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 .
Status of Claims
Claims 1-5 and 12-20 are pending.
Priority
The instant application claims priority as follows:
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Information Disclosure Statement
All references from the IDS(s) received 06/03/2024 have been considered unless marked with a strikethrough.
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.
Claims 4, 5, 12-14 and 16-20 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 treating depression, anxiety, multiple sclerosis, NASH, scleroderma, ADHD, Alzheimer's and Parkinsons, does not reasonably provide enablement for the treatment of cancer; the treatment of generic cancer generally cannot be considered enabled.
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.
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 two specific compounds which are analogues of istradefylline and pharmaceutical salts thereof.
(b) Scope of the diseases covered. The claims are drawn, in part, to the treatment of cancer.
Cancer is not a single disease. Rather, “‘Cancer’ is a catch-all term used to denote a set of diseases characterized by autonomous expansion and spread of a somatic clone. To achieve this behaviour, the cancer clone must co-opt multiple cellular pathways that enable it to disregard the normal constraints on cell growth, modify the local microenvironment to favour its own proliferation, invade through tissue barriers, spread to other organs and evade immune surveillance. No single cellular program directs these behaviours. Rather, there is a large pool of potential pathogenic abnormalities from which individual cancers draw their own combinations: the commonalities of macroscopic features across tumours belie a vastly heterogeneous landscape of cellular abnormalities.” See Aaltonen et al. (Nature 578, 82-93 (2020)) at page 82. Not even breast cancer is not a single disease. Rather “Breast cancer is a heterogeneous disease and differs greatly among different patients (intertumor heterogeneity) and even within each individual tumor (intratumor heterogeneity).” See Turashvili et al. (Front. Med. 4:227, pp 1-11) at page 1.
Some assorted categories of cancer are as follows:
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.
Others are categories of cancer include:
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 gallbladder.
(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 at Paragraph [0094] of the specification recites a dosage from about 0.01 to about 100 mg/kg of body weight per day, which 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 disease or conditions embraced by the scope.
(D) State of the Prior Art
The claimed compounds are fluoro- and thio-analogues of istradefylline. So far as the examiner is aware substituted fluoro- and thio-analogues of istradefylline have not been successfully used as anticancer agents, generally.
Kase et al. (US 7727993) teach istradefylline is an adenosine A2A receptor antagonist reduces or suppresses side effects of Parkinson’s Disease therapy, see title.
(E) Working Examples
The specification provide no working examples of treating cancer.
(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 tumor 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. “remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally.” (<https://www.uspto.gov/patents/laws/patent-examination-policy-mpep-staff-35-usc-112-1st-para-enablement#7f> 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 other 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.
(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.
Conclusion of non-enablement
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The framework for the objective analysis for determining obviousness under 35 U.S.C. 103 is stated in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Obviousness is a question of law based on underlying factual inquiries. The factual inquiries enunciated by the Supreme Court in Graham are summarized as follows:
(A) Determining the scope and content of the prior art;
(B) Ascertaining the differences between the claimed invention and the prior art; and
(C) Resolving the level of ordinary skill in the pertinent art.
Objective evidence relevant to the issue of obviousness must be evaluated by Office personnel. Id. at 17-18, 148 USPQ at 467. The evidence may be included in the specification as filed, accompany the application on filing, or be provided in a timely manner at some other point during the prosecution. The weight to be given any objective evidence is determined on a case-by-case basis. The mere fact that an applicant has presented evidence does not mean that the evidence is dispositive of the issue of obviousness.
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation (TSM) in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Rejections under 35 USC § 103
Claims 1-3, 5, 12-15 and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Nagayama et al. (Journal of the Neurological Sciences 396 (2019) 78–83) in view of Kase et al. (US-7727993-B2; issued 01 Jun 2010), Shah et al. (Journal of Enzyme Inhibition and Medicinal Chemistry, 2007, 22(5), 527-540), and Patani et al. (Chem. Rev., 1996, pp. 3147-3176).
Nagayama et al. teach that administering istradefylline to patients having Parkinson’s Disease is effective for the treatment of mood disorders, including depression, independent of improvement of motor symptoms. See Nagayama et al. at page 82, column 2.
Kase et al. teach administering istradefylline for treating Parkinson’s Disease in combination with L-DOPA. See Example 1-5, stating at column 36. Kase et al. teach the structure of istradefylline (identified as KW-6002) is as follows:
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See Kase et al. at column 31, lines 50-67.
The present application claims the following compound in claim 1:
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The present application claims the following compound in claim 2:
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The only difference between the claimed species and istradefylline is that claimed invention substitutes an F for an H on the methoxy of the phenyl ring.
Patani teaches that F is a classical bioisostere of H. See page 3149. Patani also teaches that “[t]he ability of a group of bioisosteres to elicit similar biological activity has been attributed to common physicochemical properties.” See page 3148, first full paragraph. Patani further teaches that “[b]ioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinical effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive.” See page 3147. Patani acknowledges that “[t]he substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements.” See page 3149. Patani goes on to teach that “the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained,” see page 3150. The reference further states that “[t]he pharmacological differences can be attributed to the influence of the electron-withdrawing effect that the fluorine substitution causes on interaction with either a biological receptor or enzyme, as well as its effect on the metabolic fate of the drug.” See page 3149, right-hand column, fourth full paragraph.
Shah et al. teach that “Fluorine substitution has been extensively investigated in drug research as a means of enhancing biological activity and increasing chemical or metabolic stability,” see page 527, right-hand column. Shah et al. further teaches that “The main rationale for introducing fluorine into compounds is either to improve the metabolic stability, alter the physicochemical properties or improve the binding affinity of these compounds.,” see page 537. Shah acknowledges that “[m]etabolic stability can determine the bioavailability of compounds and substitution with fluorine at the site of metabolic attack can prevent oxidative metabolism based on the fact that the C–F bond is more resistant to attack than the C–H bond. Also, substitution at adjacent or distal sites to the site of metabolic attack can also affect drug metabolism due to inductive/resonance effects or conformational and electrostatic effects.” See page 528, left-hand column. Therefore, the bioisosteric substitution of H for F is well-known in the art of medicinal chemistry as a means of enhancing biological activity and increasing chemical or metabolic stability.
“Structural similarity, alone, may be sufficient to give rise to an expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313 (CCPA 1979).
Therefore, the instant invention is prima facie obvious from the teachings of the prior art. One of ordinary skill in the art would have known to replace H with F and claim bioisosteric equivalents of prior art compounds at the time the invention was filed. The motivation would be to produce bioisosteric equivalents would have similar biological properties, and that H and F are art recognized equivalents.
“When a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” United States v. Adams, 383 U.S. 49, 50-51 (1966). Cited in KSR Int. Co. v. Teleflex Inc, 127 S.Ct 1727, 550 U.S. 398, 82 USPQ2d 1385 (2007). The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR, supra.
Therefore, claims 1-3, 5, 12-15 and 17-20 are rendered obvious over Nagayama et al. in view of Kase et al., Shah et al. and Patani et al.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US Patent No. 12,570,656
Claims 1-3, 5, 12-15 and 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,570,656 (reference patent) in view of Shah et al. (Journal of Enzyme Inhibition and Medicinal Chemistry, 2007, 22(5), 527-540) and Patani et al. (Chem. Rev., 1996, pp. 3147-3176).
The reference patent claims a compound having the following structure:
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The present application claims the following compound in claim 1:
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The present application claims the following compound in claim 2:
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The only difference between the claimed species of the instant application and compared to the species of the reference patent is that the reference patent has a fluorine atom on each of the methoxy groups whereas the instant application claims species having a fluorine atom on only one of the methoxy groups. The reference patent includes claims methods of treating depression using structurally obvious compound.
Patani teaches that F is a classical bioisostere of H. See page 3149. Patani also teaches that “[t]he ability of a group of bioisosteres to elicit similar biological activity has been attributed to common physicochemical properties.” See page 3148, first full paragraph. Patani further teaches that “[b]ioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinical effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive.” See page 3147. Patani acknowledges that “[t]he substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements.” See page 3149. Patani goes on to teach that “the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained,” see page 3150. The reference further states that “[t]he pharmacological differences can be attributed to the influence of the electron-withdrawing effect that the fluorine substitution causes on interaction with either a biological receptor or enzyme, as well as its effect on the metabolic fate of the drug.” See page 3149, right-hand column, fourth full paragraph.
Shah et al. teach that “Fluorine substitution has been extensively investigated in drug research as a means of enhancing biological activity and increasing chemical or metabolic stability,” see page 527, right-hand column. Shah et al. further teaches that “The main rationale for introducing fluorine into compounds is either to improve the metabolic stability, alter the physicochemical properties or improve the binding affinity of these compounds.,” see page 537. Shah acknowledges that “[m]etabolic stability can determine the bioavailability of compounds and substitution with fluorine at the site of metabolic attack can prevent oxidative metabolism based on the fact that the C–F bond is more resistant to attack than the C–H bond. Also, substitution at adjacent or distal sites to the site of metabolic attack can also affect drug metabolism due to inductive/resonance effects or conformational and electrostatic effects.” See page 528, left-hand column. Therefore, the bioisosteric substitution of H for F is well-known in the art of medicinal chemistry as a means of enhancing biological activity and increasing chemical or metabolic stability.
“Structural similarity, alone, may be sufficient to give rise to an expectation that compounds similar in structure will have similar properties.” In re Payne, 606 F.2d 303, 313 (CCPA 1979).
Therefore, the instant invention is prima facie obvious from the teachings of the prior art. One of ordinary skill in the art would have known to replace H with F and claim bioisosteric equivalents of prior art compounds at the time the invention was filed. The motivation would be to produce bioisosteric equivalents would have similar biological properties, and that H and F are art recognized equivalents.
“When a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” United States v. Adams, 383 U.S. 49, 50-51 (1966). Cited in KSR Int. Co. v. Teleflex Inc, 127 S.Ct 1727, 550 U.S. 398, 82 USPQ2d 1385 (2007). The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR, supra.
Therefore, claims 1-3, 5, 12-15 and 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,570,656 in view of Shah et al. and Patani et al. (Chem. Rev., 1996, pp. 3147-3176).
Conclusion
No claim is currently allowable.
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/BSM/Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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