CTNF 18/539,931 CTNF 101436 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Application and Claims Status In the claims as filed on April 4, 2024, claims 1-9 are currently pending. Additionally, the present specification is amended to change the title and replace paragraph [0135] and [0136] with amended versions. Priority The instant application claims the benefit of the provisional application JP2022-208385, filed December 26, 2022. Information Disclosure Statement The information disclosure statement (IDS) filed on April 4, 2024 is in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action. Specification – Abstract 06-16 AIA Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided. The abstract of the disclosure is objected to because : it is redundant (not concise). Specifically, paragraph 1 repeats a lot of the information contained within paragraph 2. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b). Specification - Drawings Acknowledgement is made of the drawings received April 4, 2024. The drawings are objected to for the following reasons: The sheet number and view are not oriented in the same direction. As recited in 37 CFR 1.84: (p) Numbers, letters, and reference characters. (1) Reference characters (numerals are preferred), sheet numbers, and view numbers must be plain and legible, and must not be used in association with brackets or inverted commas, or enclosed within outlines, e.g., encircled. They must be oriented in the same direction as the view so as to avoid having to rotate the sheet. Reference characters should be arranged to follow the profile of the object depicted. Currently, FIG. 12, FIG. 17, and FIG. 21 are oriented in the incorrect direction. The sheets should be numbered in consecutive Arabic numerals, starting with 1, placed in the middle top of the sheet, and the number of each sheet should be shown by two Arabic numerals placed on either side of an oblique line, with the first being the sheet number, and second being the total numbers of sheets of drawings. As recited in 37 CFR 1.84 (t) Numbering of sheets of drawings. The sheets of drawings should be numbered in consecutive Arabic numerals, starting with 1, within the sight as defined in paragraph (g) of this section. These numbers, if present, must be placed in the middle of the top of the sheet, but not in the margin. The numbers can be placed on the right-hand side if the drawing extends too close to the middle of the top edge of the usable surface. The drawing sheet numbering must be clear and larger than the numbers used as reference characters to avoid confusion. The number of each sheet should be shown by two Arabic numerals placed on either side of an oblique line, with the first being the sheet number and the second being the total number of sheets of drawings, with no other marking. 06-22 Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Specification – Disclosure 06-31 AIA The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which applicant may become aware of in the specification. Claim Objections – Minor Informalities Claims 1 and 4 are objected to for the following informalities: The definitions of the limitation R 3 , R 4 , and R 5 are repeated multiple times in each claim, at each instance of compounds of General Formula (I0), (II), and (III). The R 3 -R 5 limitations should only be written one time in each independent claim. Appropriate correction is required. They use the open ended “and/or” within a closed grouping. Each claim is a closed Markush listing of alternatives and each simultaneously use the phrase “…fluorine and/or chlorine” in the limitation of R 1 . The use of closed group language in combination with open group language is improper. Appropriate correction is required. In the limitations of Z 1 -Z 4 , Applicant recites, “an organic oxy group represented by OR 8 ”. The term “organic” seems redundant and does not lend any weight to the meaning of an oxy group as any oxy group in this set of claims would be “organic”. Meanwhile, the term “organic” is not used to describe any of the other organic groups listed in the claims. For instance, “a halogen atom” is not described as “an organic halogen atom”. Examiner suggests removing this terminology. Appropriate correction is required. In the limitation of R 3 , Applicant uses non-standard Markush claim language. Markush claims are commonly formatted as “ selected from the group consisting of A, B, and C ” or “ wherein R is A, B, C, or D” . In the instant case, Applicant recites “R 3 is a group selected from the group consisting of OH, OR 4 , NH 4 , and NR 4 R 5 …”. For brevity and clarity, proper Markush claim language could recite “R 3 is selected from the group consisting of OH, OR 4 , NH 4 , and NR 4 R 5 …”. Relevant guidance can be found in the MPEP § 2173.05(h), titled “Markush Claims,” which deals with claims that list alternatives. Claim Rejections - 35 USC § 112(d) 07-36 AIA The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. 07-36-01 AIA Claim 9 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 6 recites diseases selected from the group consisting of “obesity, liver disease, decline in liver function, renal fibrosis, renal dysfunction, and decline in motor function”. Claim 9, which depends on claim 6, recites the exact same diseases, without narrowing this limitation . Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. 07-05-05 Applicant is advised that should claim 6 be found allowable, claim 9 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim Rejections - 35 USC § 112(a) 07-30-01 AIA 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 1-9 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 (I 0 ), (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 (I 0 ), (II), or (III), (as recited in claim 4) cannot be deemed enabled. The term “anti-aging” covers a broad array of different disorders that’s 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 (I 0 ), (II), or (III) (and furthermore, activation of SIRT proteins, as recited in claims 2 and 5) 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 (I 0 ), (II), and (III), wherein compounds of Formula (III) are only enabled when the A ring is indole (not naphthalene). 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). In evaluating the enablement question, several factors are to be considered. Note In re Wands , 8 USPQ2d 1400 and Ex parte Forman , 230 USPQ 546. The factors include: 1) The nature of the invention, 2) the state of the prior art, 3) the predictability or lack thereof in the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the breadth of the claims, and 7) the quantity of experimentation needed. The determination that “undue experimentation” would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. The Nature of the invention and Breadth of Claims Claim 1 recites a method for anti-aging or rejuvenating cells in an animal, comprising administering compounds of General Formula (I 0 ), (II), or (III), and claim 2 further requires that the compounds promote the production of an SIRT protein. 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 (I 0 ), (II), or (III). Similarly, claim 7 further requires that the compounds promote the production of an SIRT protein. 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 (I 0 ), (II), or (III). Furthermore, in all of the compounds tested in Examples 1-14 and 17-21, there are no examples where a compound of General Formula (III), where the A ring is a naphthalene, is used at all. 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. Let’s take a closer look at cancer, for example, as one of the general classes of diseases disclosed as being inhibited or delayed by administration of claimed compounds, in order to drive home the point : "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 al