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 .
Claims 1-20 are pending and under examination.
The claim 1 and dependent claims thereof are objected to because wherever SEQ ID NO: 6 appears in the claims it needs to replace with the tripeptide sequence “IFS” because the USPTO system that records applicant’s sequence listing system automatically replaces any amino acid sequence of less than or equal to three amino acids with a “000” designation and this was done for SEQ ID NO: 6.
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 2-13 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.
Base claim 1 encompasses in its breadth administering a population of cells comprising a nucleic acid(s) encoding an α and/or a β chain, “wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15…” The skilled artisan would understand from the highlighted language above that the nucleic acid(s) may encode either an α chain comprising each of SEQ ID NOs: 5-7 OR a β chain comprising each of SEQ ID NOs: 13-15.
However, the metes and bounds of dependent claims 2-13 would not be clear to one of ordinary skill in the art.
In particular, some of ordinary skill in the art may argue that the language of, e.g., claim 7 (“The method of claim 1, wherein the alpha chain comprising the amino acid sequence of SEQ ID NO: 2 and the beta chain comprising the amino acid sequence of SEQ ID NO: 10”) requires that in dependent claim 7 both the alpha and beta chains are present and limited to certain sequences, which are the alpha chain sequence of SEQ ID NO: 2 and the beta chain sequence of SEQ ID NO: 10.
However, others of ordinary skill in the art may argue that the language of, e.g., claim 7, does NOT require that both the alpha and beta chains are present and limited to certain sequences, i.e., SEQ ID NOs: 2 and 7, but rather this claim should be understood to simply further limit, for example, the method of claim 1 to administering a T-cell comprising an alpha chain comprising the amino acid sequence of SEQ ID NO: 2 in the presence of any other beta chain sequence (which would be generic to the SEQ ID NO: 10 beta chain), OR to administering a T-cell comprising a beta chain comprising the amino acid sequence of SEQ ID NO: 10 in the presence of any other alpha chain sequence (which would be generic to the SEQ ID NO: 2 alpha chain).
Given this ambiguity, the metes and bounds of the instant claims would be unclear to one of ordinary skill in the art.
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 1-20 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 (i) a method of treating a patient who has cancer that presents on the cell surface a peptide consisting of the amino acid sequence of KIQEILTQV (SEQ ID NO: 1) in complex with HLA-A*02, comprising administering to the patient a population of transformed T cells comprising a nucleic acid or nucleic acids encoding an alpha chain and a beta chain, wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, and wherein the cancer is selected from non-small cell lung cancer, small cell lung cancer, renal cell cancer, glioblastoma, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, chronic lymphocytic leukemia, acute myeloid leukemia, non- Hodgkin's lymphoma, melanoma, ovarian cancer, uterine cancer, and esophageal cancer, or for
(ii) a method of treating a patient who has an HLA-A*02-positive, IGF2BP3-expressing cancer, comprising administering to the patient a population of transformed T cells comprising a nucleic acid or nucleic acids encoding an alpha chain and a beta chain, wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, wherein the cancer is selected from non-small cell lung cancer, small cell lung cancer, renal cell cancer, glioblastoma, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, chronic lymphocytic leukemia, acute myeloid leukemia, non- Hodgkin's lymphoma, melanoma, ovarian cancer, uterine cancer, and esophageal cancer,
does not reasonably provide enablement for methods of treatment wherein the administered transformed T cells comprise a nucleic or nucleic acids encoding an alpha chain and/or a beta chain, wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, and wherein said nucleic or nucleic acids will produce a TCR capable of binding a SEQ ID NO:1 (KIQEILTQV)HLA-A*02 complex. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Claim 1 and dependent claims thereof are drawn to methods of treating a patient who has cancer…comprising administering to the patient a population of transformed T cells comprising a nucleic acid or nucleic acids encoding an alpha chain and/or a beta chain, wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15…
Dependent claims 5 and 6 specify that the alpha chain comprises an alpha variable domain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 4; and the beta chain comprises a beta variable domain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 12 (claim 5) / the alpha chain comprises at least 95% sequence identity to SEQ ID NO: 2 and the beta chain comprises at least 95% sequence identity to SEQ ID NO: 10 (claim 6).
Thus, claims 1 and dependent claims thereof encompass in their breadth methods of treatment wherein the administered cells comprise a nucleic acid or nucleic acids encoding an alpha chain comprising SEQ ID NOs: 5-7 in the presence of any beta chain, or methods of treatment wherein the administered cells comprise a nucleic acid or nucleic acids encoding a beta chain comprising SEQ ID NOs: 13-15 in the presence of any alpha chain.
Likewise, claim 5 for example encompass in its breadth methods of treatment wherein the administered cells comprising a nucleic acid or nucleic acids encoding an alpha chain at least 95% identical to SEQ ID NO: 4, said alpha chain comprising SEQ ID NOs: 5-7, and a beta chain comprising any beta variable 95% identical to SEQ ID NO: 12.
The specification discloses the cloning of a particular TCR, R10P1A7, recognizing KIQEILTQV (SEQ ID NO: 1) in the context of a particular human MHC, the HLA-A*02 allele (see Examples 1 and 2).
The instant specification does not teach or guide the skilled artisan as to which particular amino acid residues of the R10P1A7 TCR alpha and beta chains CDRs are critical for binding to an KIQEILTQV:HLA-A*02 complex.
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.
The skilled artisan expects all three CDRs of the each of the TCR alpha and beta chains will be necessary 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 the peptide epitope is predominately recognized by the TCR CDR3s while the TCR CDR1 and 2 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, for some TCRs CDR1 and 2 residues directly bind peptide (see, e.g., Manning et al., Immunity, Vol. 8, 413-425, April, 1998, in particular Conclusions section on page 423; Piepenbrink et al., Nature, 2013; 4:1948, at page 2, left col., 1st paragraph and at page 6-7 bridging paragraph, both 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).
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 having certain CDR1α and 3α domains and CDR1β and 3β domains (SEQ ID NOs: 5, 7, 13 and 15) or variants thereof wherein each of SEQ ID NOs: 5, 7, 13 and 15 comprise at most one conservative amino acid substitution, insofar as said method treats a large variety of cancers including melanoma and breast cancer and insofar as said TCR is capable of binding to the amino acid sequence KIQEILTQV (SEQ ID NO: 1) in complex with an MHC class I molecule.
One reason the skilled artisan is not enabled to make and use such constructs is 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”.
Undue experimentation would be required of the skilled artisan to perform such a screen for TCRs in comparison to the antibody art because TCRs interact 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 TCR disclosed in the instant specification, will the number of non-productive pairings make it unreasonably difficult to detect productive pairings? Likewise, insofar as one is attempting to simultaneously vary, e.g., both the germline encoded α chain CDR1 and CDR2 sequences, and the germline encoded β chain CDR1 and CDR2 sequences at the same time, 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 nucleic acid(s) encoding an alpha chain and/or a beta chain, wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, and wherein said nucleic or nucleic acids will produce a TCR capable of binding a SEQ ID NO:1 (KIQEILTQV)HLA-A*02 complex in a transformed T cell which can in turn be used to treat various species of cancer as recited in the instant claims.
An additional reason the skilled artisan would consider making the TCRs encompassed in the breadth of the instant claims and using said TCRs to treat cancer an unpredictable endeavor requiring far more than routine experimentation is because, with respect to making TCRs containing amino acid substitutions in the CDR1, CDR2 and CDR3 domains the skilled artisan would reasonably expect such substitutions may change the specificity of the TCR such that it binds some class I MHC other than HLA-A*02. In particular, rather than binding an KIQEILTQV: HLA-A*02 complex the derivative TCR may now specifically bind one or more different peptide-HLA class I molecules. Indeed, as described by Goyarts et al. (Mol Immunol. 1998 Jul;35(10):593-607, cited on an IDS), given the multiple ways in which a given CDR residue can contribute to peptide:MHC binding and/or proper TCR folding, even conservative amino acid substitutions can unexpectedly produce TCR variants unable to bind its cognate peptide:MHC (see page 597-98 bridging paragraph and Discussion page 605).
However, in the instances wherein a given TCR has altered specificity, the instant specification does not instruct or guide the skilled artisan as to what other peptide:MHC complex may be bound by such a TCR, and further the nexus between this other peptide-HLA allele and how such a TCR might be used in a method of treating various human cancers. Discovering what other peptide-HLA allele said TCR binds, and further discovering a real world application for such TCRs would hardly be considered an act of routine experimentation.
In conclusion, the teachings of the instant specification and the knowledge in the art are insufficient to make the breadth of nucleic acid(s) encoding an alpha chain and/or a beta chain, wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, and wherein said nucleic or nucleic acids will produce a TCR capable of binding a SEQ ID NO:1 (KIQEILTQV)HLA-A*02 complex in a transformed T cell which can in turn be used to treat various species of cancer as recited in the instant claims in the absence of undue experimentation.
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.
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.
Claims 1-20 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.
While the specification put the skilled artisan in possession of:
(i) a method of treating a patient who has cancer that presents on the cell surface a peptide consisting of the amino acid sequence of KIQEILTQV (SEQ ID NO: 1) in complex with HLA-A*02, comprising administering to the patient a population of transformed T cells comprising a nucleic acid or nucleic acids encoding an alpha chain and a beta chain, wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, and wherein the cancer is selected from non-small cell lung cancer, small cell lung cancer, renal cell cancer, glioblastoma, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, chronic lymphocytic leukemia, acute myeloid leukemia, non- Hodgkin's lymphoma, melanoma, ovarian cancer, uterine cancer, and esophageal cancer, and of:
(ii) a method of treating a patient who has an HLA-A*02-positive, IGF2BP3-expressing cancer, comprising administering to the patient a population of transformed T cells comprising a nucleic acid or nucleic acids encoding an alpha chain and a beta chain, wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, wherein the cancer is selected from non-small cell lung cancer, small cell lung cancer, renal cell cancer, glioblastoma, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, chronic lymphocytic leukemia, acute myeloid leukemia, non- Hodgkin's lymphoma, melanoma, ovarian cancer, uterine cancer, and esophageal cancer,
The specification does not put the skilled artisan in possession of methods of treatment wherein the administered transformed T cells comprise a nucleic or nucleic acids encoding an alpha chain and/or a beta chain, wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, and wherein said nucleic or nucleic acids will produce a TCR capable of binding a SEQ ID NO:1 (KIQEILTQV)HLA-A*02 complex.
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 function as a TCR capable of distinguish cancer cells from non-cancer cells, 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 structural and functional similarities between antibodies and TCRs have long been well known to the skilled artisan, e.g., both molecules are heterodimers based on 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 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, as more recent Federal Circuit decision, 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 recently 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 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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A "representative number of species" means that the species which are adequately 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.").”
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 antibodies 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.”)
In the instant case, claim 1 and dependent claims thereof are drawn to methods of treating a patient who has cancer…comprising administering to the patient a population of transformed T cells comprising a nucleic acid or nucleic acids encoding an alpha chain and/or a beta chain, wherein the alpha chain comprises SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and the beta chain comprises SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15…
Dependent claims 5 and 6 specify that the alpha chain comprises an alpha variable domain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 4; and the beta chain comprises a beta variable domain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 12 (claim 5) / the alpha chain comprises at least 95% sequence identity to SEQ ID NO: 2 and the beta chain comprises at least 95% sequence identity to SEQ ID NO: 10 (claim 6).
Thus, claims 1 and dependent claims thereof encompass in their breadth methods of treatment wherein the administered cells comprise a nucleic acid or nucleic acids encoding an alpha chain comprising SEQ ID NOs: 5-7 in the presence of any beta chain, or methods of treatment wherein the administered cells comprise a nucleic acid or nucleic acids encoding a beta chain comprising SEQ ID NOs: 13-15 in the presence of any alpha chain.
Likewise, claim 5 for example encompass in its breadth methods of treatment wherein the administered cells comprising a nucleic acid or nucleic acids encoding an alpha chain at least 95% identical to SEQ ID NO: 4, said alpha chain comprising SEQ ID NOs: 5-7, and a beta chain comprising any beta variable 95% identical to SEQ ID NO: 12.
The specification discloses the cloning of a single TCR recognizing KIQEILTQV (SEQ ID NO: 1) in the context of a particular human MHC, the HLA-A*02 allele (see “R10P1A7”, Examples 1 and 2).
The skilled artisan would not know from the teachings of the instant specification which residues of the R10P1A7 α- and β-chains are critical for binding to a KIQEILTQV: HLA-A*02 complex nor would the skilled artisan know how representative the R10P1A7 TCR is of the genus of TCRs encompassed by the instant claims.
The genus of TCRs necessary to practice the claimed method 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.
In part, this is because 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 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 herewith).
Furthermore, there are many different methods for isolating peptide:MHC binding TCRs that would, a priori, be expected to yield structurally distinct TCRs relative to the “R10P1A7”, described in Examples 1 and 2 of the instant specification.
For example, Schendel (WO2007017201A1, cited herewith) teaches a method of isolating human TCRs that bind a peptide:HLA complex by screening T cells obtained from an HLA-A2 negative individual for their ability to bind a peptide:HLA-A2 complex that is exogenously expressed in an antigen presenting cell derived from the same HLA-A2 negative individual (see Figs. 2 and 11 and the descriptions on said figs on pages 14 and 19).
As another example, Kloosterboer et al. (Leukemia (2004) 18, 798–808, cited herewith) teaches a method of isolating TCRs that bind a particular peptide:HLA complex using blood from donors who are negative for the peptide in question but HLA-A2 positive to screen for T-cells that bind peptide:HLA-A2 (see page 806, right col., penultimate paragraph Discussion).
The instant specification does not disclose any details about how representative the TCR comprising the variable domains of SEQ ID NOs: 4 and 12 is of the total genus of TCRs that could be potentially be isolated, e.g., by the methods taught at page 39, penultimate paragraph – page 40, 4th paragraph of the specification, much less the genus of any TCR, isolated by any method, which binds a SEQ ID NO:1 (KIQEILTQV)HLA-A*02 complex. For example, the instant specification does not disclose if the TCR comprising the SEQ ID NOs: 4 and 12 variable domains was isolated many times without identifying other clones capable of binding a SEQ ID NO:1 (KIQEILTQV)HLA-A*02 complex, or if this particular clone was merely a solitary clone randomly chosen from many other possible clones (see page 39, 2nd full paragraph of the specification).
In conclusion, the teachings of the instant specification are insufficient to convincingly demonstrate the inventors had possession of TCR species representative of the genus encompassed by the instant claims, or demonstrate a knowledge of the structural features common to the members of the genus necessary for one of skill in the art to visualize or recognize the members of the claimed genus.
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 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10596242. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claim anticipate the instant claims.
In particular, insofar as the reference claims are drawn to methods of treatment wherein the administered T cells express at least one vector encoding a T cell receptor (TCR), and wherein said TCR comprises an α chain comprising the amino acid sequence of SEQ ID NO: 2 and a β chain comprising the amino acid sequence of SEQ ID NO: 10 as recited in reference claim 5, said claim necessarily encompasses in its breath the alpha / beta constant domain sequences recited in instant claims 2-4. Likewise, the vector encoding a T cell receptor (TCR) of reference claim 1 must necessarily be either DNA or RNA based as recited in instant claim 14, and the Markush group of reference claim 1 necessarily encompasses the “colorectal cancer” embodiment in its breadth.
Thus, the reference claim anticipate the instant claims.
No claims are allowed.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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