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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
The preliminary amendment filed 12/1/22 is acknowledged. Claims 1-7 are pending. Claim 6 is amended. Claims 1-7 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements filed on 12/1/22, 12/27/24, and 1/28/25 have been considered. Signed copies are enclosed.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Notice to Comply with 37 CFR §§ 1.821—1.825
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. §§ 1.821-1.825 for the following reason(s): Specification paragraphs [0056]-[0058] and Figures 1 and 7-10 contain amino acid sequences without proper reference to the corresponding sequence identifiers ("SEQ ID NO:__").
To be considered fully responsive, any reply to this action must address these deficiencies, as this requirement will not be held in abeyance.
Specification
Abstract
The abstract of the disclosure is objected to because the term “S100A8” includes an acronym and/or abbreviation that should be spelled out upon first occurrence. 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).
Trademarks
The use of the terms MAXISORP and TWEEN, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities: the term “S100A8” includes an acronym and/or abbreviation that should be spelled out upon first occurrence. Appropriate correction is required.
Applicant is advised that should claims 1 be found allowable, claims 6-7 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)
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 1-7 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 an S100A8-inhibiting peptide comprising a peptide of 5-10 residues in length containing a fifth alanine (Ala) from an N-terminus in an amino acid sequence of SEQ ID NO:1 or a peptide consisting of an amino acid sequence of SEQ ID NO:2. The dependent claims recite combinations of peptides (see e.g. instant claim 2), bivalent or tetravalent peptides (see e.g. instant claims 4-5), or disease therapeutics comprising the peptide (see e.g. instant claims 6-7). There are at least three separate issues with the instant claims regarding Written Description.
First, the peptide in instant claim 1 subpart (A) is not sufficiently described. The peptide can be an peptide comprising any 5 amino acids, as long as a single amino acid that comprises the fifth alanine from an N-terminus. The description of the peptide is indefinite (see rejection under 35 USC 112(b) below). However, given the broadest reasonable interpretation, instant claim 1 subpart (A) reads on a peptide with at least 5 amino acids, having any sequence, that contains an alanine that occurs in the fifth position as compared to SEQ ID NO:1, which can be surrounded by any other amino acid sequence. Even requiring the entire sequence of SEQ ID NO:1 is not sufficient to adequately describe the peptide as a whole. The peptide is required to have specific function of inhibiting S100A8, but the specification has provided no structure that correlates with this function for this peptide. Additionally, the claim encompasses millions of possible proteins, of any length given the open ended transitional phrase “comprising” and therefore the limited examples provided in the specification are not sufficient to adequately represent the vast genus of encompassed peptides.
Second, the peptide of instant claim 1 subpart (B) is not adequately described. The claims specifically states that the peptide consists of “an amino acid sequence of SEQ ID NO:2”. It is possible, given the language of the claim which includes "an amino acid sequence of SEQ ID NO:2", that any two amino acids in sequence would suffice to meet the limitations of the claims. Because the function of a protein is dependent on the presence of each specific amino acid residue, and with the possibility of added or deleted amino acids, a vast number of polypeptides are potentially encompassed by the instant claim. In theory, the instant claims could encompass any possible protein on earth. These peptides have no correlation between their structure and function. Like the peptide of subpart (A), the peptide of (B) must possess the specific function of inhibiting S100A8. But the specification provides no guidance to which peptides are capable of the required function. Additionally, the claim encompasses millions of possible proteins, of any length given the open ended transitional phrase “comprising” and therefore the limited examples provided in the specification are not sufficient to adequately represent the vast genus of encompassed peptides.
Third, instant claims 6 and 7 require peptides that have an additional function of treating disease. The claims encompass hundreds of possible diseases and combinations, without providing adequate structure for the recited peptides that correlate with this function or describing an adequate number of species that describe the breadth of the claimed genus of peptides.
The specification describes peptides of SEQ ID NO: 1-12 as possessing the required functional characteristics. However, the claims are not so limited as described above. The claimed peptides have no correlation between their structure and function. The claim requires that the peptide exhibit S100A8-inhibiting activity, or disease treatment activity, but the specification provides no guidance regarding which peptides are capable of the required function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. 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.)
With the exception of SEQ ID NO:1-12, the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. 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. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai 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.
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 USPQ2datl966.
Protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional peptides that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of peptides encompassed by the instant claims (see e.g. page 661, left column).
Given the teachings of these references that point out the limitations and pitfalls of using sequence to predict functions, and the lack of a representative number of species across the breadth of the genus, one of skill in the art would reasonably conclude that only SEQ ID NO:1-12, but not the full breadth of the claims, meet the written description provision of 35 USC 112(a). MPEP 2163 states that inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. Given the unpredictable nature of protein function, and absence in the art of peptides having the required functions, Applicant has not provided sufficient evidence to show possession of the claimed peptides or disease therapeutics, for which neither structure has been provided to correlate to the required functions, nor a representative number of species reduced to practice to demonstrate possession across the breadth of the genus of proteins.
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 6-7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a disease therapeutic for treating colorectal cancer comprising divalent peptide 3A5 (SEQ ID NO:1) or divalent or tetravalent ILVIK peptide (SEQ ID NO:2), does not reasonably provide enablement for a disease therapeutic comprising to treat all of the encompassed disorders with all of the encompassed peptides. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
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.”
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 Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
The claims are drawn to disease therapeutic comprising a peptide of instant claim 1. Dependent claim 7 recites several vast genera of diseases, as well as diseases with distinct etiology and pathological features.
The encompassed peptide genus is overly broad. The rejected claims depend from claim 1, which is drawn to an S100A8-inhibiting peptide comprising a peptide of 5-10 residues in length containing a fifth alanine (Ala) from an N-terminus in an amino acid sequence of SEQ ID NO:1 or a peptide consisting of an amino acid sequence of SEQ ID NO:2. The peptide can be any peptide comprising any 5 amino acids, as long as a single amino acid that comprises the fifth alanine from an N-terminus. The description of the peptide is indefinite (see rejection under 35 USC 112(b) below). However, given the broadest reasonable interpretation, instant claim 1 subpart (A) reads on a peptide with at least 5 amino acids, having any sequence, that contains an alanine that occurs in the fifth position as compared to SEQ ID NO:1, which can be surrounded by any other amino acid sequence.
Also, the genus of encompassed peptides of instant claim 1 subpart (B) is overly broad. The claims specifically states that the peptide consists of “an amino acid sequence of SEQ ID NO:2”. It is possible, given the language of the claim which includes "an amino acid sequence of SEQ ID NO:2", that any two amino acids in sequence would suffice to meet the limitations of the claims. Because the function of a protein is dependent on the presence of each specific amino acid residue, and with the possibility of added or deleted amino acids, a vast number of polypeptides are potentially encompassed by the instant claim. In theory, the instant claims could encompass any possible protein on earth. Additionally, claim 1 encompasses millions of possible proteins, of any length given the open ended transitional phrase “comprising” and therefore the limited examples provided in the specification are not sufficient to adequately represent the vast genus of encompassed peptides.
The claims are broad and inclusive of all types of cancer or neoplasia, all psychiatric diseases, all diseases that are encompassed by the vague term “lifestyle diseases”, as well as rheumatoid arthritis, COVID-19, Crohn’s disease, ulcerative colitis, cystic fibrosis, and allergic dermatitis. These diseases do not share any underlying mechanisms, symptoms, characteristics, etiology or pathology, and therefore findings for one disease would not be reasonably applied to any other disease. 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 disease types and mechanisms represented by the terms “disease therapeutic”. The encompassed diseases are not a single type of disease, and even cancer is not a single disease, or cluster of closely related disorders. As an example of the breadth of the disorders encompassed by the claims, 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, hemangioma, 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 melanomatous). 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, chordoma, 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 hemangioma 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., Marjolijn 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 extraosseous 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 colon and 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 mesenchymal, 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 hemangioma, 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.
In another example, the term “psychiatric diseases” is also extremely broad due to the vast number of possible disease types and mechanisms represented by the terms “disease therapeutic”. The encompassed diseases are not a single type of disease. As an example of the breadth of the disorders encompassed by the claims, there are at least dozens of psychiatric diseases, which are highly heterogeneous at the molecular and clinical level. Some assorted categories are:
Anxiety disorders include generalized anxiety disorders, social phobias, agoraphobia, claustrophobia, panic disorders, obsessive compulsive disorder, post-traumatic stress disorders, selective mutism, separation anxiety disorder, social anxiety disorder.
Behavioral and emotional disorders in children include oppositional defiant disorder, conduct disorder, attention deficit hyperactivity disorder
Mood disorders including depressive disorders such as disruptive mood dysregulation disorder, major depressive disorder (all types included), dysthymia, premenstrual dysphoric disorder, psychotic depression, pervasive refusal syndrome, unspecified depressive disorder; bipolar disorders such as bipolar I disorder, bipolar II disorder, bipolar disorder not otherwise specified, cyclothymia, hypomania
Trauma and stress related disorders such as reactive attachment disorder, disinhibited social engagement disorder, post-traumatic stress disorder (PTSD), post-traumatic embitterment disorder (PTED), acute stress disorder, adjustment disorder, complex post-traumatic stress disorder (C-PTSD), prolonged grief disorder
Dissociative disorders including dissociative identity disorder, dissociative amnesia (formerly psychogenic amnesia), depersonalization-derealization disorder, dissociative amnesia with dissociative fugue, dissociative neurological symptom disorder (including psychogenic non-epileptic seizures), other specified dissociative disorder (OSDD), unspecified dissociative disorder, ganser syndrome
Paranoid disorders including paranoid personality disorder, delusional paranoid disorder and schizophrenia
Cognitive disorders such as delirium, dementia, HIV-associated neurocognitive disorder (HAND), amnesia,
Substance-related and addictive disorders such as substance use disorder, Substance-induced disorder (Substance-induced psychosis, Substance-induced delirium, Substance-induced mood disorder), alcohol use disorder, alcoholic hallucinosis, cannabis use disorder, cannabis-induced delirium, cannabis-induced psychosis, cannabis-induced mood disorder, cannabis-induced anxiety, opioids induced delirium, opioids induced psychotic disorder, opioids induced mood disorder, opioids induced anxiety
Other disorders such as addictive personality, gambling disorder, video game addiction, internet addiction disorder, sexual addiction, food addiction, exercise addiction, addiction to social media, pornography addiction, shopping addiction
Paraphilias such as voyeuristic disorder, exhibitionistic disorder, frotteuristic disorder, pedophilia, compulsive sexual behavior disorder, erotic target location error, sexual masochism disorder, sexual sadism disorder, fetishistic disorder
Somatic symptom related disorders such as hypochondriasis, cyberchondria, somatization disorder, conversion disorder (Functional Neurological Symptom Disorder), factitious disorder imposed on self (Munchausen syndrome), factitious disorder imposed on another (Munchausen by proxy), pain disorder, medically unexplained physical symptoms (MUPS),
Eating disorders such as pica (disorder), rumination syndrome, avoidant/restrictive food intake disorder, anorexia nervosa, binge eating disorder, bulimia nervosa, purging disorder, diabulimia, night eating syndrome, orthorexia nervosa, atypical anorexia nervosa, other specified feeding or eating disorder (OSFED),
Disruptive impulse-control, and conduct disorders, such as intermittent explosive disorder, oppositional defiant disorder, conduct disorder, antisocial personality disorder, pyromania, kleptomania, mythomania, disruptive mood dysregulation disorder
Obsessive-compulsive and related disorders such as obsessive–compulsive disorder (OCD), body dysmorphic disorder, body integrity dysphoria, compulsive hoarding, trichotillomania, excoriation disorder (skin picking disorder), body-focused repetitive behavior disorder, olfactory reference syndrome, phantom limb syndrome, primarily obsessional obsessive-compulsive disorder, hoarding disorder
Schizophrenia spectrum and other psychotic disorders such as brief psychotic disorder, delusional disorder, delusional misidentification syndrome, paraphrenia, psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, schizotypal personality disorder, shared delusional disorder
Personality disorders such as paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder
Similarly, the term “lifestyle diseases” also likely encompasses a vast number of diseases and disorders, which causes even more variation in the possible diseases encompassed. See also Rejection under 112(b) below regarding the term “lifestyle diseases”.
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
While the state of the art is relatively high with regard to the treatment of specific disease types, the state of the art with regard to treating all of the encompassed diseases broadly is at best underdeveloped. In particular, there is no known agent that is effective against all of the diseases listed in the claims.
Predicting whether or not an agent will be able to treat a particular disease is fraught with obstacles, even if the patient population has a well-understood disease. As taught by Ma (Modern Drug Discovery 2004, 7(6)), any results from in vitro screening often poorly correlate with in vivo results because the complicated physiological environment is absent in the in vitro system (see page 30, left column).
To provide one example, the cancer treatment art involves a very high level of unpredictability. 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. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all cancer cells in a mammal, including a human subject, with the claimed active ingredient makes practicing the claimed invention unpredictable.
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.
In addition, predicting the success of a treatment for inflammatory disease such as Crohn’s disease, ulcerative colitis, rheumatoid arthritis, COVID-19, cystic fibrosis, and allergic dermatitis presents challenges beyond initial screening. For example, regarding autoimmune disease, according to Steinman et al (Nat Med. 2012 Jan 6;18(1):59-65), there are no approved clinical tests that are effective at predicting the therapeutic success or toxicity of treatments for autoimmune diseases (see page 59). Further Steinman et al teach that a single therapeutic strategy is probably not suitable for all autoimmune diseases or even for individual subsets of patients within one diagnostic category, as there may be heterogeneous biology underlying some of these clinical entities (see page 61). Steinman et al give the example of biologics targeting TNF and its receptors, which are effective in rheumatoid arthritis, Crohn's disease and psoriasis, but which cause marked worsening of disease in multiple sclerosis (see page 60). Blumberg et al (Nat Med.; 18(1): 35–41) teach that one of the greatest problems in translating therapies into clinical practice in autoimmunity are the numerous failures that have been the results of clinical trials. Despite the rapid progress that has been made in understanding the immune system, most of the underlying data has come from animal models, which necessarily only partially represent what is observed in humans. To compound this limitation, there exists no standardized definition of the normal human immune system, no comprehensive understanding of how this normal system is altered in autoimmune diseases and no understanding of the relationship between these immunophenotypic characteristics and either the genetic composition of the host or the environmental stimuli that either promote or protect from the development of autoimmunity (see pages 1-3). Given the extremely broad nature of the encompassed diseases, which have variable etiology and pathology, and the teachings of Steinman and Blumberg, one of skill in the art would not be able to predict the effectiveness of the encompassed peptides in each of the claimed inflammatory diseases.
In another example, the psychiatric disease treatment art involves a very high level of unpredictability. As taught by Zhu (Front Psychiatry. 2021 Jan 27;11:562660), Psychiatric diseases have the lowest probability of success in clinical drug development (see e.g. abstract). For example, despite the huge unmet needs to treat cognitive impairment as a core feature of schizophrenia, no effective drugs for treating this condition have been approved (see e.g. abstract). There are several limiting factors. First is the complex and poorly understood etiology and pathophysiology of the schizophrenia disease (see e.g. Zhu page 2, right column). Second is the limited translational value of animal models used in drug discovery research (see e.g. Zhu page 2, right column). Similarly, Wong et al (International Journal of Neuropsychopharmacology (2010), 13, 1269–1284) teach that in spite of major investments, targets falling outside the classical aminergic mechanisms have shown diminished returns (see e.g. Wong abstract). The disappointments are traced to failures in the target identification and target validation effort, as reflected by the poor ability of current bioassays and animal models to predict efficacy and side-effects (see e.g. Wong abstract). Mismatch between disease biology and how psychiatric diseases are categorized has resulted in clinical trials of highly specific agents in heterogeneous patients, leading to variable treatment effects and failed studies (see e.g. Wong abstract).
(6) the amount of direction or guidance presented; (7) the presence or absence of working examples;
The instant specification describes peptides of SEQ ID NO:1-12, although not all of these peptides were tested for activity. Examples 1-4 describe synthesis and in vitro testing of Peptides #1-6, in vitro activity in a competitive ELISA measuring binding of S100A8 to TLR4/MD-2 complex, testing of alanine mutations in various sites of peptide #3, and in vitro demonstration of inhibition of IL-8 in SW480 cells by divalent peptide 3A5. Example 6 describes screening of fragments of peptide 3A5 for interaction with and affinity for TLR4/MD-2.
Example 5 describes administration of divalent peptide 3A5 into mice with SW480 subcutaneous xenografts. SW480 is a colorectal cancer cell line.
Examples 7 and 8 describe administration of divalent and tetravalent ILVIK peptides to mice with SW480 xenografts.
No other peptides have been tested for disease activity, and no other diseases were treated with administration of any peptide. One of skill in the art would be required to engage in undue experimentation to practice the invention. First, a peptide would have to be selected from the millions of encompassed peptides, then the selected peptide would have to be screened against hundreds of distinct disorders that do not share mechanism, symptoms, etiology or pathology. This level of experimentation would be an undue burden on the practitioner.
In conclusion, the claimed invention does not provide enablement for the entire scope of disease therapeutics. 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 1-2 and 4-7 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.
In claim 1, the phrase “comprising (A) a peptide of 5 to 10 residues in length containing a fifth alanine from an N-terminus in an amino acid sequence of SEQ ID NO:1” renders the claim indefinite. There are several issues with the claim language. First, it is unclear if the entire peptide is 5-10 amino acids in length, or if the peptide can be longer in length. Second, it is unclear whether the alanine must be present at the fifth position in every peptide that is encompassed, or if the reference to the fifth location is only in relation to SEQ ID NO:1. Third, it is unclear exactly where the fifth residue must be placed, given the phrase “from an N-terminus in an amino acid sequence of SEQ ID NO:1”. The term “an amino acid sequence” could potentially refer to any two amino acids in sequence, therefore it is unclear how one of skill in the art would determine which residue is the fifth from the N-terminus.
In claim one the phrase “an amino acid sequence” in both subparts (A) and (B) render the claim indefinite. It is unclear if the claim requires a peptide that includes any two amino acids in sequence from SEQ ID NO:1 or 2, or if the claim requires the entire amino acid sequence as set forth in SEQ ID NO:1 or SEQ ID NO:2.
In claim 2, the phrase “is one kind or two or more kinds among peptides consisting of amino acid sequences of SEQ ID Nos: 1 and 3 to 12” renders the claim indefinite. The term “one or two or more kinds among peptides” is indefinite. The term “An S100A8-inhibiting peptide” refers to a single peptide, but claim 2 refers to multiple peptides. The scope of the claims is therefore contradictory.
In claim 2, the phrase “is one kind or two or more kinds among peptides consisting of amino acid sequences of SEQ ID Nos: 1 and 3 to 12” renders the claim indefinite. The term “is one or two or more kinds among peptides” is indefinite. It is unclear what is meant by “among peptides”. If the claim is referencing possible alternatives, the claim should be amended to recite the proper Markush language such as “wherein the peptide of (A) comprises one or more peptides selected from the group consisting of SEQ ID NO:1 and 3-12”.
Claims 4 and 5 recite the phrase “among the peptides (A) and (B)”. The scope of this phrase is indefinite. It is not clear if the term “among” is open ended such as “comprising” or closed such as “consisting of”. Further, it is unclear if the term “among” allows peptides not from (A) or (B) to be included in the composition.
Claims 6-7 recite “A disease therapeutic comprising the S100A8-inhibitng peptide according to claim 1”. However, the claim does not further limit the scope of the peptide and does not add additional components to the composition. Therefore, it is unclear whether the scope of claims 6-7 differ from the scope of claim 1. Further, it is unclear whether a “disease therapeutic” requires additional components to accomplish the required function.
In claim 7, the phrase “is one kind or two or more kinds among” renders the claim indefinite. The term “is one or two or more kinds among” is indefinite. It is unclear what is meant by “among”. If the claim is referencing possible alternatives, the claim should be amended to recite the proper Markush language such as “wherein the disease comprises one or more diseases selected from the group consisting of”. Further, it is not clear if the term “among” is open ended such as “comprising” or closed such as “consisting of”. Further, it is unclear if the term “among” allows diseases not listed to be included in the claim scope.
In claim 7, the term “lifestyle diseases” renders the claim indefinite. The term is not defined by the specification, and the scope of the diseases encompassed by the vague term “lifestyle” is not clear. The metes and bounds of the diseases encompassed by the claims are therefore indefinite.
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
Claim Rejections - 35 USC § 112(d)
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.
Claim 2, 4, and 5-7 are 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. Claims 2, 4, and 5 reference multiple peptides in the composition, while the base claim is directed to a single peptide. Claims 2, 4, and 5 broaden the scope of the base claim to recite multivalent peptides, and therefore do not further limit the subject matter of the claim upon which it depends. 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.
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 1-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter because the claimed invention is directed to a product (peptide comprising a peptide of 5-10 residues in length containing a fifth alanine (Ala) from an N-terminus in an amino acid sequence of SEQ ID NO:1 or a peptide consisting of an amino acid sequence of SEQ ID NO:2) which appears to be a product that is not markedly different in structure from naturally occurring products. See Association for Molecular Pathology v. Myriad Genetics, Inc., 106 USPQ2d 1972 (2013). As shown in UniProt Accession C0INF5 (downloaded from Uncharacterized protein - uncultured bacterium BLR12 | UniProtKB | UniProt on 8/5/25), naturally occurring polypeptides are known that comprise 5-10 amino acids containing the required alanine (Reference sequence (peptide as required by the instant claims is underlined): MMSSFLISIKAVLMRNKVKNQRAILVIKKASCLHRRSDRLKN. Therefore, the claims encompassed natural products that are not patentable subject matter. Additionally, fragments of the recited peptides are not markedly different in structure from when found in nature.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2 and 6-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by UniProt Accession A0A5K1BRW9 (last updated on 12/11/2019; downloaded from https://www.uniprot.org/uniprotkb/A0A5K1BRW9/entry).
The instant claims are directed to an S100A8-inhibiting peptide comprising: (A) a peptide of 5 to 10 residues in length containing a fifth alanine (Ala) from an N-terminus in an amino acid sequence of SEQ ID NO: 1, or (B) a peptide consisting of an amino acid sequence of SEQ ID NO: 2. Peptide (A) can be one kind or two or more kinds among peptides consisting of amino acid sequences of SEQ ID NOs: 1 and 3 to 12. Peptide (A) can consist of the amino acid sequence of SEQ ID NO: 1. The peptide can be a bivalent peptide containing two identical peptides among the peptides (A) and (B). The peptide can be a tetravalent peptide containing four identical peptides among the peptides (A) and (B). The claims are directed to a disease therapeutic agent, comprising the S100A8-inhibiting peptide according to claim1.
The disease therapeutic can be one kind or two or more kinds among metastatic cancer, psychiatric diseases, lifestyle diseases, rheumatoid arthritis, COVID-19, Crohn's disease, ulcerative colitis, cystic fibrosis, and allergic dermatitis.
The A0A5K1BRW9 reference teaches a polypeptide with the sequence DSAILVINKPPGMPVQ (see e.g. entire reference). The amino acid sequence of instant SEQ ID NO:9, which comprises the fifth alanine of instant SEQ ID NO:1, is underlined and shown in bold. The peptide possessed the required structure, and therefore would inherently possess the required functions of inhibiting S100A8 and disease therapeutic activity. Instant claims 6 and 7 do not recite additional limitations in the disease therapeutic, therefore the structure of the peptide of claim 1 meets the limitations for claims 6 and 7.
Claim(s) 1-2 and 6-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Palefsky (US 2007/0123455 A1; filed 4/2/04; published 5/31/07).
The instant claims are directed to an S100A8-inhibiting peptide comprising: (A) a peptide of 5 to 10 residues in length containing a fifth alanine (Ala) from an N-terminus in an amino acid sequence of SEQ ID NO: 1, or (B) a peptide consisting of an amino acid sequence of SEQ ID NO: 2. Peptide (A) can be one kind or two or more kinds among peptides consisting of amino acid sequences of SEQ ID NOs: 1 and 3 to 12. Peptide (A) can consist of the amino acid sequence of SEQ ID NO: 1. The peptide can be a bivalent peptide containing two identical peptides among the peptides (A) and (B). The peptide can be a tetravalent peptide containing four identical peptides among the peptides (A) and (B). The claims are directed to a disease therapeutic agent, comprising the S100A8-inhibiting peptide according to claim1.
The disease therapeutic can be one kind or two or more kinds among metastatic cancer, psychiatric diseases, lifestyle diseases, rheumatoid arthritis, COVID-19, Crohn's disease, ulcerative colitis, cystic fibrosis, and allergic dermatitis.
Palefsky teaches compositions comprising human mutant S100A8, wherein the protein comprises at least one mutation inhibiting posttranslational modification of the protein (see e.g. paragraph [0010]). The protein can be the ALAS42100A8 mutant, which is contemplated to act as an inhibitor of the wildtype S100A9 and S100A8/A9-induced growth of Pseudomonas (see e.g. paragraph [0132]). The protein can have at least 70% sequence identity to SEQ ID NO:2 (see e.g. claim 16; reference SEQ ID NO:2 shown below). The sequence of instant SEQ ID NO: 2 is underlined in the sequence below. The protein can be used to treat inflammatory disorders such as allergy, asthma, autoimmune disease and others disorders (see e.g. paragraph [0003], claims 7-8), and cystic fibrosis (see e.g. paragraph [0133], and claims 7-8).
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Conclusion
No claims are allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
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