Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s 6-1-26 election of the invention of Group I, and the species of TCR comprising SEQ ID NOs: 1 and 2 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-18 are pending.
Claims 1-12 and 18 are under examination as they read on the elected species of TCR comprising SEQ ID NOs: 1 and 2.
Claims 13-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6-1-26.
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 2, 4, 9, and 18 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.
In claim 2, the ordinarily skilled artisan would not understand how a TCR heterodimer could comprise four variable domains, two α and two β chain of SEQ ID NOs: 5, 6, 13 and 2. Moreover, in claim 4, the ordinarily skilled artisan would not understand how, e.g., SEQ ID NO: 2 could be referred to as a “TCRα polypeptide.” In claim 9, the phrase “expression vector” lacks antecedent basis in base claims 1 and 5. In claim 18, the expression vector lacks antecedent basis in claim 7.
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 1-8, 10-12 and 18 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 claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule defined solely by its ability to perform a function, such as to serve as an antigen recognizing construct, without a known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest, see MPEP 2163.
The specification provides insufficient direction or guidance concerning the relationship between the structure of the claimed TCR variable domains / TCR CDRs, and the ability of said TCR to bind to an MR1 molecule presenting a tumor-associated antigen to demonstrate possession of the breadth of TCR variants encompassed by the instant claims.
As has been long known by the skilled artisan, antibodies and TCRs have structural and functional similarities. For example, both molecules are heterodimers, with each monomer subunit having the characteristic immunoglobulin fold, genes encoding both molecules are constructed via V(D)J recombination of germline encoded nucleic acids, both molecules rely on accessory molecules to promote signal transduction upon ligand binding.
By analogy to antibodies, several recent court decisions speak to the notion that claiming a molecule with unknowable structural heterogeneity solely by reciting its function, i.e., its ability to bind to an MR1 molecule expressed on any tumour cell presenting any tumour associated antigen, is not sufficient to establish possession of a genus so claimed.
Rather, “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69).
A "representative number of species" means that the species which are described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
Likewise, the Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding, binding to a certain epitope), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Along these same lines, the more recent Federal Circuit decision of Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describes how when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself not just a description of the sequence to which the antibody binds. Amgen, 872 F.3d at 1378-79.
The importance of this court decision was expounded upon by Robert W. Bahr, Deputy Commissioner for Patent Examination Policy in a memorandum clarifying the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) as it relates to claims drawn to antibodies (see Memorandum of February 22, 2018, 2 pages, available on the USPTO website at https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf).
Specifically, the so-called “newly characterized antigen” test, which had been based on an example in previously issued USPTO training materials and had been used in the past for determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody is now considered defunct.
The Memorandum explains that USPTO personnel should continue to follow the relevant sections of the MPEP pertaining to the written description requirement of 35 U.S.C. § 112(a) (without regard for any disclosure in the MPEP concerning the use of a fully characterized antigen to provide written description support for an antibody to said antigen).
As described in MPEP § 2163, “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 Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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Note well: even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify binding proteins with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule defined solely by its ability to perform a function, such as its ability to bind to an MR1 molecule presenting a tumor-associated antigen, without a known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest, see MPEP 2163.
In the instant case for example the claims are drawn to the genus of TCR heterodimers which have, e.g., sequence specified α- and β-CDR3 domains in the context of any, non-sequence specified α- and β-variable domain (e.g. in claim 1), or the genus of TCR heterodimers having e.g., sequence specified α- and β-CDR3 domains in the context of certain sequence specified α- and β- chains, such as the TCR α- and β- variable domains which are ≥ 85% similar to SEQ ID NOs: 1 and 2 (see claim 3).
Thus, the claims read on a vast genus of TCRs capable of binding to an MR1 molecule presenting a tumor-associated antigen, said TCRs comprising various sequence-specified CDR3 domains paired with any α- and β-chains comprising any CDRs 1 and 2, or paired with any certain sequence-specified α- and β-chains comprising amino acid substitutions sufficient to, e.g., completely replace the sequence-specified CDR1 and CDR2 regions with any other sequences.
At page 37 the instant specification discloses the SEQ ID NOs: for TCR α/β clones 1-15 and TCR γ/β clone 1.
At page 28, 1st paragraph the specification describes: “The inventors detected an atypical MR1 -restricted T cell clone that did not react to microbial ligands during earlier studies on the repertoire of human MAIT cells. This T cell clone (DGB129) recognized cell lines constitutively displaying surface MR1 (CCRF-SB lymphoblastic leukemia cells, or THP-1 monocytic leukemia cells; Figure 1A) or transfected with the MR1 gene (A375 melanoma cells; A375-MR1; Figure 1A) in the absence of any exogenously added antigens (Figure 1 B)…. DGB129 T cells also failed to recognize the synthetic MAIT cell agonist 6,7-dimethyl-8-D-ribityllumazine (RL-6,7-diMe; Figure 1D), differently from a control MAIT cell clone, which instead was stimulated in MR1-dependent manner by this compound (Figure 1E). DGB129 cells did not express the canonical semi-invariant TCR typical of MAIT cells (Table 1)…. In both donors the inventors
found that a major fraction of T cell clones (126/195 and 37/57, respectively) displayed specific
recognition of A375-MR1 cells (Figure 2B,D), which was inhibited by anti-MR1 blocking mAbs
(Figure 2C,E). Staining with TCR Vβ-specific mAbs of MR1-reactive T cell clones revealed
that they expressed 7 different TRBV chains (TRBV4-3, 6-5/6-6/6-9, 9, 18, 25-1, 28, 29-1) with
some of the clones sharing the same TRBV gene. Furthermore, none expressed the TRAV1-2 chain, canonical for MAIT cells….Detailed analysis of representative T cell clones derived
from three donors confirmed that they displayed diverse TCRα and β chains and indicated
differential expression of CD4, CD8 and CD161 (Table 1 ).”
At page 33, 3rd paragraph, the specification describes how MR1T cells are functionally heterogeneous: “The inventors finally analyzed the cytokine secretion profile of representative MR1 T cell clones upon stimulation by A375-MR1 tumour cells. All clones tested released IFN-y (Figure 10A). However, the inventors also observed diverse expression profiles of Th1 (IL-2, TNF-a and TNF-13), Th2 (IL-3, IL-4, IL-5, IL-6, IL-10, IL-13) and Th17 cytokines (IL-17A, G-CSF, GM-CSF), and other soluble factors (MIP-113, soluble CD40L PDGF-AA and VEGF; Figure 10B). The variable combinations and quantities of cytokines expressed by MR1T cells suggested considerable functional plasticity within this population. For example, clone DGA4 secreted large quantities of IL-17A, IL-6, TNF-a and GM-CSF, but failed to secrete the prototypic Th2 cytokines IL-4, IL-5, IL-10 or IL-13, and thus displayed an 'atypical' Th17-like phenotype. In contrast, clone TC5A87 released substantial amounts of VEGF and PGDF-AA, but only little Th1 or Th2 cytokines, and no IL-17A. Notably, four of the seven clones studied (DGB129, CH9A3, DGB70, JMA) displayed a Th2-skewed profile of cytokine release, a functional phenotype which has been recently associated with protective anti-tumour immunity.”
To summarize, as described above the specification describes various T-cells comprising α- and β-chain (or a single γ- and δ-chain) heterodimers capable of binding to an MR1 molecule presenting a tumor-associated antigen, said T-cells:
expressing any one of 7 different TRBV chains;
with none expressing the TRAV1-2 chain which is canonical for MAIT cells;
said T-cells displaying diverse TCRβ chains;
said T-cells exhibiting differential expression of CD4, CD8 and CD161; and
said T-cells exhibiting an 'atypical' Th17-like phenotype OR a Th2-skewed phenotype OR diverse expression profiles of Th1 (IL-2, TNF-a and TNF-13), Th2 (IL-3, IL-4, IL-5, IL-6, IL-10, IL-13) and Th17 cytokines (IL-17A, G-CSF, GM-CSF), and other soluble factors (MIP-113, soluble CD40L PDGF-AA and VEGF; Figure 10B).
An alignment of the variable domains for TCR α chains of clones 1-15 displayed on the Table at page 37 of the specification is attached. This alignment shows that the α chain variable domains are structurally distinct, and the CDR3s are completely different one from the other. Given that various MR1 reactive T cell clones listed in Table 1 on page 34 also have structurally distinct β chains it can be assumed that the TCR β chain variable domains are similarly structurally distinct.
The instant specification does not disclose any details about how representative the 15 clones displayed in the Table of page 37 are of the genus of TCRs having the ability to bind to an MR1 molecule presenting a tumor-associated antigen.
Moreover, the instant specification does not describe any steps taken to probe if these clones are representative of the genus of TCR clones having the ability to bind to an MR1 molecule presenting a tumor-associated antigen.
For example, the instant specification does not disclose if the clones isolated according to the teachings at pages 28-30 were isolated many times over indicating that the screen was comprehensive, nor does the instant specification disclose if interrogating human T cells with a cancer cells other than the particular A375-MR1 species would give rise to clones bearing the same CDRs as the 15 clones shown in the Table at page 33.
The genus of TCRs necessary to practice the breadth of the instant claims may be vast or it may be small, but the skilled artisan would have no way of knowing which is true from the teachings of the specification; rather all that the skilled artisan would know is that the genus of potential TCRs that would need to be screened to determine if one has obtained members of the genus representative of its potential diversity is vast.
Note that there is an incredible diversity of TCRs due to the nature of V(D)J recombination and adaptive immunity (see, e.g., Woodsworth et al., Genome Medicine 2013, 5:98, which provides a nice summary in “Box 1” of the genesis and function of T cell repertoire diversity that would be familiar to the ordinarily skilled artisan well prior to applicant’s date of invention; see also Robins et al., Blood. 2009;114:4099-4107, Abstract and Introduction describing assessments of diversity in the TCR repertoire, both cited on an IDS).
Finally, claims 2 and 4 are not adequately described for the following reasons:
In claim 2 the ordinarily skilled artisan would not understand how the instant specification could be said to put to put them in possession of a TCR heterodimer comprising the four variable domains, two α and two β chain of SEQ ID NOs: 5, 6, 13 and 2, given the teachings of; and
in claim 4 the ordinarily skilled artisan would not understand how the instant specification could be said to put to put them in possession of a TCR heterodimer comprising two TCRα polypeptides.
In conclusion, the instant specification does not adequately teach the genus of TCR structures required for binding to an MR1 molecule presenting a tumor-associated antigen, nor does it provide TCR species representative of the claimed genus of binders.
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 1-8, 10-12 and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a TCR heterodimer comprising a TCRα and TCRβ pair selected from the following pairs: i. SEQ ID NOs: 1 and 2, or ii. SEQ ID NOs: 3 and 4… and xiv. SEQ ID NOs: 24 and 36, respectively, does not reasonably provide enablement for the TCR heterodimers of the instant claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
As a preliminary matter please note the following:
MPEP § 2111 instructs:
“The Federal Circuit’s en banc decision in Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005) expressly recognized that the USPTO employs the ‘broadest reasonable interpretation’ standard:
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The Patent and Trademark Office (‘PTO’) determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction ‘in light of the specification as it would be interpreted by one of ordinary skill in the art.’ In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must ‘conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description so that the meaning of the terms in the claims may be ascertainable by reference to the description.’ 37 CFR 1.75(d)(1).”
Likewise, MPEP § 2164.08 instructs:
“All questions of enablement are evaluated against the claimed subject matter….The focus of the examination inquiry is whether everything within the scope of the claim is enabled. Accordingly, the first analytical step requires that the examiner determine exactly what subject matter is encompassed by the claims. See, e.g., AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003) (When a range is claimed, there must be reasonable enablement of the scope of the range. Here, the claims at issue encompassed amounts of silicon as high as 10% by weight, however the specification included statements clearly and strongly warning that a silicon content above 0.5% by weight in an aluminum coating causes coating problems. Such statements indicate that higher amounts will not work in the claimed invention.). The examiner should determine what each claim recites and what the subject matter is when the claim is considered as a whole, not when its parts are analyzed individually. No claim should be overlooked. With respect to dependent claims, 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, fourth paragraph, should be followed. These paragraphs state "a claim in a dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers" and requires the dependent claim to further limit the subject matter claimed.”
(emphasis added).
The following is representative of the claims rejected under this statute:
“A T cell receptor (TCR) heterodimer comprising a TCR alpha chain (TCRα) polypeptide, and a TCR beta chain (TCRβ) polypeptide, wherein said TCRα polypeptide and said TCRβ polypeptide are characterized respectively by a pair of a TCRα complementarity determining region 3 (CDR3) and a TCRβ CDR3 selected from SEQ ID NO 065 and SEQ ID NO 080…,” (claim 1), and “The TCR heterodimer according to claim 1, that binds to an MR1 molecule presenting a tumour-associated antigen. (claim 5).
While base claim 1 does not specify how the antibody is to be used, according to the specification, e.g., at page 33, 2nd para, “…these data identify MR1T cells as a novel and heterogeneous population of human MR1-restricted T lymphocytes that i) differently react to various types of tumour cells, ii) display cytotoxic activity against tumour cells… MR1 T cells display important anti-tumour properties and deserve to be exploited for their immunotherapeutic potential.”
More particularly, as described at page 28, 1st para, one T cell clone (DGB129) was found to bind to various cancer cell lines that either naturally express the non-classical class I MHC, “MR1” (CCRF-SB, THP-1), or that have been engineered to express MR1 (A375 melanoma cells, “A375-MR1”)(see spec at page 28, last paragraph and Fig. 1B; at page 30-31 bridging paragraph), and demonstrated DGB129 T-cells efficiently killed both MR1-expressing THP-1 and A375 cells at various effector:target ratios (Figure 9A,B).
Thus, in order for the claimed TCR heterodimers to be useful consistent with 35 USC § 112(a) they must be capable of at least binding to an MR1 molecule presenting a tumor-associated antigen as recited in claim 5.
However, the instant specification does not provide sufficient direction or guidance for the skilled artisan to make and use the genus of TCR heterodimers encompassed by the instant claims which have, e.g., sequence specified α- and β-CDR3 domains in the context of any, non-sequence specified α- and β-variable domain (e.g. in claim 1), or for the genus of TCR heterodimers having e.g., sequence specified α- and β-CDR3 domains in the context of certain sequence specified α- and β- chains, such as the TCR α- and β- variable domains which are ≥ 85% similar to SEQ ID NOs: 1 and 2 (see claim 3).
The specification discloses the cloning of TCRs that bind an A375 tumour cell line engineered to express MR1. The specification does not teach or guide the skilled artisan as to which α and β chain CDR amino acid residues, or which γ and δ chain CDR amino acid residues are critical for binding to the A375 tumour cell line engineered to express MR1; moreover, the skilled artisan would not know from the teachings of the instant specification which other TCRs can mediate binding to an A375 tumour cell line engineered to express MR1, or how representative the particular TCR α/β and γ/δ chains disclosed in the instant specification are of the genus of TCRs encompassed by the instant claims. The instant specification provides insufficient direction or guidance for the skilled artisan to make and use the breadth of TCRs encompassed by the instant claims.
For example, the skilled artisan expects both Vα and Vβ TCR chains are required to create the TCR peptide-MHC binding site (see Janeway et al., Immunobiology, 5th Ed., Garland Science, pages 106-108 and 260-263, (2001), cited on an IDS). In particular, the art teaches while T-cell peptide epitope is predominately recognized by the amino acid residues of TCR CDR3, the TCR CDR1 and TCR CDR2 regions are predominately involved in MHC binding.
Notably, while this division of binding activity between CDRs 1-2 and 3 generally holds true this does not mean that the CDR3 regions are always exclusively responsible for interacting directly with the peptide. Indeed, in some instances CDR1 and CDR2 residues have been shown to directly bind peptide (see, e.g., Manning et al., Immunity, Vol. 8, 413-425, April, 1998, in particular Conclusions section on page 423, cited on an IDS).
However, the prior art provides the skilled artisan with insufficient guidance or direction as to which particular CDR residues are required for MHC or peptide binding, or which CDR and/or TCR framework residues are required to bring about the canonical diagonal interaction of the TCR with peptide-bound MHC (see, e.g., Garcia et al., Cell, Vol. 122, 333–336, August 12, 2005, especially page 333, right col., 1st-3rd paragraphs; page 336, col. bridging paragraph through right col., 1st paragraph and Figure 1, cited on an IDS). Indeed, one hypothesis in the art is that the CDR1 and 2 interactions with the MHC are dependent on the CDR3 interaction with the peptide bound to the MHC, and, if so, "there may be as many TCR/pMHC orientations as CDR3 sequences.” (see Garcia page 336, col. bridging paragraph).
Moreover, the skilled artisan is not enabled to make and use, e.g., the breadth of TCRs encompassed by the instant claims because, unlike in the antibody art where a single full length Vh or VL can be used as the starting material in a high-throughput phage-based assay employing a library of complementary VL or Vh, respectively, to identify novel antibodies that recognize the antigen of interest (see, e.g., Portolano et al., J Immunol. 1993 Feb 1;150(3):880-7, cited on an IDS), there is no routine, art accepted technique for TCR Vα or Vβ “chain shuffling.” One reason such a screen with TCRs would require undue experimentation compared to the antibody art is because the TCR interacts with two ligands simultaneously, i.e., the peptide and the MHC, and, as described above, there is considerable uncertainty in the art about which residues depend on which for these interactions. Thus, the skilled artisan would be quite uncertain of what breadth of TCR sequences should be represented in any potential screen while retaining an expectation that they can execute the screen without having to resort to undue experimentation. For example, if one includes all possible TCR sequences in a screen, including those sequences wherein the germline-encoded variable domain is different from the germline-encoded variable domain of the specific starting TCRs disclosed in the instant specification, will the number of non-productive pairings make it unreasonably difficult to detect productive pairings? Stated another way, insofar as one is attempting to pair sequence specified α- and β-chain CDR3 sequences with the vast genus any of α- / β-chain germline encoded domains, again, will the number of non-productive pairings make it unreasonably difficult to detect productive pairings?
Given the lack of substantive guidance in the instant specification, and the level of complexity in the art, undue experimentation would be required of the skilled artisan to go about making the breadth of TCRs encompassed by the instant claims which have, e.g., sequence specified α- and β-CDR3 domains in the context of any, non-sequence specified α- and β-variable domain (e.g. in claim 1), or for the genus of TCR heterodimers having e.g., sequence specified α- and β-CDR3 domains in the context of certain sequence specified α- and β- chains, such as the TCR α- and β- variable domains which are ≥ 85% similar to SEQ ID NOs: 1 and 2 (see claim 3), including those variants having 42 amino acid changes in their α chain (280 amino acid SEQ ID NO: 1), and 46 amino acid changes in their α chain (309 amino acid SEQ ID NO: 2), i.e., wherein all of the CDR1 and CDR2 residues have been changed.
Finally, claims 2 and 4 are further non-enabled for the following reasons:
In claim 2, the ordinarily skilled artisan would not understand how to make TCR heterodimer comprising the four variable domains, two α and two β chain of SEQ ID NOs: 5, 6, 13 and 2, given the teachings of the instant specification; and
In claim 4, the ordinarily skilled artisan would not know how to make a TCR heterodimer comprising two TCRα polypeptides given the teachings of the instant specification.
The teachings of the instant specification and the knowledge in the art are insufficient to make the breadth of TCRs capable of binding to an MR1 molecule presenting a tumor-associated antigen encompassed by the instant claims without having to resort to undue experimentation in view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims.
In conclusion, the instant specification fails to provide sufficient teachings or objective evidence to guide the skilled artisan to produce the TCRs encompassed by the breadth of the instant claims. Rather, the instant claims encompass an invention of tremendous scope, and essentially call for trial and error by the skilled artisan to begin discovering the claimed invention without assisting the skilled artisan in such an endeavor, which is insufficient to constitute adequate enablement.
The scope of the claims must bear a reasonable correlation with the scope of enablement. In re Fisher, 166 USPQ 18(CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute.
Therefore, undue experimentation would be required to produce the claimed invention commensurate with the scope of the claims from the written disclosure alone. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth. In view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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