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 .
Election/Restrictions
Applicant’s election without traverse of group II, MS4A1, above control value and second line therapy in the reply filed on 7/17/2026 is acknowledged.
The CD19 rejoined as a species after the searching.
Claims 1-5, 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/17/2026.
Priority
The instant application was filed 03/14/2024 and claims priority from provisional application 63502295 , filed 05/15/2023; claims priority from provisional application 63496887 , filed 04/18/2023; claims priority from provisional application 63491516 , filed 03/21/2023 and claims priority from provisional application 63490870 , filed 03/17/2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/17/2026 is being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 16, 18-27 objected to because of the following informalities:
Claim 16 is objected to as it recites “CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, TCL1A, BNIP3L, MXII, ADM, PLOD2, P4HA1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2 ” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Appropriate correction is required.
Improper Markush Group
Claims 16, 18-27 are rejected under the judicially approved ‘‘improper Markush grouping’’ doctrine. (See Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, page 7166). This rejection is appropriate when the claim contains an improper grouping of alternatively useable species. See In re Harnisch, 631 F.2d 716, 719–20 (CCPA 1980). A Markush claim contains an ‘‘improper Markush grouping’’ if: (1) the species of the Markush group do not share a ‘‘single structural similarity,’’ or (2) the species do not share a common use. Members of a Markush group share a ‘‘single structural similarity’’ when they belong to the same recognized physical or chemical class or to the same art-recognized class. However, when the Markush group occurs in a claim reciting a process or a combination (not a single compound), it is sufficient if the members of the group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. See MPEP § 803.02.
Here each species is considered to be a marker for determining whether the patient should be administered an effective dose of cell therapy as a second- or third-line therapy..
The recited alternative species in the groups set forth here do not share a single structural similarity, as each method relies on detection gene or combination of genes. Each gene or combination of genes are located in a separate region of the genome and has its own structure. The nature of genes is their expression is different in different cells and tissues. The each gene has a unique sequence encoding a unique protein- they are not structurally the same when you consider the sequence required to identify one particular gene relative to another gene. The markers recited in the instant claims, and the methods which detect them, do not share a single structural similarity since each consists of a different nucleotide sequences encoding different genes and on different chromosome. The only structural similarity present is that all detected genes is they comprise nucleotides. The fact that the genes comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being a marker for second- or third-line cell therapies. The association between the claimed genes is not considered as ‘property’ as the association is a statistical construct, it is a conclusion based on analysis of a specific population and may not be present in subject outside of the population assayed. Further there is no evidence the association was known in the prior art. While the instant specification asserts the genes have a common function of being correlated with the asserted phenotype, the association between the claimed gene is not clear from their very nature. If the instantly claimed genes are placed in a group with an equal number of genes the skilled artisan could not differentiate those associated with a phenotype from those that are not associated with a phenotype. Thus the one of skill in the art could not identify those genes. that are asserted to be associated with the phenotype by their very nature. Thus the instant claims have not met the requirements of a proper Markush group.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
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 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method of detecting expression in a patient comprising:
quantifying a gene expression level of at least one gene selected from the group consisting of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, TCL1A, BNIP3L, MXII, ADM, PLOD2, P4HA1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2,
IL21R, KIR2DL3, KIR3DL1, and KIR3DL2
does not reasonably provide enablement for selecting a therapy the patient should be treated with 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.
There are many factors to be considered when determining whether there is sufficient evidence to support that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors have been described by the court in re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in the Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention and the breadth of the claims:
A method for treating a malignancy in a patient comprising:
quantifying a gene expression level of at least one gene selected from the group consisting of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, TCL1A, BNIP3L, MXII, ADM, PLOD2, P4HA1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2,
IL21R, KIR2DL3, KIR3DL1, and KIR3DL2; determining whether the patient should be administered an effective dose of a cell therapy product as a second-line therapy, or an effective dose of a cell therapy product as a third-line therapy at least in part from the quantifying the gene expression level of at least one gene; and administering the effective dose of the cell therapy product as a second-line therapy or as a third-line therapy based on the determining step, wherein the gene expression level is quantified from a patient sample, and the patient sample is collected from the patient prior to treatment with the cell therapy product, wherein the patient is administered the effective dose of the cell therapy product as a second- line therapy if the gene expression level of the at least one of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, and TCLIA is at or above a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a third-
line therapy if the gene expression level of the at least one of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, and TCL1A is at or below a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a second- line therapy if the gene expression level of the at least one of BNIP3L, MXII, ADM, PLOD2, P4HA1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2 is at or below a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a third- line therapy if the gene expression level of the at least one of BNIP3L, MXII, ADM, PLOD2, Р4НЛ1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2 is at or above a control value for the at least one gene.
The claims encompass any malignancy in any patient.
The claim is drawn to a second-line or third-line therapy, however the claim provides no limitation requiring treatment with a first line therapy.
The claims encompass at or above or at or below any control value determined by any standard.
Claim 18 depends from claim 16 and draws the invention to wherein the at least one gene is selected from the group consisting of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, and TCL1A.
Claim 19 depends from claim 18 and draws the invention to wherein the at least one gene is selected from the group consisting of CD19, MS4A1, and TNFRSF17.
Claim 20 depends from claim 16 and draws the invention to wherein the cell therapy product is CAR T or TCR T cell therapy that recognizes a target antigen.
Claim 21 depends from claim 20 and draws the invention to wherein the cell therapy product is autologous or allogeneic.
Claim 22 depends from claim 20 and draws the invention to wherein the target antigen is a tumor antigen, preferably, selected from a tumor-associated surface antigen, such as 5T4, alphafetoprotein (AFP), B7-1 (CD80), B7-2 (CD86), BCMA, B-human chorionic gonadotropin, CA-125, carcinoembryonic antigen (CEA), CD123, CD133, CD138, CD19, CD20, CD22, CD23, CD24, CD25, CD30, CD33, CD34, CD4, CD40, CD44, CD56, CD79a, CD79b, CD123, FLT3, BCMA, SLAMF7, CD8, CLL-1,
c-Met, CMV-specific antigen, CS-1, CSPG4, CTLA-4, DLL3, disialoganglioside GD2, ductal- epithelial mucine, EBV-specific antigen, EGFR variant III (EGFRvIII), ELF2M, endoglin, ephrin B2, epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), epithelial tumor antigen, ErbB2 (HER2/neu), fibroblast associated protein (fap), FLT3, folate binding protein, GD2, GD3, glioma-associated antigen, lycosphingolipids, gp36, HBV- specific antigen, HCV-specific antigen, HER1-HER2, HER2-HER3 in combination, HERV-K, high molecular weight-melanoma associated antigen (HMW-MAA), HIV-1 envelope glycoprotein gp41, HPV-specific antigen, human telomerase reverse transcriptase, IGFI receptor, IGF-II, IL-11Ralpha, IL-13R-a2, Influenza Virus-specific antigen; CD38, insulin growth factor (IGFI)-1, intestinal
carboxyl esterase, kappa chain, LAGA-la, lambda chain, Lassa Virus-specific antigen, lectin- reactive AFP, lineage-specific or tissue specific antigen such as CD3, MAGE, MAGE-A1, major histocompatibility complex (MHC) molecule, major histocompatibility complex (MHC) molecule presenting a tumor-specific peptide epitope, M-CSF, melanoma-associated antigen, mesothelin, MN-CA IX, MUC-1, mut hsp70-2, mutated p53, mutated ras, neutrophil elastase, NKG2D, Nkp30, NY-ESO-1, p53, PAP, prostase, prostate specific antigen (PSA), prostate-carcinoma tumor antigen-1 (PCTA-1), prostate-specific antigen protein, STEAP1, STEAP2, PSMA, RAGE-1, ROR1, RU1,
RU2 (AS), surface adhesion molecule, survivin and telomerase, TAG-72, the extra domain A (EDA) and extra domain B (EDB) of fibronectin and the Al domain of tenascin-C (TnC Al), thyroglobulin, tumor stromal antigens, vascular endothelial growth factor receptor-2 (VEGFR2), virus-specific surface antigen such as an HIV-specific antigen (such as HIV gp120), GPC3 (Glypican 3), as well as any derivate or variant of these antigens.
Claim 23 depends from claim 20 and draws the invention to wherein the cell therapy product expresses a chimeric antigen receptor comprising a CD28 co-stimulatory domain.
Claim 24 depends from claim 16 and draws the invention to wherein the patient has been diagnosed with a cancer/tumor selected from the group consisting of a solid tumor, sarcoma, carcinoma, lymphoma, multiple myeloma, Hodgkin's Disease, non-Hodgkin's lymphoma (NHL), primary mediastinal large B cell lymphoma (PMBCL), diffuse large B cell lymphoma (DLBCL) (not otherwise specified), follicular lymphoma (FL), DLBCL arising from FL, transformed follicular lymphoma, high grade B cell lymphoma, splenic marginal zone lymphoma (SMZL), chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non T cell ALL), chronic lymphocytic leukemia (CLL), T-cell lymphoma, one or
more of B-cell acute lymphoid leukemia ("BALL"), T-cell acute lymphoid leukemia ("TALL"), acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, myelodysplasia and myelodysplastic syndrome, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, a plasma cell proliferative disorder (e.g., asymptomatic myeloma (smoldering multiple myeloma or indolent myeloma), monoclonal gammapathy of undetermined significance (MGUS), plasmacytomas (e.g.,
plasma cell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullary plasmacytoma, and multiple plasmacytoma), systemic amyloid light chain amyloidosis, POEMS syndrome (also known as Crow-Fukase syndrome, Takatsuki disease, and PEP syndrome), head and neck cancers, cervical cancers, ovarian cancers, non-small cell lung carcinomas, hepatocellular carcinomas, prostate cancers, breast cancers, or a combination thereof.
Claim 25 depends from claim 24 and draws the invention to wherein the cancer is (relapsed or refractory) diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma (HGBL), DLBCL arising from follicular lymphoma, or mantle cell lymphoma.
Claim 26 depends from claim 16 and draws the invention to wherein the cell therapy product is selected from axicabtagene ciloleucel, brexucabtagene autoleucel, tisagenlecleucel, lisocabtagene maraleucel, and bb2121.
Claim 27 depends from claim 16 and draws the invention to wherein the patient sample is a tumor biopsy.
The amount of direction or guidance and the Presence and absence of working examples.
The teachings of example 1 identifies prognostic markers of LBCL from tumor biopsies. The specification teaches, “The prespecified B-cell lineage signature included BLK, CD19, MS4A1, TNFRSF17, FCRL2, FAM30A, PNOC, SPIB, and TCLIA. Of those genes, expression of CD19, MS4A1, and TNFRSF17 was significantly (descriptive P<.05) elevated in patients who were in ongoing response, with fold increase of 22%, 40%, and 69%, respectively. Conversely, expression of hypoxia, nitric oxide synthase 2 (NOS2), and the NKCD56dim NanoString signature (composed of IL21R, KIR2DL3, KIR3DL1, and KIR3DL2) were associated (P<.05) with shorter EFS and/or DOR.”
Example 2 is limited to adult LBCL patients which were refractory to first line treatment or had relapsed within 12 months of first line chemoimmunotherapy. Example 2 teaches, “[0304] Patients in the axicabtagene ciloleucel (axi-cel) arm underwent leukapheresis, followed by lymphodepleting chemotherapy with cyclophosphamide (500 mg/m²/day) and fludarabine (30 mg/m²/day) 5, 4, and 3 days before receiving a single axi-cel infusion (target dose, 2x10⁶ chimeric antigen receptor [CAR] T cells/kg). Glucocorticoid could be administered as optional bridging therapy. Patients in the standard-care arm received 2 or 3 cycles of protocol- defined, platinum-based chemoimmunotherapy. Patients who had a complete or partial response proceeded to high-dose chemotherapy with autologous stem-cell transplantation.” Example 2 does not provide any specific teachings with respect to the claimed genes.
Example 3 teaches, “[0364] This example discloses classification modeling to identify patients at risk for neurotoxicity and CRS following axicabtagene ciloleucel (axi-cel) treatment in 2nd line R/R LBCL.” Example 3 does not provide any specific teachings with respect to the claimed genes.
Example 4 teaches, “[0374] Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel in patients with R/R indolent non- Hodgkin lymphoma (iNHL; N=104) including FL and marginal zone lymphoma [MZL]. In the primary analysis (17.5 months median follow-up), overall response rate (ORR) was 92% (74% complete response rate). Here we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after >2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2x10⁶ CAR T cells/kg). The primary endpoint was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n=127) and 31.8 months in MZL (n=31), ORR was comparable to the primary analysis (94% in FL; 77% in MZL). Median progression-free survival was 40.2 months in FL and not yet reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest occurring since the prior analysis were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL.”
The specification of example 5 teaches, “[0425] As disclosed in this example, embodiments of the disclosure relate to methods of treating a subject with lymphoma comprising administering to the subject a debulking regimen; and administering to the subject an immunotherapy following the debulking regimen.”
The specification does not appear to specifically teach selecting a subject based on MS4A1 expression or any advantage of such.
The the teachings of the specification appear to be limited to hematological cancers.
The state of prior art and the predictability or unpredictability of the art:
MPEP2164.03 teaches, " The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one species, what other species will work.”
The art of Cheung et al (Nature Genetics, 2003, volume 33, pages 422-425) teaches that there is natural variation in gene expression among different individuals. The reference teaches an assessment of natural variation of gene expression in lymphoblastoid cells in humans, and analyzes the variation of expression data among individuals and within individuals (replicates) p.422, last paragraph; Fig 1). The data indicates that, for example, expression of ACTG2 in 35 individuals varied by a factor of 17; and that in expression of the 40 genes with the highest variance ratios, the highest and lowest values differed by a factor of 2.4 or greater (Fig 3).
Saito-Hisaminato et al. (DNA research (2002) volume 9, pages 35-45) teaches that gene expression is not predictable across different human tissues.
The level of skill in the art:
The level of skill in the art is deemed to be high
Quantity of experimentation necessary:
In order to practice the invention as claimed, one would first have to establish that a predicative relationship exists between any expression of MS4A1 and selection of a second- or third-line cell therapy for any human malignancy in a subject which is not required to have a first line therapy. Experimentation would be replete with unpredictable trial and error analysis because the specification is limited to hematological cancers. The art demonstrates different genes are expressed in different tissues. Different cancers arise from different tissues. Further different cancers have different gene expression patters, one of skill in the art would have to recruit an enormous population of ethnically diverse patients of the recited diseases and disease-free controls and determine the association of the MS4A1 expression and selection of second- or third-line cell therapies.
Further it would be unpredictable to extrapolate the findings of one cancer to another cancer. As different cancers arise from different tissues and thus express different genes.
Further it would be unpredictable to treat a malignancy with a second- or third-line therapy when the subject is not required to have be treated with a first line therapy.
Further it would be unpredictable to use the expression of MS4A1 in any sample and relative to any control value. It would be unpredictable as using a control value from muscle or other non-B cell containing samples for control values would result in all patients with hematological cancer being treated with a second line therapy as all tumor samples would have higher expression of MS4A1, then samples lacking MS4A1 expression . Further using samples for control value determine having high MS4A1 such as B cell sample would result in no subject being treated with second line cell therapy.
It would further be unpredictable as the specification does not provide evidence of a method based on the detection of only one marker gene. The association of the specification was shown with a treatment response has been observed for the full B-cell lineage signature, including BLK, CD19, MS4A 1, TNFRSF17, FCRL2, FAM30A, PNOC, SPIB, and TCL 1 A, with only three of these genes (CD19, MS4A 1, and TNFRSF17) showing significant association when tested individually, (see example 1 ). Thus it would have been unpredictable to extrapolate the findings of the specification to a combination of genes to a single gene.
Further it would be unpredictable to use any cell therapy as different cancers are in different tissues and thus need specific treatment designed on the cancer being treated.
Finally the teachings of the specification are limited to analysis of a tumor sample. Thus it would be unpredictable to extrapolate to any sample from the patient.
Due to the scope of the claims, one of skill in the art would be required to further undertake extensive trial and error experimentation to practice the invention as claimed.
Therefore, in light of the breadth of the claims, the lack of guidance in the specification, the high level of unpredictability in the associated technology, the nature of the invention, the negative teachings in the art, and the quantity of unpredictable experimentation necessary to practice the claimed invention, it would require undue experimentation to practice the invention as claimed.
Claims 16, 18-27 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.
MPEP 2163 I. A. states:
However, as discussed in subsection I., supra, the issue of a lack of adequate written description may arise even for an original claim when an aspect of the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the applicant had possession of the claimed invention. The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
MPEP 2163 states:
The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997).
The use of siRNA or shRNA to reduce the expression of these genes and increase sensitivity demonstrates that decreasing results in sensitivity, which does not inherently suggest in the complex system of a tumor that increased expression is correlated with resistance.
To comply with the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, para. 1, or to be entitled to an earlier priority date or filing date under 35 U.S.C. 119, 120, or 365(c), each claim limitation must be expressly, implicitly, or inherently supported in the originally filed disclosure. When an explicit limitation in a claim “is not present in the written description whose benefit is sought it must be shown that a person of ordinary skill would have understood, at the time the patent application was filed, that the description requires that limitation.” Hyatt v. Boone, 146 F.3d 1348, 1353, 47 USPQ2d 1128, 1131 (Fed. Cir. 1998).
The instant claims are drawn to A method for treating a malignancy in a patient comprising: quantifying a gene expression level of at least one gene selected from the group consisting of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, TCL1A, BNIP3L, MXII, ADM, PLOD2, P4HA1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2; determining whether the patient should be administered an effective dose of a cell therapy product as a second-line therapy, or an effective dose of a cell therapy product as a third-line therapy at least in part from the quantifying the gene expression level of at least one gene; and administering the effective dose of the cell therapy product as a second-line therapy or as a third-line therapy based on the determining step, wherein the gene expression level is quantified from a patient sample, and the patient sample is collected from the patient prior to treatment with the cell therapy product, wherein the patient is administered the effective dose of the cell therapy product as a second- line therapy if the gene expression level of the at least one of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, and TCLIA is at or above a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a third- line therapy if the gene expression level of the at least one of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, and TCL1A is at or below a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a second- line therapy if the gene expression level of the at least one of BNIP3L, MXII, ADM, PLOD2, P4HA1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2 is at or below a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a third- line therapy if the gene expression level of the at least one of BNIP3L, MXII, ADM, PLOD2, Р4НЛ1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2 is at or above a control value for the at least one gene.
The claims encompass any malignancy in any patient. This is an enormous genus. CRI staff (Exploring the Different Types of Cancer and Treatment Options, 12/12/2023) teaches there are over 200 types of cancer.
While the claims are drawn to selecting and administering a second- or third-line cell therapy, the claims do not require the patient has been treated with a first line therapy.
The claims imply treatment with any first line cancer treatment for any cancer. This is an enormous genus.
The claim is drawn to a second-line or third-line cell therapy. This is an enormous genus encompassing any cell therapy..
The claim encompass any expression of any of the recited genes or combination of genes.
The claims encompass at or above or at or below any control value determined by any standard.
Claim 18 depends from claim 16 and draws the invention to wherein the at least one gene is selected from the group consisting of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, and TCL1A.
Claim 19 depends from claim 18 and draws the invention to wherein the at least one gene is selected from the group consisting of CD19, MS4A1, and TNFRSF17.
Claim 20 depends from claim 16 and draws the invention to wherein the cell therapy product is CAR T or TCR T cell therapy that recognizes a target antigen.
Claim 21 depends from claim 20 and draws the invention to wherein the cell therapy product is autologous or allogeneic.
Claim 22 depends from claim 20 and draws the invention to wherein the target antigen is a tumor antigen, preferably, selected from a tumor-associated surface antigen, such as 5T4, alphafetoprotein (AFP), B7-1 (CD80), B7-2 (CD86), BCMA, B-human chorionic gonadotropin, CA-125, carcinoembryonic antigen (CEA), CD123, CD133, CD138, CD19, CD20, CD22, CD23, CD24, CD25, CD30, CD33, CD34, CD4, CD40, CD44, CD56, CD79a, CD79b, CD123, FLT3, BCMA, SLAMF7, CD8, CLL-1,
c-Met, CMV-specific antigen, CS-1, CSPG4, CTLA-4, DLL3, disialoganglioside GD2, ductal- epithelial mucine, EBV-specific antigen, EGFR variant III (EGFRvIII), ELF2M, endoglin, ephrin B2, epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), epithelial tumor antigen, ErbB2 (HER2/neu), fibroblast associated protein (fap), FLT3, folate binding protein, GD2, GD3, glioma-associated antigen, lycosphingolipids, gp36, HBV- specific antigen, HCV-specific antigen, HER1-HER2, HER2-HER3 in combination, HERV-K, high molecular weight-melanoma associated antigen (HMW-MAA), HIV-1 envelope glycoprotein gp41, HPV-specific antigen, human telomerase reverse transcriptase, IGFI receptor, IGF-II, IL-11Ralpha, IL-13R-a2, Influenza Virus-specific antigen; CD38, insulin growth factor (IGFI)-1, intestinal
carboxyl esterase, kappa chain, LAGA-la, lambda chain, Lassa Virus-specific antigen, lectin- reactive AFP, lineage-specific or tissue specific antigen such as CD3, MAGE, MAGE-A1, major histocompatibility complex (MHC) molecule, major histocompatibility complex (MHC) molecule presenting a tumor-specific peptide epitope, M-CSF, melanoma-associated antigen, mesothelin, MN-CA IX, MUC-1, mut hsp70-2, mutated p53, mutated ras, neutrophil elastase, NKG2D, Nkp30, NY-ESO-1, p53, PAP, prostase, prostate specific antigen (PSA), prostate-carcinoma tumor antigen-1 (PCTA-1), prostate-specific antigen protein, STEAP1, STEAP2, PSMA, RAGE-1, ROR1, RU1,
RU2 (AS), surface adhesion molecule, survivin and telomerase, TAG-72, the extra domain A (EDA) and extra domain B (EDB) of fibronectin and the Al domain of tenascin-C (TnC Al), thyroglobulin, tumor stromal antigens, vascular endothelial growth factor receptor-2 (VEGFR2), virus-specific surface antigen such as an HIV-specific antigen (such as HIV gp120), GPC3 (Glypican 3), as well as any derivate or variant of these antigens.
Claim 23 depends from claim 20 and draws the invention to wherein the cell therapy product expresses a chimeric antigen receptor comprising a CD28 co-stimulatory domain.
Claim 24 depends from claim 16 and draws the invention to wherein the patient has been diagnosed with a cancer/tumor selected from the group consisting of a solid tumor, sarcoma, carcinoma, lymphoma, multiple myeloma, Hodgkin's Disease, non-Hodgkin's lymphoma (NHL), primary mediastinal large B cell lymphoma (PMBCL), diffuse large B cell lymphoma (DLBCL) (not otherwise specified), follicular lymphoma (FL), DLBCL arising from FL, transformed follicular lymphoma, high grade B cell lymphoma, splenic marginal zone lymphoma (SMZL), chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non T cell ALL), chronic lymphocytic leukemia (CLL), T-cell lymphoma, one or
more of B-cell acute lymphoid leukemia ("BALL"), T-cell acute lymphoid leukemia ("TALL"), acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, myelodysplasia and myelodysplastic syndrome, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, a plasma cell proliferative disorder (e.g., asymptomatic myeloma (smoldering multiple myeloma or indolent myeloma), monoclonal gammapathy of undetermined significance (MGUS), plasmacytomas (e.g.,
plasma cell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullary plasmacytoma, and multiple plasmacytoma), systemic amyloid light chain amyloidosis, POEMS syndrome (also known as Crow-Fukase syndrome, Takatsuki disease, and PEP syndrome), head and neck cancers, cervical cancers, ovarian cancers, non-small cell lung carcinomas, hepatocellular carcinomas, prostate cancers, breast cancers, or a combination thereof.
Claim 25 depends from claim 24 and draws the invention to wherein the cancer is (relapsed or refractory) diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma (HGBL), DLBCL arising from follicular lymphoma, or mantle cell lymphoma.
Claim 26 depends from claim 16 and draws the invention to wherein the cell therapy product is selected from axicabtagene ciloleucel, brexucabtagene autoleucel, tisagenlecleucel, lisocabtagene maraleucel, and bb2121.
Claim 27 depends from claim 16 and draws the invention to wherein the patient sample is a tumor biopsy.
The amount of direction or guidance and the Presence and absence of working examples.
The teachings of example 1 identifies prognostic markers of LBCL from tumor biopsies. The specification teaches, “The prespecified B-cell lineage signature included BLK, CD19, MS4A1, TNFRSF17, FCRL2, FAM30A, PNOC, SPIB, and TCLIA. Of those genes, expression of CD19, MS4A1, and TNFRSF17 was significantly (descriptive P<.05) elevated in patients who were in ongoing response, with fold increase of 22%, 40%, and 69%, respectively. Conversely, expression of hypoxia, nitric oxide synthase 2 (NOS2), and the NKCD56dim NanoString signature (composed of IL21R, KIR2DL3, KIR3DL1, and KIR3DL2) were associated (P<.05) with shorter EFS and/or DOR.”
Example 2 is limited to adult LBCL patients which were refractory to first line treatment or had relapsed within 12 months of first line chemoimmunotherapy. Example 2 teaches, “[0304] Patients in the axicabtagene ciloleucel (axi-cel) arm underwent leukapheresis, followed by lymphodepleting chemotherapy with cyclophosphamide (500 mg/m²/day) and fludarabine (30 mg/m²/day) 5, 4, and 3 days before receiving a single axi-cel infusion (target dose, 2x10⁶ chimeric antigen receptor [CAR] T cells/kg). Glucocorticoid could be administered as optional bridging therapy. Patients in the standard-care arm received 2 or 3 cycles of protocol- defined, platinum-based chemoimmunotherapy. Patients who had a complete or partial response proceeded to high-dose chemotherapy with autologous stem-cell transplantation.” Example 2 does not provide any specific teachings with respect to the claimed genes.
Example 3 teaches, “[0364] This example discloses classification modeling to identify patients at risk for neurotoxicity and CRS following axicabtagene ciloleucel (axi-cel) treatment in 2nd line R/R LBCL.” Example 3 does not provide any specific teachings with respect to the claimed genes.
Example 4 teaches, “[0374] Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel in patients with R/R indolent non- Hodgkin lymphoma (iNHL; N=104) including FL and marginal zone lymphoma [MZL]. In the primary analysis (17.5 months median follow-up), overall response rate (ORR) was 92% (74% complete response rate). Here we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after >2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2x10⁶ CAR T cells/kg). The primary endpoint was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n=127) and 31.8 months in MZL (n=31), ORR was comparable to the primary analysis (94% in FL; 77% in MZL). Median progression-free survival was 40.2 months in FL and not yet reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest occurring since the prior analysis were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL.”
The specification of example 5 teaches, “[0425] As disclosed in this example, embodiments of the disclosure relate to methods of treating a subject with lymphoma comprising administering to the subject a debulking regimen; and administering to the subject an immunotherapy following the debulking regimen.”
The specification does not appear to specifically teach selecting a subject based on MS4A1 expression or any advantage of such.
The teachings of the specification appear to be limited to hematological cancers.
Further the specification does not provide adequate written description to support a method based on the detection of only one marker gene. The specification teaches an association with treatment response has been observed for the full B-cell lineage signature, including BLK, CD19, MS4A 1, TNFRSF17, FCRL2, FAM30A, PNOC, SPIB, and TCL 1 A, with only three of these genes (CD19, MS4A 1, and TNFRSF17) showing significant association when tested individually, Thus the claims lack adequate written description.
Thus while the claims encompass any malignancy in any subject, selection of a second line therapy or third line cell therapy based on the expression of any the recited markers in tumor samples. However, the teachings of the specification are limited to hematological cancers, expression levels and control levels from tumor samples and CAR T or TCR T as treatments. Thus the claims lack adequate written description.
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 16, 18-27 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 16 recites, “determining whether the patient should be administered an effective dose of a cell therapy product as a second-line therapy, or an effective dose of a cell therapy product as a third-line therapy at least in part from the quantifying the gene expression level of at least one gene; and administering the effective dose of the cell therapy product as a second-line therapy or as a third-line therapy based on the determining step.” The metes and bounds are unclear as the claims does not require treatment with a first line therapy. Thus it is unclear how to treat with a second- or third-line therapy.
Claim 16 recites, “determining whether the patient should be administered an effective dose of a cell therapy product as a second-line therapy, or an effective dose of a cell therapy product as a third-line therapy at least in part from the quantifying the gene expression level of at least one gene.” The recitation of “determining whether the patient should be administered” suggests “determining whether the patient should not be administered.” The claims and specification provides no definition or standard to differentiate those that should be administered from those which should not be administered. Further the recitation of “at least in part from the quantifying the gene expression level of at least one gene” is vague and unclear sot what else is being used to make the determination.
Claim 22 recites, “preferably, selected from.” The metes and bounds are unclear if the recitations following “preferably” are required of the claims or merely preferred embodiments.
Claim 24 recites, “(not otherwise specified), “ “a plasma cell proliferative disorder (e.g., asymptomatic myeloma (smoldering multiple myeloma or indolent myeloma), monoclonal gammapathy of undetermined significance (MGUS),” “plasmacytomas (e.g.,
plasma cell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullary plasmacytoma, and multiple plasmacytoma),” “plasmacytomas (e.g., plasma cell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullary plasmacytoma, and
multiple plasmacytoma)”. The metes and bounds are unclear if the limitations in parenthesis are limitations of the claims, preferred embodiments or something else.
Claim 25 recites, “(relapsed or refractory)”. The metes and bounds are unclear if the limitations in parenthesis are limitations of the claims, preferred embodiments or something else.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 16, 18-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental step and/or abstract idea. The claim(s) recite(s) the the steps of quantifying and determining which can be considered mental steps or abstract ides. Further the determining step could be considered a natural phenomenon or correlation of gene expression with selecting a therapy. Further the wherein clauses require the mental step of comparing. This judicial exception is not integrated into a practical application because the determining step recites, “should be administered” making the step conditional. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims provide no step which require a specific reagent which provides for significantly more..
Claim analysis
The instant claim 16 is directed towards ) A method for treating a malignancy in a patient comprising: quantifying a gene expression level of at least one gene selected from the group consisting of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, TCL1A, BNIP3L, MXII, ADM, PLOD2, P4HA1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2; determining whether the patient should be administered an effective dose of a cell therapy product as a second-line therapy, or an effective dose of a cell therapy product as a third-line therapy at least in part from the quantifying the gene expression level of at least one gene; and administering the effective dose of the cell therapy product as a second-line therapy or as a third-line therapy based on the determining step, wherein the gene expression level is quantified from a patient sample, and the patient sample is collected from the patient prior to treatment with the cell therapy product, wherein the patient is administered the effective dose of the cell therapy product as a second- line therapy if the gene expression level of the at least one of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, and TCLIA is at or above a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a third- line therapy if the gene expression level of the at least one of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, and TCL1A is at or below a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a second- line therapy if the gene expression level of the at least one of BNIP3L, MXII, ADM, PLOD2, P4HA1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2 is at or below a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a third- line therapy if the gene expression level of the at least one of BNIP3L, MXII, ADM, PLOD2, Р4НЛ1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2 is at or above a control value for the at least one gene.. The correlation in the wherein clause in a natural correlation or phenomena. The quantifying and determining steps are a mental step or abstract idea.
Dependent claims set forth further limit the genes and the cell therapy, antigen targeted by gene therapy, the cancer/tumor of the patient and the patient sample..
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea and law of nature or natural phenomena.
With regards to claim 16, the claim recites, quantifying a gene expression level of at least one gene selected from the group consisting of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, TCL1A, BNIP3L, MXII, ADM, PLOD2, P4HA1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2; determining whether the patient should be administered an effective dose of a cell therapy product as a second-line therapy, or an effective dose of a cell therapy product as a third-line therapy at least in part from the quantifying the gene expression level of at least one gene” This is an abstract idea or mental step. The claim further recites, “wherein the patient is administered the effective dose of the cell therapy product as a second- line therapy if the gene expression level of the at least one of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, and TCLIA is at or above a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a third- line therapy if the gene expression level of the at least one of CD19, MS4A1, TNFRSF17, BLK, FCRL2, FAM30A, PNOC, SPIB, and TCL1A is at or below a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a second- line therapy if the gene expression level of the at least one of BNIP3L, MXII, ADM, PLOD2, P4HA1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2 is at or below a control value for the at least one gene, or wherein the patient is administered the effective dose of the cell therapy product as a third- line therapy if the gene expression level of the at least one of BNIP3L, MXII, ADM, PLOD2, Р4НЛ1, ALDOC, SLC2A1, PDK1, P4HA2, BNIP3, NOS2, IL21R, KIR2DL3, KIR3DL1, and KIR3DL2 is at or above a control value for the at least one gene “. The wherein clauses require a comparison which is a mental step or abstract idea and is correlating gene expression with selection. (UNIVERSITY OF UTAH RESEARCH v. AMBRY GENETICS CORPORATION).
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as treatment is conditional in view of “whether the patient should be administered.” Further the treating with cell therapy is set forth with a high level of generality.
Step 2B. Does the claim recite additional elements that are significantly more then the judicial exceptions? No, the claim provides no specific limitations which provide for significantly more as the steps are generic.
The only step which could be considered active is the quantifying gene expression. The specification teaches, “[0271] To identify novel prognostic markers in LBCL, gene expression analysis of pretreatment tumor biopsies (collected either at initial diagnosis or before lymphodepleting chemotherapy) was performed and leveraged the NanoString PanCancer IO360TM Panel to evaluate predefined gene expression signatures (Table 6).” Thus the methods uses commercially available kits and thus is routine and conventional.
The dependent claims are routine and conventional in view of the teachings of Rossi (WO 2019/200325 A1), Zhang (Frontieres in Immunology (2021), Washsmann ( Ocomimmunology 2022, VOL. 11, NO. 1, e2033528)
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.
Claim(s) 16, 18-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rossi (WO 2019/200325 A1), Zhang (Frontieres in Immunology (2021), Washsmann ( Ocomimmunology 2022, VOL. 11, NO. 1, e2033528)
Rossi teaches a method of determining whether a patient will respond to chimeric
receptor treatment (which is a CAR T cell therapy) comprising: (a) analyzing a
tumor biopsy from the patient to characterize the tumor microenvironment using
a gene expression profile; (b) determining an immune score based on the gene
expression profile; and (c) determining if the patient will respond to chimeric
receptor treatment based on the immune score (cl. 18). Rossi in example 1 describes
baseline TME immune gene expression as prognostic of axi-cel response for
the treatment of patients with relapsed or refractory large B cell lymphoma with
two or more prior systemic therapies. Top immune-related genes upregulated in
TME at baseline in responders vs nonresponders included CTLA4, CD3g,
CD3e, CO2?, SH2B2, and ICOSL. Rossi teaches determining expression of B-Cell genes (CD19, BLK, MS4A1, etc (table 2). Expression of other genes was relatively decreased in TME at baseline in responders compared to nonresponders
including, MHC class II genes and cancer testes antigens PRAME, MAGE, SSX
(ex. 1, Table 3). Moroever, further gene expression analysis suggests that pretreatment
T cell related genes (CD3e, CD28, and CTLA4), innate immune related genes (MX1, ISG15, and MYD88) and B cell related genes (CD19, CD79B, and PAX5) may correlate with clinical outcome (ex. 3, Fig. 11 ). Rossi does not explicitly indicate which genes should be select cell based therapy based on. However, The teachings of Rossi suggest B-cell lineage genes including CD19 and MS4A1.
However, Zhang teaches, “CD19, MS4A1 (CD20), and CD22 are specific target antigens for diseases, such as relapsed/refractory large B-cell lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). CD19, SDC1 (CD138), CD38, SLAMF7, and TNFRSF17 (BCMA) were selected for targeting multiple myeloma (MM). TNFRSF8 (CD30) is a specific marker and target antigen for Hodgkin lymphoma. These lymphomas or B leukemia originate from the B-lineage. To obtain the difference “on-target, off-tumor toxicities” for adopting individualized preventive measures, we compared the expression pattern of these seven genes in normal tissues and organs. CD19 and MS4A1 had little effect on other hematopoietic lineages and were found to be ideal targets for eliminating B-lineage-derived cells than the other target antigens.” (page 3, 1st column top)
Wachsmann teaches, “Within this context, we compared the efficacy of CAR- and TCR-transduced T cells in targeting tumor cells that express the B cell malignancy-associated antigen CD20. Using a panel of long-term expanded ALL cells that naturally differ in their CD20 expression level, we show that CAR T cells had stronger initial effector functions than eTCR T cells. We also show that a sustained strong CAR T cell expansion was limited to settings of weak to moderate antigen exposure. In contrast and despite moderate immediate effector functions, eTCR T cells outperformed CAR T cells under high antigenic pressure. Our results indicate the delicate balance needed for optimal T cell activation and have implications for the conceptual advancement of both CAR and TCR therapeutics.” (page 1, 2nd column-page 2).
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the filing date of the claims to identify and treat human patients with hematological cancers with high CD19 or CD20 (MS4A1) with CART or TCR T targeting B-cell lineage. The artisan would be motivated to treat hematological cancers with high CD19 or CD20 (MS4A1) with CART or TCR T CD19 or CD20 (MS4A1) as increased expression demonstrates the target or CART or TCR T are present in the cancer. The artisan would have a reasonable expectation of success as the artisan is merely using known methods to decide a known therapy.
With regards to claim 18 and 19, Rossi, Zhang and Waschman teach CD19 and CD20 (MS4A1)
With regards to claim 20, Waschman teaches targeting CD20.
With regards to claim 21, Rossie teaches autologous cells (0077)
With regards to claim 22, Rossi, Zhang and Waschman teach targeting CD19 and CD20 (MS4A1).
With regards to claim 23, Rossi teaches, “Stimulatory ligands include, but are not limited to, an anti-CD3 antibody, an MHC Class I molecule loaded with a peptide, a superagonist anti-CO2 antibody, and a superagonist anti-CD28 antibody.” (0095 and 0097)
With regards to claim 24, Rossi teaches DLBCL (0137)
With regards to claim 25, Rossi teaches refractory DLBCL (figure 2).
With regards to claim 26, Rossi teaches, “axi-cel, axicabtagene ciloleucel” (0045)
With regards to claim 27, Rossi teaches tumor biopsy (0036)
Summary
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/ Primary Examiner, Art Unit 1683
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