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
1. The response filed on 6/15/2026 to the restriction requirement of 5/1/2026 has been received. Applicant has elected for examination of Group I and the species of a TCR α chain as set forth in SEQ ID NO: 1 and a TCR β chain as set forth in SEQ ID NO: 2 having a T63I mutation. Because Applicant did not distinctly and specifically point out any errors in the restriction requirement, the election has been treated as an election without traverse (MPEP 818.03(a)). Claims 1-20 are pending. Claims 5-8 and 11-20 have been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 1-4 and 9-10 are currently under prosecution as drawn to the elected species.
Priority
2. Application claims the benefit and priority as a Continuation application of PCT/IL2021/050959 filed on 8/6/2021 which claims the benefit of foreign application IL276599 filed on 8/9/2020. No certified copy of application IL276599 has been received. Therefore, priority is granted to PCT/IL2021/050959 and the effective filing date of 8/6/2021.
Claim Interpretation
3. The examiner’s broadest reasonable interpretation of the claims is set forth below.
Claim 1 recites:
“A T cell receptor (TCR) comprising a TCR α chain as set forth in SEQ ID NO: 1 having at least one mutation at an amino acid position selected from the group consisting of S189, G125, W55 and Y56; and/or a TCR β chain as set forth in SEQ ID NO: 2 having at least one mutation at an amino acid position selected from the group consisting of S32, S109 and T63, the TCR binds a MAGE-A1 peptide as set forth in SEQ ID NO: 25.”
The phrase “A T cell receptor (TCR) comprising a TCR α chain as set forth in SEQ ID NO: 1…; and/or a TCR β chain as set forth in SEQ ID NO: 2,” is reasonably interpreted as a TCR comprising a TCR α chain or a TCR β chain that binds the MAGE_A1 peptide of SEQ ID NO: 25.
Allowable Subject Matter
4. Claim 3 is 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.
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.
5. Claims 1-2, 4, and 9-10 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 claims contain 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.
The claims are drawn to a T cell receptor (TCR) comprising a TCR α chain as set forth in SEQ ID NO: 1 comprising at least one mutation at an amino acid position selected from the group of S189, G125, W55, and Y56 or a TCR β chain as set forth in SEQ ID NO: 2 having at least one mutation at an amino acid position selected from the group consisting of S32, S109, and T63, that binds a MAGE-A1 peptide as set forth in SEQ ID NO: 25.
Claim 4 further recites the TCR of claim 1 as having the function of “increased avidity to said MAGE-A1 peptide as compared to a TCR having a TCR alpha chain of SEQ ID NO:1 and TCR beta chain of SEQ ID NO:2.”
Thus, the claims encompass the genus of a TCR construct by the function of binding MAGE-A1 peptide of SEQ ID NO: 25 at an increase avidity to a wildtype TCR and a partial sequence structure of either an alpha chain comprising SEQ ID NO: 1 with at least one amino acid substitution located at S189, G125, W55, or Y56 with the substitution of any amino acid; or the beta chain comprising SEQ ID NO: 2 with at least one amino acid substitution located at S32, S109, or T63 with the substitution of any amino acid. Thus the claims encompass a vast genus of TCR variants comprising either a variable TCR α or a variable TCR β chain that function to bind MAGE-A1 peptide with an increased avidity as compared to a TCR having the alpha chain of SEQ ID NO: 1 and the beta chain of SEQ ID NO:2.
The instant specification discloses the generation of 11 different somatic hypermutations in the TCR construct that lead to 8 different amino acid substitutions in both the alpha and beta chains that function to increase the avidity of the TCR over the wild type TCR (See pg. 59 lines 17-18). Additionally, the instant specification only discloses one TCR, m9, that incorporates more than one mutation. See Table 1B from page 62 of the instant specification, below:
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406
680
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The instant specification discloses that although all the mutations do not directly affect the binding regions, they influence the flexibility and conformation of the CDR regions. As stated on page 65:
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371
671
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Thus, the instant specification discloses 8 different TCR constructs comprising an alpha and a beta chain from the hT27 wild type TCR comprising distinct specific mutations on the alpha chain of S189G, G125A, G125V, W55L, or Y56F, and the beta chain of S32T, S109N, or T63I that function to increase the avidity of the TCR for MAGE-A1 peptide as compared to the wild-type TCR. The specification fails to disclose any other mutations of the positions of S189, G125, W55, or Y56 of SEQ ID NO:1 or S32, S109, or T63 of SEQ ID NO:2 amino acid sequence that could be substituted and increase the avidity to the MAGE-A1 peptide.
Alli et al., (PLoS ONE, 2011, 6(3):e18027) demonstrated the effect and sensitivity of a single amino acid substitution can have on TCR antigen binding. In their study, a single substitution of a G at position 107 within the CDR3β stalk to an S allowed for the stability of the CD3β loop due to the hydroxymethyl side chain intercalating with the core of the CD3β loop. This single amino acid substitution led to a 10-1000 fold sensitivity in the majority of the mutated TCR tested. (See Alli, abstract).
To provide adequate written description and evidence of possession of the claimed TCR genus, the instant specification can structurally describe representative TCR variants that function to increase the avidity to MAGE-A1, or describe structural features common to the members 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 the TCR function to bind a MAGE-A1 peptide at an increased avidity as compared to a wild-type TCR, and the partial amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 and the location of seven amino acids that could be substituted to any other amino acid. The instant specification fails to describe structural features common to the members of the TCR genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative TCR variants for the mutated alpha and beta chains 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 the mutated TCR chains disclosed in Table 1B, the specification fails to provide the structural features of the alpha and beta chains coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of TCR sequence variants for the genus of TCRs 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 required to make the claimed TCR constructs.
The claims broadly encompass a TCR construct with an alpha chain and at least one amino acid substitution from four different locations of any amino acids, or a beta chain and at least one amino acid substitution from three different locations of any amino acids that function to bind MAGE-A1 as set forth in SEQ ID NO: 25 with an increased avidity as compared to a wild-type TCR comprising an alpha and a beta chain. Applicants have not established any reasonable structure-function correlation with regard to the use of one alpha chain or one beta chain that could be used and increase avidity to bind MAGE-A1. Applicants have not established any reasonable structure-function correlation with regard to the amino acid substitutions that could be used and still maintain MAGE-A1 binding function. Applicants have not established any reasonable structure-function correlation, outside of the disclosed substitutions above, with regard to the amino acid substitutions that could be used and increase the binding avidity over wild-type TCR that binds MAGE-A1. Given the well-known high level of polymorphism of TCR sequence and structure as related to binding affinity and demonstrated by Alli et al., the skilled artisan would not have been in possession of the vast repertoire of TCR constructs encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single TCR construct comprising the alpha chain of SEQ ID NOs: 1 with a mutation at S189, G125, W55, or Y56, or the beta chain of SEQ ID NO: 2 with a mutation at S32, S109, or T63 to the structure of any variants required increase the avidity to MAGE-A1 as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for TCR that binds MAGE-A1 and 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 TCR yet to be discovered that may function as claimed. The MAGE-A1 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 variant TCR constructs, and lack of reasonable structure-function correlation with regards to the unknown variable sequences in the amino acid substitutions that function to increase the avidity of binding to MAGE-A1, the present claims lack adequate written description.
Thus, the specification does not provide an adequate written description of TCR variants that increase the avidity for binding to MAGE-A1 and comprise a TCR alpha chain with four potential amino acid substitutions to any amino acid or a TCR beta chain with three potential amino acid substitutions to any amino acid that is required to practice the claimed invention.
Examiner Suggestion: Examiner suggests amending claim 1 to incorporate the limitations of claim 3.
Prior Art
6. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Obenaus et al. (Nature Biotechnology, 2015, 33(4):402-409) discloses a T cell expressing a TCR comprising SEQ ID NO: 1 and SEQ ID NO:2, hT27, that binds the MAGE-A1 peptide of SEQ ID NO: 25 and the ability to encode the TCR in a polynucleotide and express the TCR through a genetically engineered T cell. (See pg. 406, “Accession Codes. GenBank: hT27:KM501069; also pg. 408 “TCR gene transfer”). Obenaus is not cited as prior art because it does not disclose the hT27 amino acid structure being mutated at the positions of S189, G125, W55, Y56 in the sequence corresponding to SEQ ID NO:1 or the positions of S32, S109, or T63 in the sequence corresponding to SEQ ID NO:2.
Conclusion
7. Claim 3 is objected to based on dependency. Claims 1-2, 4, and 9-10 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LINDSAY DUNN whose telephone number is (571)272-5825. The examiner can normally be reached Monday-Friday 8-4:30.
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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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/LINDSAY DUNN/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642
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