ANTIBODIES THAT TARGET HLA-E-HOST PEPTIDE COMPLEXES AND USES THEREOF

§112 §DP

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 . Claim Objections Claims 18 and 19 are objected to because of the following informalities: Claims 18 and 19 recite amino acid sequences without sequence identifiers (see Sequence Requirements below). Appropriate correction is required. Nucleotide and/or Amino Acid Sequence Disclosures REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES Items 1) and 2) provide general guidance related to requirements for sequence disclosures. 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted: In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying: the name of the ASCII text file; ii) the date of creation; and iii) the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying: the name of the ASCII text file; the date of creation; and the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended). When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical. Specific deficiencies and the required response to this Office Action are as follows: Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Several amino acid/nucleotide sequences appearing in the specification are not identified by a sequence identifier, including in Para. 0010, Para. 0016, Para. 0047-0048, Para. 0082, Para. 0085, Para. 0096, Para. 0110, Para. 0127, Para. 0194, Para. 0196, Para. 0268-0269, Para. 0271, Para. 0279, Para. 0284, Para. 0289, Para. 0304, Para. 0313, Para. 0315, Para. 0317, Para. 0393, and Para. 0395 as well as claims 18 and 19. Other examples in the specification may be present, and Applicant is requested to verify that any nucleotide/amino acid sequences appearing in the specification is identified by a sequence identifier. Required response – Applicant must provide: A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of: A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); A copy of the amended specification without markings (clean version); and A statement that the substitute specification contains no new matter. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. Several figures have nucleic acid/amino acid sequences that are not identified by a sequence identifier, including Fig. 1A, 1G, 1E, 2J, 5L, 6B, 7A-7K, 11, 12J, 12K, 19, 21E, 21F, 23, 24A, 26C, and 42. Other examples in the drawings may be present, and Applicant is requested to verify that any nucleotide/amino acid sequences appearing in the drawings is identified by a sequence identifier. Required response – Applicant must provide: Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers; AND/OR A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of: A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); A copy of the amended specification without markings (clean version); and A statement that the substitute specification contains no new matter. Claim Rejections - 35 USC § 112 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. Written Description Claims 1, 4, 11, 18, and 19 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. Claim 1 is directed to a recombinant HLA-E-VL9 monoclonal antibody or antigen binding fragment comprising VH and VL domains each having at least 80% sequence identity to the VH and VL domains of an antibody referenced in Table 1, including .As such, the claim encompasses antibodies having random, undefined amino acid mutations, including in the CDR domains. However, there is no guidance provided in the specification determining which specific amino acid mutations can be made, particularly in the CDR domains, that predictably result in retention of binding to the target antigen. Claims 4, 18, and 19 incorporate the limitations of claim 1 but do not cure the deficiencies of claim 1 and are thus also rejected. Claim 11 (which depends on claim 10) recites that the humanized HLA-E-VL9 antibody or antigen binding fragment heavy and light chain CDRs that collectively have an amino acid sequence that has no more than twenty variations compared to the CDRs of the parental murine antibody. Thus, claim 10 encompasses humanized antibody variants comprising CDRs having random, undefined amino acid mutations which can negatively impact antigen binding. The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by 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 genus (MPEP 2163). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230. Claim 1 is directed to a recombinant HLA-E-VL9 monoclonal antibody or antigen binding fragment comprising VH and VL domains each having at least 80% sequence identity to the VH and VL domains of an antibody referenced in Table 1, including 3H4G_v31, 3H4G_v51, 3H4G_v61, and 3H4G_v62. As such, the claim encompasses antibodies having random, undefined amino acid mutations, including in the CDR domains. The specification teaches the isolation and characterization of HLA-E-VL9 peptide complex-specific antibodies derived from the naive IgM B cell BCR repertoire in mice. Several affinity-matured variants of the murine monoclonal antibody (mAb) 34H (3H4 Gvl to 3H4 Gvl2) having mutations at positions 97-100 of the CDR-H3 loop were also generated from an scFv library (Para. 0289 and 0304). Further affinity-matured variants were also developed, including 3H4G_v31, 3H4G_v51, 3H4G_v61, and 3H4G_v62 (Para. 0023 and see Table 1). The amino acid sequences for these HLA-E-VL9-specific murine antibody variants, are disclosed in Figure 30B. As presently written, however, claim 1 recites partially defined VH and VL chains of each antibody clone in which at most 20% of the amino acid sequences can vary. Such variation can occur by amino acid substitution, deletion, or insertion and can be occur in the CDRs of the antibodies; yet, there is no guidance provided in the specification about the type of amino acid mutations that can be made in the VH and/or VL chains of the antibodies –particularly in the CDR domains – such that the ability of the antibody to bind to HLA-E-VL9 complex is retained. It is well-known in the art that amino acid substitutions in the CDR domains of an antibody can negatively impact binding activity (see, e.g. Piche-Nicholas et al, see in particular, Abstract; Colman, see entire document particularly Page 33, Col. 2; and Rudikoff et al, see Abstract). Thus, even a single amino acid substitution at a critical residue can significantly reduce or abolish binding to target antigen. Taken together, the effect of amino acid mutations on antibody binding affinity is not readily predictable. The level of skill and knowledge in the art is such that one of ordinary skill would not be able to readily identify without further testing which amino acid mutations can be made in the VH and VL sequences of the recited antibody clones—particularly in the CDR sequences— such that the ability of the antibodies to bind to target antigen is retained. Claims 4, 18, and 19 incorporate the limitations of claim 1 but do not cure the deficiencies of claim 1 because they still encompass antibody variants having undefined amino acid mutations in the CDR domains that can negatively impact antigen binding. Thus, claims 4, 18, and 19 are also rejected. Similarly, claim 11 (which depends on claim 10) recites that the humanized HLA-E-VL9 antibody or antigen binding fragment heavy and light chain CDRs that collectively have an amino acid sequence that has no more than twenty variations compared to the CDRs of the parental murine antibody. Such variation can occur by amino acid substitution, deletion, or insertion. However, there is no guidance provided in the specification about the type of amino acid mutations that can be made in the CDR domains such that the ability of the antibody to bind to HLA-E-VL9 complex is retained. Therefore, the genus of HLA-E-VL9 complex-specific antibodies recited in claims 1 and 11 lacks adequate written description because there does not appear to be any correlation between the structure of the claimed antibodies having random undefined amino acid mutations in the CDR domains and the function of binding to target antigen. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of HLA-E-VL9 complex specific antibodies at the time the instant application was filed. Scope of Enablement Claims 1, 4, 11, 18, and 19 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 murine or humanized HLA-E-VL9-specific antibodies having fully defined CDRs does not reasonably provide enablement for antibodies having CDRs comprising random, undefined amino acid mutations. 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 or use the invention commensurate in scope with these claims. The nature of the invention relates antibodies that bind to HLA-E peptide complexes, particularly HLA-E-VL9, in order to prevent the interaction between the complex and inhibitory NKG2A/CD94 heterodimeric receptors expressed on immune cells, including NK cell and CD8+T cell subsets, thereby enhancing NK and CD8+ T cell effector activities (see Technical Field, Page 1 and Background, pages 1-4) Claim 1 is directed to a recombinant HLA-E-VL9 monoclonal antibody or antigen binding fragment comprising VH and VL domains each having at least 80% sequence identity to the VH and VL domains of an antibody referenced in Table 1, including 3H4G_v31, 3H4G_v51, 3H4G_v61, and 3H4G_v62. As such, the claim encompasses antibodies having random, undefined amino acid mutations, including in the CDR domains. The specification teaches the isolation and characterization of HLA-E-VL9 peptide complex-specific antibodies derived from the naive IgM B cell BCR repertoire in mice. Several affinity-matured variants of the murine monoclonal antibody (mAb) 34H (3H4 Gvl to 3H4 Gvl2) having mutations at positions 97-100 of the CDR-H3 loop were also generated from an scFv library (Para. 0289 and 0304). Further affinity-matured variants were also developed, including 3H4G_v31, 3H4G_v51, 3H4G_v61, and 3H4G_v62 (Para. 0023 and see Table 1). The amino acid sequences for these HLA-E-VL9-specific murine antibody variants, are disclosed in Figure 30B. As presently written, claim 1 recites partially defined VH and VL chains of each antibody clone in which at most 20% of the amino acid sequences can vary. Such variation can occur by amino acid substitution, deletion, or insertion and can be made in the CDRs of the antibodies. However, there is no guidance provided in the specification about the type of amino acid mutations that can be made in the VH and/or VL chains of the antibodies –particularly in the CDR sequences – such that the ability of the antibody to bind to HLA-E-VL9 peptide complex is retained. Additionally, there is no evidence demonstrating antibody variants beyond those disclosed in the specification, but encompassed by the claim scope, possess the functional property of binding to the HLA-E-VL9 peptide complex. It is well-known in the art that amino acid substitutions in the CDR domains of an antibody can negatively impact binding activity (see, e.g. Piche-Nicholas et al, see in particular, Abstract; Colman, see entire document particularly Page 33, Col. 2; and Rudikoff et al, see Abstract). Thus, even a single amino acid substitution at a critical residue can significantly reduce or abolish binding to target antigen. Taken together, the effect of amino acid mutations on antibody binding affinity is not readily predictable. The level of skill and knowledge in the art is such that one of ordinary skill would not be able to readily identify without further testing which amino acid mutations can be made in the VH and VL sequences of the recited antibody clones—particularly in the CDR sequences— such that the ability of the antibodies to bind to target antigen is retained. Claims 4, 18, and 19 incorporate the limitations of claim 1 but do not cure the deficiencies of claim 1 because they still encompass antibody variants having undefined amino acid mutations in the CDR domains that can negatively impact antigen binding. Thus, claims 4, 18, and 19 are also rejected. Similarly, claim 11 (which depends on claim 10) recites that the humanized HLA-E-VL9 antibody or antigen binding fragment heavy and light chain CDRs that collectively have an amino acid sequence that has no more than twenty variations compared to the CDRs of the parental murine antibody. Such variation can occur by amino acid substitution, deletion, or insertion. However, there is no guidance provided in the specification about the type of amino acid mutations that can be made in the CDR domains such that the ability of the antibody to bind to HLA-E-VL9 complex is retained. A person of ordinary skill in the art at the time of filing would have had experience in antibody engineering, including random mutagenesis and screening techniques. Even at this high level of skill, however, the effect of randomly mutating amino acids in the CDR domains—on antigen binding and functional activity cannot be readily predicted without additional testing. In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement (MPEP 2164.06). Thus, the level of skill does not obviate the need for substantial experimentation across the full scope of the claimed genus to determine which antibody variants retain binding to HLA-E-VL9 peptide complexes. Therefore, the specification is not enabling over the full scope of the claims. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claims 1, 4, 10, 11, 12, 13, 16, 17, 18, 19, 23, 25, 29, 35, 37, 38, 39, 44, 45, and 47 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. As presently drafted, claim 1 recites that the VH and VL chains of a recombinant HLA-E-VL9-specific mAb each has 80% identity to the VH and VL chains of an antibody disclosed in Table 1 of the instant specification. Similarly, claim 10 recites that the humanized antibody comprises heavy and light chain CDRs derived from the antibodies disclosed in Table 1 of the instant specification. Such references to a Table in a claim are improper. As per MPEP 2173.05(s) Reference to Figures or Tables [R-10.2019]: Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). Claims 4, 18, and 19 incorporate the limitations of claim 1 but do not cure the deficiencies of claim 1 discussed above and are thus also rejected. Claims 11, 13, 16, 17, 23, 25, 29, 35, 37, 38, 44, 45, and 47 incorporate the limitations of claim 10 but do not cure the deficiencies of claim 10 discussed above and are thus also rejected. It is suggested that applicant amend the claims to remove all references to Table 1 and to use conventionally accepted formats, such as a small Markush group of SEQ ID NOs or simply reciting the sequences in alternative fashion (e.g. SEQ ID NO:A or SEQ ID NO:B) or other suitable language. Claim 10 further recites that a humanized antibody comprising a VH chain having CDRs “derived from” a murine parental antibody and a VL chain having CDRs “derived from” the murine parental antibody. However, claim 10 does not specify whether the recited CDRs are identical in amino acid sequence to those of the parental antibody or whether the term “derived from” encompasses CDRs containing amino acid substitutions relative to those of the parent antibody. Claims 11, 12, 13, 16, 17, 23, 25, 29, 35, 37, 38, 44, 45, and 47 incorporate the limitations of claim 10 but do not cure the deficiencies of claim 10 discussed above and are thus also rejected. In particular, claim 11 (which depends on claim 10) recites that the heavy and light chain CDRs “collectively have an amino acid sequence that has no more than twenty variations” compared to the CDRs of the parental antibody. In view of the ambiguity with the term “derived from “ in claim 10, it is unclear whether claim 11 limits the number of amino acid mutations permitted within the CDRs encompassed by claim 10 or instead introduces additional limitations not encompassed by claim 11. Thus, the metes and bounds of the desired patent prosecution cannot be reasonably determined. Additionally, claim 11 recites that the light chain and heavy chain CDR regions “collectively have an amino acid sequence that has no more than twenty variations” compared to the CDR regions of the parental murine antibody. The scope of this limitation is unclear because the light chain CDRs and heavy chain CDR domains comprise six non-contiguous amino acid sequences that together make up the antigen-binding region of an antibody. It is unclear what is meant by the CDRs “collectively have an amino acid sequence” and how variations are to be determined. Specifically, it is unclear whether (a) the claim requires the heavy and light chain CDRs together have no more than 20 amino acid variations when collectively compared to those of the parent antibody; or (b) each individual CDR sequences is separately required to contain no more than 20 amino acid variations compared to the corresponding CDR of the parent antibody. The claim fails to identify the sequence(s) to be compared or how amino acid variations are calculated relative to the parent antibody. Thus, the metes and bounds of patent protection desired cannot be reasonably determined. Lastly, claim 39 recites an in vitro transcription system to synthesize RNAs encoding “antibodies of the invention”. As presently written, it is unclear which antibodies the claim intends to encompass. There are numerous antibodies disclosed in the specification that may be regarded as inventive beyond those disclosed in Table 1. As such, the metes and bounds of patent prosecution desired cannot be reasonably determined. The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 11 (which depends on claim 10) recites “[t]he humanized antibody or fragment of claim 10, wherein its CDRH1-3 and CDRL1-3 regions collectively have an amino acid sequence that has no more than twenty variations as compared to the CDRH1-3 and CDRL1-3 regions of the parental murine antibody”. Without further clarification, the humanized antibody of claim 10 includes that comprising CDRs identical in sequence to those of the parent murine antibody. Thus, claim 11 introduces additional limitations (i.e. amino acid variations) that improperly broaden the scope of claim 10. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Double Patenting 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, 18, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 61-99 of copending Application No. 18245540 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants of the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. The co-pending claims recite a recombinant antibody or fragment thereof selected from a group that includes the murine antibody clone 3H4 having the VH chain of SEQ ID NO: 128 and the VL chain of SEQ ID NO: 129, wherein the recombinant antibody or fragment thereof, binds to an HLA-E-VL9 complex (co-pending claims 61-63). The VH chains of clones 3H4G_v31 (SEQ ID NO: 405), 3H4G_v51 (SEQ ID NO: 406), 3H4G_v61 (SEQ ID NO: 407), and 3H4G_v62 (SEQ ID NO: 408) of the instant claims each share at least 90% identity to the VH chain of 3H4 (see Sequence Alignments below). The VL chain (SEQ ID NO: 409) of clones 3H4G_v31, 3H4G_v51, 3H4G_v61, and 3H4G_v62 recited of instant claims is at least 90% identical to the VL chain of 3H4 (see Sequence Alignments below). Lastly, co-pending claim 79 recites that the HLA-E-VL9 complex bound by the recombinant antibody or fragment thereof comprises a peptide with an amino acid sequence of SEQ ID NO: 4 (Xaa Met Ala Pro Arg Thr Xaa Xaa Leu, wherein Xaa at position 1 is V/A/C/I/S/T/V/H/P; Xaa at position 7 can be L/V, and Xaa at position 8 can be V/L/I/F) or SEQ ID NO:1 (Val Met Ala Pro Arg Thr Xaa Xaa Leu, wherein Xaa at position 7 is L/V and Xaa at position 8 is V/L/I/F) which are identical to the sequences recited in instant claim 18 and 19, respectively. Thus, the co-pending claims meet the limitations of the instant claims. VH chain: 3H4G_v31 (SEQ ID NO: 405, instant claims) vs. 3H4 (SEQ ID NO: 128, co-pending claims) PNG media_image1.png 444 782 media_image1.png Greyscale VH chain: 3H4G_v51 (SEQ ID NO: 406, instant claims) vs. 3H4 (SEQ ID NO: 128, co-pending claims) PNG media_image2.png 458 764 media_image2.png Greyscale VH chain: 3H4G_v61 (SEQ ID NO: 407, instant claims) vs. 3H4 (SEQ ID NO: 128, co-pending claims) PNG media_image3.png 448 772 media_image3.png Greyscale VH chain: 3H4G_v62 (SEQ ID NO: 408, instant claims) vs. 3H4 (SEQ ID NO: 128, co-pending claims) PNG media_image4.png 454 790 media_image4.png Greyscale VL chain: SEQ ID NO: 409 (present in clones 3H4G_v31, 3H4G_v51, 3H4G_v61, and 3H4G_v62 of the instant claims) vs. SEQ ID NO: 129 (clone 3H4, instant claims) PNG media_image5.png 402 766 media_image5.png Greyscale Conclusion No claims are allowable. 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