AGENT FOR ANTI-AGING OR FOR CELLULAR REJUVENATION

§102 §103 §112 §DOUBLEPATENT

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 . This is a Final Office Action. Application and Claims Status Claims 1-9 were pending. In the amendment as filed on 6/25/2026, applicants have amended claims 1-2 and 4; cancelled claims 7 and 9; and added no new claims. Therefore, claims 1-6 and 8 are currently pending and claims 1-6 and 8 are presently under examination. Specification The substitute specification filed 5/31/2024 has been entered because it conforms to 37 CFR 1.125(b) and (c). The objection to the specification (abstract) is withdrawn by Examiner based on Applicant’s amendments. The objection to the specification (drawings) is withdrawn by Examiner based on Applicant’s arguments. Claim Objections The objections to claims 1 and 4 are withdrawn based on Applicant amendment. Applicant has removed the repeated definitions of R3, R4, and R5, amended the “and/or” phrasing, removed the term “organic” from “organic oxy group” of limitations Z1-Z4, and removed “a group” from the Markush claim formatting of R3. Claim Rejections - 35 USC § 112(d) The rejection of claim 9 under AIA 35 U.S.C. 112(d) is withdrawn. Specifically, Applicant cancelled the claim altogether. Claim Rejections - 35 USC § 112(a) The rejection of claims 4-9 under AIA 35 U.S.C. 112(a) (Scope of Enablement – Prevention) is withdrawn based on Applicant’s amendments. Applicant has amended claim 4 to no longer recite “prevention” and cancelled claim 9 altogether. The rejection of claims 1-6 and 8 under AIA 35 U.S.C. 112(a) (Scope of Enablement – Methods of Use) is maintained. Applicant amended claims 1-6 and 8 to remove Ring A as naphthalene and add to claim 1 and claim 4 that the “SIRT protein is two or more proteins selected from SIRT1 protein, SIRT2 protein, SIRT3 protein, SIRT4 protein, SIRT5 protein, SIRT6 protein, and SIRT7 protein.” This was simply not enough to overcome the 112(a) rejection and failed to address all the issues. The 112(a) rejection was initially made because the Applicant is not possibly enabled for a general method to treat anti-aging, which was never addressed in their Remarks. The 112(a) rejection from the Non-Final filed 3/26/2026 is recapitulated below, with edits to suit the amended claims. 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. Scope of Enablement – Methods of Use Claims 1-6 and 8 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention. 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 scope of “a method for anti-aging or rejuvenating cells” using compounds of General Formula (I0), (II), or (III), (as recited in claim 1), or “a method for preventing or ameliorating a symptom or disease associated with aging” using compounds of General Formula (I0), (II), or (III), (as recited in claim 4) cannot be deemed enabled. The term “anti-aging” covers a broad array of different disorders that have different modest of action and different origins. Indeed, the instant specification (page 24-25, para 0060) provides a definition of “anti-aging”, which is to encompass the following (emphasis added): As used herein, the term "anti-aging" means inhibiting or delaying the progression of any one symptom or any one disease among symptoms or diseases associated with aging (preferably caused by aging). In the present specification, examples of the "symptom or disease associated with aging (preferably cause by aging)" include cancers (for example, breast cancer, colorectal cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, and prostate cancer); sarcomas (osteosarcoma, such as chordoma, chondrosarcoma, and Ewing's sarcoma; and soft tissue sarcoma, such as malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, angiosarcoma, extraosseous Ewing's sarcoma, gastrointestinal stromal tumor, liposarcoma, fibrosarcoma, myxofibrosarcoma, leiomyosarcoma, alveolar soft tissue sarcoma, undifferentiated pleomorphic sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, and epithelioid sarcoma); cystic fibrosis; neurodegenerative diseases or disorders (for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and disorders caused by aggregation of polyglutamine); skeletal muscle diseases (for example, Duchenne muscular dystrophy, skeletal muscle atrophy, Becker muscular dystrophy or myotonic dystrophy); decline in motor function (for example, muscle weakness in skeletal muscle, sarcopenia, osteoporosis, and osteoarthritis); metabolic diseases (for example, insulin resistance, diabetes, obesity, impaired glucose tolerance, high blood cholesterol, hyperglycemia, dyslipidemia and hyperlipidemia, hypothalamus, pituitary, adrenal hormone lowering/hyperactivity, for example, primary aldosteronism); adult-onset diabetes mellitus, diabetic nephropathy, neuropathy (for example, sensory neuropathy, autonomic neuropathy, motor neuropathy, and retinopathy); bone diseases (for example, osteoporosis), blood diseases (for example, leukemia); liver diseases (for example, fatty liver, chronic hepatitis B, chronic hepatitis C, liver cirrhosis, liver cancer, alcohol-related liver disease, primary biliary cirrhosis, auto-immune hepatitis, and non-alcoholic steatohepatitis (NASH); and acute liver diseases such as acute viral hepatitis and drug-induced hepatopathy); obesity; bone resorption, age-related macular degeneration, AIDS-related dementia, infections, pulmonary fibrosis, ALS (amyotrophic lateral sclerosis), Fagile X syndrome, multiple sclerosis, Bell's palsy, atherosclerosis, heart diseases (for example, abnormal cardiac rhythm, chronic congestive heart failure, ischemic stroke, coronary artery disease and cardiomyopathy, abnormal cardiac rhythm), chronic degenerative disease (for example, heart muscle disease), kidney fibrosis, renal dysfunction (for example, acute renal failure, chronic renal failure; nephritis, such as acute glomerulonephritis, chronic glomerulonephritis, minimal change nephritis, nephrosclerosis, membranoproliferative nephritis, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, rapidly progressive glomerulonephritis, membranous glomerulonephritis, tubulointerstitial nephritis, acute pyelonephritis, chronic pyelonephritis, endocapillary proliferative nephritis, and lupus nephritis; amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubular necrosis, nephrosis syndrome, diabetic nephropathy, gouty kidney, nephredema, renal tumor, renal ischemic disorder, and renal ischemia/reperfusion injury), type 2 diabetes, ulcers, cataracts, presbyopia, Guillain-Barr syndrome, hemorrhagic stroke, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus (SLE), psoriasis, atopic dermatitis, osteoarthritis, osteoporosis, chronic obstructive pulmonary disease (COPD), pneumonia, skin aging, androgenic alopecia, urinary incontinence, hearing loss, visual impairment, and other conditions or symptoms characterized by death, aging, or undesired cell loss of nerve cells. When the present agent is administered to these subjects, the life span can be prolonged or the above-described diseases and symptoms can be prevented or treated by enhancing the expression of genes related to longevity, anti-aging, and the like. The present agent and the present preventive/ameliorative agent can be suitably used for the prevention or treatment of one or more selected from the group consisting of obesity, liver disease, decline in liver function, renal fibrosis, renal dysfunction, and decline in motor function (e.g., muscle strength) among the above-described diseases and symptoms. Preferred examples of such liver diseases include chronic liver diseases such as fatty liver, chronic hepatitis B, chronic hepatitis C, liver cirrhosis, liver cancer, alcohol-related liver disease, primary biliary cirrhosis, auto-immune hepatitis, and non-alcoholic steatohepatitis (NASH); and acute liver diseases such as acute viral hepatitis and drug-induced hepatopathy. Among them, fatty liver is more preferably exemplified. In the instant case, administering compounds of General Formula (I0), (II), or (III) (and furthermore, activation of SIRT proteins, as recited in claims 1 and 4) is not known as a general strategy for treating all “diseases associated with aging” of the instant claims, which includes, according to the definition provided in the specification, a general method for treating cancers, neurodegenerative diseases, skeletal muscle diseases, metabolic diseases, bone diseases, blood diseases, liver diseases, heart diseases, renal dysfunction, skin diseases, hearing loss, visual impairment, to name a few. Applicant’s disclosure is only enabling for a methods for the following: Increasing SIRT expression levels (Example 1, para 0065-0066, Example 6, para 0079-0080) Ameliorating obesity (Example 2-4, para 0067-0075) Ameliorating fatty function (Example 5, para 0076-0078) Treating a decline in motor function (Example 7, para 0081-0083, Example 9, para 0093-0095) Treating hearing loss (Example 13-14 and 17, para 0115-0133) Treating renal fibrosis (Example 20, para 0138-0141) using compounds of Formula (I0), (II), and (III). Applicant does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. 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 without undue and unreasonable experimentation. 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. BMWofN. 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 anti-aging, rejuvenating cells, or ameliorating a symptom or disease associated with aging, generally, cannot possibly be considered enabled. The following analysis will examine the Wands Factors broadly against the claimed indications, and provide specific examination against treatment of cancer. The Nature of the Invention and Breadth of the Claims: Claim 1 recites a method for anti-aging or rejuvenating cells in an animal, comprising administering compounds of General Formula (I0), (II), or (III), and further requires that the compounds promote the production of two or more SIRT proteins. Claim 4 recites a method for preventing or ameliorating a symptom or disease associated with aging in a subject, comprising administering compounds of General Formula (I0), (II), or (III) and further requires that the compounds promote the production of two or more SIRT proteins. A method for “anti-aging” or a “disease associated with aging” can, according to the definition provided by the Applicant, encompasses a general method for treating cancers, neurodegenerative diseases, skeletal muscle diseases, metabolic diseases, bone diseases, blood diseases, liver diseases, heart diseases, renal dysfunction, skin diseases, hearing loss, visual impairment, to name a few. However, no complete definition of each of these broad classes of disease is provided by applicant and no guidance is provided regarding how one skilled in the art could identify which specific diseases may be treated by compounds of General Formula (I0), (II), or (III). The nature of the invention is thus regarded as a general method for treating anything that causes aging – a gross overreach considering that there are infinite mechanisms and etiologies related to aging in living systems. Now, regarding cancer, specifically: "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." 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: 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, and pleomorphic xanthoastrocytoma. GBM exists in two forms, primary and secondary, which have very different clinical histories and different genetics, but GBM is considered to be one clinical entity. second, there are the oligodendroglial tumors (oligodendrogliomas): low grade oligodendroglioma and anaplastic oligodendroglioma. Third, there is oligoastrocytomas (“mixed glioma”), a type of tumor with both astrocytoma & oligodendroglioma features. The fourth type is the ependymomas, which are intracranial gliomas, including papillary ependymoma, myxopapillary ependymoma, tanycytic ependymoma, anaplastic ependymoma and subependymal giant-cell astrocytomas. A fifth type is the gangliogliomas (glioneuronal tumors or glioneurocytic tumors), which have both glial and neuronal components, and are extremely varied, based in part on what types of glial and what types of neuronal components are present. These include Papillary Glioneuronal Tumor (PGNT), a range of supratentorial gangliogliomas, assorted intramedullary spinal cord gangliogliomas, pineal ganglioglioma, hypothalamic ganglioglioma, cerebellar ganglioglioma, ganglioglioma of the right optic tract, rosetted glioneuronal tumor (“glioneurocytic tumor with neuropil rosettes”), composite pleomorphic xanthoastrocytoma (PXA)-ganglioglioma, desmoplastic ganglioglioma (both infantile (DIG) and non- infantile), angioganglioglioma, and others. There are also some glial tumors which do not comfortably fit into these five categories, notably astroblastoma, gliomatosis cerebri, and chordoid glioma, which is found solely in the hypothalamus and anterior third ventricle. Other neuroepithelial tumors include astrocytic tumors (e.g. astrocytomas) oligodendroglial tumors, ependymal cell tumors (e.g. myxopapillary ependymoma), mixed gliomas (e.g. mixed oligoastrocytoma and ependymo-astrocytomas) tumors of the choroid plexus(choroid plexus papilloma, choroid plexus carcinoma), assorted neuronal and neuroblastic tumors (e.g. gangliocytoma, central neurocytoma, dysembryoplastic neuroepithelial tumor, esthesioneuroblastoma, olfactory neuroblastoma, olfactory neuroepithelioma, and neuroblastomas of the adrenal gland), pineal parenchyma tumors (e.g. pineocytoma, pineoblastoma, and pineal parenchymal tumor of intermediate differentiation), embryonal tumors (e.g. medulloepithelioma, neuroblastoma, ependymoblastoma, atypical teratoid/rhabdoid tumor, desmoplastic medulloblastoma, large cell medulloblastoma, medullomyoblastoma, and melanotic medulloblastoma) and others such as polar spongioblastoma and gliomatosis cerebri. A second Division is tumors of the meninges. this includes tumors of the meningothelial cells, including meningiomas (meningothelial, fibrous (fibroblastic), transitional (mixed), psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich, metaplastic, clear cell, chordoid, atypical, papillary, rhabdoid, anaplastic meningioma) and the non- meningioma tumors of the meningothelial cells (malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma, epithelioid haemangioendothelioma, haemangiopericytoma, angiosarcoma, kaposi sarcoma). There are also mesenchymal, non-meningothelial tumors (liposarcoma, (intracranial) solitary fibrous tumor, and fibrosarcoma) as well as primary melanocytic lesions (diffuse melanocytosis, melanocytoma, malignant melanoma, and meningeal melanomatosis). A third division are the tumors of cranial and spinal nerves. This includes cellular schwannomas, plexiform schwannomas and the melanotic schwannomas (e.g. psammomatous melanotic schwannoma, neuro-axial melanotic schwannoma, dorsal dumb-bell melanotic schwannoma). There is also Perineurioma (Intraneural and Soft tissue) and malignant peripheral nerve sheath tumor (MPNST), including Epithelioid, MPNST with divergent mesenchymal differentiation, and MPNST with epithelial differentiation. A fourth division are germ cell tumors, including germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma (mature teratoma, immature teratoma, and teratoma with malignant transformation). A fifth division are the tumors of the sellar Region, viz. pituitary adenoma, pituitary carcinoma, granular cell myoblastoma and craniopharyngiomas (adamantinomatous and papillary). Yet another division are local extensions from regional tumors, including paraganglioma, chodroma, chordoma, and chondrosarcoma. There are also Primitive Neuroectodermal Tumors (PNETs) including medulloblastomas, medulloepitheliomas, ependymoblastomas and polar spongioblastomas. There are Vascular brain Tumors e.g. the hemangioblastomas, there is CNS Lymphoma (which can be primary or secondary) and Meningeal Carcinomatosis. There are lymphoma and haemopoietic neoplasms including malignant lymphomas (which can be primary or secondary), plasmacytoma, and granulocytic sarcoma. And there are many, many others. 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. Chromic leukemias include chronic lymphocytic leukemia (CLL, which exists in a B-cell and a T-cell type), prolymphocytic leukemia (PLL), large granular lymphocytic leukemia (LGLL, which goes under several other names as well), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL), and many others. Carcinomas of the Liver include hepatocellular carcinoma, combined hepatocellular cholangiocarcinoma, cholangiocarcinoma (intrahepatic), bile duct cystadenocarcinoma and undifferentiated carcinoma of the liver. There is also cancer of the blood vessels in the liver (hemangioendothelioma), primary non-hodgkin's lymphoma of the liver, undifferentiated liver sarcoma (also known as undifferentiated embryonal sarcoma), primary pleomorphic liver sarcoma, angiosarcoma of the liver, and primary malignant melanoma of the liver. Most liver cancers are secondary, especially those originating in the breast, lung, or gallbladder, as well as both Hodgkin's or non-Hodgkin's lymphoma. 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). In addition, there are also the carcinomas with pleomorphic, sarcomatoid or sarcomatous elements, including carcinomas with spindle and/or giant cells, spindle cell carcinoma, carcinosarcoma and pulmonary blastoma. The non-small cell lung carcinomas also include adenosquamous carcinoma, the carcinoid tumor (both typical carcinoid and atypical carcinoid) as well as carcinomas of salivary-gland type, including mucoepidermoid carcinoma and adenoid cystic carcinoma. There are some soft tissue tumors including localized fibrous tumor (formerly called benign fibrous mesothelioma); epithelioid haemangioendothelioma; pleuropulmonary blastoma (which occurs three fairly different substituted-types); chondroma; calcifying fibrous pseudotumor of the visceral pleura); congenital peribronchial myofibroblastic tumors, diffuse pulmonary lymphangiomyomatosis and desmoplastic round cell tumor. There are assorted bronchial adenomas (e.g. adenoid cystic carcinomas, mucoepidermoid carcinomas, mucous gland adenomas, and oncocytomatous bronchial mucous gland adenoma) as well as other adenomas, including papillary adenoma. There are some papillomas, including squamous cell papilloma and glandular papilloma. There is also malignant melanoma of the lung, cylindroma (cylindroadenoma), some germ cell tumors, thymoma and sclerosing haemangioma and many others as well. Lung cancers are quite diverse. Thus, for example, oat cell carcinoma, Signet ring adenocarcinoma, pleuropulmonary blastoma, cylindroma, and malignant mesothelioma really have very little in common, other than being cancers of the lung. Thyroid cancer comes in four forms: papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, and medullary thyroid cancer. Cancer of the skin cells is melanoma. Malignant melanomas come in form fundamental forms, superficial spreading melanoma, Nodular melanoma, lentigo maligna melanoma and acral melanoma. These sometime occur in amelanotic form, such as in desmoplastic melanoma. There are also a very wide range of carcinomas of the skin, most notably the basal cell carcinomas (BCC), including superficial BCC, nodular BCC (solid, adenoid cystic), infiltrating BCC, sclerosing BCC (desmoplastic, morpheic), fibroepithelial BCC, BCC with adnexal differentiation, follicular BCC, eccrine BCC, basosquamous carcinoma, keratotic BCC, pigmented BCC, BCC in basal cell nevus syndrome, micronodular BCC. Another important family is the squamous cell carcinomas (SCC) which include spindle cell (sarcomatoid) SCC, acantholytic SCC, verrucous SCC, SCC with horn formation, and lymphoepithelial SCC, along with less well classified SCCs such as papillary SCC, clear cell SCC, small cell SCC, posttraumatic (e.g., Marjolin ulcer) and metaplastic (carcinosarcomatous) SCC. Another family is the eccrine carcinomas including sclerosing sweat duct carcinoma (syringomatous carcinoma, microcystic adnexal carcinoma), malignant mixed tumor of the skin (malignant chondroid syringoma), porocarcinoma, malignant nodular hidradenoma, malignant eccrine spiradenoma, mucinous eccrine carcinoma, adenoid cystic eccrine carcinoma, and aggressive digital papillary adenoma/adenocarcinoma. Other carcinomas of the skin include epidermal carcinomas, Paget disease, mammary Paget disease, merkel cell carcinoma (neuroendocrine cancer of the skin), extramammary paget disease adnexal carcinomas, apocrine carcinoma, sebaceous carcinoma, tricholemmocarcinoma and malignant pilomatricoma (matrical carcinoma). There are also skin sarcoma’s, most notably Kaposi's sarcoma, but also granulocytic sarcoma of the skin, fibroblastic/myofibroblastic sarcoma of the skin, primary extraosseus Ewing's sarcoma of the skin. There is also lymphoma of the skin, called cutaneous T cell lymphoma (CTCL) which includes mycosis fungoides, reticulum cell sarcoma of the skin and Sezary syndrome. 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. There are also some carcinoid tumors, sarcomas (including GISTs, leiomyosarcoma, hemangiosarcoma, angiosarcoma, Kaposi sarcoma, fibrosarcoma, neurofibrosarcoma and Leiomyosarcoma), primary plasmacytoma of the colon and primary malignant melanoma of the colon. A wide variety of cancers are secondary to the colon, e.g. ovarian carcinoma. Renal carcinomas comprise the papillary renal cell carcinoma (which has two subtypes, type 1 and type 2, with very different prognostic values), clear cell renal carcinoma, chromophobe renal carcinoma, collecting duct renal carcinoma, and some unclassified carcinomas. Renal sarcomas include leiomyosarcoma, fibrosarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma, liposarcoma of the kidney, malignant hemangiopericytoma, angiosarcoma of the kidney, osteosarcoma, synovial sarcoma, chondrosarcoma of the kidney, malignant mesenchymoma, and clear cell sarcoma of the kidney. Lymphomas include Primary Renal Non-Hodgkin's Lymphoma, primary renal MALT lymphoma, primary renal Hodgkin's lymphoma, and secondary renal lymphomas, which can be of either Hodgkin's or Non-Hodgkin's type. Other kidney cancers include transitional cell carcinoma, Wilms Tumor, malignant rhabdoid tumor of the kidney, renal melanoma, primitive neuroectodermal tumor of the kidney, neuroepithelial tumor of the kidney, and congenital mesoblastic nephroma, some renal adenomas, and oncocytomas. Prostate cancer is not a single disease or group of very closely related disorders, but ranges over a very wide variety of cancer types. It embraces various adenocarcinomas of the prostate, including prostatic ductal adenocarcinoma, adenocarcinoma with paneth-like cells, clear cell adenocarcinoma, foamy gland adenocarcinoma, adenocarcinoma of Cowper’s glands, and atrophic adenocarcinoma. It includes a huge variety of carcinomas, including mucinous carcinomas of the prostate, prostatic carcinoma of xanthomatous type, signet ring cell carcinoma of the prostate, neuroendocrine small cell carcinoma of the prostate, and other small cell carcinomas of the prostate, adenosquamous and squamous cell carcinomas, basaloid and adenoid cystic carcinoma, sarcomatoid carcinoma of the prostate, lymphoepithelioma-like carcinoma of the prostate, urothelial (transitional cell) carcinoma (which can be primary in the prostate gland or represent secondary spread from the urinary bladder), basaloid carcinoma, pseudohyperplastic carcinoma, and primary carcinoma of the seminal vesicles. There are also assorted sarcomas of the prostate, including Angiosarcoma, Embryonal rhabdomyosarcoma, Stromal sarcoma, Synovial sarcoma, Leiomyosarcoma, and chondrosarcoma of the prostate, which can be primary or secondary to the prostate. Also included is prostatic intraepithelial neoplasia (PIN), phyllodes tumor of the prostate, primitive peripheral neuroectodermal tumor (PNET) and malignant fibrous histiocytoma. There are also lymphomas, which are usually secondary, but primary ones include diffuse large B-cell lymphoma. The great majority of this list are not treatable with pharmaceuticals. Penile carcinoma is usually a squamous cell carcinoma (including cancinoma in situ or Bowen disease), but there is also penile clear cell carcinoma, and sarcomatoid carcinoma. There is also primary reticulum cell sarcoma of the penis, Kaposi sarcoma of the penis, and Paget disease or the Penis. The carcinomas of the extrahepatic bile ducts are of numerous types, including carcinoma in situ, adenocarcinoma, papillary adenocarcinoma, adenocarcinoma (intestinal-type), mucinous adenocarcinoma, clear cell adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, squamous cell carcinoma, small cell carcinoma (oat cell carcinoma) and undifferentiated carcinoma of the extrahepatic bile ducts. Breast cancers come in great variety. The most important category of breast cancers is the ductal cancers. These come in an assortment of types. Presently, these are divided into the following categories: intraductal (in situ); invasive with predominant intraductal component; invasive, NOS; Comedo; Inflammatory (IBC); medullary with lymphocytic infiltrate; mucinous carcinoma (colloid carcinoma); papillary carcinoma; scirrhous; tubular; and other. Another category is the Lobular breast cancers, which can be in situ, Invasive with predominant in situ component, and Invasive. There is Paget’s disease of the nipple, which can be also with intraductal carcinoma or with invasive ductal carcinoma. There is adenomyoepithelioma, a dimorphic tumor characterized by the presence of both epithelial and myoepithelial cells. There is lymphoma of the breast (which exists in both Non-Hodgkin's lymphoma of the breast and Hodgkin's disease of the breast forms). There are some sarcomas, including giant cell sarcoma of the breast, leiomyosarcoma of the breast, angiosarcoma of the breast, cystosarcoma phylloides, and liposarcoma of the breast. There are carcinoid tumors which can be primary carcinoid tumors of the breast, or can arise from from nonmammary sources. There are breast salivary gland-like tumors, including acinic cell carcinoma, oncocytic carcinoma (mammary epithelial oncocytoma), and mucoepidermoid carcinoma. Other rare carcinomas include spindle cell carcinoma of the breast, squamous cell carcinoma of the breast, secretory carcinoma of the breast (juvenile secretory carcinoma), metaplastic carcinoma of the breast (a heterogeneous group of invasive breast cancers including types with squamous differentiation and those with heterologous elements), invasive micropapillary carcinoma of the breast, adenoid cystic carcinoma of the breast, cribriform carcinoma, myofibroblastoma of the breast (benign spindle stromal tumor of the breast) and glycogen-rich clear cell carcinoma of the breast. There are also nonmammary tumors, primarily adenocarcinomas, that can metastasize to the breast including bronchogenic carcinomas, malignant melanomas (primary and secondary), rhabdomyosarcomas, malignant mesotheliomas, thyroid carcinomas, renal cell carcinomas, malignant lymphomas, and gastrointestinal carcinomas (including those from the stomach, pancreas, esophagus, and colon). Complicating the treatment of breast carcinomas is the fact that a significant proportion of mammary carcinomas are not monoclonal. Ovarian cancers are a heterogeneous group of tumors. The most important are the epithelial tumors. These are themselves fairly diverse, the categories being serous cystomas (serous benign cystadenomas, serous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth and serous cystadenocarcinomas); mucinous cystomas (divided the same three ways); clear cell tumors (mesonephroid tumors, again divided the same way), endometrioid tumors (similar to adenocarcinomas in the endometrium: endometrioid benign cysts, endometrioid tumors with proliferating activity of the epithelial cells and endometrioid adenocarcinomas), mixed mesodermal (now considered to be carcinomas with areas of sarcomatous differentiation), transitional cell carcinoma, the Brenner tumor, and mixed epithelials. Second, there are the granulosa-stromal cell tumors. These include the granulosa cell tumor (which exists in juvenile and adult forms) and the tumors in the thecoma-fibroma sub-group. This sub-group also includes thecoma-fibroma group typical: thecoma and luteinized thecoma, as well as fibroma, cellular fibroma, fibrosarcoma, stromal tumor with minor sex cord elements, sclerosing stromal tumor, signet ring cell stromal tumor and others. Third, there are the Sertoli stromal cell tumors: Sertoli-Leydig cell tumor of the ovary (which comes in three different levels of differentiation, as well as a retiform version); Sertoli cell tumor (tubular androblastoma), and Stromal- Leydig cell tumor. Fourth are the Sex cord-stromal tumors of mixed or unclassified cell types: sex cord tumor with annular tubules, gynandroblastoma of the ovary (composed of sex cord and stromal cells of both ovarian and testicular types), and sex cord-stromal tumor NOS. Fifth, there are the steroid cell tumors: Ovarian Leydig cell tumor, which comes in hilus and non-hilar types, Stromal luteoma, and steroid cell tumor, NOS. Sixth, there is an assortment of Germ Cell Tumors. These include dysgerminoma; yolk sac tumors (endodermal sinus tumor, and polyvesicular vitelline tumor, hepatoid and others); embryonal carcinoma; polyembryoma; choriocarcinoma, gonadoblastoma and a wide variety of teratomas. These tetromas include immature, cystic (dermoid cyst), retiform (homunculus), and Monodermal, including struma ovarii, carcinoid (insular and trabecular), struma carcinoid, mucinous carcinoid, neuroectodermal tumors, sebaceous tumors and others. There are also the teratocarcinomas which come in many mixture types. Finally, there are an assortment of other tumors which do not fit into the above categories. There is Tumors of Rete Ovarii (which can be adenomatoid tumor or a mesothelioma). There are some tumors of uncertain origin, including small cell carcinoma, tumors of probable wolffian origin, a hepatoid carcinoma and oncocytoma. There are some soft tissue tumors not specific to ovary, and there are assorted malignant lymphomas and leukemias which land up in the ovaries. Testicular cancers. All of the germ cell tumors listed above except for dysgerminoma also appear as cancers of the testis. In addition, seminoma itself as well as spermatocytic seminoma and choriocarcinoma of the testis are germ cell cancers of the testis. There are both juvenile and adult forms of the Granulosa cell tumor, as well as other cancers of the gonadal stroma, including leiomyomas, and neurofibromas. In addition to the germ cell cancers, there are the Sex cord-gonadal stromal tumors, including Sertoli cell tumor, Leydig cell tumor, and mixed form called Sertoli-Leydig cell tumor, and Gynandroblastoma of the testis. There are both adenomas and adenocarcinomas of collecting ducts and rete testis. There are a range of secondary tumors of the testis, most commonly Lymphomas, but also leukemic infiltration of the Testis, and metastatic cancers from the prostate or lung. Paratesticular cancers (cancers of the spermatic cord, epididymis, vestigial remnants, and tunica vaginalis) are commonly classified separately from testicular cancers, and are rather varied. These include rhabdomyosarcoma of the spermatic cord (which can occur in embryonal, alveolar, and pleomorphic subtypes), liposarcomas, leiomyosarcomas, ovarian-type epithelial tumors, the desmoplastic small round cell tumor, the melanotic neuroectodermal tumor of infancy, primary paratesticular neuroblastoma, primary hematopoietic tumors of the paratesticular structures, plasmacytoma and granulocytic sarcoma of the paratestis, malignant schwannoma, malignant fibrous histiocytoma, malignant spermatic cord fibrosarcoma, and pleomorphic hyalinizing angiectatic tumor. There are also an assortment of secondary tumors, especially from the prostate, testis, kidney, and stomach. Cancers of the vulva are mostly squamous carcinoma, but these also include melanoma, Bartholin's Adenocarcinoma, basal cell carcinoma and some sarcomas. Vaginal cancers are primarily squamous carcinoma, but some are adenocarcinoma, melanoma of the vagina; sarcoma of the vagina, bowen's disease and germ cell tumors. The most important of the cancers of the uterus are the Endometrial Carcinomas. The great majority of these are endometrioid; others include uterine papillary serous tumor (upst), clear cell carcinoma, mucinous and squamous. There is also plexiform tumorlet, Intravenous leiomyomatosis, benign metastasizing leiomyoma, leiomyomatosis peritonealis disseminate and leiomyosarcoma. Endometrial Tumors include endometrial stromal nodule, endolymphatic stromal myosis, and endometrial stromal sarcoma. There are the mixed tumors: Müllerian adenosarcoma and Malignant mixed mesodermal tumors (MMMT). Other sarcomas are rhabdosarcoma, osteosarcoma, chondrosarcoma and hemangiopericytoma. Some uterine cancers are secondary, starting in e.g. the tissue that begins to develop immediately after conception: epithelioid trophoblastic tumor, choriocarcinoma, and placental site trophoblastic tumors (PSTT). There are several main types of stomach cancers, which are very different from each other. (1) Lymphomas of the stomach are found in the wall of the stomach. These come in two main categories. One is the Non-Hodgkin's lymphomas of the stomach, including MALT lymphoma, and assorted Large Cell Lymphoma of the Stomach such as anaplastic Ki-1 (CD30) positive large cell lymphoma. The other is Hodgkin Lymphoma in the Stomach. These include both lymphomas which are primary to the stomach, and nodal lymphomas that have spread to the stomach from e.g. the spleen or liver and are thus secondary. There are Tertiary gastric lymphomas as well. (2) Gastric stromal tumors (GISTs) develop from the tissue of the stomach wall. There are an assortment of these; GISTs vary from cellular spindle cell tumors to epithelioid and pleomorphic ones. (3) Carcinoid tumors are tumors of hormone-producing cells of the stomach. These are classified into are classified into those that are associated with hypergastrinemic states (type 1, atrophic gastritis, pernicious anemia); Zollinger-Ellison syndrome [ZES] tumors (type 2), and tumors without hypergastrinemia (type 3 or sporadic). (4) Carcinoma of the Stomach exists in five types: papillary, tubular, mucinous, signet-ring cell adenocarcinoma and undifferentiated carcinoma. (5) Soft tissue sarcomas, most notably leiomyosarcoma of the stomach. Cancer of the esophagus is most commonly a squamous cell carcinoma or an adenocarcinoma. However, melanomas, both primary and secondary can occur, and spindle cell carcinoma and Kaposi’s sarcoma can also occur in the esophagus. There is also primary oat cell carcinoma of the esophagus, choriocarcinoma of the esophagus, carcinoid tumor of the esophagus, adenosquamous carcinoma of the esophagus and the related mucoepidermoid carcinoma of the esophagus, and cylindroma of the esophagus. In addition, verrucous carcinomas and pseudosarcomas of the esophagus have been reported. Cancers of the spleen, which are primary are commonly devided into vascular, lymphoid and non-lymphoid. Vascular tumors include hemangiosarcoma, lymphangiosarcoma, hemangioendothelial sarcoma and malignant hemangiopericytoma of the spleen, all of which are considered malignant. Lymphoid tumors include both Hodgkin's and Non-Hodgkin's lymphoma, plasmacytoma and Castleman's tumor. Nonlymphoid tumors are more diverse, and include malignant fibrous histiocytoma, fibrosarcomas, leiomyosarcomas, malignant teratomas, and Kaposi's sarcoma of the spleen. There are also metastatic tumors, secondary to tumors most typically from the lung, stomach, pancreas, liver, breast and colon. These are typically adenocarcinomas or squamous cell carcinomas, but large cell carcinoma, small cell carcinoma, hepatocellular carcinoma, melanoma, mesothelioma and choriocarcinoma are known as well. Salivary gland carcinomas arguably represent the most heterogeneous group of tumors of any tissue in the body. The main four histopathologic types are: (1) mucoepidermoid carcinoma (2) adenoid cystic carcinoma (which has three histologic types: cribriform, tubular, and solid), (3) adenocarcinoma which includes acinic cell carcinoma, polymorphous low-grade adenocarcinoma, Sebaceous Lymphadenocarcinoma, adenocarcinoma not otherwise specified (NOS), Mucinous adenocarcinoma, and cystadenocarcinoma; (4) salivary duct carcinoma. In addition, there is an adenosquamous carcinoma, lymphoepithelial carcinoma, epithelial–myoepithelial carcinoma, basal cell adenocarcinoma, sebaceous carcinoma, oncocytic carcinoma, myoepithelial carcinoma, and clear cell carcinoma of the salivary glands NOS (hyalinizing clear cell carcinoma). In addition to the carcinomas, there are some adenomas, including carcinoma ex-pleomorphic adenoma, pleomorphic salivary adenoma, canalicular adenoma, oxyphilic adenoma, papillary cystadenoma, lymphadenoma, sebaceous adenoma, basal cell adenoma, and ductal cystadenoma. There are two ductal papillomas: inverted ductal papilloma and intraductal papilloma. There is also an assortment of perinatal salivary gland tumors. There are a group of haematolymphoid salivary Tumors: Hodgkin lymphoma, Diffuse large B-cell lymphoma and extranodal marginal zone B-cell lymphoma. In addition, there is a salivary haemangioma, warthin tumor, salivary carcinosarcoma, sialadenoma papilliferum, oncocytoma, and myoepithelioma of the salivary glands, Low-Grade Cribriform Cystadenocarcinoma (LGCCC), and sialoblastoma. Cancers of the heart (including pericardium, valves, etc.) include a wide range of primary cardiac sarcomas, including angiosarcomas, undifferentiated sarcomas, osteosarcomas, fibrosarcomas, malignant fibrous sarcomas, histiocytomas, leiomyosarcomas, myxosarcomas, synovial sarcomas, neurofibrosarcomas, rhabdomyosarcomas, reticulum cell sarcomas, desmoplastic small round cell tumors, and liposarcomas. Primary heart tumors also include atrial myxoma, rhabdomyoma, papillary fibroelastoma of the endocardium, and teratoma. There is also Purkinje cell hamartoma of the conduction tissue. In the Pericardium, there is also malignant schwannoma, aberrant synoviosarcoma, neurofibroma and aberrant thymoma. Secondary tumors of the heart are more common, and can arrive by many pathways. For example, bronchogenic carcinoma can arrive by direct extension or by a combination of lymphatic and hematogenous dissemination. breast, lung and esophagus carcinomas, hodgkin and non-hodgkin lymphomas, melanomas, mesothelioma, renal cell carcinoma, leukemias, Kaposi sarcoma and osteosarcomas are the most common forms, but there are many more. Odontogenic tumors are cancers of the jaw derived from primordial tooth-forming tissues. The epithelial tumors include squamous odontogenic tumor, adenomatoid odontogenic tumor, calcifying epithelial odontogenic tumor (Pindborg tumor), and ameloblastoma. And adamantinoma and adamantinomatous craniopharyngioma are included here as well. The mixed odontogenic tumors include ameloblastic fibro-odontoma, and ameloblastic fibroma. The mesenchymal odontogenic tumors include cementoblastoma, and odontogenic myxoma. There is also ameloblastic fibrosarcoma, granular cell ameloblastic fibroma, ameloblastic sarcoma, malignant ameloblastoma, ameloblastic carcinoma, clear cell odontogenic carcinoma, odontoameloblastoma and squamous odontogenic tumors. Cancers of the oral cavity and oropharynx, including the tongue is most commonly squamous cell carcinoma and Verrucous carcinoma. There are also lymphomas of the tonsils and base of the tongue, Nasopharyngeal carcinoma (which exists in three subtypes), as well as neurofibroma, schwannoma and rhabdomyoma of the mouth. In addition, HPV-positive oropharyngeal cancer is now considered a distinct disease entity. Salivary gland cancers and odontogenic tumors are discussed separately above. Cancers of the lymph glands are of course the lymphomas. There are also carcinomas of the lymph nodes, including large cell carcinoma of the lymph nodes, metastatic squamous cell carcinoma of the lymph nodes, primary neuroendocrine carcinoma of the lymph nodes and Merkel cell carcinoma of the lymph nodes. There is also generalized reticulum cell sarcoma of the lymph nodes, Kaposi's sarcoma of the lymph nodes and lymph node melanoma. Cancers of the adrenal glands include adrenocortical carcinoma, pheochromocytoma, adrenal neuroblastoma, and adrenal ganglioneuroma. Cancer of the eye is a very loose category, as the set of cancers involved depends very much on which structure of the eye or its adnexa is involved. Choroidal tumors include choroidal melanoma, ciliary body melanoma choroidal osteoma and metastatic choroidal tumors, including tumors from the lung, breast, prostate, kidney, thyroid and blood. Eyelid tumors include basal cell carcinoma, malignant melanoma of the eyelid, sebaceous carcinoma of the eyelid and squamous carcinoma of the eyelid. Iris tumors include iris melanoma, malignant iris melanocytoma, and anterior uveal metastasis, most commonly from breast, lung, prostate, skin, kidney, colon and thyroid. Optic nerve tumors include juxtapapillary choroidal melanoma (choroidal melanoma affecting the optic nerve), circumpapillary metastasis with optic neuropathy, and optic nerve melanocytoma. Retinal tumors include retinal pigment epithelium tumors, and retinoblastoma. Conjunctival tumors are quite varied, and include conjunctival kaposi's sarcoma, epibulbar dermoid, lymphoma of the conjunctiva, pigmented conjunctival tumors (a malignant melanoma), and squamous carcinoma (including intraepithelial neoplasia of the conjunctiva). Infiltrative intraocular tumors include chronic lymphocytic leukemia, infiltrative choroidopathy and intraocular lymphoma. Orbital tumors include adenoid cystic carcinoma of the lacrimal gland, lymphangioma of the orbit, orbital pseudotumor, and orbital rhabdomyosarcoma. Optic nerve gliomas are mentioned above in cancers of the brain. Cervical cancers. There are many different categories and sub-categories of cervical cancers. The majority of cervical cancers are Squamous Cell Carcinomas. These come in numerous types: large cell nonkeratinizing type; large cell keratinizing type; basaloid; verrucous; warty; papillary; lymphoepithelioma-like; and squamotransitional, early invasive (microinvasive) squamous cell carcinoma; Squamous intraepithelial neoplasia (including Cervical intraepithelial neoplasia and Squamous cell carcinoma in situ). There are also a variety of adenocarcinomas, the most important of which are the mucinous adenocarcinoma, which include the endocervical, intestinal, signet-ring cell, minimal deviation, and villoglandular. There is also endometrioid adenocarcinoma, clear cell adenocarcinoma, serous adenocarcinoma, mesonephric adenocarcinoma, early invasive adenocarcinoma, and adenocarcinoma in situ. In addition, there are neuroendocrine carcinomas, divided into Small Cell, large cell, classical carcinoid and atypical carcinoid. Other epithelial tumors include adenosquamous carcinoma, mixed adenosquamous carcinomas, which can be either well-differentiated or poorly differentiated, the latter including glassy cell carcinoma, adenoid cystic carcinoma, adenoid basal carcinoma and undifferentiated carcinoma. There are also some mixed carcinomas with signet-ring cells, and other types of other poorly differentiated mixed carcinomas. This group includes tumors sometimes called apudomas or argyrophil cell carcinomas. There is also an assortment of mesenchymal tumors of the cervix, including leiomyosarcoma; endometrioid stromal sarcoma, low grade; undifferentiated endocervical sarcoma; sarcoma botryoides; alveolar soft part sarcoma, angiosarcoma of the cervix, malignant peripheral nerve sheath tumor of the cervix; cervical leiomyoma; and rhabdomyoma of the cervix. There are also some mixed epithelial and mesenchymal tumors, including carcinosarcoma (malignant müllerian mixed tumor), adenosarcoma, Wilms tumor, typical and atypical polypoid adenomyoma, and papillary adenofibroma of the cervix. There are also melanocytic tumors, including primary malignant melanoma of the cervix and blue naevus of the cervix. There are also germ cell type tumors, including yolk sac tumor, dermoid cyst, and mature cystic teratoma of the cervix. There is also primary choriocarcinoma of the cervix, which does not fit well into any category. There are also numerous cancers secondary to the cervix. Gestational Trophoblastic Neoplasia is cancer of the placenta; it actually derives from the conceptus rather than from the pregnant woman. It has three different forms: choriocarcinoma, placental site trophoblastic tumor, epithelioid trophoblastic tumor. Cancer of the throat is a loose term, depending on the particular structure. Cancers of the oropharynx are discussed above in cancers of the oral cavity. Hypopharyngeal cancer is usually a form of squamous cell carcinoma, including basaloid squamous cell carcinoma, superficial spreading cancer, sebaceous cancer, adenosquamous cancer, and signet-ring and verrucous types. Less common forms of hypopharyngeal cancer include adenocarcinoma, lymphoma, and sarcoma. Nasopharyngeal cancer is usually a carcinoma, and is commonly devided into three types: keratinizing squamous cell carcinoma, non-keratinizing carcinoma, and undifferentiated carcinoma. There are also rhabdomyosarcomas and lymphomas as well. Cancer of the thymus is normal a carcinoma, called thymoma, including Type C, also called thymic carcinoma, and a clear cell carcinoma of the thymus. There are also a series of germ cell tumors of the thymus as well as both Hodgkin and non-Hodgkin lymphomas. There are also carcinoid tumors of the Kulchitsky cells. Fallopian tube cancer most commonly takes the form of a papillary serous adenocarcinoma. There are also leiomyosarcomas (arising from smooth muscle in the fallopian tubes), squamous cell carcinoma, choriocarcinoma, and transitional cell carcinomas. Secondary cancers are more common, and come from the ovaries, the endometrium, the GI tract, the peritoneum, and the breast. Bladder cancers. Most cases of bladder cancers are transitional cell (urothelial) carcinoma, which includes non-invasive papillary urothelial carcinoma, flat urothelial carcinoma in situ (CIS), superficially invasive urothelial carcinoma, and muscle invasive tumors. Adenocarcinomas of the bladder include Primary Adenocarcinoma (urachal and non-urachal), Prostatic adenocarcinoma, Gastro-intestinal adenocarcinomas and Clear cell carcinoma. Squamous cell carcinomas include Verrucous carcinomas, and a secondary squamous cell carcinoma of the bladder, from the cervix. Small cell carcinomas include Primary small cell carcinoma of the bladder and the secondary small cell carcinoma ('reserve cell carcinoma') of the lung. Lymphomas include the primary lymphomas (Low grade B-cell lymphoma of MALT type, High grade B-cell lymphoma, and T-cell lymphoma), as well as secondary lymphomas, including mantle cell lymphomas. Melanomas include Primary Malignant melanoma of the bladder, and secondary ones. The sarcomas of the bladder are leiomyosarcoma, osteosarcoma and rhabdomyosarcoma. There is also a primary primitive neuroectodermal tumour (PNET) of the bladder, Paraganglioma (which can metastasize), nephrogenic adenoma, metastatic renal cell carcinoma of the bladder, and both primary and secondary (from the uterus) choriocarcinoma of the bladder. Cancers of the gallbladder are most commonly adenocarcinomas, including non-papillary adenocarcinoma, papillary adenocarcinoma, and mucinous adenocarcinoma. There is also squamous cell, adenosquamous, and oat cell carcinoma, of the gallbladder. Primary non-Hodgkin's lymphoma of the gallbladder, exists in both MALT and non-MALT forms. Primary neuroendocrine tumors (NETs) of the gallbladder can be of either large-cell or small-cell type. Primary gallbladder sarcoma (PGBS) includes Leiomyosarcomas, myxofibrosarcomas, epithelioid angiosarcomas, and botryoid embryonal rhabdomyosarcomas. There is also primary malignant melanoma of the gall bladder, although secondary melanoma of the gallbladder is much more common. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic, curative or preventative, regimen on its face. State of the Prior Art: The state of the prior art is not aware of any single agent or single method which treats all diseases related to aging, which encompasses cancers, neurodegenerative diseases, skeletal muscle diseases, metabolic diseases, bone diseases, blood diseases, liver diseases, heart diseases, renal dysfunction, skin diseases, hearing loss, visual impairment, to name a few. This is true at least for the reason that each of these broad classes of diseases includes many distinct diseases that affect different organs, have different causes, and therefore have different modes of treatment and/or treatment requirements. Predictability in the Art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Now, regarding cancer, specifically: 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). Level of One of Ordinary Skill: The level of skill in the art is high. Now, regarding cancer, specifically: 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." Amount of Guidance/Working Examples: That provided is very limited. Applicant has provided no working examples which are successfully used as broad range anti-aging agents. Applicant does provide in vitro and in vivo mice data to show compounds of General Formula (I0), (II), and (III) for increasing SIRT expression levels (Example 1, para 0065-0066, Example 6, para 0079-0080), ameliorating obesity (Example 2-4, para 0067-0075), ameliorating fatty function (Example 5, para 0076-0078), treating a decline in motor function (Example 7, para 0081-0083, Example 9, para 0093-0095), treating hearing loss (Example 13-14 and 17, para 0115-0133), treating renal fibrosis (Example 20, para 0138-0141). Applicants have provided no working examples which are successfully used as broad range agents for a method for anti-aging or rejuvenating cells in an animal, or a method for ameliorating a symptom or disease associated with aging in a subject. The specification does not provide any guidance to one of ordinary skill in the art to extrapolate the in vitro or in vivo mice data provided by applicant to the treatment of all types anti-aging diseases. As the Supreme Court said in Brenner v. Manson, 148 USPQ at 696: “a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” As U.S. Court of Customs and Patent Appeals stated In re Diedrich 138 USPQ at 130, quoting with approval from the decision of the board: “We do not believe that it was the intention of the statutes to require the Patent Office, the courts, or the public to play the sort of guessing game that might be involved if an applicant could satisfy the requirements of the statutes by indicating the usefulness of a claimed compound in terms of possible use so general as to be meaningless and then, after his research or that of his competitors has definitely ascertained an actual use for the compound, adducing evidence intended to show that a particular specific use would have been obvious to men skilled in the particular art to which this use relates.” The quantity of experimentation needed: MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on theevidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." Given lack of working examples, state of the prior art, and unpredictability in the art, one skilled in the art, even with a high level of skill, would not be able to practice the full scope of the invention without undue and unreasonable experimentation. Now, regarding cancer, specifically: Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, 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. Claim Rejections - 35 USC § 102 The rejection of claims 1-6, and 8 under AIA 35 U.S.C. 102(a)(1) is maintained. Applicant has indicated that the sole author of the Hara reference is Fumika Hara and that the reference was published within one year of the effective filing date of the instant application. However, Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216. Claim(s) 1-6, and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hara et al. (“KAKEN Research Projects”, published December 27, 2021, cited in the IDS filed on 04/04/2024) (hereinafter, ‘Hara’). Because an intervening reference is being applied and Applicant did not provide a certified copy of an English translation of the foreign priority application, Applicant is being awarded an effective filing date of December 14, 2023. Hara teaches the administration of mitochonic acid-5 (MA-5, or 4-(2,4-difluorophenyl)-2-(1H-indole-3-yl)-4-oxobutanoic acid), shown below, in α-klotho gene-deficient mice. MA-5 is an identical species recited in instant in claim 3 and 5 and covered by the genus of General Formula (I0) of instant claims 1 and 4. The α-klotho homozygous KO model is a premature aging syndrome model and exhibits phenotypes such as early death and age-related decline in renal function. Hara concluded that MA-5 attenuates age-related renal fibrosis and mitochondrial dysfunction in an aging mice model. MA-5: PNG media_image1.png 264 188 media_image1.png Greyscale Regarding the amended wherein clause of claims 1 and 4, which recites, “…wherein the one or more compounds can promote the production of an SIRT protein, and wherein the SIRT protein is two or more proteins selected from SIRT1 protein, SIRT2 protein, SIRT3 protein, SIRT4 protein, SIRT5 protein, SIRT6 protein, and SIRT7 protein”: the present claims are directed to the mechanism by which known therapeutic agents (e.g. the compounds of claims 1 and 4) achieve their known therapeutic results. As such, any disclosure of the treatment of anti-aging using the compounds of claims 1 and 4 anticipates the claimed subject matter: if the same compounds promote the production of a SIRT protein, or multiple SIRT proteins, as a method for anti-aging in the present application, then they must necessarily do so in the prior art. Note that an inventor need not know how their invention works, only that it does. The discovery of how a known therapeutic agent achieves its known therapeutic effect, such as done in the present application, does not bestow novelty on the claimed subject matter. In effect, since the compounds of instant claims are known compounds that had been administered in subjects, as demonstrated by the cited prior art, then the compounds would have necessarily promoted the production of one, or multiple, SIRT proteins, regardless of whether inventor knew it or not. Thus, each and every required element of the claims are taught, and the claims are anticipated. Claim Rejections - 35 USC § 103 The rejection of claims 1-6, and 8 under AIA 35 U.S.C. 103 is maintained. Applicant’s arguments filed on 6/25/2026 have been fully considered but they are not persuasive. 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) 1-6, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (J. Cell Physiol., 2019, 234(12), cited by Examiner in Non-Final filed 3/26/2026)(hereinafter, ‘Huang) and Takaaki (US 10,004,718 B2, published 6/26/2018, cited by Examiner in Non-Final filed 3/26/2026)(hereinafter, ‘Takaaki’). Huang teaches that MA-5 treatment elevates the expression of SIRT3 in mouse CATH.a cells (Figure 5; Section “3.5 MA-5 augments Sirt3 via AMPK pathway”). Furthermore, Huang discloses evidence that the progression of neuroinflammation could be attenuated by MA-5 via activating SIRT3-Parkin-mitophagy pathways (Section “Discussion”). Huang teaches that neuroinflammation injury is “a primary cause for the development of chronic brain disease” (Section “Discussion”), of which the neurodegenerative diseases listed in the definition of anti-aging (Specification, page 24, para 0060) encompass. Thus, Huang teaches the use of MA-5 to elevate expression of SIRT3 as a method for anti-aging and as a method for ameliorating a symptom or disease associated with aging (neuroinflammation). Huang does not teach the administration of compound MA-5 into an animal or subject, however. Takaaki teaches the administration of MA-5 into humans as a method “for treating disease from the group consisting of anemia, liver dysfunction, ischemic injury, renal damage…”. Thus, it would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to administer the compounds in the instant disclosure to elevate the expression of SIRT3, or to “promote the production of an [sic] SIRT protein” including SIRT3 (instant claim 1) in a subject. One would have been motivated and had a reasonable expectation of success to do so given the teaching by Huang that MA-5 elevates the expression of SIRT3 in vitro; and the teaching by Takaaki that MA-5 can be safely and effectively administered to a subject in vivo. Thus, said claims are rendered obvious. Applicant traverses the rejection for the following reasons: First, Applicant agues (Remarks filed 6/25/2026, page 19) that their amended claims now recite that the compounds of instant claims “can promote the production of an [sic] SIRT protein, and that the SIRT protein is two or more proteins selected from SIRT1 protein, SIRT2 protein, SIRT3 protein, SIRT4 protein, SIRT5, protein, SIRT6 protein, and SIRT7 protein”. With the amendment, Applicant argues that “Huang and Takaaki do not disclose or suggest that the compound promotes the production of two or more proteins of SIRT1-7 proteins.” This is not persuasive. The present claims are directed to the mechanism by which known therapeutic agents (e.g. the compounds of claims 1 and 4) achieve their known therapeutic results. As such, any disclosure of the treatment of anti-aging using the compounds of claims 1 and 4 anticipates the claimed subject matter: if the same compounds promote the production of a SIRT protein, or multiple SIRT proteins, as a method for anti-aging in the present application, then they must necessarily do so in the prior art. Note that an inventor need not know how their invention works, only that it does. The discovery of how a known therapeutic agent achieves its known therapeutic effect, such as done in the present application, does not bestow novelty on the claimed subject matter. In effect, since the compounds of instant claims are known compounds that had been administered in subjects, as demonstrated by the cited prior art, then the compounds would have necessarily promoted the production of one, or multiple, SIRT proteins, regardless of whether inventor knew it or not. Second, Applicant adds (Remarks, page 19), “even if a particular compound promotes the production of SIRT3 protein, that compound does not necessarily promote the production of other SIRT proteins than SIRT3 (i.e., SIRT1-2, 4-7 proteins).” This is not persuasive. Applicant’s invention is drawn to approximately 37 species, of which instant “Compound #5” is used exclusively in almost all of Applicant’s Examples (Specification, Examples 1-4, 7-14, 17-21, pages 27-45). Instant Compound #5 is, indeed, MA-5—the compound taught by both Huang and Takaaki. So, Applicant’s argument that “even if a particular compound promotes the production of SIRT3 protein, that compound does not necessarily promote the production of other SIRT proteins than SIRT3” is especially confounding, because Applicant’s “particular compound” is the one taught in the prior art. Altogether, the scope of claims 1-6, and 8 is deemed obvious and the 35 USC § 103 rejection is maintained. Double Patenting The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. For the following non-statutory double patenting rejections, the definition of “anti-aging” from the instant specification (page 24-25, para 0060) will be relevant (see also Office Action Section: 112(a) – Scope of Enablement – Methods of Use): The rejection of claims 1-6 and 8 on the grounds of nonstatutory double patenting over U.S. Patent No. 10,004,718 B2 is maintained. Applicant requested the rejections be held in abeyance. It is not appropriate to hold rejections in abeyance. Thus, all NSDP rejections are maintained. Claims 1-6 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6-9 of U.S. Patent No. 10,004,718 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Instant claim 1 teaches a method for anti-aging or rejuvenating cells in an animal in need comprising administering compounds of General Formula (I0), (II), or (III). The instant specification defines anti-aging as “inhibiting or delaying the progression of any one symptom or any one disease among symptoms or diseases associated with aging” and includes examples, among which are “liver disease…ischemic stroke…renal ischemic disorder, and renal ischemia/reperfusion injury…type 2 diabetes”. Reference claim 1 recites a method for treating a disease selected from the group consisting of liver dysfunction, ischemic injury, and a disease associated with reduced insulin secretion to patient in need comprising administering compounds of reference formula (I), (II), or (III). The formulae of reference claim 1 all read on the formulae of instant claim 1. Reference claim 1 of ‘718 is, in essence, a “species” (liver dysfunction, ischemic injury, disease associated with reduced insulin secretion) of the instantly claimed genus (“anti-aging”), and therefore, a patent to the genus would improperly extend the right to exclude granted by a patent to the species or sub-genus should the genus issue as a patent after the species or sub-genus. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993). The rejection of claims 1-5 on the grounds of nonstatutory double patenting over U.S. Patent No. 10,869,858 B2 is maintained. Applicant requested the rejections be held in abeyance. It is not appropriate to hold rejections in abeyance. Thus, all NSDP rejections are maintained. Claims 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,869,858 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Instant claim 1 teaches a method for anti-aging or rejuvenating cells in an animal in need comprising administering compounds of General Formula (I0), (II), or (III). The instant specification defines anti-aging as “inhibiting or delaying the progression of any one symptom or any one disease among symptoms or diseases associated with aging” and includes examples, among which are “amyotrophic lateral sclerosis”. Reference claim 1 recites a method for treating amyotrophic lateral sclerosis comprising administering to patient in need a compound species disclosed in reference claim 1. The species of reference claim 1 all read on the formulae of instant claim 1. Reference claim 1 of ‘858 is, in essence, a “species” (amyotrophic lateral sclerosis) of the instantly claimed genus (“anti-aging”), and therefore, a patent to the genus would improperly extend the right to exclude granted by a patent to the species or sub-genus should the genus issue as a patent after the species or sub-genus. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993). The rejection of claims 1-5 on the grounds of nonstatutory double patenting over U.S. Patent No. 11,147,796 B2 is maintained. Applicant requested the rejections be held in abeyance. It is not appropriate to hold rejections in abeyance. Thus, all NSDP rejections are maintained. Claims 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,147,796 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Instant claim 1 teaches a method for anti-aging or rejuvenating cells in an animal in need comprising administering compounds of General Formula (I0), (II), or (III). The instant specification defines anti-aging as “inhibiting or delaying the progression of any one symptom or any one disease among symptoms or diseases associated with aging” and includes examples, among which are “hearing loss”. Reference claim 1 recites a method for treating hearing loss comprising administering to patient in need a compound species of Formula (I-2). The species of reference claim 1 all read on the formulae of instant claim 1. Reference claim 1 of ‘796 is, in essence, a “species” (hearing loss) of the instantly claimed genus (“anti-aging”), and therefore, a patent to the genus would improperly extend the right to exclude granted by a patent to the species or sub-genus should the genus issue as a patent after the species or sub-genus. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993). The rejection of claims 1-5 on the grounds of nonstatutory double patenting over U.S. Patent No. 12,357,612 B2 is maintained. Applicant requested the rejections be held in abeyance. It is not appropriate to hold rejections in abeyance. Thus, all NSDP rejections are maintained. Claims 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 12,357,612 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. Instant claim 1 teaches a method for anti-aging or rejuvenating cells in an animal in need comprising administering compounds of General Formula (I0), (II), or (III). The instant specification defines anti-aging as “inhibiting or delaying the progression of any one symptom or any one disease among symptoms or diseases associated with aging” and includes examples, among which are “cancers (for example…colorectal cancer”. Reference claim 1 recites a method for treating cancer comprising administering to patient in need a compound species of Formulae (1-1) and (2-1). The species of reference claim 1 all read on the formulae of instant claim 1. Reference claim 1 of ‘612 is, in essence, a “species” (cancer) of the instantly claimed genus (“anti-aging”), and therefore, a patent to the genus would improperly extend the right to exclude granted by a patent to the species or sub-genus should the genus issue as a patent after the species or sub-genus. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993). The rejection of claims 1-5 on the grounds of nonstatutory double patenting over copending Application No. 18/433,832 is maintained. Applicant requested the rejections be held in abeyance. It is not appropriate to hold rejections in abeyance. Thus, all NSDP rejections are maintained. Claims 1-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-19 of copending Application No. 18/433,832 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. Instant claims 1 and 4 teach methods for anti-aging or rejuvenating cells, or ameliorating a symptom or disease associated with aging, in an animal in need comprising administering compounds of General Formula (I0), (II), or (III). The instant specification defines anti-aging as “inhibiting or delaying the progression of any one symptom or any one disease among symptoms or diseases associated with aging” and includes examples, among which are “hearing loss, visual impairment”. Reference claim 16 recites a method for treating cancer comprising administering to patient in need a compound species of Formulae (A-1), which is an enantiomer of instantly claimed racemic (I-1). The species of reference claim 16 all read on the formulae of instant claim 1. Reference claim 16 of ‘832 is, in essence, a “species” (enantiomer I-1) of the instantly claimed genus (racemic I-1). Furthermore, reference claims 18 and 19 of ‘832 are, in essence, a “species” (visual impairment, hearing loss) of the instantly claimed genus (“anti-aging”) and therefore, a patent to the genus would improperly extend the right to exclude granted by a patent to the species or sub-genus should the genus issue as a patent after the species or sub-genus. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. The rejection of claims 1 and 4 on the grounds of nonstatutory double patenting over copending Application No. 18/871,589 is maintained. Applicant requested the rejections be held in abeyance. It is not appropriate to hold rejections in abeyance. Thus, all NSDP rejections are maintained. Claims 1 and 4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of copending Application No. 18/871,589 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the methods of for anti-aging or rejuvenating cells, or preventing or ameliorating a symptom associated with aging, of instant claims 1 and 4, respectively, overlap in claimed matter with at least claim 1 of copending ‘589. In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See also Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008);Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003). In the instant case, the same compounds of Formula (I0), (II), and (III) are recited in both the instant application and the reference application. Although the reference application does not claim a method of use, the disclosure of the copending ‘589 (page 10, para 0023) recites “other aspects of the present invention include: a method for preventing and/or treating a viral infection, comprising a step of administering the present compound to a subject (patient) in need of preventing and/or treating the viral infection" and also recites (page 16, para 0028) that example viruses include “hepatitis B virus” and “hepatitis C virus”. Furthermore, copending ‘589 recites claims directed to an “antiviral agent” (claims 1-4). Indeed, the instant specification defines “anti-aging” as inhibiting or delaying the progression of a disease associated with anti-aging such as hepatitis B and hepatitis C, and instant claims 1 is directed to a method for anti-aging and instant claim 4 is directed to a method for preventing or ameliorating a symptom or disease associated with aging. The ordinary artisan would recognize as obvious that determination of whether “a method of prevent and/or treating a viral infection” is present in the instant claims, is implicit in the copending claims in view of Sun Pharmaceutical Industries, LTD. v. Eli Lilly and Company which states the following: “Similarly, in Pfizer, the earlier patent claimed several compounds and the specification disclosed their use in treating inflammation and inflammation-associated disorders. 518 F.3d at 1363 & n.9; see 5,563,165 (“’165 patent”), at [57], col.1 11.11-14, col.3 11.3-27. The later patent then claimed a method of using these compounds for treating inflammation, inflammation-associated disorders, and specific inflammation-associated disorders, including arthritis, pain, and fever. Pfizer, 518 F.3d at 1363 & n.9; see U.S. Patent No. 5,760,068 (“’068 patent”) col.97 1.49- col. 108 1.29. After rejecting the patentee’s objection to our consideration of the specification of the earlier patent, we determined that the later patent “merely claims a particular use described in the [earlier] patent of the claimed compositions of the [earlier] patent.” Pfizer, 518 F.3d at 1363 & n.8. As such, we concluded that the asserted claims of the later patent were not “patentably distinct” from the claims of the earlier patent, and thus the later patent was invalid for obviousness-type double patenting. Id. at 1368. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. New Objections/Rejections Claim Objections Claims 1 and 4 are objected to because of the following informalities: After the structures of (I0), there should be a comma. After the structure of (II), there should be a comma, followed by the word “or” to connect to “a compound represented by General Formula (III)”. Appropriate correction is required. The wherein clause of each claim should recite “…wherein the one or more compounds can promote the production of a SIRT protein…” (emphasis added), and not “an SIRT protein”. Appropriate correction is required. Claim 4 is objected to because of the following informalities: the word “of” should be inserted after “…associated with aging in a subject in need amelioration…” in order to recite “…associated with aging in a subject in need of amelioration…” (emphasis added). 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. Claim 1-2, and 4 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. Claims 1 and 4 is rejected as vague for its recitation of “when A is indole, an acetic acid group and R7O are substituted at a third and fifth position of indole, respectively…”. It is unclear what Applicant intends when writing “third and fifth position of indole”. Does “third” and “fifth” indicate any “third” and “fifth” substituent or position on indole? Or does it mean position C-3 or C-5 of indole, when numbering the atoms on indole? A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 1 and 4 recite the broad recitation, “R3 is selected from the group consisting of an OH group, OR4 group, NHR4 group, and NR4R5 group”, and the claim also recites, “a pharmaceutically acceptable salt thereof when R3 is OH”, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claim 2 is rejected as vague for its recitation of “…wherein the anti-aging or rejuvenating cells is ameliorating one or more selected from the group consisting of…”. It is unclear what the anti-aging or rejuvenating cells are ameliorating one or more of? Is it one or more conditions? Is some phraseology missing, as the current claim does not make sense? Appropriate correction is required. Conclusion All claims are rejected. 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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUKE ALAN BORALSKY whose telephone number is (571)272-9746. The examiner can normally be reached Monday - Friday 7:30 am - 5:00 pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey H Murray can be reached at 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /L.A.B./Examiner, Art Unit 1624 /SUSANNA MOORE/Primary Examiner, Art Unit 1624