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 1-9 and 12-16 are pending and under consideration.
Specification
The abstract of the disclosure is objected to because of the proper content of an abstract of the disclosure. In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral antidiabetics.” Exemplification of a species could be illustrative of members of the class. For processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary.
Correction is required. See MPEP § 608.01(b).
The objection may be obviated by adding the formula of the compound at the end of the abstract.
Claim Objections
Claim 15 is objected to because of the following informalities: the term “comprisinges” is misspelled. Appropriate correction is required.
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 5-8, 12, 15 and 16 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.
Regarding claims 5 and 7, the term “about” is vague. The specification does not provide guidance with regards to the standard error for the result.
With regards to claims 6 and 8, the phrase, “substantially the same” is also vague. Terms of degree, such as “substantially” or “relatively” are indefinite when the specification contains no “explicit guidelines” to distinguish from things which are not so, Ex parte Oetiker, 23 USPQ2d 1651, 1655 (1990) and Ex parte Oetiker, 23 USPQ2d 1641, and Seattle Box Co. v. Industrial Crating & Packaging, Inc. 221 USPQ 568, 574.
In claim 12, the phrase "a disorder ameliorated by an AKR1C3 dependent KARS inhibitor” is indefinite. There is no standard list of diseases which are ameliorated by an AKR1C3 dependent KARS inhibitor. The specification on page 20, third and fourth paragraph, and page 3, second full paragraph, uses open language, "e.g. cancer" and “include… such as.” What other diseases are contemplated? It is unclear what diseases and treatments Applicant is intending to encompass. Thus, claim 12 is rejected under 112(b).
In claims 15 and 16, the phrase, “the formed solid” lacks antecedent basis.
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.
Claim 3 is 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 following claims fail to meet the written description requirement with regards to identifying the specific crystalline form of pemetrexed.
The x-ray pattern of a pure crystalline substance can be used to identify compounds because the diffraction pattern is considered to be a "fingerprint" of a compound. The d value for the most intense line is found and compared, followed by the next two intense lines, and so on.
Identification of crystal structures is taught by Bhattacharya et al. (Brittain, ed. Polymorphism in Pharmaceutical Solids, 2009, page 334). As noted in the fourth full paragraph, "it is usually convenient to identify the angles of the 10 most intense scattering peaks in a powder pattern" or the last paragraph which states 5 characteristic XRD (x-ray diffraction) scattering peaks of sodium ibandronate was sufficient to determine the difference in the two polymorphic forms.
Thus, less than five peaks cannot be used to identify an unknown compound, and, claim 3 is rejected under lack of written description.
Claims 12 and 13 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 method of treating non-small cell lung cancer, does not reasonably provide enablement for a method of treating liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, stomach, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T- ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). 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 encompass a crystalline form of the compound 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'- dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.
(b) Scope of the diseases covered. The full scope is not known, see the 112(b) rejection above.
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:
Liver Carcinomas include hepatocellular carcinoma, combined hepatocellular cholangiocarcinoma, cholangiocarcinoma (intrahepatic), bile duct cystadenocarcinoma and undifferentiated liver carcinoma. There is also cancer of blood vessels in the liver (hemangioendothelioma), primary non-hodgkin's lymphoma of the liver, undifferentiated liver sarcoma (also known as undifferentiated embryonal sarcoma), primary pleomorphic liver sarcoma, angiosarcoma of the liver, and primary malignant melanoma of the liver. Most liver cancers are secondary, especially those originating in the breast, lung, or gallbladder, as well as both Hodgkin's or non-Hodgkin's lymphoma.
The most important of uterus cancers is 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 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. tissue that begins to develop immediately after conception: epithelioid trophoblastic tumor, choriocarcinoma, and placental site trophoblastic tumors (PSTT).
There are several main types of stomach cancers, which are very different from each other. (1) Stomach Lymphomas are found in the stomach wall. These come in 2 main categories. 1 is Non-Hodgkin's stomach lymphomas, including MALT lymphoma, and assorted Large Cell Stomach Lymphoma, e.g., anaplastic Ki-1 (CD30) positive large cell lymphoma. The other is Hodgkin Stomach Lymphoma. These include both lymphomas which are primary to the stomach and nodal lymphomas that have spread to the stomach from e.g. spleen or liver and are thus secondary. There are Tertiary gastric lymphomas as well. (2) Gastric stromal tumors (GISTs) develop from stomach wall tissue. There are 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) There is a primary malignant melanoma of the stomach (6) Soft tissue sarcomas, most notably leiomyosarcoma of the stomach.
Esophagus Cancer is most commonly squamous cell carcinoma or adenocarcinoma. But, malignant melanomas, both primary and secondary, spindle cell carcinoma and Kaposi’s sarcoma can also occur in the esophagus. There is also primary oat cell esophagus carcinoma, esophagus choriocarcinoma, carcinoid esophagus tumor, adenosquamous esophagus carcinoma and the related mucoepidermoid esophagus carcinoma, and esophagus cylindroma. In addition, verrucous carcinomas and pseudosarcomas of the esophagus have been reported.
Breast cancers come in great variety. The most important category of breast cancers is 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 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 presence of both epithelial and myoepithelial cells. There is breast lymphoma (which exists in both Non-Hodgkin's breast lymphoma and Hodgkin's breast disease forms). There are some sarcomas, including giant cell breast sarcoma, breast leiomyosarc-oma, breast angiosarcoma, cystosarcoma phylloides and breast liposarcoma. There are carcinoid tumors which can be primary carcinoid tumors of the breast or can arise from from nonmammary sources. There are breast salivary gland-like tumors, including acinic cell carcinoma, oncocytic carcinoma (mammary epithelial oncocytoma) and muc-oepidermoid carcinoma. Other rare carcinomas include spindle cell breast carcinoma, squamous cell breast carcinoma, secretory breast carcinoma (juvenile secretory carcinoma), metaplastic breast carcinoma (a heterogeneous group of invasive breast cancers including types with squamous differentiation and those with heterologous elements), invasive micropapillary breast carcinoma, adenoid cystic breast carcinoma, cribriform carcinoma, breast myofibroblastoma (benign spindle stromal breast tumor) and glycogen-rich clear cell breast carcinoma. 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 treatment of breast carcinomas is the fact that a significant proportion of mammary carcinomas are not monoclonal.
rhabdomyosarcoma. Optic nerve gliomas are mentioned above in brain cancers.
Cervical cancers. There are many different cervical cancer categories and sub-categories. Most 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; squamotransitional; Early invasive (microinvasive) squamous cell carcinoma; and Squamous intraepithelial neoplasia (inc-luding Cervical intraepithelial neoplasia and Squamous cell carcinoma in situ). There are a variety of adenocarcinomas, most important of which are mucinous adenocarcinoma, including endocervical, intestinal, signet-ring cell, minimal deviation and villoglandular. There is endometrioid, clear cell, serous, mesonephric, Early invasive and adenocarcin-omas in situ. There are neuroendocrine carcinomas, Small Cell, large cell, classical carcinoid and atypical carcinoid. Other epithelial tumors include adenosquamous carci-noma, mixed adenosquamous carcinomas, which can be well-differentiated or poorly differentiated, the latter including glassy cell carcinoma, adenoid cystic carcinoma, adenoid basal carcinoma and undifferentiated carcinoma. There are some mixed carcinoma with signet-ring cells and poorly differentiated mixed carcinomas. This group includes tumors sometimes called apudomas or argyrophil cell carcinomas. There is an assortment of mesenchymal cervix tumors, including leiomyosarcoma; endometrioid stromal sarcoma, low grade; undifferentiated endocervical sarcoma; sarcoma botryoides; alveolar soft part sarcoma, cervix angiosarcoma, malignant peripheral nerve sheath cervix tumor; cervical leiomyoma; and cervix rhabdomyoma. There are also some mixed epithelial and mesenchymal tumors, including carcinosarcoma (malignant Müllerian mixed tumor), adenosarcoma, Wilms tumor, typical and atypical polypoid adenomyoma and papillary cervix adeno-fibroma. There are melanocytic tumors, including primary malignant cervix melanoma and blue naevus of the cervix. There are also germ cell type tumors, including yolk sac tumor, dermoid cyst and mature cystic cervix teratoma. There is also primary cervix choriocarcinoma, which does not fit well into any category. There are also numerous cancers secondary to the cervix.
Bladder cancers. Most bladder cancer cases 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. Bladder Adenocarcinomas include Primary Adenocarcinoma (urachal and non-urachal), Prostatic adenocarcinoma, Gastrointestinal adenocarcinomas and Clear cell carcinoma. Squamous cell carcinomas include Verrucous carcinomas and a secondary squamous cell bladder carcinoma from the cervix. Small cell carcinomas include Primary small cell bladder carcinoma and the secondary small cell lung carcinoma ('reserve cell carcinoma'). Lymphomas include primary lymphomas (Low grade B-cell lymphoma of MALT type, High grade B-cell lymphoma and T-cell lymphoma), and secondary lymphomas, including mantle cell lymphomas. Melanomas include Primary and secondary malignant bladder melanoma. Bladder sarcomas are leiomyosarcoma, osteosarcoma and rhabdomyosarcoma. There is also a primary primitive neuroectodermal bladder tumor (PNET), Paraganglioma (which can metastasize), nephrogenic adenoma, metastatic renal cell bladder carcinoma and both primary and secondary (from the uterus) bladder choriocarcinoma.
Skin cell Cancer is melanoma. Malignant melanomas come in 4 fundamental forms: superficial spreading melanoma, nodular melanoma (including Polypoid melanoma), lentigo maligna melanoma and acral melanoma. Mucosal melanomas are sometimes malignant. These sometime occur in amelanotic form, e.g., in desmoplastic melanoma.
There are many colorectal cancer types. Carcinomas include adenocarcinoma; mucinous adenocarcinoma; signet-ring cell carcinoma; small cell carcinoma; adenosquamous carcinoma; medullary carcinoma; choriocarcinoma; and undifferentiated carcinoma. 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 colon plasmacytoma and primary malignant colon melanoma. A wide variety of cancers are secondary to colon, e.g. ovarian carcinoma.
Renal carcinomas comprise the papillary renal cell carcinoma (which has 2 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, kidney liposarcoma, malignant hemangiopericytoma, kidney angiosarcoma, osteosarcoma, synovial sarcoma, kidney chondrosarcoma, malignant mesenchymoma and clear cell kidney sarcoma. 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 kidney tumor, renal melanoma, primitive neuroectodermal kidney tumor, neuroepithelial kidney tumor and congenital mesoblastic nephroma, some renal adenomas and oncocytomas.
These are just some of the categories of claimed cancers.
(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 24 of the specification gives 10-50 mg, which is generic and 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 diseases embraced by the scope.
(D) State of the Prior Art: The claimed compounds are a crystalline form of the compound 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'- dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide. So far as the examiner is aware said compound has not been successfully used as anticancer agents for the scope of the claims.
Reference WO 2021005586, discloses 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'- dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide as a solid.
(E) Working Examples: The invention is drawn to a method of treating a disorder ameliorated by an AKR1C3 dependent KARS inhibitor and those specific cancers found in claim 13. There are no in vitro nor in vivo working examples in the specification drawn to this utility to support the use of a crystalline form of the compound 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'- dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide to treat the claimed scope.
(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. “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), 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.
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. 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.
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.
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 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.
Claim Rejections - 35 USC § 102/103
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, 9 and 12-14 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Adair et al. (WO 2021005586).
The reference teaches 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, see page 111, Example 40. The reference also teaches the compositions of said compounds in a pharmaceutically acceptable carrier, see page 42, and the same utility, see page 43.
The reference shows the compound, but is silent on the particular solid form (crystalline or amorphous). MPEP 2112 states:
“SOMETHING WHICH IS OLD DOES NOT BECOME PATENTABLE UPON THE DISCOVERY OF A NEW PROPERTY
The claiming of a new use, new function or unknown property, which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
In this case, the “unknown property” is the particular solid form. This is unknown because the reference is silent on this property. MPEP 2112 goes on to state:
“A REJECTION UNDER 35 U.S.C. 102/103 CAN BE MADE WHEN THE PRIOR ART PRODUCT SEEMS TO BE IDENTICAL EXCEPT THAT THE PRIOR ART IS SILENT AS TO AN INHERENT CHARACTERISTIC.
Where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103, expressed as a 102/103 rejection.”
Again, the “CHARACTERISTIC” which the prior art is silent on is the solid form (crystalline or amorphous form is considered to be in the category of chemical properties; see Zenith Laboratories Inc. v. Bristol-Myers Squibb Co. 30 USPQ2d 1285, 1288).
This is not an ordinary inherency situation where it is not explicitly stated what the product actually is. In every reference applied, the reference explicitly teaches exactly what the compound is. In fact, it is the opposite. In a normal inherency situation, the claim is of known structure, and the reference is of unknown structure. Here, the reverse is true, and hence the legal circumstances of inherency-in-the-prior-art do not apply. The only difference is the property about which the reference happens to be silent.
See for example Ex parte Anderson, 21 USPQ 2d 1241 at 1251, discussion of Rejection E. The claims had “numerical or functional values for certain properties which [the authors of the references] did not measure”. The PTO presented no reasoning as to why the prior art material would have been expected to have those properties. Instead, the decision states, “There is ample precedent for shifting the burden to an applicant to reproduce a prior art product whose final structure or properties are, at least, in part determined by the precise process used in its manufacture.” (page 1253).
In another example, certain claims of Ex parte Raychem Corp. 25 USPQ2d 1265 required a linearity ratio of less than 1.2. The decision notes that neither reference discloses any values of the linearity ratio. The PTO presented no reasoning as to what the ratio would be expected to be in the references. The Decision states: “However, this does not end the inquiry since, where the Patent and Trademark Office is not equipped to perform the needed testing, it is reasonable to shift the burden of proof to Raychem to establish that (1) the argued difference exists….”
And indeed, there have been a number of cases in which applicants have pointed to silence of the prior art with regard to this or that property: In re Pearson, 181 USPQ 641; In re Zierden 162 USPQ 102; In re Lemin, 140 USPQ 273; Titanium Metals Corporation of America v. Banner, 227 USPQ 773; In re Benner, 82 USPQ 49. Going further, if silence about properties of prior art compounds could be relied on, then one could not reject over references with no utility (see In re Schoenwald, 22 USPQ2d 1671), since applicants could always insert the utility into the claim as a property.
It is well settled that the PTO can require an applicant to establish that a prior art product does not necessarily possess the characteristics of the claimed product when the prior art and claimed products are identical or substantially identical. An applicant's burden under these circumstances was described in In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-434 (CCPA 1977) as follows:
Where, as here, the claimed and prior art products are identical or
substantially identical, or are produced by identical or substantially
identical processes, the PTO can require an applicant to prove that the
prior art products do not necessarily or inherently possess the
characteristics of his claimed product. . . . Whether the rejection is based
on 'inherency' under 35 U.S.C. § 102, or 'prima facie obviousness' under
35 U.S.C. § 103, jointly or alternatively, the burden of proof is the same,
and its fairness is evidenced by the PTO's inability to manufacture
products or to obtain and compare prior art products (footnote omitted).
Overcoming the rejection is very straightforward. One simply replicates the prior art procedure. If the crystalline form does not appear at all in the product, or if on repetition, it sometimes does not appear in the product, then the rejection is overcome.
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 factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claim(s) 1, 9 and 12-14 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Adair et al. (WO 2021005586).
The present application claims a crystalline form of the compound 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide.
PNG
media_image1.png
222
509
media_image1.png
Greyscale
The reference teaches the same compound was synthesized but only discloses a solid, see page 111, Example 40.
However, a similar compound found on page 119, Example 56, was recrystallized from water and acetonitrile.
PNG
media_image2.png
160
302
media_image2.png
Greyscale
MPEP 2144 states, “A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963).
Since the compounds are similar, it would be obvious to make a crystalline form of the compound 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide since the reference teaches a similar compound can be made crystalline.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claim(s) 1, 9 and 12-14 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 1197497. Although the conflicting claims are not identical, they are not patentably distinct from each other because the reasons provided in the 102/103 rejections above.
Claims 1-9 and 12-14 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-22 and 65-86 of copending Application No. 18993107. Although the conflicting claims are not identical, they are not patentably distinct from each other because the present claims are drawn to a crystalline form of the compound 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide and a method of treating a disorder ameliorated by an AKR1C3 dependent KARS inhibitor.
The claims in the ‘107 application are drawn to various method claims, which all embrace elevated AKR1C3. There is no patentable distinction between products and methods of intended use of said products.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
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
Prosecution Insights