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 Status
Applicant’s amendments and remarks, filed 12/29/2025, are acknowledged.
Claim 15 is canceled.
Claims 1-14 and 16-21 are pending.
DETAILED ACTION
Election/Restrictions
Applicant's group election with traverse of Group I (claims 1-6, 11-14, and 18-21) in the reply filed on 12/29/2025 is acknowledged. The traversal is on the grounds that:
The technical solution with “special technical features” of the present application is non-obvious (see pages 28-30); and,
As long as the claimed technical solution in claim 1 is novel and non-obvious over prior arts, Groups I-IV possess unity of invention (see page 30).
This is not found persuasive because: (1) the restriction requirement stated that the instant antibodies and protein functional regions are not regarded as being of similar nature because all of the alternatives do not share a common property or activity. Each of the antibodies and functional regions possess significant structural similarities and differences that cannot readily be ascertained between the sequences. Without significant structural similarities, the antibodies do not have a shared special technical feature since each structural difference results in a different function, binding, and/or affinity. In the absence of a shared special technical feature, each of the antibodies claimed in claims 5-6 and 18-21 lack unity with one another.
(2) With respect to the teachings of Moore, the present application is drawn to a binding protein wherein the configuration was selected from: (I) the first protein functional region is of a Fab structure, the second protein functional region is of a VH structure, and the first protein functional region and the second protein functional region are arranged from the N-terminus to the C-terminus of the binding protein; or (II) the first protein functional region is of a Fab structure, the second protein functional region is of a Fab structure, and the first protein functional region and the second protein functional region are arranged from the N-terminus to the C-terminus of the binding protein; the binding protein is of (a) a monomeric structure, or (b) a dimeric structure consisting of two monomers. Moore disclose that the heterodimeric antibodies of the invention further comprise one or two additional antigen binding domains that can be either or both of an scFv and a Fab (see [0011]). Specifically, Moore disclose of Fig. 12D wherein the heterodimeric protein design depicts an additional Fab attached to the Fab monomer (see [0054] and [0093]). Because the instant claims comprise the transitional phrase “comprising” for the claimed binding protein, the additional features disclosed by Moore do not render the present application non-obvious. As configured, Fig. 12D of Moore shows a first Fab structure and a second Fab structure arranged from the N-terminus to the C-terminus of the protein, which is sufficient to demonstrate that the technical feature of the present invention is not special.
(3) In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a binding protein with enhanced immune response against specific target cells, such as by leveraging the activity of immune effector cells, thereby improving the efficacy of the antibody drug in tumor killing) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
(4) Lastly, with respect to Applicant’s argument that Groups I-IV possess unity of invention, Examiner respectfully disagrees. As stated above, each of the antibodies and functional regions possess significant structural similarities and differences that cannot readily be ascertained between the sequences. Without significant structural similarities, the antibodies do not have a shared special technical feature since each structural difference results in a different function, binding, and/or affinity. Therefore, Groups II-IV are inherently distinct because the species of Group I do not share significant structural similarities.
As such, the requirement is still deemed proper and is therefore made FINAL.
Applicant’s species election of a binding protein comprising a second protein functional region with the CDRs of PR001760 in the reply filed on 12/29/2025 is acknowledged.
Claims 7-10 and 16-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/29/2025.
As such, claims 1-6, 11-14, and 18-21 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/30/2023 and 06/07/2024 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The disclosure is objected to because of the following informalities:
[0189]: remove “kitscombination of”.
[0204]: “FIG.4shows” should read “FIG.4 shows”.
[0215]: “Bshows” should read “shows”.
[0324]: “BD FACS CANTOII” should read “BD FACSCanto II”.
[0428]: “Meltenyi” should read “Miltenyi”.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see [0242]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term Bristol-Myers Squibb, Pfizer, Bio-Rad, GE Healthcare, NanoDrop, TSKgel, Tosoh Bioscience, Agilent Technologies, GenScript, Corning, CrownBio, Alexa Fluor, BD FACSCanto II, FlowJo, GraphPad Prism, Invitrogen, AffiniPure, ATCC, PeproTech, Sigma, Miltenyi, WinNonlin, GemPharmatech, and Bio X Cell, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 2, 4, 13, 18-19, and 21 are objected to because of the following informalities:
Claim 1: “…an immune effector cell; the binding protein…” should read “…an immune effector cell; wherein the binding protein…”.
Claim 1(II): “…the binding protein; the binding protein…” should read “…the binding protein; wherein the binding protein…”.
Claim 2: remove the language “of the (a)” and “of the (b)”.
Claims 4 and 18-19 recite several antigen species that are recited as acronyms and/or abbreviations which should be spelled out on first occurrence.
Claim 13: “kit I” and “kit II” should read “a first kit” and “a second kit”, respectively.
Claim 21: “the binding protein according to claim 20 comprises the following polypeptide chains:” should read “The binding protein according to claim 20 comprises the following polypeptide chains:”. According to MPEP 608.01(m), each claim must begin with a capital letter. See also Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Appropriate correction is required.
Claim Interpretation
Claim 3 recites the transitional phrase “having”, the scope of which is not defined by the specification. As such, according to MPEP 2111.03(IV), the term will be interpreted as an open-ended transitional term, similar to the transitional phrase “comprising”. For example, the structure recited in the claims can comprise additional, unrecited elements.
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 2-6, 11-14, and 18-21 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.
The terms “preferably”, “more preferably”, and “even more preferably” in claims 2-5, 11-12, and 14 renders the claims indefinite because it is unclear whether the limitations following the term are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 2 and 4, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 3 and 21 recite “polypeptide chain 1” and “polypeptide chain 2”. It is unclear whether the polypeptide chains 1 and 2 are the same as the first and second protein functional regions as recited in claim 1, or if these structures are in addition to the protein functional regions.
Claims 3, 5, 6, and 18-21 recite “as shown in a formula of” and/or “as set forth in any one of SEQ ID NO: XXX” . The language is indefinite because it is unclear if the amino acid is limited to the full structure of the formula or the full sequence of the SEQ ID NO, or structure of the formula or the amino acid sequence can be of any length as long as the SEQ ID NO is within the sequence, respectively. The term “in any one of SEQ ID NO: XXX” could refer to any two amino acids joined by a peptide bond that appears within the sequence of SEQ ID NO:XX. As such, 3, 5, 6, 18-21, and their dependent claims, are rejected.
Claim 12 recites the limitation "the pharmaceutical composition" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 14, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 4-6 and 18-21 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of antigens are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
The phrase “recognized class of chemical compounds” means that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention, i.e. each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
The instant antibodies and protein functional regions are not regarded as being of similar nature because all of the alternatives do not share a common property or activity. Each of the antibodies and functional regions possess significant structural similarities and differences that cannot readily be ascertained between the sequences. Without significant structural similarities, the antibodies do not have a common use since each structural difference results in a different function, binding, and/or affinity.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(a) Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 11-14, and 18-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a binding protein comprising at least two protein functional regions, comprising a first protein functional region and a second protein functional region, wherein the first protein functional region comprises a targeting moiety binding to an antigen on a target cell, and the second protein functional region comprises an effector moiety binding to an antigen on an immune effector cell; the binding protein is selected from the following structures: (I) the first protein functional region is of a Fab structure, the second protein functional region is of a VH structure, and the first protein functional region and the second protein functional region are arranged from the N-terminus to the C-terminus of the binding protein; and (II) the first protein functional region is of a Fab structure, the second protein functional region is of a Fab structure, and the first protein functional region and the second protein functional region are arranged from the N-terminus to the C-terminus of the binding protein; the binding protein is of (a) a monomeric structure, or (b) a dimeric structure consisting of two monomers.
Claim 2 is drawn to the binding protein according to claim 1, wherein in the monomeric structure of the (a), the binding protein has two second protein functional regions, one of which is linked to the C-terminus of the heavy chain CH1 of the Fab structure of the first protein functional region, and the other of which is linked to the C-terminus of the light chain CL of the Fab structure of the first protein functional region; in the dimeric structure of the (b), the binding protein further comprises an Fc; preferably, the Fc is positioned between the first protein functional region and the second protein functional region; or, the Fc is positioned at the C-terminus of the second protein functional region; or, the Fc is positioned between the two second protein functional regions; more preferably, in each monomer, the number of the first protein functional region is 1, the number of the Fc is 1, and the number of the second protein functional region is 1 or more than one, e.g., 1, 2 or 3; even more preferably, the binding protein further comprises a third protein functional region, wherein the third protein functional region is positioned at the C- or N-terminus of the binding protein, or at the C- or N-terminus of the Fc structure of the binding protein; even more preferably, the number of the third protein functional region is 1 or more than one, e.g., 1, 2 or 3.
Claim 3 is drawn to the binding protein according to claim 1, wherein the binding protein comprises a polypeptide chain 1 and a polypeptide chain 2, wherein the polypeptide chain 1 is as shown in a formula of N'-VL_A-CL-C', and the polypeptide chain 2 is as shown in a formula of N'-VH_A-CH1-h-CH2-CH3-L-VH_B-C', wherein the L is a linker peptide being preferably 0 in length or having an amino acid sequence preferably as set forth in any one of SEQ ID NOs: 244-265 or an amino acid sequence of GS; or, the binding protein comprises a polypeptide chain 1 and a polypeptide chain 2, wherein the polypeptide chain 1 is as shown in a formula of N'-VL_A-CL-C', and the polypeptide chain 2 is as shown in a formula of N'-VHA-CH1-h-CH2-CH3-L1-VH_B-L2-VH_B-C’, wherein the L1 and L2 are linker peptides being preferably 0 in length or having an amino acid sequence preferably as set forth in any one of SEQ ID NOs: 244-265 or an amino acid sequence of GS; or, the binding protein comprises a polypeptide chain 1 and a polypeptide chain 2, wherein the polypeptide chain 1 is as shown in a formula of N'-VH_A-CH1-C', and the polypeptide chain 2 is as shown in a formula of N'-VL_A-CL-L1-VH_B-L2-CH2-CH3-C', wherein the L1 and L2 are linker peptides being preferably 0 in length or having an amino acid sequence preferably as set forth in any one of SEQ ID NOs: 244-265 or an amino acid sequence of GS, and the L2 further has an amino acid sequence preferably as set forth in SEQ ID NO: 253, SEQ ID NO: 262 or SEQ ID NO: 263; or, the binding protein comprises a polypeptide chain 1 and a polypeptide chain 2, wherein the polypeptide chain 1 is as shown in a formula of N'-VL_A-CL-C', and the polypeptide chain 2 is as shown in a formula of N'-VH_A-CH1-Li-VH_B-L2-CH2-CH3-C', wherein the L1 and L2 are linker peptides being preferably 0 in length or having an amino acid sequence preferably as set forth in any one of SEQ ID NOs: 244-265 or an amino acid sequence of GS, and the L2 further has an amino acid sequence preferably as set forth in SEQ ID NO: 253, SEQ ID NO: 262 or SEQ ID NO: 263; or, the binding protein comprises a polypeptide chain 1 and a polypeptide chain 2, wherein the polypeptide chain 1 is as shown in a formula of N'-VH_A-CH1-C', and the polypeptide chain 2 is as shown in a formula of N'-VL_A-CL-L1-VH_B-L2-CH2-CH3-L3-VH_B-C', wherein the L1, L2 and L3 are linker peptides being preferably 0 in length or having an amino acid sequence preferably as set forth in any one of SEQ ID NOs: 244-265 or an amino acid sequence of GS, and the L2 further has an amino acid sequence preferably as set forth in SEQ ID NO: 253, SEQ ID NO: 262 or SEQ ID NO: 263; or, the binding protein comprises a polypeptide chain 1 and a polypeptide chain 2, wherein the polypeptide chain 1 is as shown in a formula of N’-VL_A-CL-C’, and the polypeptide chain 2 is as shown in a formula of N'-VH_A-CH1-L1-VH_B-L2-CH2-CH3-L3-VH_B-C', wherein the L1, L2 and L3 are linker peptides being preferably 0 in length or having an amino acid sequence preferably as set forth in any one of SEQ ID NOs: 244-265 or an amino acid sequence of GS, and the L2 further has an amino acid sequence preferably as set forth in SEQ ID NO: 253, SEQ ID NO: 262 or SEQ ID NO: 263;or, the binding protein comprises a polypeptide chain 1, a polypeptide chain 2 and a polypeptide chain 3, wherein the polypeptide chain 1 is as shown in a formula of N'-VL_A- CL-L-VH_B-CH1-h-CH2-CH3-C', the polypeptide chain 2 is as shown in a formula of N'- VH_A-CH1-C', and the polypeptide chain 3 is as shown in a formula of N'-VL_B-CL-C', wherein the L is a linker peptide being preferably 0 in length or having an amino acid sequence preferably as set forth in any one of SEQ ID NOs: 244-265 or an amino acid sequence of GS; wherein the VL_B and the VH_B are VL and VH of the second protein functional region, respectively, and the VL_A and the VH_A are VL and VH of the first protein functional region, respectively; the h is a hinge region; the CL is a light chain constant region domain; the CH1, CH2 and CH3 are a first domain, a second domain and a third domain of a heavy chain constant region, respectively; and the L or L1 or L2 or L3 is a linker peptide.
Claim 4 is drawn to the binding protein according to claim 1, wherein the antigen on the target cell is a tumor antigen or a co-inhibitory molecule antigen; wherein the tumor antigen is CD19, BCMA, TSHR, CD171, CS-1, CLL-1, GD3, Tn Ag, FLT3, CD38, CD123, CD44v6, B7H3, B7H4, KIT, IL-13Ra2, IL-11Ra, PSCA, PSMA, PRSS21, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, MUC1, EGFR, NCAM, CAIX, LMP2, EphA2, fucosyl GM1, sLe, GM3, TGS5, HMWMAA, GD2, FOLR1, FOLR2, TEM1/CD248, TEM7R, CLDN6, CLDN18.2, GPRC5D, CXORF61, CD97, CD179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51 E2, TAARP, WT1, ETV6-AML, SPA17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, FOSL1, hTERT, ML-IAP, ERG, NA17, PAX3, AR, cyclin B1, MYCN, RhoC, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, IGLL1, CD20, CD30, HER2, ROR1, FLT3, TAAG72, CD22, CD33, GD2, gp100Tn, FAP, tyrosinase, EPCAM, CEA, IGF-1R, EphB2, mesothelin, cadherin17, CD32b, EGFRvIII, GPNMB, GPR64, HER3, LRP6, LYPD8, NKG2D, SLC34A2, SLC39A6, SLITRK6, GUCY2C or TACSTD2;preferably B7H3, B7H4, PSMA, CLDN18.2, GPC3, HER2, ROR1, CD22, EPCAM, mesothelin, EGFRvIII or TACSTD2; or, the co-inhibitory molecule antigen is PD-L1, PD- L2, CTLA4, B7H3, B7H4, VISTA, HHLA2 or CD155, preferably PD-L1, B7H3, B7H4 or HHLA2; and the antigen on the immune effector cell is a stimulatory antigen or a costimulatory molecule antigen, e.g., TCR/CD3, CD28, 4-1 BB, OX40, GITR, CD27, ICOS, CD2, CD40, CD226, CD16, NKp30, NKp44, NKp46, NKG2D or 2B4, preferably TCR/CD3, CD28, 4- 1 BB, OX40, GITR, CD40,CD226, CD16 or NKp30;preferably: the antigen on the target cell is CLDN18.2, HER2, B7H4, EPCAM, PSMA or PD-L1; and the antigen on the immune effector cell is 4-1 BB or OX40.
Claim 5 is drawn to the binding protein according to claim 1, wherein the first protein functional region is an antibody targeting CLDN18.2 or an antigen-binding fragment thereof, an antibody targeting HER2 or an antigen-binding fragment thereof, an antibody targeting B7H4 or an antigen-binding fragment thereof, an antibody targeting EPCAM or an antigen-binding fragment thereof, an antibody targeting PSMA or an antigen-binding fragment thereof, or an antibody targeting PD-L1 or an antigen-binding fragment thereof; and the second protein functional region is an antibody targeting OX40 or an antigen-binding fragment thereof, or an antibody targeting 4-1 BB or an antigen-binding fragment thereof; preferably: the antibody targeting CLDN18.2 or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 22, VH CDR2 with a sequence as set forth in SEQ ID NO: 55 and VH CDR3 with a sequence as set forth in SEQ ID NO: 88, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 108, VL CDR2 with a sequence as set forth in SEQ ID NO: 121 and VL CDR3 with a sequence as set forth in SEQ ID NO: 142;the antibody targeting HER2 or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 13, VH CDR2 with a sequence as set forth in SEQ ID NO: 42 and VH CDR3 with a sequence as set forth in SEQ ID NO: 77, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 105, VL CDR2 with a sequence as set forth in SEQ ID NO: 117 and VL CDR3 with a sequence as set forth in SEQ ID NO: 134;the antibody targeting PD-L1 or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 11, VH CDR2 with a sequence as set forth in SEQ ID NO: 40 and VH CDR3 with a sequence as set forth in SEQ ID NO: 75, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 103, VL CDR2 with a sequence as set forth in SEQ ID NO: 117 and VL CDR3 with a sequence as set forth in SEQ ID NO: 132; or, the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VH CDR2 with a sequence as set forth in SEQ ID NO: 43 and VH CDR3 with a sequence as set forth in SEQ ID NO: 78, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 106, VL CDR2 with a sequence as set forth in SEQ ID NO: 119 and VL CDR3 with a sequence as set forth in SEQ ID NO: 135; the antibody targeting B7H4 or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 20, VH CDR2 with a sequence as set forth in SEQ ID NO: 53 and VH CDR3 with a sequence as set forth in SEQ ID NO: 86, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 110, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 140; or the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 21, VH CDR2 with a sequence as set forth in SEQ ID NO: 54 and VH CDR3 with a sequence as set forth in SEQ ID NO: 87, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 111, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 141;the antibody targeting EPCAM or the antigen-binding fragment thereof comprises heavy chain variable region (VH) and light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 16, VH CDR2 with a sequence as set forth in SEQ ID NO: 47 and VH CDR3 with a sequence as set forth in SEQ ID NO: 81, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 108, VL CDR2 with a sequence as set forth in SEQ ID NO: 121 and VL CDR3 with a sequence as set forth in SEQ ID NO: 138; the antibody targeting PSMA or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 17, VH CDR2 with a sequence as set forth in SEQ ID NO: 48 and VH CDR3 with a sequence as set forth in SEQ ID NO: 82, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 109, VL CDR2 with a sequence as set forth in SEQ ID NO: 122 and VL CDR3 with a sequence as set forth in SEQ ID NO: 139;the antibody targeting 4-1 BB or the antigen-binding fragment thereof comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 16, VH CDR2 with a sequence as set forth in SEQ ID NO: 49 and VH CDR3 with a sequence as set forth in SEQ ID NO: 83; or the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 18, VH CDR2 with a sequence as set forth in SEQ ID NO: 50 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 19, VH CDR2 with a sequence as set forth in SEQ ID NO: 51 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 18, VH CDR2 with a sequence as set forth in SEQ ID NO: 57 and VH CDR3 with a sequence as set forth in SEQ ID NO: 90; or, the antibody targeting 4-1 BB or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 12, VH CDR2 with a sequence as set forth in SEQ ID NO: 41 and VH CDR3 with a sequence as set forth in SEQ ID NO: 76, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 104, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 133; or, the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 12, VH CDR2 with a sequence as set forth in SEQ ID NO: 44 and VH CDR3 with a sequence as set forth in SEQ ID NO: 76, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 104, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 133; and the antibody targeting OX40 or the antigen-binding fragment thereof comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VH CDR2 with a sequence as set forth in SEQ ID NO: 52 and VH CDR3 with a sequence as set forth in SEQ ID NO: 85.
Claim 6 is drawn to the binding protein according to claim 1, wherein the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 13, VH CDR2 with a sequence as set forth in SEQ ID NO: 42 and VH CDR3 with a sequence as set forth in SEQ ID NO: 77, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 105, VL CDR2 with a sequence as set forth in SEQ ID NO: 117 and VL CDR3 with a sequence as set forth in SEQ ID NO: 134; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 19, VH CDR2 with a sequence as set forth in SEQ ID NO: 51 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 20, VH CDR2 with a sequence as set forth in SEQ ID NO: 53 and VH CDR3 with a sequence as set forth in SEQ ID NO: 86, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 110, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 140; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 16, VH CDR2 with a sequence as set forth in SEQ ID NO: 49 and VH CDR3 with a sequence as set forth in SEQ ID NO: 83; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 20, VH CDR2 with a sequence as set forth in SEQ ID NO: 53 and VH CDR3 with a sequence as set forth in SEQ ID NO: 86, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 110, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 140; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 18, VHCDR2 with a sequence as set forth in SEQ ID NO: 50 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 20, VH CDR2 with a sequence as set forth in SEQ ID NO: 53 and VH CDR3 with a sequence as set forth in SEQ ID NO: 86, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 110, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 140; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 18, VH CDR2 with a sequence as set forth in SEQ ID NO: 57 and VH CDR3 with a sequence as set forth in SEQ ID NO: 90; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VH CDR2 with a sequence as set forth in SEQ ID NO: 43 and VH CDR3 with a sequence as set forth in SEQ ID NO: 78, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 106, VL CDR2 with a sequence as set forth in SEQ ID NO: 119 and VL CDR3 with a sequence as set forth in SEQ ID NO: 135; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises a VH CDR1 with a sequence as set forth in SEQ ID NO: 16, a VH CDR2 with a sequence as set forth in SEQ ID NO: 49 and a VH CDR3 with a sequence as set forth in SEQ ID NO: 83; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VH CDR2 with a sequence as set forth in SEQ ID NO: 43 and VH CDR3 with a sequence as set forth in SEQ ID NO: 78, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 106, VL CDR2 with a sequence as set forth in SEQ ID NO: 119 and VL CDR3 with a sequence as set forth in SEQ ID NO: 135; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 18, VH 10 DGW/at CDR2 with a sequence as set forth in SEQ ID NO: 50 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VH CDR2 with a sequence as set forth in SEQ ID NO: 43 and VH CDR3 with a sequence as set forth in SEQ ID NO: 78, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 106, VL CDR2 with a sequence as set forth in SEQ ID NO: 119 and VL CDR3 with a sequence as set forth in SEQ ID NO: 135; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 19, VH CDR2 with a sequence as set forth in SEQ ID NO: 51 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 16, VH CDR2 with a sequence as set forth in SEQ ID NO: 47 and VH CDR3 with a sequence as set forth in SEQ ID NO: 81, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 108, VL CDR2 with a sequence as set forth in SEQ ID NO: 121 and VL CDR3 with a sequence as set forth in SEQ ID NO: 138; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 16, VH CDR2 with a sequence as set forth in SEQ ID NO: 49 and VH CDR3 with a sequence as set forth in SEQ ID NO: 83; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 16, VH CDR2 with a sequence as set forth in SEQ ID NO: 47 and VH CDR3 with a sequence as set forth in SEQ ID NO: 81, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 108, VL CDR2 with a sequence as set forth in SEQ ID NO: 121 and VL CDR3 with a sequence as set forth in SEQ ID NO: 138; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 18, VHCDR2 with a sequence as set forth in SEQ ID NO: 50 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 16, VH CDR2 with a sequence as set forth in SEQ ID NO: 47 and VH CDR3 with a sequence as set forth in SEQ ID NO: 81, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 108, VL CDR2 with a sequence as set forth in SEQ ID NO: 121 and VL CDR3 with a sequence as set forth in SEQ ID NO: 138; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 19, VH CDR2 with a sequence as set forth in SEQ ID NO: 51 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 17, VH CDR2 with a sequence as set forth in SEQ ID NO: 48 and VH CDR3 with a sequence as set forth in SEQ ID NO: 82, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 109, VL CDR2 with a sequence as set forth in SEQ ID NO: 122 and VL CDR3 with a sequence as set forth in SEQ ID NO: 139; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 16, VH CDR2 with a sequence as set forth in SEQ ID NO: 49 and VH CDR3 with a sequence as set forth in SEQ ID NO: 83; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 17, VH CDR2 with a sequence as set forth in SEQ ID NO: 48 and VH CDR3 with a sequence as set forth in SEQ ID NO: 82, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 109, VL CDR2 with a sequence as set forth in SEQ ID NO: 122 and VL CDR3 with a sequence as set forth in SEQ ID NO: 139; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 18, VHCDR2 with a sequence as set forth in SEQ ID NO: 50 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 17, VH CDR2 with a sequence as set forth in SEQ ID NO: 48 and VH CDR3 with a sequence as set forth in SEQ ID NO: 82, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 109, VL CDR2 with a sequence as set forth in SEQ ID NO: 122 and VL CDR3 with a sequence as set forth in SEQ ID NO: 139; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 19, VH CDR2 with a sequence as set forth in SEQ ID NO: 51 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 22, VH CDR2 with a sequence as set forth in SEQ ID NO: 55 and VH CDR3 with a sequence as set forth in SEQ ID NO: 88, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 108, VL CDR2 with a sequence as set forth in SEQ ID NO: 121 and VL CDR3 with a sequence as set forth in SEQ ID NO: 142; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 16, VH CDR2 with a sequence as set forth in SEQ ID NO: 49 and VH CDR3 with a sequence as set forth in SEQ ID NO: 83; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 22, VH CDR2 with a sequence as set forth in SEQ ID NO: 55 and VH CDR3 with a sequence as set forth in SEQ ID NO: 88, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 108, VL CDR2 with a sequence as set forth in SEQ ID NO: 121 and VL CDR3 with a sequence as set forth in SEQ ID NO: 142; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 18, VH 13 DGW/atCDR2 with a sequence as set forth in SEQ ID NO: 50 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 22, VH CDR2 with a sequence as set forth in SEQ ID NO: 55 and VH CDR3 with a sequence as set forth in SEQ ID NO: 88, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 108, VL CDR2 with a sequence as set forth in SEQ ID NO: 121 and VL CDR3 with a sequence as set forth in SEQ ID NO: 142; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 19, VH CDR2 with a sequence as set forth in SEQ ID NO: 51 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VH CDR2 with a sequence as set forth in SEQ ID NO: 43 and VH CDR3 with a sequence as set forth in SEQ ID NO: 78, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 106, VL CDR2 with a sequence as set forth in SEQ ID NO: 119 and VL CDR3 with a sequence as set forth in SEQ ID NO: 135; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VH CDR2 with a sequence as set forth in SEQ ID NO: 52 and VH CDR3 with a sequence as set forth in SEQ ID NO: 85; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 20, VH CDR2 with a sequence as set forth in SEQ ID NO: 53 and VH CDR3 with a sequence as set forth in SEQ ID NO: 86, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 110, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 140; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VHCDR2 with a sequence as set forth in SEQ ID NO: 52 and VH CDR3 with a sequence as set forth in SEQ ID NO: 85; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 16, VH CDR2 with a sequence as set forth in SEQ ID NO: 47 and VH CDR3 with a sequence as set forth in SEQ ID NO: 81, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 108, VL CDR2 with a sequence as set forth in SEQ ID NO: 121 and VL CDR3 with a sequence as set forth in SEQ ID NO: 138; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VH CDR2 with a sequence as set forth in SEQ ID NO: 52 and VH CDR3 with a sequence as set forth in SEQ ID NO: 85; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 17, VH CDR2 with a sequence as set forth in SEQ ID NO: 48 and VH CDR3 with a sequence as set forth in SEQ ID NO: 82, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 109, VL CDR2 with a sequence as set forth in SEQ ID NO: 122 and VL CDR3 with a sequence as set forth in SEQ ID NO: 139; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VH CDR2 with a sequence as set forth in SEQ ID NO: 52 and VH CDR3 with a sequence as set forth in SEQ ID NO: 85; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 22, VH CDR2 with a sequence as set forth in SEQ ID NO: 55 and VH CDR3 with a sequence as set forth in SEQ ID NO: 88, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 108, VL CDR2 with a sequence as set forth in SEQ ID NO: 121 and VL CDR3 with a sequence as set forth in SEQ ID NO: 142; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VHCDR2 with a sequence as set forth in SEQ ID NO: 52 and VH CDR3 with a sequence as set forth in SEQ ID NO: 85; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 21, VH CDR2 with a sequence as set forth in SEQ ID NO: 54 and VH CDR3 with a sequence as set forth in SEQ ID NO: 87, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 111, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 141; and the second protein functional region comprises a heavy chain variable region (VH), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 18, VH CDR2 with a sequence as set forth in SEQ ID NO: 50 and VH CDR3 with a sequence as set forth in SEQ ID NO: 84; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 14, VH CDR2 with a sequence as set forth in SEQ ID NO: 43 and VH CDR3 with a sequence as set forth in SEQ ID NO: 78, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 106, VL CDR2 with a sequence as set forth in SEQ ID NO: 119 and VL CDR3 with a sequence as set forth in SEQ ID NO: 135; and the second protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 12, VH CDR2 with a sequence as set forth in SEQ ID NO: 41 and VH CDR3 with a sequence as set forth in SEQ ID NO: 76, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 104, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 133; or, the first protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 11, VH CDR2 with a sequence as set forth in SEQ ID NO: 40 and VH CDR3 with a sequence as set forth in SEQ ID NO: 75, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 103, VL CDR2 with a sequence as set forth in SEQ ID NO: 117 and VL CDR3 with a sequence as set forth in SEQ ID NO: 132; and the second protein functional region comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises VH CDR1 with a sequence as set forth in SEQ ID NO: 12, VH CDR2 with a sequence as set forth in SEQ ID NO: 44 and VH CDR3 with a sequence as set forth in SEQ ID NO: 76, and the VL comprises VL CDR1 with a sequence as set forth in SEQ ID NO: 104, VL CDR2 with a sequence as set forth in SEQ ID NO: 118 and VL CDR3 with a sequence as set forth in SEQ ID NO: 133.
Claim 11 is drawn to a pharmaceutical composition comprising the binding protein according to claim 1 and optionally a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition further comprises an additional anti-tumor antibody as an active ingredient.
Claim 12 is drawn to a kit comprising the binding protein according to claim 1; preferably, the kit further comprises (i) a device for administering the binding protein or the pharmaceutical composition; or (ii) instructions.
Claim 13 is drawn to a combination of kits comprising a kit I comprising the binding protein according to claim 1, and a kit II comprising an additional antibody or pharmaceutical composition.
Claim 14 is drawn to an administration device comprising the binding protein according to claim 1; preferably, the administration device further comprises a component, such as a syringe, an infusion device or an implantable administration device, for containing or administering to a subject the binding protein.
Claim 18 is drawn to the binding protein according to claim 5, wherein the antibody targeting CLDN18.2 or the antigen-binding fragment thereof comprises VH with a sequence as set forth in SEQ ID NO: 165 and VL with a sequence as set forth in SEQ ID NO: 179; the antibody targeting HER2 or the antigen-binding fragment thereof comprises VH with a sequence as set forth in SEQ ID NO: 152 and VL with a sequence as set forth in SEQ ID NO: 170; the antibody targeting PD-L1 or the antigen-binding fragment thereof comprises VH with a sequence as set forth in SEQ ID NO: 150 and VL with a sequence as set forth in SEQ ID NO: 168; or comprises VH with a sequence as set forth in SEQ ID NO: 153 and VL with a sequence as set forth in SEQ ID NO: 171; the antibody targeting B7H4 or the antigen-binding fragment thereof comprises VH with a sequence as set forth in SEQ ID NO: 163 and VL with a sequence as set forth in SEQ ID NO: 177; or comprises VH with a sequence as set forth in SEQ ID NO: 164 and VL with a sequence as set forth in SEQ ID NO: 178; the antibody targeting EPCAM or the antigen-binding fragment thereof comprises VH with a sequence as set forth in SEQ ID NO: 157 and VL with a sequence as set forth in SEQ ID NO: 175; the antibody targeting PSMA or the antigen-binding fragment thereof comprises VH with a sequence as set forth in SEQ ID NO: 158 and VL with a sequence as set forth in SEQ ID NO: 176; the antibody targeting 4-1 BB or the antigen-binding fragment thereof comprises VH with a sequence as set forth in SEQ ID NO: 159; or, comprises VH with a sequence as set forth in SEQ ID NO: 160; or, comprises VH with a sequence as set forth in SEQ ID NO: 161; or, comprises VH with a sequence as set forth in SEQ ID NO: 167; or, comprises VH with a sequence as set forth in SEQ ID NO: 151 and VL with a sequence as set forth in SEQ ID NO: 169; or, comprises VH with a sequence as set forth in SEQ ID NO: 154 and VL with a sequence as set forth in SEQ ID NO: 172; and the antibody targeting OX40 or the antigen-binding fragment thereof comprises VH with a sequence as set forth in SEQ ID NO: 162.
Claim 19 is drawn to the binding protein according to claim 18, wherein the antibody targeting CLDN18.2 or the antigen-binding fragment thereof comprises a heavy chain with a sequence as set forth in SEQ ID NO: 196 and a light chain with a sequence as set forth in SEQ ID NO: 210;the antibody targeting HER2 or the antigen-binding fragment thereof comprises a heavy chain with a sequence as set forth in SEQ ID NO: 183 and a light chain with a sequence as set forth in SEQ ID NO: 201; the antibody targeting PD-L1 or the antigen-binding fragment thereof comprises a heavy chain with a sequence as set forth in SEQ ID NO: 181 and a light chain with a sequence as set forth in SEQ ID NO: 199; or comprises a heavy chain with a sequence as set forth in SEQ ID NO: 184 and a light chain with a sequence as set forth in SEQ ID NO: 202; the antibody targeting B7H4 or the antigen-binding fragment thereof comprises a heavy chain with a sequence as set forth in SEQ ID NO: 194 and a light chain with a sequence as set forth in SEQ ID NO: 208; or comprises a heavy chain with a sequence as set forth in SEQ ID NO: 195 and a light chain with a sequence as set forth in SEQ ID NO: 209; the antibody targeting EPCAM or the antigen-binding fragment thereof comprises a heavy chain with a sequence as set forth in SEQ ID NO: 188 and a light chain with a sequence as set forth in SEQ ID NO: 206; the antibody targeting PSMA or the antigen-binding fragment thereof comprises a heavy chain with a sequence as set forth in SEQ ID NO: 189 and a light chain with a sequence as set forth in SEQ ID NO: 207; the antibody targeting 4-1 BB or the antigen-binding fragment thereof comprises a heavy chain with a sequence as set forth in SEQ ID NO: 190; or, comprises a heavy chain with a sequence as set forth in SEQ ID NO: 191; or, comprises a heavy chain with a sequence as set forth in SEQ ID NO: 192; or, comprises a heavy chain with a sequence as set forth in SEQ ID NO: 198; or, comprises a heavy chain with a sequence as set forth in SEQ ID NO: 182 and a light chain with a sequence as set forth in SEQ ID NO: 200; or, comprises a heavy chain with a sequence as set forth in SEQ ID NO: 185 and a light chain with a sequence as set forth in SEQ ID NO: 203; and the antibody targeting OX40 or the antigen-binding fragment thereof comprises a heavy chain with a sequence as set forth in SEQ ID NO: 193.
Claim 20 is drawn to the binding protein according to claim 6, wherein the first protein functional region comprises VH with a sequence as set forth in SEQ IDNO: 152 and VL with a sequence as set forth in SEQ ID NO: 170; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 161; or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 163 and VL with a sequence as set forth in SEQ ID NO: 177; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 159;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 163 and VL with a sequence as set forth in SEQ ID NO: 177; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 160;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 163 and VL with a sequence as set forth in SEQ ID NO: 177; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 167;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 153 and VL with a sequence as set forth in SEQ ID NO: 171; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 159;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 153 and VL with a sequence as set forth in SEQ ID NO: 171; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 160;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 153 and VL with a sequence as set forth in SEQ ID NO: 171; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 161;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 157 and VL with a sequence as set forth in SEQ ID NO: 175; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 159;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 157 and VL with a sequence as set forth in SEQ ID NO: 175; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 160;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 157 and VL with a sequence as set forth in SEQ ID NO: 175; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 161;or, the first protein functional region comprises VH with a sequence as set forth in SEQID NO: 158 and VL with a sequence as set forth in SEQ ID NO: 176; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 159;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 158 and VL with a sequence as set forth in SEQ ID NO: 176; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 160;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 158 and VL with a sequence as set forth in SEQ ID NO: 176; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 161;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 165 and VL with a sequence as set forth in SEQ ID NO: 179; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 159;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 165 and VL with a sequence as set forth in SEQ ID NO: 179; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 160;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 165 and VL with a sequence as set forth in SEQ ID NO: 179; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 161;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 153 and VL with a sequence as set forth in SEQ ID NO: 171; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 162;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 163 and VL with a sequence as set forth in SEQ ID NO: 177; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 162;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 157 and VL with a sequence as set forth in SEQ ID NO: 175; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 162;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 158 and VL with a sequence as set forth in SEQ ID NO: 176; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 162;or, the first protein functional region comprises VH with a sequence as set forth in SEQID NO: 165 and VL with a sequence as set forth in SEQ ID NO: 179; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 162;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 164 and VL with a sequence as set forth in SEQ ID NO: 178; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 160;or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 153 and VL with a sequence as set forth in SEQ ID NO: 171; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 151 and VL with a sequence as set forth in SEQ ID NO: 169; or, the first protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 150 and VL with a sequence as set forth in SEQ ID NO: 168; and the second protein functional region comprises VH with a sequence as set forth in SEQ ID NO: 154 and VL with a sequence as set forth in SEQ ID NO: 172.
Claim 21 is drawn to the binding protein according to claim 20 comprises the following polypeptide chains: a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 201, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 214; or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 208, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 217;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 208, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 218;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 208, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 219;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 202, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 221;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 202, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 222;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 202, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 223;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 206, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 224;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 206, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 225;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 206, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 226;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 207, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 227;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 207, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 228;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 207, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 229;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 210, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 230;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 210, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 231;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 210, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 232;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 202, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 233;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 208, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 236;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 206, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 241;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 207, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 242;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 210, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 243;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 208, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 220;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 209, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 234;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 212, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 235;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 237, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 240;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 237, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 238;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 213, a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 212, and a polypeptide chain 3 with a sequence as set forth in SEQ ID NO: 203; or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 216, a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 215, and a polypeptide chain 3 with a sequence as set forth in SEQ ID NO: 203; or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 237, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 266;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 237, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 267;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 237, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 268;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 237, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 269; or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 202, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 270;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 212, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 271;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 208, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 272;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 208, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 273;or, a polypeptide chain 1 with a sequence as set forth in SEQ ID NO: 237, and a polypeptide chain 2 with a sequence as set forth in SEQ ID NO: 274.
The specification discloses multispecific immune cell engager binding proteins based on heavy-chain antibody (see Example 1). Specifically, Table 1 lists the molecular structures of the multispecific binding proteins and Examples 1.1-1.2 explain these structures in detail (see pages 49-54). Example 3 discloses the construction of bispecific immune cell engager binding proteins targeting costimulatory molecules. Several bispecific immune cell engager binding protein molecules were listed wherein one end can bind to a costimulatory molecule on the surface of an immune cell (e.g., 4-1BB, OX40, etc.), and the other end of which can bind to a specific antigen molecule on the surface of a tumor cell (e.g., HER2, PSMA, EPCAM, CLDN18.2, B7H4, etc.) or a co-inhibitory molecule on the surface of an immune cell (e.g., PD-L1, etc.) (see [0316]). Specifically, the specification discloses of bispecific binding protein molecules targeting both 4-1BB and tumor antigens (or co-inhibitory molecules) that were constructed using an antigen-binding fragment VH of an HCAb antibody binding to 4-1BB (PR001758, PR001760, PR001836 or PR004469), and an antigen-binding fragment Fab of an IgG antibody binding to a tumor antigen HER2 (trastuzumab), or an antigen-binding fragment Fab of an IgG antibody binding to B7H4 (PR002408 or PR002410), or an antigen-binding fragment Fab of an IgG antibody binding to EPCAM (PR001081), or an antigen-binding fragment Fab of an IgG antibody binding to PSMA (PR001331), or an antigen-binding fragment Fab or an IgG antibody binding to CLDN18.2 (PR002726) or an antigen-binding fragment Fab of an IgG antibody binding to PD-L1 (PR000265) (see [0317] and Tables 3-11). Additionally, the specification discloses of bispecific binding protein molecules targeting both OX40 and a tumor antigen (or a co-inhibitory molecule) that were constructed using an antigen-binding fragment VH of an HCAb antibody binding to OX40 (PR002067), and an antigen-binding fragment Fab of an IgG antibody binding to tumor antigen EPCAM (PR001081), or an antigen-binding fragment Fab of an IgG antibody binding to PSMA (PR001331), or an antigen-binding fragment Fab of an IgG antibody binding to CLDN18.2 (PR002726), or an antigen-binding fragment Fab of an IgG antibody binding to B7H4 (PR002408) or an antigen-binding fragment Fab of an IgG antibody binding to PD-L1 (PR000265) (see [0318]; Tables 3-4 and 6).
Example 4 discloses the binding activity of the antibodies targeting 4-1BB and the bispecific immune cell engager binding proteins to 4-1BB (see [0322]-[0349]). Example 5 discloses the binding activity of the antibodies targeting OX40 and the bispecific immune cell engager binding proteins to OX40 (see [0350]-[0359]). Example 6 discloses the binding activity of the bispecific immune cell engager binding proteins to tumor antigens (see [0360]-[0394]). Example 7 discloses the T cell activation activity of the bispecific immune cell engager binding protein targeting a costimulatory molecule on the surface of a T cell by binding to the costimulatory molecule in the presence of the target cell (see [0395]-[0424]). Example 8 discloses the T cell activation effects of the PD-L1x4-1BB bispecific antibody molecules by the mixed lymphocyte reaction (MLR) (see [0425]-[0430]). Example 9 discloses the pharmacokinetic properties of the bispecific immune cell engager binding protein molecules with different structures in mice (see [0431]-[0435] and Table 13). Example 10 discloses the anti-tumor effect of B7H4x4-1BB bispecific antibody molecule PR003334 in a BALB/c-hCD137/CT26-hB7H4 mouse tumor model (see [0436]-[0440]). Example 11 discloses the physicochemical properties such as molecular stability of the B7H4x4-1BB bispecific antibody molecules (PR003334, PR003335, and PR003338) (see [0441]-[0442] and Table 14).
However, the specification fails to disclose that Applicant was in possession of the large genus of binding proteins as claimed. Specifically, the specification fails to disclose that Applicant was in possession of the large genus of binding proteins that targets any antigen on any target cell and any antigen on any immune effector cell. Further, while the specification does recite specific species of binding proteins, the specification fails to demonstrate any variants or provide guidance as to which sequences should be conserved to maintain their functions. Lastly, the specification fails to disclose that Applicant was in possession of pharmaceutical compositions or kits comprising the claimed binding protein and any other anti-tumor antibody.
Although the specification discloses of different species of bispecific antibody molecules (see Tables 3-12), the claims are not limited to these molecules, and are inclusive of any binding protein comprising at least two protein functional regions, comprising a first protein functional region and a second protein functional region, wherein the first protein functional region comprises a targeting moiety binding to an antigen on a target cell, and the second protein functional region comprises an effector moiety binding to an antigen on an immune effector cell. This indicates that there are hundreds, if not thousands, of possible binding proteins encompassed by the claims. Thus, the claims encompass a vast genus of binding proteins that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of binding proteins because, inter alia, the specification does not disclose a correlation between the necessary structure of the proteins and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the terms antibody, Fab, and VH do impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies/binding proteins and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of binding proteins. The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The instant claims do not fully describe the structure of the first and second protein functional regions to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of binding proteins, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous binding proteins had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of binding proteins claimed only by a partial structure and functional characteristic(s). Thus the binding proteins described by the instant claims encompasses an overly broad genus, the structure of the first and second protein functional regions, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of binding proteins by the functions of the first and second protein functional regions. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed binding proteins, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed components of the binding proteins that are antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible binding proteins that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of binding proteins or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed binding proteins could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of proteins, an 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 (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all binding proteins.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed binding proteins. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of binding proteins as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4 and 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Moore (US 2014/0288275 A1, published 09/25/2014; previously submitted with the Restriction Requirement mailed on 11/05/2025), Timmer (US 2017/0015753, published 01/19/2017), Weidanz (US 2019/0071502, published 03/07/2019), and Eckelman (US 2023/0124851, with priority to 10/11/2018).
With respect to instant claims 1-4, Moore et al is drawn to novel heterodimeric proteins including heterodimeric antibodies (see Abstract). Moore et al disclose that the heterodimeric antibodies of the invention further comprise one or two additional antigen binding domains that can be either or both of an scFv and a Fab (see [0011]). Moore teaches anti-CD19 binding domains and anti-CD3 binding domains which are Fab and Fv domains, respectively, comprised within a heavy chain antibody that is the first polypeptide of the invention. Figure 13D confers a single heavy chain antibody comprising from N- to C-terminus a Fab-Fv (comprising a Vh structure)-Fc comprising a first polypeptide. Figure 13D comprises a second polypeptide comprising an Fc region comprising a scFv. Other related molecules are in Figures 12-13. The prototypes taught in Moore are bispecific at least as they bind antigen 1 and 2 (Ag.1-2).
Moore discloses Fig. 12D wherein the heterodimeric protein design depicts an additional Fab attached to the Fab monomer (see [0054] and [0093]). Additionally, Figures 11B and 12D show one chain that has an scFv-hinge-CH2-CH3 while the other chain with Fc region has VH-CH1-hinge-Fc region and that is paired with a third chain comprising VL-CL. Moore discloses linker peptides at [0130; 0234].
Moore disclose that the heterodimeric proteins can target antigens such as HER2, CTLA4, OX40, BCMA, and 4-1BB (see [0185]-[0201]).
With respect to instant claim 11, Moore teaches that the therapeutic compositions used in the practice of the foregoing methods can be formulated into pharmaceutical compositions comprising a carrier suitable for the desired delivery method (see [0299]). Suitable carriers include any material that when combined with the therapeutic composition retains the anti-tumor function of the therapeutic composition and is generally non-reactive with the patient's immune system. Examples include, but are not limited to, any of a number of standard pharmaceutical carriers such as sterile phosphate buffered saline solutions, bacteriostatic water, and the like; and at [0301] The formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to provide antibodies with other specificities. Alternatively, or in addition, the composition may comprise a cytotoxic agent, cytokine, growth inhibitory agent and/or small molecule antagonist. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
However, Moore et al fails to disclose of a multispecific design that comprises a VHH as one of the binding domains. Additionally, Moore et al fails to disclose of kits as disclosed in instant claims 12-14. This is remedied by the following art.
With respect to the VHH, Timmer teaches multivalent antigen binding proteins with VHH domains to include ones with a chain like VHH-linker-VHH-linker-hinge-Fc (0054). They can be multispecific as in Figure 1 in which some are bispecific or multispecific and all use hinges and Fc regions to multimerize chain with various amounts of single domain antibodies/VHHs.
Thus, it would have been obvious to one of skill in the art before the filing of the instant case to substitute the scFv or Fab of Moore for the VHH of Timmer to arrive at a multispecific antibody design of the present invention with a reasonable expectation of success because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Moore et al is establishes heterodimeric proteins including heterodimeric antibodies (see Abstract), wherein the heterodimeric antibodies further comprise one or two additional antigen binding domains that can be either or both of an scFv and a Fab (see [0011]). The binding proteins of Timmer contains VHH domains to include ones with a chain like VHH-linker-VHH-linker-hinge-Fc (0054). They can be multispecific as in Figure 1 in which some are bispecific or multispecific and all use hinges and Fc regions to multimerize chain with various amounts of single domain antibodies/VHHs. Further, Weidanz teaches by linking VHH to hinge Fc domains as part of an antibody dimer, the modified antibody is smaller than a conventional antibody and the lower mass leads to better permeability in tissue without increasing renal clearance providing better tumor penetrance (see [0305]).
As such, the prior art shows that multiple types of binding domains can be used in multispecific antibodies and in various combinations, and so the simple substitution of one type of binding domain for another binding domain, all having been used prior in antibody-like molecules, is prima facie obvious. One would be motivated to replace the Fab of Moore with the VHH of Timmer and Weidanz to achieve these advantages in an anti-tumor, multispecific antibody. Indeed, single domain antibodies like VHH have been used in such multispecific antibodies before with Fv-containing molecules. See Eckelman at Figure 3A-E.
Additionally, with respect to instant claims 12-14, Weidanz teaches kits comprising the reagent plus a means for administration at [0192-0197] and specifically syringes at [0192].
Taken together, it would have been obvious to develop the claimed invention from the combined teachings above. One would be motivated to do so because the references combined disclose of the advantages of the claimed binding protein. First, the Fab-VH binding format has the ability to target two different antigens simultaneously while avoiding common manufacturing problems like heavy-light chain mis-pairing encountered with other bispecific formats. Second, it integrates the benefits of the smaller, highly penetrative VH or VHH domain with the properties of a conventional Fab, which when linked to an Fc domain provides for half-life extension or immune effector functions. Lastly, the ability to bring two targets into close proximity that leads to more potent therapeutic effects, such as more effective tumor cell elimination.
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.
18/013,530
Claims 1-6, 11-14, and 18-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 14-17, 19, and 21-22 of copending Application No. 18/013,530 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘530 application is drawn to a binding protein comprising at least two protein functional regions, wherein the binding protein comprises a protein functional region A and a protein functional region B; the protein functional region A and the protein functional region B target different antigens or different epitopes on the same antigen; wherein the protein functional region A is of a Fab structure; the protein functional region B is of a VH structure, and the binding protein further comprises an Fc homodimer; the number of the protein functional region A is two, and the number of the protein functional region B is two; the binding protein is of a left-right symmetric structure; the binding protein comprises a protein functional region A, a protein functional region B and an Fc homodimer sequentially from the N-terminus to the C-terminus, wherein the protein functional region A is linked to the protein functional region B via a first linker peptide (L1), and the protein functional region B is linked to the Fc via a second linker peptide (L2) (see claim 1).
Specifically, the ‘530 application is drawn to the binding protein according to claim 1, wherein the binding protein has four polypeptide chains, including two identical short chains and two identical long chains, wherein (1) the short chain comprises VH_A-CH1 sequentially from the N-terminus to the C-terminus, and the long chain comprises VL_A-CL-Li-VH_B-L2-CH2-CH3 sequentially from the N-terminus to the C-terminus; or (2) the short chain comprises VL_A-CL sequentially from the N-terminus to the C-terminus, and the long chain comprises VH_A- CH1-Li-VH_B-L2-CH2-CH3 sequentially from the N-terminus to the C-terminus; wherein the VL_A and the VH_A are VL and VH of the protein functional region A, respectively, and the VHB is VH of the protein functional region B; the CL is a domain of a light chain constant region; the CH1, CH2 and CH3 are a first domain, a second domain and a third domain of a heavy chain constant region, respectively; and the L1 or L2 is a linker peptide; preferably, the L1 and L2 are independently, e.g., "-" or GS or have amino acid sequences as shown in SEQ ID NOs: 161-182, respectively (see claim 2).
The ‘530 application is drawn to the binding protein according to claim 1, wherein the antigen is selected from one or more of PD-L1, HER2, B7H4, CTLA4, OX40, 4-1 BB and BCMA; preferably, the protein functional region A is Fab derived from a PD-L1 antibody or an antigen-binding fragment thereof, an HER2 antibody or an antigen-binding fragment thereof, a B7H4 antibody or an antigen-binding fragment thereof, or a BCMA antibody or an antigen- binding fragment thereof, and, the protein functional region B is VH derived from a CTLA4 antibody or an antigen-binding fragment thereof, a 4-1 BB antibody or an antigen-binding fragment thereof, an OX40 antibody or an antigen-binding fragment thereof, or a BCMA antibody or an antigen-binding fragment thereof (see claims 3-8 and 22). For example, instant CDR sequences SEQ ID Nos: 20, 53, and 86 are within SEQ ID NO: 113 of the ‘530 application; instant CDR sequences SEQ ID Nos: 110, 118, and 140 are within SEQ ID NO: 121 of the ‘530 application; and, instant CDR sequences SEQ ID Nos: 18, 50, and 54 are within SEQ ID NO: 111.
The ’530 application is drawn to a pharmaceutical composition comprising the binding protein according to claim 1, and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition further comprises an additional anti-tumor antibody as an active ingredient (see claim 14).
The ‘530 application is drawn a kit, combination of kits, and an administration device comprising the binding protein according to claim 1 (see claims 15-17).
The difference between the instant application and the ‘530 application is that the ‘530 application is drawn to a method of using. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121. As such, the ‘530 application anticipates the present application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
18/002,499
Claims 1-6, 11-14, and 18-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-32, 34-38, 40, and 42-49 of copending Application No. 18/002,499 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘499 application is drawn to a bispecific antibody comprising a B7-H4-targeting antigen- binding domain and a 4-1BB-targeting antigen-binding domain, wherein the B7-H4-targeting antigen-binding domain comprises a heavy chain variable region (VH) comprising a HCDR1, a HCDR2, and a HCDR3 and a light chain variable region (VL) comprising a LCDR1, a LCDR2, and a LCDR3, wherein the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3 are selected from the group consisting of the following (1)-(3):(1) the HCDR1 comprising the sequence of SEQ ID NO: 16, the HCDR2 comprising the sequence of SEQ ID NO: 60, the HCDR3 comprising the sequence of SEQ ID NO: 84, the LCDR1 comprising the sequence of SEQ ID NO: 112, the LCDR2 comprising the sequence of SEQ ID NO: 118 and the LCDR3 comprising the sequence of SEQ ID NO: 133; (2) the HCDR1 comprising the sequence of SEQ ID NO: 16, the HCDR2 comprising the sequence of SEQ ID NO: 46, the HCDR3 comprising the sequence of SEQ ID NO: 84, the LCDR1 comprising the sequence of SEQ ID NO: 112, the LCDR2 comprising the sequence of SEQ ID NO: 118 and the LCDR3 comprising the a sequence of SEQ ID NO: 131; and (3) the HCDR1 comprising the sequence of SEQ ID NO: 23, the HCDR2 comprising the sequence of SEQ ID NO: 59, the HCDR3 comprising the sequence of SEQ ID NO: 98, the LCDR1 comprising the sequence of SEQ ID NO: 113, the LCDR2 comprising the sequence of SEQ ID NO: 118 and the LCDR3 comprising the sequence of SEQ ID NO: 132 (see claims 26-28).
The ’499 application is drawn to the bispecific antibody according to claim 26, wherein: the 4-1BB-targeting antigen-binding domain comprises a heavy chain variable region (VH) comprising a HCDR1, a HCDR2, and a HCDR3 selected from the group consisting of the following (1)-(16): (1) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 18, 61, and 95, respectively; (2) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 17,47, and 85, respectively; (3) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 18,48, and 86, respectively; (4) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 18, 49, and 86, respectively; (5) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 19, 49, and 94, respectively; (6) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 18, 49, and 87, respectively; (7) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 19, 50, and 88, respectively; (8) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 20, 51, and 89, respectively; (9) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 18, 52, and 90, respectively; (10) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 18, 49, and 90, respectively; (11) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 21, 53, and 91, respectively; (12) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 21, 54, and 92, respectively; (13) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 19, 55, and 93, respectively; (14) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 22, 56, and 86, respectively; (15) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 18, 57, and 95, respectively; and (16) the HCDR1, the HCDR, and the HCDR3 comprising the sequences of SEQ ID NOs: 19, 58 and 96, respectively; or wherein the 4-1BB-targeting antigen-binding domain comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2 and HCDR3, which comprise the sequences of SEQ ID Nos: 14, 43 and 81, respectively, and a light chain variable region (VL) comprising LCDR1, LCDR2 and LCDR3, which comprise the sequences of SEQ ID Nos: 109, 118, and 128, respectively (see claims 30-32).
Specifically, instant CDR sequences SEQ ID Nos: 20, 53, and 86 are within SEQ ID NO: 160 of the ‘499 application; instant CDR sequences SEQ ID Nos: 110, 118, and 140 are within SEQ ID NO: 168 of the ‘499 application; and, instant CDR sequences SEQ ID Nos: 18, 50, and 54 are within SEQ ID NO: 144.
The ‘499 application is drawn to the bispecific antibody according to claim 35, wherein: (1) the B7-H4-targeting antigen domain is in the form of IgG and the 4-1BB-targeting antigen-binding domain is in the form of single VH; (2) the B7-H4-targeting antigen domain is in the form of IgG and the 4-1BB-targeting antigen-binding domain is in the form of ScFv; (3) the B7-H4-targeting antigen domain is in the form of IgG and the 4-1BB-targeting antigen-binding domain is in the form of a tandem of 2 or 3 VHs; (4) the B7-H4-targeting antigen domain is in the form of Fab and the 4-1BB-targeting antigen-binding domain is in the form of HCAb or in the form of HCAb-VH; or (5) the B7-H4-targeting antigen domain is in the form of Fab and the 4-1BB-targeting antigen-binding domain is in the form of single VH, or a tandem of 2 or 3 VHs (see claim 36).
The ‘499 application is drawn to the bispecific antibody according to claim 35, wherein: (1) the bispecific antibody comprises a polypeptide chain 1, which is represented by the formula, from N-terminus to C-terminus, VLB7-H4-CL, and a polypeptide chain 2, which is represented by the formula, from N-terminus to C-terminus, VHB7-H4-CH1-hinge-CH2-CH3-linker-(VH4-1BB)n, wherein n is 1, 2, or 3; (2) the bispecific antibody comprises a polypeptide chain 1, which is represented by the formula, from N-terminus to C-terminus, VLB7-H4-CL, and a polypeptide chain 2, which is represented by the formula, from N-terminus to C-terminus, VHB7-H4-CH1-hinge-CH2-CH3-linker-VH4-1BB-linker-VL4-1BB; (3) the bispecific antibody comprises a polypeptide chain 1, which is represented by the formula, from N-terminus to C-terminus, VHB7-H4-CH1, and a polypeptide chain 2, which is represented by the formula, from N-terminus to C-terminus, VLB7-H4-CL-linker-VH4-1BB-linker-CH2-CH3; (4) the bispecific antibody comprises a polypeptide chain 1, which is represented by the formula, from N-terminus to C-terminus, VHB7-H4-CH1, and a polypeptide chain 2, which is represented by the formula, from N-terminus to C-terminus, VLB7-H4-CL-linker-VH4-1BB-linker-CH2-CH3-VH4-1BB; or (5) the bispecific antibody comprises a polypeptide chain 1, which is represented by the formula, from N-terminus to C-terminus, VLB7-H4-CL, a polypeptide chain 2, which is represented by the formula, from N-terminus to C-terminus, VHB7-H4-CH1-hinge-CH2-CH3, and a polypeptide chain 3, which is represented by the formula, from N-terminus to C-terminus, VH4-1BB-linker-CH2-CH3 or (VH4-1BB)n-linker-CH2-CH3, wherein n is 2 or 3 (see claim 37).
The ’499 application is drawn to a pharmaceutical composition comprising the bispecific antibody according to claim 26 and a pharmaceutically acceptable excipient (see claim 42).
The difference between the instant application and the ‘499 application is that the ‘499 application is drawn to a method of using. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121. As such, the ‘499 application anticipates the present application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
18/002,479
Claims 1-6, 11-14, and 18-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 25, 27-36, and 38-44 of copending Application No. 18/002,479 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ’479 application is drawn to a 4- 1BB-binding protein, comprising a heavy chain variable region, wherein the heavy chain variable region comprises a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2L) and a heavy chain complementarity determining region 3 (HCDR3L) wherein: (1) the HCDR1, the HCDR2 and the HCDR3 comprise the amino acid sequences as set forth in SEQ ID NO: 20, SEQ ID NO: 71 and SEQ ID NO: 115, respectively; SEQ ID NO: 20, SEQ ID NO: 69 and SEQ ID NO: 115, respectively; SEQ ID NO: 19, SEQ ID NO: 57 and SEQ ID NO: 101, respectively; SEQ ID NO: 15, SEQ ID NO: 58 and SEQ ID NO: 102, respectively; SEQ ID NO: 20, SEQ ID NO: 59 and SEQ ID NO: 103, respectively; SEQ ID NO: 20, SEQ ID NO: 60 and SEQ ID NO: 104, respectively; SEQ ID NO: 15, SEQ ID NO: 61 and SEQ ID NO: 105, respectively; SEQ ID NO: 15, SEQ ID NO: 60 and SEQ ID NO: 106, respectively; SEQ ID NO: 20, SEQ ID NO: 63 and SEQ ID NO: 108, respectively; SEQ ID NO: 20, SEQ ID NO: 60 and SEQ ID NO: 108, respectively; SEQ ID NO: 22, SEQ ID NO: 64 and SEQ ID NO: 109, respectively; SEQ ID NO: 15, SEQ ID NO: 60 and SEQ ID NO: 110, respectively; ; SEQ ID NO: 15, SEQ ID NO: 65 and SEQ ID NO: 111, respectively; ; SEQ ID NO: 22, SEQ ID NO: 66 and SEQ ID NO: 112, respectively; ; SEQ ID NO: 15, SEQ ID NO: 49 and SEQ ID NO: 113, respectively; SEQ ID NO: 20, SEQ ID NO: 60 and SEQ ID NO: 103, respectively; SEQ ID NO: 15, SEQ ID NO: 63 and SEQ ID NO: 104, respectively; SEQ ID NO: 15, SEQ ID NO: 60 and SEQ ID NO: 114, respectively; SEQ ID NO: 23, SEQ ID NO: 67 and SEQ ID NO: 105, respectively; SEQ ID NO: 24, SEQ ID NO: 68 and SEQ ID NO: 103, respectively; SEQ ID NO: 15, SEQ ID NO: 60 and SEQ ID NO: 105, respectively; SEQ ID NO: 15, SEQ ID NO: 70 and SEQ ID NO: 116, respectively; SEQ ID NO: 300, SEQ ID NO: 308 and SEQ ID NO: 326, respectively; SEQ ID NO: 300, SEQ ID NO: 309 and SEQ ID NO: 327, respectively; SEQ ID NO: 300, SEQ ID NO: 310 and SEQ ID NO: 328, respectively; SEQ ID NO: 300, SEQ ID NO: 308 and SEQ ID NO: 329, respectively; SEQ ID NO: 300, SEQ ID NO: 311 and SEQ ID NO: 330, respectively; SEQ ID NO: 300, SEQ ID NO: 312 and SEQ ID NO: 331, respectively; SEQ ID NO: 300, SEQ ID NO: 308 and SEQ ID NO: 332, respectively; SEQ ID NO: 300, SEQ ID NO: 313 and SEQ ID NO: 330, respectively; SEQ ID NO: 300, SEQ ID NO: 314 and SEQ ID NO: 329, respectively; SEQ ID NO: 300, SEQ ID NO: 315 and SEQ ID NO: 331, respectively; SEQ ID NO: 300, SEQ ID NO: 314 and SEQ ID NO: 327, respectively; SEQ ID NO: 300, SEQ ID NO: 316 and SEQ ID NO: 331, respectively; SEQ ID NO: 300, SEQ ID NO: 308 and SEQ ID NO: 333, respectively; or SEQ ID NO: 300, SEQ ID NO: 317 and SEQ ID NO: 33, respectively, or wherein (2) the 4- 1BB-binding protein further comprises a light chain variable region comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2), and a light chain complementarity determining region 3 (LCDR3), wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences as set forth in SEQ ID NO: 133, SEQ ID NO: 145 and SEQ ID NO: 158, respectively, and the HCDR1, the HCDR2 and the HCDR3 comprising the amino acid sequences as set forth in SEQ ID NO: 16, SEQ ID NO: 50 and SEQ ID NO: 96, respectively; SEQ ID NO: 16, SEQ ID NO: 53 and SEQ ID NO: 96, respectively; or SEQ ID NO: 16, SEQ ID NO: 54 and SEQ ID NO: 96, respectively (see claims 1, 25, and 27-29).
Specifically, instant CDR sequences SEQ ID Nos: 18, 50, and 54 are within SEQ ID NO: 177 of the ‘479 application.
The ‘479 application is drawn to a bispecific antibody comprising a first protein functional region and a second protein functional region, wherein the first protein functional region is the 4-1BB-binding protein according to claim 1, and the second protein functional region targets a tumor antigen (see claims 32-36).
The ’479 application is drawn to a pharmaceutical composition comprising the 4-1BB- binding protein according to claim 1 (see claim 41).
The difference between the instant application and the ‘479 application is that the ‘479 application is drawn to a method of using. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121. As such, the ‘479 application anticipates the present application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674