor cells would be sensitized to a cell-mediated immune response via inhibiting SIK3 as evidenced by Sundberg.
As to the limitations: “inhibiting one or more of the key-kinases in claims 14 and inhibiting DDR2 in claims 17-18, those are intended results of administering dasatinib and CAR-T cells directed against a tumor antigen to a subject having cancer. The prior art teaches administering the same kinase inhibitor, dasatinib to the same patient as claimed, thus such intended results necessarily occur. It should be noted that products of identical chemical composition cannot have mutually exclusive properties and a chemical composition and its properties are inseparable. In addition, it is generally well settled in the courts that a mechanistic property of a chemical compound, or combination of chemical compounds, when administered under identical conditions, is necessarily present, despite the fact that such a property may not have been readily apparent to, or recognized by, one of ordinary skill in the art. “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Also see In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over US 8680103 (hereafter, Lajeunesse) and Hekim et al. (Cancer Immunol Res. 2017 Feb;5(2):157-169) in view of US 2017/0281766 (hereafter, WILTZIUS) and Sundberg et al. (PNAS, 111 (4): 12468-12473, 2014) in further view of Reissfelder et al. (The Journal of Clinical Investigation, 125 (2): Feb. 2015).
The teachings of Lajeunesse, Hekim et al., WILTZIUS and Sundberg et al. as applied supra are herein applied for the same teachings in their entirety.
The prior art is silent about the subject having an intratumoral concentration of TNF greater than about 1 pg/ml.
It was known in the art that the use of intratumoral TNF-α, which is indicative of T cell function, as a prognostic parameter for colorectal cancer (CRC) and an increase in TNF-α concentration (1 pg/ml TNF-α) was statistically significantly associated with a better disease-specific survival (abstract, p744, col 2, para 1, and Table 3) as evidenced by Reissfelder et al. Alao, Reissfelder et al. suggest that intratumoral TNF-α might be a more suitable factor for prognosis prediction in patients with CRC than the quantification of effector TC infiltrates (p748, col 1, para 1).
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use dasatinib in combination with CART-T cells for those subjects who have increased TNF-α concentration (e.g., greater than 1 pg/ml TNF-α) on the reasonable expectation that those would have better response to the combination therapy as evidenced by Reissfelder et al.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BONG-SOOK BAEK whose telephone number is 571-270-5863. The examiner can normally be reached 9:00AM-6:00PM Monday-Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on 571-272-6175. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
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) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611