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 .
1. The Election filed May 21, 2026 in response to the Office Action of November 28, 2025 is acknowledged. Applicant elected without traverse Group I (claims 1-3, 5-7, 13, 15, 19, 20). Applicants elected with traverse the species of:
A. TCR alpha chain CDR3 SEQ ID NO:1; and
TCR beta chain CDR3 SEQ ID NOs:2.
B. TCR is soluble (claims 6).
C. TCR is humanized (claim 7).
It is noted that Applicants did not identify the corresponding alpha and beta chain amino acid sequences and nucleotide sequences in claims 3 and 5 encompassing the elected CDR3’s, as required by the restriction requirement on page 5, section A. It appears that SEQ ID NOs:25 and 49 encompass the elected species of alpha chain CDR3, and SEQ ID NOs:26 and 50 encompass the elected species of beta chain CDR3, therefore the claims will be examined according to these sequences.
2. Applicants argue that a search of the CDRs sequences would not unduly burden the Office during examination.
The arguments have been considered but are not persuasive. Search burden does not constitute grounds for restriction when considering lack of unity for applications filed as a National Stage entry under 35 U.S.C. 371. As stated in the restriction requirement of record, the claimed special technical feature of TCRs binding to KRAS G12V mutation does not make a contribution over the prior art. Further, Applicants have not persuasively argued the structurally distinct engineered TCRs share a special technical feature.
For these reasons, the restriction requirement is deemed to be proper and is therefore made FINAL.
3. Claims 1-3, 5-7, 13, 15, 19, 20, 27-30, 32, 35, 37, 38, and 41 are pending. Claims 27-30, 32, 35, 37, 38, 41 have been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 1-3, 5-7, 13, 15, 19, and 20 are currently under prosecution as drawn to the elected species.
Claim Rejections - 35 USC § 112
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.
4. Claims 6, 7, 13, 15, 19, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 recites:
The TCR of claim 1, wherein the TCR is further defined as a soluble TCR, wherein the soluble TCR
does not comprise a transmembrane domain,
or comprises transmembrane domain that is a CD28 transmembrane domain or a CD8a transmembrane domain,
or further comprises a T-cell signaling domain of any one of the following proteins: a human CD8-alpha protein, a human CD28 protein, a human CD3-zeta protein, a human FcRy protein, a CD27 protein, an OX40 protein, a human 4-1BB protein, or any combination of the foregoing.
Claim 6 is grammatically unclear with regards to which features are required and which features are optional for the claimed TCR. Claim 6 is also unclear with regards to what features it is specifically referring to when it recites “or any combination of the foregoing”. The metes and bounds of the claimed invention cannot be determined.
Claim 7 recites:
The TCR of claim 1, wherein at least one of:
the TCR further comprising a detectable label;
the TCR is humanized;
is covalently bound to a therapeutic agent, an immunotoxin or a chemotherapeutic agent;
does not recognize wild-type RAS,
and the CDR3 is selected from SEQ ID NO: 1, 3, 5 and a beta chain CDR3 having the amino acid sequence of SEQ ID NO: 2, 4, 6;
is part of a multivalent TCR complex comprising a plurality of TCRs;
or the multivalent TCR comprises 2, 3, 4 or more TCRs associated with one another; wherein the multivalent TCR is present in a lipid bilayer, in a liposome, or is attached to a nanoparticle;
or wherein the TCRs are associated with one another via a linker molecule.
Claim 7 is grammatically unclear with regards to which features are required and which features are optional for the claimed TCR. Wherein “at least one of” what? What is required? What is “covalently bound to a therapeutic agent, an immunotoxin or a chemotherapeutic agent”? What “does not recognize wild-type RAS”? Which CDR3 is the phrase “and the CDR3 is selected from SEQ ID NO: 1, 3, 5” referring to, the alpha chain or beta chain CDR3? What does the phrase “and a beta chain CDR3 having the amino acid sequence of SEQ ID NO: 2, 4, 6” mean? Is it referring to the beta chain of claim 1 or a different beta chain? Is it requiring a beta chain to have the amino acid sequence of all SEQ ID NOs:2, 4, and 6, or have the amino acid sequence of one of SEQ ID NOs: 2, 4, or 6? What is part of a multivalent TCR complex comprising a plurality of TCRs? What plurality of TCRs is the phrase referencing in “wherein the TCRs are associated with one another via a linker molecule”? The metes and bounds of the claimed invention cannot be determined.
Claim 13 recites the limitation "the polypeptide of claim 1". There is insufficient antecedent basis for this limitation in the claim. Dependent claims 15, 19, and 20 are rejected for encompassing the rejected limitation of claim 13.
Claim 15 recites:
The polynucleotide of claim 13, wherein
the expression vector encoding the TCR is under the control of a promoter, a viral or a retroviral vector,
or the vector further encodes a linker domain positioned between the alpha chain and beta chain,
or the linker domain comprises one or more protease cleavage sites,
or wherein the one or more cleavage sites are separated by a spacer.
Claim 15 is grammatically unclear with regards to which features are required and which features are optional for the claimed polynucleotide. Further, claim 15 is unclear with regard to what vector it is referencing in the phrase “or the vector further encodes a linker domain positioned between the alpha chain and beta chain” because the claim recites an expression vector, viral vector, retroviral vector, and encompasses the “vector or an expression vector” of claim 13.
Claim 20 recites:
The host cell of claim 19, wherein
the host cell is a T cell, NK cell, invariant NK cell, NKT cell, mesenchymal stem cell (MSC), or induced pluripotent stem (iPS) cell,
the host cell is an immune cell,
the T cell is a CD8+ T cell, CD4+ T cell, or γδ T cell,
the T cell is a regulatory T cell (Treg),
or the host cell is autologous or allogeneic.
Claim 20 is grammatically unclear with regards to which features are required and which features are optional for the claimed host cell. The metes and bounds of the claimed invention cannot be determined.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
5. Claims 15, 19, and 20 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 15 depends from claim 13. Claim 13 recites the polynucleotide is optionally in a vector or an expression vector. Claim 13 does not require the polynucleotide to actually be in a vector or in an expression vector, however, claim 15 further limits the expression vector of claim 15. Claim 15 further limits a feature that is not required to be present.
Claim 19 also depends from claim 13. Claim 19 further limits the expression vector of claim 13 as located in a host cell, however, no claims required the expression vector to be present in the invention. Claim 19 further limits a feature that is not required to be present.
Claim 20 encompasses the rejected limitations of claim 19.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
6. Claim 1 recites: “An engineered T cell receptor (TCR) comprising an alpha chain CDR3 having an amino acid sequence of SEQ ID NO:1”. This language is interpreted to mean the alpha chain CDR3 comprises any amino acid sequence as small as two consecutive amino acid residues (“an amino acid sequence”) found in (“of”) SEQ ID NO:1. Therefore, claim 1 broadly encompasses alpha chain CDR3 sequences comprising as few as two consecutive amino acid residues found in SEQ ID NO:1.
Claim 1 recites “wherein the TCR is specific for a KRAS G12V mutation peptide”. This language is interpreted to mean the TCR binds to a peptide comprising a KRAS G12V mutation, however, the TCR is not required to bind to the KRAS G12V mutation itself in the peptide.
Claim 1 recites that the TCR comprises an alpha chain CDR3 “and/or” a beta chain CDR3, therefore broadly encompasses TCRs having only one defined alpha chain CDR3 or one defined beta chain CDR3.
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.
7. Claims 1-3, 5-7, 13, 15, 19, and 20 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.
Claim 1 encompasses a vast genus of TCRs comprising an alpha chain with a CDR3 having as few as two consecutive amino acids defined from SEQ ID NO:1, or comprising a beta chain with a CDR3 defined as comprising SEQ ID NO:2; wherein the TCR functions to bind a peptide having a KRAS G12V mutation. Thus, the claims identify the genus of TCR by partial alpha chain CDR3 sequence or a beta chain CDR3 sequence, and function of binding to a peptide comprising a KRAS G12V mutation. The sequence structure of the CDR1 and CDR2 of the alpha and beta chains are unknown.
Claim 2 requires a TCR function of binding to a peptide comprising a KRAS G12V mutation complexed with HLA DRB5*01:01.
Claim 3 recites a partial sequence structure where the TCR can comprise an alpha chain sequence having up to 10% sequence discrepancy from SEQ ID NO:25 including within the CDR1, CDR2, and CDR3 regions critical to the claimed peptide binding function, or the TCR can comprise a beta chain sequence having up to 10% sequence discrepancy from SEQ ID NO:26 including within the CDR1 and CDR2 regions critical to the claimed peptide binding function.
Claim 5 is similar to claim 3, encompassing a vast genus of sequence variants having up to 10% sequence discrepancy to nucleotide sequences encoding the alpha or betas chains.
Thus, the claims encompass a vast genus of TCR variants defined by one partial alpha chain CDR3 sequence, or by a single CDR3 beta chain sequence, and a function, wherein the function is to bind a peptide having a KRAS G12V mutation, or bind a peptide comprising a KRAS G12V mutation complexed with HLA DRB5*01:01. No complete alpha chain CDR1, CDR2, and CDR3, and beta chain CDR1, CDR2, and CDR3 sequence structure is recited that is required to function as claimed.
The instant specification describes 12 isolated TCRs that bind to mutant KRAS in Tables 2-4, disclosing the full alpha and beta chain SEQ ID NOs and identifying the individual CDR3 sequences within the alpha and beta chains. These include TCR “66-4-KRAS-1” comprising alpha chain SEQ ID NO:25 containing CDR3 SEQ ID NO:1, and beta chain SEQ ID NO:26, containing CDR3 SEQ ID NO:2.
Thus, the instant specification structurally describes 12 exemplary structurally distinct TCRs, each comprising their own set of alpha and beta chain sequences critical to the mutant KRAS binding function. The specification fails to disclose the structural sequence required of any sequence variants of these TCRs that function as claimed.
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. 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. Figure 3.2 displays both TCR chains binding to the antigenic peptide displayed by MHC II of the APC:
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Thus, the state of the art recognizes that the six CDRs of the TCR alpha and beta chains are critical to recognizing and binding the peptide antigen presented by an APC with an HLA molecule, 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 genus of TCR sequences capable of binding an antigen presented with an HLA molecule is vast.
To provide adequate written description and evidence of possession of the claimed genus of TCRs, the instant specification can structurally describe representative TCRs that function to bind to a KRAS peptide comprising G12V mutation, 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.).
In this case, the only factor present in the claims is a recitation of peptide binding function and partial CDR3 sequence structure. 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 discloses only 12 exemplary structurally distinct TCRs comprising defined alpha and beta chain sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the TCR does, rather than what it is. Other than for the 12 exemplary TCRs disclosed, the specification fails to provide any structural features coupled to the claimed functional characteristics. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the variable domains or CDRs that can be altered and still maintain peptide/HLA binding function as claimed. Given the well-known high level of polymorphism of TCR CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of TCRs encompassed by the claimed invention. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for TCRs that bind the claimed peptide and HLA complex to function 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 TCRs yet to be discovered that may function as claimed. The KRAS mutant peptide antigen provides no information about the structure of a TCR that binds to it.
Given the lack of representative examples to support the full scope of the claimed TCRs, and lack of reasonable structure-function correlation with regards to the unknown sequences in the alpha and beta chain variable domains or CDRs that provide KRAS mutant peptide/HLA binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of an engineered TCR that is required to practice the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claim(s) 1, 7, 13, 15, 19, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent Application Publication 2017/0304421, Wang et al.
Wang teaches an engineered TCR comprising an alpha chain CDR3 comprising the amino acid sequence of SEQ ID NO:127 (CAVSGGTNSAGNKLTF), wherein the TCR binds to a KRAS mutant G12V peptide ([16]; [20]; [33]; [34]; [41]; [44]; [76]; claims 1-3). The TCR alpha chain CDR3 SEQ ID NO:127 of Wang comprises “an amino acid sequence of SEQ ID NO:1”, including amino acid sequences 2 to 4 amino acids long found in instant SEQ ID NO:1 (see sequence alignment below).
Wang further teaches the TCR comprises a detectable label or is conjugated to a therapeutic agent ([50]; [52]; [92]; [99]).
Wang further teaches a polynucleotide encoding the TCR, an expression vector comprising the polynucleotide, and a host cell or T cell engineered to express the expression vector, wherein the expression of the TCR is under the control of a promoter (claims 16-20; [5]; [52-75]; [93]).
Instant TCR alpha chain CDR3 SEQ ID NO:1aligned with Wang TCR alpha chain CDR3 SEQ ID NO:127:
Qy = instant SEQ ID NO:1
Db = Wang SEQ ID NO:127
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9. Claim(s) 1, 6, 7, 13, 15, 19, and 20 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2021/083363, Peng et al, claiming priority to October 30, 2020 (see English translation of description for reference).
Peng teaches an engineered TCR that binds to KRAS mutant peptide comprising G12V mutation, and comprises alpha chain CDR3 as listed in the table below, wherein the CDR3 of alpha chain SEQ ID NOs:1 and 6-8 comprise the amino acid sequence “AV” that is found instant SEQ ID NO:1 (CAVSVGPGNTGKLIF).
Peng teaches the TCR is soluble and does not comprise the transmembrane domain (p. 3, 6).
Peng further teaches the TCR comprises a detectable label or a therapeutic agent (p. 4).
Peng teaches a polynucleotide encoding the TCR, an expression vector comprising the polynucleotide, and a host cell or T cell engineered to express the expression vector, wherein the expression of the TCR is under the control of a promoter (p. 4, 12, and Examples).
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10. Conclusion: No claim is allowed.
11. 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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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