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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/23/22026 has been entered.
Claims 1-14, 23, 28 and 29 are now pending. Claims 1, 5, 7, and 13 are amended. Claims 1-14, 23, 28 and 29 are now under prosecution.
Maintained Rejection
(Arguments Addressed)
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-14, 21-23, and 28-29 remain rejected under 35 U.S.C. 103 as being unpatentable over Sutherland et al (Post-translational Assembly of Protein Parts into Complex Devices by Using SpyTag/SpyCatcher Protein Ligase. Chembiochem. 2019;20(3):319-328; of record), in view of Alam et al (2018) (A novel synthetic trivalent single chain variable fragment (tri-scFv) construction platform based on the SpyTag/SpyCatcher protein ligase system, BMC Biotechnology volume 18, Article number: 55, 2018; of record), Alam et al (2017) (Synthetic Modular Antibody Construction by Using the SpyTag/SpyCatcher Protein-Ligase System. Chembiochem. 2017;18(22):2217-2221; of record), Howarth et al (US10526379 B2; of record).
Sutherland teaches the use of SpyTag/SpyCatcher technology for protein ligation. (see Figures below). Sutherland teaches an antigen binding protein, comprising: (a) two or more antigen binding fragments, each of said first antigen binding fragments comprises a first binding motif; and (b) a fusion protein comprising two or more second binding motifs, the two or more second binding motifs being fused to one another or joined by a linker sequence. Sutherland teaches that the first binding motifs of each of said two or more antigen binding fragments are covalently conjugated to the two or more second binding motifs via protein ligation. [Figures 1, 4, 5, further explanation below] Sutherland teaches that the fusion protein further comprises a third binding motif joined to the two or more second binding motifs by a linker and the antigen binding protein further comprises a polypeptide, an antigen binding fragment scFv, comprising a fourth binding motif. Sutherland teaches that the third binding motif is covalently conjugated to the fourth binding motif of the polypeptide via protein ligation. Sutherland teaches that the first binding motif-second binding motif is orthogonal to a third motif-fourth binding pair. Sutherland teaches that the antigen binding protein is bispecific, bispecific and dimeric, or bispecific and multimeric. Sutherland teaches that the binding motifs are located at the C-terminus of the antigen binding fragments. [pg 6, 2nd paragraph] Sutherland teaches that the fusion protein further comprises a detectable label, a fluorescent dye or biotin. [pg 2 and 8] Sutherland teaches that the fusion protein comprising two or more second binding motifs are joined by a linker sequence or joined directly. [Fig 4, Di-scFv, sc-Fv-Fab, scFv-Fc] Sutherland teaches that the fusion protein comprises two or more second binding motifs comprising one or more cysteine residues. [Fig 4, di-Fab, scFv-Fab]
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Figure 2A.
In Figure 1, Sutherland demonstrates the basic SpyTag/SpyCatcher protein ligase system, demonstrating binding motifs. In Figure 2A, Sutherland teaches: (a) two or more antigen binding fragments, each of said first antigen binding fragments comprises a first binding motif (SpyTaged enzymes) and (b) a fusion protein comprising two or more second binding motifs (SpyCatcher polymers), the two or more second binding motifs being fused to one another by a linker sequence. Sutherland teaches that the first binding motifs of each of said two or more antigen binding fragments are covalently conjugated to the two or more second binding motifs via protein ligation.
Further, Sutherland teaches that the use of protein ligation system, SpyTag/SpyCatcher in the use of bispecific antibodies. Sutherland teaches that with the use of this technology for bispecific antibodies, it allowed for creation of antibody fragments that differed in valency and specificity, and various targeting elements that allow for advantageous strategy for a variety of therapeutic purposes. Sutherland teaches that using a protein ligation system such as SpyTag/SpyCatcher gives the flexibility to allow modular binding of antibody fragments to create multivalent antibodies or antibody-like devices from interchangeable domains, as well as the ability to swap out functional parts to deliver therapeutic payloads.
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In Figure 4, Sutherland teaches examples of recombinant antibody-like “devices” that can be assembled through various antigen binding fragments (i.e. Fab, scFv, and Fc). In Figure 4, Sutherland further demonstrates the following: (a) two or more antigen binding fragments, each of said first antigen binding fragments comprises a first binding motif (Spy Tag parts) and (b) a fusion protein comprising two or more second binding motifs (SpyCatcher parts), the two or more second binding motifs being by a linker sequence (disulfide bone in the Fc part). Sutherland teaches that the first binding motifs of each of said two or more antigen binding fragments are covalently conjugated to the two or more second binding motifs via protein ligation. Sutherland teaches here that the second binding motifs may be the same or different. (ScFv-Fc, and Fab-Fc examples in Fig 4 above).
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In Figure 5A, Sutherland further demonstrates an example of second binding motifs fused to one another in Figure 5A. Sutherland further teaches the creation of a SpyTag/SpyCatcher system to label an anti-human EGFR antibody, and an anti-human growth factor (HER3) diabody (Figure 5B).
However, Sutherland does not explicitly teach the sequences of the binding motifs.
Alam et al (2018) teaches the use of SpyTag/SpyCatcher technology for protein ligation. (see Figure 1 below). Alam teaches an antigen binding protein, comprising: (a) two or more antigen binding fragments, each of said first antigen binding fragments comprises a first binding motif; and (b) a fusion protein comprising two or more second binding motifs, the two or more second binding motifs being fused to one another or joined by a linker sequence. Alam teaches that the first binding motifs of each of said two or more antigen binding fragments are covalently conjugated to the two or more second binding motifs via protein ligationAlam teaches that the fusion protein further comprises a third binding motif joined to the two or more second binding motifs by a linker and the antigen binding protein further comprises a polypeptide, an antigen binding fragment scFv, comprising a fourth binding motif. Alam teaches that the third binding motif is covalently conjugated to the fourth binding motif of the polypeptide via protein ligation. Alam teaches that the binding motifs are located at the C-terminus of the antigen binding fragments. Alam teaches that the fusion protein further comprises a detectable label, a fluorescent dye. [pg 6, 1st column, last paragraph]
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Figure 1 snippet from Alam et al (2018)
In Figure 1, Alam demonstrates the antigen binding protein: (a) two or more antigen binding fragments (sc-Fv) comprising a first binding motif (SpyCatcher) and (b) a fusion protein (Tri-SpyTag) comprising two or more second binding motifs (SpyTags), wherein these binding motifs are joined by a linker sequence (GGS). (a) and (b) were covalently conjugated via protein ligation.
Alam et al (2017) teaches the use of SpyTag/SpyCatcher technology for protein ligation. (see Scheme 1 Below). Alam teaches an antigen binding protein, comprising: (a) two or more antigen binding fragments, each of said first antigen binding fragments comprises a first binding motif; and (b) a fusion protein comprising two or more second binding motifs, the two or more second binding motifs being fused to one another. Alam teaches that the first binding motifs of each of said two or more antigen binding fragments are covalently conjugated to the two or more second binding motifs via protein ligation. Alam teaches that the fusion protein further comprises a third binding motif joined to the two or more second binding motifs by a linker and the antigen binding protein further comprises a polypeptide, an antigen binding fragment scFv, comprising a fourth binding motif. Alam teaches that the third binding motif is covalently conjugated to the fourth binding motif of the polypeptide via protein ligation. Alam teaches that the binding motifs are located at the C-terminus of the antigen binding fragments. Alam teaches that the fusion protein further comprises a detectable label, a fluorescent dye. Alam teaches various antigen binding fragments, Fab, scFv, and Fc domains, as SpyTag and SpyCatcher fusions. Alam teaches that the Fab and scFv express SpyTag or SpyCatcher at their C-terminus, and the Fc domain expressed SpyTag or SpyCatcher at its N-terminus. Alam teaches that the SpyTag/SpyCatcher protein-liagase system provides a site-specific, efficient technology for generating antibody-based device. Alam teaches that there are various techniques for this method, such as fusing SPytag or Spycatcher to either terminus of the protein, or positioned within the protein.
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In Scheme 1, Alam demonstrates the antigen binding protein: (a) two or more antigen binding fragments comprising a first binding motif (SpyTag) and (b) a fusion protein comprising two or more second binding motifs (SpyCatcher), wherein these binding motifs are joined by a linker sequence (GGS). (a) and (b) were covalently conjugated via protein ligation.
Howarth teaches an antigen binding protein comprising: a) two or more first antigen binding fragments comprising a first binding motif, and b) a fusion protein comprising two or more second binding motifs, joined by a linker sequence. Howarth teaches that the polypeptides of the inventions may be generated synthetically, by ligation of amino acids or peptides. [col. 32 lines 20-25] Howarth teaches that the first and second binding motifs are covalently conjugated via isopeptide bonds. Howarth further teaches that the fusion protein further comprises a third binding motif, that are joined to the second binding motif by a linker. Howarth also teaches that the protein may further comprise a fourth binding motif, wherein the third binding motif is covalently conjugated to the fourth binding motif via isopeptide bonds, and wherein a first binding motif-second binding motif pair is orthogonal to a third binding motif-fourth binding motif pair. Howarth teaches that the polypeptide is a fluorescent protein. Howarth teaches that the binding motifs are located within the fusion proteins. Howarth further teaches the SEQ ID NOs of the binding motifs for the antigen binding protein. Howarth teaches that the SEQ ID Nos 13, 1, 17, 18, 33, which match 100% to the instantly claimed SEQ ID NOs: 1, 6, 8, 9, and 12 respectively, Howarth also teaches SEQ ID NOs 2 and 39, which match 100% of the instantly claimed SEQ ID NO 7, and SEQ ID NOs 109 and 2, which match 100% of the instantly claimed SEQ ID NO 14. Howarth teaches that these SEQ ID NOs may be used in the construct of the above antigen binding protein. (Figure 1. Column 6. lines 44-67- Column 7. lines 1-32. Col. 10 lines 25-32: Claim 13)
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Figure 1 of Howarth demonstrates an example of his teachings. Howarth further teaches that this system is not limited to this example, and that the “tags” and “catchers” may be interchanged, and also provides a list of examples that can be used in his teachings, Howarth also teaches here that the tags and catchers may the same or different. [col 17 and 18] Howarth further teaches that the proteins used in this fusion protein may be enzymes, antibodies, antigen, etc. [col 40, lines 46-40]
It would have been prima facie obvious to one of the ordinary skill in the art at the time the invention was filed to use SEQ ID Nos: 1, 6, and 8, as sequences of the first or fourth binding motifs, and SEQ ID Nos: 7, 9, 12, and 14, as the sequences of the second or third binding motifs, in the antigen binding protein of Sutherland. One would have been motivated to because the prior art cited above (Sutherland, Alam (2017), Alam (2018) and Howarth) all teach the instantly claimed antigen binding protein comprising two or more antigen binding fragments, a fusion protein that comprises binding motifs joined by a linker sequence. One of ordinary skill in the art would have a reasonable expectation of success because Howarth teaches the use of the instantly claimed sequences in the formation of a fusion protein. Given the known structure instantly claimed antigen binding protein taught by the cited art above, and given the known sequences of the binding motifs as taught by Howarth, one of skill in the art could have pursued using SEQ ID Nos: 1, 6, and 8, as sequences of the first or fourth binding motifs, and SEQ ID Nos: 7, 9, 12, and 14, as the sequences of the second or third binding motifs, in the antigen binding protein of Sutherland, with a reasonable expectation of success.
Response to Relevant Arguments
Applicant argues that the OA appears to incorrectly construe where the cysteine residue(s) are located with respect to the claimed invention. Applicant argues that it is the linkers joining the second binding motifs contain cysteine residues. The Applicant argues that the Office Action appears to incorrectly construe where the cysteine residues are located and that it is the fusion protein that is joined by a linker comprises one or more cysteine residue, and it is not reasonable interpretation of the claim to consider the cysteine residues contributing to the disulfide bonds in the Fab fragments as cysteine residues existing in the claimed linker molecules.
Applicant’s arguments have been considered but are not persuasive. The prior art renders obvious that the linkers joining the second binding motifs contain cysteine residues. Claim 1 recites: “An antigen binding protein comprising: two or more first antigen binding fragments, each of said first antigen binding fragments comprising a first binding motif; and a fusion protein comprising two or more second binding motifs that are the same or different, the two or more second binding motifs being joined by a linker sequence comprising one or more cysteine residue, wherein the first binding motifs of each of said two or more first antigen binding fragments are covalently conjugated to the two or more second binding motifs via protein ligation…” The specification defines "binding motif" relates to a protein sequence that is attached to polypeptides that enables the formation of a covalent linkage to another polypeptide, and they may be used to an N-terminus, C-terminus, or embedded within the polypeptide. The specification defines "joined by a linker sequence" as the use of one or more linker sequences to connect two or more binding motifs, a binding motif and a polypeptide, or a binding motif and an antigen binding fragment. [0036] Thus, the Examiner has determined that “two or more second binding motifs joined by a linker sequence comprising one or more cysteine residues” includes the disulfide bonds that links the two or more second binding motifs.
It is well known in the art that di-Fab and scFv-Fab fragments comprise cysteine residues in the disulfide bonds. The image below, taken from Tran et al, demonstrates that between Fab fragments, there are disulfide bonds. The comparison below demonstrates that the cysteine residues in the disulfide bonds and the claimed invention refer to the same linker. The box demonstrates the 2nd binding motifs “spy catchers” that are linked by the linker sequence. The 2nd binding motifs are two Fab fragments. Tran et al demonstrates the known disulfide bonds that exist between Fab Fragments.
16/822,096
[AltContent: rect]Tran et al
[AltContent: rect]
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Therefore, Sutherland teaches that in fusion protein, there are cysteine residues, and it would have been obvious to use them as one of the binding motifs in the binding protein as taught demonstrated above by the cited references.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
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