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 .
Claim Status
Claims 1-262 are cancelled. Claims 263-283 as filed on 27 February 2025 are pending and under examination.
Information Disclosure Statement
The information disclosure statement filed 02/19/2025 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because Foreign references A1 and A2 and NPL C2 are not attached. It has been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 263-267 and 274-283 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
Claim 263 is to a polypeptide comprising an antigen binding variable region comprising a CDR1, CDR2, and a CDR3 where the CDR 1, 2, and 3 of the table below or 1 amino acid substitution per CDR sequence.
CDR 1
CDR 2
CDR 3
SEQ ID NO:
5
6
7
SEQ ID NO:
12
13
14
SEQ ID NO:
19
20
21
SEQ ID NO:
26
27
28
SEQ ID NO:
33
34
35
SEQ ID NO:
40
41
42
Claim 264 requires the polypeptide comprises the variable CDR sets from claim 263 and at least 85% sequence identity with instant SEQ ID NO: 3, 10, 17, 24, 31, or 38. This would allow for variation in the CDRs as well.
Claim 265 requires the polypeptide of claim 263 comprises a T cell receptor alpha variable region comprising the CDRs of subparts a, c, and e and a TCR alpha constant region and/or a T cell receptor beta variable region comprising the CDRs of subparts b, d, and f and a TCR beta constant region. This claim does not provide any limit on either the alpha or beta chain sequences and still allows for variability in the CDRs of the partly defined alpha or beta regions.
Claims 266-267 and 277-283 does not provide any limitations on the CDRs of the polypeptide.
Claim 274 is to a method of producing a peptide specific effector cell where the TCR binds one of instant SEQ ID NO: 43, 44, or 45. The antigen binding target of the TCR does not provide any sequence or structure limitations for the TCR.
Summary of Species Disclosed in the original specification
Applicant discloses 3 TCRs with fully defined CDRs of the alpha and beta region shown in the table below from [0089] in the Specification.
CDR 1
CDR 2
CDR 3
CDR 1
CDR 2
CDR 3
TCR Alpha
TCR Beta
SEQ ID NO:
5
6
7
12
13
14
SEQ ID NO:
19
20
21
26
27
28
SEQ ID NO:
33
34
35
40
41
42
State of the Relevant Art
The TCRs disclosed by the applicant bind FANCI, RAD51, or PBK (Examples 1-3 of Specification). Fancomi anemia complementation group I (FANCI) protein is associated with the chromosomal instability disorder Fanconi anemia (abstract) and functions in ICL repair and replication stress response (Figure 1). It is now known to be mutated in cancer (Figure 1). RAD51 is a related protein involved in fork stabilization and homologous recombination and regulated by BRCA1 (Figures 1-2). (Niraj et. al. Annu. Rev. Cancer Biol. 3:457-478. (2019) (PTO-892).
PDZ-binding kinase (PBK) is a 322 amino acid and mitogen activated serine/threonine protein kinase. It is present in healthy tissue but found upregulated in cancer tissues including breast cancer, lymphoma, and bladder cancer (Zhang et al. Journal of Cancer. 10:131-137 (2019) (PTO-892) (abstract and page 131 in col 1 in par 1).
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) (PTO-892). 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 three TCRs comprising alpha and beta regions with fully defined CDRs of the alpha and beta
Given the variability encompassed by the genus of polypeptides comprising partially defined CDRs and no binding target required the three disclosed species therefore cannot be considered representative of the genus.
Claims 263-264, 267, and 277-283 are broadly to any polypeptide comprising at least 3 CDRs where the sequences of those CDRs can have one substitution in each CDR.
Claim 265 requires either a TCR alpha or beta variable region with half the CDRs of the TCR fully undefined and each defined CDR allowing for at least one amino acid substitution.
Claim 274 has no limitations on the CDRs of the TCR and the disclosed three TCRs would provide no information on the additional members of the genus within the scope of claim 274.
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 variable regions. A set of 6 CDRs provides the structure and function of only that set of CDRs. A partial sequence of CDRs does not provide a structure/function correlation as changes to the CDRs change the structure and alter the binding function in unpredictable ways. The antigen binding target as required by claim 274 would provide no structure for the TCR produced by that method.
Conclusion:
One of skill in the art would not know which of the CDR combinations that fall within the scope of the claims would have antigen binding activity. The three disclosed species of TCRs with fully defined CDRs do not provide a representative number of species for the genus of the claims. The structure/function correlation of antigen binding is from a fully defined set of 6 CDRs. There is then no representative number of species and no structure/function correlation. 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.
Claim 268 is not included in this rejection as it is limited to TCR that comprise fully defined alpha and beta variable region CDRs.
Allowable Subject Matter
Claims 268-273 allowed.
The claims are to an engineered TCR comprising a TCR alpha and TCR beta polypeptide that comprise one of the CDR combinations shown in the table below.
CDR 1
CDR 2
CDR 3
CDR 1
CDR 2
CDR 3
TCR Alpha
TCR Beta
SEQ ID NO:
5
6
7
12
13
14
SEQ ID NO:
19
20
21
26
27
28
SEQ ID NO:
33
34
35
40
41
42
The closest prior art is Zhou (WO 2019196088 A1) (IDS). Zhou teaches tumor specific T cell receptors (abstract) including ones that bind antigens associated with breast cancer including mutations in RAD51 ([0300]). Zhou then teaches TCRs that bind cancer antigens including RAD51 which one of the TCRs of the claims binds.
Zhou does not teach the CDRs of the TCR alpha and beta variable region of claims 268-273. Changes to the CDRs of the TCR alpha and beta variable region would change the binding activity of the TCR in unpredictable ways meaning the CDRs of claims 268-273 are not obvious over Zhou either alone or in combination with other art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA EDGINGTON-GIORDANO whose telephone number is (571)272-8232. The examiner can normally be reached Mon - Fri 8:00 - 5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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