DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 12-13, 19-20, 27, and 34-35 are cancelled. Claims 1-11, 14-18, 21-26, 28-33, and 36-44 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/EP2022/067303 (filed on 06/24/2022) which claims benefit of European Patent Office Application No. EP21181704.4 (filed on 06/25/2021). Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-11, 14-18, 21-26, 28-33, and 36-44 have an effective filing date of 06/25/2021 corresponding to European Patent Office Application No. EP21181704.4.
Information Disclosure Statement
The information disclosure statement(s) filed on 05/06/2024 has/have been considered. Signed copies are enclosed.
Specification
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
Claim Objections
Claims 10, 28, 33, 39-40, and 44 are objected to because of the following informalities:
In instant claim 10, “isolation/recovery” should read “isolation or recovery.”
In instant claim 28, “at least of exactly 4 administrations” is typographical error and should read “at least or exactly 4 administrations.”
In instant claim 33, “and/or or” is a typographical error and should read “and/or.”
In instant claim 33, “in any one of claims 26” is a typographical error and should read “in claim 26.”
Instant claims 39-40 are missing the word “claim” prior to claim numbers.
In instant claim 44, “intraveneous” is typographical error and should read “intravenous.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 1-11, 14-18, 21-26, 28-33, and 36-44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Instant claims 1, 16, and 26 are drawn to methods for preparation of a composition comprising activated human CD8+ and natural killer (NK) lymphocytes (instant claims 1 and 16) and for treatment of cancer in a patient (instant claim 26) comprising an agent capable of activating T lymphocytes wherein the “agent comprises antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, or soluble receptors, which bind CD3 and/or bind CD28” (instant claims 1, 16, and 26, last 3 lines). Instant claims 11 and 36-38 further describes said agent as selected from “1) an agent, comprising comprises antibodies, antibody fragments or antibody analogues which bind CD3; 2) an agent comprising antibodies, antibody fragments or antibody analogues which bind CD28, and 3) an agent comprising antibodies, antibody fragments or antibody analogues, which bind CD3 and comprising antibodies, antibody fragments, or antibody analogues which bind CD28” (instant claim 11, lines 1-7) and wherein “the antibodies are bispecific antibodies” (instant claims 36-38, lines 1-2). This language encompasses a broad genus of structurally and functionally distinct CD3/CD28-binding molecules capable of activate T lymphocytes.
The instant specification states “[a]n ‘agent capable of activating T lymphocytes via binding to CD3 and/or CD28’ is a substance or composition of matter, which is capable of binding to CD3 (cluster of differentiation 3) and/or CD28 (cluster differentiation factor 28) with the effect that the T lymphocytes are activated” (¶ 0071).
The following details the challenges and difficulties associated with antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, and soluble receptors that bind CD3 and/or CD28 concerning predicting structure from function:
Antibodies, antibody fragments, and antibody analogues
The agent capable of activating T lymphocytes can be an antibody, antibody fragment, or antibody analogue that binds CD3 and/pr CD28. Antibodies, antibody fragments, and antibody analogues include but not limited to Fabs, scFvs, VHHs, full-length antibodies, and antibody-drug conjugates, which have distinct structures and functions. For example, Sifniotis et al. (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019) state there are numerous formats to address challenges in antibody therapeutics including “[antibody-drug conjugates] as a targeted drug delivery system, bispecific and fragment mAb platforms for tailored engagement and increased bioavailability, and recombinant Fc-fusion proteins for an increased half-life and introduced immunological engagement” (Pg. 14, ¶ 4, lines 3-5). In addition, antibody fragments include “Fabs and single chain variable fragments (scFv)” (Sifniotis et al., Pg. 9, ¶ 4, line 4). These fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). Therefore, antibodies, antibody fragments, and antibody analogues encompass a variety of species, each with their own advantages and disadvantages.
Sevy and Meiler (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014) state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antibody binds bind CD3 and/or CD28 is not a sufficient description.
Dickopf et al. (Format and geometries matter: Structure-based design defines the functionality of bispecific antibodies, Comput Struct Biotechnol J, 2020) state “[t]here is no ‘standard procedure’ to achieve [the generation of bispecific antibodies with desired functionalities], it rather has to be tackled on a case-by-case basis depending on the under lying biology and structural conditions” (Pg. 1226, ¶ 6, lines 3-5). As “the design and choice of format can have a profound impact on the antibody functionality” (Dickopf et al., Pg. 1221, Abstract, lines 2-3), particularly in regard to bispecific formats, it is not possible to predict the structures encompassed in a genus of bispecific anti-CD3 and anti-CD28 antibodies.
Furthermore, the instant specification does not specified how to create antibody fragments that exhibit the desired biological activity (i.e. retain the ability to bind said CD3 and CD28) nor the minimal number of CDRs required (i.e. the antibody fragment can contain less than 6 CDRs). Wong et al. (Comparative Analysis of the CDR Loops of Antigen Receptors, Front Immunol, 2019) teach “[a]ll six antibody CDRs can be involved in antigen recognition... As the CDRs form the majority of the binding site, their conformations are critical to the binding” (Pg. 2, column 1, ¶ 1, lines 9-15). This teaching indicates all six CDRs can be required for antigen binding.
Aptamers
Zhang et al. (Structural Biology for the Molecular Insight between Aptamers and Target Proteins, Int J Mol Sci, 2021 Apr 15) teach “structural studies for aptamer–target interactions are still the bottleneck in this field, which are facing various difficulties” (Pg. 1, Abstract, lines 4-5) as “[p]rotein surfaces present distinct structured interaction sites, or epitopes, that are recognized by aptamers and in most cases, the identical protein epitope can bind to aptamers with diverse sequences and potentially various structures” (Pg. 20, ¶ 2, lines 6-9). This teaching indicates it is difficult to predict aptamer binding to an antigen as (i) aptamer-protein structural determination is challenging and (ii) numerous aptamers can bind one antigen.
Molecular imprinted polymers
Bossi et al. (Molecularly imprinted polymers for the recognition of proteins: The state of the art, Biosensors and Bioelectronics, 2007) teach “[molecular imprinted polymer] development has been considerably slower, because it is quite difficult to create polymer cavities specific for complex molecules such as proteins. The problems associated with imprinting of relatively unstable three-dimensional conformations, possible rearrangement processes and poor solubility of the template in organic solvents are usually the main reasons why the imprinting of proteins remains difficult” (Pg. 1137, column 1, last ¶, lines 5-12). This teaching indicates the challenges associated with creating molecular imprinted polymers that bind protein targets and more work in needed to make protein imprinting practical.
Soluble receptors
Robinson et al. (Engineering soluble T-cell receptors for therapy, FEBS Journal, 22 Feb 2021) teach “natural poor stability and micromolar binding affinity of soluble [T cell receptors] are suboptimal for the development of soluble therapeutics” (Pg. 6161, column 1, ¶ 1, lines 1-2). This teaching highlights the difficulty in creating soluble receptors that retain their ability to bind the selected target.
As such, instant claims 1, 11, 16, 26, and 36-38 are drawn to methods for preparation of a composition comprising activated human CD8+ and NK lymphocytes and treatment of cancer in a patient comprising use of a genus of agents capable of activating T lymphocytes that bind CD3 and/or CD28.
The instant application teaches “CD3/CD28 Dynabeads (Human T cell activator, ThermoFisher Scientific, cat. No 111.31D, 4×107 beads/mL)” (Example 1, ¶ 0162), which are commercially available anti-CD3 and anti-CD28 antibodies conjugated to magnetic beads that are capable of activating T lymphocytes.
However, Applicant is claiming a large and structurally diverse genus of agents capable of activating T lymphocytes that bind CD3 and/or CD28 including antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, and soluble receptors. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically the structures of the antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, and soluble receptors that bind CD3 and/or CD28. Applicant uses functional language to define the genus which is not sufficient as detailed above (see explanation of challenges and difficulties associated with each class of molecules when predicting structure from function).
Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention” (MPEP 2163[II][A][2]).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has disclosed a species within the genus claimed (i.e. CD3/CD28 Dynabeads). However, given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of one adequately described species is not sufficiently representative of the entire genus.
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR amino acid sequences that confer upon an antibody the ability to bind CD3 and/or CD28. It is well-known in the art that antibodies generally comprise six parental CDRs. Absent a description of the at least minimal structural features correlating with a functional ability to bind CD3 and/or CD28 which are shared by members of a genus of antibody fragments, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish what portion of an antibody (i.e. an antibody fragment comprising CDRs) that confer the ability to bind CD3 and/or CD28.
Although screening techniques can be used to find antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, and soluble receptors that possess the ability to bind CD3 and/or CD28, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Accordingly, given the difficulty associated with predicting structures of antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, and soluble receptors that are capable of binding CD3 and/or CD28 and given the lack of particularity with which the genus is described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The specification does not reasonably convey possession of the subject matter of instant claims 1, 11, 16, 26, and 36-38. Instant claims 1, 11, 16, 26, and 36-38 fail to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed. Instant claims 2-10, 14-15, 17-18, 21-25, 28-33, and 39-44 are included in this rejection as they incorporate and/or depend on instant claims 1, 11, 16, 26, and/or 36-38.
Claims 26, 28-33, 38, and 44 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 for the treatment of breast cancer in a patient using activated human CD8+ and NK lymphocytes compositions prepared with 5-Aza-CdR and CD3/CD28 Dynabeads, does not reasonably provide enablement for a method for the treatment of all cancers in a patient using activated human CD8+ and NK lymphocytes compositions prepared with any agent that induces expression of cancer/testis antigens and any agent capable of activating T lymphocytes via binding to CD3 and/or CD28. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention, (2) the state of the prior art, and (5) the breadth of the claims
Instant claim 26 is drawn to “[a] method for treatment of cancer in a patient” (line 1) comprising an adoptive T cell therapy protocol as outlined in steps 1-5 or a-e. The adoptive T cell therapy protocol comprises (i) culturing a fraction of the sample in the presence of at least one agent capable of activating T lymphocytes via binding to CD3 and/or CD28 and (ii) contacting the proliferating T lymphocytes with an agent that induces expression of cancer/testis antigens.
Instant claim 26 further describes the agent capable of activating T lymphocytes “comprises antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, or soluble receptors, which bind CD3 and/or bind CD28” (last 3 lines). Instant claim 38 specifies “the antibodies are bispecific antibodies” (lines 1-2). This language encompasses a broad genus of structurally and functionally distinct CD3/CD28-binding molecules capable of activate T lymphocytes.
The field of invention resides in the fields of chemistry and biology, specifically clinical medicine, highly complex and unpredictable arts. The dependent claims demonstrate that practicing the claimed invention encompasses numerous variables. For example, dependent claims recite administrative parameters (instant claims 28-29 and 44), cancer types (instant claim 30), and co-treatment with an anti-cancer drug (instant claim 31-32). Collectively, the dependent claims demonstrate that the invention is directed to a method for treatment of cancer in a patient, subject matter that is highly complex and unpredictable, wherein therapeutic efficacy depends on the specific dose and route of the administered treatment, the manifestation of cancer in the subject, and combination with additional therapeutic agents.
The instant specification states “’[a]n agent that induces expression of cancer/testis antigens’ denotes a substance or composition, which is able to produce—in a treated cell—an effect corresponding to what has been observed in many cancers, namely that [cancer/testis antigens] are expressed due to genome-wide changes” (¶ 0070) and “[a]n ‘agent capable of activating T lymphocytes via binding to CD3 and/or CD28’ is a substance or composition of matter, which is capable of binding to CD3 (cluster of differentiation 3) and/or CD28 (cluster differentiation factor 28) with the effect that the T lymphocytes are activated” (¶ 0071).
The following details the state of the prior art and the breadth of the claims concerning (i) cancer treatment, (ii) agents that induce cancer/testis antigens, and (iii) agents capable of activating T lymphocytes that bind CD3 and/or CD28 as instantly claimed.
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. Even within a given cancer type, “[i]ntertumor and intratumor heterogeneity are important obstacles to overcome when designing the most effective therapeutic strategies for patients with cancer. The genotypic and phenotypic variability of tumors can have important consequences for diagnosis, prognosis, and treatment” (Lovly et al., 2016, Pg. e586, Integrating the Heterogeneity of Cancer in Clinical Decision Making, first paragraph). Therefore, the variability among tumors within a cancer type makes it difficult to predict whether a therapeutic approach effective in one tumor type will be effective in another. Accordingly, the treatment of all cancer remains an unpredictable field in which efficacy cannot be readily extrapolated across different cancers or tumor subtypes.
The breadth of the claim exacerbates the complex nature of the subject matter to which instant claim 26 is directed. The claim is extremely broad due to the vast number of possible cancer types and tumor cell growth mechanisms represented by the term “treatment of 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. They can occur in pretty much every part of the body. Here are some assorted categories as examples:
CNS cancers cover a very diverse range of cancers in many categories and subcategories. There are an immense range of neuroepithelial tumors. Gliomas, the most common subtype of primary brain tumors, most of which are aggressive, highly invasive, and neurologically destructive tumors are considered to be among the deadliest of human cancers.
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.
Carcinomas of the Liver include hepatocellular carcinoma, combined hepatocellular cholangiocarcinoma, cholangiocarcinoma (intrahepatic), bile duct cystadenocarcinoma and undifferentiated carcinoma of the liver. There is also cancer of the blood vessels in the liver (hemangioendothelioma), primary non-Hodgkin’s lymphoma of the liver, undifferentiated liver sarcoma (also known as undifferentiated embryonal sarcoma), primary pleomorphic liver sarcoma, angiosarcoma of the liver, and primary malignant melanoma of the liver. Most liver cancers are secondary, especially those originating in the breast, lung, or gallbladder, as well as both Hodgkin's or non-Hodgkin's lymphoma.
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).
Thyroid cancer comes in four forms: papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, and medullary thyroid cancer.
In addition, instant claims recites use of an agent to induce expression of cancer/testis antigens. WO2008081035A1 (filed 2008-01-03, published 2008-07-10; hereinafter referred to as WO ‘035) teaches “tumor antigens are typically cancer/testis antigens, which may be chemically induced by DNA demethylation” (Abstract), stating “DNA demethylation with 5-aza-2'-deoxycytidine (5-Aza-CdR) is preferred. Other reagents that may be used for DNA demethylation are 5-azacytldine, 5-fluoro-2'-deoxycytidine, and zebularine… There are also some non-nucleoside demethylating agents but their effect Is weaker than that of 5-Aza-CdR” (Pg. 10, lines 25-30). This teaching indicates DNA methylation agents can induce cancer/testis antigens but with a range of efficacy.
Antibodies, antibody fragments, and antibody analogues
The agent capable of activating T lymphocytes can be an antibody, antibody fragment, or antibody analogue that binds CD3 and/pr CD28. Antibodies, antibody fragments, and antibody analogues include but not limited to Fabs, scFvs, VHHs, full-length antibodies, and antibody-drug conjugates, which have distinct structures and functions. For example, Sifniotis et al. (Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation, Antibodies, 2019) state there are numerous formats to address challenges in antibody therapeutics including “[antibody-drug conjugates] as a targeted drug delivery system, bispecific and fragment mAb platforms for tailored engagement and increased bioavailability, and recombinant Fc-fusion proteins for an increased half-life and introduced immunological engagement” (Pg. 14, ¶ 4, lines 3-5). In addition, antibody fragments include “Fabs and single chain variable fragments (scFv)” (Sifniotis et al., Pg. 9, ¶ 4, line 4). These fragments show “better tissue penetration and biodistribution than whole mAb therapeutics; however, a pitfall of smaller peptides lacking an Fc region is a highly reduced in vivo half-life and poor retention times” (Sifniotis et al., Pg. 11, last ¶, lines 1-3). Therefore, antibodies, antibody fragments, and antibody analogues encompass a variety of species, each with their own advantages and disadvantages.
Sevy and Meiler (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014) state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Pg. 1, Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately i.e. stating the antibody binds bind CD3 and/or CD28 is not a sufficient description.
Dickopf et al. (Format and geometries matter: Structure-based design defines the functionality of bispecific antibodies, Comput Struct Biotechnol J, 2020) state “[t]here is no ‘standard procedure’ to achieve [the generation of bispecific antibodies with desired functionalities], it rather has to be tackled on a case-by-case basis depending on the under lying biology and structural conditions” (Pg. 1226, ¶ 6, lines 3-5). As “the design and choice of format can have a profound impact on the antibody functionality” (Dickopf et al., Pg. 1221, Abstract, lines 2-3), particularly in regard to bispecific formats, it is not possible to predict the structures encompassed in a genus of bispecific anti-CD3 and anti-CD28 antibodies.
Furthermore, the instant specification does not specified how to create antibody fragments that exhibit the desired biological activity (i.e. retain the ability to bind said CD3 and CD28) nor the minimal number of CDRs required (i.e. the antibody fragment can contain less than 6 CDRs). Wong et al. (Comparative Analysis of the CDR Loops of Antigen Receptors, Front Immunol, 2019) teach “[a]ll six antibody CDRs can be involved in antigen recognition... As the CDRs form the majority of the binding site, their conformations are critical to the binding” (Pg. 2, column 1, ¶ 1, lines 9-15). This teaching indicates all six CDRs can be required for antigen binding.
Aptamers
Zhang et al. (Structural Biology for the Molecular Insight between Aptamers and Target Proteins, Int J Mol Sci, 2021 Apr 15) teach “structural studies for aptamer–target interactions are still the bottleneck in this field, which are facing various difficulties” (Pg. 1, Abstract, lines 4-5) as “[p]rotein surfaces present distinct structured interaction sites, or epitopes, that are recognized by aptamers and in most cases, the identical protein epitope can bind to aptamers with diverse sequences and potentially various structures” (Pg. 20, ¶ 2, lines 6-9). This teaching indicates it is difficult to predict aptamer binding to an antigen as (i) aptamer-protein structural determination is challenging and (ii) numerous aptamers can bind one antigen.
Molecular imprinted polymers
Bossi et al. (Molecularly imprinted polymers for the recognition of proteins: The state of the art, Biosensors and Bioelectronics, 2007) teach “[molecular imprinted polymer] development has been considerably slower, because it is quite difficult to create polymer cavities specific for complex molecules such as proteins. The problems associated with imprinting of relatively unstable three-dimensional conformations, possible rearrangement processes and poor solubility of the template in organic solvents are usually the main reasons why the imprinting of proteins remains difficult” (Pg. 1137, column 1, last ¶, lines 5-12). This teaching indicates the challenges associated with creating molecular imprinted polymers that bind protein targets and more work in needed to make protein imprinting practical.
Soluble receptors
Robinson et al. (Engineering soluble T-cell receptors for therapy, FEBS Journal, 22 Feb 2021) teach “natural poor stability and micromolar binding affinity of soluble [T cell receptors] are suboptimal for the development of soluble therapeutics” (Pg. 6161, column 1, ¶ 1, lines 1-2). This teaching highlights the difficulty in creating soluble receptors that retain their ability to bind the selected target.
The instant application teaches “CD3/CD28 Dynabeads (Human T cell activator, ThermoFisher Scientific, cat. No 111.31D, 4×107 beads/mL)” (Example 1, ¶ 0162), which are commercially available anti-CD3 and anti-CD28 antibodies conjugated to magnetic beads that are capable of activating T lymphocytes. The instant specification also teaches “5-aza-2′-deoxycytidine (5-Aza-CdR, obtained from Sigma)” (¶ 0165) to induce cancer/testis antigens. The adoptive T cell therapy of the instant application was used in “breast cancer cell lines” (¶ 0174) to determine the lytic activity of the effector lymphocytes.
Consequently, instant claims 26 and 38 are directed to complex and unpredictable fields, where the successful treatment of all cancer cannot be readily extrapolated from administration of the adoptive cell therapy. As such, instant claims 26 and 38 are drawn to a method for the treatment of all cancer in a patient using activated human CD8+ and NK lymphocytes compositions prepared with any agent that induces expression of cancer/testis antigens and any agent capable of activating T lymphocytes via binding to CD3 and/or CD28, the full scope of which is not enabled by the method as instantly claimed (the nature of the invention).
The scope of instant claims 26 and 38 is extremely broad. The instant claims encompass treatment of multiple cancer types in a patient using activated human CD8+ and NK lymphocytes compositions prepared with any agent that induces expression of cancer/testis antigens and any agent capable of activating T lymphocytes via binding to CD3 and/or CD28 that require the specification of the instant application to provide support for the entire scope of the claim (the breadth of the claims). The specification fails to show that a person having ordinary skill in the art could treat all cancer using the broad genera recited without undue experimentation. Results obtained utilizing one agent that induces expression of cancer/testis antigens and one agent capable of activating T lymphocytes via binding to CD3 and/or CD28 for the treatment of one cancer type cannot reasonably be extrapolated to other agents or other cancer types.
The genus of agents capable of activating T lymphocytes comprise a diverse class of molecules that require a person having ordinary skill in the art to determine the structures of the antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, and soluble receptors that bind CD3 and/or CD28 (see 122[a] rejection for written description for more information).
However, Applicant is claiming a large and structurally diverse genus of agents capable of activating T lymphocytes that bind CD3 and/or CD28 including antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, and soluble receptors. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically the structures of the antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, and soluble receptors that bind CD3 and/or CD28. Applicant uses functional language to define the genus which is not sufficient as detailed above (see explanation of challenges and difficulties associated with each class of molecules when predicting structure from function in the state of the prior art). Consequently, the lack of structure delineated in the claims encompass a vast amount of agents and thus leads to a lack of enablement as Applicant failed to disclose how to use such agents in treating cancer.
In addition, agents capable of inducing cancer/testis antigens are broad including 5-aza-2'-deoxycytidine (5-Aza-CdR), 5-azacytldine, 5-fluoro-2'-deoxycytidine, zebularine, and non-nucleoside demethylating agents; these agents have a range of efficacy in inducing said antigens (see WO ‘035 in the state of the prior art).
It is unclear how the activated human CD8+ and NK lymphocytes compositions prepared with any agent that induces expression of cancer/testis antigens and any agent capable of activating T lymphocytes via binding to CD3 and/or CD28 as recited in instant claims 26 and 38 could treat all cancer. Cancers are varied and do not share common pathologies (see the breadth of the claims). There is no known agent that can broadly treat all the recited cancer (see Lovly et al. in the state of the prior art).
Instant claims 26 and 38 are directed to complex and unpredictable arts such as chemistry and biology, where the success treatment of cancer cannot be readily extrapolated from the limited number of disclosed examples in the instant application. Evidence of efficacy of activated human CD8+ and NK lymphocytes compositions prepared with 5-Aza-CdR and CD3/CD28 Dynabeads is provided in the instant specification.
Therefore, a method for the treatment of breast cancer in a patient using activated human CD8+ and NK lymphocytes compositions prepared with 5-Aza-CdR and CD3/CD28 Dynabeads is supported. A method for the treatment of all cancer in a patient using activated human CD8+ and NK lymphocytes compositions prepared with any agent that induces expression of cancer/testis antigens and any agent capable of activating T lymphocytes via binding to CD3 and/or CD28 is not supported.
(3) The relative skill of those in the art and (4) the predictability or unpredictability of the art
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
While the use of adoptive T cell therapy to treat cancer is well known by a person having ordinary skill in the art, i.e. someone with a PhD and/or MD (the relative skill of those in the art), the use of activated human CD8+ and NK lymphocytes compositions prepared with any agent that induces expression of cancer/testis antigens and any agent capable of activating T lymphocytes via binding to CD3 and/or CD28 to treat all cancer within the scope of instant claims 26 and 38 is not predictable.
The predictability of applying the adoptive T cell therapy as instant claimed for treating all cancers would be low (the predictability or unpredictability of the art) given that:
there is no known agent that can broadly treat all the recited cancers (see Lovly et al. in the state of the prior art);
agents for inducing cancer/testis antigens have a range of efficacy in inducing said antigens (see WO ‘035 in the state of the prior art);
Applicant uses functional language, not structure, to define the genus of agents capable of activating T lymphocytes and, therefore, encompasses a vast amount of molecules (see explanation of challenges and difficulties associated with each class of molecules when predicting structure from function in the state of the prior art) that a person having ordinary skill in the art could not envisage nor conclude how to use such agents in the treatment of cancer; and,
the instant application fails to demonstrate treatment of all cancers with the adoptive T cell therapy as instantly claimed.
(6) The amount of direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of the experimentation
The instant application teaches “CD3/CD28 Dynabeads (Human T cell activator, ThermoFisher Scientific, cat. No 111.31D, 4×107 beads/mL)” (Example 1, ¶ 0162), which are commercially available anti-CD3 and anti-CD28 antibodies conjugated to magnetic beads that are capable of activating T lymphocytes. The instant specification also teaches “5-aza-2′-deoxycytidine (5-Aza-CdR, obtained from Sigma)” (¶ 0165) to induce cancer/testis antigens. The adoptive T cell therapy of the instant application was used in “breast cancer cell lines” (¶ 0174) to determine the lytic activity of the effector lymphocytes.
The specification does not provide any additional examples or guidance on how to use activated human CD8+ and NK lymphocytes compositions prepared with other agents that induces expression of cancer/testis antigens and other agents capable of activating T lymphocytes via binding to CD3 and/or CD28 for the treatment of all cancer as recited in instant claims 26 and 38 (the amount of direction or guidance presented and the presence or absence of working examples). As instant claims 26 and 38 recite multiple cancers and the use of multiple agents, the specification of the instant application is required to provide support for the entire scope of the claims.
The genus of agents capable of activating T lymphocytes comprise a diverse class of molecules that require a person having ordinary skill in the art to determine the structures of the antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, and soluble receptors that bind CD3 and/or CD28 (see 122[a] rejection for written description for more information).
In addition, agents capable of inducing cancer/testis antigens are broad including 5-aza-2'-deoxycytidine (5-Aza-CdR), 5-azacytldine, 5-fluoro-2'-deoxycytidine, zebularine, and non-nucleoside demethylating agents; these agents have a range of efficacy in inducing said antigens (see WO ‘035 in the state of the prior art).
It is unclear how the activated human CD8+ and NK lymphocytes compositions prepared with any agent that induces expression of cancer/testis antigens and any agent capable of activating T lymphocytes via binding to CD3 and/or CD28 as recited in instant claims 26 and 38 could treat all cancer. Cancers are varied and do not share common pathologies (see the breadth of the claims). There is no known agent that can broadly treat all the recited cancer (see Lovly et al. in the state of the prior art).
The amount of experimentation would not be reasonable because it would require determining which agents that induces expression of cancer/testis antigens and which agents capable of activating T lymphocytes via binding to CD3 and/or CD28 to use for preparation of human CD8+ and NK lymphocytes compositions for cancer treatment. It is not routine to determine how such broad classes of molecules would be used for preparation of human CD8+ and NK lymphocytes compositions for all cancer treatment and would therefore require undue experimentation (the quantity of the experimentation, see MPEP 2164.06).
Instant claims 26 and 38 are not enabled because a person having ordinary skill in the art as of the effective filing date of the application would not be able to treat all cancer using activated human CD8+ and NK lymphocytes compositions prepared with any agent that induces expression of cancer/testis antigens and any agent capable of activating T lymphocytes via binding to CD3 and/or CD28 with a predictability of success for the reasons outlined above. Instant claims 28-33 and 44 are included in this rejection as they incorporate and/or depend on instant claim 26.
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 1-11, 14-18, 21-26, 28-33, and 36-44 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1, 3, 16, and 26, the phrases “fraction” and “second fraction” render the claims indefinite because objective boundaries for what constitutes the fractions are unclear. Fraction is a relative term because it refers to a portion of the sample without specifying the amount or characteristics of that portion. MPEP 2173.06(b) states: “Some objective standard must be provided in order to allow the public to determine the scope of the claim. A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970).” The instant specification does not provide an objective standard for “fraction” nor “second fraction” and thus these phrases are indefinite.
For the purposes of claim interpretation, the phrases “fraction” and “second fraction” will be treated as any two portions of the sample of blood cells from the subject.
Claims 1, 16, and 26 recite the limitation "said agent" in third to last line of all claims. There is insufficient antecedent basis for this limitation in the claim. Claims 1, 16, and 26 recite two agents, one for activating T lymphocytes via binding to CD3 and/or CD28 and one for inducing expression of cancer/testis antigens. It is unclear which agent is referred to by “said agent.” Claims 2-11, 14-15, 17-18, 21-25, 28-33, and 36-44 are included in this rejection as they depend on and/or incorporate claims 1, 16, and/or 26.
For the purposes of claim interpretation, “said agent” will be treated optionally as either the agent capable of activating T lymphocytes via binding to CD3 and/or CD28 or the agent inducing expression of cancer/testis antigens.
Regarding claims 1, 16, and 26, the phrase "a period of culture" renders the claims indefinite because the exact length of culture is unclear. Claims 2-11, 14-15, 17-18, 21-25, 28-33, and 36-44 are included in this rejection as they depend on and/or incorporate claims 1, 16, and/or 26.
For the purposes of claim interpretation, the phrase "a period of culture" will be treated as any length of time to induce expression of cancer/testis antigens.
Regarding claims 1, 7-11, 16-18, 23, and 26, the phrases "CD8+ and natural killer (NK) lymphocytes,” “lymphocytes,” and “T lymphocytes” render the claims indefinite because the terms switch between terminologies for the same element, creating ambiguity regarding which cells are being discussed. Claims 2-6, 14-15, 21-22, 24-25, 28-33, and 36-44 are included in this rejection as they depend on and/or incorporate claims 1, 7-11, 16-18, 23, and/or 26.
For the purposes of claim interpretation, the phrases "CD8+ and natural killer (NK) lymphocytes,” “lymphocytes,” and “T lymphocytes” will be treated as CD8+ and natural killer (NK) lymphocytes.
Regarding claims 2, 8-9, and 17, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 18 is included in this rejection as it depends on and/or incorporates claim 17.
For the purposes of claim interpretation, limitations following "preferably" will not hold patentable weight.
Claim 14 depends on claim 13, a cancelled claim, and is therefore rejected as incomplete (see MPEP 608.01[n][v]) because it is not clear what limitations are set forth in claim 13. Claims 15, 39, and 42 are included in this rejection as they depend on and/or incorporate claim 14.
For the purposes of claim interpretation, claim 14 will be treated as dependent on claim 11.
Regarding claims 16, the phrase "step 4" renders the claim indefinite because step 4 is not recited so it is unclear what comprises said step. Claims 17-18, 21-25, 37, 40, and 43 are included in this rejection as they depend on and/or incorporate claim 16.
For the purposes of claim interpretation, the phrase "step 4" will be treated “step d.”
Claim 26 recites the limitation "the cells” in fifth to last line. There is insufficient antecedent basis for this limitation in the claim. It is unclear if this refers to the cells obtained from step 4 or step e. Claims 28-33, 38, and 44 are included in this rejection as they depend on and/or incorporate claims 26.
For the purposes of claim interpretation, “the cells” will be treated optionally as either cells obtained from step 4 or step e.
Claim 29 recites the limitation "the parenteral route" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 44 is included in this rejection as it depends on and/or incorporates claims 29.
For the purposes of claim interpretation, “the parenteral route” will be treated as “a parenteral roue.”
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 30 recites the broad recitations “glioma” and “sarcoma”, and the claim also recites “in particular glioblastoma” and “(including liposarcoma, fibrosarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma)” which are the narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
For the purposes of claim interpretation, (i) glioblastoma will be treated as merely exemplary of a glioma and therefore not required and (ii) the group from which the cancer is selected will include liposarcoma, fibrosarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, and rhabdomyosarcoma.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 31 recites the broad recitation “with an anticancer drug”, and the claim also recites “in particular with a checkpoint inhibitor drug” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claims 32-33 are included in this rejection as they depend on and/or incorporate claim 31.
For the purposes of claim interpretation, a checkpoint inhibitor drug will be treated as merely exemplary of an anticancer drug and therefore not required.
Claim 44 recites the limitations "the intravenous route,” “the intraarterial route,” “the intratumoral route,” and “the intralymphatic route" in lines 2-3. There is insufficient antecedent basis for these limitations in the claim.
For the purposes of claim interpretation, "the intraveneous route,” “the intraarterial route,” “the intratumoral route,” and “the intralymphatic route" will be treated as "a intraveneous route,” “a intraarterial route,” “a intratumoral route,” and “a intralymphatic route.”
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14-15, 39, and 42 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 14 depends on claim 13, a cancelled claim, and is therefore rejected as incomplete (see MPEP 608.01[n][v]). Claims 15, 39, and 42 are included in this rejection as they depend on and/or incorporate claim 14. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-11, 14-18, 21-26, 30, and 36-41 are rejected under 35 U.S.C. 103 as being unpatentable over WO2008081035A1 (filed 2008-01-03, published 2008-07-10; hereinafter referred to as WO ‘035) in view of Rasmussen et al. (Ex vivo expansion protocol for human tumor specific T cells for adoptive T cell therapy, Journal of Immunological Methods, 2010, Vol. 355, pp. 52-60; IDS filed 05/06/2024, Cite No. 12) as evidenced by Thermo Fisher Scientific (Dynabeads Magnetic Beards, 2026).
Instant claims 1, 16, and 26
Regarding instant claims 1, 16, and 26, WO ‘035 teaches a method of preparation of a composition comprising: “A) isolation of peripheral blood lymphocytes; generation of mature dendritic cells from monocytes (step 1 of instant claims 1 and 26; step a of instant claims 16 and 26); B) stimulation of the lymphocytes by the mature dendritic cells leading to preferential proliferation of CD4+ cells (step 2 of instant claims 1 and 26; step b of instant claims 16 and 26); treatment of the activated lymphocytes with chemical agents leading to induction of expression of cancer/testis antigens (step 3 of instant claims 1 and 26; step c of instant claims 16 and 26)” (Pg. 7, line 34 through Pg. 8, line 4; see also last ¶ of Pg. 8 to first ¶ of Pg. 10 discussing isolation of lymphocytes from healthy donors). WO ‘035 further teaches “in order to induce expression of [cancer/testis antigens] in antigen presenting cells by chemical treatment (for example, with Aza-5-CdR), this culture should be proliferating” (Pg. 12, lines 12-13). This teaching indicates the cells are cultured after exposure to the agent that induces expression of cancer/testis antigens (i.e. Aza-5-CdR) and reads on a period of culture that results in said expression of cancer/testis antigens (step 3 of instant claims 1 and 26; step c of instant claims 16 and 26). The agent capable of activating T lymphocytes includes any substance or composition capable of activating T lymphocytes (see 112[a] written description section); therefore, mature dendritic cells inducing proliferation and subsequently activating T cells read on said agent. In addition, the agent that induces the expression of cancer/testis antigens includes any substance or composition that induces expression of cancer/testis antigens (see 112[a] written description section); therefore, a chemical agent, specifically Aza-5-CdR, that leads to induction of expression of cancer/testis antigens reads on said agent. These teachings read on:
isolating a sample of blood cells from a subject or patient (i.e. healthy donor), wherein the sample is enriched for lymphocytes (step 1 of instant claims 1 and 26; step a of instant claims 16 and 26);
culturing a fraction of the sample in the presence of at least one agent capable of activating T lymphocytes (i.e. mature dendritic cells) thereby stimulating proliferation of CD4+ lymphocytes (step 2 of instant claims 1 and 26; step b of instant claims 16 and 26); and
contacting the proliferating T lymphocytes with an agent that induces expression of cancer/testis antigens (step 3 of instant claims 1 and 26; step c of instant claims 16 and 26).
Regarding instant claims 1, 16, and 26, WO ‘035 further teaches the CD4+/CD8+ ratio increased (Fig. 2 shows CD4+/CD8+ ratio increased after culturing with mature dendritic cells in the 2 lefthand plots). This teaching reads on the mature dendritic cells increasing the CD4+/CD8+ ratio compared to the lymphocytes obtained from step 1/a (step 2 of instant claims 1 and 26; step b of instant claims 16 and 26).
Regarding instant claims 1, 16, and 26, WO ‘035 further teaches “employment of activated T helper cells (CD4+ lymphocytes) functioning both as antigen presenting cells and to provide help to antigen-specific CD8+ cells” (Pg. 8, lines 31-32) wherein “[s]ome cells were used in culture with autologous lymphocytes (Example 3)” (Pg. 15, lines 17-18; also see entire Example 3 on Pg. 18, line 30 to Pg. 21, line 23 describing 5-Aza-CdR-treated lymphocytes used as stimulators). These teachings read on a separating the cancer/testis antigen expressing T lymphocytes from the agent capable of activating T lymphocytes followed by mixing the cancer/testis antigen expressing lymphocytes obtained from step 3/c (i.e. 5-Aza-CdR-treated lymphocytes) with a second fraction of the sample from step 1/a (i.e. autologous lymphocytes) (step 4 of instant claims 1 and 26; step d?? of instant claims 16 and 26??).
Regarding instant claims 1, 16, and 26, WO ‘035 further teaches “[t]here were also a significant number of natural killer (NK) cells which are not unusual for cell cultures after primary stimulation” (Pg. 10, lines 9-10), indicating the activated cell population comprises natural killer cells in addition to CD8+ lymphocytes. This teaching reads on subsequently culturing the lymphocyte mixture from step 4/d to stimulate proliferation of CD8+ and NK lymphocytes (step 5 of instant claims 1 and 26; step e of instant claims 16 and 26).
Regarding instant claim 26, WO ‘035 further teaches a ‘’method of treating cancer” (Pg. 7, line 15) comprising “administering the cytotoxic composition to a cancer patient” (Pg. 7, lines 22-23). This teaching reads on a method for treatment of cancer in a patient comprising administering the composition described above (instant claim 26).
WO ‘035 does not teach an agent capable of activating T lymphocytes via binding to CD3 and/or CD28 wherein said agent comprises antibodies, antibody fragments, antibody analogues, aptamers, molecular imprinted polymers, or soluble receptors, which bind CD3 and/or bind CD28 (instant claims 1, 16, and 26).
Regarding instant claims 1, 16, and 26, Rasmussen et al. teach “a protocol for expansion of antigen-specific T cells” (Pg. 52, Abstract, line 6) using “Anti-CD3/anti-CD28 coupled Dynabeads” (Pg. 53, column 2, ¶ 1, lines 9-10; instant claims 1, 16, and 26). Rasmussen further teach the T cells are lymphocytes (Pg. 53, column 2, last ¶, line 8, “lymphocytes were enriched” after blood was drawn from patients) and “when T cells were stimulated with Dynabeads… the expansion of CD4+ T cells was increased” (Pg. 55, column 2, last ¶, lines 13-14), leading to an increased CD4+/CD8+ ratio (Pg. 56, Fig. 3; step 2 of instant claims 1 and 26; step b of instant claims 16 and 26). These teachings read on anti-CD3/anti-CD28 antibodies coupled to Dynabeads acting as an agent capable of activating T lymphocytes via binding to CD3 and CD28 wherein said agent comprises antibodies (instant claims 1, 16, and 26); the Dynabeads also stimulate proliferation of CD4+ lymphocytes and increase CD4+/CD8+ ratio (step 2 of instant claims 1 and 26; step b of instant claims 16 and 26).
Rasmussen et al. further teach “methods used for generation of high numbers of tumor specific T cells usually require long-term ex vivo culture, which frequently lead to generation of terminally differentiated effector cells, demonstrating low persistence in vivo” (Pg. 52, Abstract, lines 2-4), stating their method is optimized to “increase the chance of retaining long-term persistence following adoptive transfer” (Pg. 52, Abstract, third to last – second to last lines). This teaching provides motivation for using anti-CD3/anti-CD28 coupled Dynabeads as they increase the chance of retaining long-term persistence following adoptive transfer compared to previous ex vivo methods.
It is noted that Applicant is claiming addition of the agent capable of activating T lymphocytes via binding to CD3 and CD28 either in step 2 as recited in instant claims 1 and 26 or step e as recited in instant claims 16 and 26. However, as Rasmussen et al. teaches anti-CD3/anti-CD28 coupled Dynabeads activate T lymphocytes via binding to CD3 and CD28 without limitation to a specific timing, it is reasonable to perform this activation at any step (see MPEP 2111.01 regarding specific order of steps into method claims).
Anti-CD3/anti-CD28 coupled Dynabeads and mature dendritic cells were known and used prior to the effective filing date of the application to stimulate proliferation of CD4+ lymphocytes and increase CD4+/CD8+ ratio. In addition, both WO ‘035 and Rasmussen et al. are in analogous arts (i.e. adoptive T cell immunotherapy). Since Rasmussen et al. teach anti-CD3/anti-CD28 coupled Dynabeads increase the chance of retaining long-term persistence following adoptive transfer compared to previous ex vivo methods, there is motivation for using anti-CD3/anti-CD28 coupled Dynabeads as taught in Rasmussen et al. instead of mature dendritic cells in a method for preparation of a composition of activated human CD8+ and natural killer lymphocytes (instant claims 1 and 16) and a method for treatment of cancer in a patient using said composition (instant claim 26) as taught in WO ‘035.
MPEP § 2143(I)(B) states: “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.”
The simple substitution of one known element for another (i.e. anti-CD3/anti-CD28 coupled Dynabeads as taught in Rasmussen et al. instead of mature dendritic cells as taught in WO ‘035) would be expected to obtain predictable results with a reasonable expectation of success (anti-CD3/anti-CD28 coupled Dynabeads and mature dendritic cells were known and used prior to the effective filing date of the application to stimulate proliferation of CD4+ lymphocytes and increase CD4+/CD8+ ratio; in addition, both WO ‘035 and Rasmussen et al. are in analogous arts of adoptive T cell immunotherapy). A person having ordinary skill in the art would be motivated to make this substitution to modify a method for preparation of a composition of activated human CD8+ and natural killer lymphocytes (instant claims 1 and 16) and a method for treatment of cancer in a patient using said composition (instant claim 26) as taught in WO ‘035 using the teaching of Rasmussen et al. that anti-CD3/anti-CD28 coupled Dynabeads increase the chance of retaining long-term persistence following adoptive transfer compared to previous ex vivo methods.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to substitute anti-CD3/anti-CD28 coupled Dynabeads for mature dendritic cells in a method for preparation of a composition of activated human CD8+ and natural killer lymphocytes (instant claims 1 and 16) and a method for treatment of cancer in a patient using said composition (instant claim 26) as taught in WO ‘035.
Instant claims 2, 9 and 17
Regarding instant claims 2, 9, and 17, Rasmussen et al. further teach “[t]o obtain adequate numbers of T cells for infusion, T cells need to be cultured and expanded ex vivo” (Pg. 52, column 2, last ¶, lines 1-2), indicating the expansion can take “>45 days” using previous methods (Pg. 52, column 2, last line) or “10 days” with their method (Pg. 55, column 1, ¶ 2, line 8). This teaching indicates anti-CD3/anti-CD28 coupled Dynabeads and T lymphocytes can be incubated until the desired cell concentration is reached for the purpose of infusion in a patient. Rasmussen et al. do not teach cell incubation for 2-5 days in step 2 (instant claim 2) or 3-7 days after initiation of step 5 (instant claims 9 and 17) with an agent capable of activating T lymphocytes via binding to CD3 and CD28 (i.e. anti-CD3/anti-CD28 coupled Dynabeads).
MPEP 2144.05(II)(A) states: "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It is a common objective in the art to optimize result effective variables (i.e. days cell are incubated), so as to achieve optimal effect and maximal benefit (i.e. reach desired T lymphocyte concentration after expansion for infusion into the patient for treatment). See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
Therefore, any optimization of dosage time would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the instant application would immediately envisage the claimed days cell are incubated to achieve them without undue experimentation in order to reach desired T lymphocyte concentration after expansion for infusion into the patient for treatment.
Instant claim 3
Regarding instant claim 3, WO ‘035 further teaches “non-adherent fraction of lymphocytes, kept frozen after isolation of monocytes, was mixed with 5-Aza-CdR-treated lymphocytes” (Pg. 10, lines 1-2). This teaching indicates the autologous lymphocytes are kept frozen until mixed with 5-Aza-CdR-treated lymphocytes; therefore, this teaching reads on the second fraction of the sample is kept frozen between step 1 and until mixing in step 4 (instant claim 3).
Instant claims 4-6
Regarding instant claims 4-6, WO ‘035 further teaches “cancer/testis antigens… may be chemically induced by DNA demethylation (instant clam 4), for example, by treatment with 5-aza- 2'-deoxycytidine” also referred to as 5-Aza-CdR (Pg. 5, lines 4-6; instant claims 5-6). This teaching reads on an agent inducing the expression of cancer/testis antigens in a DNA de-methylating agent (instant claim 4), specifically 5-Aza-CdR (instant claims 5-6).
Instant claims 7 and 41
Regarding instant claims 7 and 41, WO ‘035 further teaches “IL-2 was added at day 2” of lymphocyte incubation (Pg. 10, line 3; instant claim 7) and “IL-7 and IL-15 could be used instead of IL-2” (Pg. 12, line 3; instant claim 41). This teaching reads on IL-2 is added during the course of culture of lymphocytes (instant claim 7) and wherein IL-2 is substituted with either IL-7 or IL-15 (instant claim 41).
Instant claim 8
Regarding instant claim 8, Applicant is claiming addition of the agent capable of activating T lymphocytes via binding to CD3 and CD28 either in step 2 and/or 5 of instant claim 1. However, as Rasmussen et al. teaches anti-CD3/anti-CD28 coupled Dynabeads activate T lymphocytes via binding to CD3 and CD28 without limitation to a specific timing, it is reasonable to perform this activation at any step (see MPEP 2111.01 regarding specific order of steps into method claims). Therefore, this teaching reads on addition of the agent capable of activating T lymphocytes via binding to CD3 and CD28 (i.e. anti-CD3/anti-CD28 coupled Dynabeads) in step 2 and/or step 5 (instant claim 8).
Instant claims 10 and 23
Regarding instant claims 10 and 23, WO ‘035 further teaches “preparation of vaccine from activated and treated lymphocytes” (Pg. 8, line 6), indicating the treated lymphocytes were recovered to prepare a vaccine. This teaching reads on recovery of activated CD8+ and NK lymphocytes (instant claims 10 and 23).
Instant claims 11, 14-15, 18, 21-22, and 36-40
Regarding claims 11, 18, and 36-38, Rasmussen et al. further teach “Anti-CD3/anti-CD28 coupled Dynabeads” (Pg. 53, column 2, ¶ 1, lines 9-10), indicating the use of bispecific anti-CD3/anti-CD28 antibodies. This teaching reads on the agent capable of activating T lymphocytes via binding to CD3 and CD28 (i.e. anti-CD3/anti-CD28 coupled Dynabeads) comprises bispecific antibodies (instant claims 36-38) that bind both CD3 and CD28 (instant claims 11 and 18).
Regarding instant claims 14-15, 21-22, and 39-40, Rasmussen et al. do not explicitly teach Dynabeads are a solid phase (instant claims 14 and 21), separable (instant claims 15 and 22), nor superparamagnetic (instant claims 39-40).
However, Thermo Fisher Scientific teach “Dynabeads magnetic beads are superparamagnetic, uniform, and spherical particles used for… separation” (Pg. 1, ¶ 2, line 1). This teaching indicates Dynabeads are inherently a solid phase (i.e. spherical particles; instant claims 14 and 21), separable (instant claims 15 and 22), and superparamagnetic (instant claims 39-40) as evidenced by Thermo Fisher Scientific.
Instant claims 24-25
Regarding instant claims 24-25, WO ‘035 further teaches mature dendritic cells can be co-cultured with lymphocytes before addition of chemical agents leading to induction of cancer/testis antigens (Pg. 8, lines 1-4, culture with mature dendritic cells before addition of chemical agents; corresponds to step b of instant claim 16; instant claim 24) and with cytotoxic lymphocytes that have been co-cultivated with activated lymphocytes (Pg. 8, lines 9-12, corresponds to step e of instant claim 16; instant claim 25). These teachings read on the conditions in step b entail co-culture with mature dendritic cells prepared from the sample in step a (instant claim 24) and step e comprises addition of mature dendritic cells prepared from the sample in step a (instant claim 25).
Instant claim 30
Regarding instant claim 30, Rasmussen et al. further teach “[a]doptive T cell therapy is a promising treatment strategy for patients with different types of cancer” (Pg. 52, Abstract, lines 1-2) and their therapy targeted “stage III malignant melanoma patients” (Pg. 53, column 2, last ¶, lines 14-15). This teaching reads on the cancer treated in malignant melanoma (instant claim 30).
Claims 28-29, 31-33, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over WO2008081035A1 (filed 2008-01-03, published 2008-07-10; hereinafter referred to as WO ‘035) in view of Rasmussen et al. (Ex vivo expansion protocol for human tumor specific T cells for adoptive T cell therapy, Journal of Immunological Methods, 2010, Vol. 355, pp. 52-60; IDS filed 05/06/2024, Cite No. 12) as applied to claim 26 above, and further in view of WO2018218231A1 (filed 2018-05-25, published 2018-11-29; hereinafter referred to as WO ‘231).
The WO ‘035, Rasmussen and Thermo Scientific are as discussed above and incorporated by reference herein.
WO ‘035 and Rasmussen et al. teach the method for treatment of cancer comprising steps 1-5 or a-e as recited in instant claim 26 which delineates a specific adoptive T cell therapy protocol as fully described in the previous 103 rejection.
WO ‘035 and Rasmussen et al. do not teach how or when the treatment is administered (instant claims 28-29 and 44) nor addition of an immune checkpoint inhibitor (instant claims 31-33).
Regarding instant claim 31, WO ‘231 teaches “compositions and methods for modulating or enhancing an immune response in a subject, e.g. a subject with cancer” (Abstract, indicating a method of treating cancer) comprising active agents such as “one or more checkpoint inhibitors… [and/or] adoptive T cell therapy” (¶ 0010) wherein “treatment can be administrated into patients” (¶ 0400). These teachings read on the patient subjected to a co-treatment with an anti-cancer drug, specifically a checkpoint inhibitor drug (instant claim 31).
Regarding instant claim 28, WO ‘231 further teaches the treatment is “administrated in one or more doses” (¶ 0404). This teaching reads on the patient receiving at least 2 administrations (instant claim 28).
Regarding instant claims 29 and 44, WO ‘231 further teaches “the effective amount of cells or composition comprising those cells are administrated parenterally (instant claim 29). The administration can be an intravenous administration (instant claim 44)” (¶ 0405). This teaching reads on the administration is via the parenteral route (instant claim 29), specifically he intravenous route (instant claim 24).
Regarding instant claim 32, WO ’213 further teaches “checkpoint blockade therapy may comprise… anti-PD-1 antibodies” (¶ 0363), indicating the anti-PD-1 antibody is antagonistic. This teaching reads on the co-treatment is a PD-1 inhibitor (instant claim 32).
Regarding instant claim 33, WO ‘231 further teaches “the method may further comprise sequentially or simultaneously administering an additional active agent used to treat the cancer” (¶ 0011). This teaching reads on the co- treatment is prior to, concurrent with, and/or or subsequent to the treatment of instant claim 26.
WO ‘231 further teaches “[i]mmune checkpoints are inhibitory pathways that slow down or stop immune reactions” (¶ 0415), indicating immune checkpoint inhibitors such as anti-PD-1 antibodies can enhance immune response. This teaching gives motivation for including immune checkpoint inhibitors in a method of treating cancer.
WO ‘231 does not teach the method for treatment of cancer comprising steps 1-5 or a-e as recited in instant claim 26 which delineates a specific adoptive T cell therapy protocol.
A method of treating cancer comprising adoptive T cell therapy and antagonistic anti-PD-1 antibodies was known and used prior to the effective filing date of the application. In addition, WO ‘035, WO ‘231, and Rasmussen et al. are in analogous arts (i.e. treatment of cancer with adoptive T cell therapy). Since WO ‘231 teach immune checkpoints inhibitors such as antagonistic anti-PD-1 antibodies can enhance immune response by aiding immune reactions, there is motivation for adding antagonistic anti-PD-1 antibodies in a method of treating cancer comprising the adoptive T cell therapy recited in steps 1-5 or a-e of instant claim 26 as taught in WO ‘035 and Rasmussen et al.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. immune checkpoints inhibitors such as antagonistic anti-PD-1 antibodies can enhance immune response by aiding immune reactions as taught in WO ‘231) would have led one of ordinary skill to modify the prior art reference (i.e. a method of treating cancer comprising the adoptive T cell therapy recited in steps 1-5 or a-e of instant claim 26 as taught in WO ‘035 and Rasmussen et al.) to arrive at the claimed invention. There is a reasonable expectation of success as a method of treating cancer comprising adoptive T cell therapy and antagonistic anti-PD-1 antibodies was known and used prior to the effective filing date of the application. In addition, WO ‘035, WO ‘231, and Rasmussen et al. are in analogous arts (i.e. treatment of cancer with adoptive T cell therapy).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to add antagonistic anti-PD-1 antibodies in a method of treating cancer comprising the adoptive T cell therapy recited in steps 1-5 or a-e of instant claim 26 as taught in WO ‘035 and Rasmussen et al.
Claims 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over WO2008081035A1 (filed 2008-01-03, published 2008-07-10; hereinafter referred to as WO ‘035) in view of Rasmussen et al. (Ex vivo expansion protocol for human tumor specific T cells for adoptive T cell therapy, Journal of Immunological Methods, 2010, Vol. 355, pp. 52-60; IDS filed 05/06/2024, Cite No. 12) as evidenced by Thermo Fisher Scientific (Dynabeads Magnetic Beards, 2026) as applied to claims 1, 11, 14, 16, and 21 above, and further in view of Perica et al. (Magnetic Field-Induced T Cell Receptor Clustering by Nanoparticles Enhances T Cell Activation and Stimulates Antitumor Activity, ACS Nano, 2014, Vol 8, Issue 3, Pg. 2252-2260).
The WO ‘035, Rasmussen and Thermo Scientific are as discussed above and incorporated by reference herein.
WO ‘035 and Rasmussen et al. teach the method for preparation of a composition of activated human CD8+ and NK lymphocytes as recited in instant claims 1, 11, 14, 16, and 21 as fully described in the previous 103 rejection.
WO ‘035 and Rasmussen et al. do not teach the anti-CD3 and/or anti-CD28 antibodies are linked to dextran (instant claims 42-43).
Regarding instant claims 43-44, Perica et al. teach “Iron dextran nanoparticles functionalized with T cell activating proteins” (Pg. 2252, Abstract, line 1), specifically “anti-CD28 antibody” (Pg. 2253, column 1, last ¶, line 8; see also Fig. 1A on Pg. 2253 depicting anti-CD28 coupled to the nanoparticle; instant claims 43-44).
Perica further teach the nanoparticles were used for “increased T cell expansion in vitro and after adoptive transfer in vivo” (Pg. 2252, Abstract, line 7).
Perica et al. do not teach the method for preparation of a composition of activated human CD8+ and NK lymphocytes as recited in instant claims 1, 11, 14, 16, and 21.
T cell activating proteins, specifically anti-CD28 antibodies, conjugated to dextran (i.e. the nanoparticles of Perica et al.) and magnetic beads were known and used prior to the effective filing date of the application. In addition, WO ‘035, Rasmussen et al., and Perica et al. are in analogous arts (i.e. activation of T cells). Since Perica et al. teach the nanoparticles increased T cell expansion in vitro and after adoptive transfer in vivo, there is motivation for using anti-CD28 antibodies conjugated to dextran instead of conjugated to magnetic beads in the method for preparation of a composition of activated human CD8+ and NK lymphocytes as recited in instant claims 1, 11, 14, 16, and 21.
MPEP § 2143(I)(B) states: “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.”
The simple substitution of one known element for another (i.e. anti-CD28 antibodies conjugated to dextran instead of conjugated to magnetic beads) would be expected to obtain predictable results with a reasonable expectation of success (T cell activating proteins, specifically anti-CD28 antibodies, conjugated to dextran and magnetic beads were known and used prior to the effective filing date of the application; in addition, WO ‘035, Rasmussen et al., and Perica et al. are in analogous arts of activation of T cells). A person having ordinary skill in the art would be motivated to make this substitution to modify the method for preparation of a composition of activated human CD8+ and NK lymphocytes as recited in instant claims 1, 11, 14, 16, and 21 as taught in WO ‘035 and Rasmussen et al. using the teaching of Perica et al. that the nanoparticles increased T cell expansion in vitro and after adoptive transfer in vivo.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to substitute anti-CD28 antibodies conjugated to dextran for anti-CD28 antibodies conjugated to magnetic beads in the method for preparation of a composition of activated human CD8+ and NK lymphocytes as recited in instant claims 1, 11, 14, 16, and 21 as taught in WO ‘035 and Rasmussen et al.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-11, 14-18, 21-26, 28-33, and 36-44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4 of U.S. Patent No. 10023839 (hereinafter referred to as Pat. ‘839) in view of WO2008081035A1 (filed 2008-01-03, published 2008-07-10; hereinafter referred to as WO ‘035), Rasmussen et al. (Ex vivo expansion protocol for human tumor specific T cells for adoptive T cell therapy, Journal of Immunological Methods, 2010, Vol. 355, pp. 52-60; IDS filed 05/06/2024, Cite No. 12), WO2018218231A1 (filed 2018-05-25, published 2018-11-29; hereinafter referred to as WO ‘231), and Perica et al. (Magnetic Field-Induced T Cell Receptor Clustering by Nanoparticles Enhances T Cell Activation and Stimulates Antitumor Activity, ACS Nano, 2014, Vol 8, Issue 3, Pg. 2252-2260) as evidenced by Thermo Fisher Scientific (Dynabeads Magnetic Beards, 2026).
Instant claims 1-11, 14-18, 21-26, 28-33, and 36-44 are rendered obvious by the combined teachings of the prior art as fully described in the 103 rejection section, the 103s being incorporated here. The addition of the patented claims over above over related subject matter only further supported this obviousness.
Note that WO ‘035 is the published patent application of Pat. ‘839 and WO ‘035 was used in all 103 rejections to render the instant claims obvious in view of QO ‘231, Rasmussen et al., and Perica et al. as evidenced by Thermo Fisher Scientific.
Claim 1 of Pat. ‘839 teaches a method of preparing an antigen-presenting composition enriched in CD4+ cells as compared to CD8+ cells comprising:
obtaining autologous mature dendritic cells from blood monocytes (i.e. isolating a sample of blood cells) and stimulating proliferation of autologous normal non-activated lymphoid cells (i.e. enriching sample for lymphocytes) by coculturing the autologous normal non-activated lymphoid cells with the autologous mature dendritic cells (step 1 of instant claims 1 and 26; step a of instant claims 16 and 26);
proliferating cells enriched in CD4+ cells via mature dendritic cells (i.e. agent capable of activating T lymphocytes), wherein the ratio between CD4+ and CD8+ cells in the proliferating cells is increased as compared to the ratio between CD4+ and CD8+ cells in the autologous normal non-activated lymphoid cells (i.e. stimulating proliferation of CD4+ lymphocytes and increasing the CD4+/CD8+ ratio compared to the lymphocytes obtained from step 1/a) (step 2 of instant claims 1 and 26; step b of instant claims 16 and 26; instant claims 24-25); and,
chemically treating the CD4+ enriched proliferating cells with an agent that induces expression of cancer/testis antigens and thereby obtaining the antigen-presenting composition (step 3 of instant claims 1 and 26; step c of instant claims 16 and 26).
Claim 2 of Pat. ‘839 teaches the autologous normal non-activated lymphoid cells are peripheral blood lymphocytes extracted from autologous blood (i.e. lymphocytes from blood sample) (step 1 of instant claims 1 and 26; step a of instant claims 16 and 26).
Claim 4 of Pat. ‘839 teaches the agent that induces expression of cancer/testis antigens is a DNA de-methylating agent (instant claim 4), specifically 5-aza-2′-deoxycytidine (instant claims 5-6).
The claims of Pat. ‘839 does not teach steps 4-5 or d-e of instant claims 1, 16, and 26 nor instant claims 2-3, 7-11, 14-18, 21-23, 28-33, and 36-44.
These deficiencies are remedied by WO ‘035, Rasmussen et al., WO ‘231, and Perica et al. as evidenced by Thermo Fisher Scientific as fully described in the 103 rejection section above.
The following were known and used prior to the effective filing date of the instant application: anti-CD3/anti-CD28 coupled Dynabeads and mature dendritic cells to stimulate proliferation of CD4+ lymphocytes and increase CD4+/CD8+ ratio as taught in Rasmussen et al. and WO ‘035 respectively; a method of treating cancer comprising adoptive T cell therapy with and without the addition of antagonistic anti-PD-1 antibodies as taught in WO ‘035 and WO ‘231 respectively; and, T cell activating proteins, specifically anti-CD28 antibodies, conjugated to dextran and magnetic beads to induce T cell proliferation as taught in Perica et al. and Rasmussen et al. respectively.
In addition, WO ‘035, WO ‘231, Rasmussen et al., Perica et al., and Pat. ‘839 are in analogous arts (i.e. T cell proliferation and/or therapy). There is motivation for arriving at the claimed invention of the instant application because: Rasmussen et al. teach anti-CD3/anti-CD28 coupled Dynabeads increase the chance of retaining long-term persistence following adoptive transfer compared to previous ex vivo methods; WO ‘231 teach immune checkpoints inhibitors such as antagonistic anti-PD-1 antibodies can enhance immune response by aiding immune reactions; and, Perica et al. teach anti-CD28 antibodies conjugated to dextran increased T cell expansion in vitro and after adoptive transfer in vivo.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. Rasmussen et al. teach anti-CD3/anti-CD28 coupled Dynabeads increase the chance of retaining long-term persistence following adoptive transfer compared to previous ex vivo methods; WO ‘231 teach immune checkpoints inhibitors such as antagonistic anti-PD-1 antibodies can enhance immune response by aiding immune reactions; and, Perica et al. teach anti-CD28 antibodies conjugated to dextran increased T cell expansion in vitro and after adoptive transfer in vivo) would have led one of ordinary skill to modify Pat.839 (i.e. a method of preparing an antigen-presenting composition enriched in CD4+ cells as compared to CD8+ cells) to arrive at the claimed invention. There is a reasonable expectation of success because:
In addition, WO ‘035, WO ‘231, Rasmussen et al., Perica et al., and Pat. ‘839 are in analogous arts (i.e. T cell proliferation and/or therapy). There is motivation for arriving at the claimed invention of the instant application because: anti-CD3/anti-CD28 coupled Dynabeads and mature dendritic cells to stimulate proliferation of CD4+ lymphocytes and increase CD4+/CD8+ ratio as taught in Rasmussen et al. and WO ‘035 respectively; a method of treating cancer comprising adoptive T cell therapy with and without the addition of antagonistic anti-PD-1 antibodies as taught in WO ‘035 and WO ‘231 respectively; and, T cell activating proteins, specifically anti-CD28 antibodies, conjugated to dextran and magnetic beads to induce T cell proliferation as taught in Perica et al. and Rasmussen et al. respectively. In addition, WO ‘035, WO ‘231, Rasmussen et al., Perica et al., and Pat. ‘839 are in analogous arts (i.e. T cell proliferation and/or therapy).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the teachings of WO ‘035, Rasmussen et al., WO ‘231, and Perica et al. as evidenced by Thermo Fisher Scientific as fully described in the 103 rejection section to modify a method of preparing an antigen-presenting composition enriched in CD4+ cells as compared to CD8+ cells as taught by claims 1-2 and 4 of Pat. ‘839 to arrive at the instant invention.
Conclusion
Claims 1-11, 14-18, 21-26, 28-33, and 36-44 are pending. Claims 10, 28, 33, 39-40, and 44 are objected to. Claims 1-11, 14-18, 21-26, 28-33, and 36-44 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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