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 .
Response to Amendment
The amendments received 09/11/2025 have been entered. Claims 1-19 are pending. Any objection or rejection as set forth in the Office Action mailed 04/11/2025 not maintained herein has been overcome and is withdrawn.
New grounds of rejection are set forth herein as necessitated by amendment.
Information Disclosure Statement
The Information Disclosure Statement filed on 09/22/2025 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of list of references cited from the IDS is included with this Office Action.
Claim Objections
Claim 1 is objected to because of the following informalities: (i) there is a period after the structure of Formula V; (ii) claim 1 ends in two periods. Appropriate correction is required.
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 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to recite “comprising an anti-PDL antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, or any combinations thereof.” The disclosure, at the time of filing, does not teach or suggest “combinations” of immune checkpoint inhibitors, let alone the more narrowly claimed antibodies. The limitation “or any combinations thereof” constitutes as new matter. Correction is required.
Claims 1-14 and 16-19 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 inhibiting the growth of osteosarcoma cells, Kaposi's sarcoma cells, melanoma cells, prostate cancer cells, glioblastoma cells, small cell lung carcinoma cells, breast cancer cells, liver cancer cells, colon cancer cells, ovarian cancer cells, renal cancer cells, gastric cancer cells, neuroblastoma cells, pancreatic cancer cells, and Hodgkin's lymphoma, does not reasonably provide enablement for inhibiting the growth of cancerous or pathogen-infected cells in a subject 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 incredibly broad and are generally directed toward inhibiting the growth of “a cancerous cell or a pathogen infected cell,” which include cancers, viral infections, bacterial infections, etc.
"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 astrocytomas), 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".
Regarding development of antivirals, certain viral infections remain untreatable despite progress in immunization development. The common cold, for example, remains untreatable and unpreventable via vaccine. Moreover, so-called “broad spectrum antiviral agents” have yet to demonstrate efficacy against any and all viral infections, often targeting specific pathways and receptors in order to target a particular subset of viruses. The development of broad-spectrum antivirals is unpredictable and still fraught with challenges. Zhu et al. (Frontiers in Microbiology; 2015), for example, states “[T]here are concerns of viral resistance associated with agents targeting viral components and non-specific side effects associated with agents targeting cellular machineries. Accordingly, how to reduce viral resistance and increase drug specificity are current challenges to be addressed” (p. 10).
There is currently no evidence in the art that a single therapy could be utilized to treat “a cancerous cell or a pathogen infected cell” generally.
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).
3) State of the Prior Art. The claimed combination therapy is that of a diprovocim compound, an immune checkpoint inhibitor, and a marker molecule. So far as the examiner is aware this combination therapy has not been successfully used as broad range anticancer agents, antivirals, antifungals, AND antibiotics.
4) Working Examples. Applicants have provided no working examples which are successfully used as broad range anticancer agents, antivirals, antifungals, and antibiotics. Moreover, Applicants have provided no examples of treating any virus, fungus, or bacterium, or other unicellular infection with the combination therapy as claimed.
Applicants have, however, demonstrated the cytotoxicity of a combination of a diprovocim compound, OVA, and anti-PD-L1 in the in vivo treatment of B16-OVA xenograft models (melanoma). See Specification filed 02/02/2021, p. 56-63, for working examples.
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 combination of a diprovocim compound, an immune checkpoint inhibitor, and a marker molecule for the treatment of cancerous or pathogen-infected cells generally. The scope of the claims is therefore incredibly broad.
7) The quantity of experimentation needed. Given the fact that, historically, the development of new cancer drugs, antivirals, antibiotics, antifungals, etc., 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.
Claims 1-13 and 15-19 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 CD96, CD20, DLL4, CD55, TIM-3, CXCR1, CD54, CD114, LGR5, CD105, CD56, CD13, CD271, CD34, CXCR4, CD26, CD117, CD10, CD146, Notch2, CD49f, CD24, ABCG2, PODXL-2, Cripto-1, CD326, CD90, CD133, SSEA1, TRA-1-81, TRA-1-60, SSEA4, SSEA3, CD151, CD340 and CD44, does not reasonably provide enablement for a marker molecule 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.
The instant claims are directed toward a method of inhibiting the growth of diseased cells in a subject, comprising administering a combination of a diprovocim compound, an immune checkpoint inhibitor, and a marker molecule. The specification does not define that which is intended in the use of a “marker molecule” beyond its general function which “can be but need not be expressed on the cell surface, and rather can be expressed anywhere in the diseased cell” (p. 19 of Specification filed 02/02/2021) and is presumably not expressed by non-diseased cells. The exemplary marker molecules contemplated by the instant disclosure include those listed above, as well as peptides specific to malaria and HPV (p. 36-42 of Specification filed 02/02/2021). However, Applicant has provided no working examples wherein a broad range of “marker molecules”, let alone marker molecules for the treatment of viral, bacterial, fungal, or pathogenic infection, are combined with a diprovocim compound and an immune checkpoint inhibitor for the treatment of diseases generally.
The general state of the art contends that treatment of diseases of a physiological nature is generally considered unpredictable, including the efficacy of combination therapies. The scope of “immune checkpoint inhibitor” in combination with a “diprovocim compound” and a “molecular marker” is incredibly broad, such that one of ordinary skill in the art would certainly undergo undue experimentation in order to determine whether this combination therapy is effective against cancerous cells and pathogen-infected cells generally.
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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. 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.
Claim(s) 1-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Beutler et al. (WO 2018005812 A1), Wang et al. (J Immunol; 2017; IDS filed 04/05/2024), Lu (Frontiers in Immunology; 2014), Sehgal et al. (Expert Opinion on Biological Therapy; 2015), and McNeel et al. (US 2018169224 A1).
Beutler et al. discloses a Diprovocim compound with Formula V as shown below (Fig. 1B).
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228
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wherein -A is -H (hydrido) or -C(O)NH-R4; R1, R2, R3 and R4 are the same or different and are a 2-(4-fluorophenyl)ethyl, a trans-2- phenylcyclopropyl, a trans-2-(4-fluorophenyl)- cyclopropyl or a C2-C18 hydrocarbyl group with the provisos that:
1) at least two of R1, R2, R3 and R4 (R1-4) or at least two of R1, R2, and R3 (R1-3) are a trans- 2-phenylcyclopropyl, a trans-2-(4-fluorophenyl)- cyclopropyl group or a mixture thereof, or each of R1-4 is a 2-(4-fluorophenyl)ethyl group,
2) at least one depicted pyrrolidinyldicarboxamido group has the (S,S) configuration, and each depicted R substituent other than a C2-C18 hydrocarbyl group is a trans-2- phenylcyclopropyl, a trans-2-(4-fluorophenyl)- cyclopropyl group or a mixture thereof when each of R1-4 is other than 2-(4-fluorophenyl)ethyl,
3) no more than two of R1-4 are C2-C18 hydrocarbyl groups when -A is -C(O)NH-R4, and
4) when A is hydrido, one of R1-3 can be a C2-C18 hydrocarbyl group and the depicted R3- containing pyrrolidinylcarboxamido group can have either the R or S configurations, or a mixture of both configurations;
-Z is one or more of halogen -H, -NH2, -OH, -OCH3, -NO2, -OCH2CO2H, -O(CH2CH20)nCH2CH2CO2H,
-OCH2CONH(CH2CH20)nCH2CH2CO2H, -NHCOCH20- (CH2CH20)nCH2CO2H,
-OCH2CONHCH2CONHCH(CHOH)CO2H, -OCH2CONHCH2CONHCHCO2H(CH2CO2H),
-OCH2CONHCH2CONHCH(CHOH) (CH2CH20)nCH2CH2CO2H,
-OCH2CONHCH2CONHCH[(CH2)4NH2]CO2H,
-OCH2CONHCH2CONHCH(CH2OH)CO{NHCH[(CH2)4NH2]CO}mNHCH[(CH2)4NH2]CO2H (SEQ ID NOs: 3-8),
-OCH2CONHCH2CO{NHCH[(CH2)4NH2]CO}pNHCH[(CH2)4NH]CO2H (SEQ ID NOs: 9-13) and
-OCH2CONHCH2CO{NHCH(CH2OH)CO}qNHCH(CH2OH)CO2H (SEQ ID NOs: 14-18);
W is nitrogen (N) or CH;
"n" is a number whose average value is one to about eight;
"m" is a number whose value is 1 to about 6;
"p" is a number whose value is 1 to about 6; and
"q" is a number whose value is 1 to about 6 (Claim 1).
Beutler et al. further discloses that the compound of Formula V is a TLR1/TLR2 agonist (p. 16, par 1) and has immune-adjuvant properties (abstract). Furthermore, Beutler et al. teaches a Formula Ia wherein the R1-4 and Z moieties are as described in claim 1 of Beutler et al (Claim 8).
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Beutler et al. also discloses that each of R1-4 is a trans-2-phenylcyclopropyl group or a trans-2-(4-fluorphenyl)cyclopropyl group having the (1S,2R) configuration (Claim 12) and teaches Formulas A, B, C, D, E, F, and G as shown below (Claim 14).
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587
439
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742
443
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Moreover, Beutler et al. discloses a method of enhancing an immunogen-specific humoral immune response that comprises contacting immune cells with an adjuvant-effective amount of a diprovocim compound (as above) and an immunogen to which said response is to be enhanced (claim 17). Beutler et al. further teaches a specific working example in which the diprovocim compounds, in combination with antigen model ovalbumin, increases an ovalbumin-specific immune response in C57BL/6 mice (Figure 6).
Beutler et al. does not disclose a method of inhibiting the growth of cancerous or pathogen-infected cells in a mammal comprising administering the above diprovocim compounds, an immune checkpoint inhibitor, and a marker molecule or portion thereof to the mammal and maintaining the mammal for a time period sufficient to mount an immune response. Beutler et al. does not disclose that the cells are cancerous, pathogen-infected, or solid tumor cells, or the particular marker molecules of claims 14 and 18. These limitations are obvious over Wang et al., Lu, and McNeel et al.
Wang et al. discloses a method of treating human THP-1 (leukemia) cells with a combination of diprovocim and ovalbumin, which increases production of cytotoxic T-lymphocytes and showed TLR1/2 dependent adjuvant activity (abstract, Figure 3).
Lu teaches that anti-PD-1 and anti-PD-L1 are checkpoint inhibitors used in immunotherapy and cancer therapy. Lu et al. teaches that the combination of TLR therapies with PD-1/PD-L1 blockade is extremely promising, stating, “Not only will the blockade of PD-L1 signaling likely enhance the immune stimulatory effects of TLR agonists, but we also expect TLR ligation to enhance the effect of PD-1/PDL1 blockade by increasing tumor infiltrating immune cells (TIL). The presence of TIL has been associated with good clinical response in the check-point blockade therapy. In addition to anti-PD-1/PD-L1, there will be other check-point inhibitors that will also become available for testing with TLR agonists” (p. 3, col. 1).
Sehgal et al. teaches that CTLA-4, PD-1, TIM-3, LAG-3, and BTLA are surface molecules that are up-regulated in the tumor microenvironment (p. 1191).
McNeel et al. teaches a method of eliciting an anti-tumor response in a subject in need thereof, comprising administering a TLR1/2 agonist and an anti-tumor vaccine to the subject (claim 1). McNeel et al. also teaches a method of increasing an immune response to an antigen, comprising administering a TLR1/2 agonist and a vaccine directed to said antigen to the subject, which increases the immune response to said antigen (claim 10). McNeel et al. further discloses that the tumors to be treated include pancreatic cancer, ovarian cancer, prostate cancer, head and neck cancer, lung cancer, Hodgkin's Disease, non-Hodgkin's lymphomas, etc. (par. [0068]). McNeel et al. also discloses that the methods can also be used to treat viral, bacterial, or parasitic diseases (par. [0061]), wherein the antigen can be that of an infectious agent such as a Plasmodium parasite or influenza virus, and an antigen is any molecule recognized by the immune system that stimulates an immune response (pars. [0065-66]) and a tumor antigen is preferentially expressed on the surface of a tumor cell, but not healthy cells (par. [0064]).
It would be prima facie obvious for one of ordinary skill in the art to combine the diprovocim compounds of Beutler et al. with a marker molecule and an immune checkpoint inhibitor for the treatment of diseased cells. One would have been motivated to do so, with reasonable expectation of success, because all three agents are effective against diseases including cancers and infections. Moreover, Beutler et al., Wang et al., and McNeel et al. teach that the combination of TLR1/2 agonists with an antigen stimulates a substantial immune response in diseased cells. Lu suggests that the combination of TLR1/2 agonists with immune checkpoint inhibitors would have additive effects by enhancing the PD-1/PD-L1 blockade. Therefore, in combination, the three agents would be expected to provide additive effects in the treatment of cancers and other infections. It would further be within the skillset of one of ordinary skill in the art to administer an “adjuvant-sufficient amount”, “a T-cell stimulating amount”, and an “immunizing amount” of the combined agents via routine optimization, in order to arrive at an effective treatment dose.
Response to Arguments
Applicant's arguments filed 09/11/2025 have been fully considered but they are not persuasive.
35 U.S.C. 112(a)
Regarding the rejection of claims 1-14 and 16-19 under 35 U.S.C. 112(a) scope of enablement, Applicant argues that the claims are enabled for inhibiting the growth of a diseased cell in a mammal, wherein the diseased cell is a cancerous cell or a pathogen infected cell, because the claims are directed toward not a single agent or composition but a tailored combination therapy that differs for each targeted diseased cell (Remarks, p. 11-12). This is not persuasive.
It is understood by the Examiner, as indicated in the above rejection (see, for example, “State of the prior art” and “Scope of the claims”) that the instantly claimed invention is not directed toward a single agent but a combination therapy. In fact, regarding the scope of the claims, the notion that the combination therapy is tailored to each specific disease only broadens the scope of the claims. In order to successfully make and use the invention, one of ordinary skill in the art would have to (i) select a diprovocim compound of Formula V, (ii) select an immune checkpoint inhibitor (anti-PDL, anti-PD-L1, or anti-CTLA-4 antibody), and (iii) identify and select a marker molecule expressed on the diseased cell such that the selected combination inhibits the growth of the cancerous or pathogen-infected cell upon administration. This results in thousands, if not millions, of possible combination therapies that must be predictably tailored to the specific diseased cell to be treated.
Yet, the treatment of cancer and viral infections is not considered predictable, despite a high level of skill in the art. This aspect of the Examiner’s rejection has not been challenged by applicant, and in fact Applicant states, “the claimed combination is new and would not have been considered prior to the filing of the present application” but that the present application can be used to treat diseased cells and that the working examples demonstrate this effect (Remarks, p. 12). Examiner would first like to clarify that the state of the prior art, as in the above rejection, is not an assertion or admission that the claimed invention is novel or nonobvious, but establishes that no combination therapy (regardless of the degree to which it is “tailored” to a particular disease) has been produced that can treat any cancerous or pathogen-infected cell.
Moreover, Applicant’s statement that the “examples in the present application demonstrate that an exemplary combination of a diprovocim compound, OVA, and anti-PD-L1 inhibited the growth of OVA expressing cancerous cells” (Remarks, p. 12) does not convey enablement or efficacy in tailoring the claimed invention for the treatment of such a broad array of diseases, let alone cancerous cells generally. The exemplary combination and subsequent treatment referred to by Applicant is limited to the treatment of melanoma xenograft models. This is neither indicative of efficacy against other cancers nor a demonstration of applying the claimed method to pathogen-infected cells. The working examples do not sufficiently demonstrate how to make or use the claimed method for the treatment of the many diseases encompassed by the claims. Even if one of ordinary skill in the art could identify other marker molecules overexpressed by a target cell, this does not additionally confer that one of ordinary skill in the art could tailor a composition as in the instant method in order to treat any one of the claimed diseases.
Applicant concludes their remarks stating that one of ordinary skill in the art would readily understand how to identify new marker molecules in a diseased cell, and that the need for some experimentation is not fatal (Remarks, p. 13). Examiner reminds Applicant that the instant rejection is concerned with whether the treatment of cancerous and pathogen-infected cells generally is enabled. Applicant has additionally failed to point to any part of the instant disclosure, or any evidence of record, establishing that such a broad scope of diseases would be treatable using the instant method. Thus, given the limited guidance provided by the instant disclosure, one of ordinary skill in the art would not only have to undergo “some” experimentation, but most certainly undue experimentation. "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). The rejection is therefore maintained.
Regarding the rejection of claims 1-13 and 15-19 under 35 U.S.C. 112(a) scope of enablement, Applicant argues that it would be routine for one of ordinary skill in the art to identify and select a marker molecule for inclusion in the claimed combination therapy (Remarks, p. 13). This is not persuasive. As in the above arguments, even if one of ordinary skill in the art could identify other marker molecules overexpressed by a target cell, this does not additionally confer that one of ordinary skill in the art could combine the selected marker molecule with a diprovocim compound and an immune checkpoint inhibitor to treat a particular disease in view of the limited guidance provided by the instant disclosure.
Where the utility is unusual or difficult to treat or speculative, such as in the case of treating cancer, the examiner has authority to require evidence that tests relied upon are reasonably predictive of in vivo efficacy by those skilled in the art. See In re Ruskin, 148 USPQ 221; Ex parte Jovanovics, 211 USPQ 907; MPEP 2164.05(a). Patent 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. Tossing out the mere germ of an idea does not constitute enabling disclosure. Genentech Inc. v. Novo Nordisk 42 USPQ2d 1001.
As stated in the MPEP, 2164.08 "[t]he 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). As concerns to the breadth of a claim are relevant to enablement, the relevant concern should be whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought by the claims. In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). For these reasons, the rejection is maintained.
35 U.S.C. 103 and Declaration under 37 C.F.R. 1.130(a)
The declaration filed 09/11/2025 under 37 CFR 1.130(a) is insufficient to disqualify Beutler et al. (WO 2018005812 A1, “the ‘812 application”) as prior art.
In the Remarks filed 09/11/2025, Applicant argues that the ‘812 application should be disqualified as prior art under 35 U.S.C. 102(b)(1) because the subject matter relied upon by the Examiner originated from an inventor or co-inventor of the instant application. Applicant further points to the declaration filed 09/11/2025 signed by co-inventor Dr. Bruce Beutler.
Paragraphs 6 and 7 of the declaration filed 09/11/2025 recite as follows.
I was the originator of the discovery underlying the method of enhancing an immunogen-specific humoral immune response by contacting immune cells with an adjuvant-effective amount of a diprovicim compound and an immunogen. While both Dr. Boger and I contributed to the conception of the disclosure in the '812 Publication, I initiated and was responsible for screening diprovicim compounds for activity against various targets, including the TLR receptor. Further, I recognized that the diprovicim compounds could be used as immune adjuvants once I found that they acted as TLR agonists.
Therefore, the disclosure that the diprovicim compounds disclosed in the '812 Publication had TLR agonist activity, and therefore could act as immune adjuvants, in the "method of enhancing an immunogen-specific humoral immune response that comprises contacting immune cells with an adjuvant-effective amount of a diprovicim compound ... and an immunogen to which said response is enhanced" originated with me.
However, the above statements are contradicted by the ‘812 application itself, namely the U.S. provisional application 62/356,314 (“the ‘314 provisional”) of which the ‘812 application claims priority. The ‘314 provisional recites, in claim 21, “A method of enhancing an immunogen-specific humoral immune response that comprises contacting immune cells with an adjuvant-effective amount of a compound of claim 1 and an immunogen to which said response is to be enhanced.” This subject matter is identical to the method referred to by Dr. Beutler in the declaration as above and the subject matter referred to by Examiner as disclosed in the ‘812 application.
Notably, in looking to the Filing Receipt for the ‘314 provisional (filed 07/18/2016), the only listed inventor is Dale Boger. The declaration filed 09/11/2025 does not make clear how Boger, and only Boger, was in possession of the subject matter disclosed in claim 21 of the ‘314 provisional if said subject matter allegedly originated with Dr. Beutler who is not a named inventor on the ‘314 provisional. The ‘812 application therefore still qualifies as prior art under 102(a)(1) and 102(a)(2).
For these reasons the rejection under 35 U.S.C. 103 is maintained as the record does not clearly establish that Boger is not a joint inventor of the above subject matter or that Boger obtained the above subject matter directly or indirectly from Dr. Beutler, especially in view of the ‘314 provisional.
Conclusion
No claims are 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.
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/M.E.B./Examiner, Art Unit 1624 01/06/2026
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624