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 .
Status of Claims / Response to Amendment
The Amendments and Remarks filed 06/29/2026 in response to the Office Action of 03/31/2026 are acknowledged and have been entered.
Claims 1, 29, 30, 36, 40, 41, 44, 53, 57, 60, 66-71, 73, 76, 95 and 96 are pending.
Claims 1, 57, 60 and 70 have been amended by Applicant.
Claims 95 and 96 are new.
Claims 1, 29, 30, 36, 40, 41, 44, 53, 57, 60, 66-71, 95 and 96 are under examination on the merits in the instant Office Action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Claim Objections – Withdrawn
The objection of claims 1, 57 and 70 has been withdrawn because said claims have been amended.
Claim Rejections - Withdrawn
The rejection of claims 1, 29, 30, 36, 40, 41, 44, 53, 57, 60 and 66-71 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), second paragraph has been withdrawn.
The written description rejection of claim 60 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been withdrawn.
Claim Objections – Maintained
Claims 40 and 53 remain objected as being dependent on a rejected base claim (claim 1). See maintained 103 rejections below.
Rejections Maintained
Claim Rejections - 35 USC § 103 (first) - Maintained
Claims 1, 29, 30, 36, 41, 66, 67, 68, 69 and 71 remain rejected and claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (CN110305210A Date Published 2019-10-08) in view of Xu(1) et al. (WO2017063162A1 Date Published 2017-04-20), Xu(2) et al. (US20180291103A1 Date Published 2018-10-11) and Polesso et al. (Cancer Immunol Res (2019) 7 (2): 269–281.).
Please note that the citations from Liu et al. and Xu(1) et al. below reference positions in the translations attached to the Non-Final Office Action dated 03/31/2026.
Liu et al. teaches an anti-OX40/PD-L1 bispecific antibody that is based on the schematic diagram of Figure 1D, comprising a single-domain antibody linked to the N-terminus of the variable heavy chain of a full antibody molecule. They teach that the bispecific antibody Bi-122-112LC comprises four polypeptide chains that are bilaterally symmetrical, wherein the two polypeptide chains on the left half, namely peptide chain #1 and peptide chain #2, are identical to the two polypeptide chains on the right half, namely peptide chain #3 and peptide chain #4 respectively (Pg. 60-61 paragraph spanning and Figure 1D). They also teach that peptide chain #1 comprises the amino acid sequence as shown in SEQ ID NO: 15, which comprises the light chain amino acid sequence of the anti-OX40 ADI-20112 antibody (Pg. 60-61 paragraph spanning and Figure 1D). Amino acid residues 107 to 213 of SEQ ID NO: 15 as taught by Liu et al. matches exactly with instant SEQ ID NO: 13, which comprises the light chain constant region of instant OX40 binding moiety (see Alignment 1 of Non-Final Office Action dated 03/31/2026). They further teach the anti-OX40/PD-L1 bispecific antibody comprises a human kappa or lambda light chain constant region, an IgG1 or IgG4 CH1 domain, and an Fc region that is either human IgG1 or human IgG4 heavy chain constant region (Pg. 43 fourth full paragraph).
Liu et al. also teaches polynucleotide encoding said antibody molecule, a vector comprising the polynucleotide and a host cell comprising the polynucleotide or the vector (Pg 22 third to fifth full paragraphs). They teach an immunoconjugate comprising an antibody, and a pharmaceutical composition comprising an antibody molecule for immunotherapy of a disease (Pg 23 first and second full paragraphs). They also teach a method of modulating an immune response in a subject, the method comprising administering to the subject a therapeutically effective or a prophylactically effective amount of said antibody molecule (Pg. 58 first full paragraph). They further teach that cancers treated with said antibody molecules include solid tumors, hematological cancers and metastatic lesions (Pg. 58 third full paragraph).
Liu et al. does not specifically teach the bispecific antigen-binding protein comprising instantly recited amino acid sequences for the H1CDR1, H1CDR2 and H1CDR3 comprised in the VH1 domain, and the L1CDR1, L1CDR2 and L1CDR3 comprised in the VL1 domain of the OX40 binding moiety; and also does not specifically the H2CDR1, H2CDR2 and H2CDR3 comprised in the single-domain PD-L1 antibody.
However, these deficiencies are made up in the teachings of Xu(1) et al. and Xu(2) et al.
Xu(1) et al. teaches a human antibody which specifically binds to human OX40 and has agonist activity that is used for the treatment of tumors (Abstract and Figure 7). They teach the anti-OX40 antibody comprises a heavy chain variable region of SEQ ID NO: 69 (claim 4), which matches fully with instant VH1 SEQ ID NO: 6 and comprises instant H1CDR1, H1CDR2 and H1CDR3 as set forth in instant SEQ ID NO(s): 3, 4, and 5. They also teach the light chain variable region of SEQ ID NO: 74 (claim 7), which comprises instant L1CDR1, L1CDR2 and L1CDR3 of SEQ ID NO(s): 9, 10 and 11 and matches instant VL1 of SEQ ID NO: 12 at 99.5% (one amino acid mismatch at residue 106) (See Alignments 2-5 of Non-Final Office Action dated 03/31/2026).
Xu(2) et al. teaches a single-domain antibody directed against PD-L1 that is used for treating PD-L1 related diseases such as cancer (Abstract). They teach the antibody comprises SEQ ID NO: 2 (claim 1), which matches instant SEQ ID NO: 53 exactly and comprises instant H2CDR1, H2CDR2 and H2CDR3 of SEQ ID NO(s): 29, 36 and 45 (see Alignments 6 and 7 of Non-Final Office Action dated 03/31/2026).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating a bispecific PD-L1/OX40 binding antibody molecule which comprises (i) a PD-L1 binding single-domain antibody comprising a VHH, and (ii) an OX40 binding domain, wherein the bispecific antibody comprises a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises the light chain of the OX40 binding domain, and the second polypeptide chain comprises the PD-L1 single-domain antibody that is at the N-terminus of the heavy chain of the OX40 binding domain as taught by Liu et al., and substituting the OX40 VH and VL domains of Liu et al. with the OX40 VH of SEQ ID NO: 69 and VL of SEQ ID NO: 74 as taught by Xu(1) et al., and further substituting the PD-L1 single-domain antibody of Liu et al. with SEQ ID NO:2 as taught by Xu(2) et al., because Liu et al. teaches that the anti-OX40/PD-L1 bispecific antibody of Bi-119-112LC comprising the specific format and configuration of the first polypeptide chain and the second polypeptide chain taught in Figure 1D can be produced and have 94.79% purity, Xu(1) et al. teaches that the claimed anti-OX40 antibody has good specificity, high affinity and low immunogenicity for activating T cells to effect significant inhibitory effect on tumor growth (paragraph [0062]), and Xu(2) et al. teaches that the claimed single-domain anti-PD-L1 antibody has high affinity, high specificity and ability to inhibit tumor growth (paragraphs [0081] to [0083]), and further because Polesso et al. teaches that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells for promoting tumor regression (Abstract). In addition, combining PD-L1 and OX40 binding into a single antigen-binding protein in this format provides a molecule with four binding sites which increases avidity, and also would have the advantage of (i) simultaneously being present at the target tumor site at the same time in close proximity to form a physical “bridge” that recruits and activates OX40 receptors on immune cells only upon binding to PD-L1 that is highly expressed on tumor cells; and (ii) simplifying therapy with one administration of a single bispecific antibody, rather than two antibodies, for patient convenience. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (second) - Maintained
Claims 1, 29, 30, 36, 41, 44, 66, 67, 68, 69 and 71 remain rejected and claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (CN110305210A Date Published 2019-10-08), Xu(1) et al. (WO2017063162A1 Date Published 2017-04-20), Xu(2) et al. (US20180291103A1 Date Published 2018-10-11) and Polesso et al. (Cancer Immunol Res (2019) 7 (2): 269–281.) as applied to claims 1, 29, 30, 36, 41, 66, 67, 68, 69, 70 and 71 above, in further view of Gillies et al. (US20030166877A1 Date Published 2003-09-04).
The combined teachings of Liu et al., Xu(1) et al., Xu(2) et al. and Polesso et al. already render obvious claims 1, 29, 30, 36, 41, 66, 67, 68, 69, 70 and 71as described in the first 103 rejection above.
Liu et al., Xu(1) et al., Xu(2) et al. and Polesso et al. do not specifically teach a bispecific OX40/PD-L1-binding protein that further comprises a heavy chain constant region of instant SEQ ID NO: 7.
However, these deficiencies are made up in the teachings of Gillies et al.
Gillies et al. teaches methods for producing fusion proteins with reduced immunogenicity (Abstract). They teach the human IgG1 heavy chain constant region as set forth in SEQ ID NO: 1 which can be used to derive the Fc region to be used as a fusion partner with other polypeptide chains (paragraph [0048] and Pg. 17 Sequence Listing SEQ ID NO 1 length 330 amino acids). The heavy chain constant region of instant SEQ ID NO:7 matches completely with SEQ ID NO: 1 of the human IgG1 heavy chain constant region as taught by Gillies et al. see Alignment 7 of Non-Final Office Action dated 03/31/2026).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of generating a bispecific PD-L1/OX40 binding antibody molecule as taught by Liu et al., Xu(1) et al. and Xu(2) et al., and substituting the heavy chain constant region of the antibody as taught by Liu et al. with the human IgG1 heavy chain constant region of SEQ ID NO: 1 as taught by Gillies et al. because this is a substitution of one human IgG1 constant region for another human IgG1 constant region. This is an example of (B) Simple substitution of one known element for another to obtain predictable results ; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (third) - Maintained
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 remain rejected and claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (CN110305210A Date Published 2019-10-08), Xu(1) et al. (WO2017063162A1 Date Published 2017-04-20), Xu(2) et al. (US20180291103A1 Date Published 2018-10-11), Polesso et al. (Cancer Immunol Res (2019) 7 (2): 269–281.), Gillies et al. (US20030166877A1 Date Published 2003-09-04) as applied to claims 1, 29, 30, 36, 41, 44, 66, 67, 68, 69, 70 and 71 above, in further view of Fandl et al. (US20050158829A1 Date Published 2005-07-21) and Ghayur et al. (WO2014106015A2 Date Published 2014-07-03).
The combined teachings of Liu et al., Xu(1) et al., Xu(2) et al., Polesso et al. and Gillies et al. already render obvious claims 1, 29, 30, 36, 41, 44, 66, 67, 68, 69, 70 and 71 as described in the second 103 rejection above.
Liu et al., Xu(1) et al., Xu(2) et al., Polesso et al. and Gillies et al.do not specifically teach the bispecific antigen-binding protein further comprising a linker of instant SEQ ID NOs: 14-15; or wherein the second polypeptide chain comprises instant SEQ ID NOs: 17 or 18.
However, these deficiencies are made up in the teachings of Fandl et al. and Ghayur et al.
Fandl et al. teaches fusion polypeptides that form multimeric proteins (Abstract). They teach the Gly-Ala-Pro three amino acid peptide linker for the construction of scFv fusion molecules (paragraph [0067]). The Gly-Ala-Pro (GAP) linker sequence of Fandl et al. is identical to the linker of instant SEQ ID NO: 15.
Ghayur et al. teaches multivalent binding proteins that specifically bind to one or more desired target antigens (Abstract). They teach the linker of ASTKGPSVFPLA named Elbow VH12 , which is comprised within the IgG1 constant region, used for linking VH and VL domains (Table 11, Figure 5 and Pg. 98 second full paragraph).
When one combines the teachings of Fandl et al. and Ghayur et al., the ASTKGPSVFPLA linker sequence of Ghayur et al. connected to the GAP linker sequence of Fandl et al. produces the linker sequence of ASTKGPSVFPLAGAP which is identical to instant SEQ ID NO: 14.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of generating a bispecific PD-L1/OX40 binding antibody molecule as taught by Liu et al., Xu(1) et al. and Xu(2) et al., and further include the linkers as taught by Fandl et al. and Ghayur et al. to link the heavy chain H1 of the OX-40 binding moiety to the PD-L1 binding moiety of the combined method because Fandl et al. teaches that the GAP linker produced bispecific scFv antigen-binding molecules that were capable of binding to their target antigens (paragraphs [0062] to [0064]) and because of the advantage of a flexible linker, ASTKGPSVFPLA, that is natural and thus has minimal immunogenicity as taught by Ghayur et al. (Pg. 177 first full paragraph and Table 76). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to instant claim 60, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of generating a bispecific PD-L1/OX40 binding antibody molecule as taught by Liu et al., Xu(1) et al., Xu(2) et al. and Gillies et al. and further combining the linkers as taught by Fandl et al. and Ghayur et al. to generate a second polypeptide chain that comprises amino acid as set forth in instant SEQ ID NO: 17 which is a fusion of instant SEQ ID NOs: 53, 14, 6 and 7 in this specific order from the N-terminus to the C-terminus, wherein this fusion forms the second polypeptide chain that comprises from the N-terminal, the single-domain PD-L1 binding moiety as taught by Xu(2) et al., the linker ASTKGPSVFPLA as taught by Ghayur et al. fused to the linker GAP as taught by Fandl. et al., the VH domain of the OX40 binding moiety as taught by Xu(1) et al., and the heavy chain constant region as taught by Gillies et al. Alternatively, a combined method of generating a second polypeptide chain of instant SEQ ID NO: 18 which is a fusion of instant SEQ ID NOs: 53, 15, 6 and 7 in this specific order from the N-terminus to the C-terminus, wherein this fusion forms the second polypeptide chain that comprises from the N-terminal, the single-domain PD-L1 binding moiety as taught by Xu(2) et al., the linker GAP as taught by Fandl. et al., the VH domain of the OX40 binding moiety as taught by Xu(1) et al., and the human IgG1 heavy chain constant region as taught by Gillies et al.
Response to Arguments
In the reply of 06/29/2026, Applicant argues that Liu et al. did not select for further research or testing the format of the Bi-122-112LC (Figure 1D) with 94.79% purity, that was described in the Non-Final Office Action 103 rejection dated 03/31/2026. Rather, Liu et al. selected Bi-119-112LC shown in Figure 1C which produced 99.43% purity and was tested for the described biological properties. Applicant also argues that development of a bispecific PD-L1/OX40 binding protein based on the format of Bi-122-112LC of Liu et al. would not be an appropriate selection for development of a similar antigen-binding protein. In addition, Applicant argues that antibody binding domains and fusion positions are not presumptively interchangeable modules wherein fusion position can adversely affect folding, chain assembly, aggregation, steric access, receptor clustering, agonist activity, stability, and manufacturability.
Applicant further argues that Example 3 of the instant specification shows that KN052 effectively bridges PD-L1-expressing cells and OC40-expressing cells, whereas an equimolar mixture of separate KN035 and DF004 antibodies does not produce the same cell-bridging effect. Applicant even further argues that Example 9 of the instant specification shows that KN052-2, the claimed antigen-binding format, significantly enhanced IL-2 responses relative to combination of KN-35 and DF004 antibodies, producing a strong synergistic effect. Moreover, Applicant argues that Example 10 reports dose-dependent antitumor activity for KN052-2 and that Example 11 provides results on the tumor volume in mice upon treatment with equimolar doses of KN052-2 or of KN035 and DF 044 parent antibodies combination.
Examiner’s Response: The arguments found in the Reply of 06/29/2026 have been carefully considered but are not deemed persuasive.
Regarding Liu et al.’s format of Bi-122-112LC that has 94.79% purity, this level of monomer purity was less than 5% difference compared to 99.43% purity for Bi-119-112LC which was selected for further testing. The choice of selecting a construction that has a slightly higher monomer purity level could be driven by the need for a slightly higher yield, and for time and cost savings. As is known in the art, at 94.79% purity, the Bi-122-112LC format is considered to be high for production of fusion proteins and more than likely an acceptable level for further testing and eventual applications. In addition, Liu et al. did not explicitly mention that the format of Bi-122-112LC had inferior biological activity but merely stated that “In subsequent experiments, the bispecific antibody Bi-119-112LC with a purity of 99.43% of the main monomer peak was selected for further research” (Pg 62 fourth full paragraph). Therefore, it cannot be assumed that the Bi-122-112LC would not have comparable biological functions and effects as that of the further tested Bi-119-112LC.
With regards to bispecific antibody formats that are known in the art, Brinkmann et al. (Mabs 2017 Jan 10;9(2):182–212) teaches many variations for the making of different formats of bispecific antibodies that can be employed for therapeutic applications (Title, Abstract and Table 3). They teach in Figure 2 the various bispecific antibody formats that have been reduced to practice that include symmetric or asymmetric architecture (Figure 2). The teachings of Brinkmann et al. thus exemplify how different antibody domains can be arranged and combined to form fusion proteins with uniquely different structures that retain the ability to fold and assemble to form stable, functional and manufacturable molecules with a reasonable expectation of success. Obviousness does not require absolute predictability, only a reasonable expectation of success. See MPEP 2144.08.
With regards to instant Example 3, that KN052 has the superior effect of cross linking or bridging PD-L1-expressing cells and OX40-expressing cells than a combination of KN035 and DF004 monospecific antibodies at equimolar concentration is not unexpected. This is because monospecific antibodies that express PD-L1-binding domains would be expected to not bind to OX40-binding domain and thus not be expected to bridge cells that express OX40 antigens. The same holds true for monospecific antibodies that express OX40-binding domains which would also not be expected to bridge cells that express PD-L1 antigens. Therefore, the KN035 and DF004 antibody combination is performing within the expectation of not being able to produce any cell-bridging effect, which also translates to the fact that not having the same cell-bridging effect shown by KN052 (or the PD-L1 X OX40 bispecific antibodies of Liu et al.) is fully expected for the KN035 and DF004 antibody combination.
With regards to instant Example 9, Her et al. (WO2019133817A1 Date Published 2019-07-04) teaches that bispecific proteins that comprise scFvs that specifically bind PD-L1 and OX40 show synergism in stimulating T-cell IL-2 production compared to monospecific antibody combinations (Figure 16A and paragraph [0052]; note that the graphs in Figure 16A are results from using same µg/ml concentrations rather than equimolar concentrations). Further, Fromm et al. (J Immunotherapy Cancer 6, 149, 1-16; 2018) teaches a fusion protein comprising PD1-Fv-OX40L that retains proper folding and has specific binding to PD-L1 and OX40 (Abstract). This fusion protein was able to stimulate IL2 secretion of PBMCs from healthy donors to a more significant level compared to PD-L1 binding antibodies or OX40 binding antibodies either separately or in combination (Figs 1, 2 and 4D). Therefore, the synergistic effect of KN052-2, which comprises KN035 (PD-L1-binding domain) and DF004 (OX40-binding domain), on IL-2 secretion shown in Example 9 and Figure 10A is not unexpected or surprising in view of other PD-L1 X OX40 bispecific antibodies known in the prior art.
With regards to instant Example 10 which discloses dose-dependent antitumor activity of KN052-2, such dose-dependent antitumor activity is predictable due to KN052-2 having the predictable function of having antitumor activity. This is because Her et al. teaches that their anti-PD-L1-OX40 bispecific antibody showed anti-tumor effects in a mouse tumor model at a dose of 3 mg/kg (Figure 25 and paragraph [00111]). Therefore, it would be reasonably expected that bispecific antibodies comprising PD-L1 and OX40 binding specificities, including KN052-2 would show a dose dependent antitumor effect.
With regards to instant Example 11, the results described here and in Figure 12F for KN052-2 are predictable based on the significant anti-tumor effects in mouse xenograft models after administration of the anti-PD-L1-OX40 bispecific antibody taught by Her et al. (Figure 25 and paragraph [00111]).
Double Patenting - Maintained
First NSDP: U.S. Patent No. 11225522 - Maintained
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 remain rejected and claim 70 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 5, 10, 12, 13 and 15-17 of U.S. Patent No. 11225522 (Date of Patent 18 Jan 2022) in view of Liu et al. (CN110305210A Date Published 2019-10-08), Xu(1) et al. (WO2017063162A1 Date Published 2017-04-20), Polesso et al. (Cancer Immunol Res (2019) 7 (2): 269–281), Gillies et al. (US20030166877A1 Date Published 2003-09-04), Fandl et al. (US20050158829A1 Date Published 2005-07-21) and Ghayur et al. (WO2014106015A2 Date Published 2014-07-03).
The patented claim 1 is drawn to the same VHH domain CDRs for a PD-L1 antibody as instantly recited.
Patent claims do not specifically teach an isolated antigen-binding protein that comprises both a PD-L1 binding moiety and an OX40 binding moiety, or the amino acid sequences of the OX40 binding moiety, or linkers, or the format in which the PD-L1-binding moiety and OX40-binding moiety are linked together to form the fusion protein, or immunoconjugate comprising, nucleic acid molecules encoding, or a method of treating tumor using, said antigen-binding protein.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al. have been described in the 103 rejections above.
It would be obvious to generate an isolated antigen-binding protein of the combined method of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above and substituting the PD-L1 single-domain of the combined method with the VHH PD-L1 antibody as recited by the Patent, because Liu et al. teaches that the anti-OX40/PD-L1 bispecific antibody of Bi-119-112LC comprising the specific format and configuration of the first polypeptide chain and the second polypeptide chain taught in Figure 1D can be produced and have 94.79% purity, Xu(1) et al. teaches that the claimed anti-OX40 antibody has good specificity, high affinity and low immunogenicity for activating T cells to effect significant inhibitory effect on tumor growth (paragraph [0062]), and because Polesso et al. teaches that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells for promoting tumor regression (Abstract). In addition, combining PD-L1 and OX40 binding into a single antigen-binding protein in this format provides a molecule with four binding sites which increases avidity, and also would have the advantage of (i) simultaneously being present at the target tumor site at the same time in close proximity to form a physical “bridge” that recruits and activates OX40 receptors on immune cells only upon binding to PD-L1 that is highly expressed on tumor cells; and (ii) simplifying therapy with one administration of a single bispecific antibody, rather than two antibodies, for patient convenience. Also, because Gillies et al. teaches the human IgG1 heavy constant region (paragraph [0048] and Sequence Listing), and Fandl et al. teaches that the GAP linker produced bispecific scFv antigen-binding molecules that were capable of binding to their target antigens (paragraphs [0062] to [0064]) and because of the advantage of a flexible linker, ASTKGPSVFPLA, that is natural and thus has minimal immunogenicity as taught by Ghayur et al. (Pg. 177 first full paragraph and Table 76).
Second NSDP: U.S. Patent No. 11377497 - Maintained
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 remain rejected and claim 70 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-4 of U.S. Patent No. 11377497 (Date of Patent 5 JUL 2022) in view of Liu et al. (CN110305210A Date Published 2019-10-08), Xu(1) et al. (WO2017063162A1 Date Published 2017-04-20), Polesso et al. (Cancer Immunol Res (2019) 7 (2): 269–281), Gillies et al. (US20030166877A1 Date Published 2003-09-04), Fandl et al. (US20050158829A1 Date Published 2005-07-21) and Ghayur et al. (WO2014106015A2 Date Published 2014-07-03).
The patented claim 2 is drawn in part to same VHH domain CDRs for a PD-L1 antibody as instantly recited.
Patent claims do not specifically teach an isolated antigen-binding protein that comprises both a PD-L1 binding moiety and an OX40 binding moiety, or the amino acid sequences of the OX40 binding moiety, or linkers, or the format in which the PD-L1-binding moiety and OX40-binding moiety are linked together to form the fusion protein, or immunoconjugate comprising, nucleic acid molecules encoding, or a method of treating tumor using, said antigen-binding protein.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al. have been described in the 103 rejections above.
It would be obvious to generate an isolated antigen-binding protein of the combined method of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above and substituting the PD-L1 single-domain of the combined method with the VHH PD-L1 antibody as recited by the Patent, because Liu et al. teaches that the anti-OX40/PD-L1 bispecific antibody of Bi-119-112LC comprising the specific format and configuration of the first polypeptide chain and the second polypeptide chain taught in Figure 1D can be produced and have 94.79% purity, Xu(1) et al. teaches that the claimed anti-OX40 antibody has good specificity, high affinity and low immunogenicity for activating T cells to effect significant inhibitory effect on tumor growth (paragraph [0062]), and because Polesso et al. teaches that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells for promoting tumor regression (Abstract). In addition, combining PD-L1 and OX40 binding into a single antigen-binding protein in this format provides a molecule with four binding sites which increases avidity, and also would have the advantage of (i) simultaneously being present at the target tumor site at the same time in close proximity to form a physical “bridge” that recruits and activates OX40 receptors on immune cells only upon binding to PD-L1 that is highly expressed on tumor cells; and (ii) simplifying therapy with one administration of a single bispecific antibody, rather than two antibodies, for patient convenience. Also, because Gillies et al. teaches the human IgG1 heavy constant region (paragraph [0048] and Sequence Listing), and Fandl et al. teaches that the GAP linker produced bispecific scFv antigen-binding molecules that were capable of binding to their target antigens (paragraphs [0062] to [0064]) and because of the advantage of a flexible linker, ASTKGPSVFPLA, that is natural and thus has minimal immunogenicity as taught by Ghayur et al. (Pg. 177 first full paragraph and Table 76).
Third NSDP: U.S. Patent No. 12281163 - Maintained
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 remain rejected and claim 70 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5 and 12-14 of U.S. Patent No. 12281163 (Date of Patent 22 APR 2025) in view of Liu et al. (CN110305210A Date Published 2019-10-08), Xu(1) et al. (WO2017063162A1 Date Published 2017-04-20), Polesso et al. (Cancer Immunol Res (2019) 7 (2): 269–281), Gillies et al. (US20030166877A1 Date Published 2003-09-04), Fandl et al. (US20050158829A1 Date Published 2005-07-21) and Ghayur et al. (WO2014106015A2 Date Published 2014-07-03).
Patented claim 1 is drawn in part the same VHH domain CDRs for a PD-L1 antibody as instantly recited.
Patent claims do not specifically teach an isolated antigen-binding protein that comprises both a PD-L1 binding moiety and an OX40 binding moiety, or the amino acid sequences of the OX40 binding moiety, or linkers, or the format in which the PD-L1-binding moiety and OX40-binding moiety are linked together to form the fusion protein, or immunoconjugate comprising, nucleic acid molecules encoding, or a method of treating tumor using, said antigen-binding protein.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al. have been described in the 103 rejections above.
It would be obvious to generate an isolated antigen-binding protein of the combined method of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above and substituting the PD-L1 single-domain of the combined method with the VHH PD-L1 antibody as recited by the Patent, because Liu et al. teaches that the anti-OX40/PD-L1 bispecific antibody of Bi-119-112LC comprising the specific format and configuration of the first polypeptide chain and the second polypeptide chain taught in Figure 1D can be produced and have 94.79% purity, Xu(1) et al. teaches that the claimed anti-OX40 antibody has good specificity, high affinity and low immunogenicity for activating T cells to effect significant inhibitory effect on tumor growth (paragraph [0062]), and because Polesso et al. teaches that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells for promoting tumor regression (Abstract). In addition, combining PD-L1 and OX40 binding into a single antigen-binding protein in this format provides a molecule with four binding sites which increases avidity, and also would have the advantage of (i) simultaneously being present at the target tumor site at the same time in close proximity to form a physical “bridge” that recruits and activates OX40 receptors on immune cells only upon binding to PD-L1 that is highly expressed on tumor cells; and (ii) simplifying therapy with one administration of a single bispecific antibody, rather than two antibodies, for patient convenience. Also, because Gillies et al. teaches the human IgG1 heavy constant region (paragraph [0048] and Sequence Listing), and Fandl et al. teaches that the GAP linker produced bispecific scFv antigen-binding molecules that were capable of binding to their target antigens (paragraphs [0062] to [0064]) and because of the advantage of a flexible linker, ASTKGPSVFPLA, that is natural and thus has minimal immunogenicity as taught by Ghayur et al. (Pg. 177 first full paragraph and Table 76).
Fourth NSDP: U.S. Patent No. 11634492 - Maintained
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 remain rejected and claim 70 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5 and 12-14 of U.S. Patent No. 11634492 (Date of Patent 25 APR 2023) in view of Liu et al. (CN110305210A Date Published 2019-10-08), Xu(1) et al. (WO2017063162A1 Date Published 2017-04-20), Polesso et al. (Cancer Immunol Res (2019) 7 (2): 269–281), Gillies et al. (US20030166877A1 Date Published 2003-09-04), Fandl et al. (US20050158829A1 Date Published 2005-07-21) and Ghayur et al. (WO2014106015A2 Date Published 2014-07-03).
Patented claim 1 is drawn in part to the same VHH domain CDRs for a PD-L1 antibody as instantly recited.
Patent claims do not specifically teach an isolated antigen-binding protein that comprises both a PD-L1 binding moiety and an OX40 binding moiety, or the amino acid sequences of the OX40 binding moiety, or linkers, or the format in which the PD-L1-binding moiety and OX40-binding moiety are linked together to form the fusion protein, or immunoconjugate comprising, nucleic acid molecules encoding, or a method of treating tumor using, said antigen-binding protein.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al. have been described in the 103 rejections above.
It would be obvious to generate an isolated antigen-binding protein of the combined method of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above and substituting the PD-L1 single-domain of the combined method with the VHH PD-L1 antibody as recited by the Patent, because Liu et al. teaches that the anti-OX40/PD-L1 bispecific antibody of Bi-119-112LC comprising the specific format and configuration of the first polypeptide chain and the second polypeptide chain taught in Figure 1D can be produced and have 94.79% purity, Xu(1) et al. teaches that the claimed anti-OX40 antibody has good specificity, high affinity and low immunogenicity for activating T cells to effect significant inhibitory effect on tumor growth (paragraph [0062]), and because Polesso et al. teaches that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells for promoting tumor regression (Abstract). In addition, combining PD-L1 and OX40 binding into a single antigen-binding protein in this format provides a molecule with four binding sites which increases avidity, and also would have the advantage of (i) simultaneously being present at the target tumor site at the same time in close proximity to form a physical “bridge” that recruits and activates OX40 receptors on immune cells only upon binding to PD-L1 that is highly expressed on tumor cells; and (ii) simplifying therapy with one administration of a single bispecific antibody, rather than two antibodies, for patient convenience. Also, because Gillies et al. teaches the human IgG1 heavy constant region (paragraph [0048] and Sequence Listing), and Fandl et al. teaches that the GAP linker produced bispecific scFv antigen-binding molecules that were capable of binding to their target antigens (paragraphs [0062] to [0064]) and because of the advantage of a flexible linker, ASTKGPSVFPLA, that is natural and thus has minimal immunogenicity as taught by Ghayur et al. (Pg. 177 first full paragraph and Table 76).
Fifth NSDP: Copending Appln 18/691672 - Maintained
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 remain rejected and claim 70 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4 and 5 of copending Application No. 18/691672 in view of Liu et al. (CN110305210A Date Published 2019-10-08), Xu(1) et al. (WO2017063162A1 Date Published 2017-04-20), Polesso et al. (Cancer Immunol Res (2019) 7 (2): 269–281), Gillies et al. (US20030166877A1 Date Published 2003-09-04), Fandl et al. (US20050158829A1 Date Published 2005-07-21) and Ghayur et al. (WO2014106015A2 Date Published 2014-07-03).
Copending claim 1 is drawn in part to the same VHH domain and VHH CDRs for a PD-L1 antibody as instantly recited.
Copending claims do not specifically teach an isolated antigen-binding protein that comprises both a PD-L1 binding moiety and an OX40 binding moiety, or the amino acid sequences of the OX40 binding moiety, or linkers, or the format in which the PD-L1-binding moiety and OX40-binding moiety are linked together to form the fusion protein, or immunoconjugate comprising, nucleic acid molecules encoding, or a method of treating tumor using, said antigen-binding protein.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al. have been described in the 103 rejections above.
It would be obvious to generate an isolated antigen-binding protein of the combined method of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above and substituting the PD-L1 single-domain of the combined method with the VHH PD-L1 antibody as taught by the copending claims, because Liu et al. teaches that the anti-OX40/PD-L1 bispecific antibody of Bi-119-112LC comprising the specific format and configuration of the first polypeptide chain and the second polypeptide chain taught in Figure 1D can be produced and have 94.79% purity, Xu(1) et al. teaches that the claimed anti-OX40 antibody has good specificity, high affinity and low immunogenicity for activating T cells to effect significant inhibitory effect on tumor growth (paragraph [0062]), and because Polesso et al. teaches that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells for promoting tumor regression (Abstract). In addition, combining PD-L1 and OX40 binding into a single antigen-binding protein in this format provides a molecule with four binding sites which increases avidity, and also would have the advantage of (i) simultaneously being present at the target tumor site at the same time in close proximity to form a physical “bridge” that recruits and activates OX40 receptors on immune cells only upon binding to PD-L1 that is highly expressed on tumor cells; and (ii) simplifying therapy with one administration of a single bispecific antibody, rather than two antibodies, for patient convenience. Also, because Gillies et al. teaches the human IgG1 heavy constant region (paragraph [0048] and Sequence Listing), and Fandl et al. teaches that the GAP linker produced bispecific scFv antigen-binding molecules that were capable of binding to their target antigens (paragraphs [0062] to [0064]) and because of the advantage of a flexible linker, ASTKGPSVFPLA, that is natural and thus has minimal immunogenicity as taught by Ghayur et al. (Pg. 177 first full paragraph and Table 76).
This is a provisional nonstatutory double patenting rejection.
Sixth NSDP: Copending Appln 18/454006 – Maintained
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 remain rejected and claim 70 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 and 16 of copending application 18/454006 in view of Liu et al. (CN110305210A Date Published 2019-10-08), Xu(1) et al. (WO2017063162A1 Date Published 2017-04-20), Polesso et al. (Cancer Immunol Res (2019) 7 (2): 269–281), Gillies et al. (US20030166877A1 Date Published 2003-09-04), Fandl et al. (US20050158829A1 Date Published 2005-07-21) and Ghayur et al. (WO2014106015A2 Date Published 2014-07-03).
Copending claims 13 and 16 are drawn in part to the same VHH domain and VHH CDRs for a PD-L1 antibody as instantly recited.
Copending claims do not specifically teach an isolated antigen-binding protein that comprises both a PD-L1 binding moiety and an OX40 binding moiety, or the amino acid sequences of the OX40 binding moiety, or linkers, or the format in which the PD-L1-binding moiety and OX40-binding moiety are linked together to form the fusion protein, or immunoconjugate comprising, nucleic acid molecules encoding, or a method of treating tumor using, said antigen-binding protein.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al. have been described in the 103 rejections above.
It would be obvious to generate an isolated antigen-binding protein of the combined method of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above and substituting the PD-L1 single-domain of the combined method with the VHH PD-L1 antibody as taught by the copending claims, because Liu et al. teaches that the anti-OX40/PD-L1 bispecific antibody of Bi-119-112LC comprising the specific format and configuration of the first polypeptide chain and the second polypeptide chain taught in Figure 1D can be produced and have 94.79% purity, Xu(1) et al. teaches that the claimed anti-OX40 antibody has good specificity, high affinity and low immunogenicity for activating T cells to effect significant inhibitory effect on tumor growth (paragraph [0062]), and because Polesso et al. teaches that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells for promoting tumor regression (Abstract). In addition, combining PD-L1 and OX40 binding into a single antigen-binding protein in this format provides a molecule with four binding sites which increases avidity, and also would have the advantage of (i) simultaneously being present at the target tumor site at the same time in close proximity to form a physical “bridge” that recruits and activates OX40 receptors on immune cells only upon binding to PD-L1 that is highly expressed on tumor cells; and (ii) simplifying therapy with one administration of a single bispecific antibody, rather than two antibodies, for patient convenience. Also, because Gillies et al. teaches the human IgG1 heavy constant region (paragraph [0048] and Sequence Listing), and Fandl et al. teaches that the GAP linker produced bispecific scFv antigen-binding molecules that were capable of binding to their target antigens (paragraphs [0062] to [0064]) and because of the advantage of a flexible linker, ASTKGPSVFPLA, that is natural and thus has minimal immunogenicity as taught by Ghayur et al. (Pg. 177 first full paragraph and Table 76).
This is a provisional nonstatutory double patenting rejection.
Seventh NSDP: U.S. Patent No. 10624974 - Maintained
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 remain rejected and claim 70 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 10624974 (Date of Patent 21 APR 2020) in view of Liu et al. (CN110305210A Date Published 2019-10-08), Xu(2) et al. (US20180291103A1 Date Published 2018-10-11), Polesso et al. (Cancer Immunol Res (2019) 7 (2): 269–281), Gillies et al. (US20030166877A1 Date Published 2003-09-04), Fandl et al. (US20050158829A1 Date Published 2005-07-21) and Ghayur et al. (WO2014106015A2 Date Published 2014-07-03).
Patented claim 1 is drawn to the same VHCDRs and VLCDRs as well as the same VH domain for a OX4 antibody as instantly recited. Further, VL domain of patented SEQ ID NO: 74 has 99.5% identity match to instant OX40 binding moiety VL1 domain.
Patent claims do not specifically teach an isolated antigen-binding protein that comprises both an OX40 binding moiety and a PD-L1 binding moiety, or the amino acid sequences of the PD-L1 binding moiety, or linkers, or the format in which the OX40 antibody and the PD-L1-binding moiety and are linked together to form the fusion protein, or immunoconjugate comprising, nucleic acid molecules encoding, or a method of treating tumor using, said antigen-binding protein.
However, these deficiencies are made up in the teachings of Liu et al., Xu(2) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(2) et al., Polesso et al., Gillies et al., Fandl et al. and Ghayur et al. have been described in the 103 rejections above.
It would be obvious to generate an isolated antigen-binding protein of the combined method of Liu et al., Xu(2) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above and substituting the OX40 antibody of the combined method with the OX antibody as taught by the copending claims, because Liu et al. teaches that the anti-OX40/PD-L1 bispecific antibody of Bi-119-112LC comprising the specific format and configuration of the first polypeptide chain and the second polypeptide chain taught in Figure 1D can be produced and have 94.79% purity, Xu(2) et al. teaches that the single-domain anti-PD-L1 antibody of their invention has high affinity, high specificity and ability to inhibit tumor growth (paragraphs [0081] to [0083]), and because Polesso et al. teaches that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen-specific T cells for promoting tumor regression (Abstract). In addition, combining PD-L1 and OX40 binding into a single antigen-binding protein in this format provides a molecule with four binding sites which increases avidity, and also would have the advantage of (i) simultaneously being present at the target tumor site at the same time in close proximity to form a physical “bridge” that recruits and activates OX40 receptors on immune cells only upon binding to PD-L1 that is highly expressed on tumor cells; and (ii) simplifying therapy with one administration of a single bispecific antibody, rather than two antibodies, for patient convenience. Also, because Gillies et al. teaches the human IgG1 heavy constant region (paragraph [0048] and Sequence Listing), and Fandl et al. teaches that the GAP linker produced bispecific scFv antigen-binding molecules that were capable of binding to their target antigens (paragraphs [0062] to [0064]) and because of the advantage of a flexible linker, ASTKGPSVFPLA, that is natural and thus has minimal immunogenicity as taught by Ghayur et al. (Pg. 177 first full paragraph and Table 76).
Response to Arguments
In the reply of 06/29/2026, Applicant argues that the NSDP rejections are based on (i) defective Liu et al. premise; (ii) combined references are enable to predict the results of KN052-2; (iii) patent claims recite only one binding moiety and not result in the OX40/PD-L1 combination to provide cell bridging, synergistic IL-2 activation and the claimed KN052-2 antitumor results; (iv) unsupported assumption that combined binding sequences, formats, constant regions, and linkers could yield predictable results; (v) multiple substituted components that are assumed to yield claimed functional molecule; (vi) replacement of binding moieties that would not predictably yield KN052-2 properties; and/or (vii) parent monospecific components do not predict the properties of KN052-2 disclosed in the Examples.
Examiner’s Response: The arguments found in the Reply of 06/29/2026 have been carefully considered but are not deemed persuasive. This is because of the reasons described in Examiner’s Response to the maintained 103 rejections that are on Pg 12-14 of the instant Office Action. Therefore, the NSDP rejections have also been maintained.
Claim Objections – New
Claims 95 and 96 are objected as being dependent on a rejected base claim (claims 1).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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