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 .
Priority
This application is a U.S. national phase of International Application No. PCT/CN2020/103744, filed on 07/23/2020. This application claims priority to People’s Republic of China Application No. CN201910665603.6, filed 07/23/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
The Amendment, filed on 12/02/2025, is acknowledged in which:
Claims 2-6 and 13-15 are canceled.
Claims 1, 9, and 12 are currently amended.
Claims 7, 8, 10, 11, 16, 18, and 20-24 were previously presented.
Claims 17 and 19 are original.
Claims 1, 7-12, and 16-24 are pending and found to be allowable for the following reasons discussed below.
Withdrawn Objections and Rejections
In the office action dated 09/04/2025,
All previous rejections of claims 2, 4, and 5 are moot in view of claim cancellation.
Claims 1, 7, 8, 11, and 16-24 were rejected under 35 USC 103 as being unpatentable over Zhang and Lo. Applicant’s amendment to base claim 1 to recite a bispecific antibody defined by specific CDR sequences for both CD47 and LAG-3 binding domains has overcome the rejections and rejections are withdrawn.
Regarding the nonstatutory double patenting rejections of record (Claims 1, 2, 4, 5, 7, 8, 9, 11, 16-20 and 24 as unpatentable over US 12,358,987 B2, 17/618,609, or 17/624,505, all in view of Lo and Zhang). Applicant’s amendment to the instant claim to recite specific CDR sequences for both binding domains of the bispecific CD47xLAG-3 antibody has overcome the rejections and the rejections are withdrawn.
The following grounds of objections and/or rejections are either maintained or necessitated by applicant’s amendment to the claims.
Modified Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 7-12 and 16-24 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/185040 A1 (herein Zhang), WO 2019/144895 (herein Zhao), and WO 2016/024021 A1 (herein Lo).
Regarding claims 1, 7-12, 21, 22, and 24,
Zhang teaches LAG-3 expressed on activated T cells negatively regulates cellular proliferation, activation, and homeostasis of T cells with preclinical studies demonstrating a role for LAG-3 in CD8 T cell exhaustion (¶ [0004]). Zhang teaches blockade of LAG-3 interactions with MHC II molecules using LAG-3 blocking antibodies or Ig fusion proteins have merit in cancer treatment (¶ [0004]). Zhang teaches anti-LAG-3 single-domain antibodies (sdAbs) with CDRs identical to those in the instant claim (AS20846 clones). Zhang teaches these sdAbs can be fused with a second antigen binding domain to form bispecific antigen binding proteins (BABPs), wherein the second antigen binding portion specifically recognizes an immune checkpoint molecule, such as PD-1, 4-1BB, PD-L1, TIM-3, TIGIT, CTLA-4, VISTA, B7-1, B7-H3, CD47, OX40 or GITR, which inhibit or negatively regulate the immune system (¶ [0185]-[0187]). Zhang explicitly teaches a full-length PD-1 antibody (i.e. comprising VH and VL) wherein humanized LAG3 sdAb (AS20846V12 or SEQ ID NO:304 identical to instant SEQ ID NO:40 - see alignment below) is fused via mutated IgG1 hinges (SEQ ID NO: 353 identical to instant SEQ ID NO: 45) at the C-terminus of the PD-1 heavy chain (BLP-14; SEQ ID NOs: 401 and 402) or C-terminus of the PD-1 light chain (BLP-16; SEQ ID NOs: 405 and 406) (Table 7; formats represented in FIGs 8 and 10 - shown below).
Instant SEQ ID NO:40 (Qy) aligned with Zhang AS20846V12 - SEQ ID NO:304 (Db) (CDRs highlighted)
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297
570
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447
451
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406
631
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Zhang does not explicitly disclose a CD47/LAG-3 BABP.
Zhao teaches CD47 overexpression on cancer cells transmits a “don’t eat me” signal, allowing these cells to suppress phagocytic innate immune surveillance and elimination, making CD47 antagonists desirable for cancer therapies (¶ [0004]-[0005]). Zhao teaches humanized anti-CD47 antibodies identical or within 95% framework variability of instant SEQ ID NOs: 4 (SEQ ID NOs: 401 and 403) and 6 (SEQ ID NO: 402) (¶ [00438]) comprising CDRs identical to instant SEQ ID NOs: 33-38 (see alignments below). Zhao also teaches the anti-CD47 antibody as suitable for bispecific formats (i.e. antibodies with two different antigens) (¶ [00288]-[00289]). Zhao further teaches bispecifics with CD47 can include a secondary targeting domain specific for T-cell molecules, either as a means to focus cellular defense through binding to a triggering molecule and/or target the T-cells toward a cell expressing the primary antigen (i.e. CD47) (¶ [00298]-[00299]).
Instant SEQ ID NO: 4 (Qy) aligned with Zhao SEQ ID NO: 401 (Db) (CDRs highlighted)
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561
467
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Instant SEQ ID NO: 4 (Qy) aligned with Zhao SEQ ID NO: 403 (Db) (CDRs highlighted)
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565
473
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Instant SEQ ID NO: 6 (Qy) aligned with Zhao SEQ ID NO: 402 (Db) (CDRs highlighted)
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306
469
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Lo teaches an immunoglobin fusion protein specific for tumor cell antigen and CD47 (abstract). Furthermore, Lo teaches joining an antigen binding domain to the Fc region (Fc-X) reduces FcR engagement and lowers the potential of antibody-dependent cellular cytotoxicity (ADCC) induced toxicity to normal cells that express CD47 (¶ [0088]).
A skilled artisan would have recognized the interchangeability of the full-length antibody within a BABP comprising an sdAb anti-LAG-3 as Zhang teaches known immune checkpoint molecules, including CD47, would have been suitable as a secondary target. Moreover, it would be obvious to one of ordinary skill that blockade of both LAG-3 and CD47 signaling facilitated by a bispecific antibody would have merit in cancer treatment as taught by Zhang and Zhao. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the PD-1 antibody within the PD-1/LAG3 BABP as taught by Zhang can be substituted for a known anti-CD47 antibody as taught by Zhao with a reasonable expectation of improving treatment of CD47 expressing cancers by targeting LAG-3 expressing activated T-cells and focusing cellular defense as suggested by Zhao by blocking LAG-3 mediated immunosuppression as taught by Zhang. Furthermore, a skilled artisan would be motivated to fuse the sdAb to C-terminal position on the heavy chain (i.e. Fc domain fusion) to reduce ADCC as taught by Lo.
Regarding claims 16-19, the combined teachings of Zhang, Zhao, and Lo teach claim 1 as discussed above.
Zhang further teaches the anti-LAG-3 construct may be prepared using methods known in the art comprising culturing host cell with nucleic acid (i.e. polynucleotide) or vector encoding the LAG-3 multi-specific antigen binding protein under conditions effective to express the construct; and obtaining the expressed anti-LAG-3 construct (protein/antibody) from said host cell (page 109, ¶ [0301]).
Regarding claim 20, the combined teachings of Zhang, Zhao, and Lo teach claim 1 as discussed above.
Zhang further teaches the anti-LAG-3 constructs disclosed are applicable in pharmaceutical compositions with a pharmaceutically acceptable carrier (page 98, ¶ [0272]).
Regarding claim 23, the combined teachings of Zhang, Zhao, and Lo teach claim 22 as discussed above.
Zhang teaches anti-LAG-3 bispecific constructs and compositions thereof as useful for therapeutic applications, such as treating LAG-3 related diseases, including colon cancer (i.e. colorectal cancer), resistant to immune checkpoint mono-blockade (¶ [0289]; ¶ [0293]).
Zhao teaches CD47+ cancers to include colorectal cancer among other species that overlap with the instant claim (¶ [0010]).
Response to Arguments - 35 USC 103
Applicant's arguments filed 12/02/2025, in so far as they apply to the modified rejection as discussed above, have been fully considered but they are not persuasive.
Applicant states:
“Zhang provides an anti-LAG-3 sdAb, and a bispecific combining LAG-3 with certain other antigen biding portion, such as anti-PD-1 and about 10 other immune checkpoint molecules. However, this disclosure is purely generic: Zhang provides no discussion, rationale, preference, or example indicating why a skilled artisan would select CD47, let alone the specific anti-CD47 antigen binding portion of amended claim 1, as the pairing partner for its anti-LAG-3 sdAb. Zhang's working examples, comparative data, and biological discussions are directed to LAG-3 x PD-1 co-inhibition, a pairing rooted in well-known T-cell exhaustion biology. By contrast, CD47 is not discussed in Zhang with respect to LAG-3, nor is CD47 associated with T-cell exhaustion pathways.” (Remarks, page 6, ¶ 4)
In response to applicant’s argument that there is no teaching, suggestion, or motivation (i.e. “discussion, rationale, preference, or example”) to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Zhang teaches that CD47 would be a viable secondary target in a list of molecules associated with immune checkpoint molecules (which would include but not necessarily be limited to T-cell exhaustion pathways), therefore it would be obvious to one of ordinary skill simply substituting the full-length antibody (PD-1) as taught by Zhang within a LAG-3 sdAb BABP for a full-length anti-CD47, a cancer marker associated with immune escape, as taught by Zhao would produce a bispecific antibody within scope of the instant invention.
Applicant states:
“While certain cited references disclose antibodies to CD47 or LAG-3 individually, nothing in the art suggests that a person of ordinary skill would have singled out these particular sequences-among the many disclosed alternatives-and attempted to fuse them into one bispecific construct.” (Remarks, pg 7, ¶ 4)
In response to applicant’s argument considering the number of alternative sequences, there is no absolute correlation between the size of the prior art genus and a conclusion of obviousness (See, e.g., Baird, 16 F.3d at 383, 29 USPQ2d at 1552). Moreover, the court noted that "the question under 35 U.S.C. § 103 is not whether the differences [between the claimed invention and the prior art] would have been obvious" but "whether the claimed invention as a whole would have been obvious." (Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 1537, 218 USPQ 871, 877 (Fed. Cir. 1983)). In this instance, Zhang teaches a LAG3 sdAb and fusions thereof into a bispecific antibody (LAG3 sdAb + PD-1 full-length) that differs from the instant invention in the CDRs of the secondary antigen binding domain (PD-1). Zhang teaches CD47 as a possible alternative to PD-1, and therefore it would be obvious that a known CD47 antibody as taught by Zhao (regardless of alternatives), comprising the CDRs as instantly claimed, could be substituted within the LAG-3 BABP as taught by Zhang with a reasonable expectation of success as methods of generating bispecific antibodies with C-terminal heavy chain or light chain attachment of sdAb were taught as viable bispecific formats by Zhang.
Applicant states:
“The field of bispecific antibody engineering is highly unpredictable: the two binding domains must be oriented to avoid steric clash, the folding and stability of the overall construct must be preserved, and the molecule must simultaneously retain the functional activity of both parental antibodies.” (Remarks pg 7, ¶ 4)
“As observed by Madsen [Exhibit 1]… ‘fusion of sdAbs onto IgG scaffolds cause changes in the expression yields and biophysical stability and that these changes were dependent on the molecular geometry, the sdAb fusion site on the IgG scaffold, and the number of domains fused (Madsen et al., 2023).’” (Remarks, pg 7-8)
In response to applicant’s argument, the reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016). Furthermore, conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019). As Zhang teaches generation of bispecific formats which overlap in scope with the claimed orientations, this would imply a reasonable expectation of success for a functional bispecific antibody. Though, in view of applicant’s amendment to narrow the scope of the claim (i.e. to only claim C-terminal attachment to either light or heavy chains), examiner has modified the claim rejection as discussed above in view of the teachings of Lo, suggesting motivation for Fc attachment of the sdAb (independent from steric considerations).
Regarding applicant’s reference to Madsen 2024, which references a sdAb-Ig fusion study (Madsen 2023), this argument is not persuasive. Expression yields and biophysical stability are not claimed features. As currently written, the claims are drawn to a bispecific antibody capable of binding CD47 and LAG-3. Madsen (2023) observed that while binding affinity were in some formats reduced, overall sdAbs can be fused in all investigated positions (i.e. including formats as taught by Zhang discussed above) to form functional bispecific antibodies capable of binding both antigens simultaneously (pg 7, left column, ¶ 2; Figure 3).
Conclusion
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 HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647