DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 16 January 2026 is acknowledged.
Claim 25 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 16 January 2026.
Applicant’s election without traverse of a binding molecule comprising CDRα1-3 of SEQ ID NO: 38, 39, 41 with CDRß1-3 of SEQ ID NO: 35, 44, and 45 in the reply filed on 16 January 2026 is acknowledged.
Claim Status
Claims 22-23 are cancelled. Claims 1-21 and 24-25 as filed on 16 January 2026 are pending. Claim 25 are withdrawn. Claims 1-21 and 24 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Sequence identifiers improperly written in specification by use of “SEQ ID No:” instead of “SEQ ID NO:”. This occurs on page 2 in lines 5-8, page 4 in lines 39-40, page 5 in lines 2-4 and 39-40, page 6 in lines 2-3, page 7 in lines 34-36 and the table onto page 8.
There are sequences without a SEQ ID NO: on page 5 in lines 11-15, page 6 in lines 5-24 and lines 26 and 31, page 8 in lines 20-24 and line 33, page 11 in lines 25, 27, and 31.
Please review entire specification to correct all errors in sequence identification.
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.
Claims 1-21 and 24 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.
Claims 1, 4-5, and 7 identifies a sequence by “SEQ ID No:” instead of “SEQ ID NO:”.
Claim 6 and 14 identifies “SEQ ID NOs:” instead of “SEQ ID NO:”.
By not properly incorporating the sequences from the sequence listing the claims are indefinite as the metes and bounds of the required sequence are unclear.
The dependent claims fail to correct the deficiency and are also rejected.
Claims were examined as reciting “SEQ ID NO:”.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 8-13, 15, 17-21, and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the Claimed Genus
The claims are to a specific binding molecule that binds SEQ ID NO: 1 of HLA-A*11 that comprises a TCR alpha or a TCR beta chain variable domain wherein the alpha chain.
Claim 1 has the defined CDR sequences of the alpha chain as SEQ ID NO: 32-34 and the CDRs of the beta chain as SEQ ID NO: 35-37. The claim allows for one or more mutations of these sequences meaning the claim does not define any amino acid of the CDRs. Claim 1 also requires only an alpha or beta chain of the sequences that can be mutated at one or all amino acids of the CDRs.
Claim 2 defines the framework sequences and does not provide any further limitations for the CDRs.
Claim 3 is limited to 20 specific amino acid substitutions in the alpha chain and 7 amino acid substitutions in the beta chain. The claim allows either the alpha or beta chain sequence. The claim also includes any combination of the mutations listed.
Claim 4 provides specific combinations for CDRs for the alpha or beta chain but does not require both the alpha and beta chain CDR sequences allowing for unlimited combinations of CDRs.
Claim 5 only provides CDR sequences for the alpha chain and does not provide limitations for the beta chain.
Claims 8-13, 17-21, and 24 provide no limitations to the TCR CDRs.
Claim 15 allows for 90% identity allowing for mutation to the CDRs of the alpha and beta chain.
The limitation of the epitope of SEQ ID NO: 1 does not provide any structure for the TCRs and the limitation in the claims does not provide written description for the structure of the TCR CDRs which provide its binding activity.
Summary of Species Disclosed in the original specification
Applicant discloses TCRα chains of SEQ ID NO: 2, 4, 5, and 6 and the TCRß chains of SEQ ID NO: 3, 7, and 8 (Figures 1-2). Applicant only discloses the functional pairing of alpha chain of SEQ ID NO: 2 with beta chain SEQ ID NO: 3, alpha chain of SEQ ID NO: 4 with beta chain SEQ ID NO: 7, alpha chain of SEQ ID NO: 5 with beta chain SEQ ID NO: 8, and alpha chain of SEQ ID NO: 6 with beta chain SEQ ID NO: 8 (Figures 1 and 3-7).
Applicant further discloses these TCRs in anti-CD3 fusions (Figure 3).
State of the Relevant Art
It is well established in the art that the formation of an intact antigen-binding site in a TCR usually requires the association of the complete alpha and beta chain variable regions of a given TCR, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the TCR to its target peptide-MHC (pMHC) complex (e.g. Figure 4 of Rudolph, M. et. al. “How TCRs Bind MHCs, Peptides, and Coreceptors”, 2006 Ann. Rev. Imm. Vol. 24:419-446) (PTO-892). While it is recognized that the CDR3 of each chain contributes the most to binding a specific peptide, CDR1 and 2 most strongly affect binding to the MHC and can affect the orientation of TCR binding relative the MHC groove as well as the contact between CDR3 and the peptide (see Table 2 rows 12 and 14 and page 449 paragraph 2, Figures 9-10). This peptide-determining CDR3 contact is formed by the contribution of both the alpha chain and the beta chain. Additionally, a study to increase antigen binding has shown that, unpredictably, mutations in all 6 CDRs can contribute to increases in affinity (Chlewicki et. al. “High-affinity, Peptide-specific T Cell Receptors can be Generated by Mutations in the CDR1, CDR2, or CDR3” Journal of Mol. Biol. 2005 Pages 223-239) (IDS). Further, binding may require a difficult-to-predict structural change which may require conformational changes of CDR1 and 2 (See Rudolph page 439 paragraph 2). Thus, the prediction of CDR binding to the epitope is difficult to predict. Rudolph et. al. also teaches that although there may be a common docking model for TCR/pMHC binding, the structures determined have not revealed the basis for MHC restriction (page 456, paragraph 3).
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification discloses 4 TCRs with fully defined alpha and beta chains in 6 fusions with anti-CD3 binding domains.
Given the variability encompassed by the genus of TCR that bind HLA-A*11 with each amino acid change in the CDRs able to change the binding activity of the TCR the described species therefore cannot be considered representative of the genus.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
The structure of the TCR that provides its function of binding is from the structure of CDR sequences of the alpha and beta chain. The TCR epitope does not provide structure and a partial sequence of CDRs does not provide a structure/function correlation.
Conclusion:
For all of the reasons presented above, one of skill in the art would not know which of the countless other compositions encompassed by the claims that meet the highly general structural requirements of the claims would also possess the required functional activity. Therefore, the skilled artisan would not reasonably conclude that the inventors had full possession of compositions as broadly claimed at the time the application was filed. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
Claims 6-7, 14, and 16 are not including in this rejection because they require fully defined CDRs in the alpha and beta chain.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 17-21, and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et. al. Cancer Immunol Res 4(3):204-214. (2016) (IDS), as evidenced by Thomas et. al. Nature Communications. 10:1-15. (2019) (PTO-892) and Lefranc. Front. Immunol. 5:1-22. (2014) (PTO-892).
Claim 1 allows for one or more mutation of the alpha and beta chain sequences listed meaning so CDR sequences are required for claim 1.
Regarding claim 2, Wang teaches TRAV19*01 framework sequences (page 209 in col 1 in par 2-3)
Wang teaches a TCR that binds HLA-A*11:01 KRAS variant G12D which is the sequence of instant SEQ ID NO: 1 (abstract and page 206 in col 1 in par 5).
The structure required by claim 1 of framework and CDRs is the structure of TCRs as evidenced by Thomas (Abstract and Figure 1) and Lefranc (Figures 2-3 and Table 4).
Regarding claim 12, Wang teaches the use of FACS to detect the TCRs wherein the TCR is bound by anti-murine TCR-ß antibodies (page 206 in par 1-2) and further teaches the labeling the TCR in tissue samples (page 206 in par 3).
Regarding claims 17-20 and 24, Wang teaches the insertion of nucleic acid sequences encoding the TCR into a vector and transducing of cells encoding the vector (page 205 in col 2 in par 2-4 and page 206 in col1 in col 1 in lines 1-13).
Regarding claim 21, Wang teaches the administration as a therapeutic to a mouse which would inherently be a pharmaceutical composition (page 206 in col 1 in par 3).
Claim Rejections - 35 USC § 103
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.
Claims 1 and 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et. al. Cancer Immunol Res 4(3):204-214. (2016) (IDS) and Mahr (US 2016 0280752 A1) (PTO-892), as evidenced by Thomas et. al. Nature Communications. 10:1-15. (2019) (PTO-892) and Lefranc. Front. Immunol. 5:1-22. (2014) (PTO-892).
The teachings of Wang, Thomas, and Lefranc from the 102 rejection are incorporated here in full.
Claim 1 allows for one or more mutation of the alpha and beta chain sequences listed meaning so CDR sequences are required for claim 1.
Wang teaches a TCR that binds HLA-A*11:01 KRAS variant G12D which is the sequence of instant SEQ ID NO: 1 (abstract and page 206 in col 1 in par 5).
The structure required by claim 1 of framework and CDRs is the structure of TCRs as evidenced by Thomas (Abstract and Figure 1) and Lefranc (Figures 2-3 and Table 4).
Wang does not teach the constant regions used in their TCR.
This deficiency is filled by Mahr.
Mahr teaches TCRs comprising a TRAC alpha chain with a TRBC1 or TRBC2 chain wherein the constant regions are joined by a non-native covalent disulphide bond. Mahr further teaches a single-chain T-cell receptor ([0205], [0308]).
Mahr teaches use of mutated KRAS in cancer ([0018] and [0044]).
Mahr teaches the agent can be conjugated to a second active molecule including an anti-CD3 ([0259]).
It would have been obvious at the time the application was filed to substitute the generic constant regions of the TCRs of Wang with the TCR constant regions of Mahr that are taught for use in TCRs that target KRAS mutants in cancer. The substitution of generic structures for specific known functional species of those structures would have been prima facie obvious to one of skill in the art. There would have been a reasonable expectation of success as both Wang and Mahr are teaching TCRs that are used therapeutically in cancer patients.
Claims 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et. al. Cancer Immunol Res 4(3):204-214. (2016) (IDS) and Lefranc and Lefranc. The T Cell Receptor: FactsBook. Academic Press. (2001). (“Lefranc 2001”) (IDS), as evidenced by Thomas et. al. Nature Communications. 10:1-15. (2019) (PTO-892) and Lefranc. Front. Immunol. 5:1-22. (2014) (PTO-892).
The teachings of Wang, Thomas, and Lefranc from the 102 rejection are incorporated here in full.
Claim 1 allows for one or more mutation of the alpha and beta chain sequences listed meaning so CDR sequences are required for claim 1.
Regarding claim 2, Wang teaches TRAV19*01 framework sequences (page 209 in col 1 in par 2-3)
Wang does not teach the specific framework sequences of TRAV19*01 and TRAJ28*01 of the alpha chain and TRBV6-2/3*01 and TRBJ1-6*02 which are the sequences of claim 2.
This deficiency is filled by Lefranc 2001.
Lefranc 2001 teaches the TCR framework of TRAV19*01 and TRAJ28*01 of the alpha chain and TRBV6-2/3*01 and TRBJ1-6*02 as known TCR receptors for use (page 3 in par 1-2).
It would have been obvious at the time the application was filed to substitute the generic framework sequences of Wang in a TCR that binds a RAS mutant with the known in the art functional TCR framework sequences of Lefranc 2001. One of skill in the art would have been motivated to complete the TCR structure with the obvious substitution of generic TCR pieces with specific known functional pieces. There would have been a reasonable expectation of success as Lefranc 2001 teaches functional TCR frameworks.
Conclusion
No claims allowable.
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/F.E./Examiner, Art Unit 1643
/Meera Natarajan/Primary Examiner, Art Unit 1643