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 .
Claim Status
The preliminary amendment filed 6/10/24 is acknowledged. Claims 1-47 are cancelled. New claims 48-57 are added. Claims 48-57 are pending.
Claims 48-57 are currently under consideration for patentability under 37 CFR 1.104.
Specification
Abstract
The abstract of the disclosure is objected to because the abstract contains acronyms and/or abbreviations that should be spelled out upon first occurrence. Correction is required. See MPEP § 608.01(b).
Claim Objections
Claims 48 and 57 are objected to because of the following informalities: the claims recite acronyms, abbreviations and/or initialisms that should be spelled out upon first occurrence. Appropriate correction is required.
Claim 48 is objected to because of the following informalities: the claim subparts are designated with a period. Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). It is recommended that the claim subparts be designated with parentheses, such as “(a)” or “a)”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 48-57 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are drawn to a method of identifying a cell type, comprising measuring decreased STING gene product levels, compared to a reference value in a treatment-resistant human cancer cell, or increased SPARCS gene product levels compared to a reference value in a treatment resistant human cancer cell. The cancer can be breast, or NSCLC. Claim 48 recites a “reference value,” a “treatment-resistant human cancer cell” but these terms are not defined by the disclosure. See the rejection under 35 USC 112(b).
The instant claims do not fully describe the steps of the method, or present any form of specific threshold or other standards that would allow the method to achieve the required function. The claims do not recite a cancer cell subtype to be identified, and the exact measurement steps are unclear (see also the rejection under 35 USC 112(b) below). The exact steps required by the claims cannot be identified due to inadequate description of intended outcome, identification of cancer cell subtypes that can be determined with the method, measurement steps, reference values, and specific comparisons required. The specification does not provide adequate description of the method steps, other than a generic introduction of possible assays that may work in the intended method, and the claims only provide a generic instruction to compare the STING or SPARCS levels to arbitrary and vague reference and control values without otherwise defining when the comparison would lead to identification of any specific cancer cell subtype. The specification further does not adequately describe the gene products that would be encompassed by the term “SPARCS.” The specification further does not establish a reasonably specific threshold measurement, or specific units for the threshold, that can be used to compare the biomarker values, or identify the specific reference samples or values that can be used for comparison. The specification further does not adequately describe the “cancer cell subtypes” that can be identified with the method. Thus, the method described by the instant specification encompasses an overly broad genus of possible methods, without clear thresholds, reference sources, or required comparisons, and there is no correlation between the steps of the method and the functional outcome. Therefore, the specification provides insufficient written description to support the genus encompassed by the claims. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the steps, specific assay methods and specific measurement thresholds that are required to establish specific status outcomes. In general, the art regarding establishing biomarkers is unpredictable. Waiker et al (J Am Soc Nephrol. 2012 January; 23(1): 13–21) teach that although diagnostic tests are judged based on their ability to classify individuals according to disease status, the actual disease status is often not known with certainty in clinical medicine. Waiker et al describe the specific example of predicting myocardial infarction, which is ultimately a pathologic diagnosis. While testing blood biochemical markers is accepted as a marker of potential myocardial infarction, few diagnostic tests enjoy acceptance as biomarkers (see page 2). This is particularly a problem when the new test is being compared to an imperfect standard test, such as serum creatinine (see page 1). It is also important to note that Waiker et al discuss the necessity of specific thresholds. Waiker et al describe that the measurement of ferritin is used in clinical practice to diagnose iron deficiency, but the test can result in misclassification of disease status, and this may be specifically due to exclusion of certain intermediate values that may have led to an overestimation of the accuracy of other biomarkers. This indicates that the threshold established for any given biomarker to describe any particular disease is critical for establishing the accuracy of the biomarker to predict disease (see page 8).
Application of genomic and proteomic approaches to many cancer types has produced thousands of candidate biomarker for detection and prognostication, yet very few have become established in clinical practice. According to Brooks (Genome Res. 2012 Feb;22(2):183-7), Fundamental issues related to tumor heterogeneity, cancer progression, natural history and biomarker performance have provided challenges to biomarker development (see abstract). To be effective, a screening strategy must detect malignant cells that are destined to grow, metastasize, and cause death. Unfortunately, little is known about the steps that lead transformed cells to become malignant and ultimately lethal, which has major implications for biomarker development (see page 184). Focusing on mutations or structural alterations within the malignant cells alone may be of limited utility in predicting biological and clinical behavior. Further, measurement of a biomarker at a particular time might not predict acquisition of those future genetic alterations that are the product of underlying genomic instability (see page 184). This is especially relevant, given that discovery based genomic studies have relied on samples of convenience, including tissue samples that have been banked from surgeries on individuals with relatively advanced disease in which the number of genomic changes is extraordinary. These changes make it difficult to identify critical early changes that could be used as diagnostic biomarkers (see page 185).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
Claims 48-57 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 make and/or use the invention.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
(1) The nature of the invention and (5) The breadth of the claims:
The instant claims are drawn to a method of identifying a cell type, comprising measuring decreased STING gene product levels, compared to a reference value in a treatment-resistant human cancer cell, or increased SPARCS gene product levels compared to a reference value in a treatment resistant human cancer cell. The cancer can be breast, or NSCLC. Claim 48 recites a “reference value,” a “treatment-resistant human cancer cell” but these terms are not defined by the disclosure. See the rejection under 35 USC 112(b).
The instant claims do not fully define the steps of the method, or present any form of specific threshold or other standards that would allow the method to achieve the required function. The claims do not recite a cancer cell subtype to be identified, and the exact measurement steps are unclear (see also the rejection under 35 USC 112(b) below). The exact steps required by the claims cannot be identified due to inadequate description of intended outcome, identification of cancer cell subtypes that can be determined with the method, measurement steps, reference values, and specific comparisons required. The specification does not set forth the method steps, other than a generic introduction of possible assays that may work in the intended method, and the claims only provide a generic instruction to compare the STING or SPARCS levels to arbitrary and vague reference and control values without otherwise defining when the comparison would lead to identification of any specific cancer cell subtype. The specification further does not identify the gene products that would be encompassed by the term “SPARCS.” The specification further does not establish a reasonably specific threshold measurement, or specific units for the threshold, that can be used to compare the biomarker values, or identify the specific reference samples or values that can be used for comparison. The specification further does not adequately define the “cancer cell subtypes” that can be identified with the method. Thus, the method described by the instant specification encompasses an overly broad genus of possible methods, without clear thresholds, reference sources, or required comparisons, and there is no correlation between the steps of the method and the functional outcome.
In addition, the claims are broad and inclusive of all types of cancer or neoplasia in humans generally. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The claims are extremely broad due to the vast number of possible cancer types and possible types of resistance for each of those cancer types. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. Here are some assorted categories:
A. CNS cancers cover a very diverse range of cancers in many categories and subcategories. There are an immense range of neuroepithelial tumors. Gliomas, the most common subtype of primary brain tumors, most of which are aggressive, highly invasive, and neurologically destructive tumors are considered to be among the deadliest of human cancers. These are any cancers which show evidence (histological, immunohistochemical, ultrastructural) of glial differentiation. These fall mostly into five categories. There are the astrocytic tumors (astrocytomas): pilocytic astrocytoma (including juvenile pilocytic astrocytoma, JPA, and pediatric optic nerve glioma) diffuse astrocytomas (including fibrillary astrocytomas, protoplasmic astrocytomas and gemistocytic astrocytomas), anaplastic astrocytomas (including adult optic nerve glioma), Glioblastoma multiforme (GBM), gliosarcoma and giant cell glioblastoma, 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 is 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.
B. Leukemia is any malignant neoplasm of the blood-forming tissues. Leukemia can arise from many different sources. These include viruses such as EBV, which causes Burkitt's lymphoma, and HTLV-1, linked to certain T cell leukemias. Others are linked to genetic disorders, such as Fanconi's anemia, which is a familial disorder, and Down's Syndrome. Other leukemias are caused by exposure to carcinogens such as benzene, and some are actually caused by treatment with other neoplastic agents. Still other leukemias arise from ionizing radiation, and many are idiopathic. Leukemias also differ greatly in the morphology, degree of differentiation, body location (e.g. bone marrow, lymphoid organs, etc.) There are dozens of leukemias. There are B-Cell Neoplasms such as B-cell prolymphocytic leukemia and Hairy cell leukemia (HCL, a chronic Lymphoid leukemia). There are T-Cell Neoplasms such as T-cell prolymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma (ATLL), and T-cell granular Lymphocytic leukemia. There are different kinds of acute myeloid leukemias (undifferentiated AML, acute myeloblastic, acute myelomonocytic leukemia, acute monocytic leukemias, acute monoblastic, acute megakaryoblastic (AmegL), acute promyelocytic leukemia (APL), and erythroleukemia). There is also lymphoblastic leukemia, hypocellular acute myeloid leukemia, Ph-/BCR- myeloid leukemia, and acute basophilic leukemia. 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.
C. 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.
D. The main types of lung and pleural cancer are small cell (i.e. oat cell, including combined oat cell), adenocarcinomas, bronchioloalveolar carcinomas (nonmucinous, mucinous, and mixed mucinous and nonmucinous or indeterminate cell type), acinar, papillary carcinoma, solid adenocarcinoma with mucin, adenocarcinoma with mixed subtypes, well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell adenocarcinoma), squamous cell (papillary, clear cell, small cell and basaloid), mesothelioma (including epithelioid, sarcomatoid, desmoplastic and biphasic) and large cell carcinoma (which include large-cell neuroendocrine carcinoma, combined large-cell neuroendocrine carcinoma, basaloid carcinoma, clear cell carcinoma lymphoepithelioma-like carcinoma, and large-cell carcinoma with rhabdoid phenotype). 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.
E. Thyroid cancer comes in four forms: papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, and medullary thyroid cancer.
F. Cancer of the skin cells is melanoma. Malignant melanomas come in form fundamental forms, superficial spreading melanoma, Nodular melanoma, lentigo malignant 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.
G. 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 colonand primary malignant melanoma of the colon. A wide variety of cancers are secondary to the colon, e.g. ovarian carcinoma.
H. 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.
I. 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 is not treatable with pharmaceuticals.
J. Penile carcinoma is usually a squamous cell carcinoma (including carcinoma 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 of the Penis.
K. 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.
L. 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 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.
M. 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 assortments 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.
N. Testicular cancers. All of the germ cell tumors listed above except for dysgerminoma also appears 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.
O. 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.
P. Cancers of the vulva are mostly squamous carcinoma, but these also include melanoma, Bartholin's Adenocarcinoma, basal cell carcinoma and some sarcomas.
Q. 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.
R. 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).
S. 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 assortments 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.
T. 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.
U. Cancers of the spleen which are primary are commonly divided 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.
V. 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.
W. 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.
X. 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.
Y. 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.
Z. 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.
AA. Cancers of the adrenal glands include adrenocortical carcinoma, pheochromocytoma, adrenal neuroblastoma, and adrenal ganglioneuroma.
AB. 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.
AC. 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 carcinoma 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 are 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 Mullerian 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.
AD. 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
AE. 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 divided into three types: keratinizing squamous cell carcinoma, non-keratinizing carcinoma, and undifferentiated carcinoma. There are also rhabdomyosarcomas and lymphomas as well.
AF. 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.
AG. 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.
AH. 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 tumor (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.
AI. 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) include 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.
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
The state of the art in diagnosing cancer and identifying cell types among treatment resistant cancers is unpredictable.
The skilled artisan cannot envision the steps, specific assay methods and specific measurement thresholds that are required to establish specific status outcomes. In general, the art regarding establishing biomarkers is unpredictable. Waiker et al (J Am Soc Nephrol. 2012 January; 23(1): 13–21) teach that although diagnostic tests are judged based on their ability to classify individuals according to disease status, the actual disease status is often not known with certainty in clinical medicine. Waiker et al describe the specific example of predicting myocardial infarction, which is ultimately a pathologic diagnosis. While testing blood biochemical markers is accepted as a marker of potential myocardial infarction, few diagnostic tests enjoy acceptance as biomarkers (see page 2). This is particularly a problem when the new test is being compared to an imperfect standard test, such as serum creatinine (see page 1). It is also important to note that Waiker et al discuss the necessity of specific thresholds. Waiker et al describe that the measurement of ferritin is used in clinical practice to diagnose iron deficiency, but the test can result in misclassification of disease status, and this may be specifically due to exclusion of certain intermediate values that may have led to an overestimation of the accuracy of other biomarkers. This indicates that the threshold established for any given biomarker to describe any particular disease is critical for establishing the accuracy of the biomarker to predict disease (see page 8).
Application of genomic and proteomic approaches to many cancer types has produced thousands of candidate biomarker for detection and prognostication, yet very few have become established in clinical practice. According to Brooks (Genome Res. 2012 Feb;22(2):183-7), Fundamental issues related to tumor heterogeneity, cancer progression, natural history and biomarker performance have provided challenges to biomarker development (see abstract). To be effective, a screening strategy must detect malignant cells that are destined to grow, metastasize, and cause death. Unfortunately, little is known about the steps that lead transformed cells to become malignant and ultimately lethal, which has major implications for biomarker development (see page 184). Focusing on mutations or structural alterations within the malignant cells alone may be of limited utility in predicting biological and clinical behavior. Further, measurement of a biomarker at a particular time might not predict acquisition of those future genetic alterations that are the product of underlying genomic instability (see page 184). This is especially relevant, given that discovery based genomic studies have relied on samples of convenience, including tissue samples that have been banked from surgeries on individuals with relatively advanced disease in which the number of genomic changes is extraordinary. These changes make it difficult to identify critical early changes that could be used as diagnostic biomarkers (see page 185).
Liu et al (Gene Reports 37 (2024) 102042) teach that although correlation can demonstrate the genes as a biomarker, correlation does not necessarily imply functional causality of a gene in the disease. Understanding the distinction between correlation and causality is fundamental in designing genetic studies. It encourages researchers to design experiments that not only identify gene-disease relationships but also clarify whether these relationships are causal (see e.g. page 2). Liu advocates that that gene expression alone is not a definitive marker of a gene's role in tumor progression (see e.g. page 3). Discrepancies between mRNA and protein levels due to post-transcriptional and translational regulations can significantly alter our understanding of gene roles in conditions such as cancer (see e.g. page 3). Biological regulation is a complex process influenced by many confounding factors, making simple interpretations of gene function challenging in mRNA-based sequencing data (see e.g. page 3). For example, epigenetic mechanisms play a crucial role in the regulation of gene expression without altering the underlying DNA sequence (see e.g. page 2).
Sun et al (Cancers 2024, 16, 583) teach a specific example of complexity regarding gene expression measurements for diagnosis and identifying tumor cell features (see e.g. abstract). The diagnosis of melanoma among all melanocytic lesions can be difficult and nuanced (see e.g. page 3). In terms of prognostication, as mentioned previously, Sun indicates that professional associations do not endorse interventions based on results of gene expression profiling tests (GEP) (see e.g. page 10). Commercially available GEP tests marketed to risk-stratify melanomas “do not provide clinically actionable prognostic information when combined or compared with known clinicopathologic factors” (see e.g. page 10). There remains significant controversy in the role of GEP for melanoma prognostication (see e.g. page 10). Without understanding how gene expression contributes to diagnosis or prognosis, it would be impossible to identify a specific cancer cell subtype that would have any particular characteristics based on gene expression products.
Furthermore, the cancer treatment art involves a very high level of unpredictability. In particular, there is no known anticancer agent that is effective against all cancer cell types. While the state of the art is relatively high with regard to the treatment of specific cancers with specific agents, it has long been underdeveloped with regard to the treatment of cancers broadly.
With regard to cancer treatment, Bally et al. (US 5,595,756) stated, “Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment-limiting toxicities” (col. 1, lines 17-24).
Sporn et al, “Chemoprevention of Cancer,” Carcinogenesis, Vol. 21 (2000), 525-530, teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn et al also teaches that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al (Cancer and Metastasis Reviews, 2000, 19: 167-172) indicates that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality (see p. 167, left column, 1st paragraph). Gura T (Science, 1997, 278(5340): 1041-1042, encloses 1-5) indicates that “the fundamental problem in drug discovery for cancer is that the model systems are not predictive at all” (see p. 1, 2nd paragraph). Furthermore, Gura T indicates that the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft rumors don’t behave like naturally occurring tumors in humans—they don’t spread to other tissues, for example (see p. 2, 4th paragraph). Further, when patient’s tumor cells in Petri dishes or culture flasks and monitor the cells’ responses to various anticancer treatments, they don’t work because the cells simply fail to divide in culture, and the results cannot tell a researcher how anticancer drugs will act in the body (see p. 3, 7th paragraph). Furthermore, Jain RK (Scientific American, July 1994,58-65) indicates that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain (see p. 58, left most column, 1st paragraph). Further, Jain RK indicates that to eradicate tumors, the therapeutic agents must then disperse throughout the growths in concentrations high enough to eliminate every deadly cells…solid cancers frequently impose formidable barriers to such dispersion (see p. 58, bottom of the left most column continuing onto the top of the middle column). Jain RK indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Further, as taught by HogenEsch et al (J Control Release. 2012 December 10; 164(2): 183–186.) There is no single cell culture or in vivo cancer model that faithfully predicts the efficacy of
anticancer drugs in human clinical trials. Cell culture approaches offer the advantage of human-derived cell lines or tissue fragments from primary tumors, but cannot mimic the complexity of the reciprocal interaction between the growing tumor and the co-evolving microenvironment. Xenografts in immunodeficient mice have limited added value over cell culture models as the lack of an intact immune system and insufficient interactions between the human tumor cells and mouse stromal cells do not recapitulate human cancers. Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Given Bally et al teaching of treatment-limiting toxicities in clinical use, Sporn’s teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype, Auerbach et al teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response, Gura’s teaching that the models are unpredictable, and Jain’s teaching that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain demonstrates that the treatment of cancer is highly unpredictable, if even possible for many cancers.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
Only two examples were provided by Applicant that involved STING levels. First, in Example 2, STING levels were examined in KRAS mutant lung cancer cell line cells. STING levels were also determined in neuroendocrine cell line H69, triple negative breast cancer cell lines, and SPARCS-high and SPARCS-low cell lines. Second, Example 3 measured STING expression in different breast cancer cell subtypes. The cell lines were tested for “responsiveness” to STING agonist AduroS100. This “responsiveness was measured by determining levels of CXCL10 relative to a control.
Notably, there were no examples provided that identified any cell subtype relative to any specific treatment-resistant human cancer cell. The specification also did not provide any type of relevant retrospective study showing that STING or SPARCS levels correlated with resistance to treatment or cancer cell subtypes. Therefore, Applicant has not provided any evidence that demonstrates that all types of cancer cell subtypes can be identified with any number of possible biomarkers. Applicant has also not provided reasonable steps that would allow one of ordinary skill in the art to make and use the claimed method without undue experimentation.
In conclusion, the claimed invention does not provide enablement for making and using the claimed invention. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 48-57 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.
Applicant is advised that the language describing the intended outcome and method steps for the claimed method is almost uninterpretable. Applicant is advised to amend the claims to clearly describe the intended outcome of the method as well as set forth specific steps for accomplishing that outcome.
Claim 48 recites “A method for identifying a cancer cell subtype.” However, the claim does not set forth any steps for identifying a cell subtype, and does not identify which cell subtype is being identified. The purpose of the method is unclear, and therefore the scope of the encompassed method is indefinite.
Claim 48 recites “measuring…decreased STING gene product levels.” It is unclear whether the method is measuring the level of STING, and then determining if the levels are decreased, or if the levels are required to be decreased prior to measuring. Generally, it is unclear what is required in this step of the method.
Claim 48 recites “measuring…increased SPARCS gene product levels.” It is unclear whether the method is measuring the level of SPARCS, and then determining if the levels are decreased, or if the levels are required to be decreased prior to measuring. Generally, it is unclear what is required in this step of the method.
Claim 48 recites the term “SPARCS,” which is not defined in the specification. Instant specification page 5 states that “In some embodiments, the one or more SPARCS genes are selected from TRIM22, TRIM38, IL32, SPATS2L, EPHA3, HERC3, ADAM19, SERPINB9, IFI44L, F3, BEND6, AIG1, MSRB2, TNFRSF9, and ANTXR1.” However, this gene list is merely exemplary, and does not define the metes and bounds of the term “SPARCS.”
Claim 48 recites “STING gene product levels.” It is unclear if the plural “levels” refers to measurement of more than one gene product, more than one repetition of the measurement of the same gene product, or measurement of more than one sample. The term “gene product levels” is therefore indefinite.
Claim 48 recites “SPARCS gene product levels.” It is unclear if the plural “levels” refers to measurement of more than one gene product, more than one repetition of the measurement of the same gene product, or measurement of more than one sample. The term “gene product levels” is therefore indefinite.
Claim 48 recites “compared to a reference value in a treatment-resistant human cancer cell.” It is unclear if the STING/SPARCS levels or the reference value are being measured in the treatment resistant human cancer cell, or if the treatment-resistant human cancer cell is used as part of the measurement assay. Claims 51-52 recite “the reference value” but it is unclear how this reference value is identified as discussed above.
Claim 54 contains an “(s)” at the end of the words “cell” and “tissue” that is referenced parenthetically. It is unclear, due to the presence of the parentheses, if the letter “s” is intended as a limitation of the claim. In particular, it is unclear if the cell and tissue are singular or plural.
Claim 55 recites “normal subject or normal subjects.” It is unclear if the term “or normal subjects” indicates a pool of samples from more than one normal subject, or if there are multiple reference values required from multiple normal subjects.
Claim 55 recites “is determined from cells or tissue.” It is unclear if the term “from cells” indicates a pool of cells, or if there are multiple reference values required from multiple cells.
In claim 56, it is unclear if the term “non-cancerous” applies to just the cell or cells, or if the tissue/tissues are also required to be “non-cancerous.
Claim 55 recites “cell or cells, or tissue or tissues.” It is unclear if the term “cells” and “tissues” indicates a pool of cells or tissues from more than one normal subject, or if there are multiple different cell and tissue samples required from multiple subjects.
Claim 57 recites “wherein the SPARCS gene product levels are from TRIM22…or combinations thereof.” The names recited are genes or proteins, and therefore it is unclear how a level could be “from” a gene or product. For example, it is unclear if the level is determined from TRIM22 expression, or if the level is a product of an indirect TRIM22 activity that stimulates a downstream expression of a different gene or protein. It is also unclear if the list of names are directed to the products, or the genes from which the products are derived.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 48-57 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements, which are recited at a high level of generality, provide conventional assays and samples that do not add meaningful limits to practicing the law of nature and abstract idea.
Based upon an analysis with respect to the claim as a whole, the claims are determined to be directed to a law of nature/natural principle an abstract idea. The instant claims recite a method of identifying a cancer cell subtype, comprising measuring a decreased STING gene product or an increased SPARCS gene product. The relationship between the recited biomarkers and the cell subtype is a natural principle, which is a judicial exception. This method describes correlation of a particular biomarker with a particular cell state, which is comparable to concepts identified by the Supreme Court in Mayo. (see Mayo 101 USPQ2d at 1966). Further, the selection of a therapy could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams). It is noted that selection of a therapy does not actually require administration of a therapy.
A claim that focuses on the use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. See Mayo 101 USPQ2d at 1966. Adding steps to a natural biological process that only recite well-understood, routine, conventional activity previously engaged in by researchers in the field would not be sufficient. See id. At 1966, 1970. The claims identifies assays for determining gene product expression levels. The identification of sample types and subjects from which the samples are to be collected is routine in the art of medical testing. As stated in MPEP 2106.05(d), the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity. Determining the level of a biomarker in blood by any means has been determined as one of the well-understood, routine, conventional activity: see Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017). The specification also notes that “Any type of biological sample appropriate for conducting assays described herein can be compatible with aspects of the invention, as would be understood by one of ordinary skill in the art.” See paragraph [0083] of the published application. Regarding the assays to detect gene expression products, the assays claimed are routine in the art for measuring gene expression products. This is acknowledged by the instant specification, which states that " Those of ordinary skill in the art will be able to devise multiplexing assays (i.e., assays that measure two or more markers) using the guidance provided herein and the knowledge in the art.” (see paragraph [0089]). Therefore, the additional features of the claims (i.e., measuring the level of the recited biomarkers, and identifying the source of the sample for screening) do not ensure that the claims amount to significantly more than the natural principle itself. The claims use conventional means to observe a natural correlation and therefore the steps of the claimed methods are not sufficient to transform unpatentable natural correlations into patentable applications of those regularities. This is also supported by the findings of the in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 115 USPQ2d 1152 (Fed. Cir. 2015), wherein the Federal Circuit held that claims that measure biological substances using methods that are routine and conventional do not amount to more than reliance on a correlation that is a law of nature for patentability.
The question of whether identification of the patient population amounts to significantly more than the judicial exception is addressed in Mayo Collaborative Serv. v. Prometheus Labs., Inc., 566 U.S. _, 132 S. Ct. 1289, 1293-94, 101 USPQ2d 1961, 1965-66 (2012) (citing Diehr, 450 U.S. at 187, 209 USPQ at 7), when the Supreme Court determined that process claims reciting a correlation may inhibit further discovery by improperly tying up future use of laws of nature, even though the laws of nature at issue are narrow laws that may have limited applications. After measurement of the correlation, the claims can tie up a doctor's subsequent treatment decisions, whether treatment does or does not change in light of inference the doctor has drawn using disclosed correlations, since the claims threaten to inhibit development of more refined treatment recommendations that combine the patentee's correlations with later discovered features, and since the correlation step of the claims is set forth in highly general language covering all processes that make use of the correlation. Further, the steps simply refer to a relevant patient population, which is a pre-existing audience; doctors wish to determine whether a particular patient has a disease, or if the disease has/has not progressed. The claims inform a relevant audience about certain laws of nature; and additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community, and those steps, when viewed as a whole, add nothing significant beyond the sum of the parts taken separately. Even though the laws of nature at issue are narrow laws that may have limited applications, the claim does not amount to significantly more than the natural law itself.
Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
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