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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 03/23/2023, is a 371 filing of PCT/EP2021/076324, filed 09/24/2021, and claims foreign priority to EP 20198096.8, filed 09/24/2020.
Status of Application, Amendments, and/or Claims
Applicant’s amendment of 05/20/2026 is acknowledged. Claims 1-2, 4-5, 14, and 16-18 are amended and claims 6-8, 10, 15, and 20 are cancelled. Claims 1-5, 9, 11-14, 16-19, and 21-23 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 11/20/2025,
The sequence disclosure was objected to. Applications amendment to Figure 5, the abstract, and the specification to include SEQ ID NOs for the recited sequences has overcome the objection and the objection is withdrawn.
The abstract was objected to. Applicant’s amendment to remove legal phraseology from the abstract has overcome the objection and the objection is withdrawn.
Claim 8 was rejected under 35 USC 112(b). The cancellation of the claim has rendered the rejection moot and the rejection is withdrawn.
Claim 10 was rejected under 35 USC 112(d). The cancellation of the claim has rendered the rejection moot and the rejection is withdrawn.
Claims 2, 6-8, 10, 15, and 20 were rejected under 35 USC 112(a) written description. Applicant’s amendment to claims 1 and 2, which result in the claim to all 6 TCR CDRs with 100% identity, has overcome the rejection of claim 2 and the rejection is withdrawn. The cancellation of claims 6-8, 10, 15, and 20 has rendered the rejection of these claims moot and the rejections are withdrawn.
Claims 14, 16-18, and 20 were rejected under 35 USC 112(a) scope of enablement. Applicant’s amendment to the claim to recite “ameliorating” in place of “treating” has overcome the rejections and the rejections are withdrawn.
The following grounds of objections and rejections are modified as necessitated by applicant’s amendment to the claims.
Specification Objection
The specification is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Page 54, line 14, recites the following hyperlink. The non-top level domain portion of the hyperlink is bolded for clarity: www.ebi.ac.uk/ipd/imgt/hla/
It is noted that, in the amendment filed 05/20/2026, the prefix “http://” has been removed. The hyperlink; however, still comprises non-top-level browser-executable code as bolded above.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)- Written Description
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, 3-5, 9, 11-14, 16-19, and 21-23 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.
The instant claims are drawn to a genus of TCRs claimed as being capable of binding to a polypeptide comprising an amino acid sequence of SEQ ID NO: 2 or to the HLA-A bound form of said polypeptide.
Claim 1 recites that the TCR comprises (A) a CDR3 of the alpha chain comprising the amino acid sequence of SEQ ID NO: 12, and a CDR3 of the beta chain comprising the amino acid sequence of SEQ ID NO: 14, or (B) a CDR3 of the alpha chain comprising the amino acid sequence of SEQ ID NO: 40, and a CDR3 of the beta chain comprising the amino acid sequence of SEQ ID NO: 42.
Claim 1 is drawn to genus of TCRs limited by only the alpha and beta chain CDR3 and the functional limitation of binding to SEQ ID NO: 2. The claim encompasses TCRs with any alpha CDR1 and CDR2 structures.
Claims 4 and 5 further require that the TCR of claim 1 perform the functions of inducing IFN-gamma secretion by cells comprising the TCRs and that the IFN-gamma secretion of the cells comprising the TCR be at least 5-fold higher compared to control cells that do not comprise the TCR.
Claims 14 and 16-19 all further require that the TCR of claim 1, a nucleic acid molecule encoding the TCR, a vector comprising the nucleic acid molecule, or a host cell comprising the TCR perform the claimed function of ameliorating or detecting cancer.
As such, claims 4, 5, 14, and 16-19 recite further functions required of the TCR recited in claim 1, which as discussed above, is limited by the recited alpha and beta chain CDR3s.
The instant claims encompass TCRs with any alpha CDR1 and CDR2 structures and require that the TCRs perform the claimed functions.
The instant disclosure, however, does not provide a representative number of species of the claimed genus performing the claimed functions, particularly in the absence of a full complement of 6 CDRs, specifically 3 from the alpha chain variable region and 3 from the beta chain variable region.
The examples of the instant disclosure describe an in vitro priming approach used to isolate PRAME 301-309 specific HLA-A24 restricted TCRs (page 54, Example 1). In the example, monocytes derived from HLA-A*24:02 negative healthy donors and corresponding mDCs were produced using a suitable maturation cocktail and electroporated with ivtRNA encoding for PRAME and the HLA-A*24 molecule. The prepared mDCs were subsequently co-cultured with CD8+ T cells and after 14 days PRAME 301-309 specific T cells were identified and the TCR was sequenced.
The examples detail the evaluation of antigen specificity for TCR T402-93 or TCR T116-49 and discloses that both recognized the specific PRAME 301-309 peptide as well as PRAME-transfected LCL (page 55, lines 15-20). The examples further tested killing mediated by the two TCRs and functional avidity of the TCRs (pages 56-57, Examples 3-4). Example 6 tested recognition of mismatched peptides in which mutations were made in the wild-type peptide of PRAME 301-309 (SEQ ID NO: 2). In table 2 of the example (page 58) there is a list of the five mismatched peptides out of 52 tested peptides that were recognized by either T402-93 or TCR116-49 transgenic T cells.
Table 1 on pages 41-42 disclose that T402-93 and TCR116-49 comprise the following sequences:
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These TCRs, with 100% identity in the full complement of the 6 CDRs (three from the alpha chain and 3 from the beta chain) represent the TCRs that applicant was in possession of at the effective filing date of the claimed invention.
The two TCRs sequenced and tested by applicant in the disclosure are not representative of the entire claimed genus which limits the claimed TCRs by only the alpha and beta CDR3 sequence The disclosure also does not provide a structure function correlation which would allow for the predictable identification of which TCRs within the claimed genus would perform the claimed function(s).
The state of the art around the effective filing date of the claimed invention also does not provide a representative number of species or a predictable structure-function relationship to support the full scope of the claimed genus. Rather, the art suggests that TCR binding was not predictable such that CDRs could mutated or be paired together resulting in predictable function.
For instance, Wong, W.K., et al (2019) Comparative analysis of the CDR loops of antigen receptors Frontiers in immunology 10(2454); 1-11 teaches that for both antibodies and TCRs, the main determinants of target recognition are the complementarity-determining region (CDR) loops. Five of the six CDRs adopt a limited number of backbone conformations, known as the “canonical classes”; the remaining CDR (β3 in TCRs and H3 in antibodies) is more structurally diverse (abstract). In TCRs, CDR1 and CDR2 typically contact the MHC’s conserved α-helices, while the CDR3 almost always contacts the peptide antigen. The structural complementarity between the binding sites of the antigen receptor and their cognate antigen governs the binding interactions. As the CDRs form the majority of the binding site, their conformations are critical to the binding (page 2, left column, paragraph 1).
Wong studied canonical forms in TCRs and built an auto-updating sequence-based prediction tool and compared TCR CDRs to antibody CDRs (abstract). Wong teaches that the fact that nearly 20% of the TCR CDRs that could show different conformations did so, suggests that the canonical class model will struggle to accurately predict TCR CDR conformations (page 7, right column, paragraph 5).
Jokinen, E., et al (2021) Predicting recognition between T cell receptors and epitopes within TCRGP PLOS Computational Biology 17(3); e1008814; 1-27 teaches that to initiate an adequate adaptive immune response, a peptide, called an epitope, must first be bound by the major histocompatibility complex (MHC) class I or II molecule expressed on the surface of a nucleated cell or a professional antigen-presenting cell, respectively. The peptide-MHC complex is then presented to T cells which can recognize the complex via the TCR proteins, consequently leading to T cell activation and proliferation (page 2, paragraph 1). The CDRs of a TCR determine whether the TCR recognizes and binds to an antigen or not. Of these, CDR3 is the most variable and primarily interacts with the peptide, while CDR1 and CDR2 primarily interact with the peptide binding groove of the MHC protein presenting the peptide, but they can also be directly in contact with the peptide (page 2, paragraph 3). Jokinen teaches that we can characterize which TCRs recognize certain epitopes experimentally, but this is a time consuming task and is often not possible with scarce patient samples such as biopsies. However, previously produced experimental data has enabled the development of a computational method, TCRGP, that can predict which epitopes a TCR recognizes with higher accuracy than previous methods (abstract). Jokinen; however, teaches that even this model requires a sufficient amount of experimentally produced epitope-specific TCR-sequencing data be available to train a classifier. The exact number of TCRs required to achieve a certain level of accuracy also varies greatly between different epitopes. This likely reflects the fact that different epitopes can be more selective in choosing their TCR interactions. In other words, TCRs that recognize one epitope can be more diverse than the TCRs that recognize another epitope, and, if the TCRs are very heterogenous, it requires more sampling to get a representative sample of these TCRs for the model training. Jokinen teaches that although computational methods cannot replace experimental measurements they may be used to complement them when analyzing existing unselected TCR repertoire data or to guide experimental designs for ex vivo measurements (page 15, paragraph 3). With the currently available epitope-specific TCR sequence data we have come this far, but as more data becomes available with modern high-throughput techniques presented recently, new possibilities will rise. With a larger variety of pMHC complexes and TCRs that recognize them, we hope to better consider the cross-reactivity of TCRs, similarities between epitopes, and the significance of the HLA-types of the MHC proteins presenting the epitopes, and perhaps even predict if a TCR can recognize a previously unseen epitope (page 15, paragraph 4).
The teachings of Wong and Jokinen demonstrate that the binding function of TCRs depends on the full complement of 6 CDRs, specifically 3 from the α chain and 3 from the β chain, and that, while strides had been made towards predictability, it was still not possible to predictably determine binding specificity of CDRs without experimental measurements. As such, one of ordinary skill in the art would not have been capable of predictably identifying which species of the claimed genus, would be capable of retaining the claimed functions. Additionally, as discussed by Wong and Jokinen, immune response, and therefore therapeutic outcomes, result from the recognition of a peptide in complex with MHC; a recognition which relies on the binding of a full complement of six CDRs.
The art also suggests that even conservative substitutions do not lead to predictable function when used in binding domains. For example, Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22 demonstrates that even approximately 2 years after the effective filing date of the claimed invention, conservative substitution of amino acids in binding domains was not predictable. Rojas studied manipulation of antibody-antigen interactions through combinatorial biology (page 2, paragraph 2). Rojas teaches that “epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the differences between amino acids, based on physico-chemical distance between them, mutational distance (determined by the genetic code and mutational biases) or in evolutionary exchangeability (how often a given residue is replaced by another one in conserved protein families)… the critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody” (page 11, paragraph 1). These teachings of Rojas demonstrate that even limiting structure variation to conservative substitutions is not enough to establish a predictable structure-function relationship when it comes to antigen binding domains.
It is not evident from the instant disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the full scope of the genus of TCRs encompassed by the instant claims. Additionally, there is no disclosed or art recognized structure-function relationship that would allow one of ordinary skill in the art to predictably identify which CDR1/2 sequences could be used with the claimed CDR3 sequences resulting in the claimed functions of being capable of binding to a polypeptide comprising an amino acid sequence according to SEQ ID NO: or in a method of ameliorating or diagnosing cancer. Therefore, the instant claims were found not to meet the written description requirement.
Response to Arguments
Applicant’s arguments in the response filed 05/20/2026 have been fully considered, but were not persuasive.
With regards to the rejections under 35 USC 112(a) Written Description, applicant argues that, as amended, claim 1 requires particular CDR3 sequences to be present in the TCR alpha and beta chains. Applicant references the instant specification, page 4, lines 22-24 as stating that CDR3 is the prime determinant of antigen recognition and specificity while CDRs 1 and 2 mainly interact with the MHC molecule presenting the peptide.
The paragraph of the specification referenced by applicant in the response states that antigen specificity of TCRs is conferred by the variable regions of the alpha and beta chain. The specification discloses that each variable domain comprises three CDRs (CDRs1-3) surrounded by framework (FR) regions. CDR3 is the prime determinant of antigen specificity (i.e. the ability to recognize and interact with the specific antigen), whereas CDRs 1 and 2 mainly interact with the MHC molecule presenting the antigenic peptide (page 4, lines 18-24).
This teaching alone, however, does not necessarily indicate that the alpha and beta chain CDR3s claimed could be combined with any CDR1 and CDR2 sequences while retaining binding activity and the ability to ameliorate or detect cancer as claimed.
As discussed in detail in the rejection, the prior art also acknowledges that, in TCRs, CDR3 is more structurally diverse and almost always contacts the peptide antigen; however, the prior art also demonstrates that all 6 of the CDRs are pertinent to binding and function. For instance, as discussed, Wong teaches that the structural complementarity between the binding sites of the antigen receptor and their cognate antigen govern the binding interactions. As the CDRs form the majority of the binding site, their conformations are critical to binding. Wong also teaches that models struggle to accurately predict TCR CDR conformations. Similarly, Jokinen teaches that CDR3 is the most variable and primarily interacts with the peptide, while CDR1 and CDR2 primarily interact with the peptide binding groove of the MHC protein presenting peptide, but also teaches that CDRs 1 and 2 can also be in direct contact with the peptide.
These teachings indicate that, even if the alpha and beta chain CDR3 of the claimed TCRs were the prime determinant of antigen recognition and specificity, which is not necessarily the case, the other CDRs (1 and 2 from both the alpha and beta chain) contribute and their conformations are critical to binding. Additionally, even if CDRs 1 and 2 only bound to the MHC molecule presenting the antigenic peptide, this binding is still critical in antigen binding and TCR function. Based on this, one of ordinary skill in the art would not be able to predictably identify which CDRs 1 and 2 could be paired with the claimed CDR3s while maintaining binding. This is particularly the case as the prior art demonstrates that the structure-function relationship between TCR structure and antigen binding was not predictable.
Furthermore, it is noted that applicant does not demonstrate any additional species of the claimed genus beyond T116-49 and T402-93 discussed in the rejection. Therefore, applicant does not provide any evidence that the structure of the alpha and beta chain CDRs 1 and 2 are not pertinent to binding as suggested in the response.
Allowable Subject Matter
Claim 2 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.
The following is a statement of reasons for the indication of allowable subject matter: Instant claim 2, which depends on instant claim 1, encompasses TCRs capable of binding to SEQ ID NO: 2, or to the respective HLA-A bound form of the polypeptide, and recites structural limitations of the TCRs which include all 6 CDRs, specifically three from the alpha and three from the beta chain variable region. In searches of the prior art, no TCR structures were identified having the claimed CDR combinations.
The following is the closest prior art:
US 2020/0268860 A1 (Susarchick, D., et al) 27 Aug 2020 teaches methods and apparatus for performing a patient-specific immunotherapy procedure using transfected T cells (abstract). US’860 teaches a E711-19/HLA-A*02:01 specific TCR with a TCR beta chain variable region comprising SEQ ID NO: 295 which has the following alignment with instant SEQ ID NOs: 6, 10, and 14:
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As shown, the TCR disclosed by US’860 comprises misalignments in the beta chain CDR3 compared to the instantly claimed CDRs.
In prior art searches of the CDR combinations of the instant claim, no matching structures were identified. Based on the nature of TCR functionality and the dependence of the functionality on the specific structure of the CDRs, it would not have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the teachings of US’860 to arrive at the exact TCR structures claimed without undergoing a significant amount of trial and error experimentation. As there is no reasonable expectation of success in arriving at the claimed TCR structures with the claimed properties, the claims were found to be novel and non-obvious.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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