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
Applicant's election with traverse of Group I, claims 1-6, 11, 19, 22, and 23, in the reply filed on 04/16/2026 is acknowledged. The traversal is on the ground(s) that “Shimizu discloses antigen-binding domains that are capable of binding to CD3 and CD137 but do not bind to CD3 and CD137 at the same time. In other words, Shimizu actually discloses a bispecific antibody targeting a tumor antigen and CD3 or CD137… Though Shimizu also describes a trispecific antibody, e.g., in Fig.2, they do not disclose or teach the claimed fusion protein simultaneously targeting an antigen, CD3 and CD137 having specific four peptide linkers, each of which is independently selected from the group consisting of a peptide linker comprising any of the sequences as set forth in SEQ ID NOs. 1-2, as recited in the instant claims... Accordingly, the inventions of these groups share the technical feature of the claimed fusion protein, which is a special technical feature making a contribution over the prior art in view of Shimizu.”
This is not found persuasive, because as indicated in the Requirement for Restriction/Election, dated 01/16/2026, the technical feature that links the Groups is a fusion protein that comprises an anti-CD137 antibody and an anti-CD3 antibody. Independent claim 5, for example, does not require a fusion protein comprising an anti-CD137 antibody and an anti-CD3 antibody that bind to CD137 and CD3 at the same time. In other words simultaneous targeting of CD3 and CD137 is not an element of the claims. Furthermore absent evidence to the contrary one with skill in the art would reason that the tri-specific antibody of Shimizu et al., which comprises an anti-CD3 antibody and an anti-CD137 antibody, is capable of binding to CD3 and CD137 at the same time. Given that the technical feature linking the Groups is taught by Shimuzu et al., said technical feature is not a special technical feature, and unity of invention is lacking in the instant case.
The requirement is still deemed proper and is therefore made FINAL.
Claims 5-9, 11, 13, 15, and 23-29 are pending.
Claims 1-4 and 16-22 are canceled.
Claims 7-9, 13, 15, and 27-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 04/16/2026.
Claims 5, 6, 11, and 23-26 are under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 5, 6, 11, and 23-26 have an effective filing date of 11/11/2020, corresponding to CN202011253989.9.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/10/2023, 10/28/2024, and 03/11/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claim 24 recites “[t]he fusion protein of claim 5, wherein any one of the first peptide linker to the fourth peptide linker is independently selected from the IgG1 hinge region with the C239 deletion mutation, or the IgG1 hinge region with the C239 deletion mutation and the inverted hinge region D234-S252.” At p. 3 of the instant specification, it is stated that “[i]n some embodiments, any one of the first peptide linker to the fourth peptide linker is independently selected from the IgG1 hinge region with the C229 deletion mutation, or the IgG1 hinge region with the C229 deletion mutation and the inverted hinge region D224-S242.” This passage is repeated multiple times in the specification. As such the recitation of “C239” appears to be a typographical error that should read “C229.” The recitation of “D234-S252” appears to be a typographical error that should read “D224-S242.” Appropriate correction is required. For the purposes of examination, the IgG1 hinge region with the C229 deletion mutation and the inverted hinge region D224-S242 will be searched.
Claim Rejections
35 U.S.C. 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.
Claim 26 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 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-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 26 recites “[t]he fusion protein of claim 5, wherein the antigen-binding fragment is selected from the group consisting of a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment, a diabodies and a single chain antibody molecule such as sc-Fv.” Claim 5 recites both an anti-CD3 antigen-binding fragment and an anti-CD137 antigen-binding fragment, and as such it is unclear whether claim 26 is referring to the anti-CD3 antigen-binding fragment or the anti-CD137 antigen-binding fragment
35 U.S.C. 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 5, 6, 11, and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over Gao et al. (CN 110669137, publication date: 01/10/2020, in IDS from 10/28/2024) and Shimuzu et al. (WO 2019/111871, international publication date: 06/13/2019).
Gao et al. teach “a multi-specific antibody and its preparation method and use. the multi-specific antibody comprising: a) a Fab fragment capable of specifically binding to a first antigen, wherein the Fab fragment is composed of one light chain and one heavy chain CH1 variable region, b) a first peptide linker, the N end of the first peptide linker fused to the heavy chain, c) a second peptide linker, the N-terminal of said second peptide linker fused to the light chain, wherein the first peptide linker and the second peptide linker can only form one disulfide bond, and each is independently selected from the group consisting of: comprising Seq ID No. NO.1-2 of any sequence in a peptide linker, wherein X represents any amino acid except Cys, or deletion.” See p. 7 and 8 of English translation. An example of such a multi-specific antibody is provided below, see Gao et al. Figure 1.
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As such Gao et al. teach a fusion protein comprising from the N-terminal to the C- terminal:
a) a Fab fragment of a first antibody specifically binding to a first antigen; and
b) an anti-CD3 antibody or an antigen-binding fragment thereof specifically binding to a CD3 molecule; wherein the heavy chain of each of the Fab fragment and the anti-CD3 antibody, or antigen-binding fragment thereof, is linked in sequence by a peptide linker, and the light chain of each of the Fab fragment and the anti-CD3 antibody, or antigen-binding fragment thereof, is linked in sequence by a peptide linker, wherein only one disulfide bond can be formed between the peptide linkers, and wherein the peptide linkers are each independently selected from the group consisting of a peptide linker comprising any of the sequences as set forth in SEQ ID NO(s): 1-2, wherein X represents any amino acid other than Cys, or is absent.
Gao et al. do not teach or suggest a fusion protein comprising from the N-terminal to the C- terminal:
a) a Fab fragment of a first antibody specifically binding to a first antigen;
b) an anti-CD3 antibody or an antigen-binding fragment thereof specifically binding to a CD3 molecule;
c) an anti-CD137 antibody or antigen-binding fragment thereof specifically binding to a CD137 molecule;
wherein the heavy chain of each of the Fab fragment, the anti-CD3 antibody or antigen- binding fragment thereof and the anti-CD137 antibody or antigen-binding fragment thereof, is linked in sequence by a first peptide linker and a third peptide linker, and the light chain of each of the Fab fragment, the anti-CD3 antibody or antigen-binding fragment thereof and the anti- CD137 antibody or antigen-binding fragment thereof, is linked in sequence by a second peptide linker and a fourth peptide linker,
wherein only one disulfide bond can be formed between the first peptide linker and the second peptide linker, and only one disulfide bond can be formed between the third peptide linker and the fourth peptide linker, and wherein the first peptide linker, the second peptide linker, the third peptide linker, and the fourth peptide linker are each independently selected from the group consisting of a peptide linker comprising any of the sequences as set forth in SEQ ID NO(s): 1-2, wherein X represents any amino acid other than Cys, or is absent. This deficiency is remedied by Shimuzu et al.
At [0011], Shimuzu et al. teach that “CD137 agonist antibodies have already been demonstrated to show anti-tumor effects, and this has been shown experimentally to be mainly due to activation of CD8-positive T cells and NK cells… WO2015/156268 (PTL 3) describes that a bispecific antibody which has a binding domain with CD137 agonistic activity and a binding domain to a tumor specific antigen can exert CD137 agonistic activity and activate immune cells only in the presence of cells expressing the tumor specific antigen, by which hepatotoxic adverse events of CD137 agonist antibody can be avoided while retaining the anti-tumor activity of the antibody. WO2015/156268 further describes that the anti-tumor activity can be further enhanced and these adverse events can be avoided by using this bispecific antibody in combination with another bispecific antibody which has a binding domain with CD3 agonistic activity and a binding domain to a tumor specific antigen. A tri-specific antibody which has three binding domains to CD137, CD3 and a tumor specific antigen (EGFR) has also been reported.”
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Gao et al. with those of Shimuzu et al. to develop a fusion protein comprising from the N-terminal to the C- terminal:
a) a Fab fragment of a first antibody specifically binding to a first antigen (EGFR);
b) an anti-CD3 antibody or an antigen-binding fragment thereof specifically binding to a CD3 molecule;
c) an anti-CD137 antibody or antigen-binding fragment thereof specifically binding to a CD137 molecule;
wherein the heavy chain of each of the Fab fragment, the anti-CD3 antibody or antigen- binding fragment thereof and the anti-CD137 antibody or antigen-binding fragment thereof, is linked in sequence by a first peptide linker and a third peptide linker, and the light chain of each of the Fab fragment, the anti-CD3 antibody or antigen-binding fragment thereof and the anti- CD137 antibody or antigen-binding fragment thereof, is linked in sequence by a second peptide linker and a fourth peptide linker,
wherein only one disulfide bond can be formed between the first peptide linker and the second peptide linker, and only one disulfide bond can be formed between the third peptide linker and the fourth peptide linker, and wherein the first peptide linker, the second peptide linker, the third peptide linker, and the fourth peptide linker are each independently selected from the group consisting of a peptide linker comprising any of the sequences as set forth in SEQ ID NO(s): 1-2, wherein X represents any amino acid other than Cys, or is absent. One of ordinary skill in the art would have been motivated to do so, because Gao et al. teach a fusion protein comprising from the N-terminal to the C-terminal:
a) a Fab fragment of a first antibody specifically binding to a first antigen; and
b) an anti-CD3 antibody or an antigen-binding fragment thereof specifically binding to a CD3 molecule; wherein the heavy chain of each of the Fab fragment and the anti-CD3 antibody, or antigen-binding fragment thereof, is linked in sequence by a peptide linker, and the light chain of each of the Fab fragment and the anti-CD3 antibody, or antigen-binding fragment thereof, is linked in sequence by a peptide linker, wherein only one disulfide bond can be formed between the peptide linkers, and wherein the peptide linkers are each independently selected from the group consisting of a peptide linker comprising any of the sequences as set forth in SEQ ID NO(s): 1-2, wherein X represents any amino acid other than Cys, or is absent. Furthermore in view of the teachings of Shimuzu et al., one of ordinary skill in the art would have been motivated to modify the invention of Gao et al. to include an anti-CD137 antibody and an EGFR-targeting moiety, as there would have been a reasonable expectation that the resultant trispecific molecule is effective in treating EGFR-expressing cancers. Additionally one of ordinary skill in the art would readily identify that said anti-CD137 antibody could be inserted N- or C-terminally to the anti-CD3 antibody, and placing said anti-CD137 antibody at the C-terminus of the anti-CD3 antibody would meet the limitations of the fusion protein of claims 5 and 6.
With respect to claim 11, at p. 10, Gao et al. teach that antibodies of the invention may be provided in a pharmaceutical composition that comprises a pharmaceutically acceptable carrier.
With respect to claim 23, one of ordinary skill in the art would have been motivated to treat EGFR-expressing cancers in humans, and as such one of ordinary skill in the art would have been motivated to prepare the fusion protein of Gao et al. and Shimuzu et al. to comprise anti-CD137 and anti-CD3 antibodies that bind to human CD137, and human CD3, respectively.
With respect to claim 24, as indicated above, the recitation of “C239” appears to be a typographical error that should read “C229.” Furthermore Figure 1 of Gao et al. depicts a fusion protein that comprises an IgG1 hinge mutant (C229).
Claim 25 is included in this rejection, because since the instantly claimed invention and that of the prior art are identical, both the instantly claimed invention and that of the prior art would be expected to exhibit similar functional characteristics.
With respect to claim 26, Figure 1 of Gao et al. depicts a fusion protein that comprises Fab fragments.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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