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
This action is FINAL.
Status of Claims
Claims 1, 2, 4, 6 and 9-16 are pending.
Claims 1, 2, 4, 6 and 16 are examined herein.
Claims 9-15 are withdrawn (see restriction/election in the previous action).
Priority
This application is filed 11/03/2023 and no claims the benefit of domestic priority.
Information Disclosure Statement
Four references from IDS(s) received on 1/25/2024, 4/02/2024, 6/28/2024, and 6/16/2025 have been considered unless marked with a strikethrough. Two additional IDS(s) received on 5/27/2026 and 7/06/2026.
Response to Arguments/Amendments
Applicant's arguments/amendments filed on 7/06/2026, and in the amendments, the drawings and claims 1, 2, 4 and 6 are amended; claims 3, 5 and 7-8 are cancelled; and claim 16 is newly added. No new matter has been added. With respect to the objection of drawings has been fully considered and are persuasive. Therefore, the objection of drawings has been withdrawn. However, Applicant's arguments of the rejection of claims under 35 U.S.C 112(a), 35 U.S.C 112(b) and 35 U.S.C 103 have been considered but are moot in view of the new ground of rejections for the amended claims 1, 2, 4, 6 and 16. The previous rejections of record are withdrawn in view of the amendment.
New Ground of Rejections
Claim Objections
Claims 1 and 4 are objected to because of the following informalities:
Claim 1 is objected to because the term “tougher” should be “together”.
Claim 4 is objected to because the term "a common carrier” is inconsistent with the terminology used in the specification, which describes a pharmaceutically acceptable carrier.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
The rejections under this section are made when the scope of the claimed subject matter is not clear. (See MPEP 2173)
Claims 6 and 16 is/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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 6 and 16, the phrase "wherein the anticancer drug is administered in combination with a food or beverage" in claim 6 renders the claim indefinite because the claim does not specify the required relationship between the anticancer drug and the food or beverage. It is unclear whether the claim requires administration to the anticancer drug during or near the time a food or beverage is consumed; administration of the anticancer drug as a separate dosage form together with a food or beverage; dissolution, dispersion, or incorporation of the anticancer drug into the food or beverage; or formulation of the anticancer drug as an ingredient of the food or beverage. Dependent claim 16 is also lacks clarity for the same reason.
Claim Rejections - 35 USC § 112, 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.
Claims 1, 2, 4, 6 and 16 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by applicants. (see MPEP 2163.02)
An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed. (Emphasis added)
Further, the MPEP states that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. (see MPEP 2161.01)
For instance, generic claim language in the original disclosure does not satisfy the written description requirement if it fails to support the scope of the genus claimed. Ariad, 598 F.3d at 1349-50, 94 USPQ2d at 1171 ("[A]n adequate written description of a claimed genus requires more than a generic statement of an invention’s boundaries.") (citing Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1405-06); Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002) (holding that generic claim language appearing in ipsis verbis in the original specification did not satisfy the written description requirement because it failed to support the scope of the genus claimed); Fiers v. Revel, 984 F.2d 1164, 1170, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (rejecting the argument that "only similar language in the specification or original claims is necessary to satisfy the written description requirement").
As set forth in the en banc decision in Ariad Pharmaceuticals Inc. v. Eli Lilly and Company, 94 USPQ2d 1161 (Fed. Cir. 2010) at 1171, the court stated as follows:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. At 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. At 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 [25 USPQ2d 1601] (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
With respect to claims 1, 2, 4, 6 and 16, the claims are drawn to a method for overcoming anticancer drug resistance of a patient being treated for thyroid cancer with an anticancer drug selected from Lenvatinib or sorafenib, comprising co-administering said anticancer drug to said patient, tougher with a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
In the field of cancer therapy, particular drug resistance and sensitization, is well recognized as highly unpredictable and heterogeneous. As described by Holohan et. al. (Cancer drug resistance: an evolving paradigm, Nature Review Cancer, 13(10), 714-726, pub’d 09/24/2013), mechanisms of cancer drug resistance and sensitization are broad, including drug efflux, DNA repair, apoptosis evasion, and tumor microenvironment effect, and that these mechanisms differ depending on tumor type and treatment (Key points, and table 1 and 2). Similarly, Dagogo-Jack et al. (Tumour heterogeneity and resistance to cancer therapies, Nat. Rev. Clin. Oncol., 15(2), 81-94, pub’d 11/08/2017) discloses that generic and phenotypic heterogeneity within tumors may produce differential drug sensitivity and permit resistant subpopulations to survive and evolve during treatment (Key Points and abstract).
In view of the teachings from Holohan, and Dagogo-Jack, a person of ordinary skill in the art would not reasonably expect to be able to reliably extrapolate, without a rational experimental basis, that all derivative compounds would induce equivalent changes in drug resistance and sensitivity, even among derivatives of the same type. The specification establishes that increased SERCA1 expression serves as a survival mechanism in drug-resistant metastatic papillary thyroid cancer cells treated with sorafenib or lenvatinib . It further identifies CKP1 and CKP2 as candidate selective SERCA1 inhibitors and presents experimental results, including molecular modeling, intracellular calcium concentration, cell viability, protein expression, and *in vivo* xenograft data, regarding the combination of these compounds with sorafenib or lenvatinib . Therefore, the issue is whether the disclosure concerning the specifically selected and tested compounds, CKP1 and CKP2, reasonably demonstrates possession of the invention with respect to the subgenus of compounds under the amended Formula (I) compounds that are substantially different (i.e., where R2 is hydrogen). The tested compounds, CKP1 and CKP2, are defined where R2 is methyl in Formula (I), and they do not fall within the scope of the amended Formula (I).
The specification does not need to establish that every compound encompassed by Formula (I) possesses the chemical features responsible for the reported SERCA1 interaction and resistance overcoming activity. However, the currently disclosed computational and biological analyses are directed principally to CKP1 and CKP2, and the specification describes these compounds as having similar chemical structures and identifies predicted interactions with a common SERCA1 binding region, it does not identify which structural elements of CKP1 and CKP2 are required for SERCA1 selectivity, binding orientation, intracellular calcium effects, or restoration of sensitivity to sorafenib or lenvatinib .
In particular, the specification does not provide a defended structure activity relationship across a representative compounds of Formula (I). It does not show that variation at each variable position permitted by Formula (I) preserves the pharmacophore, binding conformation, affinity, selectivity for SERCA 1 over other SERCA isoforms, cellular activity, or in vivo resistance overcoming effect reported for CKP 1and CKP2.
In view of Holohan and Dagogo-Jack, cancer drug response and resistance mechanism may vary according to tumor heterogeneity, molecular context, therapeutic agent, and treatment conditions. Here, the specification reduces some of that unpredictability by identifying SERCA1 dependent survival in the tested metastatic PTC cells and by demonstrating activity of CKP1 and CKP2 in combination with both sorafenib and Lenvatinib . While the present specification addresses this unpredictability to some extent by confirming SERCA1 dependent survival in the tested metastatic PTC cells and demonstrating the activity of CKP1 and CKP2 in combination with sorafenib and lenvatinib , it also raises issues regarding the extrapolation of results, even assuming the claimed Formula (I) genus is equivalent to CKP1 and CKP2, to the claimed genus of Formula (I), the subgenus where R2 is hydrogen, and separate food or beverage embodiments. Thus, the specification does not reasonably convey to those skilled in the art that the inventors are in possession of the full scope of claimed combination therapies with separate food or beverage embodiments.
As set forth in the en banc decision in Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010), to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention at the time of filing. Specifically, the specification must describe the claimed invention in a manner understandable to a person of ordinary skill in the art in a way that shows that the inventor actually invented the claimed invention at the time of filing. Id.; Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172. (see MPEP 2161.01).
Accordingly, in view of 1) the structural breadth of Formula (I) relative to the specifically analyzed CKP1 and CKP2 compounds and non-analyzed amended compounds; 2) the absence of a sufficiently defined structure activity relationship or representative series demonstrating which Formula (I) compounds retain SERCA1 selectivity and the claimed resistance overcoming activity; 3) the lack of specific support for the R2-hydrogen subgenus recited in claims 1 and 2 that are not represented by the tested compounds; and 4) the lack of a specific disclosure of incorporating both the Formula (I) compound and Lenvatinib or sorafenib into a food or beverage in the manner and amount as discussed above, the specification does not reasonably convey to those skilled in the art that the inventors are in possession of the full scope of claimed combination therapies at the time of filing.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
The factual inquiries 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.
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 present rejection under 35 U.S.C. 103 is directed to the co-administration of CKP1/2 with lenvatinib or sorafenib. This rejection applies to a method for enhancing sensitivity of a subject to an anticancer drug, comprising administering to the subject a pharmaceutical composition by Formular (I) in combination with lenvatinib or sorafenib.
Claim(s) 1, and 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Daeuble et. al. (US 6117884, pub’d 09/12/2000), in view of Courcambeck et. al. (US 10,179,770 B2, pub’d 01/15/2019), and in further view of Jin et. al. (EGFR activation limits the response of liver cancer to lenvatinib . Nature, 595(7869), 730-734, pub’d 07/21/2021).
With respect to independent claim 1, the claim recites that a method for overcoming anticancer drug resistance of a patient being treated for thyroid cancer with an anticancer drug selected from Lenvatinib or sorafenib, comprising co-administering said anticancer drug to said patient, tougher with a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof.
Daeuble teaches 4-substituted quinoline derivatives including styryl quinoline derivatives encompassed by Formula 1. Daeuble’s formula (1) defines R1-R4 are independently H, each X and Y is CR5, wherein R5 is H, V is C1 alkenyl, Z is N, A is a phenyl with a halogen in para position (column 1 lines 14 - column 2 line 10) that fall in the instant Formula (I) compound. Daeuble further teaches specific styryl quinoline compounds, including the exemplified compound (e.g., compound 55, column 19), which represent preferred embodiments of the disclosed quinoline genus. The Cl substituents at R1 and R3 position in compound 55 are indicated as being replaceable with hydrogen in the specification (column 1 lines 14 - column 2 line 10).
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Daeuble’s formula (1) Instant application Compound 55 (Daeuble)
Daeuble fails to teach using the Formula 1 compound as an anticancer agent, administering the compound to a patient with thyroid cancer or co-administering the compound with Lenvatinib or sorafenib to overcome anticancer drug resistance.
Courcambeck teaches 1) quinoline derivatives useful as anticancer agents and pharmaceutical compositions comprising quinoline based compounds for the treatment of cancer (column 1 lines 34-48); 2) quinoline derivatives inhibit proliferation of tumor cells and are useful for treating a variety of cancer (abstract, claims 25-26); and 3) quinoline derivatives having anticancer activity and usefulness in treating a variety of cancers, including thyroid cancer, which correspond to the cancer types recited in the instant claim 3 (claims 26-29). Thus, Courcambeck establishes that quinoline based compounds are biologically active in oncology and provide therapeutic benefit through inhibition of tumor growth. Accordingly, Courcambeck provides motivation to use quinoline based compounds, such as those disclosed in Daeuble, in thyroid cancer related therapeutic applications.
The combination teachings of Daeuble and Courcambeck fail to teach the Formula 1 compounds should be co-administered with Lenvatinib or sorafenib to overcome anticancer drug resistance.
Jin teaches that activation of compensatory EGFR signaling limits the response of cancer cells to Lenvatinib (Interaction between lenvatinib and EGFR section). Jin further teaches co-administering Lenvatinib with gefitinib, a quinazoline EGFR inhibitor, to inhibit the compensatory signaling pathway, restore tumor cell sensitivity to Lenvatinib , and improve the anticancer response (abstract, Lenvatinib activates the EGFR–PAK2–ERK5 pathway, and Clinical response to combination therapy section).
It would have been obvious to a PHOSITA at the time of the invention to combine the styryl quinoline compounds disclosed in the Daeuble in combination with the quinoline derivatives useful as anticancer agents and pharmaceutical compositions taught by Courcambeck, and methods of co-administering the Formula 1 compound with Lenvatinib according to the resistance directed combination strategy taught by Jin. A person having ordinary skill in the art would have been motivated to co-administer the Formula 1 compound disclosed by Daeuble with Lenvatinib because Courcambeck teaches that structurally related quinoline compounds possess anticancer activity and are suitable for pharmaceutical use, and Jin teaches that co-administering Lenvatinib with a quinazoline agent that suppresses compensatory survival signaling restores tumor cell sensitivity to Lenvatinib . Accordingly, the combined teachings of Daeuble, Courcambeck, and Jin would have predictably resulted in Lenvatinib efficacy and reduce anticancer drug resistance.
The references is directed to the same field of endeavor and address related to the application. The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Consistently, applying KSR example rationale (A) and (G) in the independent claim 1, it would have been prima facie obvious to combine a quinoline compound exhibiting anticancer activity with a quinazoline agent, which restores tumor cell sensitivity to lenvatinib by inhibiting compensatory survival signaling in view of the teachings, suggestions, or motivations presented by Jin. Accordingly, Jin’s teachings are considered collectively, such a combination would have yielded the predictable results of securing lenvatinib 's efficacy and reducing resistance to that anticancer agent. (see MPEP 2141)
With respect to claim 2, the claim recites that the method according to the claim 1, wherein B is N.
Daeuble teaches 4-substituted quinoline derivatives including styryl quinoline derivatives encompassed by Formula 1. Daeuble’s formula (1) defines R1-R4 are independently H, each X and Y is CR5, wherein R5 is H, V is C1 alkenyl, Z is N, A is a phenyl with a halogen in para position (column 1 lines 14 - column 2 line 10) that fall in the instant Formula (I) compound.
Conclusion
Claims 1, 2, 4, 6 and 16 are rejected.
Claims 1 and 4 are objected to.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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