DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This is the first action on the merits.
Claims 1-4, 6, 8, 12, 16-22, 24-27, 29 and 30 are pending and under consideration.
Claim Objections
Claim 25 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
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 22, 24 and 27 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 pre-AIA the applicant regards as the invention.
With regards to claims 22, 24 and 29, the phrase “for use in therapy or in the treatment or prevention of a disease or condition that is caused by an abnormal functioning of a kinase” is vague. The “for use in therapy” is not further limiting of claim 20. The “treatment or prevention of a disease or condition that is caused by an abnormal functioning of a kinase” is indefinite. The specification on pages 2 and 17, use open language, e.g. such as or include but are not limited to. There is no standard list of diseases or conditions that is caused by an abnormal functioning of a kinase or more specifically JAK. Moreover, this language covers both increases and decreases in activity.
Applicant may amend the claim by adding the limitation from claim 25 to overcome the rejection.
In claim 27, the phrase “wherein the disease or condition that is caused by an abnormal functioning of Janus kinase” lacks antecedent basis.
Applicant may amend the claim to the term “kinase” from “Janus kinase” to overcome the rejection.
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 29 and 30 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The instant specification does not adequately describe the nexus between the treatment or prevention of a disease or condition that is caused by an abnormal functioning of a kinase. The phrase “abnormal functioning" refers to the ability of a compound to increase or decrease the function, or activity of, for example, a kinase. "Abnormal functioning", in its various forms, is intended to encompass increase and decreases by the inhibition, antagonism, partial antagonism, activation, agonism and/or partial agonism of the activity associated with a kinase. Kinase inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction. Kinase activators are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, sensitize or up regulate signal transduction. These modulations are sometimes opposite reactions to the same receptor. It is not seen where the instant specification adequately describes the nexus between the modulation of the glucocorticoid receptor and a useful treatment of a single disease or condition. The ability of a compound to modulate kinase can be demonstrated in an enzymatic assay or a cell-based assay.
Thus, claims 29 and 30 lack written description.
Claims 29 and 30 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 the treatment or prevention of transplant rejection, does not reasonably provide enablement for the treatment or prevention of proliferative disease, a disease involving impairment of cartilage turnover, a disease involving the anabolic stimulation of chondrocytes, an autoimmune disease, congenital cartilage malformation(s), an inflammatory condition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The treatment or prevention of proliferative disease, a disease involving impairment of cartilage turnover, a disease involving the anabolic stimulation of chondrocytes, an autoimmune disease, congenital cartilage malformation(s), and an inflammatory condition generally cannot possibly be considered enabled.
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.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(A) Breadth of claims.
(a) Scope of the compounds. The instant claims encompass hundreds of compounds with a tricyclic imidazo-pyrrolo-pyridine scaffold with a variety of substituents at two different positions.
(b) Scope of the diseases covered. The full scope is not known, see the 112b rejection above. However, several of the umbrella terms found in claim 30 will be elaborated.
Proliferative diseases embrace cancer. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. Here are some assorted categories:
A. CNS cancers cover a very diverse range of cancers in many categories and subcategories. There are an immense range of neuroepithelial tumors. Gliomas, the most common subtype of primary brain tumors, most of which are aggressive, highly invasive, and neurologically destructive tumors are considered to be among the deadliest of human cancers. These are any cancers which show evidence (histological, immunohistochemical, ultrastructural) of glial differentiation. These fall mostly into five categories. There are the astrocytic tumors (astrocytomas): pilocytic astrocytoma (including juvenile pilocytic astrocytoma, JPA, and pediatric optic nerve glioma) diffuse astrocytomas (including fibrillary astrocytomas, protoplasmic astrocytomas and gemistocytic astrocytomas), anaplastic astrocytomas (including adult optic nerve glioma), Glioblastoma multiforme (GBM), gliosarcoma and giant cell glioblastoma, and pleomorphic xanthoastrocytoma. GBM exists in two forms, primary and secondary, which have very different clinical histories and different genetics, but GBM is considered to be one clinical entity. second, there are the oligodendroglial tumors (oligodendrogliomas): low grade oligodendroglioma and anaplastic oligodendroglioma. Third, there is oligoastrocytomas (“mixed glioma”), a type of tumor with both astrocytoma & oligodendroglioma features. The fourth type is the ependymomas, which are intracranial gliomas, including papillary ependymoma, myxopapillary ependymoma, tanycytic ependymoma, anaplastic ependymoma and subependymal giant-cell astrocytomas. A fifth type is the gangliogliomas (glioneuronal tumors or glioneurocytic tumors), which have both glial and neuronal components, and are extremely varied, based in part on what types of glial and what types of neuronal components are present. These include Papillary Glioneuronal Tumor (PGNT), a range of supratentorial gangliogliomas, assorted intramedullary spinal cord gangliogliomas, pineal ganglioglioma, hypothalamic ganglioglioma, cerebellar ganglioglioma, ganglioglioma of the right optic tract, rosetted glioneuronal tumor (“glioneurocytic tumor with neuropil rosettes”), composite pleomorphic xanthoastrocytoma (PXA)-ganglioglioma, desmoplastic ganglioglioma (both infantile (DIG) and non- infantile), angioganglioglioma, and others. There are also some glial tumors which do not comfortably fit into these five categories, notably astroblastoma, gliomatosis cerebri, and chordoid glioma, which is found solely in the hypothalamus and anterior third ventricle. Other neuroepithelial tumors include astrocytic tumors (e.g. astrocytomas) oligodendroglial tumors, ependymal cell tumors (e.g. myxopapillary ependymoma), mixed gliomas (e.g. mixed oligoastrocytoma and ependymo-astrocytomas) tumors of the choroid plexus(choroid plexus papilloma, choroid plexus carcinoma), assorted neuronal and neuroblastic tumors (e.g. gangliocytoma, central neurocytoma, dysembryoplastic neuroepithelial tumor, esthesioneuroblastoma, olfactory neuroblastoma, olfactory neuroepithelioma, and neuroblastomas of the adrenal gland), pineal parenchyma tumors (e.g. pineocytoma, pineoblastoma, and pineal parenchymal tumor of intermediate differentiation), embryonal tumors (e.g. medulloepithelioma, neuroblastoma, ependymoblastoma, atypical teratoid/rhabdoid tumor, desmoplastic medulloblastoma, large cell medulloblastoma, medullomyoblastoma, and melanotic medulloblastoma) and others such as polar spongioblastoma and gliomatosis cerebri. A second Division is tumors of the meninges. this includes tumors of the meningothelial cells, including meningiomas (meningothelial, fibrous (fibroblastic), transitional (mixed), psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich, metaplastic, clear cell, chordoid, atypical, papillary, rhabdoid, anaplastic meningioma) and the non- meningioma tumors of the meningothelial cells (malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma, epithelioid haemangioendothelioma, haemangiopericytoma, angiosarcoma, kaposi sarcoma). There are also mesenchymal, non-meningothelial tumors (liposarcoma, (intracranial) solitary fibrous tumor, and fibrosarcoma) as well as primary melanocytic lesions (diffuse melanocytosis, melanocytoma, malignant melanoma, and meningeal melanomatosis). A third division are the tumors of cranial and spinal nerves. This includes cellular schwannomas, plexiform schwannomas and the melanotic schwannomas (e.g. psammomatous melanotic schwannoma, neuro-axial melanotic schwannoma, dorsal dumb-bell melanotic schwannoma). There is also Perineurioma (Intraneural and Soft tissue) and malignant peripheral nerve sheath tumor (MPNST), including Epithelioid, MPNST with divergent mesenchymal differentiation, and MPNST with epithelial differentiation. A fourth division are germ cell tumors, including germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma (mature teratoma, immature teratoma, and teratoma with malignant transformation). A fifth division are the tumors of the sellar Region, viz. pituitary adenoma, pituitary carcinoma, granular cell myoblastoma and craniopharyngiomas (adamantinomatous and papillary). Yet another division are local extensions from regional tumors, including paraganglioma, chodroma, chordoma, and chondrosarcoma. There are also Primitive Neuroectodermal Tumors (PNETs) including medulloblastomas, medulloepitheliomas, ependymoblastomas and polar spongioblastomas. There are Vascular brain Tumors e.g. the hemangioblastomas, there is CNS Lymphoma (which can be primary or secondary) and Meningeal Carcinomatosis. There are lymphoma and haemopoietic neoplasms including malignant lymphomas (which can be primary or secondary), plasmacytoma, and granulocytic sarcoma. And there are many, many others.
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.
These are just two categories of cancer which were elaborated. Others are:
C. Carcinomas of the Liver,
D. Lung and pleural cancer,
E. Thyroid cancer,
F. Cancer of the skin cells,
G. Colorectal cancers,
H. Renal carcinomas,
I. Prostate Cancer,
J. Penile carcinoma,
K. The carcinomas of the extrahepatic bile ducts,
L. Breast cancers,
M. Ovarian cancers,
N. Testicular cancers,
O. Paratesticular cancers,
P. Cancers of the vulva,
Q. Vaginal cancers,
R. Uterus cancers,
S. Stomach cancers,
T. Cancers of the esophagus,
U. Cancers of the spleen,
V. Salivary gland carcinomas,
W. Cancers of the heart,
X. Odontogenic tumors,
Y. Cancers of the oral cavity and oropharynx,
Z. Cancers of the lymph glands,
AA. Cancers of the adrenal glands,
AB. Cancers of the eye,
AC. Cervical cancers,
AD. Gestational Trophoblastic Neoplasias (cancer of the placenta),
AE. Cancers of the throat,
AF. Cancers of the thymus,
AG. Fallopian Tube Cancer,
AH. Bladder cancers, and
AI. Cancers of the gallbladders.
Other proliferative disorders precancerous conditions such as lumps, lesions, and polyps. In addition, it embraces various non-cancerous proliferative disorders such as certain types of restenosis, vascular smooth muscle proliferation associated with atherosclerosis, glomerular nephritis, pulmonary fibrosis, clonal proliferative disorders including the various Myelodysplastic Syndromes (the assorted Refractory Anemias, Ph-Chromosome-Negative Chronic Myelocytic Leukemia, Chronic Myelomonocytic Leukemia and Agnogenic Myeloid Metaplasia) and the Myeloproliferative Disorders (Chronic myelogenous leukaemia, which exists in adult and juvenile forms; Polycythemia vera;. Agnogenic myeloid metaplasia and Essential thrombocythemia). It includes certain types of abnormal wound healings. It covers numerous types of abnormal angiogenisis e.g. in certain eye diseases (such as neovascular glaucoma, diabetic retinopathy, retinopathy of prematurity, retrolental fibroplasias, and age-related and certain other types of macular degeneration), Rosacea, some neurodegenerations, respiratory distress in the premature infant, some problems in embryonic development, and atherosclerosis. It includes the myeloproliferative disorders (such as primary polycythemia, primary (essential) thrombocythemia, chronic myelogenous leukemia and myleofibrosis). Also included are numerous Plasma cell dyscrasias, such as Multiple myeloma, Smouldering Myeloma, monoclonal gammopathy of unknown significance (MGUS), solitary plasmacytoma of bone (SPB), asymptomatic myeloma, Waldenström's macroglobulinemia, Solitary extramedullary plasmacytoma, Primary Amyloidosis, POEMS syndrome, and the three heavy-chain diseases). It also includes an assortment of skin disorders, such as psoriasis, atopic dermatitis, allergic contact dermatitis, epidermolytic hyperkeratosis, palmoplantar Pustulosis, lichenified eczema, seborrhoeic dermatitis and the keratinization disorders (including assorted ichthyoses, keratosis pilaris, keratosis follicularis, tylosis, “knuckle pads”, corns, assorted callosities, and numerous keratinization disorders found in dogs and cats). Also included are LAM (Lymphangioleiomyomatosis, a smooth muscle proliferative disorder of the lungs) rheumatoid arthritis and even Alzheimer's Disease. Indeed, almost anything that the body grows --- skin, blood cells, nerves, plasma, muscles, the vascular network, can grow too fast, or in a manner too undifferentiated.
Known autoimmune disorders, or disorders generally considered to be autoimmune include Polymyositis, Scleroderma, Osteosclerosis, Meniere's disease, Idiopathic neutropenia, Idiopathic thrombocytopenic purpura, Autoimmune hemolytic anemia, Premature ovarian failure, Idiopathic hypoparathyroidism, primary biliary cirrhosis, Pemphigus, multiple sclerosis, autoimmune uveitis, rheumatoid arthritis, Addison's disease, thyroiditis, atrophic gastritis, myasthenia gravis, idiopathic thrombocytopenic purpura, hemolytic anemia, systemic lupus erythematosus, Wegener's granulomatosis, polyarteritisnodosa, erythema nodosum leprosum, Guillain-Barré syndrome (GBS), allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss (IPBSNHL), aplastic anemia, pure red cell anemia, polychondritis, scleroderma, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Crohn's disease, Graves ophthalmopathy, sarcoidosis, primary biliary cirrhosis, type I diabetes, autoimmune optic neuritis, uveitis posterior, or interstitial lung fibrosis, alopecia, Sjogren's Syndrome, Goodpasture Syndrome, inflammatory bowel disease, Essential Mixed Cryoglobulinemia, Behçet's Syndrome, Chronic Inflammatory Polyneuritis (CIPD), CREST Syndrome, Antiphospholipid Syndrome, Relapsing Polychondritis (systemic chondromalacia or von Meyenburg disease), Retroperitoneal Fibrosis, immune dysregulation, polyendocrinopathy, enteropathy, autoimmune hepatitis, Coeliac disease, Hashimoto's Disease, opsoclonus myoclonus syndrome (OMS), psoriasis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, X-linked syndrome (IPEX), Autoimmune Atherosclerosis and many more.
This list is not exhaustive for the scope.
(B) The nature of the invention and predictability in the art: With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] …anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”. More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
(C) Direction or Guidance: That provided is very limited. The dosage range information, found on page 19 of the Specification gives 1 to 50 mg/kg. This is generic, the same for the many disorders covered by the specification. Thus, there is no specific direction or guidance regarding a regimen or dosage effective specifically for any and all proliferative diseases, diseases involving impairment of cartilage turnover, diseases involving the anabolic stimulation of chondrocytes, autoimmune diseases, congenital cartilage malformation(s), and inflammatory conditions generally.
(D) State of the Prior Art: The claimed compounds are substituted tricyclic imidazo-pyrrolo-pyridine compounds. So far as the examiner is aware substituted tricyclic imidazo-pyrrolo-pyridine compounds have not been successfully used to treat or prevent a proliferative disease, a disease involving impairment of cartilage turnover, a disease involving the anabolic stimulation of chondrocytes, an autoimmune disease, congenital cartilage malformation(s), and an inflammatory condition generally.
The prior art has established that there is no common mechanism by which all, or even most, inflammations arise. Mediators include bradykinin, serotonin, histamine, fibrin, PDE-IV, kallikrein, plasmin, thrombin, PAF, Mac-1, VLA-4, VLA-5, VLA-6, VCAM-1, LFA-1, ICAM-1, Prostaglandins and cyclic endoperoxides (particularly prostacycline, prostaglandin E2, and thromboxane A2), leukotrienes (especially LTB4, LTC4, LTD4, and LTE4) and cytokines, and many, others. Examples of pro-inflammatory cytokines include IL-1I, IL-1J, IL-6, IL-8, IL-18, MIP-1a, IFN-K and TNF-I. The Complement Pathway, which exists in two separate branches, uses C1, C4a, C4b, C2, C3a, C3b, C5a, C5b, C6, C7, C8 and C9, as well as the membrane attack complex (MAC) and other complexes, C3 and C5 convertase enzymes, Magnesium ions, and Factors B, D, F, H, etc.
The prior art knows that mediation of inflammation is among the most pervasive and complex of all body process. There are complex interactions among just the cytokines, and just in certain types of inflammatory responses. As a second example, the Hageman factor is a protein that initiates three different processes: a) the intrinsic clotting process, which operates via thrombin and fibrin, b) the fibrinolytic system which produces fibrinolysis via plasmin and 3) the kallikrein/kinin cascade, which produces the kinins, e.g. bradykinin. Further, Plasmin can also activate C3 and C5 in the complement cascade (an entirely separate set of vascular events) producing C3a and C5a, respectively, as can thrombin.
Further, the prior art knows that there are many paradoxical features in the inflammation system. As an example, in lung inflammation, nitric oxide appears to be a pro-inflammatory mediator in acute situations e.g. ARDS but anti-inflammatory in more stable situations. As a second example, the cytokine TGF-beta-1 possesses both pro-inflammatory and anti-inflammatory activities. Virtually all cells have TGF-beta-1 receptors, and the cytokine has many other roles other than in inflammation. As a third example, CRF appears to have both pro-inflammatory and anti-inflammatory activities.
Thus, the prior art knows that, treatments for inflammation are normally tailored to the particular type of inflammation present, as there is no, and there can be no "magic bullet" against inflammation generally.
(E) Working Examples: The invention is drawn to a method of treating or preventing a proliferative disease, a disease involving impairment of cartilage turnover, a disease involving the anabolic stimulation of chondrocytes, an autoimmune disease, congenital cartilage malformation(s), and an inflammatory condition generally. There are no in vivo working examples in the Specification drawn to this utility to support the use of compounds of formula (I) to treat any and all proliferative diseases, diseases involving impairment of cartilage turnover, diseases involving the anabolic stimulation of chondrocytes, autoimmune diseases, congenital cartilage malformation(s), and inflammatory conditions generally. On pages 19-20 of the specification, there is one in vitro inhibition assay presented, which provides data for JAK 1, 2 and 3.
(F) Skill of those in the art: Taken as a whole, the skill level in oncology must be considered as low. Many mechanisms have been proposed over the decades as methods of treating the assorted cancers generally. Cytotoxic agents could be applied directly to the tumors cells, directly killing them. Immunotherapy involves stimulating the patient's immune system to attack the cancer cells, either by immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets, or by the administration of therapeutic antibodies as drugs, so the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Another approach would be to increase the amount or activity of the body’s tumor suppressor genes, e.g. p53, PTEN, APC and CD95, which can for example activate DNA repair proteins, suppress the Akt/PKB signaling pathway, or initiate apoptosis of cancer cells. The angiogenesis inhibitor strategy was based on cutting off the blood supply that growing tumors need by shutting off the growth of new blood vessels by, for example, suppressing proliferation of endothelial cells or inducing apoptosis of endothelial cells. There is also the cancer stem cell paradigm, which hypothesizes that cancer could be treated generally, either by targeting the cancer stem cells themselves, or by targeting the epithelial-to-mesenchymal transition which supposedly generates the cancer stem cells. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come anywhere near such a goal.
Specifically, the prior art knows that there never has been a compound capable of treating cancers generally. “The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally.” (<http://www.uspto.gov/web/offices/pac/dapp/1pecba.htm#7> ENABLEMENT DECISION TREE, Example F, situation 1). A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. This is because it is now understood that there is no “master switch” for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body's cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environment factors.
Accordingly, there is substantive “reason for one skilled in the art to question the objective truth of the statement of utility or its scope” (In re Langer, 183 USPQ 288, 297). Similarly, In re Novak, 134 USPQ 335, 337-338, says “unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them.” There is no such evidence in this case. Likewise, In re Cortright, 49 USPQ2d 1464, states: “Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient” does what the specification surmises that it does. That is exactly the case here. Even if applicants’ assertion that cancer in general could be treated with these compounds were plausible--- which it is not ---, that would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success.”
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
One skilled in the art knows that chemotherapy of brain tumors is especially difficult. This is because 1) the blood-brain barrier, which is often intact in parts or all of a brain tumor, will block out many drugs, as it is the purpose of the blood-brain barrier to protect the brain from alien chemicals, and 2) CNS tumors are characterized by marked heterogeneity, which greatly decreases vulnerability to chemotherapy. As a result, many categories of CNS tumors simply have no chemotherapy available. These include, generally, hemangioblastomas, meningiomas, craniopharyngiomas, acoustic neuromas, pituitary adenomas, optic nerve gliomas, glomus jugulare tumors and chordomas, to name just some. With regard to gliomas, GBM is considered untreatable; no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is radiation and surgery which are used for low grade gliomas (e.g. pilocytic astrocytoma and diffuse astrocytomas), as no drug has been found effective. There is no drug treatment established as effective for optic nerve gliomas or gangliogliomas. Indeed, very few gliomas of any type are treated with pharmaceuticals; it is one of the categories of cancer that is the least responsive to drugs.
Cartilage tumors do not respond to chemotherapy, nor, generally, do cancerous teratomas. Of the thyroid cancers, only one (anaplastic thyroid cancer) can be treated with anticancer agents. The others are treated with radioactivity, surgery, or thyroid suppression hormones. Lymphomas of the stomach are not commonly treated with anti-cancer agents per se, but instead, surgery or radiation and antibiotic therapy (e.g. amoxicillin, metronidazole, bismuth, omeprazole) are the primary treatments. Neuroendocrine tumors of the cervix generally do not respond to chemotherapy. A number of sarcomas, including alveolar soft part sarcoma (ASPS), retroperitoneal sarcoma, most liposarcomas, and the assorted chondrosarcomas, are generally considered not to respond to chemotherapy; no chemotherapeutic agent has been established as effective. Aggressive NK cell leukemia is considered to be untreatable with pharmaceuticals. Myxoma of the heart (atrial myxoma) is the most common primary cardiac tumor and has no chemotherapy; excision is the only treatment. Chemotherapy of spleen tumors is rarely even attempted, and no drug has been established as effective for any primary or secondary splenic tumor types. Many cerebral metastases, such as those from non-small-cell lung cancer and melanoma, are not chemosensitive and will not respond to chemotherapy. Hepatocellular Carcinoma (HCC or hepatoma) is, in humans, possibly the most prevalent solid tumor and in certain parts of the world is the most common cancer; it has long been understood as a chemotherapy-resistant tumor, with only very recently, some success seen with the Tyrosine protein kinase inhibitor Sorafenib. Metastatic esophageal cancer, and malignant melanoma of the esophagus do not respond to chemotherapy.
It is important to note that tumors can need to be treated quite differently even though they are tumors of the same organ. For example, the drugs used most often to treat Wilms tumor, the most common malignant tumor of the kidneys in children, are actinomycin D and vincristine. Such drugs are never used with clear cell renal carcinoma, which is treated, although without much success, with Immunotherapy using the cytokines interleukin-2 and interferon-alpha. However, such immunotherapy has never been established as effective in non-clear cell RCC forms such as papillary renal cell carcinoma. Despite strenuous efforts over a period of decades, no chemotherapeutic agent has ever been found effective against this cancer. Cancers of the stomach can be lymphomas, GISTs, carcinoid tumors, carcinomas, or soft tissue sarcomas, and for a single agent to be effective against all or even most of these categories would be contrary to what is known in oncology.
So far as the examiner is aware, said compound has not been shown to treating any and all the diseases encompassed by the scope of diseases mentioned above. Furthermore, despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of autoimmune or inflammatory diseases generally. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609.
(G) The quantity of experimentation needed: Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, and especially in view of factors A and D and F, the quantity of experimentation needed is expected to be great.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SUSANNA MOORE/Primary Examiner, Art Unit 1624