DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The amended claims filed February 13, 2026 are acknowledged. Claims 25, 27-33, 47-50, and 52-55 are pending. Claims 26, 34-46, and 51 have been canceled. Claims 25 and 49 are amended. Claims 51-55 are newly added. Claims 31-33 remain withdrawn from further consideration by the Applicant pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 25, 27-30, 47-50, and 52-55 are under examination herein.
WITHDRAWN CLAIM REJECTIONS
All prior rejections over claims 26 and 51 are rendered moot by the cancelation of the claims.
The prior grounds of rejection over claims 25, 27-28, 47-50 under 35 U.S.C. § 112(a) is withdrawn in view of Applicant's claim amendments.
The prior grounds of rejection in the obviousness-type non-statutory double patenting rejections of claims 25, 27-30 and 47-50 over U.S. Patent No. 12,384,842 are withdrawn in view of Applicant's amendments to claim 25.
The prior grounds of rejection in the provisional obviousness-type non-statutory double patenting rejections of claims 25, 27-30 and 47-50 over U.S. Patent Application Nos. 18/172,928 and 19/265,026 are withdrawn in view of Applicant's amendments to claim 25.
The provisional rejections of claims 25, 27-28, and 47-50 on the grounds of non-statutory double patenting over co-pending Applications 19/333,088 is withdrawn in view of Applicant's claim amendments to the co-pending reference application.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT OR FILING OF AN IDS
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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 25, 27-30, 47-50, and 52-55 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. This is a new rejection necessitated by claim amendment.
Claims 25 and 54 recite “(corresponding to EU numbering system)” in parentheses. This renders the claims indefinite because it is unclear if the phrase in parentheses is intended to be limiting or merely exemplary of a numbering system that could be used in addition to other numbering systems not set forth. Accordingly, the metes and bounds of the claims cannot be determined and the invention is not set forth with the clarity and particularity necessary to satisfy the requirement set forth in 35 U.S.C. § 112(b) so as permit the skilled artisan to know or determine infringing subject matter.
It is noted herein that SEQ ID NO: 42 corresponds to a human IgG1 Fc amino acid sequence according to page 181 of the specification.
Claims 27-30, 47-50, and 52-55, which depend from claim 25, do not remedy this deficiency and are similarly rejected.
If Applicant is intending to limit the positions to that of the EU numbering system, it is suggested that the rejection could be obviated by amending the claim(s) to recite “according to EU numbering” where needed without any parentheses.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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 25, 27-30, 50, and 52-55 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. This is a new rejection necessitated by Applicant's amendments to the claims.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that 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, or it may be satisfied by the 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. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
The claimed invention. In one aspect, the nature and scope of the invention at issue is a method of treating an autoimmune disease that comprises administering to a subject in need thereof a multispecific molecule, said multispecific molecule comprising a first domain that binds to a TCRβV and a second domain comprising an NK cell engager, wherein the method depletes a T cell to which it is bound (as recited in claim 25). This limitation fails to satisfy the written description requirement because the method recites a functional activity (depletion or elimination of a T cell to which it is bound) without reciting a corresponding structure expected to correlate with this activity. One of ordinary skill in the art would not be able to visualize or recognize the all of the possible first antigen-binding domains that carry out the function of depleting T cells based only on knowing that said antigen-binding domain generically binds to a TCRβV. Dependent claims 27-30, 50, and 52-55 do not remedy this deficiency and are similarly rejected.
In another aspect, the nature and scope of the claimed invention at issue is a method of treating an autoimmune disease that comprises administering to a subject in need thereof a multispecific molecule, said multispecific molecule comprising a first domain that binds to a TCRβV and a second domain comprising a generic NK cell engager, wherein the multispecific molecule induces IFN-γ production by the NK cell to which it is bound (as recited in claim 50). The recited limitation that the multispecific molecule “induces IFN-γ production by the NK cell to which it is bound” (i.e., activates said NK cell) does not satisfy the written description as presently claimed because the claim seeks to define the multispecific molecule administered in the method by what it does (i.e., its function of triggering IFN-γ production in a bound NK cell) without reciting a corresponding structure that would be expected to correlate with the instantly claimed function as understood from Applicant’s disclosure and the state of the prior art.
State of the prior art. Gershoni (Biodrugs (2007) 21(3): 145-156; cited in PTO-892 mailed March 19, 2025) teaches that antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (page 146, Section 1.1). The skilled artisan therefore understands that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence.
Jensen (WO 2004/056873 A1; cited in IDS) has previously described active binding substances (e.g., antibodies or antigen-binding fragments thereof) having a first molecular component that specifically binds to NKp30 and a second molecular component that binds to a component of the T cell receptor (TCR) complex, and uses thereof in treating autoimmune diseases (e.g., Abstract; claims 1-3, 7-9). Multispecific binding molecules that specifically bind TCRβV and NKp30 are described by, e.g., Tan (US 2021/0277119 A1; cited in IDS).
Regarding the role of TCRβV in autoimmunity, Schendel (WO 2016/193301 A1; cited in IDS) teaches, "T cells with particular TCRs can become activated and attack normal body structures in an aberrant fashion as occurs in various forms of T cell mediated autoimmunity. Examples here are multiple sclerosis, insulin-dependent Type 1 diabetes mellitus and psoriasis among others. (...) Antibodies binding to TCRs can be powerful tools to eliminate unwanted T cells from a patient" (pages 1-2). Schendel discloses that there is a need for antibodies that allow for the depletion of specific populations of TCRs (and thus, specific populations of T cells) without depletion of the complete population of TCRs, to allow the patient to remain immunocompetent to respond to pathogenic challenges through the presence of remaining T cells untouched by the antibody (page 2, lines 27-29; page 3, first paragraph). Paul (Science Translational Medicine (2021) 13(584): eabd3595) expands on this idea, teaching that targeting of the TCR β chain has implications for treatment of autoimmune diseases: “Selective T cell clonal expansions have been detected in GVHD, the primary complication of allogeneic bone marrow transplantations. Furthermore, animal studies suggest that selective TRBV depletion can induce tolerance to the allograft. Certain autoimmune pathologies such as celiac disease are also driven by specific TRBV families. TCR sequencing to identify the disease causing TRBV clones followed by TRBV-directed depletion of these T cells could open up new therapeutic strategies for GVHD and celiac disease management” (Discussion). Paul notes that VDJ recombination during development results in the expression of 1 of the 30 TRBV gene families on the surface of each T cell, and that each TRBV is expressed on the surface of 1-5% of the total normal human peripheral blood T cells (Introduction). Britanova (US 2020/0332003 A1; cited in PTO-892 mailed October 16, 2025) discloses monoclonal antibodies that specifically bind to the TRBV9 family of human T-cell receptors, which are suitable for eliminating (or depleting) T cells expressing TRBV9 family TCRs (e.g., Abstract; pages 2-3; Example 3 and Figure 5) and have utility in treating autoimmune diseases such as Celiac disease (e.g., page 3). Britanova discloses an exemplary anti-TRBV9 antibody comprising a VH comprising an amino acid sequence of SEQ ID NO: 19 and a VL comprising the amino acid sequence of SEQ ID NO: 11 (e.g., ¶ 0082-0103; claims 1-5). The VH comprising the amino acid sequence of SEQ ID NO: 19 comprises the instantly claimed heavy chain CDRs of SEQ ID NO: 1251 (at residues 26-32), SEQ ID NO: 1252 (at residues 52-57), and SEQ ID NO: 1250 (residues 99-111), respectively, and the VL comprising the amino acid sequence of SEQ ID NO: 11 comprises the instantly claimed light chain CDRs of SEQ ID NO: 1257 (at residues 26-32), SEQ ID NO: 1255 (at residues 50-56), and SEQ ID NO: 1256 (at residues 89-97), respectively. The VH comprising SEQ ID NO: 19 shares 80.4% sequence identity to instant SEQ ID NO: 1260, 83.2% sequence identity to instant SEQ ID NO: 1261, 82.1% sequence identity to instant SEQ ID NO: 1262, and 81.9% sequence identity to instant SEQ ID NO: 1263. The VL comprising SEQ ID NO: 11 shares 81.6% sequence identity to instant SEQ ID NO: 1264, 83.0% sequence identity to instant SEQ ID NO: 1265, 85.4% sequence identity to instant SEQ ID NO: 1266, and 80.7% sequence identity to instant SEQ ID NO: 1267.
Regarding NK cell activity, Kucuksezer (Frontiers in Immunology (2021) 12: 622306; cited in PTO-892 mailed October 2025) teaches that NK cell cytotoxicity and NK-derived cytokines can contribute to many immune-mediated diseases, including ankylosing spondylitis (AS), multiple sclerosis (MS), and type-1 diabetes (page 2). NKp30 (NCR3, CD337) is one of the natural cytotoxicity receptors (NCRs) expressed on NK cells and is recognized as a major natural killer (NK) activating receptor (page 3). Kucuksezer discloses that reduced NK cell functions (e.g., reduced expression of NKp30, reduced IFN-γ production) have been observed in type-1 diabetes patients (page 12).
Regarding Fc functions, X. Wang (Protein Cell (2018) 9(1): 63-73) reviews ways of engineering IgG Fc domains to modulate Fc effector functions. A summary of mutations is shown in Table 1, including those that enhance antibody-dependent cell-mediated cytotoxicity (ADCC), enhance antibody-dependent cellular phagocytosis (ADCP), reduce effector function, and increase serum half-life. X. Wang teaches that Fc mutations of N297A/Q/G, L234A, L235A/E reduce effector functions in human IgG1 antibodies (e.g., Table 1). C. Wang (US 2015/0353637 A1) further describes effector-less IgG1 antibodies of allotype “f” that comprise the mutations 214R, 356E, and 358M according to EU numbering (e.g., ¶ 0250; Table 11 at page 77).
Scope of species disclosed in original specification. The Examples (pages 302-304) disclose the generation of monoclonal anti-NKp30 antibodies in Armenian hamsters immunized with the extracellular domain of human NKp30. Exemplary hamster anti-NKp30 antibody clones 15E1, 9G1, 15H6, 9D9, 3A12, and 12D10, as well as exemplary humanized anti-NKp30 antibodies based on 15E1, 9G1, and 15H6, are disclosed in Table 15 (page 268). The humanized variants comprise the same CDRs as the parent antibodies. The heavy chain CDRs and light chain CDRs of the exemplary antibodies are recited in Tables 12-13 (starting on pages 260 and 262, respectively) and in Table 14 (page 265), respectively.
Clone 15E1 comprises:
HC CDRs comprising SEQ ID NO: 7313, 6001, and 7315, respectively (according to Kabat numbering), and
LC CDRs comprising SEQ ID NO: 7326, 7327, and 7329, respectively;
Clone 9G1 comprises:
HC CDRs comprising SEQ ID NO: 6000, 6001, and 6002, respectively, or SEQ ID NO: 7313, 6001, and 6002, respectively (latter according to Kabat numbering), and
LC CDRs comprising SEQ ID NO: 6063, 6064, and 7293, respectively;
Clone 9D9 comprises:
HC CDRs comprising SEQ ID NO: 7313, 7385, and 7315, respectively (according to Kabat numbering), and
LC CDRs comprising SEQ ID NO: 6070, 6064, and 7321, respectively;
Clone 3A12 comprises:
HC CDRs comprising SEQ ID NO: 7313, 7318, and 6009, respectively (according to Kabat numbering);
LC CDRs comprising SEQ ID NO: 6070, 6064, and 7321, respectively;
Clone 12D10 comprises:
HC CDRs comprising SEQ ID NO: 7313, 6008, and 6009, respectively (according to Kabat numbering), and
LC CDRs comprising SEQ ID NO: 6070, 6071, and 6072, respectively; and
Clone 15H6 comprises:
HC CDRs comprising SEQ ID NO: 6007, 6008, and 6009, respectively, or SEQ ID NO: 7313, 6008, and 6009, respectively (latter according to Kabat numbering), and
LC CDRs comprising SEQ ID NO: 6070, 6071, and 6072, respectively.
The disclosure teaches that the anti-NKp30 antibody clones with the identifiers of “9D9-1C1”, “16F2-2F3”, and “16G3-1E5” bind to NKp30 expressed on NK92 cells (e.g., Example 3, page 302; Figure 4). It is not apparent from Applicant's disclosure what the structures (e.g., amino acid sequences) of clones “16F2-2F3”, and “16G3-1E5” are. The disclosure also recites that activity of NKp30 antibodies was measured using the NK92 cell line, with mouse NKp30 (R&D) used as a positive control (Example 4, page 303), and Figure 5 illustrates that antibody clones “15H6” and “9G1” elicited IFN-γ release.
The disclosure separately describes murine, chimeric and humanized antibody molecules which bind to TCRVB 6, e.g., TCRVB 6-5 (murine monoclonal “Antibody A” and humanized monoclonal antibodies “Antibody A-H” clones), the sequences of which are recited in Table 4 (starting on page 128). Table 10 (starting on page 210) recites amino acid sequences for murine and humanized anti-TCRβV antibodies that bind to various TCRβV clones, corresponding to “Antibody G” through “Antibody O”. The disclosed antibodies comprising a combination of CDRs as recited in claim 47 appears to correspond to murine “Antibody N” (pages 218-220), which binds to TCRVβ 9, with CDRs numbered according to Kabat, Chothia, or Combined numbering systems. The figures do not illustrate the ability of any exemplary anti-TCRβV binding domain recited in the disclosure to bind to a respective TCRβV or deplete T cells. However, Britanova (US 2020/0332003 A1; supra) does teach an exemplary anti-TRBV9 antibody with identical heavy chain and light chain CDRs to those recited in the anti-TCRβV antigen-binding domains of claims 47-49, which are suitable for depleting T cells expressing TRBV9 family TCRs.
The Examples do not appear to describe the generation of multispecific molecules comprising the monoclonal anti-NKp30 antibody clone binding domains above in combination with a binding domain that binds to a TCRβV. The figures also do not appear to illustrate any activity or other properties of exemplary multispecific molecules of the invention.
Table 6 of the specification discloses constant region amino acid sequences of human IgG heavy chain and human kappa light chains (pages 180-182). Only two mutant IgG constant region sequences (IgG4 and IgG1) and one mutant IgM constant region appear to be disclosed.
MPEP § 2163 states that 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. Although a number of species have been described, they cannot be considered representative because they are all highly structurally related, particularly in the CDRs of the antibody VH and VL domains utilized. Only two exemplary anti-NKp30 binding species are demonstrated in the disclosure to have the further ability to activate NK cells upon binding thereto, e.g., as evidenced by IFN-γ release. The ability of any TCRβV-binding moieties to bind to a TCRβV or deplete T cells does not appear to be demonstrated in the disclosure, but the ability of selected anti-TRBV9 antibodies to do so is supported elsewhere based on the teachings of Britanova (supra). With respect to mutant Fc regions, the state of the art recognizes that selected mutations in the Fc domain of IgG antibodies (and others) confer reduced effector function and/or other therapeutically relevant properties, but not all mutations universally (e.g., all possible mutations that are within the scope of an amino acid sequence having at least 90% sequence identity to instant SEQ ID NO: 42) would be expected to have reduced binding to an Fc receptor.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. As illustrated by the state of the prior art, antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure (amino acid sequence) of their antigen-binding sites. One of ordinary skill in the art would not be able to recognize or visualize species of the genus of multispecific molecules having the recited functions of depleting a T cell to which it is bound, and/or inducing IFN-γ production upon NK cell binding, and/or having reduced Fc receptor binding, without the disclosure of a specific structure correlated with these activities as supported by Applicant's disclosure.
Conclusion. For all of the reasons presented above, one of skill in the art would not know which of the countless multispecific molecules encompassed by the claim, which comprise a first antigen-binding domain that generically binds to a TCR β variable region and a second antigen-binding domain that comprises an NK cell engager, further perform the required functional activities of depleting a T cell to which it binds, inducing IFN-γ production by the NK cell to which it binds, and/or reducing Fc receptor binding. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of multispecific molecules as broadly claimed at the time the application was filed.
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.
(1.1)
Claims 25, 27-30, 47, 50, and 54-55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9-11, 13-14, and 22-23 of U.S. Patent No. 12,384,842 (cited in PTO-892 mailed October 2025) in view of Britanova (US 2020/0332003 A1; supra), C. Wang (US 2015/0353637 A1; supra), and Shitara (U.S. Patent No. 8,883,981; published November 11, 2014). This is a new rejection necessitated by claim amendment.
The reference patent claims a multispecific antibody comprising (1) an anti-NKp30 antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) comprising CDRs comprising the amino acid sequences of SEQ ID NO: 7313, 6001, and 7315, respectively, and a light chain variable region (VL) comprising CDRs comprising the amino acid sequences of SEQ ID NO: 7326, 7327, and 7329, respectively, and a VH comprising the amino acid sequence of SEQ ID NO: 7302 and a VL comprising the amino acid sequence of SEQ ID NO: 7305, which are identical to those instantly claimed sequences with the same sequence identifiers), and (2) a T cell engager that binds to an antigen present on the surface of an autoreactive T cell that is associated with an autoimmune disorder (patented claims 1-2 and 9-11), relevant to claims 25, 27-30 and 50. Patented claims 22-23 further recite a method of treating an autoimmune disorder that comprises administering to a subject in need thereof the antibody of patented claim 2.
However, the reference patent does not expressly recite administering a multispecific molecule, comprising the anti-NKp30 antigen-binding domain recited above and another antigen-binding domain that binds to a TCRβ variable region and comprises a VH and a VL comprising a combination of CDRs as set forth in claim 47, to treat an autoimmune disorder. The reference patent also does not claim that the multispecific molecule comprises a mutated Fc domain comprising (1) at least 90% sequence identity to instant SEQ ID NO: 42 and (2) a N297A mutation according to EU numbering.
Britanova discloses monoclonal antibodies that specifically bind to the TRBV9 family of human T-cell receptors, which are suitable for eliminating (or depleting) T cells expressing TRBV9 family TCRs (e.g., Abstract; pages 2-3; Example 3 and Figure 5), relevant to claim 51. Britanova notes that TCRs bearing TRBV9 family β chains are involved in the development of autoimmune diseases such as celiac disease (e.g., ¶ 0008) and discloses methods of treating celiac disease and other disorders by administering an antibody of the invention to a subject in need thereof (e.g., page 3). Britanova discloses an exemplary anti-TRBV9 antibody comprising a VH comprising an amino acid sequence of SEQ ID NO: 19 and a VL comprising the amino acid sequence of SEQ ID NO: 11 (e.g., ¶ 0082-0103; claims 1-5). The VH comprising the amino acid sequence of SEQ ID NO: 19 comprises the instantly claimed heavy chain CDRs of SEQ ID NO: 1251 (at residues 26-32), SEQ ID NO: 1252 (at residues 52-57), and SEQ ID NO: 1250 (residues 99-111), respectively, and the VL comprising the amino acid sequence of SEQ ID NO: 11 comprises the instantly claimed light chain CDRs of SEQ ID NO: 1257 (at residues 26-32), SEQ ID NO: 1255 (at residues 50-56), and SEQ ID NO: 1256 (at residues 89-97), respectively, relevant to claim 47. The VH comprising SEQ ID NO: 19 shares 80.4% sequence identity to instant SEQ ID NO: 1260, 83.2% sequence identity to instant SEQ ID NO: 1261, 82.1% sequence identity to instant SEQ ID NO: 1262, and 81.9% sequence identity to instant SEQ ID NO: 1263. The VL comprising SEQ ID NO: 11 shares 81.6% sequence identity to instant SEQ ID NO: 1264, 83.0% sequence identity to instant SEQ ID NO: 1265, 85.4% sequence identity to instant SEQ ID NO: 1266, and 80.7% sequence identity to instant SEQ ID NO: 1267.
C. Wang describes exemplary therapeutic antibodies which do not bind to Fc receptors (e.g., ¶ 0006-0018). C. Wang discloses an effectorless allotype variant of IgG1 comprising the amino acid substitutions of 214R, 356E, and 358M according to EU numbering (e.g., ¶ 0250; Table 11). C. Wang further teaches that the 297A mutation, numbered according to EU numbering, also reduces effector function (binding to FcγR) (e.g., ¶ 0589).
Shitara illustrates the amino acid sequences of the human IgG isotype constant regions (e.g., Figure 1). Compared to the wild-type constant region sequence of human IgG1 (SEQ ID NO: 76 of Shitara), the instantly claimed mutant Fc comprising instant SEQ ID NO: 42 has mutations of K214R, N297A, D356E, and L358M. See alignment in Office Action Appendix.
Based on the further teachings of Britanova, C. Wang, and Shitara, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the multifunctional molecule of the reference patent by (1) substituting the T cell engaging binding domain of the multispecific molecule taught in the reference patent with the anti-TRBV9 antigen-binding domain taught by Britanova for the purpose of treating an autoimmune disorder, and (2) incorporating into the multifunctional molecule a mutated Fc domain that has reduced effector function. The skilled artisan would have been motivated to use the antigen-binding domain taught by Britanova because Britanova teaches that TCRs bearing TRBV9 family β chains are implicated in autoimmune diseases such as celiac disease, and the exemplary anti-TRBV9 antibody taught by Britanova eliminates TRBV9-bearing T cells. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized the suitability of the anti-TRBV9 antibody taught by Britanova for binding to an antigen on the surface of autoreactive T cells associated with an autoimmune disorder. Furthermore, one of ordinary skill in the art, through routine and conventional activities, would be capable of incorporating an anti-TRBV9 binding-domain as disclosed by Britanova into a multispecific construct.
The skilled artisan would further have been motivated to use an IgG1 constant region comprising the “effectorless” mutations of 217A, 356E, and 358M, in combination with 297A, because reduced Fc receptor binding is desirable in certain therapeutic applications. There would have been a reasonable expectation of success because it is prima facie obvious to use a known technique to improve a similar product (i.e., a multispecific antigen-binding construct) in the same way.
(1.2)
Claims 25 and 47-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9-11, 13-14, and 22-23 of U.S. Patent No. 12,384,842 in view of Britanova (US 2020/0332003 A1; supra), C. Wang (US 2015/0353637 A1; supra), and Shitara (U.S. Patent No. 8,883,981; supra) as applied to claims 25, 27-30, 47, 50, and 54-55 above, further in view of Lombana (Scientific Reports (2015) 5: Article 17488; cited in PTO-892 mailed October 2025). This is a new rejection necessitated by claim amendment.
The teachings of the reference patent are recited in the non-statutory double patenting rejection above.
However, the reference patent does not teach an anti-TRBV9 antigen-binding domain comprising a VH comprising at least 90% sequence identity to the amino acid sequence of one of SEQ ID NO: 1260-1263 and a VL comprising at least 90% sequence identity to an amino acid sequence of one of SEQ ID NO: 1264-1267.
The teachings of Britanova, C. Wang, and Shitara are discussed in the non-statutory double patenting rejection above.
Lombana describes using a Bacterial Antibody Display (BAD) system to screen antibodies for variants that influence antibody expression and thermostability to improve yields for bringing therapeutics to the clinic (Abstract). Lombana teaches that several approaches have been used to increase antibody yields in Escherichia coli, including saturation mutagenesis of select positions in the antibody sequence. However, this approach increases the risk of introducing immunogenic sequences because the resulting amino acid changes are not found in the natural repertoire of antibodies (Introduction, page 1). Accordingly, Lombana investigated natural antibody diversity within a subgroup that occurs during the natural process of somatic hypermutation, since these changes are structurally desired and tolerated by the immune system (Introduction, page 1). Lombana focused on framework region variants for two therapeutically relevant antibodies against IL-13 and VEGF to maintain antibody affinity via the CDRs, concentrating on buried but not surface exposed residues of the framework regions (Introduction, page 2; Results, page 6). After demonstrating that better expressing antibodies are enriched using the BAD system (Results, pages 4-5; Figure 3), Lombana performed a BAD screen using 33 individual framework variants of an anti-IL-13 half-antibody (5 light chain variants, 28 heavy chain variants). The results illustrated that the IL-13 framework variants showed increased binding to IL-13 antigen, and several variants displayed increased functional expression and thermal stability relative to anti-IL-13 wildtype (WT) antibody (Results, pages 5-7; Figure 4). The highest expressing functional variants from E. coli also showed expression gains in a mammalian expression system, albeit to a slightly lesser extent than in E. coli (Results, page 7; Figure 4). Combining selected variants also had an additive effect on functional expression and thermal stability (Results, page 7; Figure 4). Lombana extended their analysis to an anti-VEGF.3 antibody derived from a different germline, analyzing 47 light chain framework variants and 36 heavy chain framework variants, and similarly showed that the variants had increased binding to VEGF relative to WT anti-VEGF antibody and conferred increasing functional expression in E. coli, and that high-expressing variants had improved thermostability (Results, pages 7-9; Figure 5). Double variants also displayed additive improvement of functional expression, and all variants showed improved protein stability relative to wildtype (Results, page 9; Figure 5).
It would have been obvious for one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a multispecific molecule comprising an anti-TRBV9 binding domain having a VH comprising at least 90% sequence identity to one of the amino acid sequences of SEQ ID NO: 1260-1263 and a VL comprising at least 90% sequence identity to one of the amino acid sequences of SEQ ID NO: 1264-1267, comprising identical CDRs as previously set forth, through the process of routine optimization. The skilled artisan would have been motivated to do so because modifying residues within the framework region of the antibody, particularly within non-surface exposed regions, can confer increased functional expression in a host system and improved thermal stability while also increasing affinity of the antibody for its target antigen and minimizing antibody immunogenicity, as taught by Lombana. These qualities are useful for scaling up commercial production and increasing antibody formulation stability. There would have been a reasonable expectation of success because Lombana demonstrates that antibody framework residues (alone or in combination) identified during somatic hypermutation can be modified, while the CDR residues remain unchanged, to augment expression of the antibodies in a bacterial or mammalian host and improve their thermal stability.
(1.3)
Claims 25 and 52-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9-11, 13-14, and 22-23 of U.S. Patent No. 12,384,842 (previously co-pending Application No. 17/402,320) in view of Britanova (US 2020/0332003 A1; supra), C. Wang (US 2015/0353637 A1; supra), and Shitara (U.S. Patent No. 8,883,981; supra) as applied to claims 25, 27-30, 47, 50, and 54-55 above, further in view of Gunasekaran (The Journal of Biological Chemistry (2010) 285(25): 19637-19646). This is a new rejection necessitated by claim amendment.
The teachings of the reference patent are recited in the non-statutory double patenting rejection above.
However, the reference patent does not teach that the multispecific molecule is a heterodimer comprising a paired cavity-protuberance (also known as a “knob-in-a-hole”).
The teachings of Britanova, C. Wang, and Shitara are discussed in the non-statutory double patenting rejection above.
Gunasekaran describes modifications to the IgG CH3 domain interface of the antibody Fc region that result in Fc proteins which preferentially form heterodimers (Abstract). Gunasekaran teaches that efficient heterodimerization is desirable for applications such as the production of bispecific antibodies where assembly of two different molecules is required (e.g., page 19637). Relevant to claim 53, Gunasekaran teaches an earlier strategy by Carter and colleagues which uses “knob-into-hole” mutations in the CH3 domain of the Fc, which alter “residue packing complementarity between the CH3 domain interface within the structurally conserved hydrophobic core so that formation of the heterodimer is favored compared with homodimers” (page 19637). Although the knob-into-hole does not completely eliminate the production of mono- or homodimers, Gunasekaran notes that incorporating interchain disulfide bonds into the mutations further enhances heterodimer formation up to 95% (e.g., Discussion). Gunasekaran also sets forth an alternative method in which charge mutations are introduced, which “create altered charge polarity across the Fc dimer interface such that coexpression of electrostatically matched Fc chains support favorable attractive interactions thereby promoting desired Fc heterodimer formation, whereas unfavorable repulsive charge interactions suppress unwanted Fc homodimer formation” (e.g., Abstract; Results; Figures 1-4).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to incorporate into the multifunctional molecule of the reference patent a mutated Fc domain comprising knob-into-hole mutations such as described by Gunasekaran to generate a heterodimeric Fc domain. The skilled artisan would have been motivated to do so because Gunasekaran teaches that these mutations strongly favor pairing of Fc heterodimers. There would have been a reasonable expectation of success because these modifications would constitute applying known techniques in the art to improve a similar product in the same way.
(2.1)
Claims 25, 27-30, 47, 50, and 54-55 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46-48, 52-54, 69-63, and 67 of co-pending Application No. 18/172,928 (cited in PTO-892 mailed March 19, 2025) in view of Britanova (US 2020/0332003 A1; supra), C. Wang (US 2015/0353637 A1; supra), and Shitara (U.S. Patent No. 8,883,981; supra). This is a new rejection necessitated by claim amendment.
The co-pending reference application recites a composition comprising a multispecific molecule, said multispecific molecule comprising an antibody that binds to NKp30 and comprises a VH comprising SEQ ID NO: 1 or 2 (which share 100% identity to instant SEQ ID NO: 7302) and a VL comprising SEQ ID NO: 14 (which shares 100% identity to instant SEQ ID NO: 7305), and a T cell engager that targets an antigen present on the surface of an autoreactive T cell, said antigen being a TCRβ, as recited in co-pending claims 46-48, 52, and 59-63, relevant to claims 25 and 27-30. The disclosure of the co-pending reference application states: “the T cell engager is selected from an antigen binding domain or ligand that binds to (e.g., and in some embodiments activates) one or more of CD3, TCRα, TCRβ, TCRγ, TCRζ,” and others (¶ 00289). Further, “In other embodiments, the T cell engager is selected from an antigen binding domain or ligand that binds to and does not activate one or more of CD3, TCRα, TCRβ, TCRγ, TCRζ,” and others (¶ 00289). Co-pending claim 67 further recites a method of treating an autoimmune disorder by administering to a subject in need thereof a composition comprising the anti-NKp30 antibody composition of co-pending claim 46.
Further relevant to claim 25, the antibody molecule comprises an immunoglobulin constant region which is altered to decrease Fc receptor binding (co-pending claims 53-54).
However, the co-pending reference does not expressly recite that the multispecific molecule comprises a binding domain that specifically binds to a TCRβV having a combination of heavy chain and light chain CDRs as recited in claim 47, or a method of administering such a multispecific molecule to a subject to treat an autoimmune disorder. The co-pending reference application also does not claim that the multispecific molecule comprises a mutated Fc domain comprising (1) at least 90% sequence identity to instant SEQ ID NO: 42 and (2) a N297A mutation according to EU numbering.
The teachings of Britanova, C. Wang, and Shitara are recited in the non-statutory double patenting rejection above.
Based on the further teachings of Britanova, C. Wang, and Shitara, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the multifunctional molecule of the co-pending reference application by (1) substituting the T cell engaging binding domain of the multispecific molecule with the anti-TRBV9 antigen-binding domain taught by Britanova for the purpose of treating an autoimmune disorder, and (2) incorporating into the multifunctional molecule a mutated Fc domain that has reduced effector function. The skilled artisan would have been motivated to use the antigen-binding domain taught by Britanova because Britanova teaches that TCRs bearing TRBV9 family β chains are implicated in autoimmune diseases such as celiac disease, and the exemplary anti-TRBV9 antibody taught by Britanova eliminates TRBV9-bearing T cells. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized the suitability of the anti-TRBV9 antibody taught by Britanova for binding to an antigen on the surface of autoreactive T cells associated with an autoimmune disorder. Furthermore, one of ordinary skill in the art, through routine and conventional activities, would be capable of incorporating an anti-TRBV9 binding-domain as disclosed by Britanova into a multispecific construct.
The skilled artisan would further have been motivated to use an IgG1 constant region comprising the “effectorless” mutations of 217A, 356E, and 358M, in combination with 297A, because reduced Fc receptor binding is desirable in certain therapeutic applications. There would have been a reasonable expectation of success because it is prima facie obvious to use a known technique to improve a similar product (i.e., a multispecific antigen-binding construct) in the same way.
(2.2)
Claims 25 and 47-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46-48, 52-54, 69-63, and 67 of co-pending Application No. 18/172,928 in view of Britanova (US 2020/0332003 A1; supra), C. Wang (US 2015/0353637 A1; supra), and Shitara (U.S. Patent No. 8,883,981; supra) as applied to claims 25, 27-30, 47, 50, and 54-55 above, further in view of Lombana (Scientific Reports (2015) 5: Article 17488; supra). This is a new rejection necessitated by claim amendment.
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above.
However, the reference application does not teach an anti-TRBV9 antigen-binding domain comprising a VH comprising at least 90% sequence identity to the amino acid sequence of one of SEQ ID NO: 1260-1263 and a VL comprising at least 90% sequence identity to an amino acid sequence of one of SEQ ID NO: 1264-1267.
The teachings of Britanova, C. Wang, Shitara, and Lombana are disclosed in the non-statutory double patenting rejections above.
It would have been obvious for one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a multispecific molecule comprising an anti-TRBV9 binding domain having a VH comprising at least 90% sequence identity to one of the amino acid sequences of SEQ ID NO: 1260-1263 and a VL comprising at least 90% sequence identity to one of the amino acid sequences of SEQ ID NO: 1264-1267, comprising identical CDRs as previously set forth, through the process of routine optimization. The skilled artisan would have been motivated to do so because modifying residues within the framework region of the antibody, particularly within non-surface exposed regions, can confer increased functional expression in a host system and improved thermal stability while also increasing affinity of the antibody for its target antigen and minimizing antibody immunogenicity, as taught by Lombana. These qualities are useful for scaling up commercial production and increasing antibody formulation stability. There would have been a reasonable expectation of success because Lombana demonstrates that antibody framework residues (alone or in combination) identified during somatic hypermutation can be modified, while the CDR residues remain unchanged, to augment expression of the antibodies in a bacterial or mammalian host and improve their thermal stability.
(2.3)
Claims 25 and 52-53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46-48, 52-54, 69-63, and 67 of co-pending Application No. 18/172,928 in view of Britanova (US 2020/0332003 A1; supra), C. Wang (US 2015/0353637 A1; supra), and Shitara (U.S. Patent No. 8,883,981; supra) as applied to claims 25, 27-30, 47, 50, and 54-55 above, further in view of Gunasekaran (The Journal of Biological Chemistry (2010) 285(25): 19637-19646; supra). This is a new rejection necessitated by claim amendment.
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above.
However, the co-pending reference application does not teach that the multispecific molecule is a heterodimer comprising a paired cavity-protuberance.
The teachings of Britanova, C. Wang, Shitara, and Gunasekaran are discussed in the non-statutory double patenting rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to incorporate into the multifunctional molecule of the reference patent a mutated Fc domain comprising knob-into-hole mutations such as described by Gunasekaran to generate a heterodimeric Fc domain. The skilled artisan would have been motivated to do so because Gunasekaran teaches that these mutations strongly favor pairing of Fc heterodimers. There would have been a reasonable expectation of success because these modifications would constitute applying known techniques in the art to improve a similar product in the same way.
(3.1)
Claims 25, 27-30, 47, 50, and 54-55 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 11-13, 15, 18, 20, and 43 of co-pending Application No. 19/265,026 (reference application) in view of Britanova (US 2020/0332003 A1; supra), C. Wang (US 2015/0353637 A1; supra), and Shitara (U.S. Patent No. 8,883,981; supra). This is a new rejection necessitated by claim amendment.
Co-pending claims 1-3, 11-13, and 15 recite a multispecific molecule comprising (1) an anti-NKp30 antibody or antigen-binding fragment thereof comprising a VH comprising the amino acid sequence of SEQ ID NO: 7302 (with its corresponding CDRs) and a VL comprising the amino acid sequence of SEQ ID NO: 7305 (with its corresponding CDRs), which share 100% sequence identity to those instantly claimed sequences having the same sequence identifiers as set forth in claims 28-30, and (2) a binding moiety that binds to an antigen present on the surface of an autoreactive T cell that is associated with an autoimmune disorder. Further relevant to claim 25, co-pending claims 18 and 20 recite that the multispecific molecule comprises an immunoglobulin constant region having an alteration that decreases Fc receptor binding.
Co-pending claim 43 recites a method of treating an autoimmune disorder that comprises administering the multispecific or multifunctional molecule of any of co-pending claims 1-11, 13, or 15-28.
However, the co-pending reference does not expressly recite that the multispecific molecule comprises a binding domain that specifically binds to a TCRβV having a combination of heavy chain and light chain CDRs as recited in claim 47. The co-pending reference application also does not claim that the multispecific molecule comprises a mutated Fc domain comprising (1) at least 90% sequence identity to instant SEQ ID NO: 42 and (2) a N297A mutation according to EU numbering.
The teachings of Britanova, C. Wang, and Shitara are recited in the non-statutory double patenting rejection above.
Based on the further teachings of Britanova, C. Wang, and Shitara, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the multifunctional molecule of the co-pending reference application by (1) substituting the T cell engaging binding domain of the multispecific molecule with the anti-TRBV9 antigen-binding domain taught by Britanova for the purpose of treating an autoimmune disorder, and (2) incorporating into the multifunctional molecule a mutated Fc domain that has reduced effector function. The skilled artisan would have been motivated to use the antigen-binding domain taught by Britanova because Britanova teaches that TCRs bearing TRBV9 family β chains are implicated in autoimmune diseases such as celiac disease, and the exemplary anti-TRBV9 antibody taught by Britanova eliminates TRBV9-bearing T cells. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized the suitability of the anti-TRBV9 antibody taught by Britanova for binding to an antigen on the surface of autoreactive T cells associated with an autoimmune disorder. Furthermore, one of ordinary skill in the art, through routine and conventional activities, would be capable of incorporating an anti-TRBV9 binding-domain as disclosed by Britanova into a multispecific construct.
The skilled artisan would further have been motivated to use an IgG1 constant region comprising the “effectorless” mutations of 217A, 356E, and 358M, in combination with 297A, because reduced Fc receptor binding is desirable in certain therapeutic applications. There would have been a reasonable expectation of success because it is prima facie obvious to use a known technique to improve a similar product (i.e., a multispecific antigen-binding construct) in the same way.
(3.2)
Claims 25 and 47-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 11-13, 15, 18, 20, and 43 of co-pending Application No. 19/265,026 (reference application) in view of Britanova (US 2020/0332003 A1; supra), C. Wang (US 2015/0353637 A1; supra), and Shitara (U.S. Patent No. 8,883,981; supra) as applied to claims 25, 27-30, 47, 50, and 54-55 above, further in view of Lombana (Scientific Reports (2015) 5: Article 17488; supra). This is a new rejection necessitated by claim amendment.
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above.
However, the reference application does not teach an anti-TRBV9 antigen-binding domain comprising a VH comprising at least 90% sequence identity to the amino acid sequence of one of SEQ ID NO: 1260-1263 and a VL comprising at least 90% sequence identity to an amino acid sequence of one of SEQ ID NO: 1264-1267.
The teachings of Britanova, C. Wang, Shitara, and Lombana are disclosed in the non-statutory double patenting rejections above.
It would have been obvious for one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a multispecific molecule comprising an anti-TRBV9 binding domain having a VH comprising at least 90% sequence identity to one of the amino acid sequences of SEQ ID NO: 1260-1263 and a VL comprising at least 90% sequence identity to one of the amino acid sequences of SEQ ID NO: 1264-1267, comprising identical CDRs as previously set forth, through the process of routine optimization. The skilled artisan would have been motivated to do so because modifying residues within the framework region of the antibody, particularly within non-surface exposed regions, can confer increased functional expression in a host system and improved thermal stability while also increasing affinity of the antibody for its target antigen and minimizing antibody immunogenicity, as taught by Lombana. These qualities are useful for scaling up commercial production and increasing antibody formulation stability. There would have been a reasonable expectation of success because Lombana demonstrates that antibody framework residues (alone or in combination) identified during somatic hypermutation can be modified, while the CDR residues remain unchanged, to augment expression of the antibodies in a bacterial or mammalian host and improve their thermal stability.
(3.3)
Claims 25 and 52-53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 11-13, 15, 18, 20, and 43 of co-pending Application No. 19/265,026 (reference application) in view of Britanova (US 2020/0332003 A1; supra), C. Wang (US 2015/0353637 A1; supra), and Shitara (U.S. Patent No. 8,883,981; supra) as applied to claims 25, 27-30, 47, 50, and 54-55 above, further in view of Gunasekaran (The Journal of Biological Chemistry (2010) 285(25): 19637-19646; supra). This is a new rejection necessitated by claim amendment.
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above.
However, the co-pending reference application does not teach that the multispecific molecule is a heterodimer comprising a paired cavity-protuberance.
The teachings of Britanova, C. Wang, Shitara, and Gunasekaran are discussed in the non-statutory double patenting rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to incorporate into the multifunctional molecule of the reference patent a mutated Fc domain comprising knob-into-hole mutations such as described by Gunasekaran to generate a heterodimeric Fc domain. The skilled artisan would have been motivated to do so because Gunasekaran teaches that these mutations strongly favor pairing of Fc heterodimers. There would have been a reasonable expectation of success because these modifications would constitute applying known techniques in the art to improve a similar product in the same way.
(4.1)
Claims 25, 27-29, 47, 50, and 52-55 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-263 of co-pending Application No. 19/642,327 (reference application) in view of Britanova (US 2020/0332003 A1; supra). This is a new rejection necessitated by the filing of an IDS with fee on May 1, 2026.
Co-pending claims 1-4, 11-16, 20-23, 97-100, and 124-131 recite a composition comprising a multifunctional molecule having an anti-NKp30 antigen-binding domain that comprises identical CDRs to that of claims 27-29 and a T cell engager comprising an antigen-binding domain that binds to a TCRβV, wherein the molecule comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 42 (which shares 100% sequence identity to instant SEQ ID NO: 42) and the Fc domain is a dimerized IgG1 Fc domain having a paired cavity-protuberance and having a first Fc region comprising N297A according to EU numbering, relevant to claims 25, 27-29, 50, and 52-55. Co-pending claims 246-247 and 259-260 further recite a pharmaceutical composition comprising said multifunctional molecule and a method of treating an autoimmune disease using said pharmaceutical composition.
However, the co-pending reference does not expressly recite that the multispecific molecule comprises a binding domain that specifically binds to a TCRβV and depletes T cells expressing the TCRβV, having a combination of heavy chain and light chain CDRs as recited in claim 47.
The teachings of Britanova are recited in the non-statutory double patenting rejection above.
Based on the further teachings of Britanova, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the multifunctional molecule of the co-pending reference application by (1) substituting the T cell engaging binding domain of the multispecific molecule with the anti-TRBV9 antigen-binding domain taught by Britanova for the purpose of treating an autoimmune disorder, and (2) incorporating into the multifunctional molecule a mutated Fc domain that has reduced effector function. The skilled artisan would have been motivated to use the antigen-binding domain taught by Britanova because Britanova teaches that TCRs bearing TRBV9 family β chains are implicated in autoimmune diseases such as celiac disease, and the exemplary anti-TRBV9 antibody taught by Britanova eliminates TRBV9-bearing T cells. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized the suitability of the anti-TRBV9 antibody taught by Britanova for binding to an antigen on the surface of autoreactive T cells associated with an autoimmune disorder. Furthermore, one of ordinary skill in the art, through routine and conventional activities, would be capable of incorporating an anti-TRBV9 binding-domain as disclosed by Britanova into a multispecific construct.
(4.2)
Claims 25 and 47-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-263 of co-pending Application No. 19/642,327 (reference application) in view of Britanova (US 2020/0332003 A1; supra) as applied to claims 25, 27-29, 47, 50, and 52-55, further in view of Lombana (Scientific Reports (2015) 5: Article 17488; supra). This is a new rejection necessitated by the filing of an IDS with fee on May 1, 2026.
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above.
However, the reference application does not teach an anti-TRBV9 antigen-binding domain comprising a VH comprising at least 90% sequence identity to the amino acid sequence of one of SEQ ID NO: 1260-1263 and a VL comprising at least 90% sequence identity to an amino acid sequence of one of SEQ ID NO: 1264-1267.
The teachings of Britanova and Lombana are disclosed in the non-statutory double patenting rejections above.
It would have been obvious for one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a multispecific molecule comprising an anti-TRBV9 binding domain having a VH comprising at least 90% sequence identity to one of the amino acid sequences of SEQ ID NO: 1260-1263 and a VL comprising at least 90% sequence identity to one of the amino acid sequences of SEQ ID NO: 1264-1267, comprising identical CDRs as previously set forth, through the process of routine optimization. The skilled artisan would have been motivated to do so because modifying residues within the framework region of the antibody, particularly within non-surface exposed regions, can confer increased functional expression in a host system and improved thermal stability while also increasing affinity of the antibody for its target antigen and minimizing antibody immunogenicity, as taught by Lombana. These qualities are useful for scaling up commercial production and increasing antibody formulation stability. There would have been a reasonable expectation of success because Lombana demonstrates that antibody framework residues (alone or in combination) identified during somatic hypermutation can be modified, while the CDR residues remain unchanged, to augment expression of the antibodies in a bacterial or mammalian host and improve their thermal stability.
Conclusion
Applicant's claim amendments and submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on May 1, 2026 necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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