Patent Application 18915893 - NOVEL MOLECULAR GLUE AND USES THEREOF

Title: NOVEL MOLECULAR GLUE AND USES THEREOF

Application Information

Invention Title: NOVEL MOLECULAR GLUE AND USES THEREOF
Application Number: 18915893
Submission Date: 2025-05-16T00:00:00.000Z
Effective Filing Date: 2024-10-15T00:00:00.000Z
Filing Date: 2024-10-15T00:00:00.000Z
Examiner Employee Number: 100562
Art Unit: 1691
Tech Center: 1600

Rejection Summary

102 Rejections: 0
103 Rejections: 1

Cited Patents

The following patents were cited in the rejection:

US 0137434🔗

Office Action Text

DETAILED ACTION
This office action is in response to applicant’s filing dated April 23, 2023

Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .

Status of claims
Claims 1 - 15 are pending in the instant application.

Election/Restrictions
Applicant’s election without traverse of Group I, Claims 1-12, drawn to a compound represented by Formula 1, or an enantiomeric compound thereof and a pharmaceutical composition thereon in the reply filed on April 23, 2025 is acknowledged.
Claims 13 – 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 23, 2025.
Applicant’s election without traverse of compound 2-(2,6-dioxopiperidin-3-yl)-4-(((R)-1-(4-methoxyphenyl)ethyl)amino)isoindoline-1,3-dione (Compound AST-DT-218) of the formula:
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as a single disclosed species of compound of general Formula 1 in the reply filed on April 23, 2025 is acknowledged.
Claims 1 – 12 are presently under examination as they relate to the elected species: compound AST-DT-218 and expanded species, where R1 is alkyl.

Priority
The present application was filed on October 15, 2024 and claims the benefits of priority of foreign application KR10-2023-0137434, filed October 16, 2023.

Drawings
The drawings are objected to because of the following errors:
x-axis of graphs in Figures 4 – 12 is labeled “concentration (M)” while it has negative numbers. Correction of units or label of x-axis of graphs in Figures 4 – 12 is required. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.

Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.

The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.

Claims 1 – 12 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 liver cancer, pancreatic cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal adenocarcinoma, gastric adenocarcinoma and malignant melanoma with the compound AST-DT-218, does not reasonably provide enablement for the method of preventing of any type of cancer or treating the full scope of types of cancer encompassed by the instant claims with all of the compounds of formula 1. 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 treatment of cancer generally cannot possibly be considered enabled. This is a scope of enablement rejection.
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). 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.” The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
- the quantity of experimentation necessary,
- the amount of direction or guidance provided,

- the presence or absence of working examples,
- the nature of the invention,
- the state of the prior art,
- the relative skill of those in the art,
- the predictability of the art, and
- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention and the Breadth of claims.
The claims are drawn to a compound of formula 1
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and a pharmaceutical composition thereon for preventing or treating cancer in a subject. The complex nature of the subject matter to which the present claims are directed is exacerbated by the breadth of the claims. The claims are broad and encompass treatment or prevention of a vast number of possible cancer types including solid tumors as well as blood-borne tumors using all the variety of compounds of formula 1.
Scope of the compound covered:
The number of compounds encompassed by the formula above is vast since the formula encompasses a large number of possible structural components for R1 variable of the compound of formula 1 including stereoisomers and would yield hundreds of compounds. R1 variable could be e.g.:
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These compounds encompass molecules that widely vary in the physical and chemical properties such as size, molecular weight, acidity, basicity, and properties that are known in the art to greatly influence pharmacokinetic and pharmacodynamics parameters, not to mention the ability to productively bind to claimed biological target molecules. The claims cover compounds easily in the thousands given the number of possible R1 variables covered by the claims' scope. Each of these compounds are claimed to be useful in the method of treating all types of cancer encompassed by instant claims.
Prevention of cancer:
The claims are drawn to a method for preventing cancer by administering to the subject the compounds of general formula 1. Each of the compounds of formula 1 are claimed to be useful in the method of preventing all types of cancer. With respect to cancer, this a broad term which encompasses numerous forms of neoplastic diseases, each involving different types of tissues and organs and also includes blood-borne diseases. As recognized in the art, many different anti-neoplastic drugs are used to treat a variety of cancers, but there is no one drug, which is capable of treating all cancers in general. Moreover, the prior art does not recognize the complete cure or prevention of all types of cancer.
Scope of the diseases covered:
The different types of cancer are so vast and vary considerably as detailed below:
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. Here are a few of the assorted categories:
A. CNS cancers cover a very diverse range of cancers in many categories and subcategories. There are an immense range of neuroepithelial tumors. Gliomas, the most common subtype of primary brain tumors, most of which are aggressive, highly invasive, and neurologically destructive tumors are considered to be among the deadliest of human cancers. These are any cancers which show evidence (histological, immunohistochemical, ultrastructural) of glial differentiation. These fall mostly into five categories. There are the astrocytic tumors (astrocytomas): pilocytic astrocytoma (including juvenile pilocytic astrocytoma, JPA, and pediatric optic nerve glioma) diffuse astrocytomas (including fibrillary astrocytomas, protoplasmic astrocytomas and gemistocytic astrocytomas), anaplastic astrocytomas (including adult optic nerve glioma), Glioblastoma multiforme (GBM), gliosarcoma and giant cell glioblastoma.
B. Leukemia is any malignant neoplasm of the blood-forming tissues. Leukemia can arise from many different sources. These include viruses such as EBV, which causes Burkitt's lymphoma, and HTLV-1, linked to certain T cell leukemias. Others are linked to genetic disorders, such as Fanconi's anemia, which is a familial disorder, and Down's Syndrome. Other leukemias are caused by exposure to carcinogens such as benzene, and some are actually caused by treatment with other neoplastic agents. Still other leukemias arise from ionizing radiation, and many are idiopathic. Leukemias also differ greatly in the morphology, degree of differentiation, body location (e.g. bone marrow, lymphoid organs, etc.) There are dozens of leukemias. There are B-Cell Neoplasms such as B-cell prolymphocytic leukemia and Hairy cell leukemia (HCL, a chronic Lymphoid leukemia). There are T-Cell Neoplasms such as T-cell prolymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma (ATLL), and T-cell granular Lymphocytic leukemia. There are different kinds of acute myeloid leukemias (undifferentiated AML, acute myeloblastic, acute myelomonocytic leukemia, acute monocytic leukemias, acute monoblastic, acute megakaryoblastic (AmegL), acute promyelocytic leukemia (APL), and erythroleukemia). There is also lymphoblastic leukemia, hypocellular acute myeloid leukemia, Ph-/BCR- myeloid leukemia, and acute basophilic leukemia.
C. Carcinomas of the Liver include hepatocellular carcinoma, combined hepatocellular cholangiocarcinoma, cholangiocarcinoma (intrahepatic), bile duct cystadenocarcinoma and undifferentiated carcinoma of the liver.
D. The main types of lung and pleural cancer are small cell (i.e. oat cell, including combined oat cell), adenocarcinomas, bronchioloalveolar carcinomas (nonmucinous, mucinous, and mixed mucinous and nonmucinous or indeterminate cell type), acinar, papillary carcinoma, solid adenocarcinoma with mucin, adenocarcinoma with mixed subtypes, well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell adenocarcinoma), squamous cell (papillary, clear cell, small cell and basaloid), mesothelioma (including epithelioid, sarcomatoid, desmoplastic and biphasic) and large cell carcinoma (which include large-cell neuroendocrine carcinoma, combined large-cell neuroendocrine carcinoma, basaloid carcinoma, clear cell carcinoma lymphoepithelioma-like carcinoma, and large-cell carcinoma with rhabdoid phenotype).
E. Thyroid cancer comes in four forms: papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, and medullary thyroid cancer.
F. Cancer of the skin cells is melanoma. Malignant melanomas come in four fundamental forms: superficial spreading melanoma, nodular melanoma (including its variant, Polypoid melanoma), lentigo malignant melanoma and acral melanoma. Mucosal melanomas are sometimes malignant. These sometime occur in amelanotic form, such as in desmoplastic melanoma.
H. There are many types of colorectal cancers. The carcinomas include
adenocarcinoma; mucinous adenocarcinoma; signet-ring cell carcinoma; small cell carcinoma; adenosquamous carcinoma; medullary carcinoma; choriocarcinoma; and undifferentiated carcinoma. The malignant lymphomas include marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type; mantle cell lymphoma; Diffuse large B-cell lymphoma; Burkitt lymphoma; and Burkitt-like/atypical Burkitt lymphoma.
Similarly there exists various types of Renal Cancers, Prostate cancer, Carcinomas of the bile ducts, Breast cancers, Ovarian cancers, Testicular cancers, Paratesticular cancers, Cancer of the vulva, Vaginal cancers, Endometrial carcinomas, Stomach cancers, esophagus cancers, cancers of spleen, Salivary gland carcinomas, heart cancers, cancers of the oral cavity, cervical cancers, throat cancers, gall bladder cancers, non-Hodgkin lymphomas etc.
2. The relative skill of those in the art.
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience. However, given the state of the art as set forth above, the artisan is currently unaware of any one particular anticancer agent that is effective against all cancer cell types. Furthermore, the burden of enabling the prevention or cure of all forms of cancer would be much greater than that of enabling the treatment of cancer for the purpose of alleviating, altering or ameliorating any given type of cancer. Many mechanisms have been proposed over the decades as methods of treating the diseases covered by the instant claims and all the assorted cancers generally. 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. Many of these approaches 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.
3. The predictability or unpredictability of the art and the state of the prior art.
The present claims relate to the mechanism underlying the treatment of the claimed diseases with the compounds of the instant invention. Although the discovery of such a mechanism may be an important piece of scientific knowledge, it still needs to be turned into a practical application in the form of a specified actual treatment of the pathological conditions. The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art, the examiner cites: Anderson (Chem and Biol 10:787-797, 2003), Jan et al (Nat Rev Clin Oncol 18, 401–417 (2021)) and Sasso et al (Biochemistry 2023, 62, 3, 601-623).
Anderson, cited for evidentiary purposes, teaches that the process of structure-based drug design is an iterative one and often proceeds through multiple cycles before an optimized lead goes into phase I clinical trials. Many years of research may be necessary to convert a drug lead into a drug that will be both effective and tolerated by the human body (page 787, introduction). Anderson further teaches that small molecules, which modulate the function of ion channels, proteases, kinases and nuclear hormone receptors make up 22% of the market. In addition, Anderson, cited for evidentiary purposes, teaches that cancer targets can be difficult because the targets are often somatic cells mutants of proteins that regulate essential cellular functions, resulting in the loss of a function. The disruption of oncogenic complexes is another difficult problem for anticancer drug design (page 788 – 789 “choice of a drug target”).
Furthermore, with regard to unpredictability Jan cited for evidentiary purpose, teaches: targeted protein degradation in oncology has reached an extraordinary juncture after thalidomide analogues were discovered in 2013 to exert their therapeutic effects by acting as a molecular glue to recruit disease-relevant neosubstrate proteins to an E3 ubiquitin ligase, resulting in neosubstrate ubiquitylation and, ultimately, proteasomal degradation (page 401, right column, 2nd paragraph). Drugs that induce targeted protein degradation, such as thalidomide analogues, have a number of unique pharmacological features in comparison with conventional enzyme inhibitors. These features can in turn provide unique clinically beneficial properties (page 409, right column. 1st paragraph). However treatment with thalidomide analogues often has adverse effects such as peripheral blood cytopenias, most commonly neutropenia (grade 3–4 in 28% of patients) and thrombocytopenia (page 408 “clinical toxicities”). Thalidomide analogues are also associated with an increased risk of primarily venous thromboembolism. Moreover, extended treatment with lenalidomide found to result in resistance to the drug. Mutations in CRBN, including missense mutations in the thalidomide analogue- binding domain, are associated with progressive exposure to thalidomide analogues, and ultimately occur in up to one- third of patients with pomalidomide- refractory disease (page 409, “resistance mechanism”).
Moreover, with regard to unpredictability Sasso, cited for evidentiary purposes, teaches: targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin−proteasome pathway (page 601, abstract). In one of the approaches, E3 ligases are being reprogrammed by monovalent small molecules, termed molecular glues. Despite the favorable pharmacokinetic properties of molecular glues, currently well-characterized molecular glues are limited. The understanding of their mode of action and design principles is still deficient. A profound understanding of such compound-mediated protein−protein binding events is broadly insufficient. Detailed knowledge of the interfaces involved, as in the example of immunomodulatory imide drugs (IMiD) binding to CRBN, is necessary to design novel molecular glues and develop them into a powerful new medicines. (page 618, left column). Sasso further teaches: as small molecule drugs, one of the hurdles in molecular glue advancement is their progression into clinical therapeutics. Although some progress in understanding their mechanisms of action has been achieved, the pharmacokinetic and pharmacodynamic profiles of newly developed molecular glues are still largely unknown, which obstructs their further development into drug candidates (page 618, right column 2nd paragraph).
These articles plainly demonstrate that the art of developing and testing therapies to treat any and all types of cancer with compounds of instant claims is 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).
4. The amount of direction or guidance provided and the presence or absence of working examples.
The instant claims, directed to a method of treating all different types of cancer with all the compounds of general formula 1 are too broad in contrast with the specification that only provides data, showing therapeutic activity of compound AST-DT-218 on the hepatoma cell lines (Huh7 and Hep3B), non-small cell lung cancer cell lines (NCI-H460 and NCI-H1299), pancreatic cancer cell lines (PANC-1 and MiaPaca-2), rectal cancer cell lines (HT29 and HCT116), a gastric adenocarcinoma cell line
(AGS), a malignant melanoma cell line (A375), and breast cancer cell line (MDAMB-231) (example 6). While experimentation is presented for treatment of types of cancer listed above with the compound AST-DT-218, the specification does not provide working examples of treatment of any forms of cancer that are not liver cancer, pancreatic cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal adenocarcinoma, gastric adenocarcinoma or malignant melanoma with any other than compound AST-DT-218 compounds of general formula 1. Nor is there any experimental evidence provided of administering any of compounds of general formula 1 for preventing all forms of cancer in a patient or how a patient could be kept from even being susceptible to all forms of cancer. Although specification provides general direction or guidance for determining the administration regimen or routes of pharmaceutical composition, e.g.:
- the pharmaceutical composition of the present invention may be administered in a therapeutically effective amount of the active ingredient,
- the pharmaceutical composition of the present invention may be administered to a subject or individual by any route of administration, for example, it may be administered by intraperitoneal administration, intravenous, etc., (page 23, lines 4 – 5, and 16 - 18),
- the term "treatment" refers to any act by which the symptoms of a disease are improved or beneficially changed by administering a composition according to the present invention (page 22, lines 14 – 16), necessary to treat all of the various cancers encompassed by the claims, the directions are very broad and include vast variety of known formulations.
There is no experimentation or mechanism of action presented or discussed in the specification regarding treatment of the cancers that are not liver cancer, pancreatic cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal adenocarcinoma, gastric adenocarcinoma or malignant melanoma. As of prevention of cancer, the specification provides definition: the term "prevention" refers to any act of inhibiting or delaying a disease by administering a composition according to the present invention. There is no any guidance provided as to a specific protocol to be utilized in order to show the efficacy of the presently claimed active agents for preventing or curing all forms of cancer. Absence of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164.
5. The quantity of experimentation necessary.
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that all the compounds of formula 1 are capable of treating the vast number of possible cancerous diseases encompassed by the term "cancer", nor recognize prevention of all types of cancer. Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and ‘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" (42 USPQ 2d 1001, Fed. Circuit 1997). As noted above, none of the experimentation provided is drawn to the treatment of a cancer that is not a liver cancer, pancreatic cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal adenocarcinoma, gastric adenocarcinoma or malignant melanoma. A review of the state of the art fails to reveal that compounds of formula 1 are useful as a therapeutic for the treatment of any cancers, except for a cancers listed above. Determining if any particular claimed compound would treat any particular cancerous disease state would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. Additionally, it is highly unlikely, and the Office would require experimental evidence to support the contention, that the claimed compound could actually prevent or cure cancer by simply administering, by any method, an amount of the claimed compounds. The specification fails to enable one of ordinary skill in the art to practice the prevention of cancer.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.

Claim Rejections - 35 USC § 103
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.
Claims 1 – 12 are rejected under 35 U.S.C. 103 as being unpatentable over Bradner et al (WO 2017/007612 A1 hereinafter Bradner).
Instant claims are drawn to a compound of general formula (1), e.g. a compound of formula
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(compound AST-DT-218) and a pharmaceutical composition thereon for treating cancer such as liver cancer, pancreatic cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal adenocarcinoma, gastric adenocarcinoma and malignant melanoma, wherein the cancer is incurable or drug-resistant, wherein said composition is administered via various routes (e.g. oral, intravenous or intradermal). Bradner teaches bifunctional compounds, which function to
recruit targeted proteins to E3 Ubiquitin Ligase for degradation. Bifunctional molecules, taught by Bradner, have a following structure:
Degron-Linker-Targeting Ligand,
where Degron is a small molecule binding to a ubiquitin ligase such as an E3 Ubiquitin Ligase (e.g., cereblon) (page 2, lines 29 – 32), where the Degron is a thalidomide or a derivative or analog thereof (page 18, line 14), where the Degron is selected from following:
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179
282
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(page 35, table 3, D-18),
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122
328
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(page 36, table 3, D-26) or
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77
172
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, wherein
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35
90
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is
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62
155
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or
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51
73
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(page 44, table D4). Although claimed compound AST-DT-218 and a compound
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77
172
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, where wherein
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35
90
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is
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62
155
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, taught by Bradner, are not identical, their structures are very similar and differ only by -CH2- group, also both compounds known to have similar property of binding affinity to cereblon protein. MPEP states: Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). Bradner further teaches a pharmaceutical composition comprising above compounds for treatment of cancer such as breast cancer, colon cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, melanoma (page 203, lines 23 – 25) wherein cancer is resistant to treatment with the Targeting Ligand ( page 7, line 6) and wherein said pharmaceutical composition is administered orally or intravenously (page 223, line 34). Bradner defines "Resistant to a Targeting Ligand", as a disease or condition that cannot be treated by the Targeting Ligand. For example, the Targeting Ligand is incapable of preventing the disease or condition from worsening, or alleviating or reducing one or more symptoms of the disease or condition, or improving the quality of life of a patient suffering from the disease or condition (page 223, lines 1 – 6).
Thus, since Bradner teaches compounds, thalidomide analogues, or more specifically pomalidomide derivatives, capable of binding to an E3 Ubiquitin Ligase (e.g., cereblon) which property can be utilized in treatment of cancer through targeted protein degradation mechanism, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to try to make various compounds of similar structure to a known compound (e.g. isomers or homologs) in search for a new drug with similar or better desired properties, to come to claimed compounds, with the reasonable expectation of success.

Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.

Conclusion
Claims 1 -12 are rejected. No claim is allowed.

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/E.V.V./Examiner, Art Unit 1691

/SAVITHA M RAO/Primary Examiner, Art Unit 1691