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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 15 October 2025 has been entered.
Status of the Claims
Claims 1-40 are pending in the instant application.
Claims 2, 9-10, 13-16, 25-26, and 36-37 are cancelled.
Claims 1, 3, 7, and 8 are amended.
Claims 4, 11, 17-24, 27-35, 38, and 39 are withdrawn from consideration.
Claims 1, 3, 5-8, 12, and 40 are examined herein.
Priority
The instant application claims benefit of priority to U.S. Provisional Application No. 62/746868 filed on 17 October 2018 and PCT/US219/056530, filed on 19 October 2019. The claims to the benefit of priority are acknowledged. As such, the effective filing date of the claims is 17 October 2018.
Information Disclosure Statement
The information disclosure statement (IDS), submitted on 15 April 2021, 22 April 2022, 08 June 2023, 08 November 2023, 28 February 2024, 12 June 2024, 31 July 2024, 08 January 2025, 06 February 2025, 10 July 2025, and 15 October 2025, are acknowledged and considered. The submissions are in compliance with the provisions of 37 CFR 1.97.
Response to Arguments
The amendment filed on 15 October 2025 has been entered.
In view of applicant argument, the 103 rejection of record is withdrawn as Benoit does not link the neuroprotective effect of QR2 to treating acute neural injuries, only chronic conditions.
In addition, new 103 rejections are necessitated by the request for continued examination.
All rejections and objections not found below have been withdrawn.
NEW REJECTIONS FACILITATED BY RCE
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, 3, 5, 12, and 40 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.
Claim 1 recites the method of treating acute neural injury comprising administering to a subject a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof. The applicant provides a definition of a prodrug and points to literature describing how to make prodrugs but the applicant provides no working examples of a prodrug. As the dependent claims do not remedy the issue they are subject to the rejection as well.
One of ordinary skill in the art would not be able to determine the scope of functional prodrugs of a compound of Formula I based on the specification. Strickley et al. (Formulation Challenges of Prodrugs. Prodrugs. 2007. Chapter 4.1.2. 383-410) discuss several formulation challenges presented with prodrugs, namely; chemical stability, reactive by-products, solubility, and polymorphism. The specification recites ester prodrugs as a type of prodrug the instant compounds of Formula I can be formulated into. Formulation of an ester prodrug would require the applicant to possess the knowledge of which esters would lead to a functional drug and which would not. Lillethorup et al. (RSC Med. Chem.2025;16:1037) details functional issues that arise with ester prodrugs. Due to their structure, ester prodrugs are released by both chemical and enzymatic hydrolysis. This combination of mechanisms can hinder the selectively of drug release. Additionally, an ester prodrug can by hydrolyzed in the gastrointestinal tract, releasing the active compound before it reaches its target and negating the drug’s efficacy while potentially inducing adverse side effects. Not all ester prodrugs will work; structure-function correlation is necessary to establish the bounds of a functional ester prodrug of Formula I. As the specification does not provide any structure-function correlation to support the bounds of a functional prodrug, nor are any examples presented in the instant specification, this suggests the applicant is not in possession of a functional prodrug of Formula I nor in possession of the knowledge of which prodrugs would or would not maintain the function of a compound of Formula I.
In conclusion, there is no structure-function correlation between what is and what is not a functional prodrug in the specification. Without the correlation between structure and function or an adequate representation of species functioning as a prodrug, the instant invention fails to comply with the written description requirement.
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.
Claim(s) 1, 3, 5-8, 12 and 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ware et al. (WO2006034235) in view of Cassagnes et al. (Free Radical Biology and Medicine.2018;120:56–61) and Rodriguez et al. (Current Medicinal Chemistry. 20104;21:1201-1211). This rejection pertains to the elected species.
Regarding claim 1 and 12, Ware teaches compounds of Formula I, for the inhibition of quinone reductase 2, which overlap with the scope of the instant Formula I when
R1 is H or CF3
R2 is NHR5, NR5R6, OR5 or SR5
R3 is H, Cl, or CF3
R4 is H or CF3
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Ware Formula I Instant Formula I
Ware does not explicitly teach the method of administering a compound of formula I for the treatment of acute neural injury.
Ware does teach the method of administering a compound of formula I for the inhibition of quinone reductase 2 (QR2) (claim 13).
Cassagnes teaches that inhibition of QR2 leads to reduction in reactive oxygen species and therefore a reduction in oxidative stress (page 58).
Cassagnes does not teach the inhibition of QR2 can treat acute neural injury.
Rodriguez et al. teaches traumatic brain injury (TBI), an acute neural injury, leads to oxidative stress page 1203) and explains antioxidant strategies are of great interest in the art (Abstract).
The instant application identifies the claimed quinoline derivatives as QR2 inhibitors. Cassagnes teaches QR2 inhibition reduces oxidative stress. Rodriguez links traumatic brain injury pathogenesis and oxidative stress. It would be prima facie obvious to one of ordinary skill in the art to combine the teaching of Ware, Cassagnes, and Rodriguez and arrive at the instant invention. Reduction of oxidative stress would lead to the treatment of TBI and Cassagnes teaches oxidative stress can be reduced with the inhibition of QR2. Substitution of the QR2 inhibitor identified by Cassagnes for one taught by Ware would be expected to have the same inhibitory effect.
Regarding claim 3, Ware teaches that the position corresponding to the instant Formula I X is CH (claim 1).
Regarding claim 5, Ware teaches that R1 can be H, and the positions corresponding to the instant formula R3 and R4 are H (claim 1).
Regarding claim 6, Ware teaches R3 to be Cl (claim 1).
Regarding claim 7, Ware teaches compounds of Formula I, overlapping in scope with compounds of Formula I(a) when
R1 is H
R2 is NHR5 or NR5R6
R3 is Cl
R4 is H
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Ware Formula I Instant Formula I(a)
Ware discloses several embodiments of compounds of Formula I that overlap in scope with the instant Formula I(a). Namely, compounds 2-1-2-31, 2-35, and 2-37-2-29, including the elected species, 7-chloro-N-methylquinoline-4-amine, taught as compound 2-39.
Regarding claim 8, Ware teaches the elected species, 7-chloro-N-methylquinoline-4-amine, as compound 2-39 (page 8).
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Regarding claim 40, Ware teaches compounds of Formula I, encompassing the species of claim 40 when
R1 is H
R2 is NHR5 and R5 is heteroaryl
R3 is Cl
R4 is H
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Ware does not teach a preferred embodiment of the species of instant claims 40, however Ware discloses compounds 2-4 and 2-7 (page 6). These compounds have the R5 substituent of C1-2 alkyl substituted with a heteroaryl moiety (2- or 3-pyridine).
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In KSR International Vo. V. Teleflex Inc., 82 USPQ2d (U.S. 2007), the Supreme Court particularly emphasized “the need for caution in granting a patent based on a combination of elements found in the prior art,” (Id. At 1395) and discussed circumstances in which a patent might be determined to be obvious.
In this case at least prong B of KSR applies – substitution of one known element for another. As Ware teaches R5 be heteroaryl, and has preferred embodiments with 2- and 3- pyridine, it would be obvious to one of ordinary skill in the art to replace the alkyl heteroaryl substituents of embodiment 2-4 and 2-7 with just the heteroaryl substituent, arriving at the instantly claimed compounds.
Thus, all of the elements of claims were known to one of ordinary skill in the art at the time the invention was made and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art at the time of invention. Therefore, the claimed invention, as a whole, would have been obvious to one of ordinary skill in that art at the time the invention was made.
Conclusion
Claims 1, 3-8, 12, and 40 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jerica K Wilson whose telephone number is (703)756-4690. The examiner can normally be reached Monday-Friday 9:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on (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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/J.K.W./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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