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 .
1. The Amendment filed September 29, 2025 in response to the Office Action of June 26, 2025, is acknowledged and has been entered. Claims 94, 96, 100-124, and 127 are now pending. Claims 96, 100-119, 121-124 are amended. Claim 127 is new. Claims 94, 100, 101, 103-118, 120 remain withdrawn as being drawn to a non-elected species. Claims 96, 102, and 121-124 are rejoined for examination with claim 119 and new claim 127 because they are amended to recite the elected species of T cell stimulated with an APC comprising amino acid sequence FLKAESKIM (SEQ ID NO:13438) and depend from claim 119.
Claims 96, 102, 119, 121-124 and 127 are currently being examined as drawn to the elected species.
Maintained Rejection
(amendments addressed)
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.
2. Claims 96, 102, 119, 121-124 and 127 remain/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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are now drawn to a population of ex vivo antigen-stimulated T cells comprising CD4+ or CD8+ T cells specific to a neoepitope in a peptide-HLA complex, wherein the HLA in the peptide-HLA complex is HLA class I; and wherein the neoepitope arises from a frameshift mutated GATA3 sequence, the frameshift mutated GATA3 sequence having an amino acid sequence: SEQ ID NO:1297, wherein the T cells have been stimulated ex vivo by contacting with antigen presenting cells (APCs) expressing the neoepitope arising from the GATA3 frameshift mutation, and wherein the neoepitope is selected from: FLKAESKIM (SEQ ID NO:13438).
New claim 127 recites that the step of contacting comprises:
contacting T cells isolated from a biological sample with antigen presenting cells (APCs) loaded with the neoepitope arising from a GATA3 frameshift mutation consisting of 9-10 contiguous amino acids of the frameshift mutated GATA3 sequence of SEQ ID NO: 1297; or
contacting T cells isolated from the biological sample with antigen presenting cells (APCs) comprising a recombinant nucleic acid encoding a polypeptide comprising the neoepitope arising from the frameshift mutated GATA3 sequence of SEQ ID NO: 1297; thereby producing the population of ex vivo antigen-stimulated T cells comprising CD4+ or CD8+ T cells.
Thus, the claims identify the CD4+ or CD8+ T cells by process of being made and a binding function only, where the process of being made comprises:
ex vivo stimulation of a population of CD4+ or CD8+ T cells by contacting the T cells with antigen presenting cells (APCs) expressing the neoepitope arising from the GATA3 frameshift mutation;
ex vivo contacting T cells isolated from a biological sample with antigen presenting cells (APCs) loaded with the neoepitope arising from a GATA3 frameshift mutation consisting of 9-10 contiguous amino acids of the frameshift mutated GATA3 sequence of SEQ ID NO: 1297; or
ex vivo contacting T cells isolated from the biological sample with antigen presenting cells (APCs) comprising a recombinant nucleic acid encoding a polypeptide comprising the neoepitope arising from the frameshift mutated GATA3 sequence of SEQ ID NO: 1297; thereby producing the population of ex vivo antigen-stimulated T cells comprising CD4+ or CD8+ T cells;
and wherein the function of the T cells is “specific to a neoepitope in a peptide-HLA complex”, wherein the HLA is HLA class I and wherein the neoepitope is FLKAESKIM (SEQ ID NO:13438).
No T cell structure or T cell receptor structure critical to binding the neoepitope peptide-HLA complex is recited.
The instant specification discloses epitope SEQ ID NO:13438 (FLKAESKIM) is derived from a GATA3 neoantigen in cancer and is identified as an HLA-A and HLA-B Class I restricted epitope. The instant specification discloses exemplary recurrent mutations suggested for subtype specific immunogenic compositions (Example 5). The specification discloses:
Example 5
[0773] Recurrent Mutations for Cancer Subtype Specific Immunogenic Compositions.
[0774] The Cancer Genome Atlas (TCGA) contains comprehensive large-scale genome sequencing data from tumor samples to catalogue genetic mutations responsible for cancer. Tumor-specific neoantigenic peptides for use in an immunogenic composition can be selected based on a number of criteria. The first criteria is based on gene expression. The fraction of patients (per tumor type) who express the gene at >10 transcripts per million was determined. Estimates assume a random assortment of HLA type vs. mutation status of each gene vs. gene expression (per tumor type). National yearly incidence was used to quantify the population that could be treated with each peptide. Peptides were ranked by expected population. The results of the analysis is shown in Table 9.
A few excerpts of Table 9 listing some of the GATA3 sequences are presented below (sequence “FLKAESKIM” from claim 102 is underlined and a “Mutation” ending in “fs” is considered a frameshift mutation):
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158
759
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112
745
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115
739
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241
741
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65
742
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79
736
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79
736
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95
739
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66
738
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69
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The instant specification does not disclose any representative CD4+ or CD8+ T cell compositions or CD4+ or CD8+ T cell receptor sequences/structures that are produced by ex vivo stimulation with an APC comprising, loaded with, or recombinantly expressing the recombinant GATA3 frameshift mutated amino acid sequence or neoepitope, or that are capable of binding to the claimed neoepitope sequence + HLA class I complex. The instant specification does not disclose any representative T cell receptor (TCR) sequence structures correlated to the claimed function of binding to the claimed GATA3 neoepitope sequence + HLA class I complex.
Gupta et al (Single-Cell Sequencing of T cell Receptors: A Perspective on the Technological Development and Translational Application. Adv Exp Med Biol. 2020;1255:29-50. doi: 10.1007/978-981-15-4494-1_3. PMID: 32949388; PMCID: PMC8845565) teach T cell Receptors (TCRs) are restricted to recognizing short peptides of protein antigens processed and presented by major histocompatibility complexes (MHCs) on the body’s own antigen presenting cells (APCs) (p. 30, col. 1). TCRs are composed of two heterodimeric polypeptide chains linked by a disulfide bond. Each chain of the TCR consists of two extracellular immunoglobulin domains, a transmembrane region and a short cytoplasmic tail. The two extracellular domains are made up of the variable (V) region and constant (C) region. The heterodimeric structure of the TCR is analogous to the heavy and light chain heterodimers of B cell receptors (BCRs) or antibodies. However, the forked structure of the BCR consists of two antigen binding sites, whereas each TCR possesses a single antigen binding site. The majority of TCRs possess an α chain and a β chain and are referred to as αβ TCRs. A subset of T cells possesses a γ chain and δ chain and are referred to as γδ TCRs. γδ TCRs are capable of directly recognizing antigens outside the context of MHC and are even capable of recognizing non-peptide antigens. T cells possess the ability to bind to a vast array of peptide antigens through their TCRs; it has been estimated that humans can produce between 1015 and 1020 possible unique TCR chains. This enormous variety is imparted by an unusual genetic mechanism, largely shared with BCR generation, that provides diversity concentrated in the antigen binding regions of the TCR. The V region is the portion of the TCR that participates in antigen binding. The V region is not encoded by a single segment of DNA, but rather is composed of multiple gene segments that are rearranged through somatic DNA recombination. Combinatorial diversity afforded through recombination of the gene segments is further augmented by junctional diversity through the random addition of nucleotides at the interface between segments, thus allowing for the generation of a nearly limitless array of TCRs. The DNA encoding the α chain of the TCR possesses multiple variable (V) and joining (J) segments, whereas the β chain possesses multiple V, diversity (D), and segments as represented in Fig. 3.1 (p. 30, col. 1-2). Fig. 3.1 of Gupta et al displays the mRNAs somatic VDJ recombination to form the alpha and beta chains of TCRs. As indicated, there is an arrangement step that recombines the VDJ segment for TCR β and V and J segments for the TCR α chain. The mRNAs formed have addition and deletion of nucleotides at the junctions of these segments leading to junctional diversity that leads to variability for assessing specific antigens. There may be different combinations of genes leading to the final formation of the TCR that consists of the TCR α and β subunit organized in a constant and variable region wherein the variable region is responsible for antigen recognition (p. 30). Gupta et al teach: Antigen binding within the TCR V region involves the three complementarity determining regions (CDRs) that contact the antigen MHC complex. CDR1 and CDR2 are primarily encoded in the V germline segments and therefore experience less diversity. CDR3 however includes the junctional regions and is the primary region in contact with the antigen (p. 31, col. 1). Part of Figure 3.1 showing structure of TCR comprising 3 CDRs in each of TCR α and β chains:
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Gupta et al teach (p. 31, col. 2): TCRs recognize processed peptide antigen presented on MHC on the surface of the body’s own cells. The two conventional MHCs, MHC I and MHC II are both polygenic and polymorphic noncovalent protein complexes composed of two polypeptide chains. TCRs are specific to both peptide antigen and the MHC to which it is bound, a phenomenon known as MHC restriction. MHC I is on the surface of virtually all nucleated cells in the body. Peptides presented on MHC I are generally 8–10 amino acids in length and result from the processing of foreign intracellular proteins. For this reason, MHC I is frequently used to signal viral infection to cytotoxic CD8 T cells. MHC II is only present on the surface of antigen presenting cells of the immune system including B cells, macrophages, and dendritic cells. MHC II presents peptides of 13–17, amino acids in length that have been collected from the extracellular environment. The instant claims have been amended and limited to CD4+ T cells and CD8+ T cells binding to a neoepitope in an HLA class I complex. It is well established in the art that CD8+ T cells bind and recognize peptides presented by HLA class I (MHC I) molecules on APCs utilizing their CD8 molecules, and CD4+ T cells bind and recognize peptides presented by HLA class II (MHC II) molecules utilizing their CD4 molecules:
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In response to amendments, Examiner points to Legoux et al (European Journal of Immunology, 2013, 43:3244-3253) that teaches (Introduction):
T lymphocytes (TLs) can detect infected or transformed cells and elicit protective immunity and inflammatory responses in various infectious and tumor contexts. This process relies on the recognition by clonally distributed TCR of antigenic peptides presented by major histocompatibility (MHC) gene products. T cells expressing the CD8 coreceptor are mainly cytolytic TLs (CTLs), and classically recognize 8–10 amino acid peptides bound to MHC class I molecules, whereas CD4+ T cells recognize 10–15 amino acid peptide fragments restricted by MHC class II molecules. MHC restriction of CD4+ and CD8+ T-cell subsets is linked to the ability of CD4 and CD8 coreceptors to bind conserved regions of MHC class I and class II molecules, respectively, and stabilize TCR-peptide/MHC complexes. Another salient feature of the T-cell repertoire is its cross-reactivity, which allows T cells from a given individual to recognize a set of distinct peptide-MHC (pMHC) complexes much larger than the repertoire of distinct TCRs generated through somatic TCR gene rearrangement. In this regard, both CD8+ CTLs restricted by MHC class II molecules and CD4+ T cells restricted by MHC class I molecules have been reported. However, T cells with “mismatched” MHC restriction have remained sporadic, and in most cases isolated after antigenic stimulation in vitro, leaving questions about their frequency within the human T-cell repertoire, the stability of their coreceptor phenotype and their relevance in various physiopathological contexts.
Kobayashi et al (Immunogenetics, 2001, 53:626-633) also teaches it is established that CD4+ T cells recognize antigens presented by MHC Class II, and CD8+ T cells recognize antigens presented by MHC I, however, Kobayashi teaches they were able to artificially induce CD4+ T cells reactive with “transporter associated with antigen processing (TAP)-deficient” APCs presenting peptides with MHC I molecules, and teach production of such T cells is uncommon (Introduction):
“Recognition of virus-infected cells or tumor cells by antigen-specific T cells is governed by major histocompatibility complex (MHC) class I or class II molecules expressed on the surface of the target cells. In general, CD8+ cytotoxic T lymphocytes (CTLs) recognize antigen in the form of short peptides, 8–10 amino acids long, presented by MHC class I molecules, whereas CD4+ T cells recognize peptide antigen in the form of long peptides (15–20 amino acids) presented by MHC class II molecules (Engelhard 1994). The T-cell surface accessory molecules, CD4 and CD8, which are known as markers for different functional sets of CD4+ helper T cells and CD8+ CTLs, respectively, bind to conserved regions of MHC class I or class II molecules and contribute to stabilize the T cell receptor (TCR)-peptide-MHC complexes (Janeway 1992)… there is little information available regarding CD4+ T-cell responses in the context of MHC class I molecules (Darrow et al. 1996; De Bueger et al. 1992; Mizuochi et al. 1986). Most CD4+ T-cell populations observed in primary T-cell responses against class I alloantigens appear to recognize class I determinants but in a classical class II-restricted manner (Golding et al. 1987; Mizuochi et al. 1986).”
Xue et al (Oncoimmunology, 2013, 2:1, e22590) also teaches it is established that CD4+ T cells recognize antigens presented by MHC Class II, and CD8+ T cells recognize antigens presented by MHC I. Xue teaches the importance of adoptive transfer of CD4+ T cells in tumor treatment and teaches producing CD4+ T cells recognizing MHC I peptides. Xue teaches making CD4+ T cells reactive with MHC I-restricted peptides by transfecting vectors encoding HLA-A2-restricted (MHC I-restricted) TCR-coding genes recognizing the MHC I peptide into CD4+ T cells. The resulting engineered CD4+ T cells could recognize the MHC I-restricted peptide, but with low avidity compared to CD8+ T cells. To improve avidity, Xue co-transfected CD8 molecules with the TCR-coding genes recognizing the MHC I peptide to enhance avidity of the CD4+ T cells to the peptide (abstract):
“Retroviral transfer of virus-specific, HLA-A2-restricted TCR-coding genes generated CD4+ T cells that recognized HLA-A2/peptide multimers and produced cytokines when stimulated with MHC Class II deficient cells presenting the relevant viral peptides in the context of HLA-A2. Peptide titration revealed that CD4+ T cells had a 10-fold lower avidity than CD8+ T cells expressing the same TCR. The impaired avidity of CD4+ T cells was corrected by simultaneously transferring TCR- and CD8-coding genes.”
Thus, the state of the art recognizes and establishes:
(1) CD4+ T cells do not normally recognize epitopes presented in complex with HLA class I molecules, and it is an uncommon event, that, in many cases, requires genetic manipulation of APCs or CD4+ T cells to occur. The instant specification does not provide a single exemplary species of CD4+ T cell that functions as claimed or results by the claimed process of making. The instant specification does not provide a single exemplary, recognizable species of CD8+ T cell resulting from the process of making claimed.
(2) The six CDRs of the TCR chains in a T cell are critical to the claimed function of recognizing and binding (or being “specific to”) the peptide antigen presented by an APC, and the sequences of these CDRs are highly variable and cannot be predicted based on the sequence of the peptide to which they are binding. Much like the six CDRs of antibodies, the sequences of the six CDRs of TCRs critical to antigen binding function cannot be predicted or determined based on the antigen they are binding. The TCR sequences expressed by T cells in response to APC antigen stimulation, even in response to stimulation with a single defined peptide sequence complexed with HLA class I molecule, are highly variable and unpredictable. The claimed genus of CD4+ and CD8+ T cells comprising TCR sequences produced by APC stimulation and capable of binding an antigen presented by the APC with HLA class I molecule is vast.
To provide adequate written description and evidence of possession of the claimed T cell genus, the instant specification can structurally describe representative TCRs that function to bind the claimed polypeptide sequence or result from being stimulated by the claimed APCs, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
Although Applicants may argue that it is possible to screen for CD4+ or CD8+ T cells that are produced by the claimed APC stimulation process or are capable of binding to a neoepitope consisting of 9-10 contiguous amino acids of SEQ ID NO:13438 (FLKAESKIM) complexed with an HLA class I molecule as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future CD4+ or CD8+ T cells yet to be discovered that may function as claimed. The antigen presented by the APC provides no information about the structure of a T cell that is stimulated and binds to it.
In this case, the only factor present in the claims is a recitation of the CD4+ or CD8+ T cell process of production: “stimulated with APCs” expressing a polypeptide comprising at least one neoepitope consisting of 9-10 contiguous amino acids of the frameshift mutated GATA3 sequence having an amino acid sequence: SEQ ID NO:13438 (claim 119) complexed with an HLA class I molecule, and a recitation of the CD4+ or CD8+ T cell function: “specific to a neoepitope in a peptide-HLA complex, wherein the HLA in the peptide-HLA complex is HLA class I; and wherein the neoepitope arises from a frameshift mutated GATA 3 sequence” (claim 119). The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose a single exemplary CD4+ or CD8+ T cell population or TCR sequence that functions as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the T cell does, rather than what it is. The specification fails to provide any structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of TCR sequences for the genus of CD4+ or CD8+ T cells that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Applicants have not established any reasonable structure-function correlation with regards to the sequences in the CD4+ and CD8+ T cell TCR CDRs that result from being stimulated with APCs expressing a polypeptide comprising at least one neoepitope consisting of 9-10 contiguous amino acids of the frameshift mutated GATA3 sequence having an amino acid sequence listed in claim 94 (i.e., SEQ ID NO:13438 FLKAESKIM). The instant claims attempt to claim every CD4+ or CD8+ T cell that results from being stimulated with APCs comprising a polypeptide at least one neoepitope consisting of 9-10 contiguous amino acids of the frameshift mutated GATA3 sequence having an amino acid sequence listed in claim 119 (i.e., SEQ ID NO:13438 FLKAESKIM) complexed with an HLA class I molecule, and is “specific to” the neoepitope in a peptide-HLA class I complex, wherein the instant specification does not describe representative examples to support the full scope of the claims because the instant specification fails to disclose a single exemplary CD4+ or CD8+ T cell or TCR of a CD4+ or CD8+ T cell that functions or results as claimed. Given the known high level of polymorphism of T cell CDR sequences and structure, and given CD4+ T cells specific to peptides complexed with HLA class I molecules arising from ex vivo APC stimulation are uncommon and not well described, the skilled artisan would not have been in possession of the vast repertoire of T cells encompassed by the claimed invention. One could not readily envision members of the broadly claimed genus.
Given the lack of representative examples to support the full scope of the claimed CD4+ or CD8+ T cells, and lack of reasonable structure-function correlation with regards to the unknown sequences in the TCR CDRs that provide the critical binding function resulting from stimulation with a polypeptide processed and presented by an APC complexed with HLA class I molecule, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of T cells resulting from being stimulated with APCs loaded with or recombinantly expressing the claimed GATA3 neoepitope sequence and are specific to the claimed GATA3 neoepitope complexed with an HLA class I molecule that is required to practice the claimed invention.
Response to Arguments
3. Applicants argue that Examiner has mischaracterized the Written Description standard for the claimed population of T cells because the T cells are claimed as a product-by-process. Applicants state that Examiner previously quoted MPEP 2113 stating “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself”. Applicants argue that MPEP 2113 is silent as to the Written Description standard for product-by-process claims.
Applicants argue that a composition may be claimed by (1) its structure or physical properties, or by (2) means of a process used to make it. Applicants argue that when a composition is claimed by its method of preparation, its definition by its method of preparation can establish written description. Applicants argue that the process recited in the claims limits the product.
4. The arguments have been considered but are not persuasive. Contrary to arguments, MPEP 2113 is applicable to the instant claims, particularly in identifying the product claimed by process for examination.
MPEP 2113 states:
I. PRODUCT-BY-PROCESS CLAIMS ARE NOT LIMITED TO THE MANIPULATIONS OF THE RECITED STEPS, ONLY THE STRUCTURE IMPLIED BY THE STEPS
"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself.”
In the instant case, the claimed process by which the T cells are stimulated and produced provides no information on the structure of the resulting T cell product or the expressed T cell receptor critical to identifying the T cell population and their capability of binding to the neoepitope. There is no structure implied by the claimed process of T cell production, there is only an implied function of binding to a protein presented by the APC in complex with HLA class I molecule.
Contrary to arguments, claiming a product by a process of making does not necessitate satisfying the written description for that product. Examiner previously recited MPEP 2163 related to examining written description for products claimed by a method of making and/or its function. MPEP 2163 states:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. For example, the amino acid sequence of a protein along with knowledge of the genetic code might put an inventor in possession of the genus of nucleic acids capable of encoding the protein, but the same information would not place the inventor in possession of the naturally-occurring DNA or mRNA encoding the protein. See In re Bell, 991 F.2d 781, 26 USPQ2d 1529 (Fed. Cir. 1993); In re Deuel, 51 F.3d 1552, 34 USPQ2d 1210 (Fed. Cir. 1995) (holding that a process could not render the product of that process obvious under 35 U.S.C. 103 ). (For guidance on subject matter eligibility of claims to naturally-occurring compositions, see MPEP § 2106.) The Federal Circuit has pointed out that, under United States law, a description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112. See Eli Lilly, 119 F.3d at 1567, 43 USPQ2d at 1405; compare Fonar Corp. v. Gen. Elec. Co., 107 F.3d 1543, 1549, 41 USPQ2d 1801, 1805 (Fed. Cir. 1997) ("As a general rule, where software constitutes part of a best mode of carrying out an invention, description of such a best mode is satisfied by a disclosure of the functions of the software. This is because, normally, writing code for such software is within the skill of the art, not requiring undue experimentation, once its functions have been disclosed.... Thus, flow charts or source code listings are not a requirement for adequately disclosing the functions of software.").
In the instant case, the claimed T cell composition is described solely in terms of a method of making and/or its function and lacks written descriptive support because there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. As stated in the rejection, the T cell receptor expressed by the T cells is responsible for, and critical to, performing the claimed function of binding to the tumor specific neoepitope arising from a GATA3 frameshift mutation complexed with an HLA class I molecule. One of skill in the art cannot predict what T cell population will result in response to stimulation with an APC expressing a neoepitope arising from a GATA3 frameshift mutation presented in complex with an HLA class I molecule. There is no art-recognized correlation between stimulation of a T cell with an APC comprising a protein and the structure/function of the resulting T cell population. There is no art-recognized correlation between the disclosed function of binding to the tumor specific neoepitope/HLA class I complex and the T cell receptor structure responsible for the claimed function. The T cell population resulting from the claimed process of making is expected to harbor a vast genus of different T cell receptor sequences and a vast genus of affinities to various epitopes of the recombinant polypeptide comprised, processed, and presented by the APC. The resulting T cell population is highly variable, unpredictable, and cannot be immediately envisaged based upon the claimed process of APC stimulation.
MPEP 2163 states:
Written description issues may also arise if the knowledge and level of skill in the art would not have permitted the ordinary artisan to immediately envisage the claimed product arising from the disclosed process. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a "laundry list" disclosure of every possible moiety does not necessarily constitute a written description of every species in a genus because it would not "reasonably lead" those skilled in the art to any particular species); In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967) ("If n-propylamine had been used in making the compound instead of n-butylamine, the compound of claim 13 would have resulted. Appellants submit to us, as they did to the board, an imaginary specific example patterned on specific example 6 by which the above butyl compound is made so that we can see what a simple change would have resulted in a specific supporting disclosure being present in the present specification. The trouble is that there is no such disclosure, easy though it is to imagine it." (emphasis in original)); Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1328, 56 USPQ2d 1481, 1487 (Fed. Cir. 2000) ("[T]he specification does not clearly disclose to the skilled artisan that the inventors ... considered the ratio... to be part of their invention .... There is therefore no force to Purdue’s argument that the written description requirement was satisfied because the disclosure revealed a broad invention from which the [later-filed] claims carved out a patentable portion").
In the instant case, knowledge of methods for stimulating T cells with APCs presenting a protein sequence in complex with an HLA class I molecule does not place one in possession of every T cell population resulting from such methods, nor does it allow one to immediately envisage the identifying structures and functions of the resulting T cell population. This is analogous to the concept that routine knowledge of producing antibodies by antigen stimulation does not put one in possession of every resulting antibody produced, nor can one predict or envisage the structure of the resulting antibodies produced.
As stated above, although methods of stimulating T cells with APCs presenting epitopes is known in the art and described in the specification, knowledge of these methods does not permit the ordinary artisan to immediately envisage the resulting claimed T cell product arising from this disclosed process. The genetic variability of T cell receptors expressed by T cells in response to APC antigen stimulation is vast, much like the antibody response to antigen stimulation. The ordinary artisan cannot immediately envisage or recognize the resulting claimed T cell product arising from the claimed and disclosed process of APC antigen stimulation.
MPEP 2163 states (bold emphasis added):
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." Id.
For some biomolecules, examples of identifying characteristics include a sequence, structure, binding affinity, binding specificity, molecular weight, and length. Although structural formulas provide a convenient method of demonstrating possession of specific molecules, other identifying characteristics or combinations of characteristics may demonstrate the requisite possession. As explained by the Federal Circuit, "(1) examples are not necessary to support the adequacy of a written description; (2) the written description standard may be met … even where actual reduction to practice of an invention is absent; and (3) there is no per se rule that an adequate written description of an invention that involves a biological macromolecule must contain a recitation of known structure." Falkner v. Inglis, 448 F.3d 1357, 1366, 79 USPQ2d 1001, 1007 (Fed. Cir. 2006); see also Capon v. Eshhar, 418 F.3d at 1358, 76 USPQ2d at 1084 ("The Board erred in holding that the specifications do not meet the written description requirement because they do not reiterate the structure or formula or chemical name for the nucleotide sequences of the claimed chimeric genes" where the genes were novel combinations of known DNA segments.). However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies "); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
In the instant case, as stated in the rejection, the instant specification does not provide evidence that inventor was in possession of the claimed T cell populations, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, because the instant specification does not provide any identifying structure/sequences of T cells or their TCR sequence critical to the claimed functions of being “specific to” the claimed GATA3 neoepitope sequence complexed with an HLA class I molecule.
According to MPEP 2163, when claiming an antibody product binding to an antigen/epitope, even if the antigen/epitope sequence is defined and fully characterized, and methods of producing antibodies binding to the antigen/epitope are well established, the antigen/epitope does not provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. Knowledge of the epitope sequence bound by the antibody does not give the required kind of structure-identifying information about the corresponding antibody. The same logic applies to the instant claims and specification. Knowledge of the fully defined GATA3 neoepitope peptide sequence (i.e., SEQ ID NO:13438) complexed to any known HLA class I molecule, and well-established methods of producing CD4+ and CD8+ T cells binding to the peptide-HLA complex by APC stimulation, does not provide an adequate written description of the T cells claimed by their binding to that antigen, even when preparation of such an T cell is routine and conventional. Knowledge of the sequence structure of the GATA3 neoepitope peptide sequence (i.e., SEQ ID NO:13438) complexed to any known HLA class I molecule does not give the required kind of structure-identifying information about the corresponding T cells.
To further support Examiner’s response and position that knowledge of the epitope-HLA complex sequence/structure, and knowledge making T cells specific for the peptide-HLA complex does not provide any information on the resulting T cell and its TCR critical to the peptide-HLA complex binding function, and that one cannot readily envision members of the claimed genus of cells produced by the claimed process, Examiner points to Fukui et al (J. Exp. Med. 1998, 188:897-907). Fukui demonstrates maturing CD4+ T cells on a single peptide sequence (Eα52-68) complexed to an HLA class II molecule (I-Ab) wherein the CD4+ T cells are engineered to express a fixed TCR β chain sequence, allowing for recombination and maturing of the TCRα chain sequence. Despite a single population of CD4+ T cells comprising a single TCRβ chain and maturing to a single peptide-HLA sequence, the resulting CD4+ T cell population produced a vast genus of cells harboring numerous distinct TCRα chain sequences (Table 1; Figure 4). Fukui concludes that “a single ligand, I-Ab- Eα52-68 complex, selects a quite diverse T cell repertoire” (p. 900, col. 2) and “CD4+CD8- thymocytes selected to mature on the I-Ab- Eα52-68 complex express diverse TCR-α chains with no obvious structural features” (p. 900, col. 1). The study of Fukui did not even assess the diversity of TCR β chains resulting from such production and selection of T cells. Therefore, Fukui supports and demonstrates that the resulting T cell population produced from stimulation with a single peptide-HLA complex is vast, highly diverse, and one cannot predict its identifying structural features.
With regard to amendments limiting the T cells to binding GATA3 epitope complexed to an HLA class I molecule (MHC I), the rejection above addresses this amendment. The state of the art established that CD4+ T cells do not routinely bind peptides presented in complex with HLA Class I molecules, but rather, with HLA class II molecules. CD4+ T cells binding to peptides presented in complex with HLA Class I molecules is uncommon, the instant specification does not provide any representative examples of CD4+ T cells functioning as claimed or produced as claimed, and the instant specification does not provide any recognizable TCR or CD4+ T cell structures critical to or correlated with the claimed function in order for one to immediately envision members of the claimed genus.
5. Applicants argue that the claimed process steps would reasonably lead persons skilled in the art to the claimed population of ex vivo antigen-stimulated T cells specific to the claimed neoepitope in the HLA complex. Applicants state that somatic DNA recombination of VDJ genes encoding the TCR occurs to generate a specific TCR and the genes present depend on the genomic makeup of pCTLs isolated from subject. Applicants state that somatic genomic recombination of VDJ genes occurs after stimulation with an epitope presented by an APC. Applicants state that the claims recite using a specific neoepitope sequence, specified process that uses pCTLs isolated from subjects, to arrive at the claimed population of ex vivo T cells. Applicants argue that structural details, such as TCRs, are not the focal point for product-by-process claims. The process limitations serve to restrict the scope of claim coverage.
6. The arguments have been considered but are not persuasive for the same reasons stated above citing MPEP 2113 and 2163. Contrary to arguments, the TCRs are a focal point of the invention because those are the cell structures critical to the claimed T cells performing the claimed functions of binding to (being specific to) the claimed GATA3 neoepitope complexed with HLA class I molecule. Contrary to arguments, the claimed process of making does not impart any identifying sequence/structures to the resulting T cell populations that would allow one to readily envision members of the claimed T cell populations.
7. Applicants argue that they have possession of the claimed T cell population. Applicants argue that the specification discloses methods for making the claimed T cell population and discloses the claimed GATA3 neoepitope sequences used to make the claimed T cell population. Applicants argue this disclosure places them in possession of T cells resulting from the described method of making the T cells with the disclosed neoepitope sequences. Applicants argue one would be able to make and identify the claimed T cells based on the disclosure.
With regard to Examiner’s citation of Rochester v. Searle where it was determined knowledge/disclosure of screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention, Applicants argue that the claimed CD4+ and CD8+ T cells made by a claimed process meet the standard for written description and argue that in Rochester, method-of-identifying claims were found by the Court to be supported by the specification.
8. The arguments have been considered but are not persuasive for the same reasons stated above citing MPEP 2113 and 2163. Contrary to arguments, disclosure and claiming of routine methods of T cell stimulation with APCs presenting antigen complexed with HLA class I molecule does not place Applicants in possession of the vast genus of resulting T cells instantly claimed, for the reasons stated above.
Arguments that method-of-identifying claims were found by the Court to be supported by the specification in Rochester are not persuasive because the instant claims are not drawn to a method of identifying.
9. With regard to Amgen and Centocor related to antibodies claimed by process of making, Applicants argue that the instant claims are not analogous to the decisions regarding antibodies. Applicants argue that the instant claims are drawn to CD4+ and CD8+ T cells made by a claimed process and not drawn to TCRs. Applicants argue that an activated T cell is structurally limited by its specificity to the antigen to which it responds. Applicants state they may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that Applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Applicants argue that the specification discloses how to make and characterize the claimed invention. Specifically, the specification discloses a population of ex vivo CD4+ or CD8+ T cells that are specific to a tumor specific neoepitope arising from a GATA3 frameshift mutation by virtue of the recited process. Applicants argue that the specification provides ample support on making and identifying such T cells. Applicants argue that one skilled in the art could readily envision the claimed population of ex vivo CD4+ or CD8+ T cells produced when stimulated with APCs comprising polypeptides, or nucleic acids encoding such polypeptides, comprising tumor specific neoepitopes recited in claim 119.
10. The arguments have been considered but are not persuasive for the same reasons stated above citing MPEP 2113 and 2163. Applicants argue that an activated T cell is structurally limited by its specificity to the antigen to which it responds, however, Applicants fail to admit it is the T cell’s TCR that is critical to, and responsible for, specificity of the T cell to the antigen to which it responds. Disclosure/claiming of the GATA3 antigen to which the cells bind and disclosure/claiming routine methods of producing T cells binding to the antigen complexed to HLA class I molecule do not support written description for the claimed T cell population for the reasons stated above. Examiner disagrees with Applicants and maintains the decisions regarding written description for antibodies is highly analogous and applicable to the instant claims, particularly given the significantly overlapping structure and nature of TCRs and antibodies.
11. All other objections rejections recited in the Office Action mailed June 26, 2025 are hereby withdrawn in view of amendments.
12. Conclusion: No claim is allowed.
Conclusion
13. THIS ACTION IS MADE FINAL. 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.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642