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 1 in the reply filed on 6/17/2026 is acknowledged. Applicants have amended all claims directed to T-cell Receptor D. (see specification on pages 66 and 83).
Claims 1, 3, 7, 13-16, 21, 23, 26, 28-29, 32-34, 37, 42, 66-67, and 69-70 are pending and are currently under consideration.
Specification
The disclosure is objected to because of the following informalities: The brief description of Fig. 3 has several references to colored items. For example, the specification teaches:
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Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Applicants are reminded that color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification: Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Drawings
The drawings filed 10/27/2023 are objected to for the following reasons:
FIG. 4A-4B is not sufficiently distinct. This could result in a printer query should the application pass to the issues branch resulting in delayed prosecution. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined. The weight of all lines and letters must be heavy enough to permit adequate reproduction. This requirement applies to all lines however fine, to shading, and to lines representing cut surfaces in sectional views. See 37 CFR 1.84
FIG 5 is not sufficiently distinct. For example, see the X-axis.
FIG 12 is not sufficiently distinct.
Additionally, FIG 12 denotes an amino acid sequence (VLHDDLLEA) that lacks a proper sequence identifier. See 37 CFR 1.821(c). 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.
Claim Objections
Claim 70 is objected to because of the following informalities: The claim appears to be missing the word “with” after the word “diagnosed”. Appropriate correction is requested.
Additionally, several of the amended claims end with semicolons. See for example Claims 1, 3, and 7. Ending the claim with a period would obviate this objection.
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.
Claims 1, 3, and 7 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.
Claims 1, 3, 7 recites the limitation "or Vγ" in Claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claims 1, 3, 7 recites the limitation "or Vδ" in Claim 1. There is insufficient antecedent basis for this limitation in the claim.
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, 7, 13-14, 16, 21, 23, 26, 28-29, 34, 37, 42, 66-67, and 69-70 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. This is a written description rejection.
Claim 1 is broadly drawn to a pair of nucleic acid sequences encoding a T-cell receptor or antigen-binding fragment thereof that (1) recognizes a minor histocompatibility antigen HA-1 peptide of SEQ ID NO:354 and (2) comprises a CDR3 of SEQ ID NO:51 in the Vα region and CDR3 comprising SEQ ID NO:57 in the Vβ region. The claims are further broadly drawn to nucleic acids encoding a TCR that have 90% identity to SEQ ID NO:52 (Variable alpha) and 90% identity to SEQ ID NO:58 (Variable beta). See Table 2 on page 83. Thus, the claims encompass a genus of encoded TCRs that are only defined structurally by either complementary determining region 3 (CDR3s) or by being at least 90% similarity to the Vα region and Vβ region while retaining the ability to recognize the claimed HA-1 antigen. The specification teaches [0085] that CDRs within the variable region of a TCR chain generally have more variability compared to their framework (FRs) regions. Further, CDR-3 is the main CDR responsible for antigen binding or specificity or is the most important among the three CDRs on a give TCR variable region for antigen recognition, and/or for interaction with the processed peptide portion of the peptide-MHC complex. However, in the absence of claims defining the CDRs 1-3 of the alpha and beta chains of the TCR that specifically recognize the claimed peptide, the specification does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire genus of potential TCRs.
For example, 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). Thus, claims to 90% similarity could include mutations in the CDR1 and CDR2 regions. 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 to 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. 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).
Additionally, in the field of T cell receptor biology, including in the instant application, specific binding of the TCR to MHC is often defined by the biological function of T cell activation. For example, FIG. 10 shows an IL-2 secretion assay, wherein the functionality of Jurkat T cells transduced with HA-1 targeting TCRs was assessed in the presence of APCs presenting the target "H" peptide. Rudolph et. al. teaches that thus far, determined CDR structures do not explain the large biological differences that arise from altered peptide ligands (page 448, paragraph 4), indicating the unpredictability of the CDR/MHC interaction to cause T cell activation.
A description of a genus may be achieved by means of a recitation of a representative number of species, defined by structure, falling within the scope of the genus. However, the instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of TCRs that recognize the HA-1 peptide with only CDR3 claimed or that have mutations in CDRs 1 or 2 (encompasses 90% similarity). Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the claiming to a genus of TCRs specific for a peptide is insufficient to describe the large genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe and enable the genus as broadly claimed.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the genus of T-cell receptors that would predictably bind to the claimed HA-1 peptide, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
Allowable Subject Matter
Claims 15, 32-33 are objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Additionally, claim 3, if rewritten in independent form, would be allowable assuming the antecedent basis issue is resolved.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. WO 2020/030631 (Ellinger et al., published February 2020, IDS) teaches TCRs that bind VLHDDLLEA (SEQ ID NO:2 of the prior art) but did not anticipate the currently claimed alpha and beta domains of the TCR.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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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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/GARY B NICKOL/Primary Examiner, Art Unit 1643
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