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 .
Claims Status
The amendments and remarks filed 08/25/2026 are acknowledged.
Claims 1, 10, 14-15, 17, 27, 33, 35, 38-39, 41, and 44-45 are pending.
Claims 1, 10, 14-15, 33, 35, and 38 are amended.
Claims 2-9, 11-13, 16, 18-26, 28-32, 34, 36-37, 40, and 42-43 are cancelled.
Claims 41, 44, and 45 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and/or species there being no allowable generic or linking claim.
Therefore, claims 1, 10, 14-15, 17, 27, 33, 35, and 38-39 are under examination.
Withdrawn
The objections to the drawings are withdrawn. Applicant has submitted replacement drawings to overcome the objections.
The objection to claim 1 is withdrawn. Applicant has amended claim 1 to overcome the objection.
The rejections of claims 1-5, 9-10, 14-15, 17, 25-27, 33, 35, and 38-39 under 35 U.S.C. 112(b) are withdrawn. Applicant has amended claims 1, 10, 33, 35, and 38, and cancelled claims 2-5, 9, and 25-26 to overcome the rejections.
The rejections of claims 1-5, 9-10, 14-15, 17, 25-27, 33, 35, and 38-39 under 35 U.S.C. 112(a) written description are withdrawn. Applicant has amended claim 1 and cancelled claims 2-5, 9, and 25-26 to overcome the rejections.
The rejection of claim 35 under 35 U.S.C. 112(a) written description is withdrawn. Applicant has amended the claim to overcome the rejection.
The rejections of claims 1-5, 9-10, 15, and 17 under 35 U.S.C. 102 are withdrawn. Applicant has amended claim 1 and canceled claims 2-5 and 9 to overcome the rejections.
New Grounds of Rejection Necessitated by Amendment
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 14 and 33 are 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 14 has been amended to require a new Formula Ia that has the disulfide bond between the CH and CL domains rather than between the VH and VL domains. The original disclosure does not provide support for the disulfide bond between the CH and CL domains. Applicant points to Figure 2a for support of this amendment and argues on page 12 of the remarks filed 08/25/2026 that in view of the conventional structure of human IgG1 antibodies, a person of ordinary skill in the art would understand the CH and CL configuration depicted in Figure 2A to include the corresponding disulfide bond between the CH and CL regions. However, Figure 2a is not sufficient to support this amendment because the Figure is a general illustration of the structure of Applicant’s HB0028 bispecific antibody. Neither the drawings nor the brief description of the drawings describe that the bond between the CH and CL is a disulfide bond nor do they provide enough detail to show that there is bond between specific amino acids since disulfide bonds are between the sulfur atoms of two cysteine amino acid residues.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 10, 15, 17, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (CN106103488; 06/01/2023 IDS) in view of Yu (CN109929037; 06/04/2026 PTO-892).
Regarding claims 1, 10, and 27, Lo teaches a bifunctional protein comprising an antibody or antigen-binding fragment capable of binding to at least part of TGFβ receptor II of TGFβ and an antibody or antigen binding fragment that binds to an immune checkpoint protein (e.g. PDL1) [page 3, fourth paragraph] and teaches a PDL1 antibody comprising a TGFβ-RII extracellular domain (ECD) (anti-TGFβ element) [page 2, fifth paragraph]. Lo further teaches that the soluble fragment capable of binding to TGFβ (e.g. human TGFβRII ECD) can be attached by a linker to the N-terminus (initial terminal) of the variable domain [of the PD-L1 antibody] [page 2, fifth paragraph]. Lo also teaches that the TGFβ-RII is fused to the anti-PD-L1 antibody by a flexible (Gly4 Ser)4 Gly linker [page 13, Example 1; page 21, SEQ ID NO: 11] and that the soluble TGFβ-RII (ECD) comprises SEQ ID NO: 10 [page 13, Example 1; page 21, SEQ ID NO: 10].
SEQ ID NO: 10 of Lo has 100% sequence identity to SEQ ID NO: 2 of the instant claim, and SEQ ID NO: 11 of Lo has 100% sequence identity to SEQ ID NO: 3 of the instant claim.
However, Lo does not specifically teach that the anti-PD-L1 antibody comprises a VH comprising SEQ ID NOs: 12-14 for the CDRs 1-3, a VL comprising SEQ ID NOs: 15, GIS, and 16 for the CDRs 1-3, and comprises SEQ ID NO: 4 and SEQ ID NO: 8 for the VH and VL, respectively.
Yu teaches an anti-human PD-L1 antibody [page 9, third paragraph] and teaches that the amino acid sequence of the heavy chain variable region can comprise SEQ ID NO: 8 and the light chain variable region can be SEQ ID NO: 9 [page 10].
SEQ ID NOs: 8 and 9 of Yu have 100% sequence identity to SEQ ID NOs: 4 and 8, respectively, of instant claim 27 and SEQ ID NOs: 8 and 9 of Yu comprise CDRs 1-3 with 100% sequence identity to SEQ ID NOs: 12-14 for the VH CDRs 1-3, respectively, of instant claim 25, and CDRs 1-3 with 100% sequence identity to SEQ ID NOs: 15, GIS, and 16, respectively, of instant claim 26.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the anti-PD-L1 antibody of Lo to specifically comprise the VH and VL anti-PD-L1 sequences of Yu. One would have been motivated use the sequences of Yu in the bifunctional protein of Lo because Yu teaches that these are sequences of an anti-PD-L1 antibody. Further, one would have been motivated to use the sequences taught by Yu for the anti-PD-L1 antibody of Lo because they are known sequences in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Claim 15 is included in this rejection because Lo teaches that the soluble TGFβ-RII (ECD) comprises SEQ ID NO: 10 [page 13, Example 1; page 21, SEQ ID NO: 10].
SEQ ID NO: 10 of Lo has 100% sequence identity to SEQ ID NO: 2 of the instant claim.
Regarding claim 17, Lo teaches that the TGFβ-RII is fused to the anti-PD-L1 antibody by a flexible (Gly4Ser)4 Gly linker of SEQ ID NO: 11 [page 13, Example 1; page 21, SEQ ID NO: 11].
SEQ ID NO: 11 of Lo has 100% sequence identity to SEQ ID NO: 3 of the instant claim.
Claims 1, 10, 14-15, 17, 27, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (CN106103488; 06/01/2023 IDS) in view of Yu (CN109929037; 06/04/2026 PTO-892), as applied to claims 1, 10, 15, 17, and 27 above, and further in view of Vaks et al., 2018 (06/04/2026 PTO 892).
This rejection has been modified to address the amendment of claim 14 requiring that the disulfide bond between the CH and CL of the anti-PD-L1 antibody.
The teachings of Lo and Yu are above.
However, Lo and Yu do not specifically teach that there is a disulfide bond between the CH and CL of the anti-PD-L1 antibody.
Regarding claim 14, Vaks teaches artificial disulfide bonds located between the CH1 and CL domains [see Abstract] that stabilizes the antibody by overcoming the repulsion between chains [page 4, fourth paragraph; page 23, third paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the bifunctional protein of Lo to have the disulfide bond between the CH1 domain and the CL domain as taught by Vaks, thereby arriving at bifunctional proteins with the structure of Formula Ia. One would have been motivated to have made this modification because Vaks teaches that a disulfide bond between the CH1 and CL domains stabilizes the antibody by overcoming the repulsion between chains.
Claim 33 is included in this rejection because Lo teaches that the bifunctional protein can be a homodimer [see Figure on page 1].
Claims 1, 10, 14-15, 17, 27, 33, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (CN106103488; 06/01/2023 IDS) in view of Yu (CN109929037; 06/04/2026 PTO-892), as applied to claims 1, 10, 15, 17, and 27 above, and Vaks et al., 2018 (06/04/2026 PTO 892), as applied to claims 1, 10, 14-15, 17, 27, and 33 above, and further in view of Cai (WO2009058797; 06/04/2026 PTO-892) and Spidel (WO2017213267; 06/04/2026 PTO-892).
The teachings of Lo, Yu, and Vaks are above.
However, Lo, Yu, and Vaks do not specifically teach that the bifunctional (protein) has a heavy chain (H chain) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain (L chain) comprising the amino acid sequence of SEQ ID NO: 7.
The following is in regards to the limitations set forth in instant claim 35:
SEQ ID NO: 1 of the instant claim comprises multiple sequences for different components as shown below:
Residues 1-136 correspond to SEQ ID NO: 2 for the TGFβRII-ECD
Residues 137-157 correspond to SEQ ID NO: 3 for the GS linker
Residues 158-277 correspond to SEQ ID NO: 4 for the anti-PD-L1 heavy chain variable region
Residues 278-606 correspond to SEQ ID NO: 5 for the anti-PD-L1 heavy chain constant region
SEQ ID NO: 7 of the instant claim comprises multiple sequence for different components as shown below:
Residues 1-112 correspond to SEQ ID NO: 8 for the anti-PD-L1 light chain variable region
Residues 113-219 correspond to SEQ ID NO: 9 for the anti-PD-L1 light chain constant region
To reiterate the teachings above, Lo teaches a bifunctional protein comprising an anti-PD-L1 antibody linked to a TGFβ-RII ECD, wherein the anti-PD-L1 antibody comprises a VH, VL, CH (CH1-3) and CL [see Figure on page 1], and that the soluble TGFβ-RII (ECD) of the bifunctional protein comprises SEQ ID NO: 10 [page 13, Example 1; page 21, SEQ ID NO: 10], which has 100% sequence identity to SEQ ID NO: 2 of the instant application, and teaches that the TGFβ-RII ECD is fused to the anti-PD-L1 antibody by a flexible (Gly4Ser)4 Gly linker of SEQ ID NO: 11 [page 13, Example 1; page 21, SEQ ID NO: 11], which has 100% sequence identity to SEQ ID NO: 3 of the instant application. Yu teaches an anti-human PD-L1 antibody [page 9, third paragraph] and teaches that the amino acid sequence of the heavy chain variable region can comprise SEQ ID NO: 8 and the light chain variable region can be SEQ ID NO: 9 [page 10], which have 100% sequence identity to SEQ ID NOs: 4 and 8, respectively, of instant application.
Regarding residues 278-606 of SEQ ID NO: 1 for the anti-PD-L1 heavy chain constant region, Cai teaches a heavy chain constant region comprising SEQ ID NO: 91 [page 20, lines 30-32].
SEQ ID NO: 91 of Cai has 100% sequence identity to residues 278-606 of SEQ ID NO: 1 of instant claim 35.
Regarding residues 113-219 of SEQ ID NO: 7 for the anti-PD-L1 light chain constant region, Spidel teaches a kappa light chain constant region comprising SEQ ID NO: 11 [page 1; page 74, Table 9-2].
SEQ ID NO: 11 of Spidel has 100% sequence identity to residues 113-219 of SEQ ID NO: 7 of instant claim 35.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the anti-PD-L1 antibody, as taught by Lo and Yu, to specifically comprise the heavy chain constant region of Cai and the light chain constant region of Spidel. One would have been motivated use the heavy chain constant region of Cai and the light chain constant region of Spidel for the heavy chain constant region and light chain constant region, respectively, of the bifunctional protein as taught by Lo and Yu because they are known sequences in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F). It further would have been obvious to have combined the individual sequences as listed and taught above by the respective art of Lo, Yu, Cai and Spidel, to arrive at SEQ ID NOs: 1 and 7 of the instant claim. One would have been motivated to have used these sequences for each of the components that form SEQ ID NOs: 1 and 7 because they are known sequences in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Claims 1, 10, 15, 17, 27, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (CN106103488; 06/01/2023 IDS) in view of Yu (CN109929037; 06/04/2026 PTO-892), as applied to claims 1, 10, 15, 17, and 27 above, and further in view of Casi et al., 2012 (06/04/2026 PTO-892).
The teachings of Lo and Yu are above.
However, Lo and Yu do not specifically teach that the bifunctional antibody (protein) is conjugated to a drug (in the form of a drug conjugate).
Regarding claims 38 and 39, Casi teaches antibody-drug conjugates [see page 425, Table 3] and that antibody-drug conjugates combine the desirable properties of antibodies with the cell killing activity of cytotoxic drugs, reducing systemic toxicity and increasing the therapeutic benefit of patients [see Abstract].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the bifunctional protein taught by Lo and Yu, which comprises an anti-PD-L1 antibody, to be conjugated to a drug, thereby forming an antibody-drug conjugate, as taught by Casi. One would have been motivated to have modified the bifunctional protein as taught by Lo and Yu to be conjugated to a drug, thereby forming an antibody-drug conjugate because Casi teaches that antibody-drug conjugates combine the desirable properties of antibodies with the cell killing activity of cytotoxic drugs, reducing systemic toxicity and increasing the therapeutic benefit of patients.
Response to Arguments
The rejections under 35 U.S.C. 103 are maintained. On page 17 of the remarks, Applicant argues that Lo only teaches a C-terminal fusion in which the TGF-βRII extracellular region is fused to the C-terminus of the antibody through a peptide linker, and that neither Lo nor any of the additional references cited by the Examiner suggests reversing the orientation of the fusion domains to obtain the presently claimed N-terminal fusion topology. This is not found persuasive because Lo does explicitly teach the N-terminal fusion topology. To reiterate the teachings of Lo as set forth in the rejections of the office action mailed 06/04/2026 and the rejections above, Lo teaches a bifunctional protein comprising an antibody or antigen-binding fragment capable of binding to at least part of TGFβ receptor II of TGFβ and an antibody or antigen binding fragment that binds to an immune checkpoint protein (e.g. PDL1) [page 3, fourth paragraph], Lo teaches a PDL1 antibody comprising a TGFβ-RII extracellular domain (ECD) (anti-TGFβ element) [page 2, fifth paragraph], and further teaches that the soluble fragment capable of binding to TGFβ (e.g. human TGFβRII ECD) can be attached by a linker to the N-terminus (initial terminal) of the variable domain [of the PD-L1 antibody] [page 2, fifth paragraph]. Thus, Lo does in fact teach the N-terminal fusion topology as claimed.
On page 18 of the remarks, Applicant argues that the additional references of Yu, Vaks, Cai, Spidel, and Casi do not cure the deficiencies of Lo. This is not found persuasive because no such deficiency exists. See above.
On pages 19-20 of the remarks, Applicant argues that the claimed HB0028 construct, which adopts the claimed N-terminal fusion topology, exhibits unexpectedly superior properties compared with the corresponding C-terminal fusion construction (HB0029), pointing to Examples 2-3 and 6-7 of the instant specification, further arguing that the claimed N-terminal fusion unexpectedly provides improvements in structural stability, product quality, dual-target binding, and in vivo efficacy. This is not found persuasive because the results of Examples 2-3 and 6-7 are not commensurate in scope because the claims are broadly directed to a bifunctional antibody comprising an anti-PD-L1 antibody and a TGF-BRII extracellular region connected to the N-terminus of the VH of the anti-PD-L1 antibody, and not to the specific construct Applicant refers to as HB0028. Further, as it relates to claim 14, the results Applicant relies upon to support unexpected results are allegedly to the construct set forth in this claim (i.e. HB0028). However, as claim 14 is rejected as new matter, the construct is not sufficiently described in the specification, and therefore, the Examiner cannot determine what specific construct resulted in the data presented in Examples 2-3 and 6-7.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
