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 claim amendments filed 07/07/2023 are acknowledged.
Claims 1-15, 19, and 26-28 are pending.
Claims 16-18 and 20-25 are canceled.
Claims 3-8, 10-11, 13-15, 19, and 26-28 are amended.
Claims 1-15, 19, and 26-28 are under examination.
Priority
The instant application is a 371 of PCT/CN2022/070625 and claims priority to Chinese application CN202110025240.7. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Therefore, priority is given with the earliest effective filing date of 01/08/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/07/2023, 11/04/2024, 02/12/2025, 06/04/2025, and 01/22/2026 are in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement is being considered by the examiner.
The document lined through on the 07/07/2023 IDS was not considered because it was not of sufficient quality to read.
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.
Claim Objections
Claims 1 and 7 are objected to because of the following informalities: The claims recite acronyms (i.e. PD-L1, CD47, Fab, scFv). The first time an acronym is used, it must be accompanied by the definition of the abbreviation. Further, claim 7 recites the limitation “variable domain fragments Fv.” The “Fv” is the abbreviation for “variable domain fragment”. The Examiner recommends amending the claim to recite “Fv (variable domain fragment).” Appropriate correction is required.
Claim 11 is objected to because of the following informalities: Claim 11 recites the limitation “wherein either the first Fc chain or the second Fc chain comprises T366L and D399R amino acid substitutions at positions 366 and 399, and the other comprises L351E, Y407L and K409V amino acid substitutions at positions 351,407 and 409.” The “T366L”, “D399R”, “L351E”, “Y407L” and “K409V” already indicate the amino acid position of the substitution so the limitations of “amino acid substitutions at positions 366 and 399” and “amino acid substitutions at positions 351,407 and 409” is redundant. The Examiner recommends amending the claim to recite “wherein either the first Fc chain or the second Fc chain comprises T366L and D399R amino acid substitutions, and the other comprises L351E, Y407L and K409V amino acid substitutions” Appropriate correction is required.
Claim 12 is objected to because of the following informalities: Claim 12 recites the limitation “…which no other polypeptides present…”. This is grammatically awkward and the Examiner recommends amending the claim to recite “…which no other polypeptides are present…”. Appropriate correction is required.
Claim 27 is objected to because of the following informalities: Claim 27 includes the limitation “preferably.” MPEP 2173.05(d) states, “Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim.” The “preferably” should be removed entirely. Appropriate correction is required.
Claims 2-3, 5-6, and 11-14 are objected to as being dependent upon a rejected base claim (i.e. claim 1), but would be allowable if the above corrections are made and if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7-10 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.
Claim 7 recites the limitation “Fab fragments, scFv fragments, and variable domain fragments Fv”, claim 8 recites “Fab fragments”, and claims 9 and 10 recite “Fab fragment”. Fabs, scFvs, and Fvs are antibody fragments themselves so the language of “Fab fragments, scFv fragments, and variable domain fragments Fv” makes it unclear if the antigen-binding functional regions are Fabs, scFvs, or Fvs or if the antigen-binding functional regions are fragments of Fabs, scFvs, and Fvs. Therefore, the scope of these claims is indefinite.
The Examiner recommends amending the claims to remove the redundant “fragments” in order to overcome this rejection.
Claim 9 recites the limitation “wherein the Fab fragment thereof” and depends from claim 8 which recites “wherein the first antigen-binding functional region and the second antigen-binding functional region are both Fab fragments.” Since claim 8 recites two different Fabs, it is unclear what Fab fragment the limitations of claim 9 are referring to. Therefore, the scope of this claim is indefinite.
The Examiner recommends amending claim 9 to recite “wherein each Fab has a different heavy chain variable region and different light chain variable region from the other.”
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 26-28 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 a cancer that expresses PD-L1 and CD47, does not reasonably provide enablement for preventing and/or treating any disease. 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.
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 of preventing and/or treating diseases comprising administering to a subject in need thereof the bispecific antibody (of claim 1) that specifically binds to PD-L1 and CD47. Claim 28 further limits the disease to leukemia, lymphoma, myeloma, brain tumor, head and neck squamous cell cancer, non-small cell lung cancer, nasopharyngeal cancer, esophageal cancer, gastric cancer, pancreatic cancer, gallbladder cancer, liver cancer, colorectal cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, bladder cancer, renal cell cancer, melanoma, small cell lung cancer and bone cancer.
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 diseases, let alone the specific cancer types and tumor cell growth mechanisms listed in instant claim 28, represented by the term “preventing and/or treating diseases.” Regarding the claimed cancers, 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 and 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. Carcinomas of the Liver include hepatocellular carcinoma, combined hepatocellular cholangiocarcinoma, cholangiocarcinoma (intrahepatic), bile duct cystadenocarcinoma and undifferentiated carcinoma of the liver. There is also cancer of the 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.
C. 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.
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.
E. Ovarian cancers are a heterogeneous group of tumors. The most important are the epithelial tumors. These are themselves fairly diverse, the categories being serous cystomas (serous benign cystadenomas, serous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth and serous cystadenocarcinomas); mucinous cystomas (divided the same three ways); clear cell tumors (mesonephroid tumors, again divided the same way), endometrioid tumors (similar to adenocarcinomas in the endometrium: endometrioid benign cysts, endometrioid tumors with proliferating activity of the epithelial cells and endometrioid adenocarcinomas), mixed mesodermal (now considered to be carcinomas with areas of sarcomatous differentiation), transitional cell carcinoma, the Brenner tumor, and mixed epithelials. Second, there are the granulosa-stromal cell tumors. These include the granulosa cell tumor (which exists in juvenile and adult forms) and the tumors in the thecoma-fibroma sub-group. This sub-group also includes thecoma-fibroma group typical: thecoma and luteinized thecoma, as well as fibroma, cellular fibroma, fibrosarcoma, stromal tumor with minor sex cord elements, sclerosing stromal tumor, signet ring cell stromal tumor and others. Third, there are the Sertoli stromal cell tumors: Sertoli-Leydig cell tumor of the ovary (which comes in three different levels of differentiation, as well as a retiform version); Sertoli cell tumor (tubular androblastoma), and Stromal- Leydig cell tumor. Fourth are the Sex cord-stromal tumors of mixed or unclassified cell types: sex cord tumor with annular tubules, gynandroblastoma of the ovary (composed of sex cord and stromal cells of both ovarian and testicular types), and sex cord-stromal tumor NOS. Fifth, there are the steroid cell tumors: Ovarian Leydig cell tumor, which comes in hilus and non-hilar types, Stromal luteoma, and steroid cell tumor, NOS. Sixth, 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. There are also the teratocarcinomas which come in many mixture types. Finally, there are assortments of other tumors which do not fit into the above categories. There is Tumors of Rete Ovarii (which can be adenomatoid tumor or a mesothelioma). There are some tumors of uncertain origin, including small cell carcinoma, tumors of probable wolffian origin, a 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.
(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 treatment of specific diseases and cancers, the state of the art with regard to treating any disease, let alone any cancer which is encompassed by “any disease”, 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; instant PTO-892) teaches that 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 [column 1, lines 17-24].
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 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].
Additionally, 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. 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. 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. Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve [page 6, see Conclusion section].
Finally, the art teaches the unpredictability of antibody-based cancer immunotherapy. Christiansen et al., 2004 (instant PTO-892) teaches numerous factors that inhibit successful therapeutic application of antibodies including low or heterogeneous expression of target antigens by tumor cells, high background expression of target antigen on normal cells, host antibody immune responses to the antibodies themselves, insufficient antitumor response after antibody binding, as well as significant physical barriers preventing antibody binding or delivery to a solid tumor mass, including the vascular endothelium, stromal barriers, high interstitial pressure, and epithelial barriers [see Abstract, page 1493, column 2, page 1496, column 1, last paragraph through page 1498, column 2]. Topp et al., 1998 (instant PTO-892) also teaches the complications and unpredictability involved with treating tumors using antibody therapy. Topp teaches that there are several barriers to successful delivery of antibody drugs to extravascular sites of action within target tissues: the antibody drugs must be absorbed into the blood stream, carried by the circulatory system to the capillaries in the target tissue, cross the capillary endothelial cells and the underlying basement membrane that supports the capillary structure and penetrate through the matrix of cells and extracellular components that comprises the tissue itself, bind to the cell surface receptor, initiate endocytosis, encounter possible drug degradation and drug release. Additional connective tissue barriers may also be encountered [page 15, both columns, and Figure 1]. While some antibody drugs have been shown to be effective in vitro the results of clinical trials have been disappointing. The inability of the antibodies to penetrate the tumor mass could be a cause of this lack of clinical efficacy. Topp cautions against extrapolating in vitro results to in vivo therapy stating that the cell culture system has some limitations including a lack of well-developed extracellular matrix (“stroma”) that is present in many tumors. Normal components of tumor stroma include collagen, fibronectin and glycosaminoglycans [page 21, column 2]. Given the unpredictable art of treating tumors in vivo using antibody therapy, one of skill in the art could not predictably treat cancer in vivo comprising administering any antibody without undue experimentation.
Given Bally’s teaching of treatment-limiting toxicities in clinical use, 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, 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, and Christiansen’s and Topp’s teachings of the unpredictability of antibody-based cancer immunotherapy, 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 and/or preventing all types of disease encompassed by the instant claims. Applicant has provided evidence of treating non-small cell lung cancer, lymphoma, melanoma, colorectal carcinoma, and colon cancer in vivo with the anti-PD-L1/anti-CD47 bispecific antibody of the invention [see Examples 7-12 of the instant specification]. However, Applicant has not provided any substantive evidence of preventing or treating any disease with the claimed bispecific antibody. Because the diseases encompassed by the instant claims are so disparate, and no condition can be representative of all other encompassed diseases, a demonstration of treatment or support of a given condition does not provide support for the breadth of the claim.
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 the treatment of any disease using the claimed treatment, nor any examples directed to the palliative, preventative, or curative treatment of any disease. Therefore, the instant specification does not provide evidence or substantial guidance commensurate in scope with the broadly claimed method in how to use the method to prevent any disease.
In conclusion, the claimed invention does not provide enablement for treating or preventing all types of disease encompassed by the instant claims. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, and 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 27 and 28, which depend from claim 26, are therefore rejected for the same reasons set forth above.
Note: The Examiner recommends amending claim 26 to recite “A method of treating a cancer that expresses PD-L1 and/or CD47,…” and amending claim 28 to recite “The method of claim 26, wherein the cancer is selected from the group consisting of:…” to overcome this rejection.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4, 15, 19, 26, and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, 9, 12, and 15 of copending Application No. 18/260,691 (‘691) in view of Shi et al., 2020 (instant PTO-892).
Regarding claim 1 of the instant application, claim 1 of ‘691 teaches an isolated anti-human PD-L1 antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof comprises a light chain variable region and/or a heavy chain variable region, wherein, the light chain variable region comprises a LCDR1 of the amino acid sequence set forth in SEQ ID No. 20, a LCDR2 of the amino acid sequence set forth in SEQ ID No. 21, and a LCDR3 of the amino acid sequence set forth in SEQ ID No. 22; and/or the heavy chain variable region comprises a HCDR1 of the amino acid sequence set forth in SEQ ID No. 23, a HCDR2 of the amino acid sequence at least about 94% identical to SEQ ID Nos. 24, 45, 46 or 47; a HCDR3 of the amino acid sequence set forth in SEQ ID No. 25.
SEQ ID NOs: 20-22 for the LCDRs 1-3 and SEQ ID NOs: 23, 47, and 35 for the HCDRs 1-3 of ‘691 have 100% sequence identity to SEQ ID NOs: 37-39 for the LCDRs 1-3 and SEQ ID NOs: 40-42 for the HCDRs 1-3, respectively, of instant claim 1.
However, ‘691 does not specifically teach a bispecific antibody comprising the PD-L1 antigen-binding domain and a CD47 antigen-binding domain.
Shi teaches a CD47/PD-L1 dual-specific (bispecific) antibody with limited hemagglutination [page 3, left column, first-second paragraphs].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CD47/PD-L1 dual-specific antibody of Shi to comprise the CDR sequences of the anti-PD-L1 of ‘691. One would have been motivated to have used these sequences because they are known sequences in the art, and it is obvious to use known variations in the art for predictable outcomes. See MPEP 2143 (F).
Regarding claim 4 of the instant application, claim 6 of ‘691 teaches the anti-human PD-L1 antibody or antigen-binding fragment thereof according to claim 1, wherein (c) the light chain variable region has the amino acid sequence set forth in SEQ ID No. 44; and/or the heavy chain variable region has the amino acid sequence selected from those set forth in SEQ ID Nos. 40-43 or 51-53, and claim 7 of ‘691 teaches the anti-human PD-L1 antibody or antigen-binding fragment thereof according to claim 6, wherein (b) (b) the light chain variable region has the amino acid sequence set forth in SEQ ID No. 44; and/or the heavy chain variable region has the amino acid sequence selected from those set forth in SEQ ID Nos. 41 or 51-53.
SEQ ID NOs: 44 and 53 have 100% sequence identity to SEQ ID NOs: 2 and 6, respectively, of the instant claim.
Regarding claim 15 of the instant application, claim 9 of ‘691 teaches an isolated nucleic acid molecule selected from the group consisting of: (1) DNA or RNA encoding the anti-human PD-L1 antibody or antigen-binding fragment thereof according to claim 1; (2) a nucleic acid that is completely complementary to the nucleic acid defined in (1).
Regarding claim 19 of the instant application, claim 12 of ‘691 teaches a composition comprising the anti-human PD-L1 antibody or antigen-binding fragment thereof according to claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.
Regarding claims 26 and 28 of the instant application, claim 15 of ‘691 teaches a method of preventing and/or treating PD-L1-mediated diseases or disorders,
including administering to a subject in need thereof the anti-human PD-L1 antibody or antigen binding fragment thereof according to claim 1, preferably, the diseases or disorders are tumors; more preferably, the tumors are one or more selected from the group consisting of leukemia, lymphoma, myeloma, brain tumor, head and neck squamous cell carcinoma, non-small cell lung cancer, nasopharyngeal cancer, esophageal cancer, gastric cancer, pancreatic cancer, gallbladder cancer, liver cancer, colorectal cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, bladder cancer, renal cell carcinoma, and melanoma.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4, 7-9, 15, 19, 26, and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, 9, 12, and 15 of copending Application No. 18/260,691 (‘691) in view of Shi et al., 2020 (instant PTO-892), as applied to claims 1, 4, 15, 19, 26, and 28 above, and further in view of Wu et al., 2015 (instant PTO-892).
The teachings of ‘691 and Shi are above.
However, ‘691 and Shi do not specifically teach that the first antigen-binding functional region and the second antigen-binding functional region are both Fabs.
Regarding claims 7 and 8, Wu teaches that Fab-based BsAbs have superior biophysical properties compared to the scFv-based BsAbs [see Abstract].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the bispecific antibody, as taught by ‘691 and Shi, to specifically have the first antigen-binding functional region and the second antigen-binding functional region both be Fabs. One would have been motivated to make this modification because Wu teaches that Fab-based BsAbs have superior biophysical properties compared to the scFv-based BsAbs
Regarding claim 9, since each antigen-binding functional region binds to a different antigen (i.e. PD-L1 and CD47), then each necessarily has a different heavy chain region and light chain variable region than the other.
This is a provisional nonstatutory double patenting rejection.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Copending Application 18/260,435 (‘435)
The Examiner considered the claims as they currently stand in copending application 18/260,435 as the sequences for the PD-L1 binding region are 100% identical to those as claimed in instant claim 1. However, ‘435 is drawn to a PD-L1/4-1BB bispecific antibody and the instant claims are drawn to a PD-L1/CD47 bispecific antibody. Thus, in order to modify the antibody of ‘435, it would render the antibody unsatisfactory for its intended use [see MPEP 2143.01(V)]. As such, no double patenting rejection was made.
No claims are allowed.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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