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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/09/2026 has been entered.
Response to Amendment
The amendments received 06/09/2026 have been entered. Claims 1-7, 13, 16, 22-28, 34, 40, and 42 are pending. Claims 5-7, 16, 22-28, 34, 40, and 42 are withdrawn. Any objection or rejection as set forth in the Office Action mailed 12/10/2025 not maintained herein has been overcome and is withdrawn.
Examiner has considered Applicant’s arguments regarding the outstanding rejections under 35 U.S.C. 103 over Siegel et al. (WO 2019/081486 A1) and under nonstatutory double patenting and finds them to be persuasive. The rejections are withdrawn.
Election/Restrictions
Claim 1 is directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 5-7, 16, 22-28, 34, 40, and 42, directed to the process of making or using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on 05/22/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Objections
Claims 5 and 42 are objected to because of the following informalities:
Claim 5, "the compound of" should read "a compound of", "generally formula (I)" should read "general formula (I)".
Claim 42 does not end in a period.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 25-27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 25 recites “mammary and other gynaecological tumours”. This causes confusion as mammary tumors are not considered gynecological. It is unclear, therefore, what Applicant considers to be “other gynaecological tumours”. Clarification is required. Claims 26-27 do not clarify the limitation at issue and are similarly rejected.
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 5-7, 16, 22-23, 25-28, 34, 40, and 42 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 treating a cancer selected from leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, tumors of the thorax, gastrointestinal tumors, endocrine tumors, mammary tumors, gynecological tumors, urological tumors, and skin tumors, does not reasonably provide enablement for prophylaxis of or treating diseases, hyperproliferative diseases, cancers, or cancer cells 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.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, "The Federal Circuit has repeatedly held that "the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation." In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)" (emphasis added). The "make and use the full scope of the invention without undue experimentation" language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: "A lack of enablement for the full scope of a claim, however, is a legitimate rejection." The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int'l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
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: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The treatment of cancer generally cannot possibly be considered enabled.
By way of background, four cases are of particular relevance to the question of enablement of a method of treating cancers broadly or even generally:
In In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689, the claim was drawn to "The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors" using a small genus of compounds. The Court decided that human testing "limited to one compound and two types of cancer" was not "commensurate with the broad scope of utility asserted and claimed".
In Ex parte Jovanovics, 211 USPQ 907 the claims were drawn to "the treatment of certain specified cancers in humans" by the use of a genus of exactly two compounds, the N-formyl or N-desmethyl derivative of leurosine. Applicants submitted "affidavits, publications and data" for one of the compounds, and a dependent claim drawn to the use of that species was allowed. For the other, no data was presented, applicants said only that the other derivative would be expected to be less effective; claims to the genus were refused.
In Ex parte Busse, et al., 1 USPQ2d 1908, claims were drawn to "A therapeutic method for reducing metastasis and neoplastic growth in a mammal" using a single species. The decision notes that such utility "is no longer considered to be "incredible", but that "the utility in question is sufficiently unusual to justify the examiner's requirement for substantiating evidence. Note also that there is also a dependent claim 5 which specified "wherein metastasis and neoplastic growth is adenocarcinoma, squamous cell carcinoma, melanoma, cell small lung or glioma." The decision notes that "even within the specific group recited in claim 5 some of the individual terms used actually encompass a relatively broad class of specific types of cancer, which specific types are known to respond quite differently to various modes of therapy."
In Ex parte Stevens, 16 USPQ2d 1379 a claim to "A method for therapeutic or prophylactic treatment of cancer in mammalian hosts" was refused because there was "no actual evidence of the effectiveness of the claimed composition and process in achieving that utility."
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: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
1) Breadth of claims.
The claims are directed toward methods of treatment or prophylaxis of diseases, such as hyperproliferative diseases; methods of reducing survival or inducing death in a cancer cell; methods of treating cancer; and methods of selecting a patient for cancer treatment. Examiner notes that claim 5 recites both “treatment” and “prophylaxis”.
"Cancer" is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. To be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Specifically, the prior art knows that there never has been a compound capable of treating cancers generally. "The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally." (<http://www.uspto.gov/web/offices/pac/dapp/1pecba.htm#7> ENABLEMENT DECISION TREE, Example F, situation 1). 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.
Accordingly, there is substantive "reason for one skilled in the art to question the objective truth of the statement of utility or its scope" (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally.
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. 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."
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
One skilled in the art knows that chemotherapy of brain tumors is especially difficult. This is because 1) the blood-brain barrier, which is often intact in parts or all of a brain tumor, will block out many drugs, as it is the purpose of the blood-brain barrier to protect the brain from alien chemicals, and 2) CNS tumors are characterized by marked heterogeneity, which greatly decreases vulnerability to chemotherapy. As a result, many categories of CNS tumors simply have no chemotherapy available. These include, generally, hemangioblastomas, meningiomas, craniopharyngiomas, acoustic neuromas, pituitary adenomas, optic nerve gliomas, glomus jugulare tumors and chordomas, to name just some. With regard to gliomas, GBM is considered untreatable; no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is radiation and surgery which are used for low grade gliomas (e.g. pilocytic astrocytoma and diffuse astrocytoma), as no drug has been found effective. There is no drug treatment established as effective for optic nerve gliomas or gangliogliomas. Indeed, very few gliomas of any type are treated with pharmaceuticals; it is one of the categories of cancer that is the least responsive to drugs.
Lymphomas of the stomach are not commonly treated with anti-cancer agents per se, but instead, surgery or radiation and antibiotic therapy (e.g. amoxicillin, metronidazole, bismuth, and omeprazole) are the primary treatments.
Neuroendocrine tumors of the cervix generally do not respond to chemotherapy.
A number of sarcomas, including alveolar soft part sarcoma (ASPS), retroperitoneal sarcoma, most liposarcomas, and the assorted chondrosarcomas, are generally considered not to respond to chemotherapy; no chemotherapeutic agent has been established as effective.
It is important to note that tumors can need to be treated quite differently even though they are tumors of the same organ. For example, the drugs used most often to treat Wilms tumor, the most common malignant tumor of the kidneys in children, are actinomycin D and vincristine. Such drugs are never used with clear cell renal carcinoma, which is treated, although without much success, with immunotherapy using the cytokines interleukin-2 and interferon-alpha. However, such immunotherapy has never been established as effective in non-clear cell RCC forms such as papillary renal cell carcinoma. Despite strenuous efforts over a period of decades, no chemotherapeutic agent has ever been found effective against this cancer. Cancers of the stomach can be lymphomas, GISTs, carcinoid tumors, carcinomas, or soft tissue sarcomas, and for a single agent to be effective against all or even most of these categories would be contrary to what is known in oncology.
The scope of treating inflammation generally is extraordinarily broad. Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. It is one of the most pervasive of all body processes. Inflammation is a very general term which encompasses a huge variety of specific processes.
2) The nature of the invention and predictability in the art.
With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the "general unpredictability of the field [of] …anti-cancer treatment." In re Application of Hozumi et al., 226 USPQ 353 notes the "fact that the art of cancer chemotherapy is highly unpredictable". More generally, 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).
The artisan using Applicants invention would be a Board-Certified physician in oncological diseases with an MD degree. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prophylaxis (prevention) of diseases such as cancers. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable to any agent to be able to prevent diseases such as cancers. That is, the skill is so low that no compound effective generally against the prevention of diseases such as cancers.
3) State of the Prior Art. The claimed compounds are of formula (I). So far as the examiner is aware these compounds have not been successfully used as broad range anticancer agents or prophylactics.
Moreover, the state of the art is that no general procedure is art-recognized for determining which patients generally will suffer from cancer before the fact for the purposes of prevention.
4) Working Examples. Applicants have provided no working examples which are successfully used as broad range anticancer agents. Applicants have, however, demonstrated the cytotoxicity of compounds of the claimed invention against PC9 and HCC-827 cells in in vitro assays. See specification, p. 352-353 and Table 9.
5) Skill of those in the art. Many, many mechanisms have been proposed over the decades as methods of treating the assorted cancers generally. Cytotoxic agents could be applied directly to the tumor cells, directly killing them. Immunotherapy involves stimulating the patient's immune system to attack cancer cells generally, either by immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets, or by the administration of therapeutic antibodies as drugs, so the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Another approach would be to increase the amount or activity of the body's tumor suppressor genes, e.g. p53, PTEN, APC and CD95, which can for example activate DNA repair proteins, suppress the Akt/PKB signaling pathway, or initiate apoptosis of cancer cells. The angiogenesis inhibitor strategy was based on cutting off the blood supply that growing tumors need by shutting off the growth of new blood vessels by, for example, suppressing proliferation of endothelial cells or inducing apoptosis of endothelial cells. There is also the cancer stem cell paradigm, which hypothesizes that cancer could be treated generally, either by targeting the cancer stem cells themselves, or by targeting the epithelial-to-mesenchymal transition which supposedly generates the cancer stem cells. Yet another approach is to inhibit one or more of the assorted HSP90 proteins, which will supposedly disrupt the proper folding of signaling proteins that all cancers rely on. Inhibiting telomerase was said to be able to be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Accordingly, there is substantive "reason for one skilled in the art to question the objective truth of the statement of utility or its scope" (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally. 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."
6) Scope of the claims. The scope of the claims involves the compounds of the following formula (I):
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and their use as potential prophylactics or treatment to cancers, thus, the scope of claims is very broad.
7) The quantity of experimentation needed. Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, and especially in view of factors 1 and 4 and 6, the quantity of experimentation needed is expected to be great.
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.
Allowable Subject Matter
Claims 1-4, 13, and 24 are allowed. The closest prior art is Siegel et al. (WO 2019/081486 A1) which discloses EGFR inhibitors. The compounds of Siegel et al. differ from the instant invention in that both R3 and R5 are hydrogen. Siegel et al. does not teach or suggest substituting hydrogen, let alone specifically in the R3 or R5 position, with another substituent that is not hydrogen within the scope of the instant claims. Moreover, there is no additional suggestion in the prior art to substitute the compounds in the R3 or R5 position with another substituent that is not hydrogen.
Conclusion
Claims 1-4, 13, and 24 are allowed. Claims 5-7, 16, 22-23, 25-28, 34, 40, and 42 are rejected.
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/MADELINE E BRAUN/Examiner, Art Unit 1624 06/26/2026
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