DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's amendment, filed on 04/15/2024, is acknowledged.
3. Claims 1-19 are pending and under examination as they read on an isolated or purified T-cell receptor (TCRI comprising: an a chain and a chain, each one of the α and βchains comprising a first, second and third complementarity determining regions (CDRs), wherein the first CDR (CDR1) of the a chain comprises an amino acid sequence: ETRDTTYY (SEQ ID NO: 7), wherein the second CDR (CDR2) of the a chain comprises an amino acid sequence: RNSFDEQN (SEQ ID NO: 8), wherein the third CDR (CDR3) of the a chain comprises an amino acid sequence: CALSERPGYSTLT (SEQ ID NO: 3), wherein the CDR1 of the 3 chain comprises an amino acid sequence: SGHDY (SEQ ID NO: 9), wherein the CDR2 of the 3 chain comprises an amino acid sequence: FNNNVP (SEQ ID NO: 10), and wherein the CDR3 of the 3 chain comprises an amino acid sequence: CASGTPSTYEQY (SEQ ID NO: 4).
4. Applicant’s IDS, filed 04/15/2024, is acknowledged.
5. Claim 8 is objected because claim 8 recites the CDRs/SEQ ID NOs in random order, CDR3 (SEQ ID NO: 3/4), CDR1 (SEQ ID NO: 7/9 and CDR2 (SEQ ID NO: 8/10). CDR order is required.
6. Applicant is advised that should claims 1, 6 and 7 be found allowable, claims 8, 9 and 10 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 706.03(k).
7. Claim14 is objected because the claim claims the same component using circular logic. Claim 14 depends from claims 11 and 12 which recite nucleic acid included in expression vector, however claim 14 recited the expression vector comprises the nucleic acid. Claim 14 is claiming the same thing.
8. For clarity reason it is suggested that the recitation “an isolated or purified host cell comprises the nucleic acid or the recombination expression vector” in claim 16 be changed to recite “wherein the nucleic acid or the recombination expression vector is expressed in a host cell”.
9. The specification at [0021] is objected to because the [0021] discloses that antigenic specificity for a mutated human p53R175H peptide (SEQ ID NO: 1), SEQ ID NO: 1 is not p53R175H peptide. SEQ ID NO: 1 is CTNNB1S37F peptide. Correction is required.
10. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
11. Claims 2, 4-6, 8-15 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
The recitation “the α chain further comprises an α chain . . . . and wherein the β chain further comprises an amino acid sequence of a β chain” in claim 2 is ambiguous. It is not clear how the α/β chain would comprise additional α/β chain. It is suggested that the claim “wherein the α/β chain variable region comprising the amino acid sequence of SEQ ID NO”.
The recitation “further comprising (a) the α chain comprising an amino acid sequence of SEQ ID NO . . . and the β chain comprising an amino acid sequence of SEQ ID NO: ” in claim 4 is ambiguous because it is not clear how the TCR would comprise additional α and β chains. It is suggested that the claim be changed to recite “wherein the α chain comprising the amino acid sequence of SEQ ID NO: . . . and the β chain comprising the amino acid sequence of SEQ ID NO: 6”.
The recitation “further comprising an antigenic specificity for “in claim 5 is ambiguous because it is not clear how the TCR would comprise YLDSGIHFGA of SEQ ID NO: 1. It is suggested that the claim be changed to recite “wherein the TCR has antigenic specificity for a mutated CTNNBS37F . ..”
The recitation “an isolated or purified polypeptide comprises a functional portion of the TCR” in claim 6 is ambiguous and confusing because TCR is a polypeptide. It is not clear how a polypeptide is included in a polypeptide. It is suggested that the claim be changed to recite “The isolated or purified TCR of claim 1 comprises a functional portion of the TCR and wherein the functional portion comprises the amino acid sequence set forth in (a) SEQ ID NO: . . .”
The recitation “wherein the TCR is included in an isolated or purified protein” in claims 8-10 is ambiguous and confusing because TCR is a protein it is not clear how a protein is included in a protein.
The recitation “the TCR is included in an isolated or purified nucleic acid” in claim 11 is indefinite because “TCR” is a protein/polypeptide and limited to its amino acid component, it is not clear how the TCR is included in a nucleic acid.
The recitation “SEQ ID NO: 16, 17” is indefinite because neither SEQ ID NO: 16 nor SEQ ID NO: 17 encodes the α and β chains of TCR comprising the CDRs of SEQ ID NOs 7,8,3, 9,10,4 recited in claim 1.
The recitation “expression vector is selected from the group consisting of : a mRNA” in claim 15 is indefinite because it is not clear how the expression vector is a mRAN.
The recitation “in human p53” in claim 19 is ambiguous because the claim recites “treating or preventing cancer in a mammal” it is not clear how the genus of mammals is now a species of a human.
12. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
13. Claims 1-19 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims use open language “comprising” and “an amino acid sequence of SEQ ID NO: X”, the phrase results in a TCR comprising the claimed CDRs or any portion of the claimed “SEQ ID NO: X”. The claim terminology “an amino acid sequence of SEQ ID NO: X” does not place size limits on the α chain/β chain/CDRs, but rather reads on any portion of the claimed α chain/β chain/CDRs of SEQ ID NO. The α chain/β chain/CDRs are generic with respect to size, encompassing anything from dimers on up to the full size of the claimed SEQ ID NOs. Applicant’s specification fails to describe TCR having antigenic specificity for a mutated CTNNB S37F comprising a portion of the claimed CDR sequences. The claim language would encompass any sequence of two or more amino acids fully contained within SEQ ID NOs:7,8,3,9,10,4, 5,6,11, 12,23, 24,26,27,28,46, 47-50. The “CDRs” are generic with respect to size, encompassing anything from dimers on up. The term “an amino acid sequence of SEQ ID NO: X does not impose lower limit on the size of what is encompassed by the term. For example, the specification does not explicitly define the CDR of SEQ ID NO: 4 as a peptide with at least 12 amino acids. The claims encompass a genus of CDR fragments incorporated into any larger amino acid sequence, α and β chains. The claims encompass fragments that, in addition to the tetra-, penta-, hexa-, hepta-, octa-, nona-, deca- and undeca-peptide recited in SEQ ID NO: 7,8,3,9,10,4, 5,6,11, 12,23, 24,26,27,28,46, 47-50, also have flanking α chain and β chain of considerable size up to 120 amino acids in length. However, every member of that genus does not include a common structural feature of the sequence recited in SEQ ID NOs. There are no drawings or structural formulas disclosed of CDR polypeptide fragment that binds to a mutated CTNNB1 S37F peptide of SEQ ID NO: 1. There are no teachings in the specification regarding which amino acid of α chain and β chain CDR polypeptide fragment that can be deleted while retaining the ability of the fragment to bind to CTNNB1 S37F peptide of SEQ ID NO: 1.
Further, there is no art-recognized correlation between any structure of the CDR polypeptide fragment and the activity of binding to CTNNB1 S37F peptide of SEQ ID NO: 1, based on which those of ordinary skill in the art could predict which amino acids can be deleted from a CDR polypeptide without losing the binding to CTNNB1 S37F peptide of SEQ ID NO: 1. Consequently, there is no information about which amino acids can deleted from any CDR polypeptide fragment in the claimed genus of TCRs and still retain the ability to bind a CTNNB1 S37F peptide of SEQ ID NO: 1. It is suggested that the claim be changed to “the amino acid of SEQ ID NO:X” to overcome this part of the rejection.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of antigenic specificity for a mutated CTNNB1S37F peptide of SEQ ID NO: 1. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear 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, reduction to drawings, or 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 genus.
Claims 1-4, 6-19 encompass a broad genus of TCR comprising less than the required 6 CDRs lacks frameworks and without antigenic specificity to screen for the missing frameworks and CDRs portions.
The specification at page 25 discloses the generation of CTNNB1S37F peptide specific CTL clones. To analyze and isolate CTNNB 1S37F-Specific CTL clones, CTNNB1s37F/HLA-A2 tetramer labeled with PE was generated using the CTNNB1S37F peptide (SEQ ID No: 1) and Flex-TTM HLA- A*02:01 monomer (Biolegend cat# 280003) according to manufacturer's instructions. T cells were harvested and suspended in 50 ul DPBS buffer containing lul of anti-human CD8 antibody labeled with APC (Biolegend cat# 300912) and l ul of CTNNB 1s37F/HLA-A2 tetramer labeled with PE. After incubation in 4 °C for 30 minutes, the cells were analyzed by flow cytometry (MACSQuant Analyzer 10) and the data was analyzed by Flowjo software (FlowJo, LLC). T cell clones were generated by single cell sorting with FACS sorter. CTNNB 1S37F peptide specific CTLs were stained with anti- CD8-APC and CTNNB 1s37F/HLA-A2 tetramer-PE and resuspended in 400u1 DPBS with 1% FBS, single cell sorting was conducted on Sony SH800 cell sorter according to manufacturer's instructions. The cells were sorted into 96-well U-bottom plates pre-treated overnight in 4 °C with 2ug/ml anti-CD3 antibody (Biolegend, clone OKT3 cat#317303) and 2ug/ml anti-CD28 antibody (Biolegend cat#302914). HLA-A2+ PBMCs pre-treated with Mitomycin C (Cayman, cat# 11435) at 25 g/ml for 2 hours were used as feeder cells. The sorted single cells were co-cultured with feeder cells (104 feeder cells per well) in the completed RPMI1640 medium supplemented with IL-2 100u/ml, IL-7, 15 and 21 at Sug/ml. Half of medium was changed with fresh medium containing the cytokine cocktail mentioned above every 3 days until the T cells grew to the number enough to be analyzed with CD8 antibody and CTNNB 1S37F/HLA-A2 tetramer and for isolating TCR gene.
The specification at [0097] discloses the preparation of the recombinant TCR lentiviral vector The nucleic acid with the nucleoid sequence comprising a TCR Vβ chain (SQ ID NO: 36), a nucleic acid endoing mouse TCR-β constant chain (SEQ ID NO: 27(, a TCR Vα chain (SEQ ID NO: 35), a nucleic acid encoding the mouse TCR-β constant chain (SEQ ID NO: 28) and linker nucleic acid encoding a furin enzyme cleavage peptide and a F2A peptide (SEQ ID NO: 13) between the TCR alpha and beta chains was synthesized.
The claims recite CDRs without antigen specificity. There is unpredictability on how to screen for the missing framework of the TCR in the absence of the antigen specificity. Neither the instant specification nor the prior art provides sufficient guidance or direction for one of ordinary skill in the art to make the TCRs encompassed by the breadth of the instant claims. The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of TCRs routinely requires the association of the complete α and β chains variable regions of a given TCR, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the TCR to its target antigen. The amino acid sequences and conformations of each of the α and β chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the TCR. It is expected that all of the α and β chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a TCR having antigen-binding function and that proper association of α and β chain variable regions is required in order to form functional antigen binding sites (see Wong et al. Comparative Analysis of the CDR Loops of Antigen Receptors. Front. Immunol. 10:2454, 2019. doi: 10.3389/fimmu.2019.02454).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “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.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
14. Claim 19 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 19 encompasses the claimed TCR has the potential, ability, or permission to be utilized in the treatment or prevention of cancer comprises an R175H mutation (i.e., HMTEVVRHC) in human p53 and an HLA-A2 allele.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The specification discloses that TCR, polypeptide, or protein comprises substantial or significant sequence identity or similarity to the inventive TCR, polypeptide, or protein, and retains the biological activity of the TCR, polypeptide, or protein of which it is a variant, e.g., comprising antigenic specificity for a mutated human p53R175H peptide (SEQ ID NO: 1) presented by HLA-A2 or to which the parent polypeptide or protein specifically binds, to a similar extent, the same extent, or to a higher extent, as the parent TCR, polypeptide, or protein [0022].
It is noted that the claimed TCR binds to the antigenic specificity for a mutated CTNNB1S37F YLDSGIHFGA (SEQ ID NO: 1) in context of an HLA-A*02 molecule.
Those of skill in the art do not recognize the relationship between the claimed CTNNB1-S37F-reactive TCR and P53-R175H mutation in cancers in the treatment and prevention of P53-R175H in cancer.
Eggebo et al (Nature Immunology, 26:1726-1736), 2025) revisited the possibility that CTNNB1-S37F may represent a therapeutic target. By use of MS, they demonstrated presentation of the HLA-A*24:02–SYLDSGIHF peptide and identified HLA-A*02:01 YLDSGIHFGA as a shared neopeptide. CTNNB1-S37F-reactive TCRs were identified from healthy donors. CTNNB1-S37F-engineered TCR-T cells eradicated tumors in an in vivo melanoma model and in an in vivo PDX model of endometrial adenocarcinoma, both models naturally expressing the mutation and restricting HLA. The lack of effective therapeutic modalities currently targeting the β-catenin pathway, and a clear unmet medical need in CTNNB1-mutated cancers, present an opportunity for TCR-T cell therapy (see page 1727, left col, 3rd ¶).
Further, the phrase “can be used” is only potential and lack of certainty. The treatment/ prevention could happen, but it is not yet certain, and the possibility remains uncertain.
Importantly, the specification fails to show that in context of TCR protein/polypeptide comprising the claimed CDRs of SEQ ID NO: 3-4 and 7-10, would recognize the neoepitope peptide in context of HLA-H2.
The examples are directed to the use of TCR expressed by JRT cells recognize CTNNB1S37F peptide in the context of HLA-A2 but not TCR protein/polypeptide.
The burden of enabling the prevention of a disease (i.e. the need for additional testing) would be greater than that of enabling a treatment due to the need to screen those mammals susceptible to such diseases and the difficulty of proof that the administration of the drug was the agent that acted to prevent the condition. Further, the specification does not provide guidance as to how one skilled in the art would go about screening those patients susceptible to cancer comprising an R175H mutation in human p53 and an HLA-A2 allele within the scope of the presently claimed invention. Nor is sufficient guidance provided as to a specific protocol to be utilized in order to prove the efficacy of the presently claimed CTNNB1-S37F-reactive TCR in preventing cancer comprising an R175H mutation in human p53 and an HLA-A2 allele.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
15. No claim is allowed.
16. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Hou et al. TCR-like chimeric-antigen-receptor to recognize neoepitopes derived from driver mutations. Cancer Immunology Research, (December 2022) Vol. 10, No. 12, Supp. Supplement. Abstract Number: B32.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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September 7, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
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