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 .
Applicant’s amendment and response of 7/23/25 are entered.
Claims 18-28 are amended.
Claims 29-30 are canceled.
Claims 18-28 are pending and are considered herein.
Claim Status, Canceled Claims
In light of the cancelation of Claims 29-30, all rejections/objections thereto, are withdrawn.
Drawings
In light of the amended drawings, the objections to the same, are withdrawn.
Claim Objections
In light of the amendments, the objections to the claims, are withdrawn.
Claim 19 is objected to because of the following informalities: Claim 19 recites “the 3 chain”, however, it is clear this should be the “the β chain”. Appropriate correction is required.
Claim 23 is objected to because of the following informalities: Claim 19 recites “the 3 chain”, however, it is clear this should be the “the β chain”. Appropriate correction is required.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
In light of the amendments, the rejections of Claims 18-27 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a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, are withdrawn.
Each amendment correctly addresses the issues previously addressed by the Examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 19 is newly rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, due to the amendment. Claim 19 requires only positions 22-112 of SEQ ID NO 2 for the variable region, however, Claim 18 also requires positions 113-121, at a minimum. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 19 is newly rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, due to the amendment. Claim 19 requires only positions 20-113 of SEQ ID NO 2 for the variable region, however, Claim 18 also requires positions 114-122, at a minimum. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 22-28 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 22 is drawn to several embodiments of nucleic acids encoding the TCR of Claim 18, vectors comprising the nucleic acids, and cells containing the nucleic acids, and pharmaceutical compositions similarly comprising the vector or cell containing the nucleic acid. The structure of the nucleic acid is not within the scope of the claimed TCRs, which are protein. Further, Claims 23-28 are drawn to embodiments requiring the nucleic acid encoding the TCR, and not the TCR itself. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 24 is newly rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, due to the amendment. Claim 22 requires positions of the C terminal CDR of of the alpha chain, of 334-363 (as seen from Claim 23). However, Claim 24 only requires up to position 336. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
In light of the cancelation of Claim 29, the rejections of Claims 19-20 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, are withdrawn.
To wit, it is noted that the prior office action addressed Claims 19-20, but the issue was really in Claims 29-30. However, Applicant canceled the same, and thus, the issue is withdawn and no new issue is required here.
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 18-20 and 22-28 remain 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.
Claim 18 is generic for alpha-beta TCRs, which bind HLA-A11-restricted HBc141-151 peptide, comprising an alpha chain that has the CDRs of 48-53, 71-77, and 112-121 (N to C terminal orientation) of SEQ ID NO: 2 and an alpha chain that has the CDRs (N to C termini) 46-50, 68-73, and 111-122 of SEQ ID NO: 4. In this instance, none of the rest of the alpha-beta TCR structure is specifically defined. Claim 19 removes the C-terminal CDR of the alpha and beta, while adding some constant portions of the variable region, (i.e., positions 22-112 of SEQ ID NO: 2 for the alpha chain, and 20-113 of SEQ ID NO: 4, for the beta chain). Claim 20 limits the portions of SEQ ID NO: 2 to positions 133-268, and SEQ ID NO: 4 to positions 133-305 (the overall variable region). Claim 21 requires of all of SEQ ID NO: 2 and SEQ ID NO: 4 (pointing to the generic nature of Claim 18 and separately-depending claims). Claim 22 is similarly generic as Claim 18, for the embodiments of the T cell having the receptor. Claim 28 defines the cell to a T cell or Jurkat cell (the Jerkat cell being a T cell type and not applying to the cell comprising the TCR, but a cell comprising the nucleic acid encoding the TCR as seen in element D of Claim 22), and thus, has the same scope as Claim 22 as concerns the TCR.
As concerns Claim 22, as seen above, in addition to elements C and D from above, the claims also are generic for the TCR, albeit those embodiments that do not specifically require the TCR, it is a nucleic acid encoding the TCR, and thus, has the same CDRs seen in Claim 18, being generic to the rest of the structure encoded for the alpha and beta chains of the TCR that bind the HLA-A11-restricted HBc141-151 peptide. (This applies to elements A, B, and all parts of element D, save the T cell having the TCR, which was addressed above.) Claim 23 limits the coding region of the CDRs to the specific portions of SEQ ID NO: 1 and SEQ ID NO: 3, for alpha, and beta, respectively, but similar to Claim 18, is generic for the rest of the coded alpha and beta chains. Claim 24 provides the portions of SEQ ID NO: 1 and SEQ ID NO: 3 that code for the variable region in total, but does not require all of the C terminal CDR in each case, and is remains generic for the rest. Claim 25 also requires constant region to be drawn from the N-terminal regions of alpha and beta chains, as coded (i.e., coded 3’ to the CDR region only. Claim 26 encodes the whole alpha and the whole beta chain (i.e., SEQ ID NO: 1 and SEQ ID NO: 3, respectively). Claim 27 depends from Claim 22 and is drawn to a retroviral or lentiviral vector, and thus, the coding region is generic for that scope not specifically defined in Claim 22.
The specification discusses, with regard to these CDRs of the alpha and beta chain, as recognizing the HLA-A11 restricted HBc141-151 epitope, which HLA-A11 is the most prevalent in the Chinese population (paragraphs 7-9). Additionally, paragraphs 12-26 provide literal antecedent basis for the claimed scopes of these sequences. There is no guidance as to which amino acids of the CDRs may be mutated and still obtain specificity for HBc141-151 in the HLA-A11 context, nor is there any guidance into which mutations may be had for the constant regions that contain the CDRs, or for mutations in the whole of each of SEQ ID NO: 2 or SEQ ID NO: 4, while, at the same time, it should be noted that the mutations in the nucleic acid would be covered solely by the degeneracy of the genetic code, so the nucleic acid sequences are not rejected. In the examples, Applicant induced HLA-A11/hTAP-LMP transgenic mice to produce T cells with TCRs against the HBc141-151 antigen (e.g., paragraph 65), then reverse transcribed the alpha and beta chains with degenerate primers, arriving at 40 Ag-specific CTLs, and after sequencing five of the cells, all five had the exact same alpha and beta chains for their TCRs (e.g., paragraph 77). Still further, it was shown that the use of these TCR alpha and beta chains, not further modified, can elicit the HLA-A11 HBc141-151 immunity for adoptively-transferred T-cells, both in vivo and in vitro (Examples).
Within this context, the Artisan would see that the claims allow for mutations in the constant regions of both chains, including the conserved regions of the variable regions, and also anywhere in either chain, as well as in some embodiments (e.g., Claim 19) it does not even require all of the CDRs in each variable region, yet the specification provides no information as to what mutations may be allowed and still provide the same HLA-A11 HBc141-151 restricted binding. Thus, it is left for the Art to provide the information to fill in the blanks, with regard to these mutations.
With regard to the placing the CDRs in distinct alpha and beta chains, the Artisan recognized that the CDR swapping between TCRs is not fully understood but is complex and context-dependent, including with distinct length distributions and high structural variability (e.g., Wong, et al. (2019) “Comparative Analysis of the CDR Loops of Antigen Receptors”, Frontiers in Immunology, 10: Article 2454, 11 pages long, e.g., ABSTRACT). For example, while CDR3 loops swapped across distinct TCRs have been attempted, it’s not always successful, even using when using the same variable alpha chain (e.g., Ayres, et al. (2016) “Differential utilization of binding loop flexibility in T cell receptor ligand selection and cross-reactivity”, Scientific Reports (Nature), 6: Article 25070, 14 pages long, e.g., ABSTRACT), Further the structural dynamics of TCR CDRs can vary between different TCRs, suggesting the CDR loops may not be interchangeable to provide the same function of binding (e.g., Id.). Further, given this lack of understanding of the form and function, even within the loops and their distinct mechanisms to bind, the Artisan would necessarily not know which CDR region amino acids may be altered, and provide for the proper binding.
Thus, the Artisan, given the lack of knowledge in the Art as to the interchangeability of backbone alpha and beta chains, and lack of knowledge in the Art as to which amino acids may be altered in the CDRs themselves, and provide in the same function in each case, the full scope of the claims allowing form a great many positions to be modified, thus, the Artisan would not have understood Applicant to have been in possession of the invention as claimed.
Written Description: TCR structure
Applicant’s argument of 7/23/25 has been considered but is not found persuasive.
Applicant simply argues that the amendment is sufficient to overcome the rejections (p. 8).
Such is not persuasive. The Examiner has provided art to argue that the constant portions (of the whole of each chain, including the variable region) as well as the CDRs of the variable region are critical and the movement of CDRs to alpha/beta chains are not understood enough to understand it would work.
Conclusion
No claim is allowed.
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 ROBERT M KELLY whose telephone number is (571)272-0729. The examiner can normally be reached M-F: 8a-5p.
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ROBERT M. KELLY
Examiner
Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638
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