DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Herein, “the previous Office action” refers to the Non-Final Rejection filed 8/27/2025.
Priority
As detailed on the Filing Receipt filed 8/23/2024, the instant application claims priority to as early as 9/28/2016. At this point in prosecution, all claims are accorded the earliest claimed priority date.
Claim Status
Claims 1-17 and 19-20 are pending and under examination.
Please note that claims 11 and 16 remain subject to an election of species. See Restriction Requirement filed 3/17/2025, and Applicant’s election in Remarks filed 5/17/2025.
Withdrawn Objections/Rejections
The objection to the drawings is hereby withdrawn in view of Applicant’s submission of appropriate Replacement Sheets.
The objection to the specification is hereby withdrawn in view of Applicant’s amendment of the abstract to convey the steps of the claimed method, and amendment of the specification to remove browser-executable code.
The rejection of claims 9, 12, 16 and 18 under 35 USC § 112(b) is hereby withdrawn in view of Applicant’s amendment of the claims to resolve indefinite language.
The rejection of claim 16 under 35 USC § 112(d) is hereby withdrawn in view of Applicant’s amendment of the claim to resolve uncertain claim dependency.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art (MPEP 2111-2111.01). This section documents the Examiner’s interpretation of certain recited claim language.
Optional Limitations
Claim language that suggests or makes a feature or step optional, but does not require that feature or step, does not limit the scope of a claim under the broadest reasonable claim interpretation (MPEP 2143.03).
Claim 8 recites the limitation of “the amino acid sequence variation… has an effect on the protein structure that can be evaluated by a SIFT score” (lines 1-2). This limitation is interpreted as directed to an optional method step of evaluating the recited effect via a SIFT score.
Claim 10 recites the limitation of “the LOH… can be verified by immunocytochemical methods” (lines 1-2). This limitation is interpreted as directed to an optional method step of verifying the recited LOH via immunocytochemical methods.
Claim 12 recites the limitation of “optionally wherein said antibody mimetic is selected from the group consisting of an affibody molecule… and a monobody” (lines 5-7). This limitation is interpreted as directed to optional embodiments of the alternative element “an antibody mimetic” (lines 4-5).
Response to Arguments - Claim Rejections Under 35 USC § 103
In the Remarks filed 11/25/2025, Applicant traverses the rejections under 35 USC § 103 and presents supporting arguments regarding particular alleged deficiencies of cited prior art.
Applicant asserts that none of the cited art discusses “polymorphic cell epitopes”(claim 1) as required (pg. 12, para. 11 – pg. 13, para. 1).
Rajpal discusses binding of antibodies to antigenic epitopes (pg. 5, para. 3) and display of major histocompatibility complexes (MHCs) on cell surfaces (pg. 9, para. 5), and also discloses screening of candidate antibodies for specific binding to particular epitopes via immunoassays (pg. 6, para. 4). However, Rajpal does not further discuss polymorphism of cell surface epitopes.
Fedorov describes a personalization approach wherein a target ‘iCAR antigen’ is selected through an algorithmic process and a physician orders a specific receptor (i.e., iCAR) suited for the patient’s tumor (pg. 32, para. 2). Fedorov also discusses identification of tissue-specific target antigens that are absent or downregulated in tumor tissue, but expressed by off-target tissue, from among broad classes of surface antigens such as HLAs (pg. 74, para. 2). In this way, Fedorov discusses polymorphic cell surface epitopes as claimed.
Cabrera discusses alterations in HLA class I phenotypes including allelic loss due to mutations in HLA class I genes (pg. 1, r. column, pg. 2, Table 1). Cabrera surveys allele-specific alterations in variants including HLA-A2, -A3, -B7, -Bw4, and more (pg. 4, Table 2). In this way, Cabrera discusses polymorphic cell surface epitopes as claimed.
The presented argument of deficiency in the prior art, regarding polymorphic cell epitopes, is therefore found unpersuasive.
Applicant asserts that none of the cited art teaches the claimed process of “retrieving a list of human genomic variants of protein-encoding genes from at least one database of known variants” (claim 1), and that the particular database discussed by Fedorov provides information regarding tissue-specific protein expression patterns rather than information regarding human genomic variants (e.g., HLA variants) as required (pg. 12, para. 11 – pg. 13, para. 2).
The instant specification itself exemplifies retrieval of information from the Human Protein Atlas (pg. 20, para. 2), and a review of web page captures via the Wayback Machine confirms that, at least before the effective filing date of the instant application, this database listed multiple particular splice variants of HLA-A (see cited web page capture).
The instant specification also exemplifies retrieval of information from several other publicly-accessible databases, including “the Exome Aggregation Consortium (ExAc) database… [which] provid[es], inter alia, allele frequencies of SNP variants in various populations” (pg. 20, para. 2), and states that “information regarding the various criteria for many genes and SNPs is publicly available and the techniques for retrieving it are generally known” (pg. 21, para. 3). The presented argument of deficiency in the prior art, regarding retrieval of protein-encoding genomic variant information from a database, is therefore found unpersuasive.
Applicant asserts that none of the cited art can teach the claimed process of “selecting variants resulting in amino acid sequence variation in the protein encoded by the respective gene as compared to its corresponding reference allele” (claim 1), e.g., changes in the extracellular domain of the protein, since none of the cited art teaches a database of variants as required (pg. 12, para. 11 – pg. 13, paras. 1 and 3).
Rajpal discusses determining a desired antigenic epitope via any method well known in the art, e.g., conventional immunoassays (pg. 6, para. 4), but does not explicitly disclose the claimed process of selecting nonsynonymous genomic variants of cell surface epitopes.
Rajpal does teach determining variants of a subject variable region with substitution in amino acid residues, particularly those outside a CDR region (e.g., in the framework region), by comparing the subject variable region to the variable regions of other antibodies which contain CDR1 and CDR2 sequences in the same canonical class as the subject variable region (pg. 4, para. 2).
One of ordinary skill in the art would understand that the described process of determining variants of a variable region of an antibody having particular amino acid substitution compared to canonical forms would be necessary for the purpose of binding variants of an antigenic epitope (e.g., a cell surface epitope) having complementary amino acid substitution as compared to canonical forms. In this way, Rajpal at least suggests selection of genomic variants resulting in nonsynonymous amino acid sequence variation in cell surface epitopes as claimed. However, Rajpal does not discuss use of a database as claimed.
Fedorov schematically depicts an antigen selection process comprising steps of: profiling surface antigens of a tumor biopsy, determining surface antigens that are absent or expressed at low levels in the tumor tissue (i.e., ‘viable iCAR antigens’), checking their expression in normal tissue using expression repositories, and selecting an appropriate patient specific antigen and iCAR antigen recognition domain (Fig. 23, desc. at pg. 27, para. 4). The depicted scheme exemplifies particular online repositories including the Human Protein Atlas. The presented argument of deficiency in the prior art, regarding selection of antigenic variants, is therefore found unpersuasive.
Applicant asserts that the discussion in Cabrera regarding LOH in cancer is insufficient, considered an alleged absence of teachings in Rajpal or Fedorov regarding searching/filtering a database of genomic variants, to itself make obvious the claimed process of filtering a database of variants for variants that undergo LOH in a given tumor (pg. 13, para. 4).
The alleged absence is disputed, and the teachings of Cabrera regarding LOH are not relied upon in isolation to make obvious the claimed process. Thus, the argument is found unpersuasive.
For the above reasons, the arguments are found unpersuasive and the rejections are maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 7, 10-17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rajpal et al (previously cited), in view of Fedorov et al (previously cited), Cabrera et al (previously cited) and Matsui et al (previously cited). The new grounds of rejection presented herein were necessitated by Applicant’s presentation of new claims 19-20 by amendment (filed 11/25/2025).
Claim 1 recites a method of preparing an inhibitory chimeric antigen receptor (iCAR), comprising steps of: retrieving a list of human genomic variants of protein-encoding genes from at least one database of known variants; and filtering the list of variants.
The claim further recites constituent steps of the filtering process, including: obtaining a list of variants having an amino acid sequence variation in an extracellular domain in the protein encoded by the respective gene lost in the at least one tumor due to LOH and expressed at least in a tissue of origin of the at least one tumor; defining a sequence region comprising at least one single variant from the obtained list; obtaining a variant epitope peptide and a reference epitope peptide; selecting an iCAR binding domain that specifically binds either to the variant epitope peptide or to the reference epitope peptide; and preparing an iCAR comprising an iCAR binding domain as defined and an intracellular domain comprising at least one signal transduction element that inhibits an effector immune cell.
The claim further recites constituent steps performed to obtain the list of variants, including: selecting variants resulting in an amino acid sequence variation in the protein encoded by the respective gene as compared with its corresponding reference allele; selecting variants of genes wherein the amino acid sequence variation is in an extracellular domain of the encoded protein; selecting variants of genes that undergo loss of heterozygosity (LOH) at least in one tumor; and selecting variants of genes that are expressed at least in a tissue of origin of the at least one tumor in which they undergo LOH.
The claim further recites constituent steps performed to obtain the epitope peptides, including: defining a sequence region comprising at least one single variant from the obtained list; sub-cloning and expressing the sequence region comprising the at least one single
variant and a sequence region comprising the corresponding reference allele.
With respect to claim 1, Rajpal discusses inhibitory chimeric antigen receptors (N-CARS), and discloses related method steps including: determining desired epitopes of an off-target antigen (i.e., peptide products of protein-encoding genes having amino acid sequence variation in an extracellular domain), wherein an off-target antigen is downregulated in a tumor of interest but present in all normal tissues of concern (pg. 6, para. 4; pg. 110, para. 1); selecting candidate immunoglobulin sequences for specific binding to a target, producing an antigen-binding domain (pg. 6, para. 4 – pg. 7, para. 1; pg. 107, para. 2 – pg. 108, para. 2); and preparing immune cells comprising an N-CAR (pg. 113, para. 1), wherein an N-CAR comprises an extracellular antigen-binding domain and an intracellular domain that includes an inhibitory signaling domain that blocks activation of a normal effector function of an immune cell (pg. 19, para. 4; pg. 20, para. 3; pg. 22, para. 5).
Rajpal exemplifies polyclonal antibodies (pg. 3, para. 2) and teaches that polyclonal antibody preparations typically include antibodies directed against different epitopes (pg. 5, para. 3). Rajpal additionally discloses screening candidate antibodies for specific binding to given epitopes via immunoassays (pg. 6, para. 4), which requires expression of said epitopes. However, Rajpal does not disclose retrieving a list of human genomic variants of protein-encoding genes from at least one database of known variants; selecting variants that undergo loss of heterozygosity in at least one tumor; or subcloning.
Fedorov discusses methods of using immunoresponsive cells expressing an inhibitory chimeric antigen receptor (iCAR), and teaches that the iCAR approach requires the ability to identify tissue-specific target antigens that are downregulated on a tumor but expressed by the off-target tissues (pg. 74, para. 2). Fedorov mentions the Protein Atlas database as a source of information regarding surface antigen expression (the ‘surfaceome’) in human tissues (pg. 74, para. 2). Fedorov does not teach selecting variants of genes that undergo loss of heterozygosity in at least one tumor; or subcloning.
Cabrera reviews human leukocyte antigen (HLA) expression in human tumor tissues and teaches that normal cells express large amounts of HLA class I molecules, while their loss on tumor cells is widespread and allows tumor cells to avoid T cell response (pg. 1, r. column). Cabrera further teaches that loss of heterozygosity (LOH) is the most widespread of the described mechanisms of altered HLA presentation in tumors, and can be quantified by characterizing HLA allele expression in tumor tissue using known STR markers (pg. 5, r. column – pg. 6, r. column).
Cabrera thus teaches that LOH is a prominent, detectable mechanism of allele-specific human leukocyte antigen downregulation in tumor tissue. In this way, the teachings of Cabrera indicate that selecting variants of genes, encoding proteins including extracellular domains, that undergo LOH in a tumor is a readily enabled means of identifying epitopes of antigens that are downregulated in a tumor. Cabrera does not teach subcloning.
Matsui presents a study investigating the effects of various introduced HLA point mutations on T cell recognition of tumor cells, and describes generation of a construct library by subcloning using genes bearing different point mutations (pg. 9, Plasmid Constructs). Matsui presents findings that particular tested mutations (e.g., H74L and H74A) enhance T cell recognition as compared to wild-type, while particular tested mutations (e.g., H74E and H74K) impair T cell recognition (pg. 3, Results). In this way, Matsui teaches subcloning as an enabled means for generating constructs expressing different antigen epitopes to perform comparative analysis of their functional effects.
With respect to claim 4, Fedorov mentions the Protein Atlas database as a source of information regarding surface antigen expression (the ‘surfaceome’) in human tissues (pg. 74, para. 2).
With respect to claim 5, Fedorov exemplifies design of iCARs targeting HLA-Is, and teaches that HLA-Is are universally expressed in different tissues (pg. 31, para. 2).
With respect to claim 7, Fedorov mentions the Protein Atlas database as a source of information regarding surface antigen expression (the ‘surfaceome’) in human tissues (pg. 74, para. 2).
With respect to claim 10, Cabrera exemplifies immunostaining with HLA locus-specific antibodies to characterize allelic losses and presents suitable antibodies that can be employed (pg. 2, r. column; pg. 3, Fig. 3; pg. 4, l. column and Table 2).
With respect to claim 11, Fedorov teaches that HLAs are found in virtually all cell types, but are downregulated on tumors, making them useful target antigen candidates (pg. 7, l. column). Fedorov exemplifies design of T cells reactive against HLA-A1 (pg. 77, para. 2).
With respect to claim 12, Rajpal discloses embodiments wherein the antigen binding domain is a human antibody, a humanized antibody, a functional fragment thereof, a single-domain antibody including a nanobody domain, a recombinant antibody, or a single chain variable fragment (pg. 107, para. 2; pg. 108, para. 3).
With respect to claim 13, Rajpal discloses embodiments wherein the subject is a human (pg. 15, para. 2), i.e., the tissue of interest is human tissue.
With respect to claim 14, Rajpal discloses embodiments wherein the immune cell is a T cell (pg. 20, para. 3).
With respect to claims 15-16, Rajpal exemplifies known inhibitory receptors including 1LILRB1 (pg. 22, para. 6), which is also known as LIR1.
With respect to claim 17, Rajpal discloses embodiments wherein the extracellular domain is attached to a transmembrane domain, which may include transmembrane regions of naturally-occurring proteins (i.e., transmembrane canonic motifs), via a hinge (pg. 106, paras. 2-4)
With respect to claim 19, Rajpal discusses determining a desired antigenic epitope via any method well known in the art (pg. 6, para. 4). Rajpal also discusses determining variants of a subject variable region with substitution in amino acid residues, particularly those outside a CDR region (e.g., in the framework region), by comparing the subject variable region to the variable regions of other antibodies which contain CDR1 and CDR2 sequences in the same canonical class as the subject variable region (pg. 4, para. 2).
One of ordinary skill in the art would understand that the described process of determining variants of a variable region of an antibody would be necessary for the purpose of binding particular complementary variants of an antigenic epitope (e.g., a cell surface epitope). In this way, Rajpal at least suggests selection of polymorphic cell surface epitopes. Rajpal does not teach selecting a polymorphic cell surface epitope that undergoes LOH.
Fedorov teaches that downregulation of HLA molecules represents a major mechanism of tumor escape from T-cell immune responses, and discusses identification of tissue-specific target antigens that are absent or downregulated in tumor tissue, but expressed by off-target tissue, from among broad classes of surface antigens such as HLAs (pg. 74, para. 2). Fedorov schematically depicts an antigen selection process comprising steps of: profiling surface antigens of a tumor biopsy, determining surface antigens that are absent or expressed at low levels in the tumor tissue (i.e., ‘viable iCAR antigens’), checking their expression in normal tissue using expression repositories (e.g., the exemplified online databases), and selecting an appropriate patient specific antigen and iCAR antigen recognition domain (Fig. 23, desc. at pg. 27, para. 4). HLAs that are absent or downregulated in tumor tissue, but expressed by off-target tissue, are HLAs that undergo LOH.
Additionally, Cabrera teaches that LOH is the most widespread of the described mechanisms of altered HLA presentation in tumors, and can be quantified (pg. 5, r. column – pg. 6, r. column).
With respect to claim 20, Fedorov describes a personalization approach wherein a target ‘iCAR antigen’ is selected through an algorithmic process and a physician orders a specific receptor (i.e., iCAR) suited for the patient’s tumor (pg. 32, para. 2). Fedorov also schematically depicts an antigen selection process comprising steps of profiling and determining surface antigens that are absent or expressed at low levels in a tumor biopsy (i.e., ‘viable iCAR antigens’ that undergo LOH) and selecting an appropriate patient specific antigen and iCAR antigen recognition domain (Fig. 23, desc. at pg. 27, para. 4). In this way, Fedorov is considered to teach the claimed process.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have retrieved surface antigen information from a database, as suggested by Fedorov, in combination with the chimeric antigen expression methodology taught by Rajpal, because Fedorov teaches that the mentioned database aims to characterize surface antigens of all human tissues (pg. 74, para. 2). Said practitioner would have had a reasonable expectation of success because Rajpal and Fedorov both discuss methods of preparing immune cells expressing inhibitory chimeric antigen receptors.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented selection of variants based on LOH in a tumor, as discussed by Cabrera, in combination with the chimeric antigen expression methodology taught by Rajpal, because Cabrera teaches that detecting LOH in a tumor is a readily enabled means of identifying epitopes of antigens that are downregulated in a tumor (pg. 5, r. column – pg. 6, r. column). Said practitioner would have had a reasonable expectation of success because Rajpal and Cabrera both discuss differential expression of antigens between normal and tumor tissues.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented subcloning of antigen variants, as taught by Matsui, in combination with the chimeric antigen expression methodology taught by Rajpal, because Rajpal teaches expression of different epitopes but does not elaborate a means for achievement while Matsui teaches that subcloning is an enabled means for generating constructs expressing different antigen epitopes (pg. 3, Results; pg. 9, Plasmid Constructs). Said practitioner would have had a reasonable expectation of success because Rajpal and Matsui both discuss expression of antigen epitopes.
In this way the disclosure of Rajpal, in view of Fedorov, Cabrera and Matsui, makes obvious the limitations of claims 1, 4, 7 and 10-18. Thus, the invention is prima facie obvious.
Claims 2-3 are rejected under 35 USC 103 as being unpatentable over Rajpal, in view of Fedorov, Cabrera and Matsui, as applied to claim 1 above, and further in view of Maiers et al (previously cited). This rejection is maintained from the previous Office action.
With respect to claim 2, Rajpal exemplifies polyclonal antibodies (pg. 3, para. 2) and teaches that polyclonal antibody preparations typically include antibodies directed against different epitopes (pg. 5, para. 3).Rajpal does not disclose embodiments wherein each protein-coding gene has at least two expressed alleles and the minor allele frequency equals or exceeds 1, 2, 3, 4, or 5%.
Fedorov teaches that HLAs are found in virtually all cell types, but are downregulated on tumors, making them useful target antigen candidates (pg. 7, l. column). Fedorov exemplifies design of T cells reactive against HLA-A1 (pg. 77, para. 2). Fedorov does not teach embodiments wherein each protein-coding gene has at least two expressed alleles and the minor allele frequency equals or exceeds 1, 2, 3, 4, or 5%.
Cabrera reviews human leukocyte antigen (HLA) expression in human tumor tissues and teaches that normal cells express large amounts of HLA class I molecules (pg. 1, r. column). Cabrera does not teach embodiments wherein each protein-coding gene has at least two expressed alleles and the minor allele frequency equals or exceeds 1, 2, 3, 4, or 5%.
Matsui presents a study investigating the effects of various introduced HLA point mutations on T cell recognition of tumor cells (pg. 1, Abstract). Matsui does not teach embodiments wherein each protein-coding gene has at least two expressed alleles and the minor allele frequency equals or exceeds 1, 2, 3, 4, or 5%.
Maiers presents a study on HLA allele and haplotype frequencies in the United States population. Maiers presents findings regarding multiple alleles in each of 5 HLA categories (A, B, C, DRB1 and DQB1; pg. 781, Table 3), which show that minor alleles were present in the sampled European (EUR), Hispanic (HIS), and Asian/Pacific Islander (API) populations with frequencies > 1% (pg. 785, Figure 1).
With respect to claim 3, Maiers presents findings which show that a minor allele was present in the sampled European (EUR) population with frequency > 5% (pg. 785, Figure 1).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented use of a gene having a minor allele with frequency over 5%, in combination with the chimeric antigen expression methodology taught by Rajpal, in view of Fedorov, Cabrera and Matsui, because at least Fedorov and Cabrera teach that HLAs are favorable target antigens while Maiers teaches that at least some HLAs have minor alleles with the specified frequency in at least some populations (pg. 785, Figure 1). Said practitioner would have had a reasonable expectation of success because Rajpal and Maiers both discuss expression of antigen epitopes.
In this way the disclosure of Rajpal, in view of Fedorov, Cabrera, Matsui and Maiers, makes obvious the limitations of claims 2-3. Thus, the invention is prima facie obvious.
Claims 6 and 9 are rejected under 35 USC 103 as being unpatentable over Rajpal, in view of Fedorov, Cabrera and Matsui, as applied to claim 1 above, and further in view of Boegel et al (previously cited). This rejection is maintained from the previous Office action.
With respect to claim 6, Rajpal discloses determining desired epitopes of an off-target antigen, wherein an off-target antigen is downregulated in a tumor of interest but present in all normal tissues of concern (pg. 6, para. 4; pg. 110, para. 1); Rajpal does not disclose consideration of target expression level in terms of reads per kilobase of transcript per million mapped reads (RPKM).
Fedorov teaches criticality of target expression level, stating: “In settings of… low expression of iCAR or iCAR-targeted antigen, sufficient blockade could not be achieved… In applying the iCAR strategy in a clinical setting, the functionality of every iCAR will need to be optimized on the basis of… selection of suitable target antigens based, in part, on their expression level” (pg. 75, para. 2). However, Fedorov does not teach consideration of target expression level in terms of RPKM.
Cabrera teaches that normal cells express large amounts of HLA class I molecules (pg. 2, r. column). Cabrera does not teach consideration of target expression level in terms of RPKM. Matsui teaches consideration of antigen expression levels (pg. 3, l. column), but not in terms of RPKM.
Boegel discusses HLA typing, and consideration of expression levels in various cancer cell types in terms of RPKM and presents findings that HLA I alleles exhibited overall expression greater than or equal to 100 RPKM across 8 cell lines (pg. 5, Table 3 and r. column).
With respect to claim 9, Boegel teaches determination of HLA alleles and heterozygosity in various tumor tissues, including non-synonymous SNVs (pg. 7 – pg. 8, l. column). SNPs constitute a species that one of ordinary skill in the art would ‘at once envisage’ upon reading the disclosure (see In re Petering, 301 F.2d 676, 681 (CCPA 1962)).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented use of genes having expression across tissues greater than 10 RPKM and having SNP variants, in combination with the chimeric antigen expression methodology taught by Rajpal, in view of Fedorov, Cabrera and Matsui, because at least Fedorov and Cabrera teach that HLAs are favorable target antigens while Boegel teaches that at least some HLAs have alleles with the specified RPKM across tissues (pg. 5, Table 3 and r. column) and resulting from SNVs, e.g., SNPs (pg. 7 – pg. 8, l. column). Said practitioner would have had a reasonable expectation of success because Rajpal and Boegel both discuss expression of antigen epitopes.
In this way the disclosure of Rajpal, in view of Fedorov, Cabrera, Matsui and Boegel, makes obvious the limitations of claims 6 and 9. Thus, the invention is prima facie obvious.
Claim 8 is rejected under 35 USC 103 as being unpatentable over Rajpal, in view of Fedorov, Cabrera and Matsui, as applied to claim 1 above, and further in view of Sim et al (previously cited). This rejection is maintained from the previous Office action.
With respect to claim 8, Rajpal discloses solving the structure of the antibody-ligand complex to delineate complementarity-determining regions (pg. 4, para. 3). Rajpal does not disclose evaluation of protein structural variation by a SIFT score.
Fedorov teaches modification of iCARs based on structural considerations (pg. 61, para. 2). Fedorov does not teach evaluation of protein structural variation by a SIFT score.
Cabrera teaches that allelic losses are often a consequence of structural gene alterations (pg. 7, r. column). Cabrera does not teach evaluation of protein structural variation by a SIFT score.
Matsui teaches that the similarity of residues at position 74 across all HLA-A molecules indicates that the residue at this position may play an important role in conformational stability (pg. 7, r. column). Matsui does not teach evaluation of protein structural variation by a SIFT score.
Sim discusses the Sorting Intolerant from Tolerant algorithm (SIFT), a tool that predicts the potential impact of amino acid substitutions on protein function and has been used in the field of cancer research (pg. W452, Abstract and r. column). Sim further teaches that SIFT is implemented as a publicly available web server (pg. W454, l. column).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented evaluation of protein structure by a SIFT score, in combination with the chimeric antigen expression methodology taught by Rajpal, in view of Fedorov, Cabrera and Matsui, because at least Rajpal and Fedorov teaches consideration of protein structure but do not further describe means for achievement while Sim presents SIFT as an enabled, publicly-available means for achievement (pg. W452, Abstract and r. column; pg. W454, l. column). Said practitioner would have had a reasonable expectation of success because Rajpal and Sim both discuss analysis of protein structure.
In this way the disclosure of Rajpal, in view of Fedorov, Cabrera, Matsui and Sim, makes obvious the limitations of claim 8. Thus, the invention is prima facie obvious.
Conclusion
At this point in prosecution, no claims are allowed.
The following prior art, made of record and not relied upon, is considered pertinent to applicant's disclosure:
Boegel et al (OncoImmunology 3(8): article e954893, 12 pages; published 8/1/2014) discusses construction of a catalog of HLA class I and II genotypes, heterozygosity, expression, and predicted antigenic mutations in numerous cancer cell lines using publicly-available RNA-Seq data (Abstract);
Brogdon et al (US 2016/0311907; effectively filed 12/20/2013) discloses compositions and methods relating to regulatable chimeric antigen receptors (RCARs), wherein an RCAR can comprise an inhibitory member (iCAR) that comprises an antigen binding domain that recognizes an antigen on a non-target, e.g., a noncancer cell (paras. 1497-1500);
Lim et al (US 2019/0202918; effectively filed 8/26/2016) discloses methods of using chimeric polypeptides (Abstract), including inhibitory chimeric antigen receptors (iCARs) which may be used as a component of a bispecific CAR system, where binding of a secondary CAR binding domain results in inhibition of primary CAR activation (para. 0091);
Oostvogels et al (Haematologica 99(12): 1854-1859; published December 2014) discusses identification of known minor histocompatibility antigens, as targets for cancer therapy, using 1000 Genomes Project databases;
Robinson et al (Human Immunology 77: 233-237; published 1/27/2016) presents the IPD-IMGT/HLA Database, an online, searchable, locus-specific database of allelic variants of the genes in the HLA system; and
Schuler et al (Immunogenetics 57: 816–820; published 12/10/2005) presents the single nucleotide polymorphism (SNP)-derived Epitope Prediction Program (SNEP), an algorithmic tool that predicts polymorphic T-cell epitopes with binding affinity to particular HLA class I and II alleles using protein data from the SWISS-PROT database.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to whose telephone number is (571)272-1860. The examiner can normally be reached Mon-Fri 12pm-8pm ET.
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/T.C.S./Examiner, Art Unit 1685
/JESSE P FRUMKIN/Primary Examiner, Art Unit 1685 March 6, 2026