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 .
Applicants’ amendments to the claims and arguments filed on June 23, 2026, have been received and entered. Claims 3- 7, 9-13, 16, 19, 22, 24-26, 28, 32, 34-37, 42-47 and 49 have been canceled. Claims 1-2, 21, 23 have been amended, while claims 50-57 have been newly added. Claims 1-2, 8, 15, 18, 20, 21, 23, 27, 29-31, 33, 38-41, 50-56 and 57 are pending in the instant application.
Election/Restrictions
Applicants’ 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 was acknowledged. Upon further consideration, restriction between group I and II is hereby withdrawn and previously withdrawn claim 2 is hereby rejoined with the elected invention of group I. Please note the examiner has required restrictions between product claims and process claims. Once the product claims are found allowable, withdrawn process claims that include all the limitations of the allowable product would be considered for rejoinder. Additionally, upon further consideration, election of species requirement between different species is hereby withdrawn and all the non-elected species are rejoined with the elected invention.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 was deemed proper and is therefore made FINAL.
Claims 29-33, 38-41, and 48 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 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.
Claims 1-2, 8, 15, 18, 20, 21, 23, 27, 50-56 and 57 are under consideration.
Maintained-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 1-2, 8, 15, 18, 20, 21, 23, 27 remain rejected and claims 50-56 and 57 are newly 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) 16 , wherein the TCR comprises a TCRb chain amino acid sequence and TCRa chain amino acid set forth respectively in SEQ ID NOs: 59 and 60, SEQ ID NOs: 61 and 62, or SEQ ID NOs: 65 and 66 . The, claimed TCRs encompass a TCRp chain amino acid sequence and TCRa chain amino acid that show specificity for a large number of known or yet to be antigenic epitope specific 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 or 217 , 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 CDR3 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 of TCR embraced by the breadth of the claims is an important region responsible for binding to the antigen comprising at least one epitope, 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 especially for claim. 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 CDRs could lead to unpredictable recognition outcome as CDR 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, it 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.
Response to arguments
Applicant asserts that claim 1 has been amended to recite specific TCR construction for E5-NLD, E2-TLQ and E6-TIH and therefore rejection should be withdrawn. Applicants’ arguments have been fully considered but are not found persuasive.
In response it should be noted that previous office explicitly indicated that the claimed TCRs encompass a genus of TCRp chain amino acid sequence and TCRa chain amino acid (now amended to specific SEQ ID NO from table 10) that show specificity for a large number of known or yet to be antigenic epitope specific for HPV16 peptide E1, E2, E3, E4, E5, E6 or E7 and whose effects on HPV-related diseases such as tumors cannot be determined. Claim 1 recite a TCR comprising a TCR alpha chain construct (TRA) and TCR beta chain construct (TRB) of a that is not specific for any epitope from a defined HPV 16 antigen presented on an MHC. Likewise, claim 2 encompasses a encompasses a genus of 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 or 217. Therefore, claims embrace a TCR polypeptide having unknown or yet to be identified amino acid sequences of CDR3 alpha and CDR3 betas, which is specific to the antigen containing said specific epitope.
It was indicated that guidance provided in the specification is limited to E5-NLD-TCR and E2-TLQ-TCR specifically bind to the epitopes of SEQ ID NO: 1 and SEQ ID NO: 3 of the present application (see Table 1 of he specification). The specification is silent on any additional combination of TCRa and TCRb species binding to a genus of HPV16 epitope as embraced by breadth of claim 1, except for that of specifically described in specification (see table 1 and example 7 and 8 of the specification). Previous office action explicitly recognized that 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 especially for claim (see Chlewicki (J. Mol. Biol. (2005) 346, 223–239) , Deng (Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14960-149605) , and Lynch (Mol. Immunol, 2013, 283-294 all art of record).. In view of foregoing teaching in prior art, it is apparent that ignoring TCR construction could lead to unpredictable recognition outcome as CDR 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 that could having antigenic specificity for HPV16 having antigenic specificity for HPV16 comprising at least one epitope having an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs:1-12,or217, 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. It is emphasized that antigenic specificity depends heavily on exact HLA restriction, peptide conformation, and viral sequence variations. Additionally, there is expected to be natural sequence polymorphisms in HPV16 (such asE2, E6 or E7 as disclosed in Table 1 of the specification) that would alter the peptide-MHC conformation or reduce binding affinity, leading to unexpected immune escape or failure to recognize variant strains. Therefore, skilled artisan cannot envision the detailed chemical structure of the amino acid, nucleic acid encoding the a genus of TCR having antigenic specificity for HPV16 El, E2, E3, E4, E5, E6 or E7other than those described and exemplified in the specification (see table 1 and 10), and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation.
Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Withdrawn-Claim Rejections - 35 USC § 112
Claims 1, 3, 8, 15, 18, 20, 21, 23 and 27 were 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. Applicants’ amendments to the claims obviate the basis of the rejection. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn- Claim Rejections - 35 USC § 102
Claim 2 was rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lorenz et al (WO2016146618, dated 09/22/2016). In view of Applicants’ amendment of base claim 2 deleting the limitation “SEQ ID NO: 218”, the previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are, however, subject to new rejections over the prior record of art.
New-Claim Rejections - 35 USC § 103- necessitated by amendments
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 2 is rejected under 35 U.S.C. 102(a) (1) or 101(a) (2) as being anticipated by Goldfless et al (WO2019195486, dated 10/10/2019, filed on 3/4/2019. EFD 05/04/2018)
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.
With respect to claim 2, Goldfless 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 set forth in TIHDIILECV SEQ ID NO. 268 that has 100% sequence identity to SEQ ID NO: 4 (see para. 38-39 table 1).
Accordingly, Goldfless anticipates claim 2.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Satte (US Patent no 7026443 04/11/206) teaches an epitope of human papillomavirus 16 oncoprotein E5 comprising the amino acid sequence as set forth in SEQ ID NO: 2488 that has 100% sequence identity to SEQ ID NO: 1 (Col. 131). Sette et al. further teaches the "epitope approach", which allows the incorporation of various antibody, CTL and HTL epitopes, from various proteins, in a single vaccine composition. Such a composition may simultaneously target multiple dominant and subdominant epitopes and thereby be used to achieve effective immunization in a diverse population (see col. 4, lines 29-34).
Brandt ()WO2019070541 or US20210284709A1) teaches TCRs or antigen binding fragments thereof and antibodies and antigen-binding fragments thereof, such as those that recognize or bind human papilloma virus (HPV) 16, including HPV 16 E6 and HPV 16 E7.
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.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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