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
This action is responsive to the amended claims of 04/03/2026. Claims 1-7 and 9-20 are pending. Claims 12-20 are new. Claims 1-7 and 9-20 have been examined on the merits.
Election/Restrictions
Applicant's election with traverse of compound TG15-132 (below) and traumatic brain injury (TBI) in the reply filed on 04/03/2026 is acknowledged. The traversal is on the ground(s) that the examination of the claims does not create an undue search burden. This is not found persuasive because search burden is not the standard by which election requirements are made in 371 National Stage applications - instead Unity of Invention analysis is applied. As stated in the action of 02/04/2026 (Pg. 5-7 ¶5), the species of the invention lack unity because they differ in structure or etiology. The requirement is still deemed proper and is therefore made FINAL.
The search for the elected species TG15-132
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did not retrieve any art (see SEARCH 6 of the attached search notes). Thus, the Markush search was extended. The search encompassed the entire scope of Formula (I), salt, and prodrug thereof – no prior art was retrieved. Since the search did not return prior art for the full scope of the Markush group of Formula (I), the election requirement for both the compound of Formula (I) and the Nox related disease is rendered moot and is withdrawn.
Thus, claims 1-7 and 9-20 have been examined on the merits.
Priority
The effective filing date is 04/19/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/16/2024 and 05/20/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claim 10 is objected to because of the following informalities: there is a typo in line 2. Please add the word “a” before “subject” in line 2. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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, 4-7, and 9-20 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. This is a written description rejection.
MPEP 2163(I) states “The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant [inventor] has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee [inventor] was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005).”
Factors considered in making the determination as to whether the artisan would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing include: (a) Actual reduction to practice; (b) Disclosure of drawings or structural chemical formulas; (c) Sufficient relevant identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and knowledge in the art and (f) Predictability in the art.
The Instant Disclosure:
Claim 1 is broadly drawn to any possible prodrug of Formula (I) wherein “prodrug” is not limited to any defined structural subset. The dependent claims 4-7 and 9-20 do not provide any further limitations to “prodrug” of Formula (I). The claimed compounds are expected to have pharmacological utility in the treatment of diseases (instant claims 6-7, 9-10, 13-14, and 16-20). This lack of structural definition does not allow the artisan to envisage the compounds which are part of the invention (see Factors (b) and (c) above).
The specification discloses the term “prodrug” refers to an agent that is converted into a biologically active form in vivo by various mechanisms including enzymatic and metabolic processes (Pg. 8 ¶1). The same paragraph provides generic examples of prodrugs defined by generic functional groups (e.g., esters, formamide, etc.), but these are non-limiting.
Moreover, the specification provides synthetic schemes for a handful of compounds of Formula (I) (Pg. 21-22), but does not call out any exemplary prodrugs of the Formula (I). The specification discloses exemplary species of Formula (I) and some related compounds in Table 2: e.g.,
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(Pg. 23),
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(Pg. 24), and
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(Pg. 25). However, Applicant does not refer to these related compounds as prodrugs of Formula (I), nor does Applicant provide any data/support to show that these compounds function as prodrugs of Formula (I). Thus, Factors (a) and (d), above, are not met.
MPEP 2163(II)(A)(2) states “The disclosure of an element may be critical where those of ordinary skill in the art would require it to understand that inventor was in possession of the invention… Amgen, Inc. v. Chugai Pharm.Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) ("it is well established in our law that conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it").” After review of the specification and claims, the Examiner finds that Applicants have not defined the prodrug of Formula (I) in a way that distinguishes it from other materials (i.e., see the prior art references applied below) and Applicants have not described how to obtain prodrugs of Formula (I). Thus, it has not been demonstrated that the Applicant was in possession of the invention that is claimed (i.e., any and all prodrugs of Formula (I)). Moreover, as drafted, “prodrug” would encompass compounds which have not yet been discovered and/or those with uncharacterized metabolic pathways.
Level of Skill and Knowledge in the Art:
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a synthetic chemist and/or health practitioner with several years of professional experience. However, this factor is outweighed by the unpredictable nature of the pharmaceutical art. It is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which prodrugs exhibit the desired pharmacological activity (e.g. the ability to inhibit Nox).
HAN (Han, H., AAPS PharmsciTech., 2000, 2, 1-11) describes that some prodrug forms are not chemically or structurally related to their active form, for example, both glucose
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and hypoxanthine
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are prodrug forms of hydrogen peroxide
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(Pg. 5 Table 1). In view of HAN and the open-ended nature of “prodrug” as defined by the instant disclosure, the artisan would not have sufficient guidance as to what a “prodrug” of Formula (I) encompasses.
FDA (FDA Drug Safety Communication: Reduced Effectiveness of Plavix (Clopidogrel) in Patients Who are Poor Metabolizers of the Drug, 2017, pp. 1-2) states that a prodrug, Plavix, was found to have reduced effectiveness in patients who are poor metabolizers of Plavix (Pg. 1 P4). Thus, given that the enzyme responsible for transformation of the prodrug into the parental drug was unable to convert the drug to its active form, patients who are poor metabolizers had reduced effectiveness of the drug (Pg. 1). As a result, predictability of “prodrug” efficacy in the art is understood as a challenge facing the artisan.
Without guidance as to what structures correspond to viable prodrugs of the Formula (I), especially in view of their use in method claims 6-7, 9-10, and 12-20, Factors (e) and (f) are not met.
Conclusions:
Due to the breadth of “prodrug” of Formula (I), the lack of direction given in the claims/specification regarding embodiments of such which show the desired activity, and the challenges in the art, the artisan would not be able to immediately envisage the breadth of prodrug of Formula (I).
Methods of making compounds, in general, are known to the artisan, however the instant disclosure does not inform the artisan of what combination of elements are present in the instant prodrugs and if a prodrug possesses the required pharmacological activity. As such, the instant specification fails to provide guidance to overcome the complexity and difficulties known to the artisan, as discussed above. Accordingly, the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to the artisan that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Thus, claims 1, 4-7, and 9-20 are rejected as lacking written description for the full scope of “prodrug” of Formula (I). To overcome this rejection, Applicants are encouraged to strike prodrug from the claims.
Claims 6-7, 9-10, and 12-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of Nox related diseases (claim 6) including central nervous system disorders (claim 9) and tissue injury (claim 10), does not reasonably provide enablement for prevention thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
The Wands Factors used in a scope of enablement rejection include (per MPEP 2164.01(a)):
The nature of the invention & breadth of the claims:
The invention belongs to pharmaceutical technology, more specifically, medicinal therapy involving administration of an NADPH oxidase (Nox) inhibitor.
Claims 6-7 and 12-17 are drawn to the treatment of Nox related diseases by administering a compound of Formula (I) – wherein the compound inhibits Nox (see specification Pg. 1-2 bridge ¶). Claims 9 and 18-20 are drawn to treatment of central nervous system diseases by administering the compound of Formula (I). Claim 10 is drawn to prevention of tissue injury by administering the compound of Formula (I). Thus, claims 9-10 and 18-20 are understood as similarly drawn to inhibition of Nox to effect treatment. The specification defines “treat” and “treating” as inclusive of delaying onset of disease progression (Pg. 8 last ¶). Since delaying onset includes not having the disease at all, treat/treating is understood to include prevention.
The claims are somewhat broad in the compound administered. Formula (I) encompasses a multitude of species; however, these species share a significant core structure.
The level of one of ordinary skill, the state of the prior art, & predictability of the art:
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant's invention would generally be a physician with an M.D. degree and several years of experience. This factor is outweighed, however, by the unpredictable nature of the art. It is well established that "the scope of enablement varies with the degree of unpredictability of the factors involved" and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved).
DEVALLENCE (DeVallence, E. et al., Antioxidants & Redox Signaling, 2019, 31(10), 687-709) and BEDARD (Bedard, K. et al., Antioxidants & Redox Signaling, 2015, 23(5), 357-359) are representative of the state of the prior art and predictability thereof.
DEVALLENCE discusses the targeting of Nox enzymes as potential therapy (Pg. 687 Abstract); however, they acknowledge the challenge of addressing the exact mechanisms through which redox signaling is propagated – whether Nox directly oxidizes kinase cysteines is poorly understood and remains a critical question in the field (Pg. 688 Right Col. ¶1). DEVALLENCE notes multiple other observations of pathways involving Nox signaling are still unknown (Pg. 695 Right Col. ¶1; Pg. 689 Left Col. ¶3 & Right Col. last ¶; Pg. 690 Left Col. ¶1). Further, DEVALLENCE states it is likely that pan inhibition of Nox enzymes will not be a plausible therapeutic strategy (Pg. 700 Conclusion).
BEDARD teaches much evidence indicates Nox enzymes are a valid target in pharmacology; despite this, as of the time of publication, no Nox targeting molecules were available in the clinic (Pg. 355 Left Col. ¶1). While expression levels of Nox enzymes are often increased in pathological states it is not always clear if this increased expression translates into oxidative damage and contributes to pathology (Pg. 355 Right Col. ¶1). BEDARD states “we are still at the early stages of the comprehension of the full range of biological roles of Nox derived ROS” (Pg. 355 Right ¶1).
In view of the relevant prior art, the artisan would not be enabled to prevent the instantly claimed diseases by administration of the instant compound of Formula (I) which acts as a Nox inhibtor. Since BEDARD and DEVALLENCE both teach a lack of understanding surrounding the exact role of Nox in oxidative damage and disease progression, the artisan would not be able to predict the success of disease prevention by inhibition of Nox.
The level of one of ordinary skill includes the ability to engage in a reasonable amount of experimentation to treat the claimed diseases, such as by reducing symptoms of the disease. However, the skill of the artisan, especially in view of the relevant prior art, does not overcome the undue burdensome level of experimentation required to provide enablement for completely delaying disease onset or preventing Nox related diseases, central nervous system disorders, and tissue injury by inhibiting Nox.
The amount of direction provided by the inventor and the existence of working examples:
Inventors have provided experimental data of the pharmacokinetics of exemplary compounds of Formula (I) (see Pg. 22-26 Table 1-2 of the instant Specification). These results show the exemplary compounds have good CNS permeability, water solubility, and liver microsomal stability (Pg. 22 last ¶). Table 2 describes the inhibitory activity of exemplary compounds against Nox isoforms 1, 2, and 4. Further, Figure 7 provides evidence that treatment with an exemplary compound of Formula (I) suppresses inflammatory markers of Nox2. Thus, the artisan would expect the instant compounds of Formula (I) to have some inhibitory action on Nox enzymes.
Applicant does not provide any in vivo data of treatment of disease progression in an animal model. Importantly, no data is provided which shows the instant compounds can delay the onset of or prevent Nox related diseases including central nervous system disorders and tissue injury.
This guidance does not support preventing the claimed diseases, especially in view of the relevant prior art. Applicant has guidance/enablement in their Specification for treating the claimed diseases by administering the compound of Formula (I) – except wherein treatment delays progression of disease so that the disease is effectively prevented.
The quantity of experimentation needed to make or use the invention:
Applicants’ invention requires a high level/quantity of experimentation to use the invention for prevention of Nox related diseases including central nervous system disorder and tissue injury. While Applicants have provided guidance in their Specification for inhibiting Nox with the instant compounds, they have not provided enough evidence that said compounds can prevent the claimed diseases. At best, the Specification does provide enablement/guidance for using the instant compounds of Formula (I) to treat (not prevent) the claimed diseases. Furthermore, in view of the challenges discussed above, the artisan would not be able to turn to the art to supplement the instant guidance and enable the prevention of such diseases.
Therefore, claims 6-7, 9-10, and 12-20 are rejected under 35 USC 112(a) for lacking scope of enablement for preventing the claimed diseases.
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 6-7 and 12-17 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.
Claim 6 recites the limitation "a composition of claim 1" in line 1-2. There is insufficient antecedent basis for this limitation in the claim. Parent claim 1 is drawn to a compound not a composition; however, claim 6 recites a composition of claim 1. Thus, the metes and bounds of the claim are undefined rendering the claim indefinite.
Claims 7 and 12-17 are similarly rejected since they depend from claim 6 and do not rectify the underlying issue.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6-7 and 12-17 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 6-7 and 12-17 recite “a composition of claim 1”; however, parent claim 1 does not recite a composition – only a compound. Thus, claims 6-7 and 12-17 are drawn to a scope outside of parent claim 1 and do not properly further limit the parent claim. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
Claims 1, 4-7, and 9-20 are rejected.
Claims 2-3 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: the closest prior art is considered HARUTYUNYAN (Harutyunyan et al., Russian Journal of Organic Chemistry, 2019, 55(9), 1363-1369; provided in IDS 05/20/2025) and LAMBETH (WO 2013/181135; provided in IDS 01/26/2024).
HARUTYUNYAN teaches compound 4g
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where R3 is 1-methyl-1H-indol-3-yl (Pg. 1364 Scheme 1); i.e.,
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. Compound 4g reads on the prodrug of Formula (I): R1, R3-R5, and R7-R10 are each H; R2 is halogen; R6 is methyl; X is –(Q)n-Y wherein n is 2, each Q is CH2, and Y is aryl; and m is 2. The compound of HARUTYUNYAN differs from the instant: Z cannot be CH=CH. Further, HARUTYUNYAN does not teach the compound as having any confirmed pharmacological properties (the compound is not taught as a Nox inhibitor). This constitutes 2 differences from the instant compounds. Further, the reference does not teach any other species analogous to the instant Formula (I). Thus, HARUTYUNYAN cannot teach or suggest the instant compound of Formula (I).
LAMBETH teaches compound AS148A
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(Pg. 22 Table 3). Compound AS148A shares with instant Formula (I) the quinazoline core wherein X is –(Q)n-Y, n is 3, each Q is CH2, and Y is dialkylamine. Further, Z is S-CH2-C(O)-NH and m is 4. AS148A does not have R2 = halogen and is missing the instant indole. AS148A is the most analogous species taught by LAMBETH. Thus, LAMBETH cannot teach or suggest the instant compound of Formula (I). Furthermore, the artisan would not combine the references HARUTYUNYAN and LAMBETH since: 1) HARUTYUNYAN teaches not pharmacological properties of the compound and 2) the two exemplary compounds comprise many more than 2 structural differences.
Thus, the claims 1-7 and 9-20 are found free of the prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA ELIZABETH BELL whose telephone number is (703)756-5372. The examiner can normally be reached Monday-Friday 9:00-5:30.
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/S.E.B./Examiner, Art Unit 1625
/NOBLE E JARRELL/Primary Examiner, Art Unit 1699
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