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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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.
Status of Claims
Claims 1, 29, 30, 36, 40, 41, 44, 53, 57, 60, 66-71, 73 and 76 are currently pending.
Claims 1, 29, 30, 41, 68, 69 and 71 have been amended by Applicant.
Claims 1, 29, 30, 36, 40, 41, 44, 53, 57, 60 and 66-71 are under examination on the merits in the instant Office Action.
Claim Objections – Withdrawn
The objection of claims 1, 29, 30, 41, 68, 69, 71 has been withdrawn because said claims have been amended.
Claim Rejections - Withdrawn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30, 36, 40, 41, 44, 53, 57, 60 and 66-71 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), second paragraph has been withdrawn.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/new matter rejection of claims 1, 29, 30, 36, 40, 41, 44, 53, 57, 60 and 66-71 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been withdrawn.
New Objections
Claim Objections
Claims 1, 40, 53, 57 and 70 are objected to because of the following informalities:
Claim 1 is better recited if it includes the word “and” in line 10 to recite “…a heavy chain H1CDR2, as set forth in SEQ ID NO: 4, and the light chain variable domain….”.
Claim 1 is better recited if it includes the word “and” in line 13 to recite “….SEQ ID NO:11; and”.
Claim 1 is better recited if it includes the word “and” in line 17 to recite “….said PD-L1 binding moiety, and in said second polypeptide chain,….”.
Claim 57 is better recited if it includes the phrase “of said OX40 binding moiety” in line 3 to recite “…wherein said heavy chain H1 of said OX40 binding moiety is linked to said PD-L1 binding moiety through a linker,….”.
Appropriate correction is required.
Claims 40, 53 are objected to as being dependent on a rejected base claim (claim 1).
Claim 70 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent cannot depend from any other multiple dependent claims; in the instant case, the other multiple dependent claims are claims 67 and 69. See MPEP § 608.01(n). Accordingly, the claim has not been further treated on the merits.
New Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 29, 30, 36, 40, 41, 44, 53, 57, 60 and 66-71 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), 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-AlA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “the heavy chain H1 of said OX40 binding moiety” in lines 16-17. There is insufficient antecedent basis for " the heavy chain H1 of said OX40 binding moiety” in the claim. Further, claim 1 recites “the N-terminus of said heavy chain H1” and “the C-terminus of said PD-L1 binding moiety” lines 17 and 18. There is insufficient antecedent basis for “the N-terminus of said heavy chain H1” and “the C-terminus of said PD-L1 binding moiety” in the claim. Because all claims depend on claim 1, claims 29, 30, 36, 40, 41, 44, 53, 57, 60 and 66-71 are also rejected here.
Claim Rejections - 35 USC § 103 (first)
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.
Claims 1, 29, 30, 36, 41, 66, 67, 68, 69 and 71 are 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 this Office Action.
Liu et al. teaches a novel artificially designed antibody molecule, which comprises (i) a single domain antigen binding site; (ii) an antigen binding Fab fragment; wherein (i) is located at the N-terminus of a heavy chain variable domain (VH) of the (ii), wherein (i) and (ii) can bind different antigens, and wherein a linking peptide can be present between (i) and (ii),and an (iii) immunoglobulin Fc domain is positioned at the C-terminus of (i) and (ii) (Abstract). They teach polynucleotide encoding the antibody molecule, a vector comprising the polynucleotide, a host cell comprising the polynucleotide or the vector, an immunoconjugate comprising the antibody molecule, and a pharmaceutical composition comprising the antibody molecule for immunotherapy of a disease (Abstract). They teach a method of modulating an immune response in a subject or preventing the onset or recurrence of a disease in a subject, the method comprising administering to the subject a therapeutically effective or a prophylactically effective amount of the said antibody molecule (Pg. 58 first full paragraph). They also teach that cancers treated and/or prevented with said antibody molecules include, but are not limited to, solid tumors, hematological cancers and metastatic lesions (Pg. 58 third full paragraph).
Liu et al. teaches an anti-OX40/PD-L1 bispecific antibody that is capable of binding to both PD-L1 and OX40 proteins simultaneously, that is capable of blocking the PD-1/PD-L1 signaling pathway and activating the OX40/OX40 ligand signaling pathway in T cells and natural killer (NK) cells, as such can be used in the treatment, prevention or diagnosis of diseases associated with such signaling pathways (Pg. 45 first full paragraph, Table 1 and Table 2). They teach the bispecific antibody Bi-119-112LC that binds to PD-L1 and OX40 proteins in solution (Pg. 63 first full paragraph). They also teach the anti-OX40/PD-L1 bispecific antibody can comprise a human kappa light chain constant region or a human lambda light chain constant region, either 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. teaches based on the schematic diagram of Figure 1D (see below), the bispecific antibody Bi-122-112LC that 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, Figure 1D and claim 14). 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, and peptide chain #2 comprises the amino acid sequence as shown in SEQ ID NO: 17, wherein peptide chain #2 comprises, from the N-terminus to the C-terminus, the anti-PD-L1 single-domain antibody of SEQ ID NO: 2, the linker peptide amino acid sequence shown in SEQ ID NO: 9, the VH amino acid sequence of the anti-OX40 monoclonal antibody ADI-20112 as shown in SEQ ID NO: 11, the human IgG1 CH1 amino acid as shown in SEQ ID NO: 12 and the amino acid sequence of the human IgG1 Fc region as set forth in SEQ ID NO: 13 (Pg. 60-61 paragraph spanning, Pg. 42 first full paragraph, Figure 1D and claim 14).
Figure A: Schematic diagram of the anti-OX40/PD-L1 bispecific antibody taught by Liu et al. as shown in Figure 1D of Liu et al. Peptide chain #1 and peptide chain #2 are indicated on the left half of the diagram
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Alignment of the OX40-binding light chain sequence of SEQ ID NO: 15 as taught by Liu et al. with instant SEQ ID NO: 13 comprising the light chain constant region of instant OX40 binding moiety showed that residues 107 to 213 of SEQ ID NO: 15 of Liu et al. matches exactly with the entire 107 amino acid residues of instant SEQ ID NO: 13 (see Alignment 1).
Alignment 1: Alignment of instant SEQ ID NO: 13 (top; OX40 binding moiety light chain constant region) with SEQ ID NO: 15 as taught by Liu et al. which comprises the OX40 light chain constant region.
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Liu et al. does not specifically teach the bispecific antigen-binding protein wherein the heavy chain variable domain VH1 of the OX40 binding moiety comprises a heavy chain H1CDR3 as set forth in SEQ ID NO: 5, a heavy chain H1CDR1 as set forth in SEQ ID NO: 3, a heavy chain H1CDR2 as set forth in SEQ ID NO: 4, and the light chain variable domain VL1 of the OX40 binding moiety comprises a light chain L1CDR1 as set forth in SEQ ID NO: 9, a light chain L1CDR2 as set forth in SEQ ID NO: 10, a light chain L1CDR3 as set forth in SEQ ID NO: 11; and the PD-L1 binding moiety comprises an H2CDR3 as set forth in SEQ ID NO:45, an H2CDR1 as set forth in SEQ ID NO: 29, an H2CDR2 as set forth in SEQ ID NO: 36.
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 that can be used for the treatment of tumors (Abstract). They teach in Figure 7 the results of in vitro agonist activity detection of the anti-human OX40 antibody. They also teach that the anti-OX40 antibody comprises a heavy chain variable region as set forth in SEQ ID NO: 69 (claim 4). They further teach the anti-OX40 antibody comprises a light chain variable region having a sequence as set forth in SEQ ID NO: 74 (claim 7). Sequence alignment showed that instant H1CDR1, H1CDR2 and H1CDR3 as set forth in instant SEQ ID NO(s): 3, 4, and 5 are comprised within SEQ ID NO: 69 as taught by Xu(1) et al (see Alignment 2). Also, instant VH1 of SEQ ID NO: 6 matches completely with SEQ ID NO: 69 of Xu(1) et al. (see Alignment 3).
Alignment 2: Alignment of instant SEQ ID NOs: 3, 4 and 5 (top; H1CDRs of instant OX40 binding moiety) with SEQ ID NO: 69 as taught by Xu(1) et al. which comprises the OX40 VH domain.
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Alignment 3: Alignment of instant SEQ ID NO: 6 (top; VH1 of instant OX40 binding moiety) with SEQ ID NO: 69 as taught by Xu(1) et al. which comprises the OX40 VH domain.
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Further, a separate sequence alignment showed that instant L1CDR1, L1CDR2 and L1CDR3 of SEQ ID NO(s): 9, 10 and 11 are comprised within the SEQ ID NO: 74 as taught by Xu(1) et al. (see Alignment 4). Moreover, instant VL1 of SEQ ID NO: 12 is 99.5% identical to SEQ ID NO: 74 as taught by Xu(1) et al. wherein a single amino acid residue mismatch is present at the 4th from the last amino acid of both sequences (amino acid L of instant in contrast to amino acid V of Xu(1) et al.; see Alignment 5).
Alignment 4: Alignment of instant SEQ ID NOs: 9, 10 and 11 (top; VLCDRs of instant OX40 binding moiety) with SEQ ID NO: 74 as taught by Xu(1) et al. which comprises the OX40 VL domain.
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Alignment 5: Alignment of instant SEQ ID NO: 12 (top; VL1 of instant OX40 binding moiety) with SEQ ID NO: 69 as taught by Xu(1) et al. which comprises the OX40 VL domain.
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Xu(2) et al. teaches a single-domain antibody directed against PD-L1 that can be used for treating PD-L1 related diseases such as cancer (Abstract). They teach the single variable domain PD-L1-binding antibody comprises an amino acid sequence as set forth in SEQ ID NO: 2 (claim 1). Sequence alignment of instant H2CDR1, H2CDR2 and H2CDR3 of SEQ ID NO(s): 29, 36 and 45 respectively are comprised within SEQ ID NO: 2 as taught by Xu(2) et al (See Alignment 6). In addition, instant single-domain PD-L1 binding antibody comprising an amino acid sequence as set forth in instant SEQ ID NO: 53 matches exactly with SEQ ID NO: 2 as taught by Xu(2) et al. (see Alignment 7).
Alignment 6: Alignment of instant SEQ ID NOs: 29, 36 and 45 (top; H2CDRs of instant PD-L1 binding moiety) with SEQ ID NO: 2 as taught by Xu(2) et al. which comprises the single-domain PD-L1 antibody.
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Alignment 7: Alignment of instant SEQ ID NO: 53 (top; VH2 of instant PD-L1 binding moiety) with SEQ ID NO: 2 as taught by Xu(2) et al. which comprises the single-domain PD-L1 antibody.
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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 (namely the VL and light chain constant region) 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 and VL amino acid sequences as set forth in SEQ ID NOs: 69 and 74 as taught by Xu et al. which comprises instant H1CDR1, H1CDR2 and H1CDR3 and instant L1CDR1, L1CDR2 and L1CDR3, and further substituting the PD-L1 single-domain antibody of Liu et al. with the SEQ ID NO:2 as taught by Xu(2) et al. which comprises instant H2CDR1, H2CDR2 and H2CDR3, 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 effectively induce cross-linking of CHO-PD-L1 cells and CHO-OX40 cells (Pg. 65 fifth full paragraph), Xu(1) et al. teaches that their 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 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 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). This is an example of (B) Simple substitution of one known element for another to obtain predictable results; (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)
Claims 1, 29, 30, 36, 41, 44, 66, 67, 68, 69 and 71 are 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 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 and 71 as 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 the bispecific OX40/PD-L1-binding protein wherein the OX40 binding moiety comprising a light chain constant region as set forth in instant SEQ ID NO: 13, further comprises a heavy chain constant region that comprises an amino acid sequence as set forth in 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). Sequence alignment showed that 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.
Alignment 8: Alignment of instant SEQ ID NO: 7 (top; heavy chain constant region) with SEQ ID NO: 1 as taught by Gillies et al. which is the human IgG1 heavy chain constant region.
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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 OX40 monoclonal antibody that comprises human IgG1 CH1 (SEQ ID NO: 12) and human IgG1 Fc (SEQ ID NO: 13) 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)
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 are 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 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 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 antigen-binding protein according to instant claim 1, wherein the heavy chain H1 is linked to said PD-L1 binding moiety through a linker; wherein said linker comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 14-15; or wherein the second polypeptide chain comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 17-20.
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 linkers used for the construction of antibody molecules that link the VH and VL domains, wherein one such linker is the amino acid peptide linker of ASTKGPSVFPLA named Elbow VH12 , which is comprised within the IgG1 constant region (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. would produce the linker sequence of ASTKGPSVFPLAGAP that is be identical to the amino acid sequence of the instant linker of 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 including 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 Ghayur et al. teaches that natural flexible linkage between the antibody variable domain and the CH1/CL constant domain include the sequence of ASTKGPSVFPLA that can act as flexible linkers between two variable domains, and also teaches that because this linker is part of the natural IgG sequence, it would have minimal immunogenicity compared to other linker peptides when used at junctions of fusion proteins (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; or to generate 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.
Claim Rejections - 35 USC § 112
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 60 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
Claim 60 recites “The isolated antigen-binding protein according to claim 1, wherein said second polypeptide chain comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 17-20.”. A close inspection of instant SEQ ID NOs: 19 and 20 shows that in both these sequences, the C-terminus of the heavy chain H1 is linked to the N-terminus of the PD-L1 binding moiety, rather than the recited limitation in claim 1 of “said second polypeptide chain, the N-terminus of said heavy chain H1 is linked to the C-terminus of said PD-L1 binding moiety…” wherein claim 60 depends on claim 1. Descriptions of constructs of claim 1 comprising SEQ ID NO:19 or SEQ ID NO:20 are not found in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventors, at the time the invention was filed, had possession of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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First NSDP: U.S. Patent No. 11225522
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 are 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 a PDL1 antibody that comprises an immunoglobulin single variable domain which is a VHH domain. The VHH amino acid sequence of patented SEQ ID NO: 33 (claim 3) is an exact match to the PD-L1 VHH domain of the instant SEQ ID NO: 53. The VHCDR1, VHCDR2 and VHCDR3 as set forth in instant SEQ ID NO(s): 29, 36 and 45 are comprised within the VHH amino acid sequences of patented SEQ ID NO(s): 28, 35 and 37 (claims 2 and 3).
Patent claims do not specifically teach an isolated antigen-binding protein, comprising a PD-L1 binding moiety and an OX40 binding moiety, wherein: the isolated antigen-binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein, said first polypeptide chain comprises a light chain variable domain VL1 of said OX40 binding moiety, said second polypeptide chain comprises a heavy chain variable domain VH1 of said OX40 binding moiety and said PD-L1 binding moiety; the heavy chain variable domain VH1 of said OX40 binding moiety comprises a heavy chain H1CDR3 as set forth in SEQ ID NO: 5, a heavy chain H1CDR1 as set forth in SEQ ID NO: 3, a heavy chain H1CDR2, as set forth in SEQ ID NO: 4, the light chain variable domain VL1 of said OX40 binding moiety comprises a light chain L1CDR1 as set forth in SEQ ID NO: 9, a light chain L1CDR2 as set forth in SEQ ID NO: 10, a light chain L1CDR3 as set forth in SEQ ID NO: 11; wherein said second polypeptide chain comprises the heavy chain H1 of said OX40 binding moiety and said PD-L1 binding moiety, in said second polypeptide chain, the N-terminus of said heavy chain H1 is linked to the C-terminus of said PD-L1 binding moiety directly or indirectly.
Patent claims also do not specifically teach wherein said OX40 binding moiety comprises a heavy chain variable domain VH1, said VH1 comprises an amino acid sequence as set forth in instant SEQ ID NO: 6; or wherein said OX40 binding moiety comprises a light chain constant region, said light chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 13; or wherein the antigen-binding protein according to instant claim 41 further comprises a heavy chain constant region, said heavy chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 7; or wherein said heavy chain H1 is linked to said PD-L1 binding moiety through a linker; wherein said linker comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 14-15; or wherein said second polypeptide chain comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 17-20.
Patent claims further do not specifically teach an immunoconjugate comprising the isolated antigen-binding protein according to instant claim 1; or an isolated cell or an isolated vector comprising isolated nucleic acid molecules encoding the isolated antigen-binding protein according to instant claim 1; or a method of treating tumor comprising administering to a human subject with tumor expressing human PD-L1 and human OX40 the isolated antigen-binding protein according to instant claim 1; wherein said tumor is selected from a group consisting of: blood tumor and solid tumor.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) 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 by substituting the PD-L1 single variable domain as recited by the Patent for the single-domain PD-L1 binding site as taught by Liu et al. comprised within the bispecific PD-L1/OX40 binding antibody molecule generated by performing the combined methods of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above 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 effectively induce cross-linking of CHO-PD-L1 cells and CHO-OX40 cells (Pg. 65 fifth full paragraph), Xu(1) et al. teaches that their 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 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), 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 further Ghayur et al. teaches that natural flexible linkage between the antibody variable domain and the CH1/CL constant domain include the sequence of ASTKGPSVFPLA that can act as flexible linkers between two variable domains, and also teaches that because this linker is part of the natural IgG sequence, it would have minimal immunogenicity compared to other linker peptides when used at junctions of fusion proteins (Pg. 177 first full paragraph and Table 76).
Second NSDP: U.S. Patent No. 11377497
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 are 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 an isolated polypeptide which is capable of specifically binding to human PD-L1, wherein the PD-L1 binding antibody comprises SEQ ID NO:1. The instant H2CDR1, H2CDR2 and H2CDR3 of instant SEQ ID NO(s): 29, 36 and 45 are comprised within the amino acid sequence of patented SEQ ID NO: 1.
Patent claims do not specifically teach an isolated antigen-binding protein, comprising a PD-L1 binding moiety and an OX40 binding moiety, wherein: the isolated antigen-binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein, said first polypeptide chain comprises a light chain variable domain VL1 of said OX40 binding moiety, said second polypeptide chain comprises a heavy chain variable domain VH1 of said OX40 binding moiety and said PD-L1 binding moiety; the heavy chain variable domain VH1 of said OX40 binding moiety comprises a heavy chain H1CDR3 as set forth in SEQ ID NO: 5, a heavy chain H1CDR1 as set forth in SEQ ID NO: 3, a heavy chain H1CDR2, as set forth in SEQ ID NO: 4, the light chain variable domain VL1 of said OX40 binding moiety comprises a light chain L1CDR1 as set forth in SEQ ID NO: 9, a light chain L1CDR2 as set forth in SEQ ID NO: 10, a light chain L1CDR3 as set forth in SEQ ID NO: 11; wherein said second polypeptide chain comprises the heavy chain H1 of said OX40 binding moiety and said PD-L1 binding moiety, in said second polypeptide chain, the N-terminus of said heavy chain H1 is linked to the C-terminus of said PD-L1 binding moiety directly or indirectly.
Patent claims also do not specifically teach wherein said OX40 binding moiety comprises a heavy chain variable domain VH1, said VH1 comprises an amino acid sequence as set forth in instant SEQ ID NO: 6; or wherein said OX40 binding moiety comprises a light chain constant region, said light chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 13; or wherein the antigen-binding protein according to instant claim 41 further comprises a heavy chain constant region, said heavy chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 7; or wherein said heavy chain H1 is linked to said PD-L1 binding moiety through a linker; wherein said linker comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 14-15; or wherein said second polypeptide chain comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 17-20.
Patent claims further do not specifically teach an immunoconjugate comprising the isolated antigen-binding protein according to instant claim 1; or an isolated cell or an isolated vector comprising isolated nucleic acid molecules encoding the isolated antigen-binding protein according to instant claim 1; or a method of treating tumor comprising administering to a human subject with tumor expressing human PD-L1 and human OX40 the isolated antigen-binding protein according to instant claim 1; wherein said tumor is selected from a group consisting of: blood tumor and solid tumor.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) 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 by substituting the PD-L1 single variable domain as recited by the Patent for the single-domain PD-L1 binding site as taught by Liu et al. that is comprised within the bispecific PD-L1/OX40 binding antibody molecule generated by performing the combined methods of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above 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 effectively induce cross-linking of CHO-PD-L1 cells and CHO-OX40 cells (Pg. 65 fifth full paragraph), Xu(1) et al. teaches that their 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 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), 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 further Ghayur et al. teaches that natural flexible linkage between the antibody variable domain and the CH1/CL constant domain include the sequence of ASTKGPSVFPLA that can act as flexible linkers between two variable domains, and also teaches that because this linker is part of the natural IgG sequence, it would have minimal immunogenicity compared to other linker peptides when used at junctions of fusion proteins (Pg. 177 first full paragraph and Table 76).
Third NSDP: U.S. Patent No. 12281163
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 are 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).
The patented claim 1 is drawn in part to an immunoglobulin single variable domain (ISVD) that is specific for PD-L1. The heavy chain variable domain of the PD-L1 ISVD comprises an amino acid sequence as set forth in SEQ ID NOs: 6, 13, 14 and 15 (claim 5).
Patented SEQ ID NOs: 6, 13, 14 and 15 comprises instant H2CDR1, H2CDR2 and H2CDR3 of instant SEQ ID NO(s): 29, 36 and 45. Further, patented SEQ ID NO 6 is an exact match to the PD-L1 binding domain of instant SEQ ID NO: 53.
Patent claims do not specifically teach an isolated antigen-binding protein, comprising a PD-L1 binding moiety and an OX40 binding moiety, wherein: the isolated antigen-binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein, said first polypeptide chain comprises a light chain variable domain VL1 of said OX40 binding moiety, said second polypeptide chain comprises a heavy chain variable domain VH1 of said OX40 binding moiety and said PD-L1 binding moiety; the heavy chain variable domain VH1 of said OX40 binding moiety comprises a heavy chain H1CDR3 as set forth in SEQ ID NO: 5, a heavy chain H1CDR1 as set forth in SEQ ID NO: 3, a heavy chain H1CDR2, as set forth in SEQ ID NO: 4, the light chain variable domain VL1 of said OX40 binding moiety comprises a light chain L1CDR1 as set forth in SEQ ID NO: 9, a light chain L1CDR2 as set forth in SEQ ID NO: 10, a light chain L1CDR3 as set forth in SEQ ID NO: 11; wherein said second polypeptide chain comprises the heavy chain H1 of said OX40 binding moiety and said PD-L1 binding moiety, in said second polypeptide chain, the N-terminus of said heavy chain H1 is linked to the C-terminus of said PD-L1 binding moiety directly or indirectly.
Patent claims also do not specifically teach wherein said OX40 binding moiety comprises a heavy chain variable domain VH1, said VH1 comprises an amino acid sequence as set forth in instant SEQ ID NO: 6; or wherein said OX40 binding moiety comprises a light chain constant region, said light chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 13; or wherein the antigen-binding protein according to instant claim 41 further comprises a heavy chain constant region, said heavy chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 7; or wherein said heavy chain H1 is linked to said PD-L1 binding moiety through a linker; wherein said linker comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 14-15; or wherein said second polypeptide chain comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 17-20.
Patent claims further do not specifically teach an isolated cell or an isolated vector comprising isolated nucleic acid molecules encoding the isolated antigen-binding protein according to instant claim 1.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) 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 by substituting the PD-L1 single variable domain as recited by the Patent for the single-domain PD-L1 binding site as taught by Liu et al. that is comprised within the bispecific PD-L1/OX40 binding antibody molecule generated by performing the combined methods of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above 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 effectively induce cross-linking of CHO-PD-L1 cells and CHO-OX40 cells (Pg. 65 fifth full paragraph), Xu(1) et al. teaches that their 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 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), 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 further Ghayur et al. teaches that natural flexible linkage between the antibody variable domain and the CH1/CL constant domain include the sequence of ASTKGPSVFPLA that can act as flexible linkers between two variable domains, and also teaches that because this linker is part of the natural IgG sequence, it would have minimal immunogenicity compared to other linker peptides when used at junctions of fusion proteins (Pg. 177 first full paragraph and Table 76).
Fourth NSDP: U.S. Patent No. 11634492
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 are 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).
The patented claim 1 is drawn in part to an immunoglobulin single variable domain (ISVD) that is specific for PD-L1. The heavy chain variable domain of the PD-L1 ISVD comprises an amino acid sequence as set forth in SEQ ID NOs: 6, 13, 14 and 15 (claim 5).
Patented SEQ ID NOs: 6, 13, 14 and 15 comprises instant H2CDR1, H2CDR2 and H2CDR3 of instant SEQ ID NO(s): 29, 36 and 45. Further, patented SEQ ID NO 6 is an exact match to the PD-L1 binding domain of instant SEQ ID NO: 53.
Patent claims do not specifically teach an isolated antigen-binding protein, comprising a PD-L1 binding moiety and an OX40 binding moiety, wherein: the isolated antigen-binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein, said first polypeptide chain comprises a light chain variable domain VL1 of said OX40 binding moiety, said second polypeptide chain comprises a heavy chain variable domain VH1 of said OX40 binding moiety and said PD-L1 binding moiety; the heavy chain variable domain VH1 of said OX40 binding moiety comprises a heavy chain H1CDR3 as set forth in SEQ ID NO: 5, a heavy chain H1CDR1 as set forth in SEQ ID NO: 3, a heavy chain H1CDR2, as set forth in SEQ ID NO: 4, the light chain variable domain VL1 of said OX40 binding moiety comprises a light chain L1CDR1 as set forth in SEQ ID NO: 9, a light chain L1CDR2 as set forth in SEQ ID NO: 10, a light chain L1CDR3 as set forth in SEQ ID NO: 11; wherein said second polypeptide chain comprises the heavy chain H1 of said OX40 binding moiety and said PD-L1 binding moiety, in said second polypeptide chain, the N-terminus of said heavy chain H1 is linked to the C-terminus of said PD-L1 binding moiety directly or indirectly.
Patent claims also do not specifically teach wherein said OX40 binding moiety comprises a heavy chain variable domain VH1, said VH1 comprises an amino acid sequence as set forth in instant SEQ ID NO: 6; or wherein said OX40 binding moiety comprises a light chain constant region, said light chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 13; or wherein the antigen-binding protein according to instant claim 41 further comprises a heavy chain constant region, said heavy chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 7; or wherein said heavy chain H1 is linked to said PD-L1 binding moiety through a linker; wherein said linker comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 14-15; or wherein said second polypeptide chain comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 17-20.
Patent claims further do not specifically teach an isolated cell or an isolated vector comprising isolated nucleic acid molecules encoding the isolated antigen-binding protein according to instant claim 1.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) 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 by substituting the PD-L1 single variable domain as recited by the Patent for the single-domain PD-L1 binding site as taught by Liu et al. that is comprised within the bispecific PD-L1/OX40 binding antibody molecule generated by performing the combined methods of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above 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 effectively induce cross-linking of CHO-PD-L1 cells and CHO-OX40 cells (Pg. 65 fifth full paragraph), Xu(1) et al. teaches that their 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 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), 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 further Ghayur et al. teaches that natural flexible linkage between the antibody variable domain and the CH1/CL constant domain include the sequence of ASTKGPSVFPLA that can act as flexible linkers between two variable domains, and also teaches that because this linker is part of the natural IgG sequence, it would have minimal immunogenicity compared to other linker peptides when used at junctions of fusion proteins (Pg. 177 first full paragraph and Table 76).
Fifth NSDP: Copending Appln 18/691672
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 are 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 an antigen-binding fragment that comprises an immunoglobulin single variable domain capable of specifically binding to PD-L1 and comprising CDR1-3, wherein CDR1 comprises an amino acid sequence set forth in SEQ ID NO: 48, CDR2 comprises an amino acid sequence set forth in SEQ ID NO: 46, and the CDR3 comprises an amino acid sequence set forth in SEQ ID NO: 47. The immunoglobulin single variable domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-6 (claim 4).
Copending PD-L1 binding single variable domain comprising CDR1, CDR2 and the CDR3 as set forth in SEQ ID NOs: 48, 46 and 47 match exactly with instant H2CDR1, H2CDR2 and H2CDR3 of instant SEQ ID NO(s): 29, 36 and 45 respectively. In addition, copending SEQ ID NOs: 2 and 4 comprises instant H2CDR1, H2CDR2 and H2CDR3 of instant SEQ ID NO(s): 29, 36 and 45. Further, copending SEQ ID NO: 2 is an exact match to the PD-L1 binding domain of instant SEQ ID NO: 53.
Copending claims do not specifically teach an isolated antigen-binding protein, comprising a PD-L1 binding moiety and an OX40 binding moiety, wherein: the isolated antigen-binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein, said first polypeptide chain comprises a light chain variable domain VL1 of said OX40 binding moiety, said second polypeptide chain comprises a heavy chain variable domain VH1 of said OX40 binding moiety and said PD-L1 binding moiety; the heavy chain variable domain VH1 of said OX40 binding moiety comprises a heavy chain H1CDR3 as set forth in SEQ ID NO: 5, a heavy chain H1CDR1 as set forth in SEQ ID NO: 3, a heavy chain H1CDR2, as set forth in SEQ ID NO: 4, the light chain variable domain VL1 of said OX40 binding moiety comprises a light chain L1CDR1 as set forth in SEQ ID NO: 9, a light chain L1CDR2 as set forth in SEQ ID NO: 10, a light chain L1CDR3 as set forth in SEQ ID NO: 11; wherein said second polypeptide chain comprises the heavy chain H1 of said OX40 binding moiety and said PD-L1 binding moiety, in said second polypeptide chain, the N-terminus of said heavy chain H1 is linked to the C-terminus of said PD-L1 binding moiety directly or indirectly.
Copending claims also do not specifically teach wherein said OX40 binding moiety comprises a heavy chain variable domain VH1, said VH1 comprises an amino acid sequence as set forth in instant SEQ ID NO: 6; or wherein said OX40 binding moiety comprises a light chain constant region, said light chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 13; or wherein the antigen-binding protein according to instant claim 41 further comprises a heavy chain constant region, said heavy chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 7; or wherein said heavy chain H1 is linked to said PD-L1 binding moiety through a linker; wherein said linker comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 14-15; or wherein said second polypeptide chain comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 17-20.
Copending claims further do not specifically teach an immunoconjugate comprising the isolated antigen-binding protein according to instant claim 1; or an isolated cell or an isolated vector comprising isolated nucleic acid molecules encoding the isolated antigen-binding protein according to instant claim 1; or a method of treating tumor comprising administering to a human subject with tumor expressing human PD-L1 and human OX40 the isolated antigen-binding protein according to instant claim 1; wherein said tumor is selected from a group consisting of: blood tumor and solid tumor.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) 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 by substituting the PD-L1 single variable domain as disclosed by the copending application for the single-domain PD-L1 binding site as taught by Liu et al. that is comprised within the bispecific PD-L1/OX40 binding antibody molecule generated by performing the combined methods of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above 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 effectively induce cross-linking of CHO-PD-L1 cells and CHO-OX40 cells (Pg. 65 fifth full paragraph), Xu(1) et al. teaches that their 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 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), 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 further Ghayur et al. teaches that natural flexible linkage between the antibody variable domain and the CH1/CL constant domain include the sequence of ASTKGPSVFPLA that can act as flexible linkers between two variable domains, and also teaches that because this linker is part of the natural IgG sequence, it would have minimal immunogenicity compared to other linker peptides when used at junctions of fusion proteins (Pg. 177 first full paragraph and Table 76).
This is a provisional nonstatutory double patenting rejection.
Sixth NSDP: Copending Appln 18/454006
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 are 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 an immunoglobulin single variable domain (ISVD) that is specific for PD-L1, wherein CDR1 comprises an amino acid sequence set forth in SEQ ID NO: 3, CDR2 comprises an amino acid sequence set forth in SEQ ID NO: 5, and the CDR3 comprises an amino acid sequence set forth in SEQ ID NO: 4. The ISVD specific for PD-L1 comprises a heavy chain variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NO: 6, 13, 14 and 15 (claims 13 and 16)
Copending PD-L1 binding single variable domain comprising CDR1, CDR2 and the CDR3 as set forth in SEQ ID NOs: 3, 5 and 4 match exactly with instant H2CDR1, H2CDR2 and H2CDR3 of instant SEQ ID NO(s): 29, 36 and 45 respectively. In addition, copending SEQ ID NOs: 6, 13, 14 and 15 comprise instant H2CDR1, H2CDR2 and H2CDR3 of instant SEQ ID NO(s): 29, 36 and 45. Further, copending SEQ ID NO: 6 is an exact match to the PD-L1 binding domain of instant SEQ ID NO: 53.
Copending claims do not specifically teach an isolated antigen-binding protein, comprising a PD-L1 binding moiety and an OX40 binding moiety, wherein: the isolated antigen-binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein, said first polypeptide chain comprises a light chain variable domain VL1 of said OX40 binding moiety, said second polypeptide chain comprises a heavy chain variable domain VH1 of said OX40 binding moiety and said PD-L1 binding moiety; the heavy chain variable domain VH1 of said OX40 binding moiety comprises a heavy chain H1CDR3 as set forth in SEQ ID NO: 5, a heavy chain H1CDR1 as set forth in SEQ ID NO: 3, a heavy chain H1CDR2, as set forth in SEQ ID NO: 4, the light chain variable domain VL1 of said OX40 binding moiety comprises a light chain L1CDR1 as set forth in SEQ ID NO: 9, a light chain L1CDR2 as set forth in SEQ ID NO: 10, a light chain L1CDR3 as set forth in SEQ ID NO: 11; wherein said second polypeptide chain comprises the heavy chain H1 of said OX40 binding moiety and said PD-L1 binding moiety, in said second polypeptide chain, the N-terminus of said heavy chain H1 is linked to the C-terminus of said PD-L1 binding moiety directly or indirectly.
Copending claims also do not specifically teach wherein said OX40 binding moiety comprises a heavy chain variable domain VH1, said VH1 comprises an amino acid sequence as set forth in instant SEQ ID NO: 6; or wherein said OX40 binding moiety comprises a light chain constant region, said light chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 13; or wherein the antigen-binding protein according to instant claim 41 further comprises a heavy chain constant region, said heavy chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 7; or wherein said heavy chain H1 is linked to said PD-L1 binding moiety through a linker; wherein said linker comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 14-15; or wherein said second polypeptide chain comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 17-20.
Copending claims further do not specifically teach an immunoconjugate comprising the isolated antigen-binding protein according to instant claim 1; or an isolated cell or an isolated vector comprising isolated nucleic acid molecules encoding the isolated antigen-binding protein according to instant claim 1; or a method of treating tumor comprising administering to a human subject with tumor expressing human PD-L1 and human OX40 the isolated antigen-binding protein according to instant claim 1; wherein said tumor is selected from a group consisting of: blood tumor and solid tumor.
However, these deficiencies are made up in the teachings of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(1) 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 by substituting the PD-L1 single variable domain as disclosed by the copending application for the single-domain PD-L1 binding site as taught by Liu et al. that is comprised within the bispecific PD-L1/OX40 binding antibody molecule generated by performing the combined methods of Liu et al., Xu(1) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above 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 effectively induce cross-linking of CHO-PD-L1 cells and CHO-OX40 cells (Pg. 65 fifth full paragraph), Xu(1) et al. teaches that their 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 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), 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 further Ghayur et al. teaches that natural flexible linkage between the antibody variable domain and the CH1/CL constant domain include the sequence of ASTKGPSVFPLA that can act as flexible linkers between two variable domains, and also teaches that because this linker is part of the natural IgG sequence, it would have minimal immunogenicity compared to other linker peptides when used at junctions of fusion proteins (Pg. 177 first full paragraph and Table 76).
This is a provisional nonstatutory double patenting rejection.
Seventh NSDP: U.S. Patent No. 10624974
Claims 1, 29, 30, 36, 41, 44, 57, 60, 66, 67, 68, 69 and 71 are 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 an anti-OX40 antibody or an antigen-binding part thereof with recited heavy chain variable region CDR1, CDR2 and CDR3 and recited light chain variable region CDR1, CDR2 and CDR3. The heavy chain variable region comprises a sequence selected from the group consisting of SEQ ID NO(s): 4, 22, 40, 62, 66, 69, 72 and 79 (claim 2), while the light chain variable region comprises a sequence selected from the group consisting of SEQ ID NO(s): 13, 31, 49 and 74 (claim 3).
The instant H1CDR1, H1CDR2 and H1CDR3 as set forth in instant SEQ ID NO(s): 3, 4 and 5 are comprised within patented VH SEQ ID NO: 69. The VH amino acid sequence of patented SEQ ID NO: 69 is also an exact match to the instant OX40 binding moiety VH1 domain of instant SEQ ID NO: 6. In addition, the L1CDR1, L1CDR2 and L1CDR3 of instant SEQ ID NO(s): 9, 10 and 11 are comprised within the amino acid sequence of patented SEQ ID NO: 74. Further, the amino acid sequence of patented SEQ ID NO: 74 has 99.5% identity match to the instant OX40 binding moiety VL1 domain comprising amino acid sequence as set forth in instant SEQ ID NO: 12.
Patent claims do not specifically teach an isolated antigen-binding protein, comprising a PD-L1 binding moiety and an OX40 binding moiety, wherein: the isolated antigen-binding protein comprises a first polypeptide chain and a second polypeptide chain, wherein, said first polypeptide chain comprises a light chain variable domain VL1 of said OX40 binding moiety, said second polypeptide chain comprises a heavy chain variable domain VH1 of said OX40 binding moiety and said PD-L1 binding moiety; the heavy chain variable domain VH1 of said OX40 binding moiety comprises a heavy chain H1CDR3 as set forth in SEQ ID NO: 5, a heavy chain H1CDR1 as set forth in SEQ ID NO: 3, a heavy chain H1CDR2, as set forth in SEQ ID NO: 4, the light chain variable domain VL1 of said OX40 binding moiety comprises a light chain L1CDR1 as set forth in SEQ ID NO: 9, a light chain L1CDR2 as set forth in SEQ ID NO: 10, a light chain L1CDR3 as set forth in SEQ ID NO: 11; wherein said second polypeptide chain comprises the heavy chain H1 of said OX40 binding moiety and said PD-L1 binding moiety, in said second polypeptide chain, the N-terminus of said heavy chain H1 is linked to the C-terminus of said PD-L1 binding moiety directly or indirectly.
Patent claims also do not specifically teach wherein said OX40 binding moiety comprises a heavy chain variable domain VH1, said VH1 comprises an amino acid sequence as set forth in instant SEQ ID NO: 6; or wherein said OX40 binding moiety comprises a light chain constant region, said light chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 13; or wherein the antigen-binding protein according to instant claim 41 further comprises a heavy chain constant region, said heavy chain constant region comprises an amino acid sequence as set forth in instant SEQ ID NO: 7; or wherein said heavy chain H1 is linked to said PD-L1 binding moiety through a linker; wherein said linker comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 14-15; or wherein said second polypeptide chain comprises an amino acid sequence as set forth in any one of instant SEQ ID NOs: 17-20.
Patent claims further do not specifically teach an immunoconjugate comprising the isolated antigen-binding protein according to instant claim 1; or an isolated cell or an isolated vector comprising isolated nucleic acid molecules encoding the isolated antigen-binding protein according to instant claim 1; or a method of treating tumor comprising administering to a human subject with tumor expressing human PD-L1 and human OX40 the isolated antigen-binding protein according to instant claim 1; wherein said tumor is selected from a group consisting of: blood tumor and solid tumor.
However, these deficiencies are made up in the teachings of Liu et al., Xu(2) et al., Gillies et al., Fandl et al. and Ghayur et al.
The teachings of Liu et al., Xu(2) 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 by substituting the OX40 binding part as recited by the Patent for the OX40 binding site as taught by Liu et al. comprised within the bispecific PD-L1/OX40 binding antibody molecule generated by performing the combined methods of Liu et al., Xu(2) et al., Gillies et al., Fandl et al. and Ghayur et al. as described above 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 effectively induce cross-linking of CHO-PD-L1 cells and CHO-OX40 cells (Pg. 65 fifth full paragraph), 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 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), 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 further Ghayur et al. teaches that natural flexible linkage between the antibody variable domain and the CH1/CL constant domain include the sequence of ASTKGPSVFPLA that can act as flexible linkers between two variable domains, and also teaches that because this linker is part of the natural IgG sequence, it would have minimal immunogenicity compared to other linker peptides when used at junctions of fusion proteins (Pg. 177 first full paragraph and Table 76).
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642