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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/14/2025 has been entered.
Response to Amendment
The amendment filed 11/14/2025 is acknowledged. Claims, 1, 34, 58, and 82 are amended. Claims 26, 41, 43, 48, 50, and 148 are cancelled.
Claim Status
Claims 1, 34, 36, 56, 58, 65, 71, 72, 75, 77, 82, 90, and 149-150 are pending and under examination in the instant office action.
Withdrawal of Rejections
The rejection of claims 34, 48, and 58 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the amendment to the claims.
The rejection of claim 48 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is moot due to the cancellation of claim 48.
The rejection of claim 82 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for scope of enablement is withdrawn in view of the amendment to the claims.
The rejection of claims 1, 26, 34, 36, 56, 58, 65, 71, 72, 75, 77, 82, 90, and 148-150 under 35 U.S.C. 103 as being unpatentable over WO2017040344 to Schellenberger et. al. published 9 March 2017 (Of Record, 892 dated 27 January 2025) is withdrawn in view of the amendment to the claims.
The rejection of claims 1, 26, 34, 56, 58, 65, 71, 72, 77, and 148-150 on the ground of nonstatutory double patenting over claims 1, 8, 9, 11, 18, 29, 36, and 39 of U.S. Patent No. 11713358 is withdrawn in view of the amendment to the claims.
The rejection of claims 36, 75, 82, and 90 on the ground of nonstatutory double patenting over claims 1, 8, 9, 11, 18, 29, 36, and 39 of U.S. Patent No. 11713358 as applied to claims further in view of WO2017040344 to Schellenberger et. al. published 9 March 2017 is withdrawn in view of the amendment to the claims.
The provisional rejection of claims 1, 26, 34, 36, 41, 43, 48, 50, 56, 58, 65, 71, 72, 75, 77, 82, 90, and 148-150 on the ground of nonstatutory double patenting over claims 1, 2, 5-9, 11, 20, 22, 25, 35, 36, 39, 47, 50, 58, 59, 60-62, 64, 65, and 66 of copending Application No. 18636855 is withdrawn in view of the abandonment of Copending application No. 18636855 on July 30, 2025.
Claim Objections- New
Claim 1 is objected to because of the following informalities: the claim recites “comprises at least three different amino acid sequences selected from the group consisting of SEQ ID NOs: 672-675 and amino acid sequence at least 90% identical to any one of SEQ ID NOs: 676-734”. The recitation appears to inadvertently omit an “s” for plural “sequences least 90% identical to any one of SEQ ID NOs: 676-734” in line 19. Appropriate correction is required.
Claim 150 is objected to because of the following informalities: the claims recites "and a heavy chain variable region (VL)" in lines 2-3. It appears that the “VL” in parentheses is an inadvertent error and should be “VH” to refer to the heavy chain variable region. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)- New
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 1, 34, 36, 56, 58, 65, 71, 72, 75, 77, 82, 90, and 149-150 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.
Scope of the claims
Regarding claim 1, the claim is directed towards a polypeptide comprising a first antibody binding fragment, a second antibody binding fragment, a first extended recombinant polypeptide (XTEN1), and a first release segment (RS1) between the XTEN1 and the AF1, wherein the RS1 comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 99. The specification and the state of the art do not allow for predictable variation in SEQ ID NO: 99 up to 10% while preserving the claimed release segment peptide function as described.
SEQ ID NO: 99 is 16 amino acids long. Therefore, 90% identity to SEQ ID NO: 99 allows for any amino acids at one unspecified position in SEQ ID NO: 99. The breadth of the genus, therefore, includes at least 304 possible RSs (19 standard amino acid substitutions possible across 16 different positions), just starting with the 20 standard amino acids.
State of the Relevant Art
Regarding masking peptides for antibodies and protease-cleavable release segments, these are known in the art. For example, Chen, IJ., Chuang, CH., Hsieh, YC. et al. Selective antibody activation through protease-activated pro-antibodies that mask binding sites with inhibitory domains. Sci Rep 7, 11587 (2017) teaches and anti-EGFR antibody linked to a masking peptide by a substrate of MMP-2 (See Abstract, Fig. 1). Chen et. al. teaches that the MMP-2 substrate sequence is GPLGVR. WO2017040344 to Schellenberger et. al. published 9 March 2017 (Of Record, PTO-892 dated 27 January 2025) describes an anti-EGFR antibody linked by a release-segment to a protease cleavable linker, wherein the release segment is selected from embodiments including those in Table 4 (starting on p. 128). Schellenberger teaches a release segments BSRS3 and BSRS6 that are cut by MMP-2, 7, 9, 14, matriptase, uPA, and legumain which are 62.8% and 44.2% identical to the instant RS SEQ ID NO: 99, respectively as shown in the alignment below:
RESULT 1
AASEQ2_12082025_171446
Query Match 62.8%; Score 54; DB 1; Length 16;
Best Local Similarity 71.4%;
Matches 10; Conservative 1; Mismatches 3; Indels 0; Gaps 0;
Qy 2 AGRSANHTPAGLTG 15
|||| ||:| || |
Db 2 AGRSDNHSPLGLAG 15
RESULT 1
AASEQ2_12082025_171129
Query Match 44.2%; Score 38; DB 1; Length 16;
Best Local Similarity 66.7%;
Matches 8; Conservative 0; Mismatches 4; Indels 0; Gaps 0;
Qy 2 AGRSANHTPAGL 13
|||| || | |
Db 2 AGRSDNHEPLEL 13
Schellenberger also teaches some additional cleavage sequences consensus sequences, stating “the listing of multiple amino acids before, between, or after a slash indicate alternative amino acids that can be substituted at the position” (p. 132, bottom). For example, RS112 for Legumain teaches PTAWS/TPASI/N, indicating that the legumain cleavage site in BSRS3 may equally be “SAN” rather than “SDN”. However, the consensus sequences described are not sufficient to allow an artisan to at once envision how all variants of any single amino acid at any position may be cleaved. Song, Jiangning, et al. "iProt-Sub: a comprehensive package for accurately mapping and predicting protease-specific substrates and cleavage sites." Briefings in bioinformatics 20.2 (2019): 638-658 teaches the identification of protease substrates using a bioinformatic cleavage site prediction model. Song et. al. teaches “The specificity of proteases can vary significantly, depending on the protease and the active sites, with the cleavage site selectivity ranging from preferences for limited and specific amino acids at specific positions, to more general preferences with little discrimination. Current experimental methods for proteolytic cleavage characterization include one-dimensional and two-dimensional gel-based methods (used for identifying the substrates) [12], N-terminal peptide identification methods (for identifying both substrates and cleavage sites), methods using mass spectrometry, as well as quantitation methods of proteolysis to better understand the dynamics and extent of proteolytic events such as the TAILS method [13]. Despite the advances of these experimental methods, they are labor intensive, expensive and time-consuming, and are often limited to the investigation of one protease each time” (Introduction ¶2). Song et. al. further teaches “Third, the accuracy of protease-specific cleavage site prediction varies substantially between different proteases and different protease families. The difficult cases include cleavage site prediction of the MMP family and other proteases (e.g. thrombin) whose activities are also regulated by confounding factors such as the presence of exosites (sites that are located outside the active sites)” (Results and discussion, “Performance evaluation based on a different sequence encoding schemes”, ¶2). Thus, it is difficult to predict and describe all protease sites for all proteases, since each protease requires different, sometimes unpredictable, structural features to both the cleavage site and sometimes to other aspects of the target protein. As an additional example, US20150218217 to Moore et. al. teaches activatable antibodies comprising substrates cleavable by matriptase and/or uPA, but not by plasmin and/or tPA ([0579], Example 7). Moore et. al. teaches a library of potentially cleavable substrates (“CYTX-DP Display Platform), wherein 148 independent substrate-containing display platforms were tested; of these, from pools selected for matriptase and uPA, matriptase, and combined substrates, the cleavage rate for one of the two enzymes alone producing >20% cleavage was between 35% and 96% ([0580], Example 7). Given the wide range and the requirement for screening a library of substrate sequences, it is clear that an artisan would not immediately envision all of the variants 90% identical SEQ ID NO: 99 that preserve matriptase, uPA, legumain, and MMP-2, 7, 9, and 14 substrate function as described.
Summary of species disclosed in the original specification
The original specification discloses 88 different sequences that comprise SEQ ID NO: 99, but there are no variants comprising a sequence only 90% identical to SEQ ID NO: 99 disclosed. There are no amino acid substitutions, insertions, or deletions at any position resulting in a sequence less than 100% identical but more than 90% identical to SEQ ID NO: 99.
Do the species disclosed in the specification describe a genus?
MPEP 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The instant specification only discloses one sequence more than 90% identical to instant SEQ ID NO: 99. Given the breadth of the genus including at least 304 sequences at least 90% identical to SEQ ID NO: 99 with no additional guidance or examples provided, an artisan would not understand applicant to be in possession of the entire genus at the time of filing.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by the disclosure of relevant, identifying characteristics (i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with a known or discloses correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet the requirement in the instant case, the specification must describe structural features that the skilled artisan, as of the effective filing date, would have expected to convey the claimed activity.
As noted above, the art teaches that although consensus sequences may be described for some proteases, this does not necessarily result in predictability of the cleavage interaction between the protease and the substrate sequence of the release site. There are no alternate residues within SEQ ID NO: 99 disclosed in the specification, nor particular guidance of where and how SEQ ID NO: 99 may be altered in order to preserve the disclosed function of being a multi-protease substrate (Fig. 6). Therefore, there insufficient structure/function correlation to define a genus of release segments comprising an amino acid at least 90% identical to SEQ ID NO: 99.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for release segment residues for the recited function of matriptase, uPA, legumain, and MMP-2, 7, 9, and 14 cleavage substrate. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the SEQ ID NO: 99 that indicate which amino acid residues: i) are essential for protease binding; ii) can be changed and still allow protease binding and substrate cleavage; and iii) disrupt protease binding and substrate cleavage. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polypeptide of claim 1 at the time of filing. Regarding claims 34, 36, 56, 58, 65, 71, 72, 75, 77, 82, 90, and 149-150 the claims are ultimately dependent on the rejected claim 1 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 103- New
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.
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.
Claims 1, 34, 36, 56, 58, 65, 71, 72, 75, 77, 82, 90, and 149-150 are rejected under 35 U.S.C. 103 as being unpatentable over WO2017040344 to Schellenberger et. al. published 9 March 2017 (Of Record, PTO-892 dated 1/27/2025) in view of WO2019126576 to Yang et. al. effectively filed 21 December 2017 (Of record, IDS dated 11/14/2025).
The applied reference (WO2019126576 to Yang et. al.) has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Regarding claims 1, 34, 58, and 149-150, Schellenberger et. al. teaches a chimeric polypeptide comprising a first portion, wherein the first portion comprises a first binding domain with binding specificity to a target cell marker and a second binding domain with binding specificity to an effector cell, and further comprising a third portion comprising a bulking moiety (claim 1) and wherein the first binding domain and the second binding domain are scFvs (claim 10); wherein the effector cell antigen is CD3 (claim 14); The chimeric polypeptide assembly of any one of the preceding claims, wherein the first binding domain comprises VH and VL regions derived from a monoclonal antibody capable of binding said tumor specific marker (claim 21); The chimeric polypeptide wherein the bulking moiety is XTEN (claim 33) and wherein the XTEN comprises an amino acid sequence at least 90% identical to a sequence selected from the group set forth in Table 5 (claim 34). “[T]he first binding domain VH and VL regions are arranged in the order VL— VH. In other cases, the first binding domain comprises a CDR-H1 region, a CDR-H2 region, a CDR-H3 region, a CDR-L1 region, a CDR-L2 region, and a CDR-H3 region, wherein each of said regions is derived from monoclonal antibody sequences selected from the group of sequences set forth in Table 2” [0010]. Table 2 teaches the sequence of panitumumab, an anti-HER1 (EGFR) antibody VH SEQ ID NO: 97 (100% identical to instant SEQ ID NO: 36) and VL of SEQ ID NO: 194 (100% identical to instant SEQ ID NO: 35). Regarding claim 149, because the VH and VL are identical the CDRs by Kabat numbering are also identical. Additionally, Schellenberger et. al. teaches “In some embodiments, wherein less than 100% of amino acids of an XTEN in the chimeric polypeptide assembly compositions are selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and praline (P), or wherein less than 100% of the sequence consists of the XTEN sequences of Table 5, the remaining amino acid residues of the XTEN are selected from any of the other 14 natural L-amino acids, but are preferentially selected from hydrophilic amino acids such that the XTEN sequence contains at least about 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99% hydrophilic amino acids. The content of hydrophobic amino acids in the XTEN utilized in the chimeric polypeptide assembly compositions can be less than 5%, or less than 2%, or less than 1% hydrophobic amino acid content” [00296]. Table 5 teaches an XTEN sequence called “AE144” which is 100% identical to instant SEQ ID NO: 676, is at least 36 amino acid residues in length, comprises at least 4 different amino acids selected from the group consisting of G, A, S, T, E, and P, and comprises each of the different amino acid sequences from SEQ ID NOs: 672-675 (Table 5, p. 138, [00297]).
Schellenberger et. al. teaches the polypeptide further comprising a release segment between the XTEN and the AF1: “thus the RS is located between the first [binding] portion and the XTEN or other bulking moiety” [00277]. Schellenberger teaches that “the invention relates to chimeric polypeptide assembly compositions incorporating release segment peptide sequences capable of being cleaved by one or more mammalian proteases, wherein upon exposure of the RS to the protease (or proteases) the RS is cleaved and the bispecific binding domains are released from the composition. Upon release of the bispecific binding domains and the shielding bulking moiety of the subject chimeric polypeptide compositions, the binding domains regain, due to the loss of the shielding effect of the bulking moiety, their full capacity to concurrently bind to an effector T cell and a cancer, tumor or target cell, resulting in damage or cytolysis of the cancer, tumor or target cell” [00276]. Schellenberger et. al. teaches that the RS is a substrate from a group of proteases which includes MMP-2, MMP-9, MMP-11, MMP-14, urokinase, and matriptase [00282]; “In one embodiment, the RS of the chimeric polypeptide assembly composition is a substrate for at least two proteases selected from the group consisting of MMP-2, MMP-9, uPA, and matriptase” [00282].
Schellenberger et. al. teaches that the RS may be one of the exemplary RSs in Table 4 (p. 128), including RS “BSRS3” that is 62.6% identical to instant SEQ ID NO: 99 (see alignment in the 112(a) rejection above).
Regarding claim 36, Schellenberger et. al. teaches that the polypeptide of the invention is expressed as a fusion protein and depicts a configuration wherein the fusion protein is arranged tumor-associated binding moiety (equivalent to AF1), RS, XTEN (See Fig. 6B and Fig. 6D, for example and Fig. 11) as well as tandem scFv constructs where the structural arrangement from N-terminus to C-terminus is AF1-RS1-XTEN1 (See bottom two examples Fig. 13B).
Regarding claim 56, Schellenberger et. al. teaches that the first and second binding domain are connected by a flexible linker as disclosed in Table 8 and Table 9 [00306], wherein the linkers comprise at least two of glycine, serine, and proline (e.g. L1 is a (G4S)3 linker).
Regarding claim 65, Schellenberger et. al. teaches an embodiment of the polypeptide comprises a second release segment (RS2) wherein the RS2 is a substrate for cleavage by a mammalian protease from the group recited in Table 3 ([0007], [0016]), wherein Table 3 includes MMP-2, MMP-9, MMP-11, MMP-14, urokinase, and matriptase.
Regarding claims 71, 72, and 75, Schellenberger et. al. teaches embodiments that further comprise a second bulking moiety, wherein the bulking moiety is an XTEN of the same composition as the first XTEN, comprising at least 90% of amino acids G, A, S, T, E, P, and is at least 36 amino acids in length (e.g. AE144, as described above), and comprises at least four different amino acids from the group G, A, S, T, E, P as described from the first XTEN domain above (See Fig. 9A, [0016], [00186]). The fifth portion comprising the second bulking moiety (e.g. XTEN) from Table 5, including AE144 which is 100% identical to instant SEQ ID NO: 676. Schellenberger et. al. describes:
“In another embodiment, the invention provides a composition having the configuration of formula III (depicted N-terminus to C-terminus):
(fifth portion)-(fourth portion)-(first portion)-(second portion)-(third portion) III wherein first portion is a bispecific comprising two scFv wherein the first binding domain has specific binding affinity to a tumor-specific marker or an antigen of a target cell and the second binding domain has specific binding affinity to an effector cell; the second portion comprises a release segment (RS) capable of being cleaved by a mammalian protease; the third portion is a bulking moiety; the fourth portion comprises a release segment (RS) capable of being cleaved by a mammalian protease which may be identical or different from the second portion; and the fifth portion is a bulking moiety that may be identical or may be different from the third portion. In the foregoing embodiment, the first portion binding domains can be in the order (VL-VH)1-(VL-VH)2, wherein "1" and "2" represent the first and second binding domains, respectively, or (VL-VH)1-(VH-VL)2, or (VH-VL)1-(VLVH)2, or (VH-VL)1-(VH-VL )2, wherein the paired binding domains are linked by a polypeptide linker as described herein, below” [320].
Regarding claim 77, Schellenberger et. al. teaches pharmaceutical compositions comprising the polypeptide and a suitable carrier or excipient [00322].
Regarding claim 82, Schellenberger et. al. discloses a method of treating a disease comprising administering the chimeric polypeptide or pharmaceutical composition to a subject with cancer, wherein the cancer is selected from a large group such as that recited in claim 82, including for example, breast cancer [00326].
Regarding claim 90, Schellenberger et. al. teaches a polynucleotide encoding the polypeptide [00345].
Schellenberger et. al. does not teach a working example with the particular embodiment comprising the anti-EGFR binding domain comprising the VH and VL of panitumumab.
Schellenberger et. al. teaches that bispecific antibodies, in particular T cell engagers with the embodiment of an anti-EPCAM x anti-CD3 have a significantly longer half-life than the cleaved bispecific (Example 9, [00427]). Schellenberger et. al. teaches that the protease sensitive bispecific has anti-tumor properties in vivo in mouse models of colorectal cancer and ovarian cancer (Examples 10, 11, 16, 18, 19), and that at particular doses of proTIA the proteases in the tumor microenvironment are sufficient to cleave the XTEN domain from the pro form and activate the anti-tumor activity of the T-cell engaging bispecific antibody. Schellenberger et. al. also teaches that the cleavable chimeric polypeptides of the invention because they are “superior in one or more aspects including enhanced terminal half-life, targeted delivery, and reduced toxicity to healthy tissues compared to conventional bispecific antibody preparations in use” ([0004], See also Fig. 10).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to create the particular embodiments of a subgenus of bispecific polypeptide comprising binding a binding domain against the tumor antigen EGFR further comprising the VH/VL of panitumumab, a second anti-effector cell binding domain comprising an anti-CD3 binding domain, and a bulking moiety comprising an XTEN domain comprising at least 90% of the amino acid residues of which are selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and which is at least 36 amino acid residues in length; at least 4 different amino acids selected from the group consisting of G, A, S, T, E and P; and at least three different amino acid sequences selected from the group consisting of SEQ ID NOS:672-675 and amino acid sequence at least 90% identical to any one of SEQ ID NOs: 676-734 as taught in Schellenberger et. al. to benefit from the extension of half-life of anti-tumor bispecific T-cell engagers with targeted delivery and reduced toxicity to healthy tissues as taught by Schellenberger et. al. while developing a polypeptide to target EGFR-positive cancers. This would have a predictable effect because Schellenberger et. al. teaches that the format of a bispecific T-cell engager with an XTEN domain is an improvement over existing bispecific T-cell engagers and an artisan would expect the mechanism to work well with existing anti-tumor binding domains such as panitumumab coupled with art-known anti-CD3 domains.
Schellenberger et. al. does not explicitly teach that the release segment comprises an amino acid sequence at least 90% identical to SEQ ID NO: 99.
This deficiency is resolved by Yang et. al.
Yang et. al. teaches release segments to attach antigen-binding domains to bulky masking domains in order to make activatable bispecific antibodies [0004-0005]. Yang et. al. teaches an anti-EGFR x anti-CD63 antibody and activity of the bispecific against HCT-16 cells with human PBMC ([00105], Example 61, Fig. 80). Yang et. al. teach a release segment of amino acid sequence EAGRSANHEPLGLVAT that is cleaved by legumain, MMP-2, MMP-7, MMP-9, MMP-14, uPA, and matriptase [00209]. Yang et. al. teach an embodiment of the anti-EGFR x CD3 bispecific with release segment RSR2295 which is 100% identical to instant SEQ ID NO: 99 (p. 64 Table 1, Example 47, Table 17 p. 224) and that it is expected anti-EGFR x CD3 bispecific comprising RSR2295 was able to bind to CD3 and EGFR positive cells after protease treatment [00550] and that it is expected that the bispecific will activate PBMC in the presence of HCT-116 target cells when activated by protease treatment [00554]. Yang et. al. also teach that the RSR2295 is effective in the context of an anti-EpCAM x CD3 bispecific antibody at protecting mice from in vivo activity of the cleaved bispecific (Example 56, [00579]) and that cleaved EpCAM x CD3 bispecific comprising RSR2295 had the highest in vitro cytotoxic activity against HCT-116 cancer cells (Example 55, Table 20, [00575-00576]).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the RS of the anti-EGFR x CD3 bispecific of Schellenberger et. al. between the antigen-binding segment and the XTEN segment for the RS2295 as taught by Yang et. al. in order to benefit from the release segment with the best in vitro cytotoxicity after exposure to protease (and therefore the best unmasking) that still masks the antibody in the absence of protease to reduce toxicity as taught by Yang et. al. This would have a predictable effect because Yang et. al. teach that the anti-EGFR x CD3 antibody comprising the RSR2295 would be expected to have a similar cytotoxicity and protection benefit as the anti-EpCAM x CD3 bispecific and both Yang et. al. and Schellenberger et. al. teach release segments cleaved by MMP-2, MMP-9, MMP-11, MMP-14, urokinase, and matriptase for the release segment portion of an activatable antibody joined to an XTEN by a release segment.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Response to arguments
Applicant’s arguments with respect to claim(s) 1, 34, 36, 56, 58, 65, 71, 72, 75, 77, 82, 90, and 149-150 (Remarks 11/14/2025 p. 7) have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Double Patenting- New
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 34, 56, 58, 65, 71, 72, 77, and 149-150 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 9, 11, 18, 29, 36, and 39 of U.S. Patent No. 11713358 (Of record, cited in PTO-892 dated 1/27/2025) in view of WO2019126576 to Yang et. al. effectively filed 21 December 2017 (Of record, IDS dated 11/14/2025).
The applied reference (WO2019126576 to Yang et. al.) has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
‘358 teaches a chimeric polypeptide comprising a first, second, and third portion where the first portion comprises a binding domain with specificity to a target cell marker and a binding domain specific for a effector cell antigen, wherein the effector cell antigen is CD3 (claim 5); the second portion comprises a release segment capable of being cleaved by one or more mammalian proteases (claim 1, 29, 36); the target cell marker is a tumor specific marker from a group including EGFR (claim 2); the chimeric polypeptide wherein the first binding domain comprises a VH and VL regions derived from a monoclonal antibody capable of binding the target cell marker (claim 8) and have VH and VL or the sequences SEQ ID NOs: 141-236. SEQ ID NO: 194 is identical to instant SEQ ID NO: 35; wherein the first and second binding domains are scFvs (claim 29).
Additionally, the third portion comprises an extended recombinant polypeptide wherein the extended recombinant polypeptide is capable of being released from the first portion (reads on XTEN) (claim 1). The extended recombinant polypeptide is selected from the amino acids sequences of SEQ ID NO: 374-417 (claim 2), wherein SEQ ID NO: 374 is AE144, which is equivalent to instant SEQ ID NO: 676 and at least 90% of the amino acid residues of which are selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and which is at least 36 amino acid residues in length; comprises at least 4 different amino acids selected from the group consisting of G, A, S, T, E and P; and comprises at least three different amino acid sequences selected from the group consisting of SEQ ID NOS:672-675.
Although the claims do not recite the VH sequence of the anti-EGFR antibody, the scope of claim 8 is broad and therefore the specification was consulted in order to better understand the scope of the VH sequences claimed. Table 2 teaches VH sequence of SEQ ID NO: 97, which comprises the identical CDRs of instant SEQ ID NO: 36. ‘358 teaches the polypeptide further comprises a release segment with an amino acid sequence capable of being cleaved by a protease from among a group including MMP-2, MMP-7, MMP-9, MMP-11, MMP-14, urokinase (uPA), and matriptase, wherein the extended recombinant polypeptide comprises an amino acid sequence selected from amino acid sequences of SEQ ID NOs: 374-417, or a second release segment of SEQ ID NOs: 243-358 (claims 11, 18, 29, 39).
Regarding claims 65, 71, 72, and 75, ‘358 teaches the polypeptide comprising a fourth portion comprising a RS capable of being cleaved by a protease (e.g. MMP-2) and a fifth portion comprising an extended recombinant polypeptide, wherein the extended recombinant polypeptide comprises SEQ ID NO: 374-417, wherein SEQ ID NO: 374 is identical to instant SEQ ID NO: 676 and at least 90% of the amino acid residues of which are selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P), and which is at least 36 amino acid residues in length; comprises at least 4 different amino acids selected from the group consisting of G, A, S, T, E and P; and comprises at least three different amino acid sequences selected from the group consisting of instant SEQ ID NOs: 672-675.
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make a species of the invention as recited in the claim of ‘358 in order to make an effective polypeptide with half-life extension for the treatment of EGFR-positive cancers with a bispecific T-cell engager.
‘358 claims do not teach the release segment comprises an amino acid sequence 90% identical to instant SEQ ID NO: 99.
This is resolved by Yang et. al.
Yang et. al. teaches release segments to attach antigen-binding domains to bulky masking domains in order to make activatable bispecific antibodies [0004-0005]. Yang et. al. teaches an anti-EGFR x anti-CD63 antibody and activity of the bispecific against HCT-16 cells with human PBMC ([00105], Example 61, Fig. 80). Yang et. al. teach a release segment of amino acid sequence EAGRSANHEPLGLVAT that is cleaved by legumain, MMP-2, MMP-7, MMP-9, MMP-14, uPA, and matriptase [00209]. Yang et. al. teach an embodiment of the anti-EGFR x CD3 bispecific with release segment RSR2295 which is 100% identical to instant SEQ ID NO: 99 (p. 64 Table 1, Example 47, Table 17 p. 224) and that it is expected anti-EGFR x CD3 bispecific comprising RSR2295 was able to bind to CD3 and EGFR positive cells after protease treatment [00550] and that it is expected that the bispecific will activate PBMC in the presence of HCT-116 target cells when activated by protease treatment [00554]. Yang et. al. also teach that the RSR2295 is effective in the context of an anti-EpCAM x CD3 bispecific antibody at protecting mice from in vivo activity of the cleaved bispecific (Example 56, [00579]) and that cleaved EpCAM x CD3 bispecific comprising RSR2295 had the highest in vitro cytotoxic activity against HCT-116 cancer cells (Example 55, Table 20, [00575-00576]).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to substitute the RS of the anti-EGFR x CD3 bispecific of the ‘358 claims between the antigen-binding segment and the XTEN segment for the RS2295 as taught by Yang et. al. in order to benefit from the release segment with the best in vitro cytotoxicity after exposure to protease (and therefore the best unmasking) that still masks the antibody in the absence of protease to reduce toxicity as taught by Yang et. al. This would have a predictable effect because Yang et. al. teach that the anti-EGFR x CD3 antibody comprising the RSR2295 would be expected to have a similar cytotoxicity and protection benefit as the anti-EpCAM x CD3 bispecific and both Yang et. al. and the ‘358 claims teach release segments cleaved by MMP-2, MMP-9, MMP-11, MMP-14, urokinase, and matriptase for the release segment portion of an activatable antibody joined to an XTEN by a release segment.
This non-statutory double patenting (NSDP) rejection might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claims 36, 75, 82, and 90 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 9, 11, 18, 29, 36, and 39 of U.S. Patent No. 11713358 (Of record, cited in PTO-892 dated 1/27/2025) in view of WO2019126576 to Yang et. al. effectively filed 21 December 2017 (Of record, IDS dated 11/14/2025) as applied to claims 1 and 71 above, and further in view of WO2017040344 to Schellenberger et. al. published 9 March 2017 (Of Record, PTO-892 dated 1/27/2025).
The claims of ‘358 do not explicitly teach the structure of the polypeptide from N to C terminus of claims 36 and 75; do not explicitly teach a method for treating a disease in a subject comprising administering the polypeptide of claim 82; and do not explicitly teach an isolated nucleic acid comprising a polynucleotide encoding the polypeptide of claim 90.
These deficiencies are resolved by Schellenberger et. al.
As described in the 103 rejection above:
Regarding claim 36, Schellenberger et. al. teaches that the polypeptide of the invention is expressed as a fusion protein and depicts a configuration wherein the fusion protein is arranged tumor-associated binding moiety (equivalent to AF1), RS, XTEN (See Fig. 6B and Fig. 6D, for example and Fig. 11) as well as tandem scFv constructs where the structural arrangement from N-terminus to C-terminus is AF1-RS1-XTEN1 (See bottom two examples Fig. 13B).
Regarding claims 75, Schellenberger et. al. teaches embodiments that further comprise a second bulking moiety, wherein the bulking moiety is an XTEN of the same composition as the first XTEN, comprising at least 90% of amino acids G, A, S, T, E, P, and is at least 36 amino acids in length (e.g. AE144, as described above), and comprises at least four different amino acids from the group G, A, S, T, E, P as described from the first XTEN domain above (See Fig. 9A, [0016], [00186]). The fifth portion comprising the second bulking moiety (e.g. XTEN) from Table 5, including AE144 which is 100% identical to instant SEQ ID NO: 676. Schellenberger et. al. describes:
“In another embodiment, the invention provides a composition having the configuration of formula III (depicted N-terminus to C-terminus):
(fifth portion)-(fourth portion)-(first portion)-(second portion)-(third portion) III wherein first portion is a bispecific comprising two scFv wherein the first binding domain has specific binding affinity to a tumor-specific marker or an antigen of a target cell and the second binding domain has specific binding affinity to an effector cell; the second portion comprises a release segment (RS) capable of being cleaved by a mammalian protease; the third portion is a bulking moiety; the fourth portion comprises a release segment (RS) capable of being cleaved by a mammalian protease which may be identical or different from the second portion; and the fifth portion is a bulking moiety that may be identical or may be different from the third portion. In the foregoing embodiment, the first portion binding domains can be in the order (VL-VH)1-(VL-VH)2, wherein "1" and "2" represent the first and second binding domains, respectively, or (VL-VH)1-(VH-VL)2, or (VH-VL)1-(VLVH)2, or (VH-VL)1-(VH-VL )2, wherein the paired binding domains are linked by a polypeptide linker as described herein, below” [320].
Regarding claim 77, Schellenberger et. al. teaches pharmaceutical compositions comprising the polypeptide and a suitable carrier or excipient [00322].
Regarding claim 82, Schellenberger et. al. discloses a method of treating a disease comprising administering the chimeric polypeptide or pharmaceutical composition to a subject with cancer, wherein the cancer is selected from a large group such as that recited in claim 82, including for example, breast cancer [00326].
Regarding claim 90, Schellenberger et. al. teaches a polynucleotide encoding the polypeptide [00345].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the polypeptide of ‘358 in the specific configuration, method for treating disease, and polynucleotide encoding the polypeptide as taught by Schellenberger et. al. in order to make and use a specific embodiment of the invention. This would have a predictable effect because Schellenberger et. al. teaches embodiments of the same polypeptides of the claims of ‘358.
Claims 1, 34, 36, 56, 58, 65, 71, 72, 75, 77, 82, 90, and 149-150 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-71 of copending Application No. 19346310 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the '310 application anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of ’310 teach a chimeric polypeptide comprising a bispecific antibody domain, wherein the bispecific antibody domain comprises a first antigen binding domain that specifically binds EGFR and a second antigen binding domain that binds CD3, wherein the first antigen binding domain comprises VH CDRs 1-3 SEQ ID NOs: 562, 563, and 564 identical to the CDRs of instant SEQ ID NO: 36 and VL CDRs 1-3 SEQ ID NOs: 565, 566, and 567 identical to the CDRs of instant SEQ ID NO: 35. The chimeric polypeptide further comprises a mask polypeptide joined to the bispecific antibody via a linker comprising a protease-cleavable release segment position between the mask polypeptide and the bispecific antibody such that the mask polypeptide is capable of reducing the binding of the bispecific to CD3 or EGFR (claim 1). Claim 5 recites wherein the linker is cleaved at a rate that is less than 25% of the rate that RSR-2295 is cleaved by legumain, wherein the sequence of RSR-2295 is 100% identical to instant SEQ ID NO: 99. Claim 9 teaches wherein the structural arrangement from N to C is first antigen binding domain – second antigen binding domain – linker – mask polypeptide; second antigen binding domain – first antigen binding domain – linker – mask polypeptide; mask polypeptide – linker – first antigen binding domain – second antigen binding domain; or mask polypeptide – linker – second antigen binding domain – first antigen binding domain. Claim 10 teaches wherein the mask is an extended length non-natural polypeptide. Claim 11 teaches wherein the is a second mask polypeptide joined to the second antigen binding domain. Claim 20 teaches the release segment (RS) comprises an amino acid sequence SEQ ID NO: 7627 wherein X is any amino acid other than N, wherein SEQ ID NO: 7627 is 91.9% identical to instant SEQ ID NO: 99. Claims 26-29 teach wherein the first and second antigen binding domains are Fab, an scFv, or an ISVD, optionally wherein the ISVD is a VHH domain (reads on single domain antibody). Claim 38 teaches the scFv wherein the first antigen binding domain comprises SEQ ID NO: 449, wherein SEQ ID NO: 449 is an scFv comprising a VL which is 98% identical to instant SEQ ID NO: 35 and a VH 96.5% identical to SEQ ID NO: 36. Claims 39-41 recite wherein the