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 .
Current Status of 17/629,966
This Office Action is responsive to the amended claims of 20 June 2025. Claims 1-11 have been examined on the merits.
Priority
Acknowledgement is made of Applicant’s claim for foreign priority under 35 U.S.C. §119 (a)-(d). The certified copy has been filed in parent Application No. PCT/IB2020/055168, filed 1 June 2020.
The effective filing date is 1 June 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5 May 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Objections to the Specification
Applicants have amended the names of the claimed chemical compounds and corrected improperly labeled compounds. These amendment render moot the previous objection and the previous objections to the specification are withdrawn.
Objection to the Claims
Applicants have separated the potential R1 groups by commas and added “and/or” before the final entry listed. The addition of “and/or” to the Markush group makes the group improper. This objection is sustained until this phrase is deleted. Applicants have amended the compound structures of claims 1, 3, 5,6, and 8 as suggested by the Examiner. Applicants amended the names of the compounds listed in claims 4 and 9. The previous objection to the claims on the basis of the structures and the names of the structures of claims 1, 3-6, 8, and 9 are withdrawn. Claims 1 and 6 remain objected to until “and/or” from the Markush groups is removed.
Rejections under 35 U.S.C. §112(b)
Applicants have amended the claim language of claim 1 to clearly define the proviso of the excluded compounds. Applicants have also removed all instances of “[Chem XX]” from claims 1,3, 5, 6, and 8. These amendments render moot the previous rejection. The previous rejections are withdrawn.
Rejections under 35 U.S.C. §102
Applicants have made amendments to the proviso of base claim 1 to clearly exclude the compounds of do Rocio Andrade. Applicants contend that this amendment disclaims the compounds of the prior art reference. This argument is persuasive, and the previous rejection is withdrawn.
Rejections under 35 U.S.C. §103
Applicants contend that the amendments to the proviso properly exclude the compounds of prior art reference do Rocio Andrade which served as the basis for the previous rejection. Applicants contend that the claimed compounds demonstrate improved properties compared to the compounds disclosed by do Rocio Andrade. These arguments have been fully considered by the Examiner and found persuasive to overcome the previous rejection.
Specification
The disclosure is objected to because of the following informalities: The following structures/figures are grainy and difficult to read [Chem 26] pg. 14; [Chem 29] pg. 17; [Chem 30] pg. 19; and [Chem 51] pg. 47. This objection can overcome by amending the specification with clear, legible figures that clearly depict all functionalities of the molecules.
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.
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.
Claims 1, 2, and 5 are rejected under 35 U.S.C. 103 as being unpatentable over do Rocio Andrade Pires (Pires, Amanda do Rocio Andrade, et al. "New, highly potent and non-toxic, chromone inhibitors of the human breast cancer resistance protein ABCG2." European journal of medicinal chemistry 122 (2016): 291-301, found in IDS submitted 05/05/2022) in view of Weiss (Morrison, Kim L., and Gregory A. Weiss. "Combinatorial alanine-scanning." Current opinion in chemical biology 5.3 (2001): 302-307. (Year: 2001).
do Rocio Andre Pires discloses MBL-II-141 derivatives as potent and non-toxic ABCG2 inhibitors. do Rocio Andre Pires teaches that rational structural modification sot the scaffold affect activity, including (1) halogenation at ring A, (2) substitution at the 5-postion of the indole ring, and (3) conjugation with amino acid residues (Table 1, pg. 294). do Rocio Andre Pires specifically discloses compounds having Br substitution at the 4-postion of ring A, Z as carbonyl, R1 selected from CH(CH3)2, CH2CH(CH3)2, or CH(CH3)CH2CH3, and Y is either OH or OMe (see do Rocio Andre Pires Table 1). These compounds fall within the scope of the Markush group recited in claims 1 and 2.
The instant claims differ from the compounds of do Rocio Andre Pires only by virtue of the proviso, which excludes compounds wherein each of the following are satisfied: Br substitution at the 4-postion of ring A, Z as carbonyl, R1 selected from CH(CH3)2, CH2CH(CH3)2, or CH(CH3)CH2CH3, and Y is either OH or OMe. Thus, the difference between the instant claims and do Rocio Andre Pires is limited to substitution of one or more of these functionalities with alternative substituents encompassed by the claims.
It would have been obvious to the artisan to modify the compounds of do Rocio Andre Pires to arrive at the instantly claimed compounds because the reference itself teaches that halogenation pattern and substitution position on ring A affect the inhibitory activity, and provides examples of both fluoro- and bromo-substituted analogs. The artisan would therefore have been motivated to substituted Br with F, or alter the halogenation position on the aromatic ring, with a reasonable expectation that such changes would yield compounds with similar or improved activity.
do Rocio Andre Pires discloses amino acid conjugates (e.g., valine, leucine) and expressly suggests that further investigation of other residues would be worthwhile. Weiss teaches alanine scanning and related amino acid substitutions as routine practices to evaluate the contribution of side chains to biological activity (Abstract, pg. 302). In light of these teachings, it would have been obvious to substitute different amino acid residues, such as phenylalanine, as encompassed by the claims, with a reasonable expectation that the scaffold would tolerate such modifications.
do Rocio Andre Pires demonstrates that the scaffold tolerates and responds predictably to modification at ring A, the indole 5-postion, and the amino acid residue. Weiss confirms that residue substation is a conventional optimization step. The artisan therefore would have been motivated to make the claimed substitutions with a reasonable expectation of success in retaining or improving ABCG2 inhibitory activity. Thus, the claimed subject matter represents no more than the predictable variation of known compounds. The modifications reflect routine substitution of known substituents already taught by do Rocio Andre Pires and amino acid residues taught by do Rocio Andre Pires and Weiss. The art provides explicit motivation to undertake such substitutions.
The reaction scheme of instant claim 5 is unpatentable over do Rocio Andre Pires because the reference discloses the same sequence of reaction steps used to prepare MBLII-141 derivatives. do Rocio Andre Pires teaches steps (a), (b), and (d) of the claimed method ((2. Chemistry, page 292; 5.1.1.1. General procedure A, page 294, 31-008-CAS-16081046; General procedure B, page 295, 31-331-CAS-21366447; General procedure D, page 297, 31-367-CAS-16081070). Step (c), a hydrolysis to form a carboxylic acid, represents a fundamental and routine transformation in organic synthesis that the artisan would have recognized as necessary to convert the intermediate of (b) into a suitable form for the coupling of step (d). Incorporating such a conventional step into do Rocio Andre Pires’s process would have been an obvious modification with a reasonable expectation of success. The synthetic procedures for the synthesis of chromones-2-carboxylic acids (General procedure C, do Rocio Andrade Pires) differ from the instant application with regard to the specified ratios of THF/EtOH/H2O and the reaction temperature.
The artisan would be motivated to modify the solvent ratios and the reaction temperature of the reaction conditions of General procedure C of do Rocio Andrade Pires as part of routine optimization of reaction conditions (see evidentiary reference US 9,642,841 B1, Col 6, lines 46-55). It would have been obvious to one skilled in the art at the time of invention to determine all optimum and operable conditions (e.g. solvent ratios and reaction temperature), because such conditions are art-recognized result-effective variables that are routinely determined and optimized in the art through routine experimentation. Furthermore, neither the Specification nor the claims indicate that the solvent ratios of THF/EtOH/H2O nor the reaction temperature of 50°C are critical. Generally, differences in solvent ratios or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such ratios or temperatures are critical. ("[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.05(II)(A)).
Claims 1, 4-7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over do Rocio Andrade Pires in view of Weiss.
Do Rocio Andrade Pires and Weiss teach the limitations of claim 1, see above.
Do Rocio Andrade Pires teaches modifications to the chromone derivative MBL-II-141 to generate a more potent, selective inhibitor of ABCG2 for the treatment of BCRP with multidrug resistance, reading on instant claims 4, 6, 7, and 9 (Abstract, page 291). The reference discloses rational structural modifications to MBLII-141 in series I, II, and III (Table 1, page 294). The reference also teaches the treatment/inhibition of ABCG2 transport activity in human embryonic kidney HEK293 cells, reading on instant claims 6, 7, and 9 (Table 1, page 294; 5.2 Biology, page 300).
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The reference additionally teaches that although the introduction of amino acid residues into the structure did not provide more active modulators, it indicated that further efforts could be spent, for example by investigating other amino acid residues, and introducing D-amino acids, or even dipeptides, in the structure (4. Conclusion, page 294).
Furthermore, the reference teaches procedures for the synthesis of chromones-2-carboxylic acids (5.1.3.1. General procedure C, page 296).
The prior art does not explicitly teach the instantly claimed compounds (5-((2-bromobenzyl)-oxy)-4-oxo-4H-chromene-2-carbonyl)-L-alloisoleucine; (5-((2-bromobenzyl)-oxy)-4-oxo-4H-chromene-2-carbonyl)-L-phenylalanine; (5-((4-bromobenzyl)-oxy)-4-oxo-4H-chromene-2-carbonyl)-L-phenylalanine; or (5-((4-bromobenzyl)-oxy)-4-oxo-4H-chromene-2-carbonyl)-D-tryptophan.
The references do not explicitly teach the use of the instantly claimed compounds for the treatment/inhibition of BCRP/ABCG2.
The instant claims 1, 4, 6-7 and 9 are prima facie obvious in view of the reference do Rocio Andrade Pires. Do Rocio Andrade Pires teaches the limitations of claim 1, see above.
A person of ordinary skill in the art would be motivated to modify the structures taught by do Rocio Andrade Pires
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by incorporating other amino acid residues as part of the core structure (do Rocio Andrade Pires 4. Conclusion, page 294). The artisan would expect that such modifications would enhance the biological activity of the compounds as modulators of ABCG2, given that prior studies on structurally similar inhibitors, such as FTC and Ko143, have demonstrated that the presence of an isobutyl moiety is important for inhibition (do Rocio Andrade Pires, 3. Results and Discussion, page 292). The artisan would recognize that introducing an amino acid residue, which can contain similar structural features, could enhance inhibitory activity, thereby increasing therapeutic effectiveness of these compounds for treatment of BCRP/ABCG2-related conditions. (do Rocio Andrade Pires 4. Conclusion, page 294).
The incorporation of an amino acid residue into a series I structure, where X is a bromine at the 2-position of the phenyl ring, would logically involve attachment of the amino acid residue to the amino functionality of the core structure. This modification would yield a structure corresponding to
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, ((5-((2-bromobenzyl)-oxy)-4-oxo-4H-chromene-2-carbonyl)-L-alloisoleucine) of instant claims 4 and 9. Furthermore, do Rocio Andrade Pires explicitly teaches the feasibility of modifying the core structure by incorporating amino acid residues, reinforcing the motivation for an artisan to pursue such modifications. (do Rocio Andrade Pires 4. Conclusion, page 294).
Claims 1, 10, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over do Rocio Andrade Pires and Weiss in view of Mokhtari (Bayat Mokhtari R, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, Yeger H. Combination therapy in combating cancer. Oncotarget. 2017 Jun 6;8(23):38022-38043. doi: 10.18632/oncotarget.16723. PMID: 28410237; PMCID: PMC5514969.).
do Rocio Andrade Pires and Weiss teach the limitations of claim 1. The above discussion regarding these teachings is incorporated by reference into this rejection. The combined teachings of the above references disclose obvious variants of compounds known to be useful and effective in targeting and treating cancers associated with BCRP/ABCG2. The references do not explicitly teach a pharmaceutical composition comprising the claimed compounds of formula (I) with additional pharmaceutically active agents such as anti-cancer compounds. Mokhtari teaches that combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumor growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis (Abstract). Formulating a pharmaceutical composition comprising the claimed inhibitor of formula (I) with additional anticancer agents would have been obvious to the artisan because drug combinations are a cornerstone of cancer therapy and represent a standard approach to cancer therapy. The artisan would expect that the combination of (I) and at least one pharmaceutically active agent would have the potential to enhance the efficacy of the treatment and possibly overcome drug resistances, affording an enhanced treatment compared to the monotherapy.
Conclusion
Claims 1, 2, 4-7, and 9-11 are rejected.
Claims 3 and 8 are objected to as being dependent upon a rejected base claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625