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 .
DETAILED ACTION
Claim Status
Applicant's amendment filed August 25, 2026 has been received and entered.
Claims 1, 7, 32-33, 67, 83, 86, 88, 92, 113, 132, 139, and 143 have been amended.
Claim 31 has been canceled.
Claims 2-6, 8, 10, 12-15, 17-30, 33, 35-41, 44-66, 68-73, 80, 82, 84-85, 87, 89-91, 94-112, 114-117, 119-131, 133-135, 137-138, 141-142, and 144-149 were previously canceled.
Claim 150 has been added.
Claims 1, 7, 9, 11, 16, 32, 34, 42-43, 67, 74-79, 81, 83, 86, 88, 92-93, 113, 118, 132, 136, 139-140, 143, and 150 are pending and under consideration.
Election/Restrictions
Applicant’s election with traverse of Group I, encompassing claims 1, 7, 9, 11, 16, 75-76, and 150, in the reply filed on August 25, 2026 is acknowledged.
The traversal is on the ground(s) that instant claim 1 has been amended to recite the six specific CDR amino acid sequences (SEQ ID NOs) of a single elected binding protein (i.e., TCR), and that the remaining pending claims, represented by Groups II-VII, depend from or recite nucleic acids, vectors, host cells, compositions, methods, or expression vectors that encode, express, use, or comprise the binding protein of claim 1 and are thereby linked to the same binding protein with the specific six CDR sequences. Therefore, the binding protein comprising the recited CDR sequences thus constitutes a single general inventive concept linking all pending claims.
In addition, Applicant elects with traverse as described above, a single species of TCR comprising a TCR alpha chain variable domain comprising a CDR1 having residues 45-49 of SEQ ID NO: 19, a CDR2 having residues 67-73 of SEQ ID NO: 19, and a CDR3 having residues 107-120 of SEQ ID NO: 19; and a TCR beta chain variable domain comprising a CDR1 having residues 46-50 of SEQ ID NO: 21, a CDR2 having residues 68-73 of SEQ ID NO: 21, and a CDR3 having residues 111- 123 of SEQ ID NO: 21.
This is not found persuasive.
For purposes of the initial requirement, a serious burden on the examiner may be prima facie shown by appropriate explanation of separate classification, or separate status in the art, or a different field of search as defined in MPEP § 808.02. The Requirement mailed June 26, 2026 set forth an explanation of the separate categories of inventions. Accordingly, the inventions of Groups I-VII have acquired a separate status within the art and separate search strategies.
The requirement is still deemed proper and is therefore made FINAL.
Accordingly, claims 32, 34, 42-43, 67, 74, 77-79, 81, 83, 86, 88, 92-93, 113, 118, 132, 136, 139-140, and 143 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 election requirement in the reply filed on August 25, 2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Priority
This application claims the benefit of U.S. Provisional Application No. 63/342,479 filed May 16, 2022, which claims the benefit of U.S. Provisional Application No. 63/317,326 filed March 7, 2022, which claims the benefit of U.S. Provisional Application No. 63/277,901 filed November 10, 2021.
U.S. Provisional Application No. 63/277,901 filed November 10, 2021 provides support for the instant claims currently under examination as a result of the restriction/election requirement set forth above.
Claim Objections
Claims 1, 7, 9, 11, 16, 75-76, and 150 are objected to because of the following informalities:
Claim 1 – should be amended to read “a CDR1…”, “a CDR2…”, and “a CDR3”.
Claim 7 sets forth a plurality of elements. MPEP § 608.01(m) states that each element or step of the claim should be separated by a line indentation. There may be plural indentations to further segregate subcombinations or related steps. Additionally, the elements are numbered within the claim, which makes it hard to distinguish the numbered elements from the claims. It is suggested that the elements be listed using lowercase letters (e.g., a) and b)), with each element separated by a line indentation.
Claim 7 (lines 1 and 4) – CDR should be amended to read “CDRs”.
Claim 7 (lines 6 and 8) – “and/or” is repeated twice.
Claim 9 sets forth a plurality of numbered elements, which makes it hard to distinguish the numbered elements from the claims. It is suggested that the elements be listed using lowercase letters (e.g., a), b), c), etc.), with each element separated by a line indentation.
Claim 9 - “T-cell” is hyphenated throughout the claim, however, the term appears as T cell (unhyphenated) in the other instant claims.
Claim 9 (parts 6-7) – are missing the term “complex” after (pMHC).
Claim 9 (part 7) – should read “”1.05-fold”.
Claim 9 (part 8) - should read “i) a CaSki, an SCC1552, or an SCC090 cell line”.
Claim 11 sets forth a plurality of numbered elements, which makes it hard to distinguish the numbered elements from the claims. It is suggested that the elements be listed using lowercase letters (e.g., a), b), c), etc.), with each element separated by a line indentation. Each subelement recited in the claim should be listed using lowercase roman numerals (e.g., i and ii).
Claim 11 (line 7) – should read “a CD34 enrichment tag”.
Claim 11 (line 7) – should read “glutathione-S-transferase”.
Claim 11 (line 8) – should read “Protein C tag”.
Claim 11 (line 8) – should read “FLAG tag”.
Claim 16 sets forth a plurality of numbered elements, which makes it hard to distinguish the numbered elements from the claims. It is suggested that the elements be listed using lowercase letters (e.g., a), b), c), etc.), with each element separated by a line indentation.
Claim 16 (line 4) – the term “allele” in the last line of the claim is redundant. It is suggested that the claim be amended to read “the group consisting of HLA-A*0201, HLA-A*0202, HLA- A*0203, HLA-A*0205, HLA-A*0206, and HLA-A*0207 .”
Claims 75-76 set forth a plurality of elements. MPEP § 608.01(m) states that each element or step of the claim should be separated by a line indentation.
Claim 150 sets forth a plurality of elements. MPEP § 608.01(m) states that each element or step of the claim should be separated by a line indentation. There may be plural indentations to further segregate subcombinations or related steps. Additionally, the elements are numbered within the claim, which makes it hard to distinguish the numbered elements from the claims. It is suggested that the elements be listed using lowercase letters (e.g., a) and b)) and the subelements listed using lowercase roman numerals (e.g., i and ii), with each element separated by a line indentation.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 7, 9, 11, 16, and 75-76 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 7 recites the terms “TCR Va domain”, “TCR Vb domain”, and “immunogenic peptide”. However, there is no antecedent basis for these limitations in the claims.
Claim 9 recites the term “immunogenic peptide”. However, there is no antecedent basis for this limitation in the claims.
Claim 9 recites the term “optionally” several times, which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(h). For the purpose of examination, the limitations wherein the binding domain comprises a transmembrane domain and an effector domain that is intracellular, wherein the immune response is a T cell response, wherein the T cell response is selected from the group consisting of T cell expansion, cytokine release, and/or cytotoxic killing, wherein the target cell is a CaSki, an SCC152, or an SCC090 cell line are not being interpreted as being required limitations. The limitations wherein the cancer cell is a head & neck cancer cell, an oropharyngeal cancer cell, a cervical cancer cell, an anal cancer cell, a vaginal cancer cell, a vulval cancer cell, or a penile cancer cell, and wherein the binding peptide does not bind to any of the pMHC complexes recited in part 10 and 11 are being interpreted as required limitations.
Claim 9 recites the terms “higher binding affinity” and “higher T cell expansion” which are relative terms that render the claim indefinite. The specification does not provide a definition for the terms. Therefore the terms “higher binding affinity” and “higher T cell expansion” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
For the purpose of examination, the claim is interpreted as the binding affinity is at least 1.05 fold higher than a known T cell receptor and induces at least 1.05-fold increase in expansion.
Claim 11 recites the term “optionally” several times, which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(h). For the purpose of examination, the limitations wherein the TCR alpha chain and the TCR beta chain are covalently linked through a linker peptide; and/or are covalently linked to a moiety comprising an affinity tag or a label selected from those recited in claim 11 are interpreted as not being required .
Claim 11 recites “the binding protein of claim 1, wherein the TCR alpha chain and the TCR beta chain”, however, there is no antecedent basis for this limitation in the claims as claim 1 is drawn to the TCR alpha variable domain and the TCR beta variable domain.
Claim 11 contains the trademark/trade name HaloTag®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a self-labeling protein tag and, accordingly, the identification/description is indefinite.
Claim 16 recites ”the MHC”, however, there is no antecedent basis for this limitation as the claim depends from claim 1 which recites a “pMHC”.
Claim 16 recites the term “optionally” twice, which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(h). For the purpose of examination, the limitations wherein the MHC multimer is a tetramer and wherein the HLA allele is selected from the group consisting of HLA-A*0201, HLA-A*0202, HLA- A*0203, HLA-A*0205, HLA-A*0206, and HLA-A*0207 alleles are interpreted as not being required .
Claims 75-76 are drawn to the binding protein according to claim 1, an isolated nucleic acid according to claim 32, a vector according to claim 34, a host cell according to claim 42, and/or a population of host cells according to claim 74. However, claims 32, 34, 42, and 74 correspond to a nonelected invention. As such, the claims will be interpreted only in regard to the binding protein according to claim 1.
Claim 76 recites the term “optionally”, which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(h). For the purpose of examination, the limitation wherein the claimed device or kit comprises a reagent to detect binding of binding protein, a host cell according to claim 42, and/or a population of host cells according to claim 74 to a pMHC complex is interpreted as not being required .
Claim Rejections - 35 USC § 112(a)
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.
WRITTEN DESCRIPTION
Claim 150 is rejected under 35 U.S.C. 112(a), 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, at the time the application was filed, had possession of the claimed invention.
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 claimed genus. See MPEP § 2163.
Claim 150 is drawn to an isolated HPV16 E711-19 peptide-MHC (pMHC) complex binding protein comprising a TCR alpha chain variable domain comprising an amino acid sequence with at least 80% identity to residues 1-131 of SEQ ID NO: 19 and a TCR beta chain variable domain comprising an amino acid sequence with at least 80% identity to residues 1-133 of SEQ ID NO: 21; or a TCR alpha chain variable domain comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 19 and a TCR beta chain variable domain comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 21.
The claim encompasses a large genus of structurally distinct TCRs allowing for up to 20% variability in each of the recited TCR alpha and beta chain variable domain amino acid sequences. However, neither the claims nor the specification disclose how the sequences may vary (i.e., insertion, deletion, substitution) or where in the sequence such variation may occur. Therefore, it can be considered that the inventions defined by claim 150 encompass countless possible substitutions. Combinations of single or double substitutions further multiply the possibilities.
The full length TCR alpha chain variable domain sequence (SEQ ID NO: 19) is 270 amino acids in length and the full length TCR beta chain variable domain sequence (SEQ ID NO: 21) is 320 amino acids in length. The claim also recites fragments of the TCR alpha chain variable domain sequence (residues 1-131 of SEQ ID NO: 19) and TCR beta chain variable domain sequence (residues 1-133 or SEQ ID NO: 21).
Regarding the TCR alpha chain variable domain comprising SEQ ID NO: 19, when considering only substitutions, a polypeptide that is 80% identical to the full length sequence of 270 amino acids would allow for up to 55 amino acid substitutions, while a fragment of the sequence comprising 131 amino acids would allow for up to 26 amino acid substitutions.
Regarding the TCR beta chain variable domain comprising SEQ ID NO: 21, when considering only substitutions, a polypeptide that is 80% identical to the full length sequence of 320 amino acids would allow for up to 65 amino acid substitutions, while a fragment of the sequence comprising 133 amino acids would allow for up to 27 amino acid substitutions.
Example 2 of the instant specification discloses that 74 HPV16-E711-19 specific TCRs were isolated. Out of those, 24 TCRs had desired cell surface expression and effector function (i.e., cytotoxicity and/or cytokine production). Of all TCRs identified, TCR28 had comparable cytotoxicity and superior effector function relative to the comparator TCR [pg. 186, Figs. 3-4 and 7-8].
It is well understood in the art that the engineering of T cells with genes encoding TCR chains is a complex and fairly unpredictable process, in such that substituting even one amino acid within the sequence can change the structure and function of said TCR. Ghoreyshi et al. (2018) teach that understanding the molecular interactions underlying T-cell receptor (TCR) recognition of peptide-major histocompatibility complex (pMHC) complexes is essential for elucidating fundamental principles of immune specificity and tolerance, as well as for informing the design of novel immunotherapeutic strategies. Alanine-scan mutagenesis is an experimental approach that systematically interrogates the contributions of individual peptide residues to TCR recognition. While highly informative, this technique alone lacks predictive capability regarding structural rearrangements and compensatory interactions that may arise upon residue substitution. Therefore, the integration of such experimental data with computational modeling is crucial for accurately capturing the complex landscape of TCR-pMHC interactions, particularly in scenarios involving subtle changes that critically affect T cell activation [Introduction]. The reliable identification of TCR-pMHC recognition making (or breaking) single amino acid variants is a difficult problem, originating from the fact that point mutated amino acid sequences often behave very differently from their nearly identical WT analog [Discussion, par. 1]. Ghoreyshi et al. combined a structure-informed scoring model with exhaustive single amino acid mutagenesis to quantify how peptide substitutions alter recognition by the diabetogenic 1E6 TCR (HLA-A*02:01–restricted), classify variants whose activity is retained or lost relative to the wild type (WT), and (iii) search the CDR3 sequence space for minimal TCR edits that could restore recognition on the same decoy-normalized scale [Results, par. 1]. ]. Ghoreyshi et al. found that central peptide residues act as energetic hot spots, whereas terminal positions contribute less directly to recognition [Discussion, par. 2]. However, most single amino acid substitutions reduced 1E6 activity [Results, par. 4].
The instant specification discloses 74 TCRs that specifically bind HPV16 E711-19 [YMLDLQPET (SEQ ID NO: 1)] peptide, however, only 24 demonstrated adequate cell surface expression and effector function. Further, only a single TCR (TCR28) was identified and demonstrated an increase in effector function compared to the wild type TCR. Thus, one cannot readily extrapolate the properties of an isolated HPV16 E711-19 peptide-MHC complex binding protein comprising a TCR alpha chain variable domain represented by SEQ ID NO: 19 or a TCR beta chain variable region represented by SEQ ID NO: 21 to TCRs with up to 20% variability encompassed by claim 150, as the properties of an HPV16 E711-19 peptide specific TCR comprising the recited alpha and beta chain variable domains are not predictive of the full genus of proteins that can be generated.
The instant application has not provided a sufficient description showing possession of the necessary 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 of TCRs encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc., 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002). In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 48 USPQ2d 1398 (Fed Cir. 1997)).
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 Vas-Cath, p. 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, p. 1116). Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in
“possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support
need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein
v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning —
i.e., what the written description and knowledge in the art would lead one to speculate as to
modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also
ensures that when a patent claims a genus by function, the specification recites sufficient materials to
accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3.
Given the claimed broadly class of HPV16 E711-19 specific TCRs, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed polypeptides to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
ENABLEMENT
Claim 150 is rejected under 35 U.S.C. 112(a), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains 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.
Applicant has claimed an isolated HPV16 E711-19 peptide-MHC (pMHC) complex binding protein comprising a TCR alpha chain variable domain comprising an amino acid sequence with at least 80% identity to residues 1-131 of SEQ ID NO: 19 and a TCR beta chain variable domain comprising an amino acid sequence with at least 80% identity to residues 1-133 of SEQ ID NO: 21; or a TCR alpha chain variable domain comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 19 and a TCR beta chain variable domain comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 21.
The specification disclosure is insufficient to enable one skilled in the art to practice the
invention as claimed without an undue amount of experimentation. Undue experimentation must be
considered in light of factors including: the breadth of the claims, the nature of the invention, the state
of the prior art, the level of one of ordinary skill in the art, the level of predictability in the art, the
amount of direction provided by the inventor, the existence of working examples, and the quantity of
experimentation needed to make or use the invention, see In re Wands, 858 F.2d at 737, 8 USPQ2d at
1404 (Fed. Cir. 1988).
In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) states, “The amount of guidance or
direction needed to enable the invention is inversely related to the amount of knowledge in the state of
the art as well the predictability in the art.” “The “amount of guidance or direction” refers to that
information in the application, as originally filed, that teaches exactly how to make or use the invention.
The more that is known in the prior art about the nature of the invention, how to make, and how to use
the invention, and the more predictable the art is, the less information needs to be explicitly stated in
the specification. In contrast, if little is known in the prior art about the nature of the invention and the
art is unpredictable, the specification would need more detail as to how to make and use the invention
in order to be enabling” (MPEP § 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable. With these teachings in mind, an enabling disclosure, commensurate in scope with the breadth of the claimed invention, is required.
Nature of invention and breadth of the claims:
Claim 150 is drawn to an isolated HPV16 E711-19 peptide-MHC (pMHC) complex binding protein comprising a TCR alpha chain variable domain comprising an amino acid sequence with at least 80% identity to residues 1-131 of SEQ ID NO: 19 and a TCR beta chain variable domain comprising an amino acid sequence with at least 80% identity to residues 1-133 of SEQ ID NO: 21; or a TCR alpha chain variable domain comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 19 and a TCR beta chain variable domain comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 21.
Relative skill in the art:
The relative skill of those in the art is high with an M.D. or Ph.D..
Level of unpredictability in the art; State of the prior art:
Regarding the unpredictability of TCR structure, Ghoreyshi et al. teaches point mutated TCR alpha chain and beta chain amino acid sequences often behave very differently from their nearly identical WT analog [Discussion, par. 1]. Ghoreyshi et al. combined a structure-informed scoring model with exhaustive single amino acid mutagenesis to quantify how peptide substitutions alter recognition by the diabetogenic 1E6 TCR (HLA-A*02:01–restricted), classify variants whose activity is retained or lost relative to the wild type (WT), and (iii) search the CDR3 sequence space for minimal TCR edits that could restore recognition on the same decoy-normalized scale [Results, par. 1]. ]. Ghoreyshi et al. found that central peptide residues act as energetic hot spots, whereas terminal positions contribute less directly to recognition [Discussion, par. 2]. However, most single amino acid substitutions reduced activity [Results, par. 4].
Direction or guidance and working examples:
The disclosure only recites 74 TCRs that specifically bind HPV16 E711-19 peptide, in which only 24 demonstrated adequate cell surface expression and effector function. Further, only a single TCR (TCR28) was identified which demonstrated an increase in effector function compared to the wild type TCR. No data is presented with TCRs expressing fragments of the alpha and/or beta chain variable domains. Thus, it would be difficult for one of ordinary skill in the art to envisage a TCR having 80% identity to the TCR alpha and/or beta chain variable domains of the TCRs specific for the HPV16 E711-19 peptide that were generated that would also have the same properties as the amino acid sequences recited in the instant claims.
The quantity of experimentation needed:
The disclosure does not specify how the sequences may vary (i.e., insertion, deletion, substitution) or where in the sequence such variation may occur. Therefore, it can be considered that the inventions defined by claim 150 encompass countless possible substitutions.
There are 55 possible substitutions that can be made in the full length TCR alpha chain variable domain comprising SEQ ID NO: 19, and 65 possible substitutions that can be made in the full length TCR beta chain variable domain comprising SEQ ID NO: 21 when considering a TCR alpha and/or beta chain variable region at least 80% identical to the recited sequences.
There are 26 possible substitutions that can be made in residues 1-131 of the TCR alpha chain variable domain comprising SEQ ID NO: 19, and 27 possible substitutions that can be made in residues 1-133 of the TCR beta chain variable domain comprising SEQ ID NO: 21 when considering a fragment of a TCR alpha and/or beta chain variable region at least 80% identical to the recited sequences. Combinations of single or double substitutions further multiply the possibilities. Additionally, the variation could occur anywhere in the sequence, e.g., three in a row, spread over the entire sequence. However, which residues are critical for proper binding and recognition by the MHC complex is highly unpredictable and the instant application has not provided any correlation between what specific structure is needed for binding the HPV16 E711-19 peptide, as seen by the data that show of 74 TCRs that specifically bind the HPV16 E711-19 peptide, only 24 demonstrated adequate cell surface expression and effector function. Further, only a single TCR (TCR28) was identified which demonstrated an increase in effector function compared to the wild type TCR.
Thus, based on the unpredictability of the art, breadth of the claims, lack of working examples, and quantity of experimentation needed, the instant specification must provide a sufficient and enabling disclosure commensurate in scope with the instant claims. It would require enormous amount of trial and error in order to obtain a TCR that is specific for the HPV16 E711-19 peptide other than the specific alpha and beta chain variable domain amino acid sequences described in the detailed description of the invention. This is not in commensurate in scope with the instant claims, which encompass making up to 55 and 65 substitutions in the alpha and beta chain variable domain amino acid sequences, respectively, to obtain a TCR that is specific for the HPV16 E711-19 peptide. Thus, it would require undue experimentation to practice the full scope of the claimed method. Specifically, one cannot envisage a TCR alpha chain variable domain comprising an amino acid sequence with at least 80% identity to residues 1-131 of SEQ ID NO: 19 and a TCR beta chain variable domain comprising an amino acid sequence with at least 80% identity to residues 1-133 of SEQ ID NO: 21; or a TCR alpha chain variable domain comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 19 and a TCR beta chain variable domain comprising an amino acid sequence with at least 80% identity to SEQ ID NO: 21 and also having the same properties as the TCR recited in the instant claims. However, the explicit examples provided in the instant specification fall within a genus that is not fully enabled, including TCRs that are 80% to 99% identical to the recited sequences.
Statement Regarding Prior Art
A search of the art indicates that the amino acid sequences for the claimed TCR specific for the HPV16 E711-19 peptide, comprising a TCR alpha chain variable domain of SEQ ID NO: 19 and a TCR beta chain variable domain of SEQ ID NO: 21), are novel. The closest available prior art identified in the Examiner's search is Jin et al. (JCI Insight, 2018; 3(8):e99488) (“Jin”) which teaches TCRs specific for the HPV16 E711-19 peptide, however, Jin does not teach or suggest the same amino acid sequences as recited in the instant claims.
Double Patenting
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 7, 9, 11, 16, 32, 34, 42-43, 67, 74-79, 81, 83, 86, 88, 92-93, 113, 118, 132, 136, 139-140, and 143 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 7-9, 11, 16, 20, 32, 34, 42-43, 74-75, 97, 100, and 109 of U.S. Application No. 18/860,341.
Copending claim 1 is drawn to a composition comprising a T cell receptor (TCR) that is capable of binding to an immunogenic peptide derived from a target protein as an immunogenic peptide-MHC (pMHC) complex. Copending claim 4 recites the TCR alpha chain sequences are selected from Table 1, 4, or 6 of the specification. Copending claim 7 recites the TCR alpha chain is encoded by a TRAV, TRAJ, and/or TRAC gene. Copending claim 8 recites the immunogenic peptide amino acid sequence is one of those listed in Table 3 of the specification. Copending claim 9 recites properties of the TCR, including being humanized or human and inducing T cell expansion. Copending claim 11 recites the TCR alpha and beta chains are covalently linked. Copending claim 16 recites the MHC is an MHC class 1 molecule comprising an HLA allele such as HLA-A*02. Copending claim 20 recites the pMHC complex elicits an immune response as well as the Kd values. Copending claim 32 is drawn to isolated nucleic acid molecules encoding the TCR. Copending claim 34 is drawn to tagged vectors comprising the nucleic acid encoding the TCR. Copending claims 42-43 are drawn to a host cell comprising the nucleic acid or vector and expression of the TCR. Copending claim 74 is drawn to a population of host cells. Copending claim 75 is drawn to a method of preventing and/or treating a non-malignant disorder, a hyperproliferative disorder. Copending claim 97 is drawn to the MHC class I HLA serotype. Claim 100 recites the target cell a non-malignant cell or a hyperproliferating cell expressing the antigen and a pharmaceutical composition. Copending claim 109 recites administration of at least one additional treatment for the non-malignant disorder, the hyperproliferative disorder or the relapse of a hyperproliferative disorder.
The instantly claimed TCR alpha and beta chains and their respective CDRs are recited in Table 1 of the copending specification. The instantly claimed TCR (TCR28) alpha and beta chains comprising SEQ ID NOs: 19 and 21, respectively, are identical to the copending application TCR28 alpha and beta chains comprising SEQ ID NOs: 34 and 36, respectively [pg. 28]. Therefore, the instant claims read on the identical TCR as recited in the copending claims, including those drawn to a non-elected invention, and differ from the copending claims only in order of presentation.
As such, the instant claimed invention is an obvious modification of the copending claims.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642
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