DETAILED ACTION
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 response to restriction requirement filed on October 30, 2026 have been received and entered. Claims 4-5, 7, 9-14, 16-17, 19, 22, 24-26, 28, 32, 34-37, 42-47 and 49 have been canceled. Claims 1-3, 6, 8, 15, 18, 20, 21, 23, 27, 29-33, 38-41 and 48 are pending in the instant application.
Election/Restrictions
Applicant's election with traverse of claims 1, 3, 6, 8, 15, 18, 20-21, 23 and 27 (group I) in the reply filed on October 30, 2025 is acknowledged. The traversal is on the ground(s) that the claimed TCRs are defined by unique CDR3 sequences, including SEQ ID NOs: 13-52 and 219-226, which are not disclosed or suggested in Goldfless or Khanna. Applicant further assert that these TCRs are specific for HPV16 early antigens E1, E2, E4, and E5, whereas Goldfless is limited to E6 and E7. This is not found persuasive because the special technical feature linking the invention of groups I-IV is TCR specific to HPV16. This specifical technical feature linking inventions of group I-IV does not contribute over prior art for the reasons of record. In response to applicant’s argument that TCRs are defined by unique CDR3 sequences, including SEQ ID NOs: 13-52, it should be noted that said phrase is indefinite because it is unclear which of "SEQ ID NOs: 13 to 52 or 219 to 226" is the amino acid sequence of CDR3 alpha and which is the amino acid sequence of CDR3 beta. The metes and bounds of the specific combination of CDR3 alpha amino acid sequence and CDR3 beta amino acid could not be ascertained. The TCR polypeptide having antigenic specificity for HPV16 that is specific for antigen comprising at least one epitope as set forth in SEQ ID NO: 38 that has 100% sequence identity to SEQ ID NO: 218 has been explicit disclosed in Khanna (art of record.). Upon further consideration, restriction between invention of group I and II are hereby withdrawn and previously withdrawn claim 2 is hereby rejoined with the elected invention of group I. Please note the examiner has required restriction between product claims and process claims. Once the product claims are found allowable, withdrawn process claims that include all the limitations of the allowable product would be considered for rejoinder. Additionally, upon further consideration, election of species requirement between different species is hereby withdrawn and all the non-elected species are rejoined with the elected invention.
The requirement is still deemed proper and is therefore made FINAL.
Claims 29-33, 38-41, and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on . October 30, 2026.
Priority
This application is a 371 of PCT/IB2021/000158 filed on 03/22/2021, which claims priority from US provisional application no 62/993,442 filed on 03/23/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/23/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 1-3, 6, 8, 15, 18, 20, 21, 23 and 27 are under consideration.
Claim Rejections - 35 USC § 112-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, 6, 8, 15, 18, 20, 21, 23 and 27 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 claim embraces a T cell receptor (TCR) polypeptide having antigen specificity for human papillomavirus (HPV), wherein the TCR includes at least one complementarity determining region 3 alpha (CDR3 alpha) amino acid sequence and at least one CDR3 beta amino acid sequence selected from the amino acid sequences described in SEQ ID NOs: 13 to 52 or 219 to 226". The claims as written recite aCDR3 alpha and CDR3 beta that do not uniquely correspond and include any combination of sequence. Additionally, claimed TCRs encompass CDR3 alpha and CDR3 beta of various TCRs that show specificity for a large number of known or yet to be antigenic epitope specificy for HPV16 peptide E1, E2, E3, E4, E5, E6 or E7 and whose effects on HPV-related diseases such as tumors cannot be determined. Further, claims 2 encompasses "a TCR polypeptide having antigen specificity to HPV16, wherein the TCR is specific to an antigen containing at least one epitope having an amino acid sequence selected from the amino acid sequences described in SEQ ID NO: 1-12, 217 or 218", and it is considered that the claims embrace a TCR polypeptide having unknown or yet to be identified amino acid sequences of CDR3 alpha and 3 betas, which is specific to the antigen containing said specific epitope.
In analyzing whether the written description requirement is met for the genus claim, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics, specific features and functional attributes that would distinguish different members of the claimed genus. Vas-Cath Inc. v. Mahurkar , 19USPQ2d 1111 (Fed. Cir. 1991), clearly states 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.'' Vas-cath Inc. v. Mahurkar , 19USPQ2d at 1 117. The specification does not ''clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.'' Vas-cath Inc. v.Mahurkar , 19USPQ2d at 1116.
The genus the CDR of the TCR embraced by the breadth of the claim is an important region responsible for binding to the antigen, and it is recognized that a total of six CDRs of the alpha chain and the beta chain that is responsible for the antigen-binding properties. The independent claim further encompasses TCR having antigenic specificity for any of HPV16 peptides El, E2, E3, E4, E5, E6 or E7. The art teaches while CDR3 alpha and CDR3 beta are the main determinant of HPV peptide specificity, however, all six CDR3 loops contribute to the functional full antigen recognition that would requires the entire TCR structure especially for MHC recognition. In this regard, Chlewicki (J. Mol. Biol. (2005) 346, 223–239) teaches mutating CDR1 and CDR2 affect the peptide-MHC specificity and all the CDRs could contribute to peptide specificity (abstract). Deng (Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14960-149605) teaches CDR3 can modulate germ-line–encoded interactions between CDR1 and CDR2 and MHC (see page 14960, col. 2, para. 3). Lynch (Mol. Immunol, 2013, 283-294) teaches changes in the CDR1 and 2 loops can also alter TCR recognition of pMHC. The study shows that two mutations in the CDR1α loop of the TCR that increased the affinity of a TCR by increasing the on-rate of the reaction (abstract) suggesting altering germline loops could change the specificity profile in unpredictable manner. In view of foregoing, it is apparent that ignoring other CDRs could lead to unpredictable recognition outcome as CDR3 function would be constrained by how the overall TCR engages with MHC. Further, Applicant did not demonstrate a reduction to practice of a genus of immune cells expressing the TCR, nor did Applicant adequately describe the distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of immune cells expressing TCR having antigenic specificity for HPV16.
The specification teaches HPV-infected cell killing effect by TCR-expressing T cells could be achieved only by E5-NLD-TCR , E2-TLQ-TCR and E6-TIH-TCR (see examples 8 and 9). The TCR polypeptide sequences having antigenic specificity for human HPV16, other than E5-NLD-TCR and E2-TLQ-TCR expressing T cells within the genus of TCR polypeptide or TCR polypeptide expressing any other immune cell expressing have not been disclosed. Based upon the prior art as discussed above is expected to be sequence variation among different species of CDR3a and CDR3b amino acid sequences. There is no evidence on the record of a relationship between the structures of the E5-NLD-TCR, E2-TLQ-TCR and E6-TIH-TCR to any of the embraced TCR amino acid sequence or any other immune cell expressing the TCR sequence that would provide any reliable information about the any other structure of TCR polypeptide within the claimed genus.
As such, the Artisan of skill could not conclude that Applicant possessed any additional combination of TCRa and TCRb species binding to a genus of HPV16 epitope, except for that of specifically described in specification (see example 7 and 8 of the specification). Hence, only TCRs showing the same specificity as a specific TCR are limited to those in which all of the CDRs comprising amino acid sequence as set forth in SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 31 and SEQ ID NO: 32 or SEQ ID NO: 25 and SEQ ID NO: 26 that bind to desired HPV16 antigenic epitope of SEQ ID NO: 1, 4 or 3 respectively and a T cell expressing said TCR, could be demonstrated as possessed. There is no evidence on the record that any combination of CDR3 alpha and any CDR3 beta that does not uniquely correspond to specific combination of amino acid sequence and could include any combination of CDR3a and CDR3b sequences set forth in SEQ ID NO: 13 to 52 or 219 to 226 that could bind to any desired HPV16 antigenic epitope or yet to be identified epitope of HPV16 in genus of other immune cells. The art teaches non-T cell such as B cells do not express TCR on the cell surface (see Hall et al International Immunology, Vol. 3, No. 4, pp. 359 - 36). Additionally, claimed TCRs encompass CDR3 alpha and CDR3 beta of various TCRs that show specificity for a large number of known or yet to be identified epitopes and whose effects on HPV-related diseases such as tumors cannot be determined. Likewise, even though the amino acid sequence of the epitope is specified in claim 2, it is necessary to screen for antigen-binding properties one by one from an innumerable of combinations of the amino acid sequences of the CDR3 alpha chain and the CDR3 beta chain and the resulting biological activity would be unpredictable other than those specifically identified in the instant application as discussed above.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which is not conventional in the art before the effective filing date of the invention. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics. Inc., 48 USPQ2d 1641, 1646 (1998). As such, the Artisan of skill could not conclude that Applicant possessed any additional species of sequences, except for that of CDRs comprising amino acid sequence as set forth in SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 25 and SEQ ID NO: 26 that bind to desired HPV16 antigenic epitope of SEQ ID NO: 1 and 3 respectively and an isolated T cell expressing said TCR.
The skilled artisan cannot envision the detailed chemical structure of the amino acid, nucleic acid encoding the TCR showing contemplated biological activity other than those described and exemplified in the specification, 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. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). In conclusion, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that Applicant is in possession of genus of TCRs or immune cells expressing said TCR as broadly claimed at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
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.
Claims 1, 3, 8, 15, 18, 20, 21, 23 and 27 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.
Claim 1 is directed to a TCR comprising at least one complementarity determining region 3 alpha (CDR3 alpha) amino acid sequence and at least one CDR3 beta amino acid sequence selected from the amino acid sequences described in SEQ ID NOs: 13 to 52 or 219 to 226", however, it is unclear which of "SEQ ID NOs: 13 to 52 or 219 to 226" is the amino acid sequence of CDR3 alpha and which is the amino acid sequence of CDR3 beta. The metes and bounds of the specific combination of CDR3 alpha amino acid sequence and CDR3 beta amino acid could not be ascertained. Claims 2-3, 8, 15, 18, 20, 21, 23 and 27 are included in the rejection because they directly or indirectly depend from the rejected base claims. Claim 23 is vague because of the multiple "and/or" phrases within the claims. This is because given the broadest reasonable interpretation, it is unclear what combination of immune checkpoint molecules are expressed or not expressed by the immune cell. Appropriate correction and/or clarification is required.
Regarding claim 21, the phrase " eg. (for example)" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 2 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lorenz et al (WO2016146618, dated 09/22/2016).
Claims are directed to a TCR polypeptide having antigenic specificity for HPV16, wherein the TCR is specific for antigens comprising at least one epitope having an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 1-12, 217 or 218.
With respect to claim 2, Lorenz teaches a TCR polypeptide having antigenic specificity for HPV16, wherein the TCR is specific for antigens comprising at least one epitope having an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 1-12, 217 or 218.
With respect to claim 2, Lorenz teaches a TCR polypeptide encoded by a nucleic acid encoding a T cell receptor (TCR) alpha chain and TCR beta chain specific for an epitope in complex with a human MHC I, wherein the epitope is an epitope of human papillomavirus 16 oncoprotein E5 comprising the amino acid sequence as set forth in SEQ ID NO: 1 (see claims 1, 3 and 7 of ‘618) that has 100% sequence identity to SEQ ID NO: 218.
Query Match 100.0%; Score 49; Length 9;
Best Local Similarity 100.0%;
Matches 9; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SAFRCFIVY 9
|||||||||
Db 1 SAFRCFIVY 9
Accordingly, Lorenz anticipates claim 2.
Conclusion
No claims allowed.
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/ANOOP K SINGH/Primary Examiner, Art Unit 1632