ENAMINE N-OXIDES: SYNTHESIS AND APPLICATION TO HYPOXIA-RESPONSIVE PRODRUGS AND IMAGING AGENTS

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 This action is in response to a request for continued examination received August 31st, 2026. Status of Claims Claims 1, 50, 96-97, 106, and 124 are pending in the instant application. Claims 2-49, 51-95, 98-105, and 107-123 have been canceled. Information Disclosure Statement The Information Disclosure Statements received on May 15th, 2026 and August 31st, 2026 have been fully considered by the examiner, except where marked with a strikethrough. Withdrawn Objections/Rejections Applicant’s amendment is sufficient to overcome the rejection of Claims 1-2, 4, 10, 13, 15-16, 22, 24-25, 31-34, 37, 40, 43, 45, 50, 96-97, and 106 on the basis that it contains an improper Markush grouping of alternatives. Applicant’s cancellation of Claims 2, 4, 10, 13, 15-16, 22, 24-25, 31-34, 37, 40, 43, and 45 renders the rejection thereof moot. This rejection is hereby withdrawn. Applicant’s amendment is sufficient to overcome the rejection of Claims 1-2, 4, 10, 13, 15-16, 22, 24-25, 31-34, 37, 40, 43, 50, 96-97, and 106 under 35 U.S.C. 112(a). Applicant’s cancellation of Claims 2, 4, 10, 13, 15-16, 22, 24-25, 31-34, 37, 40, 43, and 45 renders the rejection thereof moot. This rejection is hereby withdrawn. Applicant’s cancellation of Claims 52 and 107 renders the rejection thereof under 35 U.S.C. 112(a) moot. This rejection is hereby withdrawn. Applicant’s amendment is sufficient to overcome the rejection of Claim 97 under 35 U.S.C. 112(a). This rejection is hereby withdrawn. Applicant’s amendment is sufficient to overcome the rejections of Claims 1-2, 22, 31-33, 43, 52, 97, and 106-107 under 35 U.S.C. 112(b). Applicant’s cancellation of Claims 2, 22, 31-33, 43, 45, and 52 renders the rejections thereof moot. These rejections are hereby withdrawn. Applicant’s cancellation of Claim 22 renders the rejection thereof under 35 U.S.C. 112(d) moot. This rejection is hereby withdrawn. Applicant’s amendment is sufficient to overcome the rejection of Claims 1-2, 13, and 43 under 35 U.S.C. 102(a)(1). Applicant’s cancellation of Claims 2, 13, and 43 renders the rejection thereof moot. This rejection is hereby withdrawn. 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, 50, 96-97, 106, and 124 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Nature of the invention: The invention is drawn to compounds having a structure represented by formula I as recited at instant Claim 1, a method of treating a disease or disorder comprising administration of said compounds as recited at instant Claim 97, a process of preparing said compounds as recited at instant Claim 106, or compounds represented by formula II as recited at instant Claim 124. Breadth of the invention: The scope of the claimed invention is very broad, as compounds of both formula I and II must possess the moiety A, wherein A is a therapeutic moiety comprising an anticancer agent or apoptotic agent. This includes a myriad of chemical moieties readily envisaged by a person having ordinary skill in the art, but also includes moieties either presently unknown, or those that are known, but later to be discovered to have anticancer and/or apoptotic properties. Can Applicant simply “reach through” and obtain patent protection for compounds that either are yet to be discovered, or those that are discovered, but later classified as anticancer or apoptotic agents? The specification does not sufficiently define “anticancer agent” or “apoptotic agent” such that a person having ordinary skill in the art would readily understand which moieties reading on these limitations are appropriate for use within the context of the instant invention. Level of ordinary skill in the art: An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems. State of the prior art and predictability in the art: With respect to anticancer agents, Meegan et. al., (“Special Issue ‘Anticancer Drugs’”, Pharmaceuticals, 2019; hereinafter referred to as Meegan) represents the state of the prior art. At the Abstract, Meegan teaches anticancer agents include chemotherapeutic agents, targeted therapies, and biological agents. Further, Meegan states, “We have included articles that report the design of small molecules with promising anticancer activity as tubulin inhibitors, vascular targeting agents, and topoisomerase targeting agents…” At the Third Paragraph of the first page, Meegan states, “Chemotherapy is one of the most powerful tools available for treating cancer, and research continues to find new chemotherapy drugs, as well as new uses for existing ones.” Taken together, Meegan demonstrates that the term “anticancer agent” is readily understood to encompass an array of chemical moieties with distinct functionalities and structures that are not obvious variants of each other. Further, Meegan establishes the ongoing discovery of new anticancer agents or the repurposing of known agents for anticancer applications. In view of Meegan, the inclusion of an “anticancer agent” as a component of a compound of formula I or II encompasses a diverse array of distinct chemical moieties that are not obvious variants of each other. The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F. 2d 833, 839, 166, USPQ 18, 24 (CCPA 1970). In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F. 2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F. 2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F. 2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657. The amount of direction provided and working examples: The specification provides no examples of compounds of formula I or II. As such, it is unreasonable for a person having ordinary skill in the art to ascertain which anticancer agents or apoptotic agents are suitable for inclusion in the compounds of formula I or II. To this end, claims drawn to a process of making such compounds, or claims to methods comprising administration of the claimed compounds are not enabled, as the instant disclosure provides no working examples of making or administering such a compound. Within the specification, “specific operative embodiments of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims.” Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the dislcsure is not sufficient to support claims identifying the compound by such composition or formula. See MPEP 608.01(p). MPEP § 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here that Applicant is not enabled for compounds of formula I or formula II. 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 1, 50, 96-97, 106, and 124 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 1 is rendered indefinite, as R4 can be hydrogen or halogen, which are monovalent groups. R4 must be a divalent group, as it is bound to the core structure of formula I and the moiety A. Additionally, Claim 1 is rendered indefinite due to the limitation that “A is a therapeutic moiety comprising an anticancer agent or apoptotic agent.” Based on the instant disclosure, a person having ordinary skill in the art would not reasonably be able to ascertain the metes and bounds of this limitation, as these limitations would readily be understood by a person having ordinary skill in the art would readily understand “anticancer agent” and “apoptotic agent” to encompass a number of distinct chemical moieties. Claims 96-97 do not resolve these issues of indefiniteness, and are therefore included in this rejection. Claim 50 recites several structures that lack antecedent basis. The following structures lack antecedent basis as R7 and R8 do not allow for substituted alkyl groups: PNG media_image1.png 162 156 media_image1.png Greyscale , PNG media_image2.png 192 646 media_image2.png Greyscale The following structures do not read on a compound of formula I: PNG media_image3.png 168 418 media_image3.png Greyscale PNG media_image4.png 153 661 media_image4.png Greyscale PNG media_image5.png 211 669 media_image5.png Greyscale PNG media_image6.png 107 171 media_image6.png Greyscale . The following structures lack antecedent basis, as they require either substitution of variables R2-R4: PNG media_image7.png 106 151 media_image7.png Greyscale PNG media_image8.png 247 195 media_image8.png Greyscale , and PNG media_image9.png 204 315 media_image9.png Greyscale . Additionally, at Claim 50, the structure PNG media_image10.png 198 286 media_image10.png Greyscale is not charge-balanced, and therefore is not a compound. Claim 106 is rendered indefinite, as R4 can be hydrogen or halogen, which are monovalent groups. R4 must be a divalent group, as it is bound to the core structure of formula I or formula II and the moiety A. Additionally, Claim 106 is rendered indefinite due to the limitation that “A is a therapeutic moiety comprising an anticancer agent or apoptotic agent.” Based on the instant disclosure, a person having ordinary skill in the art would not reasonably be able to ascertain the metes and bounds of this limitation, as these limitations would readily be understood by a person having ordinary skill in the art would readily understand “anticancer agent” and “apoptotic agent” to encompass a number of distinct chemical moieties. Claim 124 is rendered indefinite, as R4 can be hydrogen or halogen, which are monovalent groups. R4 must be a divalent group, as it is bound to the core structure of formula I and the moiety A. Additionally, Claim 124 is rendered indefinite due to the limitation that “A is therapeutic moiety comprising an anticancer agent or apoptotic agent.” Based on the instant disclosure, a person having ordinary skill in the art would not reasonably be able to ascertain the metes and bounds of this limitation, as these limitations would readily be understood by a person having ordinary skill in the art would readily understand “anticancer agent” and “apoptotic agent” to encompass a number of distinct chemical moieties. 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. Claim 97 is 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. Claim 97 improperly expands the scope of Claim 1, as it defines A as a therapeutic moiety. This limitation can include therapeutic moieties that do not comprise an anticancer agent or apoptotic agent as recited at Claim 1. Therefore, this limitation, as recited at Claim 97 can include A moieties that do not read on the limitation as recited at Claim 1. 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, 50, 96-97, 106, and 124 are rejected. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIEL JOHN BURKETT whose telephone number is (703)756-5390. The examiner can normally be reached Monday - Friday. 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 use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /D.J.B./ Examiner, Art Unit 1624 /BRENDA L COLEMAN/ Primary Examiner, Art Unit 1624