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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/27/2026 has been entered.
Claim Status
Applicant’s reply filed on 01/27/2026 is acknowledged. Claims 1, 20, and 21 have been amended. Claims 1, 8, 14-15, 20-22, 26-27, 32, 34, 36 are pending. Claims 22, 32, 34, 36 remain withdrawn from consideration as being drawn to nonelected inventions.
Claims 1, 8, 14-15, 20-21, 26-27 are under examination.
Rejections Withdrawn
The following rejections are withdrawn in view of applicant’s amendments filled 01/27/2026:
The objection to claim 1 for missing sequence identifiers.
The rejection of claim 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite.
The rejection of claim 12 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form.
New and Maintained Grounds of Rejection
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
SEQ ID NO: 49 (deleted)
(GGGGGGS)(GGGGS)(GGGGS)SSSSKAPPPS
SEQ ID NO: 50
(GGGGS)(GGGGS)(GGGGS)SSSSKAPPPS
SEQ ID NO: 51
(GS)(GGGGS)(GGGGS)SSSSKAPPPS
SEQ ID NO: 52
(GGGGS)SSSSKAPPPSLPSPSRLPGPSDTPILPQ
Claim 21 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The antibodies set forth in SEQ ID NOs: 55, 57, 59 and 61 all comprise the linker of SEQ ID NO:49. In claim 1, Applicant has deleted the linker SEQ ID NO: 49, therefore claim 21 no longer includes all the limitations of the claim on which it depends. An example of the discrepancy is shown below:
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Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1, 8, 14-15, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Ng (US2016/0355588A1, published 12/08/2016, PTO-892 04/24/2025), Yoon (J Cancer Res Clin Oncol. 2014 Feb;140(2):227-33, IDS filed 04/30/2021), Li (CN106317226A, published 01/11/2017), Baehner (US2012/0251531A1, published 10/04/2012, PTO-892 04/24/2025), McDonagh (US2009/0136526A1, published 05/28/2009, PTO-892 04/24/2025), Kischel (US2009/0252683A1, published 10/08/2009, PTO-892 04/24/2025).
The disclosure of Ng is directed to bispecific antigen binding constructs comprising a first antigen binding polypeptide which specifically binds CD19, a second polypeptide which specifically binds CD3, and a heterodimeric Fc ([0006], Lines 1-6, see Fig 1A). Ng teaches the use of anti-CD19 x anti-CD3 bispecific antibodies for targeting T cells to tumor cells in the treatment of B cell-related tumors ([0005), Lines 1-8).
Regarding the bispecific antibody of claim 1, Ng discloses the following limitations:
A dual/bispecific scFv heterodimer Fc antibody that comprises a first single chain Fv specific for CD19 and a second single chain Fv specific for CD3, both bound to an Fc region (Ng claim 1 and Fig. 1A).
The IgG1 Fc polypeptide is linked to the antigen binding polypeptide construct with or without a linker (Ng claim 1, claim 9)
The disclosed antigen-binding construct displays reduced Fc gamma receptor binding and no associated immune-cell mediated effector activity (Ng claim 14).
A (GGGGS)3 linker between the heavy and light chain of the scFv ([0247], Lines 6-8)
The antibody of the disclosure binds human CD19, as seen in the binding studies of the immortalized human cell lines, Raji and Jurkat (Pg. 28, Tables 4 and 5).
Regarding claim 14, wherein the linker peptide that links the Fc fragment to the second scFv consists of (GGGGS)n, wherein n = 1, 2, 3, or 4, Ng teaches exemplary non-immunogenic linker peptide (G4S)n wherein n is a number between 1 and 10, typically between 2 and 4.
Regarding claim 26, pertaining to a pharmaceutical composition comprising the claim bispecific antibody and a pharmaceutically acceptable excipient, Ng teaches pharmaceutical compositions comprising a therapeutically effective amount of the antibody and a pharmaceutically acceptable carrier ([0224], Lines1-4).
Regarding claim 27, further comprising a pharmaceutically active agent administered before, after, concurrently with the pharmaceutical composition of claim 26, Ng discloses co-administration of the antibody with at least one additional therapeutic agent such as immunomodulatory agents and cytotoxic agents ([0237], Lines 1-14).
The disclosure of Ng does not teach: (1) the bispecific antibody is tetravalent, (2) the first scFv is linked to the second scFv by a linker peptide selected from SEQ ID NO: 50, 51, or 52, (3) the human IgG1 Fc fragment comprises the amino acid substitutions L234A/L235A/P331S/N297A, (4) the CD19 scFv comprises VH SEQ ID NO:22 and VL SEQ ID NO:23, and (5) the CD3 scFv comprises VH SEQ ID NO:46 and VL SEQ ID NO:47.
These deficiencies are taught by Yoon, Li, Baehner, McDonagh and Kischel.
Regarding the bispecific antibody of the instant invention, the prior art teaches the following limitations:
Yoon:
The disclosure of Yoon teaches a tetravalent antibody construct, the same as in the instant invention with linked tandem scFvs and a fusion of two polypeptide chains to form a tetravalent construct (Fig. 1).
Li:
The disclosure of Li teaches the linkers comprising a (1) a flexible peptide (GS)a(GGS)b(GGGS)c(GGGGS)d where all are integers ≥ 0 and a+b+c+d ≥1 (Li [0015]) and (2) a rigid peptide comprising, for example, SSSSKAPPPS (Li, [0029]. These teachings anticipate the instant linkers, for example instant SEQ ID NO:50 corresponding to (GS)0(GGS)0(GGGS)0(GGGGS)3SSSSKAPPPS and instant SEQ ID NO:51 corresponding to (GS)1(GGS)0(GGGS)0(GGGGS)4SSSSKAPPPS. Li teaches there claimed flexible-rigid linker overcomes common fusion protein issues, specifically proteasomal degradation due to incorrect folding and shielding of active sites due to spatial proximity of the polypeptides fused together ([0004, Paragraph 2). Li provides evidence that a fusion protein comprising the linker peptide has a significantly prolong half-life and high biological activity (Li, [0103]).
Baehner:
The disclosure of Baehner teaches engineered polypeptides comprising Fc variants that exhibit reduced effector function and teaches mutations L234A, L235A, and P331S which disrupt binding at the Fc/FcγR interface and prevent CDC, ADCC, ADCP ([0004], Lines 7-9).
Regarding claim 15, wherein the Fc fragment further comprises one or more disclosed amino acid substitutions, deletions or additions, Baehner teaches N297A ([0151], Line 4).
McDonagh:
The disclosure of McDonagh teaches CD19 binding agents and discloses the anti-CD19 antibody clone hBU12 ([0041], Lines 1-6). McDonagh teaches that variants of the CD19-binding antibody were optimized for improved binding to CD19 on human cancer cell lines (Table on Pg. 57) and subsequent experiments show the effectiveness of the hBU12 clone at delivering a drug conjugate and producing anti-tumor effects in rituximab resistant tumors ([0606], Lines 1-4 and Fig 17D).
McDonagh discloses an anti-CD19 antibody clone comprising heavy chain SEQ ID NO:9 and light chain SEQ ID NO:24 (McDonagh claims 22-23), which are identical to instant SEQ ID NOs:22 and 23 and which comprise the instant claimed CDR sequences as shown below:
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Kischel:
The disclosure of Kischel teaches a humanized anti-CD3 antibody that specifically binds human and cynomolgus CD3, the clone exhibiting improved binding compared to the murine parental antibody (Fig. 22 and [0217], Lines 1-5).
Regarding the anti-CD3 scFv of claim 1, Kischel discloses the anti-CD3 antibody pairing comprising VH set forth in SEQ ID NO:110 and VL set forth in SEQ ID NO:168 ([0210], Lines 4-8 and Pg. 170, claim 9), which are identical to instant VH SEQ ID NO:46 and instant VL SEQ ID NO:47 (claim 11) and comprise the instant claimed CDR sequences (claim 10). The sequences with underlined CDRs are shown below:
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Regarding the limitation of claim 8, wherein the second scFv binds to an effector cell at an EC50 value greater than about 10 nM, this property is inherent to the anti-CD3 antibody of Kischel as evidenced by the instant specification (Pg. 62)
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the anti-CD3 anti-CD19 bispecific antibody of Ng (1) using the tetravalent bispecific structure of Yoon, (2) linking the first scFv to the second scFv with a linker peptide selected from SEQ ID NO: 50, 51, or 52 as taught by Li, (3) modifying the human IgG1 Fc fragment to comprise the amino acid substitutions L234A/L235A/P331S/N297A as taught by Baehner, (4) using the CD19 scFv comprising VH SEQ ID NO:22 and VL SEQ ID NO:23 as taught by McDonagh, and (5) using the CD3 scFv comprising VH SEQ ID NO:46 and VL SEQ ID NO:47 as taught by Kischel. One would have been motivated to do so because (1) Yoon provides an alternate bispecific antibody construct that is tetravalent, providing twice as many binding sites for CD3 and CD19, (2) Li teaches flexible-rigid linkers that provide appropriate spatial orientation of the two scFv, (3) Baehner teaches that the Fc mutations disrupt Fc/FcγR and prevent antibody- and complement-mediated effector functions, allowing for T cells effector functions, (4) McDonagh teaches that hBU12 is optimized to bind CD19 and has proven use in anti-tumor methods, and (5) Kischel validates the binding specificity of the anti-CD3 antibody of the disclosure and demonstrates cross-species specify required for pre-clinical trial. Optimization of antibodies is routine in the art and modification using the discloses teachings constitutes combining prior art elements according to known methods to yield predictable results. There would be an expectation of success in performing the modifications because each prior art reference provides evidence of their respective components functioning to optimize antibody binding, effector function or stabilize the antibody structure.
U.S. Patent No. 12,030,939
Claims 1, 8, 14-15, 20-21, and 26-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12,030,939 in view of McDonagh (US2009/0136526, published 05/28/2009, PTO-892 04/24/2025) and Li (CN106317226A, published 01/11/2017).
Pat No. ‘939 is directed to any antibody format that is identical to that of the instant invention, including the structure, anti-CD3 scFv, linkers, and modified Fc region. The inventions differ only in the specificity of the TAA region of the antibody and the sequence of the rigid peptide.
‘939 does not teach: (1) the bispecific antibody binds CD19 or (2) the first scFv and second scFv are linked by a linker peptide selected from SEQ ID NO:50, 51, or 52.
These deficiencies are taught by McDonagh and Li.
The disclosure of McDonagh is directed to CD19 binding agents and discloses the anti-CD19 antibody clone hBU12 ([0041], Lines 1-6). McDonagh also contemplates the use of the disclosed anti-CD19 binding domain in bispecific antibodies (see [0215]).
The disclosure of Li teaches the linkers comprising a (1) flexible peptide (GS)a(GGS)b(GGGS)c(GGGGS)d where all are integers ≥ 0 and a+b+c+d ≥1 (Li [0015]) and (2) a rigid peptide comprising, for example, SSSSKAPPPS (Li, [0029]. These teachings anticipate the instant linkers, for example instant SEQ ID NO:50 corresponding to (GS)0(GGS)0(GGGS)0(GGGGS)3SSSSKAPPPS and instant SEQ ID NO:51 corresponding to (GS)1(GGS)0(GGGS)0(GGGGS)4SSSSKAPPPS. Li teaches there claimed flexible-rigid linker overcomes common fusion protein issues, specifically proteasomal degradation due to incorrect folding and shielding of active sites due to spatial proximity of the polypeptides fused together ([0004, Paragraph 2). Li provides evidence that a fusion protein comprising the linker peptide has a significantly prolong half-life and high biological activity (Li, [0103]).
It would have been obvious to one having ordinary skill in that art to modify the bispecific antibody of ‘939 by (1) swapping out the BCMA-binding region with the CD19 binding region as taught by McDonagh and (2) linking the first scFv to the second scFv with a linker peptide selected from SEQ ID NO: 50, 51, or 52 as taught by Li. It would have been obvious to do so because (1) CD19 is another type of tumor-associated antigen and making the modification would enable the use of the antibody for treating CD19-mediated diseases and (2) Li teaches flexible-rigid linkers that provides appropriate spatial orientation of the two scFv. Such a modification constitutes combining prior art elements according to known methods to yield predictable results.
Copending Application 18/671,707
Claims 1, 8, 14-15, 20-21, and 26-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 28 of copending Application No. 18/671,707 in view of McDonagh (US2009/0136526, published 05/28/2009, PTO-892 04/24/2025) and Li (CN106317226A, published 01/11/2017).
Copending ‘707 is directed to treating comprising administering a bispecific antibody format that is identical to that of the instant invention, including the structure, anti-CD3 scFv, linkers, and modified Fc region. The inventions differ only in the specificity of the TAA region of the antibody and sequence of the rigid peptide.
‘707 does not teach: (1) the bispecific antibody binds CD19 or (2) the first scFv and second scFv are linked by a linker peptide selected from SEQ ID NO:50, 51, or 52.
These deficiencies are taught by McDonagh and Li.
The disclosure of McDonagh is directed to CD19 binding agents and discloses the anti-CD19 antibody clone hBU12 ([0041], Lines 1-6). McDonagh also contemplates the use of the disclosed anti-CD19 binding domain in bispecific antibodies (see [0215]).
The disclosure of Li teaches the linkers comprising a (1) flexible peptide (GS)a(GGS)b(GGGS)c(GGGGS)d where all are integers ≥ 0 and a+b+c+d ≥1 (Li [0015]) and (2) a rigid peptide comprising, for example, SSSSKAPPPS (Li, [0029]. These teachings anticipate the instant linkers, for example instant SEQ ID NO:50 corresponding to (GS)0(GGS)0(GGGS)0(GGGGS)3SSSSKAPPPS and instant SEQ ID NO:51 corresponding to (GS)1(GGS)0(GGGS)0(GGGGS)4SSSSKAPPPS. Li teaches there claimed flexible-rigid linker overcomes common fusion protein issues, specifically proteasomal degradation due to incorrect folding and shielding of active sites due to spatial proximity of the polypeptides fused together ([0004, Paragraph 2). Li provides evidence that a fusion protein comprising the linker peptide has a significantly prolong half-life and high biological activity (Li, [0103]).
It would have been obvious to one having ordinary skill in that art to modify the bispecific antibody of copending ‘707 by (1) swapping out the BCMA-binding region with the CD19 binding region as taught by McDonagh and (2) linking the first scFv to the second scFv with a linker peptide selected from SEQ ID NO: 50, 51, or 52 as taught by Li. It would have been obvious to do so because (1) CD19 is another type of tumor-associated antigen and making the modification would enable the use of the antibody for treating CD19-mediated diseases and (2) Li teaches flexible-rigid linkers that provides appropriate spatial orientation of the two scFv. Such a modification constitutes combining prior art elements according to known methods to yield predictable results.
This is a provisional nonstatutory double patenting rejection.
Response to Applicant’s Remarks
Applicant's arguments filed 01/27/2026 have been fully considered but they are not persuasive.
The applicant argues that the instant claims are patentably distinct from the '939 Patent, either alone or with a purported modification using the teachings of McDonagh. The patent, whether considered alone or in light of McDonagh, does not disclose, "first single-chain Fv is linked to the second single-chain Fv by a linker peptide selected from SEQ ID NOs: 50, 51, and 52," as recited in amended claim I (i.e., lacking a recitation of SEQ ID NO. 49). (Remarks, Pg. 10)
In response, the rigid peptide linkers as set forth in instant SEQ ID NOs: 50, 51, and 52 are known in the prior art, therefore the differences between Patent ‘939 and the instant application were obvious to one having ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646