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 .
Status of Claims
Claims 1-2, 4, 10, 13, 15-16, 22, 24-25, 31-34, 37, 40, 43, 45, 50, 52, 96-97, and 106-107 are pending in the instant application.
Claims 3, 5-9, 11-12, 14, 17-21, 23, 26-30, 35-36, 38-39, 41-42, 44, 46-49, 51, 53-95, 98-105, and 108-123 have been canceled.
Withdrawn Objections/Rejections
Applicant’s amendment is sufficient to overcome the objection to the specification. This objection is hereby withdrawn.
Applicant’s amendment is sufficient to overcome the rejection of Claims 1-2, 13, 22, 40, and 43 under 35 U.S.C. 102(a)(1). This rejection is hereby withdrawn.
Information Disclosure Statement:
The Information Disclosure Statement received January 23rd, 2026 has been fully considered by the examiner, except where marked with a strikethrough.
Claim Rejections – Improper Markush Grouping
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 is maintained. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Applicant has traversed this rejection in the remarks received May 8th, 2026. First, at Page 25 of the remarks, Applicant asserts “Thus, the joining features of the claimed compounds are recited in the claim (structurally) as the N-oxide molecules. The design of the enamine N-oxide itself (including the α,β-unsaturation) facilitates selection of the other moieties at issue.”
The examiner does not find this argument persuasive. With regard to a single structural similarity, the N-oxide moiety and α,β-unsaturation are not substantial enough to constitute a proper Markush grouping. In fact, at Page 25 of the remarks, Applicant emphasizes from Paragraph [00271] of the specification that “… confirming the essentiality of the internal olefin in translating an N-oxide reduction event to the release of a leaving group.” This underscores that the common structure necessary to lead to the common function of the Markush grouping instantly recited is an internal olefin. As recited, Claim 1 allows R1 to be defined as hydrogen. Defining R1 as hydrogen results in a compound of formula II possessing a terminal, rather than internal, olefin.
Additionally, Applicant traverses the rejection stating at Page 25 of the remarks, “These disclosures, taken together with the other teachings in the specification, the working examples, and the state of the art, emphasize why the groups at issue should not have to be separated in terms of structure and are appropriately written in claim 1.”
The examiner does not find this reasoning persuasive. In addition to the presence of the N-oxide moiety and α,β-unsaturation not being significant enough of a structural similarity to constitute a proper Markush grouping, the substantial lack of variability or recitation of any further limitations beyond “therapeutic moiety” and “diagnostic moiety” leads to a grouping of compounds that share no substantial structural variability, do not share a common use, and are not obvious variants of each other. Applicant points to the instant disclosure in rebuttal of this. Applicant points to paragraphs [0063] and [00104]-[00110] of the instant specification as sufficient to explain the structure and role of therapeutic moieties. This is insufficiently limiting so as to constitute a proper Markush grouping. Paragraph [0063] is directed to an active moiety, which is not recited as a limitation in the instant Claims. Paragraph [0064] defines the term therapeutic moiety as “a portion of a portion of an inventive compound that provides a therapeutic effect with respect to a disease or disorder when it reaches it intended site of action, which in this case is hypoxic tissue.” Paragraphs [00104]-[00110] of the instant application provides representative examples of anti-cancer agents (paragraphs [00104] and [00106]), non-targeted agents (paragraph [00105]), a hypoxia-inducible factor inhibitor (paragraph [00107]), apoptotic agents (paragraph [00108]), non-steroidal anti-inflammatory drugs (NSAIDs) (paragraph [00109]), and disease-modifying antirheumatic drugs (DMARDs) (paragraph [00110]). Within these representative examples are broad categories of potential moieties such as alkylating agents or substituted ureas. Further, these are representative, non-limiting examples. Based on the recited claim limitations and the instant disclosure, a person having ordinary skill in the art is unable to ascertain which therapeutic moieties are appropriately included in this Markush grouping. Further, these include moieties with disparate functions sharing no structural similarity and can include structurally diverse compounds that significantly alter the core structure and function of compounds including in this Markush grouping.
Similarly, Applicant points to paragraphs [0071]-[0078] to explain the structure and role of diagnostic moieties. Paragraph [0071] states “Diagnostic moieties typically contain a detectable moiety such as a label.” Paragraph [0072] states “In certain embodiments, the label comprises a fluorescent dye.” Paragraph [0073] states “In certain embodiments, the diagnostic moiety includes a rhodamine dye.” Paragraph [0074] states “In some embodiments, the diagnostic moiety is an affinity tag, which is known in the art refers to agents that take part in an interaction (e.g., antigen and antibody, enzyme and substrate, receptor and ligand) that facilitates capture and/or purification of the molecule.” Paragraph [0075] states “In some embodiments, the diagnostic moiety is a chromogenic agent, which as known in the art refers to a chemical compound that induces a color reaction.” Paragraph [0076] states, “In some embodiments, the diagnostic moiety is a PET tracer, which as known in the art refers to a radioligand used for imaging purposes.” Paragraph [0077] states “In some embodiments, the diagnostic moiety is a MRI contrast agent, which as known in the art refers to an agent that is used to improve the visibility of internal body structures.” Paragraph [0078] states “In some embodiments, the diagnostic moiety is an intercalating agent, which as known in the art refers to an agent that inserted between the stacked base pairs of DNA.” In view of these examples, it is clear that the limitation “diagnostic moiety” includes compounds with disparate functions lacking any structural similarity, and are capable of producing compounds in this Markush grouping that are structurally diverse such that no significant structural similarity or common function is shared.
Regarding the term “leaving group”, Applicant points to paragraph [0070] which defines a leaving group as “an atom or group of atoms which breaks away from the rest of the molecule, taking with it the electron pair which used to be the bond between the leaving group and the rest of the molecule.” The representative examples shared are non-limiting and results in a grouping of moieties with distinct structural characteristics and functions.
In view of the foregoing, this Markush grouping is improper. Despite the requirement that compounds share an N-oxide and α,β-unsaturated moiety, this limitation is insufficient to properly define a Markush grouping as the variability in the other moieties present are such that this structural limitation is insignificant in consideration of the diverse number of compounds with disparate structures that are non-obvious variants of each other encompassed by this Markush grouping, and as noted above, these compounds do not share a common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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.
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 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is maintained, because the specification, while being enabling for a compound of Formula I or II wherein R1 is hydrogen, R2-4 are hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or halogen and R7 and R8 are C1-8 alkyl, C3-10 carbocyclyl, or R7 and R8 together form a 4- to -7membered heterocyclyl comprising 1 to 2 heteroatoms selected from N or O, does not reasonably provide enablement for compounds of Formula I or II in which R1-4 and R7-8 are defined as variables other than these. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Applicant has traversed this rejection, stating at the remarks filed May 8th, 2026 at Page 27, second paragraph that, “the claims are adequately supported in terms of apprising persons skilled in the art as to their meaning of each of the terms and provide numerous representative examples of each such that a skilled artisan would understand their meaning.” Further, at the third paragraph at Page 27, Applicant states, “The working examples, conducted in vitro and in vivo, support the scope of the claims. In establishing proof-of-principle, they show that the operability of the compounds does not depend on a specific cleavable linking group, leaving group, therapeutic or diagnostic moiety, and those skilled in the art would appreciate the meaning of each term, as described and exemplified in the application.”
The examiner does not find this persuasive. The representative examples that Applicant refers to are non-limiting and structurally diverse. The instantly rejected claims are drawn to compounds themselves, a method of treatment comprising administration of these compounds, or a process of preparing these compounds. The existence of such compounds comprising such distinct moieties illustrated by representative examples, for example at Paragraphs [0071-0078] and [00104-00110] are speculative. The working examples are not enabling for the breadth of compounds instantly claimed. This, in addition to preponderance of the Wands factors, revisited below, supports the propriety of this rejection.
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 a compound having a structure represented by formula I or formula II.
Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to any compounds of the formulas:
PNG
media_image1.png
106
356
media_image1.png
Greyscale
allowing not only of a myriad of substituents recited as definitions for R1-4 and R7-8, but also the broadly defined “linking group”, “diagnostic moiety”, and “therapeutic moiety”.
State of the prior art and predictability in the art:
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.
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.
The amount of direction provided and working examples:
The compound core depicted with specific substituents represents a narrow subgenus for which applicant has provided sufficient guidance to make and use; however, this disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts thereof where R1-4 and R7-8 were not defined as mentioned above in the present application.
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 disclosure 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 making these compounds.
The rejection of Claims 52 and 107 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 is maintained. 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.
Applicant has traversed this rejection, stating at the remarks filed May 8th, 2026 at Page 27, second paragraph that, “the claims are adequately supported in terms of apprising persons skilled in the art as to their meaning of each of the terms and provide numerous representative examples of each such that a skilled artisan would understand their meaning.” Further, at the third paragraph at Page 27, Applicant states, “The working examples, conducted in vitro and in vivo, support the scope of the claims. In establishing proof-of-principle, they show that the operability of the compounds does not depend on a specific cleavable linking group, leaving group, therapeutic or diagnostic moiety, and those skilled in the art would appreciate the meaning of each term, as described and exemplified in the application.”
The examiner does not find this persuasive. The representative examples that Applicant refers to are non-limiting and structurally diverse. Applicant has pointed to no working examples of a compound of formula III or IV. The existence of such compounds comprising such distinct moieties illustrated by representative examples, for example at Paragraphs [0071-0078] and [00104-00110] are speculative. The working examples are not enabling for the breadth of compounds instantly claimed. This, in addition to preponderance of the Wands factors, revisited below, supports the propriety of this rejection.
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 of Formula III or IV.
Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to any compounds of the formulas:
PNG
media_image2.png
132
326
media_image2.png
Greyscale
State of the prior art and predictability in the art:
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.
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.
The amount of direction provided and working examples:
Applicant has provided no working examples of a compound of formula III or a compound of formula IV. Beginning at Page 59 of the instant specification, Applicant has provided structures of a compound of formula (III), listing variables R1-4 and A. Further, at Page 60, structures are provided with generic labels of, for example, “Therapeutic Moiety”, “Diagnostic Moiety”, and “LG”. Similarly, Applicant presents structures for compounds of formula (IV) beginning at Page 67 of the instant specification. As above, these structures include the variables R1-4 and “A”. Further, beginning at Page 68 of the instant specification, Applicant provides structures of compounds of formula IV using generic labels like “Diagnostic Moiety” and “Therapeutic Moiety”.
Nowhere in the instant disclosure has Applicant provided a specific working example with sufficient characterization data of a compound of formula III and/or formula IV, with all variables fully defined. As presented, Applicant has disclosed speculative examples of compounds of a generic formula III or formula IV, with ambiguous labels leading to innumerable compounds that could be encompassed by these formulas to be envisaged by a person having ordinary skill in the art. Insufficient guidance has been provided for a person having ordinary skill in the art to understand, for example, which moieties should be selected as a “diagnostic moiety” or a “therapeutic moiety” to be included as a part of a compound III or IV, nor would it be readily understood based on the instant disclosure the motivation for selecting a particular moiety that could satisfy this broad characterization.
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 disclosure 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 making these compounds.
The rejection of Claim 97 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is maintained, because the specification, while being enabling for treating lung cancer, skin cancer, and pancreatic cancer, does not reasonably provide enablement for treating any disease or disorder characterized by, or associated with or exhibiting tissue hypoxia. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Applicant has traversed this rejection, suggesting at Page 27, Fifth Paragraph of the remarks filed May 8th, 2026 that the in vitro experimental evidence described serves as “proof-of-principle demonstrating that hypoxia-selective drug release can be accomplished using the claimed enamine N-oxide compounds, and would have reasonably expected the same or similar results with other therapeutic agents (based on the ease with which drugs can be caged by the enamine N-oxide motif) and as well as with other cleavable linking groups.”
The examiner does not find this persuasive, as this is highly speculative, and is not commensurate with the very broad scope of the claim, which is drawn to treatment of treating any disease or disorder characterized by, or associated with or exhibiting tissue hypoxia. This, in preponderance with the Wands factors, reconsidered below, supports the rejection of record as raised in the non-final rejection mailed February 9th, 2026.
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 a method of treating a disease or disorder characterized by, or associated with or exhibiting tissue hypoxia.
Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to the treatment of any disease or disorder characterized by, or associated with or exhibiting tissue hypoxia. This covers a myriad of diseases or disorders with mutually exclusive and distinct etiologies. Further, the method is drawn to administration of any compound of formula I or II. Additionally, this covers an array of diseases or disorders, both known presently, or diseases or disorders discovered years from now that are associated with tissue hypoxia. Can an Applicant simply “reach through” and obtain patent protection for diseases yet unknown, or diseases currently known, but later are classified as being associated with tissue hypoxia?
Further, at Page 87, Paragraph [00239] of the instant specification, Applicant is clear that the invention is drawn to the treatment of cancer, in general.
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:
No compound has ever been found to treat cancers of all types generally. Since this assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits. The existence of such a “silver bullet” is contrary to our present understanding of oncology. The state of the art is not indicative of any pharmaceutical agents that are useful in the treatment of cancer generally. At Page 1004, Cecil Textbook of Medicine states that “each specific type has unique biologic and clinical features that must be appreciated for proper diagnosis, treatment and study”. Different types of cancers affect different organs and have different methods of growth and harm to the body. Also see In re Buting, 163 USPQ 689 (CCPA 1969), wherein ‘evidence involving a single compound and two types of cancer, was held insufficient to establish the utility of the claims directed to disparate types of cancers’. Thus, it is beyond the skill of oncologists today to get an agent to be effective against cancers generally.
A similar statement appears at In re Application of Hozumi et. al., 226 USPQ 353: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. This is because it is now understood that there is no “master switch” for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body’s cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environmental factors.
Similarly, In re Novak, 134 USPQ 335, 337-338 says “unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them.” There is no such evidence in this case for a compound that treats all types of cancer. Likewise, In re Cartright, 49 USPQ2d 1464, states: “Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient” does what the specification surmises that it does. That is exactly the case here. Moreover, even if Applicant’s assertion that cancer in general could be treated with these compounds were plausible -- which it is not --, that “plausible” would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success.
Recently, Wu et. al. (“Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA- approved novel therapeutic drugs for solid tumors from 1991 to 2021; Journal of Hematology & Oncology, 15, 143, 2022; hereinafter referred to as Wu), at the Abstract, discloses that between 1991 and 2021 there have been 228 new cancer drugs approved by the U.S. Food and Drug Administration of which 120 of these are drawn to the treatment of solid tumors alone. At Page 5, Table 1 Wu teaches that there are 21 different approved drugs for treating lung cancers, some of which have cellular targets. At Page 10, Table 2, Wu teaches breast cancer has 22 different drugs that have varied cellular targets and are indicated for different types of breast cancer. At Page 17, Table 4, Wu teaches there are 17 different drugs available to treat different forms of gastrointestinal cancers. At Page 38, Figure 12, Wu summarizes the protein structure of some cellular targets and the binding site of their respective drugs. Taken together, Wu teaches that no single therapeutic has ever been identified as a treatment for all forms of cancer; and closer examination of Figure 12 provides a logical explanation. As highlighted in Figure 12, molecular protein targets implicated in different cancers (e.g. EGFR for lung cancer in Table 1, VEGFR2 for gastric cancer in Table 4) have different three-dimensional protein structures, different active sites, and therefore require different drugs with the right shape and chemical groups in order to bind the target active site and have an effect in treating cancer. In other words, there is no one size fits all approach to treating cancer simply for the reason that no single molecule will have the shape and chemical functional groups necessary to bind and modulate all modular targets of cancer, all of which have varied shapes. It is commonly known in the pharmaceutical arts that shape dictates function wherein drugs which have a shape complimentary to the protein target will bind and have an effect (this is often referred to simplistically as a “Lock and Key” model). Given the varied shape of protein targets in cancer (e.g. EGFR and VEGFR2), it is pure fantasy to speculate that a single drug with a single three dimensional shape will bind all protein targets implicated in cancer therapy and have an effect in treating all forms of the disease. As such, at present the “silver bullet” drug therapy to treat all forms of cancer is elusive and such a therapy is not recognized in the art where the reality is that different forms of cancer require different drug therapies.
The amount of direction provided and working examples:
Beginning at Page 157, Example 77, of the instant specification, Applicant discloses the methods employed for a variety of biological testing of the instantly claimed compounds.
In terms of utility in treating a disease, protocol for testing the instantly claimed compounds is provided in cell viability assays for H460 and A341 cells, which are, respectively, a lung cancer cell line and a skin cancer cell line. Figure 3E demonstrates the efficacy of an instantly claimed compound, compound 37 in treating a skin cancer cell line. Figure 3F provides data of the same compound in treating a lung cancer and a skin cancer cell line.
Beginning at Page 163, Applicant discloses the methods for a Bx-PC xenograft tumor model. The Bx-PC3 cell line is a pancreatic cancer cell line. The results thereof are shown, for example, at Figures 5A and 5B.
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. As referenced above, a person having ordinary skill in the art would need not only to identify and/or develop suitable methods for determining the efficacy of the instantly claimed compounds in treating disorders or diseases other than lung cancer, skin cancer, or pancreatic cancer, but also need to employ these methods, with no reasonable expectation of success.
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.
The specification fails to provide enough support for the broadly claimed method of treating a disease or disorder associated with hypoxia.
Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent protection is granted in return for enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person having ordinary skill in the art would have to engage in undue experimentation to determine the efficacy of treatment of diseases or disorders other than those mentioned above, with no assurance of success.
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.
The rejection of Claims 1-2, 22, 31-33, 43, 45, 52, 97, and 106-107 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 is maintained.
Regarding the lack of antecedent basis in Claims 106-107, Applicant’s amendment is sufficient to overcome this rejection. This amendment, however, introduces the indefinite terms “linking group”, “diagnostic moiety”, “inductive electron withdrawing group”, “π-electron withdrawing group”, “leaving group”, and “therapeutic moiety.” Therefore, the rejection as applied to Claims 1-2, 22, 31-33, 43, 52, and 97 as noted in the non-final rejection mailed February 9th, 2026 is extended to these claims as amended.
Applicant has traversed this rejection on the basis that these terms are adequately defined in the specification.
The examiner does not find this argument persuasive. Applicant points to the representative examples throughout the specification, stating at pager 27 of the remarks that “As stated previously, the claims are adequately supported in terms of apprising persons skilled in the art as to their meaning of each of the terms and provide numerous representative examples of each such that a skilled artisan would understand their meaning. A person skilled in the art would immediately appreciate the correlations in the art between function and structure with respect to these recited groups.” As noted above, the definitions of these groups are broadly defined such that a person having ordinary skill in the art would not readily ascertain the metes and bounds of the recited limitations thereof. The representative examples are non-limiting and do not clarify the metes and bounds of the recited limitations.
To this end, “therapeutic moiety” is defined at Page 19, Paragraph [0064] of the instant specification as “a portion of a portion of an inventive compound that provides a therapeutic effect with respect to a disease or disorder when it reaches its intended site of action, which in this case is hypoxic tissue.” Even in view of the non-limiting representative examples, the breadth of this definition is such that the metes and bounds of the limitation of a compound having a “therapeutic moiety” are indiscernible by a person having ordinary skill in the art.
For these reasons, as well as those stated in the non-final rejection mailed February 9th, 2026, this rejection is maintained.
The following rejections are necessitated by amendment:
Claim Rejections - 35 USC § 112
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.
Claim 22 is 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 22 recites the limitation "R3 is hydrogen" in the first line of the claim. There is insufficient antecedent basis for this limitation in the claim, as this claim depends from Claim 1, which does not allow for R3 being defined as hydrogen.
Claim Rejections - 35 USC § 112
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 22 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 22 improperly expands the scope of Claim 1, from which it depends, by reciting the limitation that R3 may be defined as hydrogen, which expands the scope 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.
Claim Rejections - 35 USC § 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 1-2, 13, and 43 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bernier et. al., (“Improved Procedure for the Synthesis of Enamine N-Oxides”, Journal of Organic Chemistry, 2008; cited in non-final rejection mailed February 9th, 2026; cited on Applicant’s Information Disclosure Statement filed September 21st, 2023; hereinafter referred to as Bernier) as evidenced by Bickel (“The Pharmacology and Biochemistry of N-Oxides”, Pharmacological Reviews, 21, 1969; cited in non-final office action mailed February 9th, 2026; hereinafter referred to as Bickel).
At Page 4231, Bernier teaches the following table of compounds in Figure 2:
PNG
media_image3.png
285
209
media_image3.png
Greyscale
For clarity, the compound labeled 1db has the following structure:
PNG
media_image4.png
124
286
media_image4.png
Greyscale
Additionally, the compound 1dd has the following structure:
PNG
media_image5.png
200
324
media_image5.png
Greyscale
Compound 1db reads on a compound of formula I as recited at instant Claim 1 when the variables are recited as follows:
R1 is hydrogen.
R2 is hydrogen.
R3 is C3-alkyl.
R4 is hydrogen.
R7 and R8 together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl comprising one heteroatom that is nitrogen.
A is absent.
Compound 1dd reads on a compound of formula I as recited at instant Claim 1 when the variables are recited as follows:
R1 is hydrogen
R2 is hydrogen
R3 is C1-alkyl, further substituted by phenyl.
R4 is hydrogen.
R7 and R8 together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl comprising one heteroatom that is nitrogen.
A is absent.
Regarding the limitation “provided that the compound of formula (I or II) contains at least one –[L]-diagnostic moiety or therapeutic moiety”, Bickel teaches at page 327 that “Several N-oxides have become pharmacological agents used in therapy (alkaloids, chemotherapeutics, antibiotics, psychotropic drugs)”. Therefore, under the broadest reasonable interpretation of requiring a compound of formula I to contain a therapeutic moiety, the N-oxide moiety itself is recognized in the art as a therapeutic moiety.
Conclusion
Claims 1-2, 4, 10, 13, 15-16, 22, 24-25, 31-34, 37, 40, 43, 45, 50, 52, 96-97, and 106-107 are rejected.
No claim is 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 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.
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.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at (571) 272-9023. 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.
/D.J.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
Prosecution Insights