Go toNotice 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
Claims 1-9, 11-14, 19-21, and 24-28 are pending.
Claims 10, 15-18, and 22-23 are canceled.
Claim 6 is amended.
Applicant’s election without traverse of Group I, claims 1-9, 11-14, 19-21, and 24-26 in the reply filed on 12/22/2025 is acknowledged. Applicant’s election of the following species without traverse in the reply filed on 12/22/2025 is acknowledged: CRS for what the method further comprises treating, tocilizumab as the specific anti-cytokine agent to treat CRS, pyrexia for what the CRS comprises, and dimethyl sulfoxide for the excipient.
Claims 11-14, 19-21, 27 and 28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/22/2025.
Therefore, claims 1-9 and 24-26 are under examination.
Priority
The instant application claims priority to provisional application 63/314,968. Priority is given with the earliest effective filing date of 02/28/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/07/2023 and 12/22/2025 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 documents lined through on the 12/22/2025 IDS were not considered because they were not of sufficient quality and therefore could not be 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.
Further, the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains embedded hyperlinks and/or other forms of browser-executable code (see pages 147 and 164 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
Claim 9 is objected to because of the following informalities: Claim 9 recites the limitation “optionally symptom of HLH or MAS”. This is grammatically awkward and the Examiner recommends amending the claim to recite “optionally a symptom of HLH or MAS”. Further, Claim 9 recites the limitation “wherein CRS comprises fever, pyrexia”. It is well accepted in the art that fever and pyrexia are equivalent terms, with pyrexia being the medial term for fever. Therefore, having both fever and pyrexia is redundant. The Examiner recommends amending the claim to delete one of the terms. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-9, 24, and 26 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 1 recites the limitation “ a method of treating a subject, comprising administering to the subject a single infusion of a dose of a composition comprising T cells comprising a CAR…”. It is unclear how the composition comprising the CAR can treat anything in any subject (i.e. one that is not in need of treatment). Therefore, the scope of this claim is indefinite.
Claims 2-9 and 24, which depend from claim 1, are therefore indefinite for the same reasons.
This rejection can be overcome by amending claim 1 to recite “a subject in need thereof.”
Claims 1, 6-8, and 24 recite the limitation “about”. Applicant has provided an explicit definition for “about” meaning “being within a statistically meaningful range of a value.” (see paragraph 76 of the Specification). However, the metes and bounds for “about” are dependent on the interpretation of others for determining what is a “meaningful” error range. Given a single value, one person of ordinary skill in the art could determine that the value is acceptably in the error range. Yet, another person of ordinary skill in the art could determine that it is unacceptable, leading to two different interpretations on if the claim infringes with “about.” Therefore, these claims are indefinite.
Claims 2, 6-9, and 24 recite the limitation(s) “optionally” and/or “further optionally.” The use of “optionally” and “further optionally” in these claims renders the claims indefinitely as it is unclear if the terms that follow, which further limit the preceding limitations, are part of the claimed invention or are exemplary embodiments. See MPEP 2173.05(d). For purposes of examination, the Examiner will interpret the limitations following the terms “optionally” and “further optionally” as exemplary embodiments rather than required limitations of the claims.
Claim 9 recites the limitation “(e.g., retroperitoneal, intracerebral or gastrointestinal hemorrhage)”. It is unclear, due to the presence of the parentheses, if the terms/phrases are intended as limitations of the claims, or are merely exemplary. 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.” Therefore, the scope of this claim is indefinite.
Claim 26 recites the limitation “a method for treating relapsed or refractory multiple myeloma in a patient in need thereof, comprising administering an approved drug product comprising a ciltacabtagene autoleucel suspension in an amount and manner that is described in a drug product label for the approved drug product.” It is unclear how the drug product could treat a patient in need thereof if the composition is not administered to the patient. Therefore, the scope of this claim is indefinite.
The Examiner recommends amending the claim to recites “…comprising administering to the subject an approved drug product…” to overcome this rejection.
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 1-9 and 24 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 relapsed or refractory multiple myeloma in a subject in need thereof comprising administering a composition comprising T cells comprising a CAR with the amino acid sequence of SEQ ID NO: 17 (i.e. ciltacabtagene autoleucel), does not reasonably provide enablement for a method of treating a subject without any requirement for what is to be treated in the subject. 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.
(4) The nature of the invention and (8) The breadth of the claims:
The claims are drawn to a method of treating a subject, comprising administering to the subject a single infusion of a dose of a composition comprising T cells comprising a chimeric antigen receptor (CAR), wherein the CAR comprises the amino acid sequence of SEQ ID NO: 17; wherein the dose comprises 0.5 x 106 to 1.0 x 106 of the T cells/kg of body weight of the subject; and wherein the method comprises completing administering to the subject the dose of T cells within about 2.5 hours at a temperature of about 20°C to 25°C. Claim 2 adds the limitation of wherein the subject has relapsed or refractory multiple myeloma. However, there is no requirement that the method of treating is for treating the relapsed or refractory multiple myeloma in the subject.
The nature of the invention is a chemical case, where there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; see MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to use the claimed product, with a reasonable expectation of success, because it would not be predictable from the disclosure of any one particular species what other species may or may not work; see MPEP 2164.03. The claims broadly encompass treating any disease, disorder, or condition in any subject, whether they require treatment or not, by administering a composition comprising T cells comprising a CAR with the sequence of SEQ ID NO: 17. 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, disorders, or conditions encompassed by “a method of treating”. One genus of disease encompassed by the claims is 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 the composition comprising T cells comprising a CAR with the amino acid sequence of SEQ ID NO: 17 would treat any disease, disorder, or condition, let alone any cancer, in any subject, whether they are in need of treatment or not. There is no support provided in the instant specification or in the prior or instant art that teaches or supports the ability treat any disease, disorder, or condition encompassed by these broad claims. The only working example in the specification is towards the treatment of relapsed or refractory multiple myeloma in patients in need thereof [see Examples 2-7].
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
Regarding the encompassed genus of cancer in the broad claims, 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. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all cancers with the claimed composition 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 disease, disorder, or condition as encompassed by the instant claims. Applicant has provided evidence of treating relapsed or refractory multiple myeloma [see Examples 1-7 of the instant specification]. However, Applicant has not provided any substantive evidence that the administration of a composition comprising T cells comprising a CAR with the amino acid sequence of SEQ ID NO: 17 would treat any disease, disorder, or condition, let alone any cancer.
In conclusion, the claimed invention does not provide enablement for treating any disease, disorder, or condition. 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 2-9 and 24, which depend from claim 1, are rejected for the same reasons set forth above.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Madduri et al., 2019 (12/22/2025 IDS), in view of Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892).
Regarding claim 1, Madduri teaches JNJ-68284528 (JNJ-4528; ciltacabtagene autoleucel), a chimeric antigen receptor T cell (CAR-T) therapy, administered to subjects as a single infusion at a target range of 0.5-1.0x106 CAR+ T cells/kg to treat refractory multiple myeloma [page 1, paragraphs 1-2].
Note: SEQ ID NO: 17, as claimed in instant claim 1, is termed ciltacabtagene autoleucel (cilta-cel), as disclosed in the instant specification [see paragraph 86], which is also termed JNJ-68284528 and LCAR-B38M as taught by Madduri et al., 2020 (12/22/2025 IDS). Therefore, the CAR taught by Madduri is the same as the claimed CAR of SEQ ID NO: 17.
However, Madduri does not specifically teach that the CAR T cells are administered within about 2.5 hours at a temperature of about 20-25 degrees Celsius.
Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes [page 1].
Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes [page 4]. Rioufol also teaches that the CAR T cells are administered by a nurse in a hematology department [page 4], and that CAR T-cells are stored in bags or syringes (container; package) in cryogenic containers prior to administration [pages 2-3].
ECA teaches that controlled room temperature is 20-25 degrees Celsius [page 2].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to one of ordinary skill in the art to have administered the CAR T cells of Madduri within 2.5 hours, as taught by Dana-Farber, and at a temperature of 20-25 degrees Celsius, as taught by Rioufol and ECA. One would have been motivated to have administered the CAR T cells of Madduri within 2.5 hours at a temperature of 20-25 degrees Celsius because Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes, Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes and that the CAR T cells are administered by a nurse in a hematology department, i.e. a controlled temperature environment, and ECA teaches that that controlled room temperature is 20-25 degrees Celsius. Further, there would be a reasonable expectation of success in administering the CAR T cells within 2.5 hours at a temperature of 20-25 degrees Celsius because these are known values of known parameters in the art.
Claims 2 and 3 are included in this rejection because Madduri teaches that patients had received a median of 5 prior lines of treatment [page 2, third paragraph].
Claim 4 is included in this rejection because Madduri teaches that the patients were triple refractory to a PI (proteasome inhibitor), IMiD (immunomodulatory drug), and anti-CD38 antibody, thereby indicating that these were prior lines of therapy [page 2, third paragraph].
Claim 5 is included in this rejection because the CAR T cells of Madduri are necessarily autologous T cells, as evidenced by Abebe et al., 2022 (instant PTO-892) that teaches that Cilta-cel (i.e. SEQ ID NO: 17) is an autologous, gene edited CAR T-cell therapy [see Abstract].
Claim 6 is included in this rejection because Madduri teaches that cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days were used as the conditioning regimen (i.e. lymphodepleting chemotherapy regimen), and that the CAR T cells were administered 5-7 days after the start of the conditioning regimen [page 1, second paragraph – page 2, first paragraph].
Claim 7 is included in this rejection because Rioufol teaches that the CAR T cells are thawed in a 37 +/- 2 degrees Celsius [page 4]. Thus, since Rioufol teaches that the CAR T cells are thawed at the same temperature, then they necessarily would thaw completely in no more than about 15 minutes.
Claim 8 is included in this rejection because Madduri teaches that a majority of the patients treated had grade 1-2 CRS, and that tocilizumab and corticosteroids were administered to treat patients with CRS [page 2 , paragraphs 4-5].
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Madduri et al., 2019 (12/22/2025 IDS), in view of Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892), as applied to claims 1-8 above, and further in view of Le et al., 2018 (instant PTO-892).
The teachings of Madduri, Dana-Farber, Rioufol, and ECA are above. To reiterate, Madduri teaches that a majority of the patients treated had grade 1-2 CRS, and that tocilizumab and corticosteroids were administered to treat patients with CRS.
However, Madduri, Dana-Farber, Rioufol, and ECA do not specifically teach that the CRS comprises pyrexia (fever).
Regarding claim 9, Le teaches that characteristics of CRS include fever, fatigue, headache, encephalopathy, hypotension, tachycardia, coagulopathy, nausea, capillary leak, and multiorgan dysfunction, often occurring after CAR T-cell therapy [page 943, left column, first paragraph of introduction].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically treated CRS after administering the dose of the T cells, as taught by Madduri, Dana-Farber, Rioufol, and ECA, wherein the CRS comprises pyrexia, as taught by Le. One would have been motivated to have treated CRS comprising pyrexia because Madduri teaches that a majority of the patients treated had grade 1-2 CRS, and that tocilizumab and corticosteroids were administered to treat patients with CRS, and Le teaches that a characteristic of CRS includes fever, often occurring after CAR T-cell therapy.
Claims 1-8 and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over Madduri et al., 2019 (12/22/2025 IDS), in view of Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892), as applied to claims 1-8 above, and further in view of Kaiser et al., 2021 (instant PTO-892).
The teachings of Madduri, Dana-Farber, Rioufol, and ECA are above. To reiterate, Madduri teaches that the patients with refractory multiple myeloma had received a median of 5 prior lines of treatment [page 2, third paragraph] and were triple refractory to a PI (proteasome inhibitor), IMiD (immunomodulatory drug), and anti-CD38 antibody, thereby indicating that these were prior lines of therapy [page 2, third paragraph], and Rioufol teaches that CAR T-cells are stored in bags or syringes (container; package) in cryogenic containers prior to administration [pages 2-3].
However, Madduri, Dana-Farber, Rioufol, and ECA do not specifically teach that the composition further comprises an excipient of dimethyl sulfoxide at 5%.
Regarding claims 24-26, Kaiser teaches that cryopreservation in serum-free freezing medium supplemented with 10% HAS and 5% DMSO (dimethyl sulfoxide) facilitates improved T cells recovery and functionality [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 specifically formulated the composition of JNJ-68284528 CAR T-cells, as taught by Madduri, to comprise 10% HAS and 5% DMSO, as taught by Kaiser. One would have been motivated to have formulated the CAR T-cells in a container (packaged) with 10% HAS and 5% DMSO (i.e. a ciltacabtagene autoleucel suspension) because Rioufol teaches that CAR T-cells are stored in bags or syringes for infusion in cryogenic containers prior to administration and Kaiser teaches that cryopreservation in serum-free freezing medium supplemented with 10% HAS and 5% DMSO facilitates improved T cells recovery and functionality.
Further regarding claims 25 and 26, the claims do not require any further steps that have not already been taught by the prior art above. The claims simply add the limitation of comprising a drug product label. MPEP 2112.01 (III) states “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art” In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). Additionally, The Examiner is interpreting the JNJ-68284528 CAR T cells (i.e. SEQ ID NO: 17) as an approved drug product, a limitation of instant claims 25-26, since the drug is administered to patients in order to treat refractory multiple myeloma, as taught by Madduri.
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.
Copending Application No. 17/540,736 (‘736)
Claims 1-8 and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 12-13, 19-21, 24-26, 35-36 and 38-39 of copending Application No. 17/540,736 (‘736) in view of Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892).
Regarding claim 1 of the instant application, claims 1 and 85 of ‘736 teach a method of treating a subject who has multiple myeloma, comprising administering to the subject a dose of T cells via a single intravenous infusion comprising a chimeric antigen receptor (CAR) comprising the amino acid sequence of SEO ID NO: 17, wherein the dose comprises 0.5 x 106 to 1.0 x 106 of the T cells per kilogram of the mass of the subject, claim 6 teaches that the method comprises administering to the subject a single bag (package) of the T cells, and wherein the T cells are contained in a single cryopreserved bag (i.e. single infusion).
SEQ ID NO: 17 of ‘736 has 100% sequence identity to SEQ ID NO: 17 of the instant claim.
However, ‘736 does not specifically teach that the CAR T cells are administered within about 2.5 hours at a temperature of about 20-25 degrees Celsius.
Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes [page 1].
Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes [page 4]. Rioufol also teaches that the CAR T cells are administered by a nurse in a hematology department [page 4], and that CAR T-cells are stored in bags or syringes (container; package) in cryogenic containers prior to administration [pages 2-3].
ECA teaches that controlled room temperature is 20-25 degrees Celsius [page 2].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to one of ordinary skill in the art to have administered the CAR T cells of ‘736 within 2.5 hours, as taught by Dana-Farber, and at a temperature of 20-25 degrees Celsius, as taught by Rioufol and ECA. One would have been motivated to have administered the CAR T cells of ‘736 within 2.5 hours at a temperature of 20-25 degrees Celsius because Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes, Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes and that the CAR T cells are administered by a nurse in a hematology department, i.e. a controlled temperature environment, and ECA teaches that that controlled room temperature is 20-25 degrees Celsius. Further, there would be a reasonable expectation of success in administering the CAR T cells within 2.5 hours at a temperature of 20-25 degrees Celsius because these are known values of known parameters in the art.
Claims 2 and 4 of the instant application are included in this rejection because claim 1 of ‘736 teaches the subject has received prior treatment with at least three prior lines of treatment, and wherein the at least three prior lines of treatment comprise treatment with at least one medicament, and the at least one medicament comprises:
(a) a PI; (b) an IMiD; or (c) an anti-CD38 antibody, or any combination thereof, claim 35 of ‘736 teaches that the subject has relapsed after the at least three lines of treatment, claim 36 of ‘736 teaches that the multiple myeloma is refractory to at least two medicaments following the at least three prior lines of treatment, claim 38 of ‘736 teaches that the multiple myeloma is refractory to at least three medicaments.
Claim 3 of the instant application is included in this rejection because claim 39 of ‘736 teaches that the multiple myeloma is refractory to at least four or five medicaments, thereby indicating that the subject has received four or more prior lines of therapy.
Claim 5 of the instant application is included in this rejection because claim 82 of ‘736 teaches that the T cells are autologous T cells.
Claim 6 of the instant application is included in this rejection because claim 12 of ‘736 teaches that the method comprises administering to the subject a lymphodepleting regimen prior to administering the T cells, claim 13 of ‘736 teaches that the lymphodepleting regimen comprises: (a) administration of cyclophosphamide; and/or (b) administration of fludarabine.
Claim 7 of the instant application is included in this rejection because Rioufol teaches that the CAR T cells are thawed in a 37 +/- 2 degrees Celsius [page 4]. Thus, since Rioufol teaches that the CAR T cells are thawed at the same temperature, then they necessarily would thaw completely in no more than about 15 minutes.
Claim 8 of the instant application is included in this rejection because claim 19 of ‘736 teaches that the method further comprises treating the subject for cytokine release syndrome (CRS) more than 3 days following administering the T cells without significantly reducing expansion in vivo of the T cells, claim 20 of ‘736 teaches that the treating for CRS comprises administering to the subject an IL-6R inhibitor, claim 21 of ‘736 teaches that the IL-6R inhibitor is an antibody, claim 24 teaches that the IL-6R inhibitor is tocilizumab.
Claim 24 of the instant application is included in this rejection because claim 32 of ‘746 teaches that the dose of T cells further comprises an excipient comprising dimethylsulfoxide or dextran-40.
Claims 25 and 26 of the instant application are included in this rejection because the claims do not require any further steps that have not already been taught by the teachings above. The claims simply add the limitation of comprising a drug product label. MPEP 2112.01 (III) states “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art” In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). Additionally, the Examiner is interpreting the CAR T cell of ‘349 as an approved drug product, a limitation of instant claims 25-26, since the drug is administered to patients in order to treat relapsed and/or refractory multiple myeloma.
This is a provisional nonstatutory double patenting rejection.
Claims 1-8 and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 12-13, 19-21, 24-26, 35-36 and 38-39 of copending Application No. 17/540,736 (‘736) in view of Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892), as applied to claims 1-8 and 24-26 above, and further in view of Le et al., 2018 (instant PTO-892).
The teachings of ‘736, Dana-Farber, Rioufol, and ECA are above. To reiterate, claim 19 of ‘736 teaches that the method further comprises treating the subject for cytokine release syndrome (CRS) more than 3 days following administering the T cells without significantly reducing expansion in vivo of the T cells, claim 20 of ‘736 teaches that the treating for CRS comprises administering to the subject an IL-6R inhibitor, claim 21 of ‘736 teaches that the IL-6R inhibitor is an antibody, claim 24 teaches that the IL-6R inhibitor is tocilizumab.
However, ‘736, Dana-Farber, Rioufol, and ECA do not specifically teach that the CRS comprises pyrexia (fever).
Regarding claim 9, Le teaches that characteristics of CRS include fever, fatigue, headache, encephalopathy, hypotension, tachycardia, coagulopathy, nausea, capillary leak, and multiorgan dysfunction, often occurring after CAR T-cell therapy [page 943, left column, first paragraph of introduction].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically treated CRS after administering the dose of the T cells, as taught by ‘736, Dana-Farber, Rioufol, and ECA, wherein the CRS comprises pyrexia, as taught by Le. One would have been motivated to have treated CRS comprising pyrexia because claim 19 of ‘736 teaches that the method further comprises treating the subject for cytokine release syndrome (CRS) more than 3 days following administering the T cells without significantly reducing expansion in vivo of the T cells, claim 20 of ‘736 teaches that the treating for CRS comprises administering to the subject an IL-6R inhibitor, claim 21 of ‘736 teaches that the IL-6R inhibitor is an antibody, claim 24 teaches that the IL-6R inhibitor is tocilizumab, and Le teaches that a characteristic of CRS includes fever, often occurring after CAR T-cell therapy.
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 18/052,349 (‘349)
Claims 1-7 and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 104,151,189, 220-221, and 223-224 of copending Application No. 18/052,349 (‘349) in view of Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892).
Regarding claim 1 of the instant application, claims 1-3 of ‘349 teach a method of treating a subject, said method comprising administering to the subject a composition comprising a therapeutically effective number of T cells comprising a chimeric antigen receptor (CAR), to deliver to the subject a dose of CAR expressing T cells (CAR-T cells), wherein said subject has multiple myeloma, claims 189, 221, and 224 teach that the CAR comprises the amino acid sequence of SEQ ID NO: 17, claims 151, 220, and 223 teaches that the administration of said CAR-T cells is via a single intravenous infusion, wherein the single intravenous infusion is administered using a single bag (package) of CAR-T cells and that the dose comprises 1.0 x 105 to 5.0 x 106 of said CAR-T cells per kilogram of the mass of the subject.
SEQ ID NO: 17 of ‘349 has 100% sequence identity to SEQ ID NO: 17 of the instant claim.
However, ‘349 does not specifically teach that the CAR T cells are administered within about 2.5 hours at a temperature of about 20-25 degrees Celsius.
Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes [page 1].
Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes [page 4]. Rioufol also teaches that the CAR T cells are administered by a nurse in a hematology department [page 4], and that CAR T-cells are stored in bags or syringes (container; package) in cryogenic containers prior to administration [pages 2-3].
ECA teaches that controlled room temperature is 20-25 degrees Celsius [page 2].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to one of ordinary skill in the art to have administered the CAR T cells of ‘349 within 2.5 hours, as taught by Dana-Farber, and at a temperature of 20-25 degrees Celsius, as taught by Rioufol and ECA. One would have been motivated to have administered the CAR T cells of ‘349 within 2.5 hours at a temperature of 20-25 degrees Celsius because Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes, Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes and that the CAR T cells are administered by a nurse in a hematology department, i.e. a controlled temperature environment, and ECA teaches that that controlled room temperature is 20-25 degrees Celsius. Further, there would be a reasonable expectation of success in administering the CAR T cells within 2.5 hours at a temperature of 20-25 degrees Celsius because these are known values of known parameters in the art.
Claims 2 and 3 of the instant application are included in this rejection because claim 104 of ‘349 teaches that the subject received prior treatment with at least four prior lines of therapy and the subject has relapsed after said at least one prior line of therapy, claim 151 of ‘349 teaches that the multiple myeloma is refractory to at least four or at least five medicaments, and claim 220 of ‘349 teaches that the multiple myeloma is refractory to at least at least four or at least five medicaments, thereby indicating that the subject has relapsed and/or refractory myeloma.
Claim 4 of the instant application is included in this rejection because claim 104 of ‘349 teaches that the at least four medicaments further comprises a proteasomal inhibitor, an immunomodulatory drug and an anti-CD38 antibody.
Claim 5 of the instant application is included in this rejection because claims 189, 221, and 224 of ‘349 teaches that the T cells are autologous.
Claim 6 of the instant application is included in this rejection because claim 151, 220, and 223 of ‘349 teaches that a lymphodepleting regimen precedes said administration of CAR-T cells by approximately 5 days to approximately 7 days, further optionally wherein said lymphodepleting regimen is administered intravenously, further optionally wherein said lymphodepleting regimen comprises administration of cyclophosphamide; or administration of fludarabine.
Claim 7 of the instant application is included in this rejection because Rioufol teaches that the CAR T cells are thawed in a 37 +/- 2 degrees Celsius [page 4]. Thus, since Rioufol teaches that the CAR T cells are thawed at the same temperature, then they necessarily would thaw completely in no more than about 15 minutes.
Claim 24 of the instant application is included in this rejection because claims 151, 220, and 223 of ‘349 teach that the composition comprising CAR-T cells administered to the subject further comprises an excipient selected from dimethylsulfoxide or dextran-40.
Claims 25 and 26 of the instant application are included in this rejection because the claims do not require any further steps that have not already been taught by the teachings above. The claims simply add the limitation of comprising a drug product label. MPEP 2112.01 (III) states “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art” In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). Additionally, the Examiner is interpreting the CAR T cell of ‘349 as an approved drug product, a limitation of instant claims 25-26, since the drug is administered to patients in order to treat relapsed and/or refractory multiple myeloma.
This is a provisional nonstatutory double patenting rejection.
Claims 1-9 and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 104,151,189, 220-221, and 223-224 of copending Application No. 18/052,349 (‘349) in view of Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892), as applied to claims 1-7 and 24-26 above, and further in view of Le et al., 2018 (instant PTO-892).
However, ‘349, Dana-Farber, Rioufol, and ECA do not specifically teach that the CRS comprises pyrexia (fever).
Regarding claims 8 and 9 of the instant application, Le teaches that tocilizumab is for the treatment of CAR T-cell-induced CRS [see Abstract] characteristics of CRS include fever, fatigue, headache, encephalopathy, hypotension, tachycardia, coagulopathy, nausea, capillary leak, and multiorgan dysfunction, often occurring after CAR T-cell therapy [page 943, left column, first paragraph of introduction].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically treated CRS after administering the dose of the T cells, as taught by ‘349, Dana-Farber, Rioufol, and ECA, by administering tocilizumab and wherein the CRS comprises pyrexia, as taught by Le. One would have been motivated to have treated CRS with tocilizumab wherein the CRS comprises pyrexia because Le teaches that a characteristic of CRS includes fever and often occurs after CAR T-cell therapy and that tocilizumab is for the treatment of CAR T-cell-induced CRS.
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 18/592,234 (‘234)
Claims 1-2, 3-9, and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, 23, 26, 34, 37, and 40 of copending Application No. 18/592,234 (‘234) in view of Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892).
Regarding claims 1-2 of the instant application, claim 1 of ‘234 teaches a method of treating a subject, comprising administering to the subject a dose of T cells comprising a chimeric antigen receptor (CAR), wherein the subject has multiple myeloma, has received one to three prior lines of therapies, including a therapy with an immunomodulatory drug (IMiD), and is refractory to the IMiD (i.e. refractory multiple myeloma), claim 26 of ‘234 teaches that the dose of T cells is 0.5-1.0 x 106 cells/kg and that the dose is administered in a single infusion, and claim 40 of ‘234 teaches that the CAR comprises the amino acid sequence of SEQ ID NO: 17.
SEQ ID NO: 17 of ‘234 has 100% sequence identity to SEQ ID NO: 17 of the instant claim.
However, ‘234 does not specifically teach that the CAR T cells are administered within about 2.5 hours at a temperature of about 20-25 degrees Celsius.
Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes [page 1].
Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes [page 4]. Rioufol also teaches that the CAR T cells are administered by a nurse in a hematology department [page 4], and that CAR T-cells are stored in bags or syringes (container; package) in cryogenic containers prior to administration [pages 2-3].
ECA teaches that controlled room temperature is 20-25 degrees Celsius [page 2].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to one of ordinary skill in the art to have administered the CAR T cells of ‘234 within 2.5 hours, as taught by Dana-Farber, and at a temperature of 20-25 degrees Celsius, as taught by Rioufol and ECA. One would have been motivated to have administered the CAR T cells of ‘234 within 2.5 hours at a temperature of 20-25 degrees Celsius because Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes, Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes and that the CAR T cells are administered by a nurse in a hematology department, i.e. a controlled temperature environment, and ECA teaches that that controlled room temperature is 20-25 degrees Celsius. Further, there would be a reasonable expectation of success in administering the CAR T cells within 2.5 hours at a temperature of 20-25 degrees Celsius because these are known values of known parameters in the art.
Claim 4 of the instant application is included in this rejection because claim 1 of ‘234 teaches that the subject has received prior therapy of an immunomodulatory drug (IMiD) and claim 17 of ‘234 teaches that the prior therapy further comprises treatment with an anti-CD38 antibody and a proteasome inhibitor.
Claim 5 of the instant application is included in this rejection because the CAR T cells of ‘234 are necessarily autologous T cells, as evidenced by Abebe et al., 2022 (instant PTO-892) that teaches that Cilta-cel (i.e. SEQ ID NO: 17) is an autologous, gene edited CAR T-cell therapy [see Abstract].
Claim 6 of the instant application is included in this rejection because claim 23 of ‘234 teaches that the patient has received a lymphodepletion therapy, wherein the lymphodepletion therapy comprises cyclophosphamide and/or fludarabine, and claim 26 of ‘234 teaches that the T cells are administered after the start of lymphodepletion therapy.
Claim 7 of the instant application is included in this rejection because Rioufol teaches that the CAR T cells are thawed in a 37 +/- 2 degrees Celsius [page 4]. Thus, since Rioufol teaches that the CAR T cells are thawed at the same temperature, then they necessarily would thaw completely in no more than about 15 minutes.
Claims 8 and 9 of the instant application are included in this rejection because claim 37 of ‘234 teaches that the subject is further treated for a CAR-T-associated adverse event after administering the dose of the T cells, wherein the adverse event is CRS, and the treatment comprises tocilizumab, and claim 34 of ‘234 teaches that the adverse event comprises pyrexia.
Claim 24 of the instant application is included in this rejection because claim 40 of ‘234 teaches that the dose of T cells is formulated in a composition comprising 5% dimethyl sulfoxide (DMSO).
Claims 25 and 26 of the instant application are included in this rejection because the claims do not require any further steps that have not already been taught by the teachings above. The claims simply add the limitation of comprising a drug product label. MPEP 2112.01 (III) states “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art” In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). Additionally, the Examiner is interpreting the CAR T cell of ‘234 as an approved drug product, a limitation of instant claims 25-26, since the drug is administered to patients in order to treat refractory multiple myeloma.
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 19/045,247 (‘247)
Claims 1-9 and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 31, 39, 86, 88, 95-96, 99, 116-117, and 119 of copending Application No. 19/045,247 (‘247) in view of Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892).
Regarding claims 1-2 of the instant application, claim 1 of ‘247 teaches a method of treating a subject with multiple myeloma, the method comprising administering to the subject a dose of T cells comprising a chimeric antigen receptor (CAR), claim 39 of ‘247 teaches that the dose of T cells is in a single infusion, claim 116 of ‘247 teaches that the CAR comprises the amino acid sequence of SEQ ID NO: 17, and claim 119 of ‘247 teaches a method of treating a subject with multiple myeloma, wherein the subject has not achieved a complete response after receiving an initial therapy comprising (1) 4 to 8 cycles of an induction therapy, (2) a high-dose chemotherapy, and (3) an autologous stem cell transplantation (ASCT) (i.e. refractory), the method comprising administering to the subject a dose of T cells comprising a chimeric antigen receptor (CAR) comprising the amino acid sequence of SEQ ID NO: 17.
SEQ ID NO: 17 of ‘247 has 100% sequence identity to SEQ ID NO: 17 of the instant claim.
However, ‘247 does not specifically teach that the CAR T cells are administered within about 2.5 hours at a temperature of about 20-25 degrees Celsius.
Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes [page 1].
Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes [page 4]. Rioufol also teaches that the CAR T cells are administered by a nurse in a hematology department [page 4], and that CAR T-cells are stored in bags or syringes (container; package) in cryogenic containers prior to administration [pages 2-3].
ECA teaches that controlled room temperature is 20-25 degrees Celsius [page 2].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to one of ordinary skill in the art to have administered the CAR T cells of ‘247 within 2.5 hours, as taught by Dana-Farber, and at a temperature of 20-25 degrees Celsius, as taught by Rioufol and ECA. One would have been motivated to have administered the CAR T cells of ‘247 within 2.5 hours at a temperature of 20-25 degrees Celsius because Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes, Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes and that the CAR T cells are administered by a nurse in a hematology department, i.e. a controlled temperature environment, and ECA teaches that that controlled room temperature is 20-25 degrees Celsius. Further, there would be a reasonable expectation of success in administering the CAR T cells within 2.5 hours at a temperature of 20-25 degrees Celsius because these are known values of known parameters in the art.
Claims 3 and 4 of the instant application are included in this rejection because claim 2 of ‘247 teaches that the initial (prior) therapy further comprises 4 to 8 cycles of an induction therapy, wherein the induction therapy comprises a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), and further comprises an anti-CD38 antibody.
Claim 5 of the instant application is included in this rejection because the CAR T cells of ‘247 are necessarily autologous T cells, as evidenced by Abebe et al., 2022 (instant PTO-892) that teaches that Cilta-cel (i.e. SEQ ID NO: 17) is an autologous, gene edited CAR T-cell therapy [see Abstract].
Claim 6 of the instant application is included in this rejection because claim 31 of ‘247 teaches that the subject has further received a lymphodepletion therapy at least about 5 to about 7 days prior to the administering of the dose of the T cells, wherein the lymphodepletion therapy comprises administering cyclophosphamide and fludarabine.
Claim 7 of the instant application is included in this rejection because Rioufol teaches that the CAR T cells are thawed in a 37 +/- 2 degrees Celsius [page 4]. Thus, since Rioufol teaches that the CAR T cells are thawed at the same temperature, then they necessarily would thaw completely in no more than about 15 minutes.
Claims 8 and 9 of the instant application is included in this rejection because claim 86 of ‘247 teaches that the method further comprises treating the subject for an adverse event after the administering of the dose of the T cells, claim 88 of ‘247 teaches that the adverse event comprises a treatment-emergent adverse event, claim 96 teaches that the treatment0emergent adverse event is CRS, claim 99 of ‘247 teaches that treatment for the CRS comprises tocilizumab, and claim 95 of ‘247 teaches that the treatment-emergent adverse event comprises pyrexia.
Claim 24 of the instant application is included in this rejection because claim 117 of ‘247 teaches that the dose of T cells is formulated in a composition comprising 5% dimethyl sulfoxide (DMSO).
Claims 25 and 26 of the instant application are included in this rejection because the claims do not require any further steps that have not already been taught by the teachings above. The claims simply add the limitation of comprising a drug product label. MPEP 2112.01 (III) states “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art” In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). Additionally, the Examiner is interpreting the CAR T cell of ‘247 as an approved drug product, a limitation of instant claims 25-26, since the drug is administered to patients in order to treat refractory multiple myeloma.
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 19/076,517 (‘517)
Claims 1-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 13, 16-17, and 21 of copending Application No. 19/076,517 (‘517) in view of Madduri et al., 2019 (12/22/2025 IDS), Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892).
Regarding claims 1-2 of the instant application, claims 1-3 of ‘517 teach a method of treating a multiple myeloma in a subject in need thereof, the method comprising administering ciltacabtagene autoleucel to the subject, wherein the subject has received one, two, or three prior lines of therapy, wherein at least one of the prior lines of therapy comprise treatment with an immunomodulatory drug (IMiD), and the subject is refractory to the IMiD, claim 17 of ‘517 teaches that the ciltacabtagene autoleucel is administered to the subject at a dose of about 0.5 to about 1.0 x 106 CAR-positive viable T cells/kg.
Note: SEQ ID NO: 17, as claimed in instant claim 1, is termed ciltacabtagene autoleucel (cilta-cel), as disclosed in the instant specification [see paragraph 86]. Therefore, the ciltacabtagene autoleucel taught by ‘517 is the same as the claimed CAR of SEQ ID NO: 17.
However, ‘517 does not specifically teach that the CAR T cells are administered in a single infusion and within about 2.5 hours at a temperature of about 20-25 degrees Celsius.
Madduri teaches JNJ-68284528 (JNJ-4528; ciltacabtagene autoleucel), a chimeric antigen receptor T cell (CAR-T) therapy, administered to subjects as a single infusion at a target range of 0.5-1.0x106 CAR+ T cells/kg to treat refractory multiple myeloma [page 1, paragraphs 1-2].
Note: SEQ ID NO: 17, as claimed in instant claim 1, is termed ciltacabtagene autoleucel (cilta-cel), as disclosed in the instant specification [see paragraph 86], which is also termed JNJ-68284528 and LCAR-B38M as taught by Madduri et al., 2020 (12/22/2025 IDS). Therefore, the CAR taught by Madduri above is the same as the claimed CAR of SEQ ID NO: 17.
Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes [page 1].
Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes [page 4]. Rioufol also teaches that the CAR T cells are administered by a nurse in a hematology department [page 4], and that CAR T-cells are stored in bags or syringes (container; package) in cryogenic containers prior to administration [pages 2-3].
ECA teaches that controlled room temperature is 20-25 degrees Celsius [page 2].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to one of ordinary skill in the art to have administered the CAR T cells of ‘517 in a single infusion, as taught by Madduri. One would have been motivated to have administered the CAR T cells of ‘517 in a single infusion because Madduri teaches doing so with an identical CAR T cell, and therefore, there would be a reasonable expectation of success because this is a known parameter in the art.
It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to one of ordinary skill in the art to have administered the CAR T cells of ‘517 within 2.5 hours, as taught by Dana-Farber, and at a temperature of 20-25 degrees Celsius, as taught by Rioufol and ECA. One would have been motivated to have administered the CAR T cells of ‘517 within 2.5 hours at a temperature of 20-25 degrees Celsius because Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes, Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes and that the CAR T cells are administered by a nurse in a hematology department, i.e. a controlled temperature environment, and ECA teaches that that controlled room temperature is 20-25 degrees Celsius. Further, there would be a reasonable expectation of success in administering the CAR T cells within 2.5 hours at a temperature of 20-25 degrees Celsius because these are known values of known parameters in the art.
Claim 3 of the instant application is included in this rejection because Madduri teaches that patients had received a median of 5 prior lines of treatment [page 2, third paragraph].
Claim 4 of the instant application is included in this rejection because claim 1 of ‘517 teaches that the subject had at a prior line of therapy comprising an IMiD, claim 13 of ‘517 teaches that the prior lines of therapy further comprise a proteasome inhibitor, and claim 16 of ‘517 teaches that the prior lines of therapy further comprise treatment with an anti-CD38 antibody.
Claim 5 of the instant application is included in this rejection because the CAR T cells of ‘517 are necessarily autologous T cells, as evidenced by Abebe et al., 2022 (instant PTO-892) that teaches that Cilta-cel (i.e. SEQ ID NO: 17) is an autologous, gene edited CAR T-cell therapy [see Abstract].
Claim 6 of the instant application is included in this rejection because claim 21 of ‘517 teaches that the subject has further received a lymphodepletion therapy, wherein the lymphodepletion therapy comprises cyclophosphamide and/or fludarabine, and Madduri teaches that cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days were used as the conditioning regimen (i.e. lymphodepleting chemotherapy regimen), and that the CAR T cells were administered 5-7 days after the start of the conditioning regimen [page 1, second paragraph – page 2, first paragraph].
Claim 7 is included in this rejection because Rioufol teaches that the CAR T cells are thawed in a 37 +/- 2 degrees Celsius [page 4]. Thus, since Rioufol teaches that the CAR T cells are thawed at the same temperature, then they necessarily would thaw completely in no more than about 15 minutes.
Claim 8 is included in this rejection because Madduri teaches that a majority of the patients treated had grade 1-2 CRS, and that tocilizumab and corticosteroids were administered to treat patients with CRS [page 2 , paragraphs 4-5].
Claims 1-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 13, 16-17, and 21 of copending Application No. 19/076,517 (‘517) in view of Madduri et al., 2019 (12/22/2025 IDS), Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892), as applied to claims 1-8 above, and further in view of Le et al., 2018 (instant PTO-892).
The teachings of ‘517, Madduri, Dana-Farber, Rioufol, and ECA are above. To reiterate, Madduri teaches that a majority of the patients treated had grade 1-2 CRS, and that tocilizumab and corticosteroids were administered to treat patients with CRS.
However, ‘517, Madduri, Dana-Farber, Rioufol, and ECA do not specifically teach that the CRS comprises pyrexia (fever).
Regarding claim 9, Le teaches that characteristics of CRS include fever, fatigue, headache, encephalopathy, hypotension, tachycardia, coagulopathy, nausea, capillary leak, and multiorgan dysfunction, often occurring after CAR T-cell therapy [page 943, left column, first paragraph of introduction].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically treated CRS after administering the dose of the T cells, as taught by ‘517, Madduri, Dana-Farber, Rioufol, and ECA, wherein the CRS comprises pyrexia, as taught by Le. One would have been motivated to have treated CRS comprising pyrexia because Madduri teaches that a majority of the patients treated had grade 1-2 CRS, and that tocilizumab and corticosteroids were administered to treat patients with CRS, and Le teaches that a characteristic of CRS includes fever, often occurring after CAR T-cell therapy.
This is a provisional nonstatutory double patenting rejection.
Claims 1-8 and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 13, 16-17, and 21 of copending Application No. 19/076,517 (‘517) in view of Madduri et al., 2019 (12/22/2025 IDS), Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892), as applied to claims 1-8 above, and further in view of Kaiser et al., 2021 (instant PTO-892).
The teachings of ‘517, Madduri, Dana-Farber, Rioufol, and ECA are above. To reiterate, Rioufol teaches that CAR T-cells are stored in bags or syringes (container; package) in cryogenic containers prior to administration [pages 2-3].
However, ‘517, Madduri, Dana-Farber, Rioufol, and ECA do not specifically teach that the composition further comprises an excipient of dimethyl sulfoxide at 5%.
Regarding claims 24-26, Kaiser teaches that cryopreservation in serum-free freezing medium supplemented with 10% HAS and 5% DMSO (dimethyl sulfoxide) facilitates improved T cells recovery and functionality [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 specifically formulated the composition of ciltacabtagene autoleucel (i.e. SEQ ID NO: 17), as taught by ‘517, Madduri, Dana-Farber, Rioufol, and ECA to comprise 10% HAS and 5% DMSO, as taught by Kaiser. One would have been motivated to have formulated the CAR T-cells in a container (packaged) with 10% HAS and 5% DMSO (i.e. a ciltacabtagene autoleucel suspension) because Rioufol teaches that CAR T-cells are stored in bags or syringes for infusion in cryogenic containers prior to administration and Kaiser teaches that cryopreservation in serum-free freezing medium supplemented with 10% HAS and 5% DMSO facilitates improved T cells recovery and functionality.
Claims 25 and 26 of the instant application are included in this rejection because the claims do not require any further steps that have not already been taught by the teachings above. The claims simply add the limitation of comprising a drug product label. MPEP 2112.01 (III) states “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art” In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). Additionally, the Examiner is interpreting the ciltacabtagene autoleucel of ‘517 and Madduri as an approved drug product, a limitation of instant claims 25-26, since the drug is administered to patients in order to treat refractory multiple myeloma.
This is a provisional nonstatutory double patenting rejection.
U.S. Patent No. 10,934,363 (‘363)
Claims 1-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 10-12 of U.S. Patent No. 10,934,363 (‘363) in view of Madduri et al., 2019 (12/22/2025 IDS), Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892).
Regarding claims 1 of the instant application, claim 1 of ‘363 teaches a chimeric antigen receptor (CAR), claim 7 of ‘363 teaches that the CAR comprises the amino acid sequence of SEQ ID NO: 265, claim 10 of ‘363 teaches an engineered immune effector cells comprising the CAR of claim 1, claim 11 of ‘363 teaches an engineered immune effector cell according to claim 10, wherein the immune effector cell is a T cell, claim 12 of ‘363 teaches a pharmaceutical composition, comprising the engineered immune effector cell of claim 11, and a pharmaceutically acceptable carrier.
SEQ ID NO: 265 of ‘363 has 100% sequence identity to SEQ ID NO: 17 of the instant claim.
However, ‘363 does not teach a method of treating a subject with relapsed or refractory multiple myeloma with the composition comprising the T cells comprising the CAR, that wherein the dose comprises 0.5 x 106 to 1.0 x 106 of the T cells /kg of body weight of the subject, or wherein the method comprises completing administering to the subject the dose of T cells within about 2.5 hours at a temperature of about 20°C to 25°C.
Madduri teaches JNJ-68284528 (JNJ-4528; ciltacabtagene autoleucel), a chimeric antigen receptor T cell (CAR-T) therapy, administered to subjects as a single infusion at a target range of 0.5-1.0x106 CAR+ T cells/kg to treat refractory multiple myeloma [page 1, paragraphs 1-2].
Note: SEQ ID NO: 17, as claimed in instant claim 1, is termed ciltacabtagene autoleucel (cilta-cel), as disclosed in the instant specification [see paragraph 86], which is also termed JNJ-68284528 and LCAR-B38M as taught by Madduri et al., 2020 (12/22/2025 IDS). Therefore, the CAR taught by Madduri is the same as the claimed CAR of SEQ ID NO: 17 and the CAR of SEQ ID NO: 265 of ‘363.
Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes [page 1].
Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes [page 4]. Rioufol also teaches that the CAR T cells are administered by a nurse in a hematology department [page 4] and that CAR T-cells are stored in bags or syringes (container; package) in cryogenic containers prior to administration [pages 2-3].
ECA teaches that controlled room temperature is 20-25 degrees Celsius [page 2].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the CAR T cells of ‘363 to treat the subject with refractory multiple myeloma of Madduri in a single infusion at a dose of 0.5 x 106 to 1.0 x 106 of the T cells /kg of body weight, as taught by Madduri. One would have been motivated to administer the CAR T cells of ‘363 to treat a subject with refractory multiple myeloma, because Madduri teaches administering an identical CAR T cell in a single infusion at a dose of 0.5 x 106 to 1.0 x 106 of the T cells/kg of body weight to treat refractory multiple myeloma. Therefore, there would be a reasonable expectation of success in administering the CAR T cells of ‘363 to treat refractory multiple myeloma because it is a known treatment method in the art.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the CAR T cells of ‘363 within 2.5 hours, as taught by Dana-Farber, and at a temperature of 20-25 degrees Celsius, as taught by Rioufol and ECA. One would have been motivated to have administered the CAR T cells of ‘363 within 2.5 hours at a temperature of 20-25 degrees Celsius because Dana-Farber teaches that CAR T cell infusion takes up to 30 minutes, Rioufol teaches that CAR T cells are thawed to room temperature before administration and are stable for 30 to 90 minutes and that the CAR T cells are administered by a nurse in a hematology department, i.e. a controlled temperature environment, and ECA teaches that that controlled room temperature is 20-25 degrees Celsius. Further, there would be a reasonable expectation of success in administering the CAR T cells within 2.5 hours at a temperature of 20-25 degrees Celsius because these are known values of known parameters in the art.
Claims 2 and 3 are included in this rejection because Madduri teaches that patients had received a median of 5 prior lines of treatment [page 2, third paragraph].
Claim 4 is included in this rejection because Madduri teaches that the patients were triple refractory to a PI (proteasome inhibitor), IMiD (immunomodulatory drug), and anti-CD38 antibody, thereby indicating that these were prior lines of therapy [page 2, third paragraph].
Claim 5 is included in this rejection because the CAR T cells of ‘363 are necessarily autologous T cells, as evidenced by Abebe et al., 2022 (instant PTO-892) that teaches that Cilta-cel (i.e. SEQ ID NO: 17) is an autologous, gene edited CAR T-cell therapy [see Abstract].
Claim 6 is included in this rejection because Madduri teaches that cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days were used as the conditioning regimen (i.e. lymphodepleting chemotherapy regimen), and that the CAR T cells were administered 5-7 days after the start of the conditioning regimen [page 1, second paragraph – page 2, first paragraph].
Claim 7 is included in this rejection because Rioufol teaches that the CAR T cells are thawed in a 37 +/- 2 degrees Celsius [page 4]. Thus, since Rioufol teaches that the CAR T cells are thawed at the same temperature, then they necessarily would thaw completely in no more than about 15 minutes.
Claim 8 is included in this rejection because Madduri teaches that a majority of the patients treated had grade 1-2 CRS, and that tocilizumab and corticosteroids were administered to treat patients with CRS [page 2 , paragraphs 4-5].
Claims 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 10-12 of U.S. Patent No. 10,934,363 (‘363) in view of Madduri et al., 2019 (12/22/2025 IDS), Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892), as applied to claims 1-8 above, and further in view of Le et al., 2018 (instant PTO-892).
The teachings of ‘363, Madduri, Dana-Farber, Rioufol, and ECA are above. To reiterate, Madduri teaches that a majority of the patients treated had grade 1-2 CRS, and that tocilizumab and corticosteroids were administered to treat patients with CRS.
However, ‘363, Madduri, Dana-Farber, Rioufol, and ECA do not specifically teach that the CRS comprises pyrexia (fever).
Regarding claim 9, Le teaches that characteristics of CRS include fever, fatigue, headache, encephalopathy, hypotension, tachycardia, coagulopathy, nausea, capillary leak, and multiorgan dysfunction, often occurring after CAR T-cell therapy [page 943, left column, first paragraph of introduction].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically treated CRS after administering the dose of the T cells, as taught by ‘363, Madduri, Dana-Farber, Rioufol, and ECA, wherein the CRS comprises pyrexia, as taught by Le. One would have been motivated to have treated CRS comprising pyrexia because Madduri teaches that a majority of the patients treated had grade 1-2 CRS, and that tocilizumab and corticosteroids were administered to treat patients with CRS, and Le teaches that a characteristic of CRS includes fever, often occurring after CAR T-cell therapy.
Claims 1-8 and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 10-12 of U.S. Patent No. 10,934,363 (‘363) in view of Madduri et al., 2019 (12/22/2025 IDS), Dana-Farber, 2018 (instant PTO-892), Rioufol et al., 2022 (instant PTO-892), and ECA, 2017 (instant PTO-892), as applied to claims 1-8 above, and further in view of Kaiser et al., 2021 (instant PTO-892).
The teachings of ‘363, Madduri, Dana-Farber, Rioufol, and ECA are above. To reiterate, Madduri teaches that the patients with refractory multiple myeloma had received a median of 5 prior lines of treatment [page 2, third paragraph] and were triple refractory to a PI (proteasome inhibitor), IMiD (immunomodulatory drug), and anti-CD38 antibody, thereby indicating that these were prior lines of therapy [page 2, third paragraph], and Rioufol teaches that CAR T-cells are stored in bags or syringes (container; package) in cryogenic containers prior to administration [pages 2-3].
However, ‘363, Madduri, Dana-Farber, Rioufol, and ECA do not specifically teach that the composition further comprises an excipient of dimethyl sulfoxide at 5%.
Regarding claims 24-26, Kaiser teaches that cryopreservation in serum-free freezing medium supplemented with 10% HAS and 5% DMSO (dimethyl sulfoxide) facilitates improved T cells recovery and functionality [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 specifically formulated the composition of CAR T-cells, as taught by ‘363, Madduri, Dana-Farber, Rioufol, and ECA, to comprise 10% HAS and 5% DMSO, as taught by Kaiser. One would have been motivated to have formulated the CAR T-cells in a container (packaged) with 10% HAS and 5% DMSO (i.e. a ciltacabtagene autoleucel suspension) because Rioufol teaches that CAR T-cells are stored in bags or syringes for infusion in cryogenic containers prior to administration and Kaiser teaches that cryopreservation in serum-free freezing medium supplemented with 10% HAS and 5% DMSO facilitates improved T cells recovery and functionality.
Further regarding claims 25 and 26 of the instant application, the claims do not require any further steps that have not already been taught by the teachings above. The claims simply add the limitation of comprising a drug product label. MPEP 2112.01 (III) states “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art” In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). Additionally, the Examiner is interpreting the CAR T cells of ‘363 and Madduri as an approved drug product, a limitation of instant claims 25-26, since the drug is administered to patients in order to treat refractory multiple myeloma.
Examiner’s Note Regarding Double Patenting
Efforts were made to discover any pending application or granted U.S. patent that claimed patentably indistinct subject matter. However, it is also noted that the number of patent applications filed on this or related subject matter is significant. Applicant is in the best position to identity any other pending applications or U.S. patents that are a) directed to the instantly claimed CAR and/or CAR T cells and b) discloses treatment of refractory and/or relapsed myeloma. Assistance in identifying such documents is appreciated.
Conclusion
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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