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 .
Claims Status
The preliminary amendments filed 05/12/2023 are acknowledged.
Claims 1-9 are canceled.
Claims 10-16 are new.
Claims 10-16 are pending and under examination.
Priority
The instant application is a 371 of PCT/KR2021/016301 and claims priority to Republic of Korea application KR10-2020-0151618.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C.
119 (a)-(d) and receipt is acknowledged of certified copies of papers required by 37
CFR 1.55. Although the certified copy of the foreign priority document was received, the
Examiner is unable to determine whether or not the Korean foreign priority document
discloses what is presently claimed because the document is in Korean. Therefore,
priority is given with the effective filing date of 11/10/2021, which is the PCT filing date.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/12/2023 and 01/02/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Drawings
The drawings are objected to because:
(1) Figures 3, 4, and 26 comprise multiple panels. 37 CFR 1.84(u) states that the different views must be numbered in consecutive Arabic numerals and that "partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter". Each panel should be separately numbered.
(2) Figure 27 is of poor quality and does not comply with 37 CFR 1.84(a)(1) which states “india ink, or its equivalent that secures solid black lines, must be used for drawings.”
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains embedded hyperlinks and/or other forms of browser-executable code (see paragraph [61] of the specification). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 10-11, and 15-16 are objected to because of the following informalities: the claims recite “Bifidobacterium longum RAPO”. The genus and species should be italicized or underlined for proper binomial nomenclature. Appropriate correction is required.
Claim 14 is objected to because of the following informalities: The claim recites acronyms (i.e. PD1, PDL1, CTLA, Tim3, LAG3). The first time an acronym is used, it must be accompanied by the definition of the abbreviation. 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 12 and 14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 12, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 12 recites the broad recitations “skin cancer”, and “hematopoietic tumor”, and the claim also recites “melanoma”, “squamous cell carcinoma”, “mast cell tumor” and “epidermal carcinoma” which are the narrower statements of the limitation of “skin cancer” and also recites “leukemia” and “lymphoma” which are the narrower statements of the limitation of “hematopoietic tumor”. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 14 recites the limitation “where the immuno-anticancer agent comprises at least one selected from the group consisting of anti-PD1, anti-PDL1, anti-CTLA, anti-Tim3 and anti-LAG3”. It is unclear what is encompassed by “anti-PD1, anti-PDL1, anti-CTLA, anti-Tim3 and anti-LAG3.” For example, any of these options could be an antibody, protein, peptide, nucleic acid, small molecule, or any other possible molecule type. Therefore, the scope of this claim is indefinite.
Claim Rejections - 35 USC § 112(a)
Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 10-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 10 recites “Bifidobacterium longum RAPO having accession no. KCTC13773BP” and as such this material is a required element needed to make and use the claimed invention. As a required element, the specific bacterium must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 U.S.C. 112, first paragraph, may be satisfied by a deposit of the pertinent cell line. See 37 CFR 1.801-1.809.
The specification does not disclose that wherein the Bifidobacterium longum RAPO having accession no. KCTC13773BP has been deposited under the terms of the Budapest treaty and does not provide assurances that the recited materials will be irrevocably and without restriction or condition released to the public upon the issuance of a patent, or indicate that said material will be replaced if the material becomes unviable.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that Bifidobacterium longum RAPO having accession no. KCTC13773BP have been deposited under the Budapest Treaty and that Bifidobacterium longum RAPO having accession no. KCTC13773BP will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent, whichever is longer. See 37 CFR 1.806 and MPEP 2410-2410.01. If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit was made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the Bifidobacterium longum RAPO having accession no. KCTC13773BP described in the specification as filed are the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant's possession at the time the application was filed.
Scope of Enablement
Claims 10-16 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 enhancing the effects of an anti-PD1 antibody in treating breast cancer, comprising administering Bifidobacterium longum RAPO having accession no. KCTC13773BP in combination with the anti-PD1 antibody to a subject in need thereof, does not reasonably provide enablement for a method of preventing or treating cancer comprising administering a composition comprising Bifidobacterium longum RAPO having accession no. KCTC13773BP to a subject in need thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or 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.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
The claims are drawn to a method for preventing or treating cancer, the method comprising administering a composition comprising Bifidobacterium longum RAPO having accession no. KCTC13773BP to a subject in need thereof. Claim 12 adds the limitation wherein the cancer comprises at least one selected from the group consisting of melanoma, squamous cell carcinoma, breast cancer, head and neck cancer, thyroid cancer, soft tissue sarcoma, osteosarcoma, testicular cancer, prostate cancer, ovarian cancer, bladder cancer, skin cancer, brain cancer, hemangiosarcoma, mast cell tumor, leukemia, lymphoma, liver cancer, lung cancer, pancreatic cancer, stomach cancer, kidney cancer, colorectal cancer, hematopoietic tumor, neuroblastoma, epidermal carcinoma, and metastatic cancer thereof. Claim 13 adds the limitation wherein the method further comprises administering an immuno-anticancer agent, and claim 14 adds the limitation wherein the immuno-anticancer agent comprises at least one selected from the group consisting of anti-PD1, anti-PDL1, anti-CTLA, anti-Tim3 and anti-LAG3
The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The claims are extremely broad
due to the vast number of possible cancer types and tumor cell growth mechanisms represented by the term “preventing or treating cancer.” Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty
much every part of the body. Here are some assorted categories:
A. 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.
B. The main types of lung and pleural cancer are small cell (i.e. oat cell, including combined oat cell), adenocarcinomas, bronchioloalveolar carcinomas (nonmucinous, mucinous, and mixed mucinous and nonmucinous or indeterminate cell type), acinar, papillary carcinoma, solid adenocarcinoma with mucin, adenocarcinoma with mixed subtypes, well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell adenocarcinoma), squamous cell (papillary, clear cell, small cell and basaloid), mesothelioma (including epithelioid, sarcomatoid, desmoplastic and biphasic) and large cell carcinoma (which include large-cell neuroendocrine carcinoma, combined large-cell neuroendocrine carcinoma, basaloid carcinoma, clear cell carcinoma lymphoepithelioma-like carcinoma, and large-cell carcinoma with rhabdoid phenotype). In addition there are also the carcinomas with pleomorphic, sarcomatoid or sarcomatous elements, including carcinomas with spindle and/or giant cells, spindle cell carcinoma, carcinosarcoma and pulmonary blastoma. The non-small cell lung carcinomas also include adenosquamous carcinoma, the carcinoid tumor (both typical carcinoid and atypical carcinoid) as well as carcinomas of salivary-gland type, including mucoepidermoid carcinoma and adenoid cystic carcinoma. There are some soft tissue tumors including localized fibrous tumor (formerly called benign fibrous mesothelioma); epithelioid haemangioendothelioma; pleuropulmonary blastoma (which occurs three fairly different substituted-types); chondroma; calcifying fibrous pseudotumor of the visceral pleura); congenital peribronchial myofibroblastic tumors, diffuse pulmonary lymphangiomyomatosis and desmoplastic round cell tumor. There are assorted bronchial adenomas (e.g. adenoid cystic carcinomas, mucoepidermoid carcinomas, mucous gland adenomas, and oncocytomatous bronchial mucous gland adenoma) as well as other adenomas, including papillary adenoma. There are some papillomas, including squamous cell papilloma and glandular papilloma. There is also malignant melanoma of the lung, cylindroma (cylindroadenoma), some germ cell tumors, thymoma and sclerosing haemangioma and many others as well. Lung cancers are quite diverse. Thus, for example, oat cell carcinoma, Signet ring adenocarcinoma, pleuropulmonary blastoma, cylindroma, and malignant mesothelioma really have very little in common, other than being cancers of the lung.
C. Prostate Cancer is not a single disease or group of very closely related disorders, but ranges over a very wide variety of cancer types. It embraces various adenocarcinomas of the prostate, including prostatic ductal adenocarcinoma, adenocarcinoma with paneth-like cells, clear cell adenocarcinoma, foamy gland adenocarcinoma, adenocarcinoma of Cowper’s glands, and atrophic adenocarcinoma. It includes a huge variety of carcinomas, including mucinous carcinomas of the prostate, prostatic carcinoma of xanthomatous type, signet ring cell carcinoma of the prostate, neuroendocrine small cell carcinoma of the prostate, and other small cell carcinomas of the prostate, adenosquamous and squamous cell carcinomas, basaloid and adenoid cystic carcinoma, sarcomatoid carcinoma of the prostate, lymphoepithelioma-like carcinoma of the prostate, urothelial (transitional cell) carcinoma (which can be primary in the prostate gland or represent secondary spread from the urinary bladder), basaloid carcinoma, pseudohyperplastic carcinoma, and primary carcinoma of the seminal vesicles. There are also assorted sarcomas of the prostate, including Angiosarcoma, Embryonal rhabdomyosarcoma, Stromal sarcoma, Synovial sarcoma, Leiomyosarcoma, and chondrosarcoma of the prostate, which can be primary or secondary to the prostate. Also included is prostatic intraepithelial neoplasia (PIN), phyllodes tumor of the prostate, primitive peripheral neuroectodermal tumor (PNET) and malignant fibrous histiocytoma. There are also lymphomas, which are usually secondary, but primary ones include diffuse large B-cell lymphoma. The great majority of this list is not treatable with pharmaceuticals.
D. Breast cancers come in great variety. The most important category of breast cancers is the ductal cancers. These come in an assortment of types. Presently, these are divided into the following categories: intraductal (in situ); invasive with predominant intraductal component; invasive, NOS; Comedo; Inflammatory (IBC); medullary with lymphocytic infiltrate; mucinous carcinoma (colloid carcinoma); papillary carcinoma; scirrhous; tubular; and other. Another category is the Lobular breast cancers, which can be in situ, Invasive with predominant in situ component, and Invasive. There is Paget’s disease of the nipple, which can be also with intraductal carcinoma or with invasive ductal carcinoma. There is adenomyoepithelioma , a dimorphic tumor characterized by the presence of both epithelial and myoepithelial cells. There is lymphoma of the breast (which exists in both Non-Hodgkin's lymphoma of the breast and Hodgkin's disease of the breast forms). There are some sarcomas, including giant cell sarcoma of the breast, leiomyosarcoma of the breast, angiosarcoma of the breast, cystosarcoma phylloides, and liposarcoma of the breast. There are carcinoid tumors which can be primary carcinoid tumors of the breast, or can arise from nonmammary sources. There are breast salivary gland-like tumors, including acinic cell carcinoma, oncocytic carcinoma (mammary epithelial oncocytoma), and mucoepidermoid carcinoma. Other rare carcinomas include spindle cell carcinoma of the breast, squamous cell carcinoma of the breast, secretory carcinoma of the breast (juvenile secretory carcinoma), metaplastic carcinoma of the breast (a heterogeneous group of invasive breast cancers including types with squamous differentiation and those with heterologous elements), invasive micropapillary carcinoma of the breast, adenoid cystic carcinoma of the breast, cribriform carcinoma, myofibroblastoma of the breast (benign spindle stromal tumor of the breast) and glycogen-rich clear cell carcinoma of the breast. There are also nonmammary tumors, primarily adenocarcinomas, that can metastasize to the breast including bronchogenic carcinomas, malignant melanomas (primary and secondary), rhabdomyosarcomas, malignant mesotheliomas, thyroid carcinomas, renal cell carcinomas, malignant lymphomas, and gastrointestinal carcinomas (including those from the stomach, pancreas, esophagus, and colon). Complicating the treatment of breast carcinomas is the fact that a significant proportion of mammary carcinomas are not monoclonal.
The instant specification does not provide any evidence that the administration of Bifidobacterium longum RAPO having accession no. KCTC13773BP would prevent or treat any cancer, let alone the specific cancer types listed in claim 12. There is no support provided in the instant specification or in the prior or instant art that teaches or supports the ability to prevent or treat any cancer encompassed by these broad claims. The only working example in the specification is towards an enhancement effect of an anti-PD1 monoclonal antibody in a mouse breast cancer model when the Bifidobacterium longum RAPO having accession no. KCTC13773BP is combined with the anti-PD1 antibody.
Additionally, the term "preventing" is generally understood in the art to encompass a total protection from disease or injury. Thus, given the high level of required effect, a high level of evidence showing prevention is also required. As noted above, however, there are no working examples in the instant specification demonstrating any therapy using the claimed treatment, nor any examples directed to the palliative, preventative, or curative treatment of any cancer. Therefore, the instant specification does not provide evidence or substantial guidance commensurate in scope with the broadly claimed method and how to use the method to prevent any cancer.
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regard to treating cancer broadly is underdeveloped. In particular, there is no known anticancer agent that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability. While the state of the art is relatively high with regard to the treatment of specific cancers with specific agents, it has long been underdeveloped with regard to the treatment of cancers broadly. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all cancer cells in a mammal, including a human subject, with the claimed active ingredient makes practicing the claimed invention unpredictable.
With regard to cancer treatment, Bally et al. (US 5,595,756) stated, “Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment-limiting toxicities” (col. 1, lines 17-24).
Sporn et al., 2000 (instant PTO-892) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed [page 525, left column, second paragraph]. Sporn also teaches that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure” [page 525, left column, third paragraph].
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al., 2000 (instant PTO-892) indicates that “one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to
permit screening of hybridoma supernatants” and that “in vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality [page 167, left column, 1st paragraph].
Further, as taught by HogenEsch et al., 2012 (instant PTO-892), there is no single cell culture or in vivo cancer model that faithfully predicts the efficacy of anticancer drugs in human clinical trials [page 6, third paragraph]. Cell culture approaches offer the advantage of human-derived cell lines or tissue fragments from primary tumors, but cannot mimic the complexity of the reciprocal interaction between the growing tumor and the co-evolving microenvironment [page 6, third paragraph]. Xenografts in immunodeficient mice have limited added value over cell culture models as the lack of an intact immune system and insufficient interactions between the human tumor cells and mouse stromal cells do not recapitulate human cancers [page 6, third paragraph]. Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Given Bally’s teaching of treatment-limiting toxicities in clinical use, Sporn’s teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype, Auerbach’s teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response, and HogenEsch’s teaching that there is no single cell culture or in vivo cancer model that faithfully predicts the efficacy of anticancer drugs in human clinical trial, these teachings collectively demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers.
(6) the amount of direction or guidance presented; (7) the presence or absence of working examples:
There is a lack of working examples in the specification for treating or preventing any type of cancer as encompassed by the instant claims. Applicant has provided evidence of enhancing the effect of an anti-PD1 monoclonal antibody in a mouse breast cancer model when the Bifidobacterium longum RAPO having accession no. KCTC13773BP is combined with the anti-PD1 antibody [see Example 1 of the instant specification]. However, Applicant has not provided any substantive evidence that the administration of Bifidobacterium longum RAPO having accession no. KCTC13773BP would prevent or treat any cancer.
In conclusion, the claimed invention does not provide enablement for treating or preventing any type of cancer. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claims 11-16, which depend from claim 10, are rejected for the same reasons set forth above.
Written Description
Claims 13-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Claim 13 is drawn to the method according to claim 10 further comprising administering an immuno-anticancer agent. Claim 14 adds the limitation wherein the immuno-anticancer agent comprises at least one selected from the group consisting of anti-PD1, anti-PDL1, anti-CTLA, anti-Tim3 and anti-LAG3. The claims are directed to agents that are defined only by their function (i.e. immuno-anticancer or anti-PD1, anti-PDL1, anti-CTLA, anti-Tim3 and anti-LAG3). The specification does not define immune-anticancer agent. Further, the specification does not define what is encompassed by an immuno-anticancer agent that is anti-PD1, anti-PDL1, anti-CTLA, anti-Tim3 and anti-LAG3.
The claimed genera of “immune-anticancer agent”, “anti-PD1”, “anti-PDL1”, “anti-CTLA”, “anti-Tim3” and “anti-LAG3” must exhibit the specific function of being anti-cancer, anti-PD1, anti-PDL1, anti-CTLA, anti-Tim3 and anti-LAG3. There is no defined structure that correlates to the function, and a sufficient representative number of species have not been described in the specification. The immuno-anticancer agents, anti-PD1 agents, anti-PDL1 agents, anti-CTLA agents, anti-Tim3 agents, and anti-LAG3 agents can include antibodies, proteins, peptides, nucleic acids, small molecules, and any other possible molecule type. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Regarding the encompassed protein and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein. As taught by Skolnick et al., 2000 (instant PTO-892) sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins [see Abstract]. Further, just knowing the structure of the protein is also insufficient for prediction of functional sites [see Abstract]. Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells [page 34, right column]. Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works [page 34, right column].
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al., 1990 (instant PTO-892) who teaches that replacement of a single lysine reside at position 132 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein [see e.g. Abstract] and by Lazar et al., 1988 (instant PTO-892) who teaches that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge et al., 2015 (instant PTO-892) teaches that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference [page E5189, left column]. However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations [page E5196, left column, first paragraph]. The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations [page E5195, right column, last paragraph]. The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible [page E5197, left column, first paragraph]. Additionally, Bork, 2000 (instant PTO-892) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate [page 398, column 1]. One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered [page 398, column 2]. Conclusions from the comparison analysis are often stretched with regard to protein products [page 398, column 3].
Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable [Bork: page 399, column 2]. Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality [see legend for table 1, page 399]. As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search [page 399, paragraph bridging columns 2 and 3]. The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further [page 400, paragraph bridging columns 1 and 2].
One key issue is the prediction of protein function based on sequence similarity. Kulmanov et al., 2018 (instant PTO-892) teaches that there are key challenges for protein function prediction methods [page 661, left column]. These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function [page 661, left column]. Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction [page 661, left column]. Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation [page 661, left column]. Due to these challenges, it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides encompassed by the instant claims [page 661, left column].
Regarding the encompassed antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al., 2002 (instant PTO-892) teaches that even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen [page 416, left column, second paragraph]. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site [page 416, left column, second paragraph – right column, first paragraph]. The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al., 1996 (instant PTO-892) describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region [see Abstract].
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed nucleic acids, the efficacy of any possible DNA or RNA based modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al., 2007 (instant PTO-892), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses [see page 79], the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses [see page 79], competition with cellular RNAi components [see page 83], the side effect of suppressing off targets [see page 80], and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al., 1997 (instant PTO-892) teaches that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three dimensional RNA structures [see page 269], while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins [see page 269]. These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al., 2012 (instant PTO-892) teaches that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions and they are easily degraded in blood. Further, they have less chemical diversity than other antagonist molecules [see page 2], and have issues associated with determining the Kd measurements for a given molecule [see page 13]. Given the teachings of Aagaard, Warzocha, and McKeague, the claimed nucleic acid therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
Regarding the encompassed small molecules, the prediction of function of small molecules is highly unpredictable. According to Guido et al., 2008 (instant PTO-892) accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery [see page 37]. There are a vast number of possible compounds that may bind a particular target, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido teaches that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity [see page 40]. As taught by Clark et al., 2014 (instant PTO-892) even when guided by structural data, developing selective structure-activity relationships has been challenging [see page 5028]. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to inhibit a particular protein or cellular process.
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
To the extent that the claims read on a method of enhancing the effects of an anti-PD1 antibody in breast cancer, comprising administering Bifidobacterium longum RAPO in combination with the anti-PD1 antibody to a subject in need thereof, a rejection under 35 U.S.C. 102 is set forth below.
Claims 10 and 12-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al., July 2021 (instant PTO-892).
Regarding claims 10, and 12-14, Kim teaches injecting metastatic breast cancer cells into BALB/c mice and when the tumor reaches a specific size, mice were administered an anti-PD-1 antibody, B. longum RAPO, or a combination of the anti-PD-1 antibody and B. longum RAPO [see page 1, Methods section]. Kim further teaches that tumor volume was significantly inhibiting in the combination group compared to the control or anti-PD-1 group, suggesting that the combination therapy with B. longum RAPO and the anti-PD1 antibody modulates anti-tumor immunity and gut microbiota, contributing to a better response to anti-PD-1immunotherpy in mice with triple negative breast cancer.
Regarding claim 15, Kim teaches that the anti-PD-1 antibody was injected i.p. 5 times at 3 day intervals and the B. longum RAPO was orally administered daily from 2 days before the first injection of the anti-PD-1 (i.e. sequentially in separate formulations) [ see page 1, Methods section].
Regarding claim 16, the claim merely recites effects or results of B. longum RAPO and the immuno-anticancer agent (anti-PD1 antibody) together. Since Kim teaches the administration of the combination of B. longum RAPO and the anti-PD1 antibody, and the B. longum RAPO’s effects are an inherent property of the bacterium, a person of ordinary skill in the art would have reasonably expected these effects to occur, absent evidence to the contrary.
Conclusion
No claims are allowed.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675