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 .
1. Claims 1-12 and 18-20 are pending and being examined.
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.
2. Claims 5, 6, 11, 12, and 18-20 are 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.
Claims 5 and 11 recite the limitation "the amino acid sequence of the alpha chain and/or beta chain or comprising CDRs 1, 2, and 3 therein, or variants thereof" in. There is insufficient antecedent basis for this limitation in the claims because there is no previously recited amino acid sequence of the alpha chain, beta chain, or CDRs 1, 2, and 3.
Claim 6 recites “A TCR of claim 1 with a heterologous segment or a variant with one amino acid mutation, addition, and/or deletion…”. The claim is unclear with regards to the association the TCR “with” the heterologous segment or variant, and is unclear with regards to the association of the variant “with” one amino acid mutation, addition, and/or deletion. How are these items associated “with” each other? Examiner suggests amending the claim to replace the word “with” with the word “comprising”.
Claim 12 recites “The polypeptide of claim 7, comprising a heterologous peptide sequence, fluorescent tag, or other label”. Claim 12 does not recite a first label, so it is unclear what the “other label” is. The metes and bounds of the claimed invention cannot be determined.
Claim 18 recites: “A heterologous nucleic acid comprising a nucleotide sequence encoding the TCR of claim 1”. The claim is unclear with regard to what the nucleic acid is heterologous to, because it is a relative term. Heterologous to what? Dependent claims 19 and 20 are rejected for encompassing the rejected limitation of claim 18.
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.
3. Claims 1-12 and 18-20 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a T cell receptor (TCR) having specificity for HPV 16 E2 or E5 and comprising a human variable domain and a constant region;
wherein the TCR has specificity for HPV 16 E2 151-159 comprising the amino acid sequence of SEQ ID NO:1, HPV 16 E2 329-337 comprising the amino acid sequence of SEQ ID NO:2, or HPV 16 E5 46-54 comprising the amino acid sequence of SEQ ID NO:3; and
wherein the TCR comprises the amino acid sequences of the alpha chain and/or beta chain or comprising CDRs 1, 2, and 3 therein or variants thereof.
Thus, the claims identify the TCR by function only, where the function is to have specificity for HPV 16 E2, E5, or SEQ ID NO:1, 2, or 3. No TCR sequence structure is recited for the claimed genus.
The instant specification discloses SEQ ID NOs:1, 2, and 3 are immunogenic T cell epitopes of HPV 16 early proteins E2 and E5. The specification discloses, in the examples, analyzing HPV-specific CD8+T cell epitopes from HNSCC patients. The specification discloses analyzing TCR of HPV-specific CD8 T cells by identifying their responses to HPV E2, E5, and E6 epitopes. PBMC were isolated from patients and T cells were expanded in the presence of 251 predicted HPV peptides. The T cells were then tested for reactivity against peptide pools or single peptides using ELISpot, intracellular cytokine staining, and tetramer staining. Forty-three peptides reacted in the ELISpot assay. From those, nine CD8 T cell epitopes were identified (Figure 1B) including SEQ ID NOs:1-3 (Examples). The instant specification discloses the variable domain sequences and CDR1-3 sequences for the alpha and beta chains of 10 TCRs that bind SEQ ID NO:2, 25 TCRs that bind SEQ ID NO:1, and 4 TCRs that bind SEQ ID NO:3 (Figures 2-3), wherein they appear to all be structurally distinct.
Other than for the 10 TCRs that bind SEQ ID NO:2, 25 TCRs that bind SEQ ID NO:1, and 4 TCRs that bind SEQ ID NO:3, the instant specification does not disclose any other representative TCR sequences or structures that have specificity for HPV 16 E2 and E3 or for the claimed amino acid sequences, SEQ ID NOs:1-3.
In relevant art, Gupta et al (Single-Cell Sequencing of T cell Receptors: A Perspective on the Technological Development and Translational Application. Adv Exp Med Biol. 2020;1255:29-50. doi: 10.1007/978-981-15-4494-1_3. PMID: 32949388; PMCID: PMC8845565) teach T cell Receptors (TCRs) are restricted to recognizing short peptides of protein antigens processed and presented by major histocompatibility complexes (MHCs) on the body’s own antigen presenting cells (APCs) (p. 30, col. 1). TCRs are composed of two heterodimeric polypeptide chains linked by a disulfide bond. Each chain of the TCR consists of two extracellular immunoglobulin domains, a transmembrane region and a short cytoplasmic tail. The two extracellular domains are made up of the variable (V) region and constant (C) region. The heterodimeric structure of the TCR is analogous to the heavy and light chain heterodimers of B cell receptors (BCRs) or antibodies. However, the forked structure of the TCR consists of two antigen binding sites, whereas each TCR possesses a single antigen binding site. The majority of TCRs possess an α chain and a β chain and are referred to as αβ TCRs. A subset of T cells possesses a γ chain and δ chain and are referred to as γδ TCRs. γδ TCRs are capable of directly recognizing antigens outside the context of MHC and are even capable of recognizing non-peptide antigens. T cells possess the ability to bind to a vast array of peptide antigens through their TCRs; it has been estimated that humans can produce between 1015 and 1020 possible unique TCR chains. This enormous variety is imparted by an unusual genetic mechanism, largely shared with BCR generation, that provides diversity concentrated in the antigen binding regions of the TCR. The V region is the portion of the TCR that participates in antigen binding. The V region is not encoded by a single segment of DNA, but rather is composed of multiple gene segments that are rearranged through somatic DNA recombination. Combinatorial diversity afforded through recombination of the gene segments is further augmented by junctional diversity through the random addition of nucleotides at the interface between segments, thus allowing for the generation of a nearly limitless array of TCRs. The DNA encoding the α chain of the TCR possesses multiple variable (V) and joining (J) segments, whereas the β chain possesses multiple V, diversity (D), and segments as represented in Fig. 3.1 (p. 30, col. 1-2). Fig. 3.1 of Gupta et al displays the mRNAs somatic VDJ recombination to form the alpha and beta chains of TCRs. As indicated, there is an arrangement step that recombines the VDJ segment for TCR β and V and J segments for the TCR α chain. The mRNAs formed have addition and deletion of nucleotides at the junctions of these segments leading to junctional diversity that leads to variability for assessing specific antigens. There may be different combinations of genes leading to the final formation of the TCR that consists of the TCR α and β subunit organized in a constant and variable region wherein the variable region is responsible for antigen recognition (p. 30). Gupta et al teach: Antigen binding within the TCR V region involves the three complementarity determining regions (CDRs) that contact the antigen MHC complex. CDR1 and CDR2 are primarily encoded in the V germline segments and therefore experience less diversity. CDR3 however includes the junctional regions and is the primary region in contact with the antigen (p. 31, col. 1). Part of Figure 3.1 showing structure of TCR comprising 3 CDRs in each of TCR α and β chains:
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Gupta et al teach (p. 31, col. 2): TCRs recognize processed peptide antigen presented on MHC on the surface of the body’s own cells. The two conventional MHCs, MHC I and MHC II are both polygenic and polymorphic noncovalent protein complexes composed of two polypeptide chains. TCRs are specific to both peptide antigen and the MHC to which it is bound, a phenomenon known as MHC restriction. MHC I is on the surface of virtually all nucleated cells in the body. Peptides presented on MHC I are generally 8–10 amino acids in length and result from the processing of foreign intracellular proteins. For this reason, MHC I is frequently used to signal viral infection to cytotoxic CD8 T cells. MHC II is only present on the surface of antigen presenting cells of the immune system including B cells, macrophages, and dendritic cells. MHC II presents peptides of 13–17, amino acids in length that have been collected from the extracellular environment. Figure 3.2 displays both TCR chains binding to the antigenic peptide displayed by MHC II of the APC:
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Thus, the state of the art recognizes that the six CDRs of the TCR chains in a T cell are critical to recognizing and binding the peptide antigen presented by an APC, and the sequences of these CDRs are highly variable and cannot be predicted based on the sequence of the peptide to which they are binding. Much like the six CDRs of antibodies, the sequences of the six CDRs of TCRs critical to antigen binding function cannot be predicted or determined based on the antigen they are binding. The genus of TCR sequences capable of binding a single defined amino acid sequence is vast.
To provide adequate written description and evidence of possession of the claimed TCR genus, the instant specification can structurally describe representative TCRs that function to bind the claimed HPV E2, E5, and amino acid sequences, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
In this case, the only factor present in the claims is a recitation of the TCR function: have specificity for HPV 16 E2, E5, or the amino acid sequence of SEQ ID NO:1, 2, or 3. Other than for the 10 structurally distinct TCRs that bind SEQ ID NO:2, 25 structurally distinct TCRs that bind SEQ ID NO:1, and 4 structurally distinct TCRs that bind SEQ ID NO:3, the instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose a critical shared, recognizable sequence across the vast genus of TCRs that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the TCR does, rather than what it is. The specification fails to provide any structural features coupled to the claimed functional characteristics. Other than for the 10 structurally distinct TCRs that bind SEQ ID NO:2, 25 structurally distinct TCRs that bind SEQ ID NO:1, and 4 structurally distinct TCRs that bind SEQ ID NO:3, the instant specification fails to describe a representative number of TCR sequences for the vast genus of TCRs that function as claimed. Given the known high level of polymorphism of TCR CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of TCRs encompassed by the claimed invention. One could not readily envision members of the broadly claimed genus based on the few exemplary species dislcosed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Although Applicants may argue that it is possible to screen for TCRs that have specificity for HPV 16 E2, E5, and SEQ ID NOs:1-3, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future TCRs yet to be discovered that may function as claimed. The HPV 16 E2 and E5 epitopes provide no information about the structure of a TCR that binds to them.
Given the lack of representative examples to support the full scope of the claimed TCRs, and lack of reasonable/recognizable structure-function correlation with regards to the sequences in the TCR CDRs that provide the critical binding/specificity function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of TCRs having the claimed specificity that is required to practice the claimed invention.
Examiner Suggestion: Amend the claims to recite and require, at minimum, the three CDR SEQ ID NOs from the alpha chain and the three CDR SEQ ID NOs from the beta chain of the TCR that are critical to performing the claimed specificity function.
Examiner further suggests reciting/requiring a feature in the TCR that distinguishes it from the TCR sequence that was isolated from nature to avoid issues under 35 USC 101.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
4. Claims 1-5, 7-11, and 18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claim(s) recite(s) a T cell receptor (TCR) having specificity for human papillomavirus (HPV) 16 E2 or E5 and comprising a human variable region and constant region, wherein the TCR has specificity for HPV 16 E2 151-159 comprising the amino acid sequence of SEQ ID NO:1, HPV 16 E2 329-337 comprising the amino acid sequence of SEQ ID NO:2, or HPV 16 E5 46-54 comprising the amino acid sequence of SEQ ID NO:3; wherein the TCR comprises the amino acid sequences of the alpha chain and/or beta chain or comprising CDRs 1, 2, and 3 therein or variants thereof. This judicial exception is not integrated into a practical application because the claims do not recite practically applying the TCR in any methods. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the TCRs are not markedly different from what occurs in nature. For example, US Patent 7,026,443, Sette, teaches SEQ ID NO:117 (Table VII, E2 151), SEQ ID NO:106 (Table VII, E2 329), and SEQ ID NO:24815 (Table XIV, E5 46), identical to instant SEQ ID NOs:1-3, respectively, as naturally occurring sequences comprised in the HPV genome that infects humans, wherein humans develop naturally occurring cytotoxic T lymphocyte (CTL) responses (comprising TCRs with human variable regions and constant regions) against the HPV (section III.B; col. 12). Vaccines encoding these HPV sequences administered to humans induce naturally occurring CTL responses (sections III.K, J, and L; col. 31-40). Ulrich (2020, Dissertation: “CD8+ T cell Receptor Characterization in HPV Associated Head and Neck Cancer”, Arizona State University) teaches detecting naturally occurring CTL from the blood of NSCLC human patients that recognize and bind HPV E2 329-337 peptide (instant SEQ ID NO:2) (see Figure 3.1 on page 54; p. 52-53). Eberhardt et al (published online September 1, 2021; Nature, Vol. 597:279-284 + extended data) demonstrates detecting naturally occurring CD8+ T cells from human HNSCC patients that comprise TCRs naturally recognizing and binding HPV E2 (p. 280, col. 2; Methods “Patients, Isolation of TILs and HLA-typing”; Extended Data Figure 2). Extended Data Figure 2d demonstrates naturally occurring human CD8+ T cells comprising TCRs comprising human variable regions, CDRs1-3, and constant region that have specificity for HPV 15 E2 151-159 (instant SEQ ID NO:1), E2 329-337 (instant SEQ ID NO:2), and E5 46-54 (instant SEQ ID NO:3):
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The naturally occurring TCRs fall under the scope of the claimed “polypeptides having specificity for HPV 16 E2 or E5” as claimed. The instantly claimed TCRs and polypeptides are not markedly different from what occurs in nature. Further, given the TCRs are naturally occurring, their encoding nucleic acids are also.
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.
5. Claim(s) 1, 3, 5, 7, 9, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ulrich (2020, Dissertation: “CD8+ T cell Receptor Characterization in HPV Associated Head and Neck Cancer”, Arizona State University); as evidenced by Gupta et al (Single-Cell Sequencing of T cell Receptors: A Perspective on the Technological Development and Translational Application. Adv Exp Med Biol. 2020;1255:29-50. doi: 10.1007/978-981-15-4494-1_3. PMID: 32949388; PMCID: PMC8845565).
Ulrich teaches naturally occurring cytotoxic T lymphocytes (CTL) from the blood of NSCLC human patients that specifically recognize and bind HPV E2 329-337 peptide (instant SEQ ID NO:2) (see Figure 3.1 on page 54; p. 52-53).
As evidenced by Gupta (see Gupta in the 35 USC 112(a) rejection above), human CTL inherently comprise TCR with alpha and beta chains that are responsible for the CTL specifically recognizing and binding HPV E2 329-337 peptide (instant SEQ ID NO:2) and comprise human variable and constant regions.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
6. Claim(s) 1-5, 7-11 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 7,026,443, Sette et al, published 2006; in view of Ulrich (2020, Dissertation: “CD8+ T cell Receptor Characterization in HPV Associated Head and Neck Cancer”, Arizona State University).
Sette identified immunogenic HPV E2 and E5 peptides predicted to stimulate CTL responses in human patients for the production of a vaccine to treat HPV. Sette identified immunogenic peptide epitopes: SEQ ID NO:117 (Table VII, E2 151), SEQ ID NO:106 (Table VII, E2 329), and SEQ ID NO:24815 (Table XIV, E5 46), identical to instant SEQ ID NOs:1-3, respectively, as naturally occurring sequences comprised in the HPV genome predicted to bind human patient HLA molecule and induce cytotoxic T lymphocyte (CTL) responses (wherein human CTL inherently comprise TCRs with human variable regions and constant regions) against the HPV epitopes (section III.B; col. 12). Sette teaches administering vaccines encoding these HPV sequences to humans to induce CTL responses against HPV (sections III.K, J, and L; col. 31-40; Example 15).
Sette suggests producing CTL against their peptide epitopes, however, Sette does not exemplify producing and isolating CTLs comprising TCRs that specifically bind their peptide epitopes.
Ulrich demonstrates that CTLs isolated from humans (inherently comprising TCRs comprising human variant and constant regions and alpha/beta chains) naturally and successfully specifically bind and recognize HPV peptides, including E2 329-337 (instant SEQ ID NO:2), as set forth above. Ulrich further teaches known methods for inducing CTL responses specific to HPV peptide epitopes (i.e., producing TCRs that are specific to peptide epitopes), by pulsing patient APCs with a specific HPV 16 peptide epitope, then incubating the APCs with patient PBMCs + HPV. CTL specificity of TCRs for the peptide epitope can be verified by staining for HPV 16 peptide tetramers on the CTLs or by ELISpot detection of IFNγ secretion in the presence of peptide (p. 51-54; 63-64).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was effectively filed to make TCRs that specifically bind HPV 16 E2 SEQ ID NO: 1, E2 SEQ ID NO:2 or E5 SEQ ID NO:3. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Sette suggests inducing the production of CTLs (comprising TCRs) in humans by administering these immunogenic HPV E2 and E5 peptides, (2) Ulrich demonstrates such CTLs are successfully naturally produced in humans, specifically recognizing various HPV peptide epitopes including SEQ ID NO:2; and (3) Ulrich teaches known, routine methods for successfully producing human CD8+ CTLs having TCRs with human variable and constant regions and alpha/beta chains, that are specific for the HPV peptide epitopes they are produced with. Given the known immunogenic HPV E2 and E5 peptide epitopes identified by Sette for the induction of CTLs, and given the known methods for inducing and identifying CTLs having TCRs that specifically bind and recognize immunogenic HPV peptide epitopes taught by Ulrich, it is well within the level of the ordinary skilled artisan to produce and/or isolate human CTLs having TCRs specific for the instantly claimed HPV 16 E2 and E5 peptide sequences with a reasonable expectation of success.
7. Claim(s) 6, 12, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 7,026,443, Sette et al, published 2006; and Ulrich (2020, Dissertation: “CD8+ T cell Receptor Characterization in HPV Associated Head and Neck Cancer”, Arizona State University); as applied to claims 1-5, 7-11 above, and further in view of Mercier-Letondal et al (Human Gene Therapy, 2018, Vol. 29, No. 10; p. 1202-1212).
Sette and Ulrich (the combined references) teach producing human CTLs comprising human TCRs that specifically recognize and bind instant HPV 16 SEQ ID NOs:1-3 peptide epitopes, as set forth above.
The combined references do not teach isolating the TCR specific to instant SEQ ID NOs:1-3, producing a nucleic acid sequence encoding the TCR, producing an expression vector comprising a nucleic acid encoding the TCR, with a label or heterologous peptide sequence, and transducing host cells with the vector to express the TCR.
Urlich further teaches isolating TCR sequences from the CTLs having specificity for HPV epitopes in order to transfect the epitope-specific TCRs into T cells for administration to subjects having HPV-related cancer. Ulrich teaches known, successful methods for isolating a single CD8+ T cell, sequencing the TCR, producing a TCR retroviral nucleic acid construct/ expression vector (i.e., heterologous nucleic acid comprising a nucleotide sequence encoding the TCR alpha and beta chains), and transfecting host cells with the expression vector (p. 63-73).
Similar to Ulrich, Mercier-Letondal teaches isolating TCRs specific for HPV immunogenic HPV 16 E peptide epitope in order to transfect the TCR gene into T cells for immunotherapy of HPV-related cancers (abstract). Mercier-Letondal exemplifies successfully isolating and sequencing a TCR gene from a T cell specific for an HPV peptide epitope, inserting the TCR gene into an expression vector (i.e. heterologous nucleic acid comprising a nucleotide sequence encoding the TCR alpha and beta chains), wherein the vector comprises heterologous inducible suicide iCASP9 safety sequence and ΔCD19 selection transgene (“other label”); and transducing host T cells with the vector to express the TCR (Materials and Methods; Figures 1-5).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was effectively filed to isolate the TCR specific to instant SEQ ID NOs:1-3, produce a nucleic acid sequence encoding the TCR, produce an expression vector comprising the nucleic acid encoding the TCR, with a label or heterologous peptide sequence, and transduce host cells with the vector to express the TCR. One would have been motivated to, and have a reasonable expectation of success to, because: (1) all of the cited references teach motivation to produce CTLs specific for the immunogenic HPV 16 E peptide epitopes for the treatment of HPV-related cancers; (2) Ulrich and Mercier-Letondal teach motivation to isolate the TCR from the CTLs for transduction into T cells for treatment of HPV-related cancers; and (3) Ulrich and Mercier-Letondal teach and demonstrate known and successful laboratory methods to accomplish isolation of TCR sequences, production of expression vectors comprising the TCR sequences, including labels and heterologous peptide sequences, and transduction of T cells with the vectors to express the TCR specific to the HPV 16 E peptide epitope.
8. Conclusion: No claim is allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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