DETAILED ACTION
A non-final Office action was mailed 9 July 2025 (“Office Action”).
Applicant’s reply to the Office Action was received 10 November 2025 (“Reply”).
Status of the Claims
The listing of claims filed with the Reply has been examined.
Claims 1–5 and 7–20 are pending. Claim 6 is canceled.
Claims 1, 3, 9, and 20 are amended.
Status of Rejections and Objections
The text of those sections of Title 35, U.S. Code and/or text providing the basis for non-statutory double patenting rejections not included in this action is in the Office Action.
Unless repeated herein, any objection or rejection in the Office Action is withdrawn.
Claim Objections
Claims 2, 8, and 10 are objected to for minor informalities.
Claim 2 recites “alkylnylene-alkyl,” which appears to be a typographical error of “alkynylene-alkyl.”
Claim 8 is missing a period at the end.
Claim 10 recites “0. 01” with a space between digits.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 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, 17, and 19 are rejected under 35 U.S.C. §§ 102(a)(1) and (a)(2) as being anticipated by US 4,118,561 (“Ledig”) [IDS].
Ledig discloses compounds of Formula I,
PNG
media_image1.png
112
265
media_image1.png
Greyscale
, in which X = H; Y = CH2R or R1; R = 3-nitrophenyl; 4-cyanophenyl, 2-fluorophenyl, 2-trifluoromethylphenyl, 1-bromo-2-naphthalenyl, etc. (see Table 1 below) (Ledig, col. 4–5, 9–14). The compounds read on instantly claimed Formula (I) when n = 0; Y = NR13R14; R1, R3, R4, R5, R13, R14 = H; A = aryl; R2 = cyano, nitro, fluoro, bromo, fluoroalkyl, etc.
Ledig discloses formulating and administering the compounds in a composition. (Id., 3:46–63; 4:46–7:17; 27:20–41:12) (col:lines).
Ledig discloses the compounds are present in an amount sufficient to exhibit anticancer properties when administered in vivo. (Id., 4:62–5:17).
Regarding claim 19, IC50 value is an inherent property of a compound of the instantly claimed Markush group of Formula (I). The Ledig compounds are encompassed by the Markush group and therefore would be expected to possess the same or similar inherent properties as other members of the Markush group.
PNG
media_image2.png
775
690
media_image2.png
Greyscale
PNG
media_image3.png
784
527
media_image3.png
Greyscale
Claim Rejections - 35 U.S.C. § 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.
Graham v. John Deere Co., 383 U.S. 1, 17 (1966); MPEP § 2141(II).
Claims 2–5, and 7–20 are rejected under 35 U.S.C. § 103 as being unpatentable over Ledig in view of Santa Maria et al., ACS Chemical Biology (2017), 12(9), 2448–2456 (“Santa Maria”) and the compound having Registry Number RN 2131044-41-0, STN/CAPLUS (28 September 2017) (“Compound RN 2131044-41-0”).
The Graham factors are addressed in turn below.
Determining the scope and contents of the prior art
Ledig discloses compounds that read on Formula (I) of the instant claims and pharmaceutical compositions thereof, as discussed in the anticipation rejection above. The contents of the rejection are incorporated by reference for the purposes of this rejection.
Ledig further discloses screening the compounds at a dose as low as 5 mg/kg. (Id., col. 5 (table); col. 38 (Table IX)).
Ledig further discloses administering the compounds with a sulfa drug to give a synergistic effect. (Id., 3:64–68).
Santa Maria discloses the results of a high throughput screening study comprising 55,000 compounds with respect to ability to effect bacterial targets. (Santa Maria, Abstract).
Santa Maria identifies compounds considered active against certain bacterial strains using data from previous studies (an antibacterial phenotypic screen and a screen for bacterial targets in ALIS-based biophysical biding assays). (Id., pp.2449, 2453 (Methods)).
Compound RN 2131044-41-0 (shown below) was indexed in the Registry database for Santa Maria:
PNG
media_image4.png
371
711
media_image4.png
Greyscale
Compound RN 2131044-41-0 reads on instantly claimed Formula (I): n = 1 (adjacent to A); A = aryl; R2 = ethyne; Y = NR13R14; n = 0 (adjacent to R1); and R1, R3, R4, R5, R13, R14 = H.
Ascertaining the differences between the prior art and the claims at issue
Ledig does not disclose Y = CH2R or R1 in which R or R1 = aryl substituted by an alkynyl group. Compound RN 2131044-41-0 is relied on for those claim elements.
The units for a dose of compound in Ledig is reported in mg/kg, whereas the instant claims recites units in nM and mM. The weight of the subject in the instant claims is not known. As such, the corresponding dosage may be different.
Resolving the level of ordinary skill in the pertinent art
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
Considering objective evidence present in the application indicating obviousness or nonobviousness
The instant application provides comparative data for Compound 1 against pemetrexed and methotrexate in the context of cells down-regulating RFC. (Spec., 43:24–44:8) (page:lines).
The question of obviousness
Based on the above factors, it would have been obvious for a person having ordinary skill in the art prior to the filing of the instant application to combine the teachings of Ledig, Santa Maria, and Compound RN 2131044-41-0 and arrive at the claimed subject matter because the references disclose compounds with the same tricyclic heteroaryl core structure having a substituent attached to the 5-membered ring of the tricyclic heteroaryl core, and the substituent comprises a substituted aryl moiety. In Ledig, the aryl substituents include alkyl groups with single bonds, alkenyl groups with double bonds, and nitrile groups with triple bonds. Compound RN 2131044-41-0 has an alkynyl-substituted aryl with a triple bond. Further, Ledig and Santa Maria disclose using the compounds as pharmaceutical agents for the treatment of one or more diseases. Thus, the compounds in Ledig, Santa Maria, and Compound RN 2131044-41-0 are related in structure and utility. Accordingly, there would have been a reasonable expectation of success at arriving at the claimed invention because Ledig discloses compounds having the claimed tricyclic heteroaryl core structure can be successfully modified with various aryl substituents and Santa Maria and Compound RN 2131044-41-0 provide an alternative aryl substituent for the core structure.
Regarding claims 10 and 11, the concentration ranges for a compound of Formula (I) recited in the claims are not specifically disclosed in the cited references, however determining the concentration of an active ingredient is considered optimization for one of ordinary skill in the art and therefore generally not sufficient to support patentability. MPEP § 2144.06.
Regarding claims 12–15 and 18: The inhibition of purine or thymine biosynthesis in pancreatic cancer cells in recited claims 12 and 13, exhibition of higher potency relative to pemetrexed or methotrexate for cancer cells down-regulating reduced folate carrier recited in claim 14, inhibition of colorectal tumor growth recited in claim 15, and down-regulation of reduced folate carrier by cancer cells recited in claim 18 are each considered inherent properties of a compound of the instantly claimed Markush group. Thus, any compound encompassed by the Markush group, including the Ledig compounds, would be expected to possess the inherent properties of other members of the Markush group. MPEP § 2117(I) (“A Markush grouping is proper if the members of a group share a single structural similarity and a common use.”).
Regarding claim 16, Ledig discloses a combination of the disclosed compounds and a sulfa drug, which reads on the claimed adjuvant.
Regarding claim 19, the IC50 value of less than 0.1 nM recited in the claim is considered an intended result. Courts have held that expressions of an intended result in a method claim are not given much patentable weight. MPEP § 2111.04(I).
The examples and data in the instant specification have been considered. The examples and data compare Compound 1 to pemetrexed and methotrexate in the context of cells down-regulating RFC. That data is not commensurate in scope with the claimed compositions with the compounds of Formula (I). Further, there is no evidence of criticality with respect to the concentration of the compound of Formula (I) recited in claims 10 and 11.
Double Patenting
(i) Claims 1–5 and 7–16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1–22 of copending App. No. 18/014,032 (reference claims).
18/013,302
18/014,032
PNG
media_image5.png
138
269
media_image5.png
Greyscale
PNG
media_image6.png
155
295
media_image6.png
Greyscale
The instant claims are directed to a pharmaceutical composition comprising a compound of Formula (I) above left, and the reference claims are directed to a compound of Formula (I) above right and pharmaceutical compositions comprising the compound. The respective Formula (I) structures cover identical compounds. For example, the instant claims, when A = aryl and R2 = alkynyl, cover the same embodiments in the reference claims when R2 = arylene-alkynyl.
The instant claims recite, “wherein the compound of Formula (I) is present in the pharmaceutical composition in an amount sufficient to exhibit anticancer properties.” The reference composition claims recite, “wherein the compound of Formula (I) is present in the pharmaceutical composition in an amount sufficient to exhibit antibacterial properties.” Those clauses are directed to the amount of compound present, and the respective dependent claims recite overlapping ranges for a sufficient amount. Furthermore, the functional language tied to the amount (to exhibit anticancer or antibacterial properties) does not distinguish the structural features of the compounds and compositions. Thus, an infringer of a patent granted based on the instant claims or the reference claims would also be an infringer of a patent granted from the other claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(ii) Claims 1–5 and 7–16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4–12, and 26–32 of copending App. No. 17/314,196 (reference claims).
18/013,302
17/314,196
PNG
media_image5.png
138
269
media_image5.png
Greyscale
PNG
media_image7.png
158
293
media_image7.png
Greyscale
The instant claims are directed to a pharmaceutical composition comprising a compound of Formula (I) above left, and the reference claims are directed to a pharmaceutical composition comprising a compound of Formula (I) above right. The respective Formula (I) structures cover identical compounds. For example, the instant claims, when A = aryl and R2 = alkynyl, cover the same embodiments in the reference claims when R2 = aryl substituted by alkynyl.
The instant claims recite, “wherein the compound of Formula (I) is present in the pharmaceutical composition in an amount sufficient to exhibit anticancer properties.” The reference claims recite, “wherein the compound of Formula (I) is present in the pharmaceutical composition at a minimum inhibitory concentration (MIC) of 0.1 mg/ml to 10 mg/ml to inhibit growth of cells of a disease.” Those clauses are directed to the amount of compound present, and the instant dependent claims recite a range that overlaps with the clause in the reference claims. Furthermore, the functional language tied to the amount (to exhibit anticancer properties or inhibit growth of cells of a disease) does not distinguish the structural features of the compounds and compositions. Thus, an infringer of a patent granted based on the instant claims or the reference claims would also be an infringer of a patent granted from the other claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reply to Arguments
Applicant requests that the rejections be held in abeyance until a claim is allowed. (Remarks, p.6). The rejections are maintained.
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 C.F.R. § 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 C.F.R. § 1.17(a)) pursuant to 37 C.F.R. § 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.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jason Nolan at (571) 272-2480. The examiner can normally be reached Monday through Friday between 9:00–5:00.
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 submit an Automated Interview Request: http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan, can be reached on 571-270-7674.
The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JASON M. NOLAN/Patent Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623