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
The amendments to the claims filed June 10, 2024 are acknowledged and entered. Claims 1-22 are pending.
Priority
This application claims benefit of 63/471,968, filed June 8, 2023.
Information Disclosure Statement
Acknowledgement is made of the Information Disclosure Statement filed on October 16, 2024. All references have been considered except where marked with a strikethrough.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code(see e.g. [0053], [0054]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which applicant may become aware of in the specification.
Allowable Subject Matter
Claim 1-6 are allowed.
Claim 12, 15, 18 and 21 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is an examiner’s statement of reasons for allowance: The closest reference to the instant claims is Buhrlage et al. (US2021/0347761 A1, now US12,503,453B2; cited by Applicant in IDS filed October 16, 2024) (hereinafter “Buhrlage”). Buhrlage teaches compound 5 (page 13; pictured below for convenience). The difference between Buhrlage and the instant claims is that the instant claims require a group corresponding to
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. Buhrlage does not teach this group. There is no teaching which would have motivated one of ordinary skill in the art before the effective filing date of the claimed invention to selectively modify compound 5 of Buhrlage into the claimed invention with any reasonable expectation of success.
Buhrlage et al. (US2021/0347761 A1)
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Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Claim Rejections - 35 USC § 112a
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 7-11, 13-14, 16-17, 19-20 and 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of TNBC, kidney cancer, head and neck cancer, liver cancer, melanoma, non-small cell lung cancer (NSCLC), bladder cancer, cervical cancer, colon cancer, renal cell cancer, stomach cancer, rectal cancer, gastrointestinal, pancreatic cancer, thymic carcinoma, ovarian cancer, prostate cancer, glioma, endometrial cancer, leukemia, lymphoma or myeloma does not reasonably provide enablement for
Treating cancer generally; or
Treating a p53-independent cancer generally
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. Applicant teaches that a compound of the invention degrades FOXM1. However, FOXM1 is not known to be correlated with the treatment of the entire scope of cancers embraced by the claims. Applicant’s disclosure is only enabling for the treatment of conditions which Applicant has demonstrated may be treated by the instant compound, and of conditions which the prior art is already aware may be treated by a compound with the disclosed activity and for which Applicant has written support. Case law is clear on this point. In an unpredictable art, such as drug therapy to treat disease, models may be used for enablement only if there is a reasonable correlation between the activity in question and the asserted utility. 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 a 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.
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 1) The nature of the invention, 2) the state of the prior art, 3) the predictability or lack thereof in the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the breadth of the claims, and 7) the quantity of experimentation needed. The determination that “undue experimentation” would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations.
The nature of the invention & breadth of claims:
Claims 7 and 8 are drawn to a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound regarded as PU7-1. The specification teaches the compound mediates FOXM1 degradation (see e.g. [0017], FIGS. 5A-5G show that PU7-1 mediates FOXM1 degradation).
Claims 9-10, 13, 16, 19 and 22 depend from claims 7 or 8 and include the full scope of cancer.
Claims 11, 14, 17 and 20 depend from claims 7 or 8 and recite wherein the cancer is p53-independent.
The specification does not provide any scope limiting definition of cancers embraced by claims.
The nature of the invention is a method of treating cancer comprising administration of a compound that inhibits or degrades FOXM1. The scope of the method is very broadly drawn to the treatment of cancer generally and a subset of cancers regarded as p53-independent. The method includes the treatment of cancers, including p53-independent cancers, for which there is no known association with FOXM1 and treatment of the cancer.
The state of the prior art
FOXM1 and Cancer
State of the prior art reference Gartel et al. (Mol Cancer Ther. 2013, 12(3) 245-254) teaches FOXM1 is an oncogenic transcription factor and it has a well-defined role in cell proliferation and cell cycle progression. Overexpression of FOXM1 has been reported in more than 20 types of human cancers. Experimental data has underlined the relevance of FOXM1 in tumorigenesis (Abstract). Gartel teaches since FOXM1 is one of the key cell cycle regulators, overexpression of FOXM1 in cancer cells and all the effects of FOXM1 on cancer could reflect its important role in cell proliferation and could simply be the sign of a passenger effect of the enhanced proliferation capacity of cancer cells. However, it has been shown recently that there are breast cancers with low proliferation and high FOXM1 expression as well as with high proliferation and low FOXM1 expression. In addition, certain cancer cells with FOXM1 knockdown are viable and proliferating (page 4).
State of the prior art reference Liao (Cell Communication and Signaling, 2018, 16, 57) teaches FOXM1 is a crucial regulator of many biological processes and tissues, and dysregulation of FOXM1 can significantly contribute to tumorigenesis and cancer progression. However, there are important challenges that limit the translation of promising drugs into clinical practice. Before the entry of FOXM1 inhibitors into clinical trials, more thorough preclinical studies on their anti-tumor efficacy are still needed. In addition, the toxicity of the above drugs should also be fully evaluated. It is not quite clear how the interaction and isoforms switch between FOXM1a and FOXM1b or FOXM1c or FOXM1d. It also remains unclear how the isoforms of FOXM1 interact and what role they may play in the regulation of FOXM1, in disease progression, or in response to relevant therapeutic strategies (Conclusion).
The state of the prior art appears to recognize that there are challenges associated with targeting FOXM1 and treatment of cancer, and also that FOXM1 expression is not consistently associated with proliferation of cancer cells (e.g. it has been shown recently that there are breast cancers with low proliferation and high FOXM1 expression as well as with high proliferation and low FOXM1 expression, certain cancer cells with FOXM1 knockdown are viable and proliferating)
Cancer Treatment Generally
As per the broad treatment of cancer, 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 any pharmaceutical agents that are useful in the treatment of cancer generally. 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” (see the enclosed article, page 1004). 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. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. 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 environment 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 Cortright, 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 applicants’ 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 (Journal of Hematology & Oncology 2022 (15) 143) 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 (Abstract). Wu teaches that there are 21 different approved drugs for treating lung cancers, some of which have different cellular targets (Table 1, page 5). Similarly, breast cancer (see Table 2, page 10) has 22 different drugs that have varied cellular targets and are indicated for different types of breast cancer. More still, Table 4 (page 17) indicates that there are 17 different drugs available to treat different forms of gastrointestinal cancers. See also Table 6 (page 25), drugs approved for urologic cancers, Table 7 (page 28), drugs approved for skin cancers, and Table 8 (page 33), drugs approved for thyroid cancer. Wu further provides an illustration summarizing the protein structure of some cellular targets and the binding site of their respective drugs (Fig 12, page 38). Taken as a whole, Wu teaches that no single therapeutic has ever been identified as a treatment for all forms of cancer; and closer examination of Fig 12 provides a logical explanation: As highlighted in Fig 12, molecular protein targets implicated in different cancers (e.g. EGFR for lung cancer (see Table 1), VEGFR2 for gastric cancer (see 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 the 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 molecular targets of cancer, all of which all 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, the state of the prior art is unaware of any “silver bullet” drug therapy to treat all forms of cancer as is claimed presently, at least for the reason that persons skilled in the art recognize that different forms of cancer have different treatment requirements and therefore require different drug therapies.
The Level of One of Ordinary Skill
The level of skill in the art is high. The artisan using the claimed invention would be a person with medical training such as a medical doctor or physician with an MD degree or the equivalent.
Predictability in the art
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Given the state of the prior art, treatment of cancer with a compound that inhibits or degrades FOXM1 is highly unpredictable.
Amount of guidance/working examples
Applicant demonstrates that the compound of the invention mediates FOXM1 degradation in TNBC (see e.g. [0017], FIGS. 5A-5G show that PU7-1 mediates FOXM1 degradation) and inhibits growth in carcinoma cells, prostate cancer cells, and brain cancer cells (page 34, FIG. 12C and 12D). The prior art appears aware that FOXM1 is associated with kidney cancer, head and neck cancer, liver cancer, melanoma, non-small cell lung cancer (NSCLC), bladder cancer, cervical cancer, colon cancer, renal cell cancer, stomach cancer, rectal cancer, gastrointestinal, pancreatic cancer, thymic carcinoma, ovarian cancer, prostate cancer, glioma, endometrial cancer, leukemia, lymphoma or myeloma.
No experimental or other data is provided to show the instant compound treats the entire scope of diseases claimed. Applicant has provided no evidence to suggest that their models are indicative of a treatment of all forms of disease within the scope of the claim.
The quantity of experimentation needed:
MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on theevidence 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 and one skilled in the art could not practice the full scope of the claimed invention without undue and unreasonable experimentation.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN MARTIN whose telephone number is (571)270-0917. The examiner can normally be reached Monday - Friday 8 am - 5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached on (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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October 5, 2026
/K.S.M./Examiner, Art Unit 1624
/BRUCK KIFLE/Primary Examiner, Art Unit 1624
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