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 .
Election/Restrictions
Applicant’s election without traverse of Group II (i.e., claims 13-16) in the reply filed on 4/24/2026 is acknowledged.
Applicants’ amendment (previously) of claim 13 is acknowledged. Applicant’s cancellation of claims 1-8 and 17-20 is acknowledged.
There are two new claims; 21-22.
Furthermore, applicant’s election of the species “stomach cancer” for Group II without traverse is acknowledged.
Since, the applicant elected group II (i.e., claims 13-16), therefore, based on that election, claims 9-12 are withdrawn as being drawn to a non-elected group.
Claims 13-16, and 21-22 are under consideration in this office action and will be examined on the merits.
Status of Claims
Claims 9-16, and 21-22 are pending. The preliminary amendment was filed on 6/21/2024, wherein the applicant amended claims 9 and 13, and canceled claims 1-8 and 17-20. There are two new claims; 21-22.
Claims 13-16, and 21-22 are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/21/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112(a)
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 13-16, and 2-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph because the specification, while enabling the use of aristoloxazine C in connection with certain cancer models and providing limited animal and early-phase human data, does not reasonably provide enablement for “preventing, ameliorating or treating” the full scope of the “cancer disorders” and the various cancer types listed in claims 21 and 22.
Additionally, the specification relates to the use of aristoloxazine C represented by Chemical Formula 1, an isomer or a pharmaceutically acceptable salt thereof, as an anticancer agent. However, the working disclosure appears limited to specific in vitro or in vivo cancer models and does not reasonably provide enablement across the broad genus of “cancer disorders” recited in claims 21 and 22, nor does it provide sufficient guidance on dosing regimens, routes of administration, combination therapies, or patient subpopulations across the entire scope. 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.
Accordingly, the claims are far broader than what is actually taught and reasonably predictable, particularly as to preventing, ameliorating or treating cancer across all claimed cancer disease types.
The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Nature of the Invention:
The instant invention relates to a therapeutic method for preventing, ameliorating or treating cancer in human or animal subjects using a small molecule natural product derivative (aristoloxazine C), comprising the step of administering aristoloxazine C. Therapeutic methods for treating cancer are recognized as complex and highly context-dependent, involving heterogeneous disease biology, patient variability, PK/PD, resistance mechanisms, and potential off-target toxicities. Reviews of oncology drug discovery emphasize the complexity of cancer as a disease class, noting that “cancer” is not a single disease but hundreds of distinct molecularly defined entities requiring tailored therapeutic strategies (Das, S., Thakur, S., Korenjak, M. et al. Aristolochic acid-associated cancers: a public health risk in need of global action. Nat Rev Cancer 22, 576–591 (2022).
As a result, where claims sweep across numerous cancer types and therapeutic endpoints (prevention, amelioration or treatment), the “nature of the invention” tends to magnify the need for detailed guidance, robust data, and mechanistic rationale to cover the full scope.
The complex and somewhat unpredictable nature of cancer therapy, especially when repurposing natural product derivative (aristoloxazine C), or structurally diverse compounds, means that successful treatment is not a matter of routine oncology practice across the full range of cancers claimed
The State of the Prior Art:
At the time of filing, the cited prior art included Asarum heterotropoides root-derived compounds and their biological activities, including acaricidal and larvicidal activities against mites and mosquito larvae. These references demonstrate that compounds from Asarum heterotropoides exhibit various biological activities, but they do not show that aristoloxazine C has broad, predictable anticancer efficacy across multiple cancer types and clinical contexts.
More broadly, the oncology prior art shows that many single small-molecule agents exhibit narrow, cancer-type-specific efficacy and often fail or require combination therapy when applied to other cancers. Reviews of natural-product-derived anticancer agents highlight that many compounds show promise in vitro cytotoxicity but fail to translate into broad clinical efficacy across diverse tumrs, reflecting gaps between initial discovery and wide therapeutic applicability (Zhang, Shu-Han et al. “Comparative Analysis of Aristolochic Acids in Aristolochia Medicinal Herbs and Evaluation of Their Toxicities.” Toxins vol. 14,12 879. 16 Dec. 2022).
Thus, at the time of filing, while the prior art in specification demonstrated the non-cancer activities (e.g., acaricidal and larvicidal) of compounds derived from Asarum heterotropoides, it does not establish a robust, field-wide understanding that aristoloxazine C is universally effective against diverse cancers. The relevant prior art does not fill the gap between limited disclosed anticancer data and the very broad claim scope covering essentially all cancer disorder and types claimed here. This is because the prior art underscores the need for detailed, drug-specific and indication-specific development
The Relative Skill of those in the Art:
The level of skill in the art is a neuro-oncologist or clinician with a Ph.D., and/or an M.D.
The Predictability or Lack thereof in the Art:
The field of oncology is generally regarded as an unpredictable art. Responses to a given anticancer agent can vary dramatically among different cancer types, stages, genetic backgrounds, and microenvironments, and many compounds that show in vitro cytotoxicity fail to translate into broad clinical efficacy.
Reviews of cancer drug attrition rates highlight that the majority of anticancer candidates fail in clinical development due to lack of efficacy or unexpected toxicity, reflecting the inherent unpredictability of translating cytotoxicity into broad therapeutic benefit (Wang, Guangyu et al. “Astaxanthin Induces Apoptosis in Human Osteosarcoma MG-63 Cells.” Folia biologica vol. 69,5-6 (2023): 186-193.).
Given this unpredictability, as the art of treating diverse cancers with a single small molecule, cancer modulation and pharmacology, and the lack of efficacy data for all cancer types, it is not reasonable to assume that any and all combinations of claimed cancers and their treatment regimens will achieve the full array of outcomes (treatment, prevention, and amelioration) without extensive empirical work.
The Breadth of the Claims:
Claims 13 and 21 are broad along multiple axes:
Claims 13 and 21 recite methods using aristoloxazine C (or isomer/salt) for preventing, ameliorating or treating “cancer disorders”, which by ordinary and customary interpretation, encompass essentially all malignancies (solid and hematologic; primary and metastatic; treatment naïve and refractory; multiple organs and etiologies).
In addition, claim 21 explicitly recites various cancer types, further expanding the scope to a wide genus of distinct diseases that differ in origin, molecular drivers, microenvironments, and clinical response profiles
In contrast, the enabling disclosure is essentially focused on:
A narrow set of cancer models (e.g., one or a few cell lines or xenograft models) and does not provide data or even reasoned extrapolation for many classes of cancers (e.g., leukemias vs. solid tumors, hormone-driven vs. non-hormone malignancies, immune-evasive tumors and/or rare cancers).
The prior art and reviews of cancer drug development note that anticancer agents typically show highly context-dependent efficacy, with many compounds active in one tumor type while failing in others, underscoring that broad “all cancers” claims are not supported by narrow set of experimental data. This particularly reinforces that even within cancer therapy, narrower claims tied to particular compounds, concentrations, vehicles, and clinical contexts need to be supported by detailed examples and clinical data, unlike the broad, multi-indication claims here (Wang, Guangyu et al. “Astaxanthin Induces Apoptosis in Human Osteosarcoma MG-63 Cells.” Folia biologica vol. 69,5-6 (2023): 186-193).
Accordingly, the breadth of the claims is not commensurate with the scope of the enabling disclosure. The breadth of these claims far exceeds the limited examples and data actually provided.
As such, the breadth of the claims is great.
The Amount of Direction or Guidance Presented:
Although the specification describes aristoloxazine C’s anticancer activity and provides certain experimental procedures (e.g., isolation methods, some in vitro or in vivo assays, and exemplary formulations). However, with respect to the broad scope of “preventing, ameliorating or treating” multiple cancer disorders and the numerous types recited in claim 21, the disclosure is largely generic: it identifies aristoloxazine C as an anticancer agent but does not supply detailed, cancer-type-specific dosing ranges, schedules, patient selection criteria, biomarkers, or combination strategies for the many cancers encompassed by the claims. Since the teachings appear limited: general statement, “comprising the step of administering aristoloxazine C represented by Chemical Formula 1, an isomer or a pharmaceutically acceptable salt thereof to a subject in need thereof” do not meaningfully instruct PHOSITA how to achieve those endpoints across different cancer types, including highly aggressive or drug-resistant tumors.
Existing prior art and the reviews of preclinical to clinical translation in oncology demonstrates the need for detailed, indication-specific data (e.g., tumor type, stage, biomarkers, dosing etc.) to guide rational clinical use of formulation and delivery of small molecules to the target cells surface requires specific optimization for each drug, including vehicle selection, particle size and preservative choice rather than generic “anticancer” assertions (Bader et al. “Oncology Drugs Granted FDA Designations in August 2025.” Toxins 3 Sep. 2025).
Thus, while the specification’s guidance is too general to support the broad, multi-endpoint and multi-cancer scope of claims 13 and 21 without substantial additional work by the PHOSITA.
Consequently, the specification does not provide sufficient guidance to practice the full scope of claims 13, and 21-22 across the diverse cancer disease states recited without extensive, individualized experimentation.
The Presence or Absence of Working Examples and Quantity of Experimentation:
The specification contains working examples primarily in limited in vivo tumor models and cell lines. Figures 3A-3N and related description demonstrate aristoloxazine C showed anti-proliferative activity against all cancer cells that were tested (melanoma, non- melanoma skin cancer, prostate cancer, lung cancer, fibrosarcoma, ovarian cancer, colon cancer, stomach cancer, liver cancer, breast cancer, leukemia, glioma and renal cancer.
However, the specification does not provide:
In vivo therapeutic examples showing administration of aristoloxazine C to the full scope of “cancer disorders” and numerous types recited in claim 21; or
Clinical data in human subjects with or the other claimed conditions (e.g., head and neck cancer, thyroid cancer, soft tissue sarcoma, osteosarcoma, testicular cancer, bladder cancer, hemangiosarcoma, mastocytoma, lymphoma, pancreatic cancer, hematopoietic tumor, and neuroblastoma among others claimed).
By contrast, in therapeutic fields, working examples limited to a few cell lines or tumor types do not automatically enable treatment claims covering broad disease categories, especially when claims include cancers known to differ markedly in pathogenesis and therapeutic response). Moreover, the prior art on the analyses of oncology drug pipelines notes that compounds often show activity in only a subset of tumor types despite initial broad claims, and that robust, diverse preclinical models are needed to justify broad clinical indications (Das, S., Thakur, S., Korenjak, M. et al. Aristolochic acid-associated cancers: a public health risk in need of global action. Nat Rev Cancer 22, 576–591 (2022)).
Given that the working examples in the instant application are confined to a narrow murine context and largely mechanistic, they do not reasonably enable the full clinical breadth of claim 1, 10, and 18.
To enable and practice the full claim scope of claims 13 and 21-22, a skilled artisan would have to engage in extensive, iterative, unduly burdensome clinical experimentation, including:
Screening aristoloxazine C (and its isomers/salts) across numerous cancer cell lines and in vivo models representing each recited cancer type and clinical context.
Determining specific and effective dosing regimens (including dosage ranges, routes of administration, schedules, formulations etc.) and treatment durations for each underlying disease state (e.g., solid vs, hematologic, early stage vs. metastatic etc.).
Assessing safety and toxicities in relevant animal models, and, ultimately, human subjects for preventive vs therapeutic use; and
Evaluating combination therapies and resistance patterns for refractory cancers and immune-evasive tumors (Wang, Guangyu et al. “Astaxanthin Induces Apoptosis in Human Osteosarcoma MG-63 Cells.” Folia biologica vol. 69,5-6 (2023): 186-193.).
This level of trial-and-error analysis, across many cancers’ disease etiologies, goes well beyond routine optimization and constitutes undue experimentation.
Note that lack of a working example, is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164.
Genentech, Inc. v. Novo Nordisk, 108 F.3d at 1366, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an 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, e.g., the amount of direction or guidance provided, absence of working examples, and the predictability of the art discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation in order to practice invention based on the details provided and scope of invention defined in claims 13-16 and 21-22.
Consequently, claims 13-16 and 21-22 are rejected for lacking scope of enablement.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Applicant Claims
2. Determining the scope and contents of the prior art.
3. Ascertaining the differences between the prior art and the claims at issue, and 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.
Claims 13-16 and 21-22 are rejected under 35 U.S.C. 103(a) as being unpatentable over Jeong et al. (“(-)-Asarinin from the Roots of Asarum sieboldii Induces Apoptotic Cell Death via Caspase Activation in Human Ovarian Cancer Cells”. Molecules (Basel, Switzerland) vol. 23,8 1849. 25 Jul. 2018) in view of Ohta et al. (“Asaroidoxazines from the Roots of Asarum asaroides Induce Apoptosis in Human Neuroblastoma Cells.” J. Nat. Prod. 23 October 2020; 83).
Regarding claims 13-16 and 21-22, Jeong teaches Asarum sieboldii Miq. (Aristolochiaceae) is a herbal plant that is widely distributed in Korea, China, and Japan. In traditional medicine, the roots of A. sieboldii are used as treatment for all types of colds, fever, chills, headaches, acute toothaches, sinusitis, cough, and dyspnoea, due to retention of phlegm, pharyngitis, chronic gastritis, and rheumatoid arthritis [1,2]. It has been demonstrated that A. sieboldii has a broad range of biological activity, such as anti-allergic [3], antitussive [4], anti-inflammatory [5], anti-nociceptive [6], anti-fungal [7,8], neuroprotective [9], and anticancer activity (e.g., ovarian cancer cells) (Introduction; lines 1-6). Jeong specifically teaches that the roots of A. sieboldii induces caspase-dependent apoptotic cell death in human cancer cells (abstract; lines 13-14). However, Jeong does not explicitly teach the compound aristoloxazine C represented by Chemical Formula 1, an isomer or a pharmaceutically acceptable salt thereof to a subject in need thereof.
Ohta teaches the structure of the claimed compound;
PNG
media_image1.png
100
129
media_image1.png
Greyscale
(Scheme 1. Page 3053). Ohta teaches Asaroidoxazines that represent aristolochic acid derivatives that. These derivatives are related to the previously reported aristoloxazines A and B, which were the first aristolochic acid derivatives with an oxazinone moiety isolated from the genus Aristolochia.22., Ohta teaches asaroidoxazines A (1) and B (2) were obtained as the first 1,3-dioxolophenanthrene-attached oxazines isolated from the genus Asarum. Asaroidoxazine A (1) was found to elicit cell death in neuroblastoma cells, characterized through the presentation of typical apoptotic features such as nuclear condensation and caspase activation, indicating strong apoptosis induction in cancer cells (Page 3055, para. 1, lines 9-15). Ohta further teaches Compound 2 was obtained as a pale-yellow oil, and its molecular formula was determined to be C20H16N2O7S by positive-ion HRESIMS analysis {m/z 451.0569 ([M + Na] +; calcd for C20H16N2O7SNa+, 451.0570)}, indicating 2 to be an isomer of 1 (Page 3052, para. 2, lines 1-5).
In view of the above, it would have been obvious to a person having ordinary skill in the art at the time the invention was filed to combine the teachings of Jeong and Ohta, to arrive at the claimed method of preventing, ameliorating or treating cancer disorders by administering aristoloxazine C represented by Chemical Formula 1, for a variety of cancer types, including the specific cancers recited in claims 21-22. One skilled in the art would be motivated to do so, with a reasonable expectation of success, because these references show that aristoloxazine-type compounds are known in the art and have characterized structures and bioactivity. Given the known aristoloxazine A/B and asaroidoxazines, PHOSITA would view aristoloxazine C as an obvious variant with the similar anti-apoptotic and anti-cancerous, biologic activity as taught by Ohta and Jeong. The references combined teach Asarum-derived small molecules with phenanthrene-oxazine or related structures are useful for killing cancer cells via apoptosis, which PHOSITA would recognize as a standard mechanism of treating or ameliorating cancer. Thus, selecting and administering aristoloxazine C is an obvious implementation of treating various cancer types via claimed method.
Conclusion
Claims 13-16 and 21-22 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHAR INAM whose telephone number is (571)272-0821. The examiner can normally be reached 7:30 am-5:00 pm EST.
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, James H Alstrum-Acevedo can be reached at (571) 272-5548. 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.
/SAHAR INAM/
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
Prosecution Insights