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 .
Priority
The instant application is a 371 National Stage Entry of PCT/US2021/047100 filed on August 23, 2021 which claims benefit to domestic provisional application No. 63/094,621 filed on October 21, 2020.
Status of Claims
Acknowledgement is made of original (1-2) and previously presented (3-19) claims filed on February 23, 2026. Claims 1-19 are pending in instant application.
Information Disclosure Statement
The information disclosure statement filed on February 23, 2026 has been considered.
Response to Arguments
Acknowledgement is made of the Denko declaration under 37 C.F.R. 1.130 filed February 23, 2026. Previously applied WO 2020/023537 A1 (with overlapping inventors, filed July 23, 2019 and published January 30, 2020) no longer constitutes prior art. The rejection of claims 1-19 are under 35 U.S.C. 103 over WO 2020/023537 A1 to Denko in view of Derer as exemplified by Rodriguez-Abreu is withdrawn.
Applicant's arguments filed February 23, 206 have been fully considered but they are not persuasive.
Regarding unexpected results, it is the Examiner’s understanding that Applicant alleges the existence of unexpected results commensurate in scope with the requirements of MPEP §716, §716.01, and §716.02, wherein such results are sufficient to rebut prima facie obviousness (see, e.g., Reply filed 2/23/26 at p. 12-23). However, to establish unexpected results, the evidence must establish that the expected results occur to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), on the basis of statistically and practically significant evidence (see, e.g., MPEP § 716.02(b)(I)), which is fully explained (see, e.g., MPEP § 716.02(b)(II)), commensurate in scope with the claimed invention (see, e.g., MPEP § 716.02(d)), and wherein a comparison of the claimed invention with the closest prior art of record is provided (see, e.g., MPEP § 716.02(e)). Furthermore, even if evidence satisfying MPEP §§ 716.02, 716.02(a), 716.02(b), 716.02(d), and 716.02(e) is set forth on record, such evidence may not be sufficient to rebut prima facie obviousness because the evidence of expected and unexpected results must be weighed (see, e.g., MPEP § 716.02(c)(I)) and the totality of the record considered (see, e.g., MPEP § 716.02(f)), including teachings in the prior art and evidence of expected results which weigh in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)).
If Applicant means to allege the existence of unexpected results commensurate in scope with the requirements of MPEP § 716.02 based upon instant “Example 1” (see, e.g., Reply filed 6/25/2024 at p. 12 ¶6-7, see also instant spec. at p. 49-50 “SMV32”) this is also not persuasive because the requirements of MPEP § 716.02 have not been satisfied. Specifically,
I. MPEP § 716.02(b) is not satisfied because no evidence of statistical significance has been placed on record.
II. MPEP § 716.02(d) is not satisfied because such proffered evidence is not commensurate in scope with the instant claims with respect to:
i) covering a diverse and representative range of cancer species (see instant spec. at. p. 49 line 11 “colorectal tumor line” and p. 50 lines 4-5 “PD-1 blockade resistant tumor model Lewis Lung Carcinoma”) vs instant claims “treating cancer”)
ii) covering a diverse and representative range of species of Formula I and immunotherapies (see instant Fig 1, noting only SV-23 and SV-32 perform better than PPV, and instant Figs 3-5 noting only one species of Formula I, SMV-32, is tested in combination with one immunotherapy, one PD-1 blocking antibody).
III. MPEP § 716.02(e) is not satisfied because no comparison to the closest prior art is provided or explained.
Accordingly, for at least these reasons, the proffered data provided in the instant specification is insufficient to establish unexpected results commensurate in scope with the requirements of MPEP § 716.02 at this time.
Regarding increase tumor growth, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “increase tumor growth delay in immunotherapy resistant tumors”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The Examiner notes Applicant states “the amended claims are non-obvious…” (see 2/23/26 Remarks at p. 13 ¶3), but no amended claims were submitted.
Regarding the double patenting rejection, the Examiner appreciates Applicant’s acknowledgement that it is difficult to compare the scope of claims in copending applications undergoing prosecution. Regrettably, the Examiner cannot hold the rejection in abeyance until allowable subject matter has been determined. The rejection has been modified in light of claim amendments in the copending application.
Maintained/Modified Rejections
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.
Claims 1-2, 6-19 are rejected under 35 U.S.C. 103 as being unpatentable over US 6638939 B2 to Uckun et. al.1 in view of Cook et. al.2 and Remington et. al.3 as exemplified by Rodriguez-Abreu et. al.4
Regarding claims 1, 2, 7, 9, 19, and compounds of Formula I or compositions, Uckun teaches quinazoline compounds and compositions thereof containing amine linker that reads on instant Formula I for treating cancer such as leukemia, breast cancer, or brain tumors (see Uckun at Abstract, at cols. 59-60, and claims 1, 9, 11-12), wherein Uckun R1 reads on instant R1 and R2 specifically R2 is alkoxy, Uckun Ra and Rb corresponds to instant R3-R7, instant E is N in the fused ring and instant E, G, H are C in the monocyclic ring specifically phenyl and A-D is NR’, specifically NH (compare Uckun claim 1 with instant claim 1 Formula I).
Regarding claims 6 and 8, Rodriguez-Abreu explains leukemia is a hematological cancer (see Rodriguez-Abreu at p. i3 “incidence rates”), and one skilled in the art would readily appreciate a brain tumor is a solid tumor.
Uckun General Formula
Instant Formula I
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The prior art differs from the instant claims as follows: While Uckun teaches compounds of Formula I for treating cancer, App’989 does not specify further combining with immunotherapy or chemotherapy, nor specify a dosing regimen.
Regarding instant claims 1, 10-12, 18 and combinations, Cook teaches chemotherapy and immunotherapy are anti-cancer treatments (see Cook at p. 23 “Introduction”). Cook teaches anti-cancer immunotherapies include checkpoint targeting agent such as CTLA-4, PD-1, and PD-L1 inhibitors (see Cook at p. 25 “Combining chemotherapy and checkpoint blockade”).
Regarding instant claims 13-17 and dosage regimens, Cook teaches cancer patients receive treatment cycles (see Cook at p. 26 right col.), and emphasizes the importance of scheduling individual components in chemoimmunotherapy combinations (see Cook at p. 25 right col. ¶2).
Regarding claim 18 and administration routes, Remington teaches various methods of formulating for administration routes (see Remington at p. xxi Contents and e.g. p.837 Chapter 42 “Intravenous Admixtures”).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding combinations, per MPEP § 2144.06(I), "[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to combine known anti-cancer treatments including the compounds of Uckun with chemotherapeutic or immunotherapeutic agents to treat cancer because Cook teaches chemotherapeutic and immunotherapeutic agents are anti-cancerous and can be used in combinations.
Regarding dosage regimens or administration routes, it would have been obvious to one skilled in the art to arrive at a dosage schedule through routine experimentation because Cook emphasizes the importance of timing when using anti-cancer combinations, and to have formulated the composition for an administration route because in order to treat a patient, the composition must be administered and Remington teaches formulations for different administration routes (see MPEP § 2144.05(II)).
Accordingly, claims 1-2, 6-19 are obvious over Uckun in view of Cook and Remington as exemplified by Rodriguez-Abreu.
Claim(s) 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Uckun in view of Cook and Remington as exemplified by Rodriguez-Abreu as applied to claims 1-2, 6-19 above and in further view of Popp et. al.5 and Patani et. al.6
Regarding claim 4, Uckun teaches compound 25 (see Uckun at col. 37) wherein the phenyl is a fused ring system and contemplates no substituents (see Uckun claim 5).
Uckun Compound 25
Instant Exemplary Compound
Claim 4
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The prior art differs from the claims as follows: While Uckun teaches compounds of instant Formula I, Uckun does not teach wherein the A-D linker is other than NH.
However,
Regarding instant linkers A and D, Popp teaches papaverine derivatives Formulas I-III wherein A-D is CH2, CHOH, or C=O (see Popp at p. 3773).
Instant Formula I
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Uckun General Formula
Popp Formulas I-III
Instant Exemplary Compound 17
Claim 3
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Popp even teaches compounds that differ only by -CH2- from instant (see Popp at 3773 and below).
Popp Formula I
Instant Exemplary Compound Claim 3
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Regarding -CH2- for -NH-, Patani teaches -NH- and -CH2- bioisosteric linkers result in analogues which retain activity (see Patani at p. 3156 right col. ¶1).
Regarding claim 5, Popp teaches an isomer of instant claim 5 (see Popp at p. 3773 and below).
Popp Formula II
Instant Exemplary Compound
Claim 5
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Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding linker changes, given that the Popp and Uckun’s teachings involve compounds that share core structural features and fall within the general class of papaverine derivatives (see also instant claim 3), a person of ordinary skill in the art would combine the teachings of Popp and Uckun by replacing NH with CH2 or CHOH or C=O to arrive at a claimed compound for treating cancer, because Uckun teaches the cores are for treating cancer, Popp teaches they are suitable linkers for papaverine derivatives, and additionally because the CH2 for NH approach is known to retain activity as taught by Patani.
Regarding changes in -CH2-, per MPEP § 2144.09(I)-(II), “[a] prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities” because compounds which are homologs, compounds differing e.g. by -CH2- groups, are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties (see, e.g., MPEP § 2144.09(I)-(II)). In addition, the Court has stated that “[i]f a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR, 127 S.Ct. at 1740.
Regarding isomers, MPEP § 2144.09(II) also states position isomers are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.
Accordingly claim(s) 3-5 are rejected as being obvious over over Uckun in view of Cook and Remington as exemplified by Rodriguez-Abreu as applied to claims 1-2, 6-19 and in further view of Popp and Patani.
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 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 15-17, 19-25, 27, 29 of copending Application No. 17/262,9897 (reference application) in view of Cook et. al.8 and Remington et. al.9 as exemplified by Rodriguez-Abreu. Although the claims at issue are not identical, they are not patentably distinct from each other.
The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis.
Regarding a compound of Formula I and claims 1-6, App’989 teaches compounds of Formula I with overlapping structural limitations (see App’989 claims 1, 15-17, 19-25, 27) and composition comprising said compounds (see App’989 claim 29).
App’989 Formula I
Instant Formula I
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Regarding a method and claims 1-9, per MPEP §804(II)(B)(1), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010). In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02. App’989 discloses the utility of treating hypoxic tumors (see App’989 at p. 2 lines 6-7) including cancerous tissues such as colorectal, breast, bladder, brain, cervical, gastrointestinal, genitourinary, head and neck, lung, pancreatic, prostate, renal, skin, or testicular (see App ‘989 at p. 4 lines 7-16), or sarcomas, leukemias, lymphomas, or multiple myelomas (see App’989 at p. 40 lines 15-30). Rodriguez-Abreu explains leukemia and lymphoma are hematological cancers (see Rodriguez-Abreu at p. i3 “incidence rates”).
The copending claims differ as follows: While App’989 claims the same compounds for the same uses, App’989 does not specify further combining with immunotherapy or chemotherapy, nor specify a dosing regimen.
However,
Regarding instant claims 1, 10-12, 18 and combinations, Cook teaches chemotherapy and immunotherapy are anti-cancer treatments (see Cook at p. 23 “Introduction”). Cook teaches anti-cancer immunotherapies include checkpoint targeting agent such as CTLA-4, PD-1, and PD-L1 inhibitors (see Cook at p. 25 “Combining chemotherapy and checkpoint blockade”).
Regarding instant claims 13-17 and dosage regimens, Cook teaches cancer patients receive treatment cycles (see Cook at p. 26 right col.), and emphasizes the importance of scheduling individual components in chemoimmunotherapy combinations (see Cook at p. 25 right col. ¶2).
Regarding claim 18 and administration routes, Remington teaches various methods of formulating for administration routes (see Remington at p. xxi Contents and e.g. p.837 Chapter 42 “Intravenous Admixtures”).
Therefore, it would have been obvious to one of ordinary skill in the art to arrive at the instantly claimed invention with a reasonable expectation of success in view of the copending application for at least the following reason(s):
Regarding combinations, per MPEP § 2144.06(I), "[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would have been obvious to combine known anti-cancer treatments including the compounds of App’989 with chemotherapeutic or immunotherapeutic agents to treat cancer because Cook teaches chemotherapeutic and immunotherapeutic agents are anti-cancerous and can be used in combinations.
Regarding dosage regimens or administration routes, it would have been obvious to one skilled in the art to arrive at a dosage schedule through routine experimentation because Cook emphasizes the importance of timing when using anti-cancer combinations, and to have formulated the composition for an administration route because in order to treat a patient, the composition must be administered and Remington teaches formulations for different administration routes (see MPEP § 2144.05(II)).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-19 are rejected.
THIS ACTION IS MADE FINAL. 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.
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/S.R./Examiner, Art Unit 1627
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613
1 Patented October 28, 2003. Hereinafter Uckun.
2 Cook et. al. "Chemotherapy and immunotherapy: mapping the road ahead" Current Opinion in Immunology 2016, 39, 23–29. DOI: 10.1016/j.coi.2015.12.003. Hereinafter Cook.
3 Remington's Pharmaceutical Sciences (21st Ed) New York, NY: Lippincott Williams and Wilkins 2005. Hereinafter Remington.
4 Rodriguez-Abreu et. al. “Epidemiology of hematological malignancies” Annals of Oncology 2007, 18, i3-i8. DOI: 10.1093/annonc/mdl443. Hereinafter Rodriguez-Abreu.
5 Popp et. al. "Synthesis of Papaverine, Papaverinol, and Papaveraldine from Reissert Compounds" J. Am. Chem. Soc. 1957, 79, 14, 3773-3777. DOI: 10.1021/ja01571a043. Hereinafter Popp.
6 Patani et. al. "Bioisosterism: A Rational Approach to Drug Design" Chem Rev 1996 96, 8, 3147-3176. DOI: 10.1021/cr950066q.
7 371 of PCT/US2019/043082 filed July 23, 2019 claiming benefit of PRO 62/702,201 filed July 23, 2018. Hereinafter App’989.
8 Cook et. al. "Chemotherapy and immunotherapy: mapping the road ahead" Current Opinion in Immunology 2016, 39, 23–29. DOI: 10.1016/j.coi.2015.12.003. Hereinafter Cook.
9 Remington's Pharmaceutical Sciences (21st Ed) New York, NY: Lippincott Williams and Wilkins 2005. Hereinafter Remington.