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 a Final Office Acton.
Claims 1-8, 11, 12 and 14-16 are pending and under consideration. Claims 14-16 are new claims.
Specification
The substitute specification filed February 5, 2026 has been entered because it does conform to 37 CFR 1.125(b) and (c).
Claim Objections
The objection to claims 1, 2 and 6 because of the term “none” is withdrawn based on the amendments.
The objection to claim 1 because of the term “substituted” is withdrawn based on the amendments.
Claim Rejections - 35 USC § 112
The rejection of claim 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase “a disease associated with EP4 receptor” is withdrawn based on the amendments.
The rejection of claims 1-8 and 11-13 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for pharmaceutically acceptable salts, does not reasonably provide enablement for prodrugs, is withdrawn based on the amendments.
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 12 is 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 inhibiting EP4 receptor and treating pain, osteoarthritis and RA, does not reasonably provide enablement for a method of treating pancreatic adenocarcinoma, clear cell carcinoma of the kidney, squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), serous epithelial ovarian cancer, cervical cancer, transitional cell bladder cancer, skin cancer, glioblastoma, kidney cancer, prostate cancer, pancreatic cancer, triple- 4897-6093-1980, v 1 negative breast cancer (TNBC) and stomach cancer. 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 hundreds of thousands of compounds with a bicyclic thieno[3,2-b]pyrrole scaffold with a variety of substituents at six different positions.
(b) Scope of the diseases covered. Cancer will be elaborated further.
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 that are embraced by the claims:
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.
Prostate Cancer is not a single disease or group of closely related disorders, but ranges over a very wide variety of cancer types. It embraces various prostate ade-nocarcinomas, including prostatic ductal adenocarcinoma, adenocarcinoma with pan-eth-like cells, clear cell adenocarcinoma, foamy gland adenocarcinoma, Cowper’s glands adenocarcinoma and atrophic adenocarcinoma. It includes a huge variety of carcinomas, including mucinous prostate carcinomas, prostatic xanthomatous type carcinoma, signet ring cell prostate carcinoma, neuroendocrine small cell prostate car-cinoma and other small cell prostate carcinomas, adenosquamous and squamous cell carcinomas, basaloid and adenoid cystic carcinoma, sarcomatoid prostate carcinoma, lymphoepithelioma-like prostate carcinoma, urothelial (transitional cell) carcinoma (can be primary in prostate gland or represent secondary spread from urinary bladder), bas-aloid carcinoma, pseudohyperplastic carcinoma and seminal vesicle primary carcin-oma. There are also assorted prostate sarcomas, including Angiosarcoma, Embryonal rhabdomyosarcoma, Stromal sarcoma, Synovial sarcoma, Leiomyosarcoma and chondrosarcoma of the prostate, which can be primary or secondary to the prostate. Included is prostatic intraepithelial neoplasia (PIN), phyllodes tumor prostate, primitive peripheral neuroectodermal tumor (PNET) and malignant fibrous histiocytoma. There are also lymphomas, usually secondary, but primary ones include diffuse large B-cell lymphoma. The great majority of this list is not treatable with pharmaceuticals.
Ovarian cancers are a heterogeneous group of tumors. Most important are epithe-lial tumors. These are themselves fairly diverse, categories being serous cystomas (serous benign cystadenomas, serous cystadenomas with proliferating activity of epith-elial cells and nuclear abnormalities but with no infiltrative destructive growth and ser-ous cystadenocarcinomas); mucinous cystomas (divided the same 3 ways); clear cell tumors (mesonephroid tumors, again divided the same way), endometrioid tumors (similar to adenocarcinomas in endometrium: endometrioid benign cysts, endometrioid tumors with proliferating activity of epithelial cells and endometrioid adenocarcinomas), mixed mesodermal (now considered to be carcinomas with areas of sarcomatous diffe-rentiation), transitional cell carcinoma, Brenner tumor and mixed epithelials. 2nd are gra-nulosastromal cell tumors. These include granulosa cell tumor (which exists in juvenile and adult forms) and tumors in the thecoma-fibroma sub-group. This sub-group also includes thecoma-fibroma group typical: thecoma, luteinized thecoma, fibroma, cellular fibroma, fibrosarcoma, stromal tumor with minor sex cord elements, sclerosing stromal tumor, signet ring cell stromal tumor and others. 3rd are Sertoli stromal cell tumors: Sertoli-Leydig cell ovary tumor (which comes in 3 different differentiation levels, as well as a retiform version); Sertoli cell tumor (tubular androblastoma), and Stromal-Leydig cell tumor. 4th are the Sex cord-stromal tumors of mixed or unclassified cell types: sex cord tumor with annular tubules, ovary gynandroblastoma (composed of sex cord and stromal cells of both ovarian and testicular types), and sex cord-stromal tumor NOS. 5th are steroid cell tumors: Ovarian Leydig cell tumor, which comes in hilus and non-hilar types, Stromal luteoma, and steroid cell tumor, NOS. 6th, there is an assortment of Germ Cell Tumors. These include dysgerminoma; yolk sac tumors (endodermal sinus tumor, and polyvesicular vitelline tumor, hepatoid and others); embryonal carcinoma; polyembryoma; choriocarcinoma, gonadoblastoma and a wide variety of teratomas. These tetromas include immature, cystic (dermoid cyst), retiform (homunculus) and Monodermal, including struma ovarii, carcinoid (insular and trabecular), struma carcinoid, mucinous carcinoid, neuroectodermal tumors, sebaceous tumors and others. Teratocarcinomas come in many mixture types. There is an assortment of other tumors which do not fit the above categories. There are Tumors of Rete Ovarii (which can be adenomatoid tumor or a esothelioma). There are some tumors of uncertain origin, including small cell carcinoma, tumors of probable Wolffian origin, hepatoid carcinoma and oncocytoma. There are some soft tissue tumors not specific to ovary, and there are assorted malignant lymphomas and leukemias which land up in the ovaries.
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.
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.
Pancreas Cancer are primarily carcinomas. There is duct cell carcinoma, acinar cell carcinoma, papillary mucinous carcinoma, signet ring carcinoma, medullary carcin-oma, squamous carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, colloid carcinoma (mucinous carcinoma or mucinous non-cystic carcinoma), giant cell carcinoma and small cell carcinoma. Cancers of the endocrine part of the pancreas (islet cell tumors) include insulinoma, glucagonoma, somatostatinoma, gastrinoma, VIPoma, carcinoid, ACTHoma, GRFoma, PTF-like-oma, neurotensinoma and Multiple Endocrine Neoplasia Type 1 (MEN1). Neurofibromatosis (NF) Type 1 is usually inclu-ded with this category. There are mixed types, notably pancreatoblastoma, and ductal-endocrine or acinar-endocrine types. There is also cystadenocarcinoma which comes in serous and mucinous types, pancreatic lymphoma, pseudopapillary solid pancreas tumor (Frantz’s tumor) and mucinous cystic tumor with dysplasia.
This list is not exhaustive.
(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 is found on pages 21-22 of the Specification, which gives 0.0001-0.lwt% for a pharmaceutical composition and teaches generically dosages for approved therapeutic agents are known. Moreover, this is broad and 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 all the diseases embraced by the scope.
(D) State of the Prior Art: The claimed compounds are substituted bicyclic thieno[3,2-b]pyrroles. So far as the examiner is aware substituted thieno[3,2-b]pyrroles have not been successfully used to treat or prevent all the diseases embraced by the scope.
(E) Working Examples: The invention is drawn to a method of treating or preventing a disease associated with EP4 receptor and all cancers. There are no in vivo working examples in the specification drawn to this utility to support the use of substituted thieno[3,2-b]pyrroles to treat said diseases. On pages 27-28 of the specification there is one in vitro assay presented which provides data antagonistic activity against the EP4 receptor and another assay drawn to pharmacokinetics determination.
(F) Skill of those in the art: Taken as a whole, the skill level in oncology must be considered as low. The previously cited skill is still applicable.
(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.
Claim Rejections - 35 USC § 103
The rejection of claims 1-8 and 11-13 under AIA 35 U.S.C. 103(a) as being unpatentable over Yuan, Wei (CN 102149384) and Sowaileh et al. (ChemMedChem, 2017, 23(18), 1481-1490), is withdrawn based on the amendments.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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