DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The amended claims filed on March 26, 2026 are acknowledged. Claims 10-31 are amended. Claims 32-34 are newly added.
Claims 10-34 are pending and under examination herein.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, support for the claimed invention cannot be determined because the foreign priority documents provided for CN202210712836.9 are not in English. Therefore, the instant application is not entitled to the benefit of the foreign priority date of June 22, 2022.
Accordingly, the filing date of the PCT/CN2023/087998 application (April 13, 2023) will be used for the purpose of applying prior art.
Information Disclosure Statement
It is noted for Applicant that an updated version of the Information Disclosure Statement (IDS) form is available at https://www.uspto.gov/patents/apply/forms. The IDS form version(s) submitted on March 27, 2025 and March 26, 2026 are approved for use through May 31, 2024.
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.
Claim 19-20, 29, and 32-33 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.
Claim 19 recites the limitation that the anti-CD73 antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising mutations selected from “L234A and L235A; L234A and G237A; L235A and G237A; and L234A, L235A and G237A”. However, the claim does not recite a corresponding numbering system (e.g., Kabat numbering, EU numbering), antibody isotype (e.g., human IgG1, human IgG2, etc.), amino acid sequence, or other suitable frame of reference against which to compare the intended locations of the amino acid substitutions, rendering the intended claim scope ambiguous. By way of example, IMGT.org illustrates that the wildtype positions 234, 235, and 297, respectively, of the IgG1 heavy chain correspond to “L”, “L”, and “G”, respectively, under EU numbering, but not under Kabat numbering. See Office Action Appendix.
Claim 20 recites the limitation that the anti-CD73 antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising mutations selected from the group consisting of N297A, D265A, D270A, and several others. However, the claim does not recite a corresponding numbering system, antibody isotype, amino acid sequence, or other suitable frame of reference against which to compare the intended locations of the amino acid substitutions, rendering the intended claim scope ambiguous. By way of example, IMGT.org illustrates that the wildtype positions of 297, 265, and 270 correspond to “N”, “D”, and “”D”, respectively, under EU numbering, but not under Kabat numbering. See Office Action Appendix. Furthermore, these positions can vary by antibody isotype. By way of example, Shitara (U.S. Patent No. 8,883,981) illustrates that wildtype position 330 in the human IgG1, IgG2, and IgG3 corresponds to “A” while the same position corresponds to “S” in human IgG4 under EU numbering, and that wildtype position 268 in the human IgG1, IgG2, and IgG3 corresponds to “H” while the same position corresponds to “Q” in human IgG4 under EU numbering. See Figure 1.
Claim 29 recites the limitation that “the antigen-binding fragment thereof … is selected from the group consisting of” Fab, Fab’, and several other members. There is insufficient antecedent basis for this limitation in the claim. The claim depends from earlier claim 1, which recites a combination which can contain an anti-CD73 antigen-binding fragment as well as an anti-PD-1/VEGFA antigen-binding fragment. Accordingly, the claim is indefinite because it is unclear whether “the antigen-binding fragment thereof” as recited in claim 29 refers to the anti-CD73 antigen-binding fragment, the anti-PD-1/VEGFA antigen-binding fragment, or both.
Claim 32 recites the limitation that the anti-PD-1/anti-VEGFA bispecific antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising mutations selected from “L234A and L235A; L234A and G237A; L235A and G237A; and L234A, L235A and G237A”. However, the claim does not recite a corresponding numbering system, antibody isotype, amino acid sequence, or other suitable frame of reference against which to compare the intended locations of the amino acid substitutions, rendering the intended claim scope ambiguous. By way of example, IMGT.org illustrates that the wildtype positions 234, 235, and 297, respectively, of the IgG1 heavy chain correspond to “L”, “L”, and “G”, respectively, under EU numbering, but not under Kabat numbering. See Office Action Appendix.
Claim 33 recites the limitation that the anti-PD-1/anti-VEGFA bispecific antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising mutations selected from the group consisting of N297A, D265A, D270A, and several others. However, the claim does not recite a corresponding numbering system, antibody isotype, amino acid sequence, or other suitable frame of reference against which to compare the intended locations of the amino acid substitutions, rendering the intended claim scope ambiguous. By way of example, IMGT.org illustrates that the wildtype positions of 297, 265, and 270 correspond to “N”, “D”, and “”D”, respectively, under EU numbering, but not under Kabat numbering. See Office Action Appendix. Furthermore, these positions can vary by antibody isotype. By way of example, Shitara (U.S. Patent No. 8,883,981) illustrates that wildtype position 330 in the human IgG1, IgG2, and IgG3 corresponds to “A” while the same position corresponds to “S” in human IgG4 under EU numbering, and that wildtype position 268 in the human IgG1, IgG2, and IgG3 corresponds to “H” while the same position corresponds to “Q” in human IgG4 under EU numbering. See Figure 1.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 23 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The invention appears to employ novel biological materials, in particular an anti-CD73 antibody produced by a hybridoma cell line LT014 deposited at China Center for Type Culture Collection (CCTCC) with the accession number CCTCC C2018137. Since the biological materials are essential to the claimed invention, they must be obtainable by a repeatable method set forth in the specification or otherwise readily available to the public. If the biological materials are not so obtainable or available, the requirements of 35 U.S.C. § 112 may be satisfied by a deposit of the biological materials.
The specification does not disclose a repeatable process to obtain the biological materials and it is not apparent if the biological materials are readily available to the public. It is noted that Applicant has deposited the biological materials at the China Center for Type Culture Collection (CCTCC) on June 21, 2018 (e.g., Example 1 at page 33 of the specification), but there is no indication in the specification as to public availability. If the deposit is made under the Budapest Treaty, then an affidavit or declaration by Applicant, or a statement by an attorney of record over his or her signature and registration number, stating that the specific biological materials have been deposited under the Budapest Treaty and that the biological materials will be irrevocably and without restriction or condition released to the public upon the issuance of a patent, would satisfy the deposit requirement made herein. If the deposit has not been made under the Budapest Treaty, then in order to certify that the deposit meets the criteria set forth in 37 C.F.R. 1.801-1.809, Applicant may provide assurance of compliance by an affidavit or declaration, or by a statement by an attorney of record over his or her signature and registration number, showing that:
during the pendency of this application, access to the invention will be afforded to the Commissioner upon request;
all restrictions upon availability to the public will be irrevocably removed upon granting of the patent;
the deposit will be maintained in a public depository for a period of 30 years or 5 years after the last request or for the effective life of the patent, whichever is longer;
a test of the viability of the biological material at the time of the deposit will be made (see 37 C.F.R. 1.807); and
the deposit will be replaced if it should ever become inviable.
Applicant’s attention is directed to MPEP § 2400 in general, and specifically to § 2411.05, as well as to 37 C.F.R. 1.809(d), where it is set forth that the “specification shall contain the accession number for the deposit, the date of the deposit, the name and address of the depository, and a description of the deposited material sufficient to specifically identify it and to permit examination.” The specification should be amended to include this information. However, Applicant is cautioned to avoid the entry of new matter into the specification by adding any other information.
Applicant is advised that the address for the American Type Culture Collection (ATCC) should appear in the specification. The address is:
American Type Culture Collection
10801 University Boulevard,
Manassas, VA 20110-2209, United States of America
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
(1)
Claims 10-25, 27-29, 31, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Lonsberg (US 2017/0253665 A1; cited in IDS) in view of Zhang (CN113527501A; published October 22, 2021; cited in IDS; machine and original translations attached), Li (WO 2020/043184 A1; published March 5, 2020; machine and original translations attached), Chen (Immunotherapy (2019) 11(11): 983-997), and Voron (Journal of Experimental Medicine (2015) 212(2): 139-148).
Lonsberg discloses anti-CD73 antibodies that inhibit the activity of CD73 and methods of use thereof for inhibiting the growth of CD73-expressing tumors and treating various cancers such as colorectal cancer (e.g., Abstract; ¶ 0006-0048). Lonsberg further discloses that the anti-CD73 antibodies of the invention may be administered in combination with a second agent, such as an anti-PD-1 antibody/antagonist or bevacizumab (i.e., an anti-VEGF-A antibody comprising the heavy chain and light chain CDRs and variable domain sequences recited in claims 10 and 24-251) (e.g., ¶ 0048; 0618-0676), relevant to claims 10, 24-25, 31, and 34.
However, Lonsberg does not expressly describe the combination of (1) an anti-CD73 antibody or antigen-binding fragment thereof and (2) an anti-PD-1/anti-VEGFA bispecific antibody or antigen-binding fragment thereof, wherein the anti-CD73 antibody comprises the heavy chain and light chain CDRs set forth in SEQ ID NOs: 15, 16, 17, 18, FAS, and 20, respectively, the anti-PD-1 antigen-binding portion comprises the heavy chain and light chain CDRs set forth in SEQ ID NOs: 41, 42, 43, 44, RAN, and 46, respectively, and the anti-VEGFA antigen-binding portion comprises the heavy chain and light chain CDRs set forth in SEQ ID NOs: 31, 32, 33, 34, FTS, and 36, respectively.
Zhang discloses an anti-CD73/anti-PD-1 bispecific antibody having utility in the treatment of various solid tumors (e.g., Abstract; ¶ 0001, 0028, 0131-0132 of machine translation). Relevant to claims 10 and 22-23, Zhang discloses a monoclonal antibody (“19F3”) and humanized variants thereof produced from a hybridoma cell line LT014 (also known as CD73-19F3), deposited at the CCTCC with accession number CCTCC NO: C2018137, that specifically binds to and inhibits enzymatic activity of CD73, and promotes T cell activity and tumor suppression (e.g., ¶ 0021-0028). The anti-CD73 antibody clone “19F3” comprises heavy chain CDRs comprising the amino acid sequences of SEQ ID NO: 3-5 and light chain CDRs comprising the amino acid sequences of SEQ ID NO: 8-10 (which share 100% sequence identity to instant SEQ ID NOs: 15-17 and 18, FAS, and 20, respectively) (e.g., ¶ 0147-0164).
Relevant to claims 10 and 13-14, the 19F3 heavy chain and light chain variable domains (VH and VL) comprising the amino acid sequences of SEQ ID NOs: 2 and 7, respectively, share 100% sequence identity to instant SEQ ID NOs: 2 and 4, respectively (e.g., ¶ 0148-0149; pages 49-50 of original translation).
Relevant to claims 10, 13, and 15, the 19F3H1L1 heavy chain and light chain variable domains (VH and VL) comprising the amino acid sequences of SEQ ID NOs: 93 and 95, respectively, share 100% sequence identity to instant SEQ ID NOs: 6 and 8, respectively (e.g., ¶ 0280-0283; page 60 of original translation).
Relevant to claims 10, 13, and 16, the 19F3H2L2 heavy chain and light chain variable domains (VH and VL) comprising the amino acid sequences of SEQ ID NOs: 20 and 22, respectively, share 100% sequence identity to instant SEQ ID NOs: 10 and 12, respectively (e.g., ¶ 0157-0160, 0284-0286; page 50 of original translation).
Relevant to claims 10, 13, and 17, the 19F3H2L3 heavy chain and light chain variable domains (VH and VL) comprising the amino acid sequences of SEQ ID NOs: 20 and 24, respectively, share 100% sequence identity to instant SEQ ID NOs: 10 and 14, respectively (e.g., ¶ 0161-0164, 0287-0289; pages 50-51 of original translation).
Relevant to claims 18-212, Zhang teaches that the anti-CD73 antibody comprises an IgG1 heavy chain constant region with Accession No. P01857 and immunoglobulin kappa light chain constant region with Accession No. P01834 (e.g., Examples at ¶ 0262-0280 of machine translation; claim 16 of machine translation). Zhang teaches that mutations of L234A and L235A were introduced into one construct, and mutations of L234A, L235A, and G237A were introduced into another (e.g., ¶ 0293-0295 of machine translation; claim 16 of machine translation).
Relevant to claim 29, the antigen-binding domains of the anti-CD73 antibody are Fab, Fab’, or single-chain antibodies (e.g., ¶ 0064 of machine translation). Relevant to claim 30, Zhang discloses kits comprising the anti-CD73 antibody of the invention (e.g., ¶ 0128 of machine translation).
Li discloses a bispecific antibody that specifically binds to PD-1 and VEGFA and inhibits tumor-induced angiogenesis, which is based on the previously obtained anti-PD-1 clone 14C12H1L1 and the marketed anti-VEGFA antibody bevacizumab, having utility in treatment of solid tumors (e.g., Abstract; ¶ 0017-0021). Relevant to claims 10-12, 29, 31, and 34, Li discloses that the bispecific antibody is an IgG-scFv format antibody wherein the anti-PD-1 antigen-binding domain comprises heavy chain and light chain CDRs comprising the amino acid sequences of SEQ ID NOs: 21-26, respectively (which share 100% sequence identity to instant SEQ ID NO: 41, 42, 43, 44, RAN, and 46, respectively), wherein the anti-PD-1 antigen-binding domain is an scFv or immunoglobulin (Fab), and the anti-VEGFA antigen-binding domain comprises heavy chain and light chain CDRs comprising the amino acid sequences of SEQ ID NOs: 15-20, respectively (which share 100% sequence identity to instant SEQ ID NO: 31, 32, 33, 34, FTS, and 36, respectively), wherein the anti-VEGFA antigen-binding domain is a Fab or scFv (e.g., ¶ 0021-0043, 0140-0174 of machine translation).
Li teaches that the anti-PD-1 antigen-binding domain comprises a VH and a VL comprising the amino acid sequences of SEQ ID NOs: 9 and 11, respectively (which share 100% sequence identity to instant SEQ ID NOs: 37 and 39, respectively), and the anti-VEGFA antigen-binding domain comprises a VH and VL comprising the amino acid sequences of SEQ ID NOs: 5 and 7, respectively (which share 100% sequence identity to instant SEQ ID NOs: 27 and 29, respectively) (e.g., ¶ 0021-0043, 0140-0174 of machine translation; pages 28-30 of original translation), pertinent to claims 24-25. Relevant to claims 27-28, the linker connecting the anti-PD-1 and anti-VEGFA binding portions comprises the amino acid sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 13), which shares 100% sequence identity to instant SEQ ID NO: 48 (e.g., ¶ 0056-0057, 0307-0314 of machine translation; claims 1-2 and 10 of machine translation).
Chen discloses, “While single agent CD73 blockade is not curative, CD73 inhibition improves the antitumor activity of blockade immune checkpoint treatments including … PD-1-mAb. Strikingly, tumor cell CD73 expression attenuates the immune response evoked by anti-PD-1 mAb treatment, while anti-PD-1 mAb treatment augments the expression level of A2AR, especially on CD8+ tumor-infiltrating lymphocytes. As expected, the combination of anti-PD-1 and anti-CD73 mAbs … results in more effective antitumor T cell-mediated immune responses” (page 987).
Voron teaches that immune escape by tumors is mediated in part by promoting T cell exhaustion, which is characterized by expression of immune inhibitory receptors such as PD-1 (e.g., Abstract; Introduction). Voron further teaches that VEGFA is a proangiogenic molecule produced by tumors that plays a key role in the development of an immunosuppressive microenvironment (e.g., Abstract; Introduction) and that VEGFA also enhances the expression of PD-1 in intratumoral T cells in a dose-dependent manner (e.g., Results; Figure 2). Voron presents experimental data showing that VEGFA blockade via an anti-VEGFA antibody significantly reduces PD-1 expression on intratumoral CD8+ T cells (e.g., Results; Figure 1, Figure 4) and that the combination of anti-PD-1 antibodies with VEGFA blockade has a synergistic anti-tumor effect (e.g., Results; Figure 4). Regarding the latter finding, Voron states, “This result suggests that high VEGF-A levels may be involved in resistance to anti–PD-1 treatments and that anti-angiogenic therapies targeting VEGF-A–VEGFR in these tumors expressing high levels of VEGF-A could synergize with anti–PD-1 treatment strategies and enhance anti–PD-1 dependent antitumor effects” (page 145).
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the treatment combinations taught by Lonsberg by substituting an anti-CD73 antibody (such as that taught by Zhang) and a bispecific IgG-scFv format anti-PD-1/VEGFA antibody (such as that taught by Li) for the purpose of treating a solid tumor. The skilled artisan would have been motivated to do so because (1) the combination of an anti-CD73 and an anti-PD-1 antibody results in more effective anti-tumor activity than either agent alone and improves the efficacy of anti-PD-1 immunotherapy (as provided by Chen), and (2) inhibition of VEGFA (e.g., via an anti-VEGFA antibody) further serves to inhibit PD-1 expression on intratumoral CD8+ T cells and creates a synergistic anti-tumor effect (as provided by Voron). There would have been a reasonable expectation of success because each of anti-CD73, anti-PD-1, and anti-VEGFA antibodies have known utility in the treatment of cancer, and because the anti-CD73, anti-PD-1, and anti-VEGFA antibodies/antigen-binding domains disclosed by Zhang and Li are functional equivalents to those recited by Lonsberg. As set forth in MPEP § 2144.06(I): “‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”.
(2)
Claims 10, 26, and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Lonsberg (US 2017/0253665 A1; supra) in view of Zhang (CN113527501A; supra), Li (WO 2020/043184 A1; supra), Chen (Immunotherapy (2019) 11(11): 983-997; supra), and Voron (Journal of Experimental Medicine (2015) 212(2): 139-148; supra) as applied to claims 10-25, 27-29, 31, and 34 above, and further in view of McCarthy (US 2015/0337053 A1; cited in IDS).
The teachings of Lonsberg are provided in the 35 U.S.C. § 103 rejection above.
However, Lonsberg does not expressly disclose an anti-PD-1/VEGFA bispecific antibody comprising a heavy chain comprising the amino acid sequence of instant SEQ ID NO: 233 and a light chain comprising the amino acid sequence of instant SEQ ID NO: 254, nor that the heavy chain constant region of said bispecific antibody comprises one or more mutations such as those recited in claims 32-33.
The teachings of Zhang, Li, Chen, and Voron are set forth above.
Li further teaches that in embodiments of the invention, the bispecific antibody comprises a human IgG1 heavy chain constant region (Accession: P01857) and an immunoglobulin Kappa chain constant region (Accession: P01834) (e.g., ¶ 0050-0055 of machine translation).
McCarthy describes antibodies and other Fc-containing molecules with Fc variations that reduce binding to Fc gamma receptors (FcγRs) which can be used in the treatment of various diseases (e.g., Abstract). Among these, McCarthy discloses IgG1 Fc mutants having the mutations of L234A and L235A among others (e.g., ¶ 0007-0011; claims 1-2, 18).
Based on the further teachings provided by Li and McCarthy, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a combination comprising an anti-CD73 antibody and a bispecific IgG-scFv anti-PD-1/VEGFA antibody, wherein the latter comprises a heavy chain comprising the amino acid sequence of instant SEQ ID NO: 23 (including L234A and L235A in the Fc region) and the light chain comprises the amino acid sequence of instant SEQ ID NO: 25. The skilled artisan would have been motivated to do so because such an antibody construct would have specificity for both of PD-1 and VEGFA (which Voron provides has synergistic anti-tumor properties) and reduced Fc effector functions via the Fc mutations (as set forth by McCarthy). There would have been a reasonable expectation of success because those of ordinary skill in the art would recognize that there are a finite number of ways in which antigen-binding domains can be arranged in a bispecific antibody, and further, the application of a known technique (i.e., adding Fc mutations to reduce effector function) to improve similar products in the same way is considered prima facie obvious based on the state of the prior art.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 See pages 52-53 of the instant specification.
2 Regarding claim 21, the instant specification (e.g., page 10) recites that the amino acid sequence of instant SEQ ID NO: 21 corresponds to a human IgG1 constant region (Accession: P01857) having the mutations of L234A and L235A, and that the amino acid sequence of instant SEQ ID NO: 22 corresponds to an Ig kappa constant region (Accession: P01834).
3 The heavy chain comprising instant SEQ ID NO: 23 includes:
the bevacizumab VH corresponding to instant SEQ ID NO: 27 (at residues 1-123),
a human IgG1 constant region with L234A and L235A substitutions corresponding to instant SEQ ID NO: 21 (at residues 124-453),
the (GGGGS)4 linker corresponding to instant SEQ ID NO: 48 (at residues 454-473 and at residues 592-611),
the anti-PD-1 VH corresponding to instant SEQ ID NO: 37 (at residues 474-591), and
the anti-PD-1 VL corresponding to instant SEQ ID NO: 39 (at residues 612-719).
4 The light chain comprising instant SEQ ID NO: 25 includes:
the bevacizumab VL corresponding to instant SEQ ID NO: 29 (at residues 1-107), and
a human Ig kappa constant region corresponding to instant SEQ ID NO: 22 (at residues 108-214).
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