DETAILED ACTION
This Office Action is in response to Applicant’s remark (see attached interview summary PTO-413) that the evidentiary reference “Cancer Cell. 2025 Jan 13;43(1):49-68.e9. doi: 10.1016/j.ccell.2024.11.006. Epub 2024 Dec 5” (cited in the 102 rejection below as “Chen”) was not properly made of record in the previous Office Action (5/13/2026). The present Office Action is identical to the previous Office Action but includes a copy of the reference and properly cites the reference in a PTO-892 form.
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 .
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.
Election/Restrictions
Applicant's election with traverse of the species of "(a) CD19 as the B cell antigen; (b) the upregulation of CD80; (c) ACPP as the antigen binding domain; and (d) 4-1 BB as the signaling domain" (page 6 last paragraph and page 7 para. 1) in the reply filed on 12/31/2025 is acknowledged. Regarding the species requirements “(b) the upregulation of CD80; (c) ACPP as the antigen binding domain”, there were no prior art references found that taught these species, therefore the species requirement “(b)” and “(c)” set forth above, is hereby withdrawn.
The traversal is on the ground(s) that "[t]he species of each group are functionally related in that they are used to perform the claimed method, which involves remodeling the tumor microenvironment by activating antigen-presenting cells and enhancing anti- tumor lymphocyte function. Accordingly, Applicant respectfully submits that there is no burden to search and examine all the species of each group in the same application, as the search for one species of each group would provide relevant art for the other species of the group” (page 7 para. 2). This is not found persuasive because "each species has a different binding or regulation effect. In addition, these species are not obvious variant of each other based on the current record...There is a serious search and/or examination burden for the patentably distinct species...because...[each species requires] different electronic database searches" (page 2 paras. 2 and 4 of Restriction Requirement 7/2/2025).
The requirement is still deemed proper and is therefore made FINAL.
Applicant timely traversed the restriction (election) requirement in the reply filed on 7/2/2025.
Priority
The present application claims benefit under 35 U.S.C. 119(e) to provisional application 63/288,959 filed on 12/13/2021.
Information Disclosure Statement
The information disclosure statement filed 12/13/2022 is being considered by the examiner.
Claim Objections
Claims 1, 4, and 24-28 are objected to because of the following informalities:
In claim 1 line 10, "the lymphocytes" appears to be a typographical error, namely it is suggested that "the lymphocytes" read as "the modified lymphocytes" (emphasis added) as per line 7.
In claim 4 lines 1-3, “the lymphocytes” (3 instances) appears to be a typographical error, namely it is suggested that “the lymphocytes” read as “the modified lymphocytes” (emphasis added) as per claim 1 line 7
In claims 16-17, Applicant uses a series of abbreviations, it is recommended that abbreviations be accompanied by their full meaning at least at first instance that the abbreviation is used in order to improve clarity of the record and avoid confusion.
In claims 24-28, line 3, “the modified lymphocyte” appears to be a typographical error, namely it is suggested that “the modified lymphocyte” read as “the modified lymphocytes” (emphasis added) as per claim 1 line 7.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-31 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. This is a written description rejection.
Claim 1 and its dependent claims require an “agent” that “stimulates or activates one or more antigen presenting cells (APCs) in the subject”. Claim 5 requires wherein the agent that stimulates or activates one or more APCs “comprises a CAR T cell that binds a B cell, a bispecific antibody that binds a B cell and a T cell, a cytokine that differentiates a B cell into a plasma cell, an antibody that binds a B cell, or a combination thereof”. Claim 6 requires “wherein the agent comprises an antibody that binds a B cell”. Claim 7 requires “wherein the agent comprises a scFv that binds a B cell”. Claim 9 requires “wherein the agent binds a B cell antigen”. Claim 11 requires “wherein the APCs comprise B cells, and stimulating or activating the APCs comprises stimulating or activating the B cells to upregulate CD40, CD80, CD86, or a combination thereof on the B cells”. Claim 12 requires “wherein the APCs comprise B cells, and stimulating or activating the APCs comprises causing the B cells to differentiate into B cells with upregulated CCL17 and CCL22”. Claim 13 requires “wherein the APCs comprise B cells, and wherein the agent stimulates or activates the B cells such that at least a portion of the B cells differentiate into plasma cells or into cells having one or more phenotypes of a plasma cell”.
The specification does not describe which amino acid residues, nucleic acid residues, or other molecular components are present in the genus of agents encompassed by claim 1-31. The specification fails to disclose the structures common to all members of the genus and fails to provide sufficient specific examples of agents to be used. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described. Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement.
Regarding the claimed scope that includes antibodies, the Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies and variants, fragments or derivates of the antibodies of the claims.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the full genus of antibodies encompassed by the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of encompassed antibodies.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Without detailed written description from the instant specification, the skilled artisan cannot envision the detailed chemical structure of each genus of claimed “agents”, i.e.,
a) agents that stimulate or activate one or more APCs (claim 1), and
b) that comprise a CAR T cell that binds a B cell, a bispecific antibody that binds a B cell and a T cell, a cytokine that differentiates a B cell into a plasma cell, an antibody that binds a B cell, or a combination thereof (claim 5),
c) that comprise an antibody or scFv that binds a B cell (claims 6-7),
d) wherein the APCs comprise B cells, and stimulating or activating the APCs comprises stimulating or activating the B cells to upregulate CD40, CD80, CD86, or a combination thereof on the B cells (claim 11).
e) wherein the APCs comprise B cells, and stimulating or activating the APCs comprises causing the B cells to differentiate into B cells with upregulated CCL17 and CCL22 (claim 12).
f) wherein the APCs comprise B cells, and wherein the agent stimulates or activates the B cells such that at least a portion of the B cells differentiate into plasma cells or into cells having one or more phenotypes of a plasma cell (claim 13).
Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
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 4, 17, 20 and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “…administering an effective amount of modified lymphocytes to the subject…allowing the lymphocytes to expand in the subject”.
Claim 4 recites “wherein allowing the lymphocytes to expand comprises allowing the lymphocytes to expand before contacting the lymphocytes with an antigen that the lymphocytes bind”.
However, it is not clear how one can contact the lymphocytes with an antigen that the lymphocytes bind if the lymphocytes are administered to the subject. Given that the lymphocytes are in the subject a person having ordinary skill in the art would be confused as to how the contacting step is performed. Because of this, there is a question as to the metes and bounds of the claim.
Claim 17 recites the limitation "the CAR that comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain, and the intracellular signaling domain comprises a signaling domain or a primary signaling domain and one or more co-stimulatory signaling domains" in lines 1-4. There is insufficient antecedent basis for this limitation in the claim. Although claim 15 recites “wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain”, there is no mention of “and the intracellular signaling domain comprises a signaling domain or a primary signaling domain and one or more co-stimulatory signaling domains”. It is not clear what CAR is being referred to because a CAR comprising an intracellular signaling domain comprising a signaling domain or a primary signaling domain and one or more co-stimulatory signaling domains is not recited in claims 1, 14-15 or 17.
Claim 20 recites “wherein enhancing the infiltration of lymphocytes into tumor tissue comprises enriching the lymphocytes and/or enhancing entry of lymphocytes into the TME or enhancing or increasing number of lymphocytes in the TME”. However, “enhancing or increasing number of lymphocytes in the TME” is not clear; specifically it is not clear what is encompassed by the enhancing of lymphocytes in the TME. The specification fails to clarify what is meant by the “enhancing…lymphocytes in the TME” claimed. Therefore, a person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claim 24 recites the limitation "the number of B cells" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. It is not clear what B cells are being referred because a number of B cells is not recited in claim 1.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-31 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Chang et al. (WO 2021035194 A1) (“Chang”) as evidenced by Li et al. Front. Immunol., 31 March 2022 Sec. Inflammation Volume 13 - 2022 | https://doi.org/10.3389/fimmu.2022.857808 (“Li”), Melnick et al. Blood Rev. 2022 November ; 56: 100988. doi:10.1016/j.blre.2022.100988. (“Melnick”), Ku et al. Blood. 2012 Jan 20;119(10):2242–2251. doi: 10.1182/blood-2011-07-366070 (“Ku”), Chen et al. Cancer Cell. 2025 Jan 13;43(1):49-68.e9. doi: 10.1016/j.ccell.2024.11.006. Epub 2024 Dec 5 (“Chen”) an Zou et al. Discov Oncol. 2024 Sep 6;15:412. doi: 10.1007/s12672-024-01210-x (“Zou”).
Regarding claims 1-2, 8 and 14-15, Chang teaches a method of enhancing infiltration of lymphocytes into tumor tissue, enhancing anti-tumor lymphocyte activities in tumor microenvironment (TME), inhibiting regulatory lymphocyte activities in TME, and/or providing long term benefit of cell therapies (“methods, uses, and articles of manufacture of combination therapies involving immunotherapies and cell therapies” Abstract, “the method increases the number of the CAR-expressing T cells able to infiltrate a tumor microenvironment (TME) in the subject” para. 10), the method comprising: collecting a first sample from a subject having a solid tumor, the first sample comprising a first group of cells from the TME of the solid tumor; administering an effective amount of modified lymphocytes to the subject, wherein the modified lymphocytes comprise T cells and a CAR or TCR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain (“the tumor biopsy sample is a lymph node biopsy. In some embodiments, the tumor biopsy sample is obtained at a time prior to administering the T cell therapy to the subject, such as within at or about 1 month prior to the subject receiving the T cell therapy. In some embodiments, T cell therapy is autologous to the subject and the tumor biopsy sample is obtained at a time that is at or about at the same time as obtaining (e.g. by apheresis) the T cells from the subject for manufacturing or producing the T cell therapy, e.g. engineered with a recombinant receptor (e.g. CAR)” para. 50, “the recombinant receptor, e.g., a chimeric antigen receptor, includes an extracellular portion containing one or more ligand- (e.g., antigen-) binding domains, such as an antibody or fragment thereof, and one or more intracellular signaling region or domain (also interchangeably called a cytoplasmic signaling domain or region)… CAR, further includes a spacer and/or a transmembrane domain or portion” para. 480). Chang further teaches administering an effective amount of an agent to the subject, wherein the agent stimulates or activates one or more antigen presenting cells (APCs) in the subject, wherein the APCs comprise macrophages (“e.g. a T cell therapy, and the use of an inhibitor of an enhancer of zeste homolog 2 (EZH2)” Abstract). Note that EZH2 inhibitors activate or stimulate macrophages as evidenced by Li (“EZH2i not only suppress CRC cell proliferation directly, but also regulate macrophage by skewing M2 into effector M1 macrophage to exert a tumor suppressive effect” Abstract). Chang further teaches allowing the lymphocytes to expand in the subject; collecting a second sample from the subject, the second sample comprising a second group of cells from the TME of the solid tumor (“3-months post-treatment with CART cells are identified herein” para. 190, “the methods involve monitoring response in a subject who has received administration of the therapy…the methods include assessment of a first sample at a time prior to the administering of the therapy and a second sample at a time after administering the therapy… the second sample is a sample from the subject after receiving administration of the therapy… the sample is a tumor sample, e.g. tumor biopsy sample” para. 713). Note that although Chang fails to use the language “allowing the lymphocytes to expand in the subject” the teachings of monitoring response and using a sample “at a time after administering the therapy”, “3-months post-treatment” inherently provides the allowing of the lymphocytes to expand in the subject. Chang further teaches comparing cell phenotypes of the first and second samples, and determining in the second sample, infiltration of lymphocytes into tumor tissue is enhanced as compared to the first sample, anti-tumor lymphocyte activities in TME is enhanced as compared to the first sample, regulatory lymphocyte activities in TME is inhibited as compared to the first sample, and/or long term benefit of cell therapies is provided as compared to the first sample (“to examine the role that the pre-treatment and post-infusion tumor microenvironment (TME) plays in response and resistance to CART cell monotherapy, tumor biopsies from a large cohort of CART cell-treated diffuse large B-cell lymphoma (DLBCL) subjects with long-term follow up were analyzed. It was observed, as described herein, that pre-treatment TME influences response to CART cell therapy. Notably, distinct gene expression signatures within the pre-treatment TME of subjects who go on to exhibit PD vs. CR 3-months post-treatment with CART cells are identified herein. Thus, pre-treatment tumor biopsy gene signatures associated with 3-month PD or CR may be predictive of and distinguish between long term responses (e.g. PD or CR after 3 months). For example, gene expression signatures of subjects who go on to exhibit PD 3 months post-treatment are associated with genes that prevent T cell infiltration into post-infusion tumors” para. 190).
Regarding claim 3, Chang further teaches wherein the APCs comprise B cells (“an inhibitor of an enhancer of zeste homolog 2 (EZH2)” Abstract). Note that as evidenced by Melnick, EZH2 inhibitors activate or stimulate B cells (“Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that controls the normal biology of germinal B cells” Abstract, “When EZH2 mutations occur in the context of B cells that already harbor BCL2 translocations [37,60], the combined effect of aberrant survival and immune reprogramming that would occur in GC B cells due to BCL2 and EZH2 mutations yields a potent oncogenic effect. Indeed, preclinical studies administering EZH2 and BCL2 inhibitors show dramatic synergy against EZH2 mutant lymphomas in vitro and in vivo” page 8 para. 2).
Regarding claim 4, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “wherein administering an effective amount of modified lymphocytes to the subject comprises a first step of allowing the lymphocytes to expand before contacting the lymphocytes with an antigen that the lymphocytes bind”.
Chang further teaches wherein administering an effective amount of modified lymphocytes to the subject comprises a first step of allowing the lymphocytes to expand before contacting the lymphocytes with an antigen that the lymphocytes bind (“the cells are incubated and/or cultured prior to or in connection with genetic engineering” para. 621, “the cells are cultivated in the presence of one or more cytokines. In particular embodiments, the one or more cytokines are recombinant cytokines. In some embodiments, the one or more cytokines are human recombinant cytokines. In certain embodiments, the one or more cytokines bind to and/or are capable of binding to receptors that are expressed by and/or are endogenous to T cells” para. 648).
Regarding claims 5-7 and 9-10, Chang teaches wherein the agent comprises an antibody, scFv, that binds a B cell antigen CD19 (Applicant’s elected species) (Abstract, “The dose(s) of the cells may include a particular number or relative number of cells or of the engineered cells, and/or a defined ratio or compositions of two or more sub-types within the composition” para. 379 “some embodiments, the administration of the dose comprises administration of a first composition comprising a dose of CD8+ T cells or a dose of CD4+ T cells and administration of a second composition comprising the other of the dose of CD4+ T cells and the CD8+ T cells” para. 410 “the recombinant receptor, such as a chimeric receptor (e.g. CAR), includes an extracellular antigen binding domain, such as an antibody or antigen-binding fragment (e.g. scFv), that binds, such as specifically binds, to an antigen (or a ligand)… such as lymphomas, leukemias, and/or myelomas, such as B” 469, “the antibody or an antigen-binding fragment (e.g. scFv or VH domain) specifically recognizes an antigen, such as CD19” para. 472). Note that although Chang fails to use the language “wherein the agent comprises…” the teaching of using a second population of CAR T cells with an anti-CD19 scFv for B cell malignancies in the composition in combination with the EZH2 inhibitor inherently provides wherein the agent comprises an antibody, scFv, that binds a B cell antigen CD19 because the combination of the EZH2 inhibitor and the second CAR T cell population are reasonably interpreted as the agent and the second population of CART cells are reasonably interpreted as the modified lymphocytes.
Regarding claim 11, Chang further teaches wherein the APCs comprise B cells, and stimulating or activating the APCs comprises stimulating or activating the B cells to upregulate CD40, CD80, CD86, or a combination thereof on the B cells (“Antigens targeted by the receptors in some embodiments include antigens associated with a B cell malignancy, such as any of a number of known B cell marker” para. 471, “Table 2: Genes with expression negatively correlated to PD and positively correlated to T cell infiltration…CD40L” para. 764). Note that as evidenced by Melnick, EZH2 inhibitors activate or stimulate B cells (Abstract, page 8 para. 2). Note also that although Chang fails to use the language “stimulating or activating the B cells to upregulate CD40, CD80, CD86, or a combination thereof on the B cells” the teachings of targeting B cell markers and activating the CD40 ligand gene on biopsy tumors of B cell lymphoma inherently provides the stimulating or activating the B cells to upregulate CD40, CD80, CD86, or a combination thereof on the B cells.
Regarding claim 12, Chang further teaches wherein the APCs comprise B cells, and stimulating or activating the APCs comprises causing the B cells to differentiate into B cells with upregulated CCL 17 and CCL22 (“T cell therapy, and the use of an inhibitor of an enhancer of zeste homolog 2 (EZH2)” Abstract). Note that EZH2 inhibitors cause B cells to differentiate into B cells with upregulated CCL17 and CCL22 as evidenced by Zou (“Tazemetostat, a histone-lysine N-methyltransferase enzyme (EZH2) inhibitor, has been approved in Japan for the treatment of patients with EZH2 functionally acquired mutations in FL [59]. It has been shown that the CCL17 promoter region is enriched in inhibitory histone modified H3K27me3. Tazemetostat enhances CCL17 promoter activity by inhibiting EZH2 leading to H3K27me3 demethylation, which promotes the secretion of CCL17 from B-cell lymphomas, activates the anti-lymphoma response and promotes the migration of potentially cytotoxic T-cells, which can be toxic to Lymphoma cells with toxic effects” page 6 para. 2).
Regarding claim 13, Chang further teaches wherein the APCs comprise B cells, and
wherein the agent stimulates or activates the B cells such that at least a portion of the B
cells differentiate into plasma cells or into cells having one or more phenotypes of a
plasma cell (Abstract). Note that as evidenced by Melnick, EZH2 inhibitors activate or stimulate B cells such that at least a portion of the B cells differentiate into plasma cells or into cells having one or more phenotypes of a plasma cell (“The role of EZH2 in GC B cells is to induce transient silencing of genes involved in cell cycle checkpoints, immune signaling pathways, and to restrain plasma cell differentiation through its H3K27me3 actions” page 3 para. 4).
Regarding claim 16, Chang further teaches wherein the antigen binding domain binds
a solid tumor antigen comprising MUC16, CEA, EphA2, GPC3, Mesothelin, PSMA, ROR1, VEGFR-II, GD2, or EGFR (“the CAR includes an extracellular antigen-recognition domain that
specifically binds to the antigen and an intracellular signaling domain comprising an ITAM. In some embodiments, the antigen is a tumor antigen or is expressed on cells of the cancer. In some
embodiments, the antigen is selected from among…carcinoembryonic antigen (CEA)…epidermal growth factor protein (EGFR)… ephrin receptor A2 (EPHa2),… folate receptor alpha, ganglioside GD2…glypican-3 (GPC3),… mesothelin…MUC16, …prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (RORI),… vascular endothelial growth factor receptor 2 (VEGFR2),” para. 18).
Regarding claim 17, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “wherein the CAR that comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain,
Chang further teaches wherein the CAR that comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein the intracellular signaling domain comprises a signaling domain or a primary signaling domain and one or more co-stimulatory signaling domains wherein the signaling domain and co-stimulatory signaling domain comprise a functional signaling domain of a protein comprising 4-1BB (Applicant’s elected species) (“In some embodiments, the intracellular signaling region further includes a costimulatory signaling region. In some embodiments, the costimulatory signaling region includes a signaling domain of CD28 or 4-IBB” para. 19).
Regarding claim 18, Chang further teaches wherein the TCR is a modified TCR, the TCR is derived from spontaneously occurring tumor-specific T cells in a patient, and/or the TCR binds a tumor antigen (Abstract, “T cell therapy includes cells that are autologous to the subject. In some embodiments, the T cell therapy is selected from among the group consisting of a tumor infiltrating lymphocytic (TIL) therapy, an endogenous T cell therapy, a transgenic T cell receptor (TCR) therapy” para. 104, “a chimeric antigen receptor or transgenic TCR, specifically binds to an antigen associated with the cancer” para. 226, “The receptors may include chimeric receptors, e.g., chimeric antigen receptors (CARs), and other transgenic antigen receptors including transgenic T cell receptors (TCRs)” para. 443).
Regarding claim 19, Chang further teaches wherein the tumor antigen comprises CEA, gp100, MART-1, p53, MAGE-A3, NY-ESO-1, or a combination thereof (“the antigen associated with the disease or disorder such as cancer is selected from the group consisting of… CEA,… MAGE-A3… NY-ESO-1, MART-I, gpl00” para. 228).
Regarding claim 20, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “wherein enhancing the infiltration of lymphocytes into tumor tissue comprises enriching the lymphocytes and/or enhancing entry of lymphocytes into the TME or enhancing or increasing number of lymphocytes in the TME”.
Chang further teaches wherein enhancing the infiltration of lymphocytes into tumor tissue comprises enriching the lymphocytes and/or enhancing entry of lymphocytes into the TME or increasing number of lymphocytes in the TME (“the method increases the number of the CAR-expressing T cells able to infiltrate a tumor microenvironment (TME) in the subject” para. 10).
Regarding claim 21, Chang further teaches wherein enhancing anti-tumor lymphocyte activities in the TME comprises enhancing gene expression of genes associated with cell cycle and cytotoxicity of the lymphocytes ( “Table 2: Genes with expression negatively correlated to PD and positively correlated to T cell infiltration…FYN oncogene related to…FGR…GATA3” page 226 para. 764). Note that Fig. 6 of the instant application discloses that FGR is a gene associated with cytotoxicity. Also note that as evidenced by Ku, GATA3 is associated with cell cycle (“Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages in the thymus and for Th2 differentiation in the peripheral organs. Although it is well documented that GATA-3 is expressed in HSCs, a role for GATA-3 in any prethymic progenitor cell has not been established. In the present study, we show that Gata3-null mutant mice generate fewer LT-HSCs and that fewer Gata3-null LT-HSCs are in cycle” Abstract).
Regarding claim 22, Chang further teaches wherein the subject is infused with mixed CART cells comprising a first population of CART cells targeting B cells and a second population of CAR T cells targeting a solid tumor (“Antigens targeted by the receptors in some embodiments include antigens associated with a B cell malignancy, such as any of a number of known B cell marker” para. 471, “the first and second cell compositions contain a defined ratio of the engineered cells, e.g., CD4+ and CD8+ cells (e.g., 1:1 ratio of CD4+:CD8+ CAR+ T cells)” para. 996). Note that the CD4+ and CD8+ CART cells in the combination therapy of Chang are reasonably interpreted as a first population of CART cells targeting B cells and a second population of CAR T cells targeting a solid tumor because both are capable of targeting B cells, since they include B cell marker targeted receptors, and the solid tumor, since they are also engineered CART cells for cancer treatment of B cell malignancies which includes solid tumors (“non-Hodgkin lymphoma (NHL), a large B cell lymphoma. In some embodiments, the cancer is a non-Hodgkin lymphoma (NHL). In some embodiments, the NHL is a follicular lymphoma (FL). In some embodiments, the NHL is a diffuse large B-cell lymphoma (DLBCL). In some embodiments, the DLBCL is a germinal center B-cell (GCB) subtype of DLBC” para. 132, “Tumor biopsies from an initial cohort of 50 subjects with diffuse large B-cell lymphoma (DLBCL) were collected” para. 1026).
Regarding claim 23, Chang further teaches wherein the method further comprises killing tumor cells in the subject (“the provided combination therapies and methods improve responses to the therapy by activity of the inhibitor to increase the number of the cells of the cell therapy in the tumor microenvironment of the subject, thereby increasing the tumor targeted cytolytic effector-mediated killing and/or decreasing the tumor burden” para. 182).
Regarding claim 24, Chang further teaches wherein the method further comprises killing and/or reducing the number of B cells as compared to a tumor that has not been administered the modified lymphocyte and agent (para. 182, “and uses of such compositions and combinations to treat or prevent cancers, such as a B cell malignancy” para. 183, and para. 471).
Regarding claims 25-26, Chang further teaches wherein the method further comprises increasing M1 macrophages in tumor tissue as compared to a tumor that has not been administered the modified lymphocyte and agent, and wherein the method further comprises reducing M2 macrophages in tumor tissue as compared to a tumor that has not been administered the modified lymphocyte and agent (“T cell therapy, and the use of an inhibitor of an enhancer of zeste homolog 2 (EZH2)” Abstract). Note that EZH2 inhibitors increase M1 macrophages and reduce M2 macrophages as evidenced by Li (“EZH2i not only suppress CRC cell proliferation directly, but also regulate macrophage by skewing M2 into effector M1 macrophage to exert a tumor suppressive effect” Abstract). Therefore, the T cell therapy and use of EZH2 inhibitors taught by Chang inherently anticipates the claim.
Regarding claims 27-28, Chang further teaches wherein the method further comprises reducing T regulatory cells in tumor tissue as compared to a tumor that has not been administered the modified lymphocyte and agent, and wherein the method further comprises reduced inhibition of CD8+ T cells in tumor tissue as compared to a tumor that has not been administered the modified lymphocyte and agent (“T cell therapy, and the use of an inhibitor of an enhancer of zeste homolog 2 (EZH2)” Abstract). Note that EZH2 inhibitors reduce T regulatory cells and inhibition of CD8+ T cells as evidenced by Chen (“EZH2 inhibitors do not harm tumor-controlling T cells or CAR-T cells. Instead, they reduce regulatory T cells, promote memory chimeric antigen receptor (CAR) CD8 phenotypes, and reduce exhaustion, resulting in a decreased tumor burden” Abstract). Therefore, the T cell therapy and use of EZH2 inhibitors taught by Chang inherently anticipates the claim.
Regarding claim 29, Chang further teaches wherein the method further comprises producing new normal T cells with high clonal expansion capacity in tumor tissue (“treatment of outcomes includes improved immune function, e.g., immune function of the T cells administered for cell based therapy and/or of the endogenous T cells in the body. In some embodiments, exemplary treatment outcomes include, but are not limited to, enhanced T cell proliferation, enhanced T cell infiltration into a tumor, enhanced T cell functional activity,” para. 931, “that endogenous T cells (CD3+Rt-) also increased in the tumor microenvironment after CAR T cell infusion” para. 1051). Note that although Chang fails to use the language “high clonal expansion capacity” the teaching of “enhanced T cell proliferation, enhanced T cell infiltration into a tumor, enhanced T cell functional activity” inherently provides a high clonal expansion capacity because endogenous T cells that have enhanced proliferation would also have a high clonal expansion capacity.
Regarding claim 30, Chang further teaches wherein the first and second samples comprise biopsy samples (para. 713).
Regarding claim 31, Chang further teaches wherein the cell phenotypes comprise cell types and/or cell gene expression (para. 764).
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.
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Claims 1-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. US 10869888 B2 in view of Chang as evidenced by as evidenced by Melnick, Zou, Ku and Chen, and as further evidenced by Yu et al. Int J Clin Exp Pathol 2016;9(9):8963-8972 www.ijcep.com /ISSN:1936-2625/IJCEP0035905 (“Yu”) and Elsner et al. Nat Immunol. Author manuscript; available in PMC: 2025 Jul 1 (“Elsner”).
Regarding claims 1-2, 8, 14-15, 25-26 and 30-31, U.S. Patent No. US 10869888 B2 recites a method of enhancing infiltration of lymphocytes into tumor tissue, enhancing anti-tumor lymphocyte activities in tumor microenvironment (TME), inhibiting regulatory lymphocyte activities in TME, and/or providing long term benefit of cell therapies, the method comprising; administering an effective amount of modified lymphocytes to the subject, wherein the modified lymphocytes comprise T cells and a CAR or TCR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain (“A method of enhancing expansion of cells in a subject, the method comprising: administering an effective amount of a composition to the subject having a form of cancer expressing a tumor antigen, wherein the composition comprises…a second population of cells comprising a second CAR binding a second antigen, the first and second population of cells comprising T cells,…wherein expansion of the second population of cells in the subject is enhanced as compared to a subject administered a composition comprising the second population of cells without the first population of cells” claim 1). U.S. Patent No. US 10869888 B2 further recites administering an effective amount of an agent to the subject, wherein the agent stimulates or activates one or more antigen presenting cells (APCs) in the subject, wherein the APCs comprise macrophages (“wherein the first population of cells comprises a lentiviral vector encoding the first CAR and a therapeutic agent” claim 8, “wherein the therapeutic agent comprises a cytokine” claim 9, “wherein the cytokine is at least one of IL6, IL12, TNF-α, or IFN-γ” claim 11). Note that although U.S. Patent No. US 10869888 B2 fails to use the language “administering an effective amount of an agent”, the teaching of a first population of cells comprising a lentiviral vector encoding the first CAR and a therapeutic agent inherently provides the agent claimed because the recited cells inherently produce the therapeutic agent. Also note that IL6, IL12, TNF-α, or IFN-γ inherently stimulates or activates macrophages, increasing M1 phenotype and reducing M2 phenotype as evidenced by Yu (“Overexpression of IL-12 reverses the phenotype and function of M2 macrophages to M1 macrophages” Title). U.S. Patent No. US 10869888 B2 further recites allowing the lymphocytes to expand in the subject (“allowing the first and second population of cells to expand” claim 1). U.S. Patent No. US 10869888 B2 further recites determining infiltration of lymphocytes into tumor tissue is enhanced (“wherein expansion of the second population of cells in the subject is enhanced as compared to a subject administered a composition comprising the second population of cells without the first population of cells” claim 1).
U.S. Patent No. US 10869888 B2 fails to recite collecting a first sample from a subject having a solid tumor, the first sample comprising a first group of cells from the TME of the solid tumor, collecting a second sample from the subject, the second sample comprising a second group of cells from the TME of the solid tumor and comparing cell phenotypes of the first and second samples, wherein the first and second samples comprise biopsy samples, and wherein the cell phenotypes comprise cell types and/or cell gene expression.
Chang teaches a method of enhancing infiltration of lymphocytes into tumor tissue, enhancing anti-tumor lymphocyte activities in tumor microenvironment (TME), inhibiting regulatory lymphocyte activities in TME, and/or providing long term benefit of cell therapies (Abstract, para. 10), the method comprising: collecting a first sample from a subject having a solid tumor, the first sample comprising a first group of cells from the TME of the solid tumor; administering an effective amount of modified lymphocytes to the subject, wherein the modified lymphocytes comprise T cells and a CAR or TCR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain (paras. 50 and 480). Chang further teaches administering an effective amount of an agent to the subject, wherein the agent stimulates or activates one or more antigen presenting cells (APCs) in the subject, wherein the APCs comprise macrophages (Abstract). Chang further teaches allowing the lymphocytes to expand in the subject; collecting a second sample from the subject, the second sample comprising a second group of cells from the TME of the solid tumor (paras. 190 and 713). Chang further teaches comparing cell phenotypes of the first and second samples, and determining in the second sample, infiltration of lymphocytes into tumor tissue is enhanced as compared to the first sample, anti-tumor lymphocyte activities in TME is enhanced as compared to the first sample, regulatory lymphocyte activities in TME is inhibited as compared to the first sample, and/or long term benefit of cell therapies is provided as compared to the first sample (para. 190). Chang further teaches wherein the first and second samples comprise biopsy samples (para. 713). Chang further teaches wherein the cell phenotypes comprise cell types and/or cell gene expression (para. 764). Chang further teaches that comparing cell phenotypes of the first and second samples enables the monitoring of the lymphocyte infiltration into the tumor tissue (para. 713), “predict or assess response to treatment (e.g. responsiveness or resistant to treatment) and/or for monitoring treatment outcomes” (para. 703).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. 10869888 B2 to rely on the collecting a first sample from a subject having a solid tumor, the first sample comprising a first group of cells from the TME of the solid tumor, collecting a second sample from the subject, the second sample comprising a second group of cells from the TME of the solid tumor and comparing cell phenotypes of the first and second samples, wherein the first and second samples comprise biopsy samples, and wherein the cell phenotypes comprise cell types and/or cell gene expression taught by Chang because Chang teaches that this enables the monitoring of the lymphocyte infiltration into the tumor and the treatment outcome of such method. Furthermore, a person having ordinary skill in the art would have been motivated to make such a modification because Chang teaches this also enables the assessment or prediction of response to a cancer treatment. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 10869888 B2 and Chang are drawn to methods of enhancing lymphocyte infiltration.
Regarding claim 3, U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 1 as discussed above.
U.S. Patent No. US 10869888 B2 further recites wherein the APCs comprise B cells (“IL12” claim 11). Note that as evidenced by Elsner, IL12 activates or stimulates B cells (“We identify IL-12 as a cytokine switch, acting directly on B cells to promote EF and suppress GC responses. IL-12 initiates a B cell intrinsic feed-forward loop between IL-12 and IFNγ, amplifying IFNγ production, which promotes proliferation and plasmablast (PB) differentiation from mouse and human B cells, in synergy with IL-12. IL-12 sustains the expression of a portion of IFNγ-inducible genes” Abstract).
Regarding claim 4, U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 1 as discussed above.
U.S. Patent No. US 10869888 B2 further recites wherein administering an effective amount of modified lymphocytes to the subject comprises a first step of allowing the lymphocytes to expand before contacting the lymphocytes with an antigen that the lymphocytes bind (“a second population of cells comprising a second CAR” claim 1). Note that the specification of U.S. Patent No. US 10869888 B2 discloses that generating the CAR T cells involves allowing the lymphocytes to expand before contacting the lymphocytes with an antigen that the lymphocytes bind (“Several methods were used to generate CAR T cells. For FLXY, MFPH, and MIBIX1, CD3+cells were obtained from PBMCs and were cultured using X-vivo 15 medium containing IL-2” para. 310). Therefore, the CAR T cells inherently provides a step of expanding before contacting the lymphocytes with an antigen that the lymphocytes bind, i.e. during their generation.
Regarding claims 5-7 and 9-10, U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 1 as discussed above.
U.S. Patent No. US 10869888 B2 further recites wherein the agent activates B cells and comprises an antibody, scFv, that binds a B cell antigen CD19 (Applicant’s elected species) (“wherein the first CAR comprises a scFv binding CD19, an intracellular domain of 4-1BB or CD28” claim 5).
Regarding claims 11-13, U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 1 as discussed above.
U.S. Patent No. US 10869888 B2 fails to recite stimulating or activating the APCs comprises stimulating or activating the B cells to upregulate CD40, CD80, CD86, or a combination thereof on the B cells, causing the B cells to differentiate into B cells with upregulated CCL 17 and CCL22, wherein at least a portion of the B cells differentiate into plasma cells or into cells having one or more phenotypes of a plasma cell.
Chang teaches wherein stimulating or activating the APCs comprises stimulating or activating the B cells to upregulate CD40, CD80, CD86, or a combination thereof on the B cells, causing the B cells to differentiate into B cells with upregulated CCL17 and CCL22, wherein at least a portion of the B cells differentiate into plasma cells or into cells having one or more phenotypes of a plasma cell (Abstract, paras. 471 and 764). Note that as evidenced by Melnick, EZH2 inhibitors activate or stimulate B cells (Abstract, page 8 para. 2) such that at least a portion of the B cells differentiate into plasma cells or into cells having one or more phenotypes of a plasma cell (page 3 para. 4). Note that EZH2 inhibitors also cause B cells to differentiate into B cells with upregulated CCL17 and CCL22 as evidenced by Zou (page 6 para. 2). Chang further teaches that the combination therapy which includes an agent that activates B cells to upregulate CD40, CD80, CD86, or a combination thereof on the B cells and causes the B cells to differentiate into B cells with upregulated CCL 17 and CCL22, wherein at least a portion of the B cells differentiate into plasma cells or into cells having one or more phenotypes of a plasma cell, increases the efficacy of cancer treatment methods (“ Subsets of cancers are resistant to or develop resistance to such therapies. Improved methods are therefore needed, for example, to overcome this resistance and increase the efficacy of such methods. Provided are methods and uses that meet such needs” para. 4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. US 10869888 B2 to rely on the agent that activates B cells to upregulate CD40, CD80, CD86, or a combination thereof on the B cells and causes the B cells to differentiate into B cells with upregulated CCL 17 and CCL22, wherein at least a portion of the B cells differentiate into plasma cells or into cells having one or more phenotypes of a plasma cell taught by Chang because Chang teaches that this agent increases the efficacy of cancer treatment methods, a current need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 10869888 B2 and Chang are drawn to methods of enhancing lymphocyte infiltration.
Regarding claim 16, U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 15 as discussed above.
U.S. Patent No. US 10869888 B2 further recites wherein the antigen binding domain binds a solid tumor antigen comprising ACPP, MUC16, CEA, EphA2, GPC3, Mesothelin, PSMA, tMUC 1, VEGFR-II, GD2, or EGFR (“wherein the solid tumor antigen is tMUC 1, PRLR, CLCA1, MUC12, GUCY2C, GPR35, CR1L, MUC 17, TMPRSS11B, MUC21, TMPRSS11E, CD207, SLC30A8, CFC1, SLC12A3, SSTR1, GPR27, FZD10, TSHR, SIGLEC15, SLC6A3, KISS1R, QRFPR, GPR119, CLDN6, UPK2, ADAM12, SLC45A3, ACPP, MUC21, MUC16, MS4A12, ALPP, CEA, EphA2, FAP, GPC3, IL13-Rα2, Mesothelin, PSMA, ROR1, VEGFR-II, GD2, FR-α, ErbB2, EpCAM, EGFRvIII, B7-H3, or EGFR” claim 2).
Regarding claim 17, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “wherein the CAR that comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain,
U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 15 as discussed above.
U.S. Patent No. US 10869888 B2 further to recites wherein the CAR that comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein the intracellular signaling domain comprises a signaling domain or a primary signaling domain and one or more co-stimulatory signaling domains wherein the signaling domain and co-stimulatory signaling domain comprise a functional signaling domain of a protein comprising 4-1BB (Applicant’s elected species) (claim 5).
Regarding claim 18, U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 14 as discussed above.
U.S. Patent No. US 10869888 B2 fails to recite wherein the TCR is a modified TCR, the TCR is derived from spontaneously occurring tumor-specific T cells in a patient, and/or the TCR binds a tumor antigen.
Chang teaches wherein the TCR is a modified TCR, the TCR is derived from spontaneously occurring tumor-specific T cells in a patient, and/or the TCR binds a tumor antigen (Abstract, paras. 104, 226 and 443). Chang further teaches that the modified lymphocytes in the combination therapy enables effective treatments for B cell malignancy without toxic components (“Such compositions can be used in accord with the provided methods and/or with the provided articles of manufacture or compositions, such as in the treatment of a B cell malign” para. 381, “effective, and which contains no additional components which are unacceptably toxic to a subject” para. 382).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. US 10869888 B2 to rely on the modified lymphocytes having a modified TCR, the TCR being derived from spontaneously occurring tumor-specific T cells in a patient, and/or the TCR binding a tumor antigen taught by Chang because Chang teaches that these cells in the combination therapy enables effective treatments for B cell malignancy without toxic components. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 10869888 B2 and Chang are drawn to methods of enhancing lymphocyte infiltration.
Regarding claim 19, U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 15 as discussed above.
U.S. Patent No. US 10869888 B2 further recites wherein the tumor antigen comprises CEA, or a combination thereof (claim 2).
Regarding claim 20, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “wherein enhancing the infiltration of lymphocytes into tumor tissue comprises enriching the lymphocytes and/or enhancing entry of lymphocytes into the TME or
U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 1 as discussed above.
U.S. Patent No. US 10869888 B2 further recites wherein enhancing the infiltration of lymphocytes into tumor tissue comprises enriching the lymphocytes and/or enhancing entry of lymphocytes into the TME or increasing number of lymphocytes in the TME (claim 1).
Regarding claims 21, 23-24 and 27-29, U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 1 as discussed above.
U.S. Patent No. US 10869888 B2 fails to recite wherein enhancing anti-tumor lymphocyte activities in the TME comprises enhancing gene expression of genes associated with cell cycle and cytotoxicity of the lymphocytes, wherein the method further comprises killing tumor cells in the subject, killing and/or reducing the number of B cells, regulatory T cells and inhibition of CD8+ T cells as compared to a tumor that has not been administered the modified lymphocyte and agent, and wherein the method further comprises producing new normal T cells with high clonal expansion capacity in tumor tissue.
Chang further teaches wherein enhancing anti-tumor lymphocyte activities in the TME comprises enhancing gene expression of genes associated with cell cycle and cytotoxicity of the lymphocytes ( page 226 para. 764). Note that Fig. 6 of the instant application discloses that FGR is a gene associated with cytotoxicity. Also note that as evidenced by Ku, GATA3 is associated with cell cycle (Abstract). Chang further teaches wherein the method further comprises killing tumor cells in the subject (para. 182). Chang further teaches wherein the method further comprises killing and/or reducing the number of B cells as compared to a tumor that has not been administered the modified lymphocyte and agent (paras. 182-183 and 471). Chang further teaches wherein the method further comprises reducing T regulatory cells in tumor tissue as compared to a tumor that has not been administered the modified lymphocyte and agent, and wherein the method further comprises reduced inhibition of CD8+ T cells in tumor tissue as compared to a tumor that has not been administered the modified lymphocyte and agent (Abstract). Note that EZH2 inhibitors reduce T regulatory cells and inhibition of CD8+ T cells as evidenced by Chen (Abstract). Chang further teaches wherein the method further comprises producing new normal T cells with high clonal expansion capacity in tumor tissue (paras. 931 and 1051).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of U.S. Patent No. US 10869888 B2 to rely on the enhancing gene expression of genes associated with cell cycle and cytotoxicity of the lymphocytes, wherein the method further comprises killing tumor cells in the subject, killing and/or reducing the number of B cells, regulatory T cells and inhibition of CD8+ T cells as compared to a tumor that has not been administered the modified lymphocyte and agent and wherein the method further comprises producing new normal T cells with high clonal expansion capacity in tumor tissue taught by Chang because it would have been a simple matter of applying a known technique to a known method. In this case, both U.S. Patent No. US 10869888 B2 and Chang teach a method of enhancing expansion of lymphocytes in a solid tumor in a subject comprising administering to the subject an effective amount of modified lymphocytes and an agent that stimulates or activates APCs. Chang simply applies the art-recognized technique of enhancing gene expression of genes associated with cell cycle and cytotoxicity of the lymphocytes and wherein the method further comprises killing tumor cells in the subject, killing and/or reducing the number of B cells, regulatory T cells and inhibition of CD8+ T cells as compared to a tumor that has not been administered the modified lymphocyte and agent and wherein the method further comprises producing new normal T cells with high clonal expansion capacity in tumor tissue. Therefore, a person having ordinary skill in the art would have found it obvious to apply the technique taught by Chang to the base method taught by both references. A person having ordinary skill in the art would have had a reasonable expectation of success because both U.S. Patent No. 10869888 B2 and Chang are drawn to methods of enhancing lymphocyte infiltration in the context of solid tumors.
Regarding claim 22, U.S. Patent No. US 10869888 B2 in view of Chang recite the method of claim 1 as discussed above.
U.S. Patent No. US 10869888 B2 further recites wherein the subject is infused with mixed CART cells comprising a first population of CART cells targeting B cells and a second population of CAR T cells targeting a solid tumor (“the first antigen comprising CD19 or BCMA and the second antigen comprising a solid tumor antigen” claim 1).
Conclusion
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/Fernando Ivich/ Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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