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 .
Detailed Action
The Amendments and Remarks filed 7/28/26 in response to the Office Action of 5/12/26 are acknowledged and have been entered.
Claims 1, 5, 8, 9, 15, 16, 22, 26, 27, 30, 31, 35, 37, 39, and 40 are pending.
Claims 1, 5, 8, 9, 15, 16, 22, 26, and 30 have been amended by Applicant.
Claims 1, 5, 8, 9, 15, 16, 22, 26, 27, 30, 31, 35, 37, 39, and 40 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
Rejections Withdrawn
The rejection of claims under 35 U.S.C. 102(a)(2) as being anticipated by Feng et al (US 2022/0073620 A1; 3/10/22), as evidenced by Juneja et al (JEM, 2017, 214(4): 895-904) is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 102
Claim(s) 1, 9, 15, 22, 27, 31, 35, 37, 39, and 40 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tian et al (US 2020/0172623 A1; 6/4/20; 12/15/23 IDS).
Tian et al teaches a bispecific fusion protein comprising first binding domains and second binding domains, where the first binding domains comprise an antibody that specifically binds PD-L1 and the antibody comprises a first light chain, a second light chain, a first heavy chain, and a second heavy chain, wherein the light chains and heavy chains are linked by disulfide bonds, and wherein the second binding domains each comprise an extracellular Ig-like domain of VEGFR, wherein N-terminus of each Ig-like domain of VEGFR is linked via a linker to the C-terminus of a heavy chain (see Abstract, [0025], and Fig. 1, in particular). See IMM260111 of Figure 1:
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Tian et al further teaches said bispecific fusion protein wherein VEGFR of the Ig-like domain of VEGFR is VEGFR1 and VEGFR2 (see the “first aspect” at [0020] and “The VEGFR describe in the first aspect and the second aspect may be VEGFR1 and/or VEGFR2….” at [0032], in particular). At [0032], Tian et al further teaches said bispecific fusion protein wherein the Ig-like domain of VEGFR1 is VEGFR1D2 and the Ig-like domain of VEGFR2 is VEGFR2D2. Tian et al further teaches said bispecific fusion protein wherein the anti-PD-L1 antibody light chain comprises SEQ ID NO:18 and the heavy chain comprises SEQ ID NO:2 ([0091], in particular). SEQ ID NO:18 comprises CDRs of instant SEQ ID NOs:4-6 and instant SEQ ID NO:16. SEQ ID NO:2 comprises CDRs of instant SEQ ID NOs:7-9 and instant SEQ ID NO:18. Tian et al further teaches a pharmaceutical composition comprising said bispecific fusion protein and a pharmaceutically acceptable carrier ([0069], in particular). Tian et al further teaches a nucleic acid encoding the bispecific fusion protein ([0083], in particular). Tian et al further teaches a method of treating solid (such as breast cancer) and not solid tumors expressing PD-L1 comprising administering the bispecific fusion protein to a subject in need thereof ([0085] and claims 18-19, in particular).
Response to Arguments
In the Reply of 7/28/26, Applicant argues Tian et al does not teach a claimed bispecific fusion protein comprising both an Ig-like domain VEFR1 and an Ig-like domain of VEGFR2. Applicant further argues Tian et al’s generic language “VEGFR1 and/or VEGFR2” does not disclose a combination of VEGFR1 D2 and VEGFR2 D3 recited in the present claims. Applicant further argues IMM25031 of Tian et al differs from claimed bispecific fusion proteins.
The amendments to the claims and the arguments found in the Reply of 7/28/26 have been carefully considered, but are not deemed persuasive. In regards to the argument that Tian et al does not teach a claimed bispecific fusion protein comprising both an Ig-like domain VEFR1 and an Ig-like domain of VEGFR2, the examiner disagrees. Tian et al teaches a bispecific fusion protein comprising a first binding domain an a second binding domain, where the first binding domain comprise an antibody that specifically binds PD-L1 and the antibody comprises a first light chain, a second light chain, a first heavy chain, and a second heavy chain, wherein the light chains and heavy chains are linked by disulfide bonds, and wherein the second binding domain comprises an extracellular Ig-like domain of VEGFR, wherein an N-terminus of the Ig-like domain of VEGFR is linked via a linker to the C-terminus of each heavy chain (see Abstract and Fig. 1, in particular). Tian et al further teaches said bispecific fusion protein wherein VEGFR of the Ig-like domain of VEGFR is VEGFR1 and VEGFR2 (see “The VEGFR describe in the first aspect and the second aspect may be VEGFR1 and/or VEGFR2….” at [0032], in particular). Such a bispecific fusion protein comprises both an Ig-like domain VEFR1 and an Ig-like domain of VEGFR2. Further, at [0032], Tian et al further teaches said bispecific fusion protein wherein the Ig-like domain of VEGFR1 is VEGFR1D2 and the Ig-like domain of VEGFR2 is VEGFR2D2. Tian et al further teaches said bispecific fusion protein wherein the anti-PD-L1 antibody light chain comprises SEQ ID NO:18 and the heavy chain comprises SEQ ID NO:2 ([0091], in particular). SEQ ID NO:18 comprises CDRs of instant SEQ ID NOs:4-6 and instant SEQ ID NO:16. SEQ ID NO:2 comprises CDRs of instant SEQ ID NOs:7-9 and instant SEQ ID NO:18. Tian et al further teaches a pharmaceutical composition comprising said bispecific fusion protein and a pharmaceutically acceptable carrier ([0069], in particular).
In regards to the argument that Tian et al’s generic language “VEGFR1 and/or VEGFR2” does not disclose a combination of VEGFR1 D2 and VEGFR2 D3 recited in the present claims, the claims do not recite “VEGFR1 D2” or “VEGFR2 D3”. Rather, the claims recite “an Ig-like domain of VEGFR1 and an Ig-like domain of VEGFR2.” Tian et al teaches VEGFR1 (which comprises an Ig-like domain of VEGFR1) and VEGFR2 (which comprises an Ig-like domain of VEGFR2). See “The VEGFR describe in the first aspect and the second aspect may be VEGFR1 and/or VEGFR2….” at [0032], in particular). Such a bispecific fusion protein comprises both an Ig-like domain VEFR1 and an Ig-like domain of VEGFR2. Further, at [0032], Tian et al further teaches said bispecific fusion protein wherein the Ig-like domain of VEGFR1 is VEGFR1D2 and the Ig-like domain of VEGFR2 is VEGFR2D2.
In regards to the argument IMM25031 of Tian et al differs from claimed bispecific fusion proteins, teachings of Tian et al are not limited to IMM25031. IMM25031 is an illustration of the “or” of “The VEGFR describe in the first aspect and the second aspect may be VEGFR1 and/or VEGFR2….” at [0032], in particular).
Claim Rejections - 35 USC § 103
Claim(s) 1, 5, 8, 9, 15, 16, 22, 26, 27, 30, 31, 35, 37, 39, and 40 remain rejected under 35 U.S.C. 103 as being unpatentable over Feng et al (US 2022/0073620 A1; 3/10/22) in view of Yang et al (US 2016/0319022 A1; 11/3/16).
Feng et al teaches a bispecific fusion protein comprising a first binding domain and a second binding domain, where the first binding domain comprise an antibody that specifically binds PD-L1 and the antibody comprises a first light chain, a second light chain, a first heavy chain, and a second heavy chain, wherein the light chains and heavy chains are linked by disulfide bonds, and wherein the second binding domain comprises TRAP (SEQ ID NO:1 of Feng et al comprising instant SEQ ID NOs:1-2; comprising Ig-like domains of VEGFR1 and VEGR2), wherein an N-terminus of the Ig-like domain of VEGFR1 or VEGFR2 is linked via a linker to the C-terminus of each heavy chain (see claim 2, Figure 3, [0104], and [0135], in particular). Figure 3:
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Feng et al further teaches said bispecific fusion protein with heavy chains comprising SEQ ID NO:6 and light chains comprising SEQ ID NO:9 ([0135], in particular). SEQ ID NO:6 comprises instant SEQ ID NOs: 1, 20, and 28. Feng et al further teaches a pharmaceutical composition comprising said bispecific fusion protein and a pharmaceutically acceptable carrier ([0126], in particular). Feng et al further teaches a nucleic acid encoding the bispecific fusion protein ([0058], in particular). Feng et al further teaches a method of treating solid and not solid tumors comprising administering the bispecific fusion protein to a subject in need thereof (claim 21, in particular), including where the subject has MC38 colorectal cancer cells – which results in decreased tumor volume as compared to controls (Example 7 and Figure 11, in particular). As evidenced by Juneja et al, MC38 colorectal cancer cells express PD-L1 (Abstract, in particular).
In particular regards to instant claim 30, SEQ ID NOs 6 and 9 of Feng et al both contain “an amino acid sequence of” each sequence recited by instant claim 30. This rejection is based on any polypeptide comprising as little as two consecutive amino acids of a recited SEQ ID NO comprises “an amino acid sequence of” a recited SEQ ID NO.
Feng et al does not specifically teach bispecific fusion proteins comprising an anti-PD-L1 antibody wherein the anti-PD-L1 antibody comprises CDRs comprising SEQ ID NOs: 4-9, SEQ ID NO:16, and SEQ ID NO:18. However, these deficiencies are made up in the teachings of Yang et al.
Yang et al teaches an anti-PD-L1 antibody with a light chain comprising SEQ ID NO:7 and a heavy chain comprising SEQ ID NO:32 ([0029], in particular). SEQ ID NO:7 comprises CDRs of instant SEQ ID NOs:4-6 and instant SEQ ID NO:16. SEQ ID NO:32 comprises CDRs of instant SEQ ID NOs:7-9 and instant SEQ ID NO:18. Yang et al teaches said an anti-PD-L1 antibody wherein the light chains of the antibody are kappa or lambda ([0090] and [0140], in particular). Yang et al further teaches the anti-PD-L1 antibody is to be administered to subjects to treat tumors ([0301]-[0305], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and administer to subjects with tumors of Feng et al the bispecific antibody constructs of Feng et al wherein the anti-PD-L1 antibody of the bispecific antibody constructs is just any anti-PD-L1 antibody of Yang et al because the bispecific antibody constructs comprise and anti-PD-L1 antibody domain used to treat tumors and the anti-PD-L1 antibodies of Yang et al are taught to treat the same tumors. This is an example of a simple substitution of one known element for another to obtain predictable results. 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.
Response to Arguments
In the Reply of 7/28/26, Applicant argues replacing CDR sequences of one antibody with those of another is not a simple “component replacement” and may affect PD-L1 binding affinity, overall folding and stability of a fusion protein, and special synergy between two binding domains of a fusion protein. Applicant further argues a person of skill in the art would not have predicted selecting any arbitrary PD-L1 antibody and any arbitrary VEGFR domain to form a PD-L1/VEGF bispecific fusion would preserve original PD-L1 and VEGF antigen binding activities and one of skill in the art would no reasonable expectation of success in grafting a PD-L1 antibody of Yang et al onto the framework of Feng et al while retaining bifunctional activity. Applicant further states a technical problem intended to be solved by the present application is to eliminate ADCC effect, prevent the killing of PD-L1-positive normal immune cells, and improve safety of tumor therapy on the basis of maintaining effective tumor inhibition rate and argues Feng et al does not provide any implication or teaching that screening or using other PD-L1 antibodies with different CDR sequences can solve problems of eliminating ADCC effects, improving tumor treatment and safety and effectively inhibiting tumor growth. Applicant further indicates the claims are non-obvious because 12VF1 and 12VF8 of the instant specification demonstrate tumor growth inhibition and a better safety profile than IMM25011 of Tian et al. Applicant further indicates that even though different PD-L1/VEGFR bispecific fusion proteins are known in the prior art, it is difficult to predict whether fusion of the two domains will affect their respective binding activities and that specific sequence selection of different PD-L1 antibodies and different VEGF binding domains may affect the functional activity of a bispecific PD-L1/VEGFR bispecific fusion protein. Applicant further indicates 12VF1, 12VF2, and 12VF8 of the instant specification effectively bind PD-L1 and VEGF, block PD-1 binding to PD-L1, block binding of VEGF to VEGFR1, inhibit HUVEC cell proliferation, and inhibit angiogenesis.
The amendments to the claims and the arguments found in the Reply of 7/28/26 have been carefully considered, but are not deemed persuasive. In regard to the arguments that (i) replacing CDR sequences of one antibody with those of another is not a simple “component replacement” and may affect PD-L1 binding affinity, overall folding and stability of a fusion protein, and special synergy between two binding domains of a fusion protein; (ii) a person of skill in the art would not have predicted selecting any arbitrary PD-L1 antibody and any arbitrary VEGFR domain to form a PD-L1/VEGF bispecific fusion would preserve original PD-L1 and VEGF antigen binding activities; (iii) one of skill in the art would no reasonable expectation of success in grafting a PD-L1 antibody of Yang et al onto framework of Feng et al while retaining bifunctional activity; and (iv) it is difficult to predict whether fusion of the two domains will affect their respective binding activities and that specific sequence selection of different PD-L1 antibodies and different VEGF binding domains may affect the functional activity of a bispecific PD-L1/VEGFR bispecific fusion protein, it is first noted the rejection does not propose just replacing CDR sequences of one antibody for another. Rather, the combined method proposes swapping an entire anti-PD-L1 antibody for another (anti-PD-L antibody of Yang et al) onto the anti-PD-L1/anti-VEGF framework of Feng et al. Note that the anti-PD-L1 antibody of Feng et al comprises the antibody sequences of the well-known anti-PD-L1 therapeutic Atezolizumab. Further, one skill in the art would have a reasonable expectation of success that swapping a second antibody in place of first antibody would predicably maintain characteristics of the second antibody while maintaining VEGF binding of the PD-L1/anti-VEGF construct. Obviousness does not require absolute predictability; rather, obviousness requires some degree of predictability. MPEP 2143.02. Even the instant specification discloses (at page 15) that, for disclosed PD-L1/anti-VEGF bispecific constructs, “any known PD-L1 antibody can be used in the first binding domain, as long as it has light chain and heavy chain variable regions that may specifically bind PD-L1.” The anti-PD-L antibody of Yang et al has light chain and heavy chain variable regions that may specifically bind PD-L1.
In regards to the argument that Feng et al does not provide any implication or teaching that screening or using other PD-L1 antibodies with different CDR sequences can solve problems of eliminating ADCC effects, improving tumor treatment and safety and effectively inhibiting tumor growth, the rationale of the combined method is different than Applicant’s rationale. However, rationale different from Applicant’s is permissible. See MPEP 2144.
In regards to the indication that the claims are non-obvious because 12VF1 and 12VF8 of the instant specification demonstrate tumor growth inhibition and a better safety profile than IMM25011 of Tian et al, the examiner disagrees. The "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." See MPEP 716.02(d). In the instant case, provided evidence is not commensurate in scope with the claims because the claims are not limited to 12VF1 and 12VF8 of the instant specification. 12VF1 of the instant specification comprises instant SEQ ID NOs:23 and 25 (page 22 of the instant specification), while no claims require structures comprises instant SEQ ID NOs:23 and 25. 12VF8 comprises instant SEQ ID NOs:23 and 27 (pages 22-23 of the instant specification), while no claims require structures comprises instant SEQ ID NOs:23 and 25.
In regards to the statement 12VF1 (comprising instant SEQ ID NOs:23 and 25), 12VF2 (comprising instant SEQ ID NOs:24 and 26), and 12VF8 (comprising SEQ ID NOs:23 and 27) of the instant specification effectively bind PD-L1 and VEGF, block PD-1 binding to PD-L1, block binding of VEGF to VEGFR1, inhibit HUVEC cell proliferation, and inhibit angiogenesis: the claims do not require 12VF1, 12VF2, and 12VF8. It is further noted 12VF2 does not comprise the CDR sequences of the fusion protein rendered obvious by the combined method.
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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/SEAN E AEDER/ Primary Examiner, Art Unit 1642
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