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 .
Status of Claims
Receipt of Arguments/Remarks filed on 6/17/2026 is acknowledged. Claims 1-17 and 21-24 are pending. Claims 1 and 3-5 were amended. New claims 21-24 were added. Claims 18-20 were canceled. Claims 6-17 are withdrawn as being directed to a non-elected invention.
Withdrawn Rejections
The rejection of claims 1-2 and 4-5 under 35 U.S.C. § 112(b) is withdrawn in view of claim amendments.
New rejections necessitated by amendment
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 1-3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Steward et al., US 2007/0166332 A1 (hereinafter Steward ‘332) in view of Steward et al., US 2011/0070621 A1 (hereinafter Steward ‘621).
Regarding claim 1, Steward ‘332 teaches modified Clostridial toxins, including Botulinum neurotoxins, BoNT (Steward ‘332 p. 1 para. 2-4). Steward ‘332 teaches a single chain BoNT comprising (d) a first functional amino acid structural region, i.e. an enzymatic domain with zinc dependent endopeptidase activity; (e) a protease cleavage site; and (f) a second functional amino acid structural region, i.e. a translocation domain which facilitates release of the LC from intracellular vesicles into the target cell cytoplasm, and a binding domain which determines receptor binding to the target cell (Steward ‘332 p. 4 para. 22, Fig. 1).
Steward ‘332 additionally teaches that the modified Clostridial toxin can further comprise an epitope-binding region, and that the epitope-binding region may be a tag such as a polyhistidine tag or the glutathione binding domain of glutathione-S-transferase (Steward ‘332 p. 43 para. 184). Steward ‘332 teaches that the epitope-binding domain (tag) may be at the amino terminus (N-terminus) of the modified Clostridial toxin (Steward ‘332 p. 43 para. 186).
Steward ‘332 teaches that the modified toxin can further comprise an exogenous protease cleavage site, for removal of the epitope-binding region (Steward ‘332 p. 44 para. 188). The protease cleavage site may be a human rhinovirus 3C protease cleavage site (Steward ‘332 p. 44 para. 188; Table 9). The cleavage site may be located between an epitope-binding region and a modified Clostridial toxin in order to facilitate removal of the epitope-binding region by proteolytic cleavage (Steward ‘332 p. 45 para. 190).
Steward ‘332 teaches that the modified toxin can further comprise a flexible spacer, such as a G-spacer, GGGGS (Steward ‘332 p. 42 para. 182). Steward ‘332 teaches that the flexible spacer can be used to adjust the length of a polypeptide region to optimize a characteristic or property, such as to better expose a protease cleavage site (Steward ‘332 para. 182). As the GS flexible spacer can be placed within the polypeptide for the purpose of better exposing a protease cleavage site, it would have been obvious that such a spacer could be placed adjacent to the epitope-binding region (tag) and protease cleavage site as discussed above, to better expose the cleavage site.
Therefore, Steward ‘332 teaches a first polypeptide fragment as instantly claimed, comprising (a) a tag protein (epitope-binding region), (b) a rhinovirus protease cleavage site located next to the epitope-binding region, and (c) a linker peptide having no more than 5 amino acid residues and comprising a GS sequence. As the epitope-binding region may be at the N-terminus of the toxin polypeptide, this would result in a single chain polypeptide with the N-terminus comprising (a), (b), and (c) of claim 1; connected to a second polypeptide fragment comprising the neurotoxin polypeptide with (d), (e), and (f) of claim 1 as discussed above.
Steward ‘332 teaches that the toxin comprises BoNT/A, with a sequence according to SEQ ID NO: 1 (Steward ‘332 p. 9 para. 48). The enzymatic domain corresponds to amino acids 1-448 of SEQ ID NO: 1, the translocation domain corresponds to amino acids 449-871 of SEQ ID NO: 1, and the binding domain corresponds to amino acids 872-1296 of SEQ ID NO: 1 (Steward ‘332 p. 9 para. 48). SEQ ID NO: 1 of Steward ‘332 is 99.3% identical to instant SEQ ID NO: 7, which is the sequence of the second polypeptide fragment (see sequence alignment in OA Appendix). The difference between the second polypeptide fragment (instant SEQ ID NO: 7) and SEQ ID NO: 1 of Steward ‘332 is in amino acid positions 438-448 (see sequence alignment in OA Appendix). The loop sequence of BoNT/A (see instant specification p. 3 para. 1) corresponds to positions 431-453 of Steward ‘332 SEQ ID NO: 1 (see sequence alignment in OA Appendix). Thus, the difference between the polypeptide of Seward ‘332 and the second polypeptide fragment of the instantly claimed neurotoxin is in the loop region.
Steward ‘332 teaches that the naturally occurring protease cleavage site in the loop region of the toxin polypeptide is replaced with a Clostridial toxin substrate cleavage site (Steward ‘332 p. 5 para. 24). Steward ‘332 teaches that the natural protease cleavage in BoNT/A occurs at residue K448-A449 (Steward ‘332 p. 40 para. 171). Steward ‘332 does not teach that the protease cleavage site in the loop region is substituted with a rhinovirus protease cleavage site.
Regarding claim 1, Steward ‘621 teaches modified BoNT/A polypeptides, with an enzymatic domain, protease site, translocation domain, and binding domain (Steward ‘621 Fig. 4D). The sequence of the BoNT/A polypeptide is set forth in SEQ ID NO: 1, which is identical to SEQ ID NO: 1 of Steward ‘332 (Steward ‘621 p. 9 para. 42; see sequence alignment in OA Appendix). Steward ‘621 teaches that the protease cleavage site in the loop region of the toxin polypeptide is replaced with an exogenous protease cleavage site, which may be a human rhinovirus 3C site (Steward ‘621 p. 187 para. 941-942; Table 10). Steward ‘621 teaches that replacement of an endogenous protease cleavage site with an exogenous protease cleavage site will enable cleavage when expressed in an organism that does not produce the naturally-occurring protease used to cleave the di-chain loop region of a toxin, and cleavage at an exogenous site can facilitate a change in the conformational structure of the binding domain which affects receptor binding (Steward ‘621 p. 187 para. 942). Steward teaches that when the exogenous cleavage site is added in the loop region, the naturally-occurring protease cleavage site is made inoperable and cannot be cleaved by its protease, and the exogenous protease cleavage site can be cleaved by its corresponding exogenous protease (Steward ‘621 p. 188 para. 944).
It would have been obvious for a skilled artisan to modify the polypeptide taught by Steward ‘332 and replace the loop region with an exogenous protease cleavage site, as taught by Steward ‘621. Both references teach modified neurotoxin polypeptides which comprise a second polypeptide fragment with regions as recited in (d), (e), and (f) of instant claim 1. Both references teach that the naturally occurring protease cleavage site in the loop region (e) can be substituted with a different protease cleavage site. As the polypeptide sequences in each of these references are identical, it would have been obvious to a skilled artisan that the protease cleavage site in the second polypeptide fragment of Steward ‘332 could be substituted with a rhinovirus protease cleavage site, as taught by Steward ‘621.
A person of ordinary skill in the art would have been motivated to make this substitution because Steward ‘621 teaches that replacing the naturally occurring protease cleavage site with an exogenous protease cleavage site provides benefits such as enabling cleavage in an organism that does not express the protease for the naturally occurring site, and can allow for beneficial conformational changes. Thus, a skilled artisan would have been motivated to replace the natural protease in the loop region of the polypeptide in Steward ‘332 with an exogenous rhinovirus protease as taught by Steward ‘621.
A skilled artisan would have had a reasonable expectation of success in making this substitution because Steward ‘332 and Steward ‘621 teach identical polypeptide sequences which correspond to the structure of the second polypeptide fragment as instantly claimed. As the sequences are identical, and Steward ‘621 teaches successful substitution of a rhinovirus protease cleavage site in the loop region of the polypeptide, a skilled artisan could expect success in doing so in the polypeptide of Steward ‘332.
Regarding the limitation in claim 1 that the first and second protease cleavage sites are not recognized and cleaved by a host cell, Steward ‘621 teaches that when an exogenous protease site is substituted, the only cleavage that occurs is with the exogenous protease corresponding to the substituted site (i.e. rhinovirus 3C), and thus it would be expected that the polypeptide would not be cleaved by the host cell (Steward ‘621 p. 188 para. 944).
Regarding claim 2, Steward ‘332 teaches using a rhinovirus protease cleavage site between an epitope-binding region (tag) and a modified Clostridial toxin in order to facilitate removal of the epitope-binding region by proteolytic cleavage, i.e., the first protease cleavage site is a human rhinovirus C3 site (Steward ‘332 p. 45 para. 190; Table 9). Steward ‘621 teaches that the loop region of the neurotoxin polypeptide (i.e. the second polypeptide fragment of Steward ‘332) can be substituted with a human rhinovirus C3 site (Steward ‘621 p. 187 para. 941-942; Table 10). Thus, both the first and second protease cleavage sites are identical.
Regarding claim 3, Steward ‘332 teaches that the linker peptide has a sequence of GGGGS (Steward ‘332 p. 42 para. 182).
Regarding claim 5, Steward ‘332 teaches that the first functional amino acid region, the enzyme binding domain, comprises a metalloprotease region containing a zinc-dependent endopeptidase activity. Steward ‘332 teaches that the second functional amino acid region, the translocation and binding domains, comprise the receptor-binding domain of the heavy chain (HC) and a translocation domain mediating transfer of the polypeptide across a vesicle membrane (Steward ‘332 p. 4 para. 22).
Claims 4 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Steward ‘332 and Steward ‘621 as applied to claims 1-3 and 5 above, and further in view of Ullah et al., PloS one. 2016 Apr 19;11(4):e0153436.
Both Steward ‘332 and ‘621 teach the sequence of the rhinovirus protease cleavage site is EVLFQGP (Steward ‘332 Table 9; Steward ‘621 Table 10). These references do not teach the first Leu residue in the protease cleavage site (claim 4).
Regarding claim 4, Ullah teaches that the human rhinovirus 3C protease cleavage site has a sequence of LEVLFQ/GP (Ullah p. 2 first partial para.).
It would have been obvious for a skilled artisan to substitute the protease cleavage site for human rhinovirus 3C as taught by Ullah, LEVLFQGP, in place of the sequence EVLFQGP in the polypeptide of Steward ‘332 and ‘621. The difference between the protease cleavage site sequence of Steward ‘332 and ‘621 compared to the sequence of Ullah is the additional L residue at the beginning of the sequence taught by Ullah. Ullah teaches that this is the canonical human rhinovirus 3C protease cleavage site, wherein the protease cleaves between glutamine and glycine (Ullah p. 2 first partial para.). The sequence of Steward ‘332 and ‘621 is also cleaved by the human rhinovirus 3C protease between glutamine and glycine (Steward ‘332 Table 9). Thus, a skilled artisan would have found it obvious to substitute the sequence as taught by Ullah, with the additional L residue, in the polypeptide of Steward ‘332 and ‘621. This would be considered a simple substitution of one known element for another, with a reasonable expectation of obtaining predictable results, because both of these cleavage sites are compatible with the same protease and the cleavage position is present in both. Therefore, a skilled artisan could substitute one for the other with the expectation that both would have the same cleavage function.
Regarding claim 22, SEQ ID NO: 1 of Steward ‘332 is 99.3% identical to instant SEQ ID NO: 7, which is the sequence of the second polypeptide fragment (see sequence alignment in OA Appendix). The difference between the second polypeptide fragment (instant SEQ ID NO: 7) and SEQ ID NO: 1 of Steward ‘332 is in amino acid positions 438-448, or the loop region (see sequence alignment in OA Appendix). As discussed above, it would have been obvious for a skilled artisan to substitute the loop region amino acids with an exogenous protease cleavage site from a rhinovirus. The amino acid residues which differ between instant SEQ ID NO: 7 and SEQ ID NO: 1 of Steward ‘332 are the rhinovirus protease cleavage site residues which have been inserted in instant SEQ ID NO: 7 (see sequence alignment in OA Appendix). Thus, if the natural protease cleavage site of the loop region of Steward ‘332 is substituted with a rhinovirus protease cleavage site, the sequence would be the same as instant SEQ ID NO: 7.
Claims 21 and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Steward ‘332, Steward ‘621 and Ullah et al., PloS one. 2016 Apr 19;11(4):e0153436, as applied to claims 4 and 22 above, and further in view of Chen et al., Advanced drug delivery reviews. 2013 Oct 15;65(10):1357-69.
Steward ‘332 and ‘621 in view of Ullah teach the protease cleavage site as set forth in SEQ ID NO: 23, as discussed above. Steward ‘332 teaches that the modified toxin can further comprise a flexible spacer, such as a G-spacer, GGGGS (Steward ‘332 p. 42 para. 182). Steward ‘332 teaches that the flexible spacer can be used to adjust the length of a polypeptide region to optimize a characteristic or property, such as to better expose a protease cleavage site (Steward ‘332 para. 182).
Steward ‘332 does not expressly teach that the short linker is GS, as set forth in claims 21-24.
Regarding claim 21, Chen teaches that flexible linkers are generally composed of small, non-polar (Gly) or polar (Ser or Thr) amino acids, as the small size of these amino acids provides flexibility and allows for mobility of connecting functional domains, and that GS linkers are the most common flexible linkers (Chen pp. 1359-1360 Section 3.1 para. 1-2). Chen teaches that the length of the GS linker can be optimized to achieve appropriate separation of functional domains or maintain necessary inter-domain interactions (Chen p. 1360 para. 1).
It would have been obvious for a skilled artisan to modify the flexible spacer/linker of Steward ‘332, utilizing a linker comprised of GS rather than GGGGS. As taught by Chen, linkers comprising G and S residues are commonly used for separation of domains in fusion proteins, and the number of GS residues is commonly optimized depending on the specific requirements. Thus, a skilled artisan would have found it obvious, in the process of routine optimization, to arrive at a linker with the residues GS as set forth in SEQ ID NO: 23 of claim 21.
Regarding claim 23, Steward ‘332 teaches an N-terminal epitope-binding region, which can be glutathione-S-transferase, followed by a protease cleavage site which can be a rhinovirus protease cleavage site (LEVLFQGP), and a flexible spacer (which can be GGGGS); upstream of the BoNT/A light chain, a rhinovirus protease cleavage site (LEVLFQGP), and the heavy chain of BoNT/A, as discussed above. Chen teaches that flexible linkers are established in the art for use in recombinant proteins and commonly include the residues GS, and that the length of the GS linker can be optimized, as discussed above regarding claim 21. Thus, a skilled artisan would have found it obvious to utilize GS as the flexible linker/spacer, resulting in a linker as claimed in SEQ ID NO: 23, in combination with the other elements recited in claim 23.
Regarding claim 24, the amino acid sequence as set forth in SEQ ID NO: 11 corresponds to the structural elements recited in instant claim 23. As discussed above, a polypeptide having these structural elements is obvious in view of Steward ‘332 and ‘621, and such a polypeptide would have the sequence set forth in SEQ ID NO: 11.
Double Patenting
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 1-5 and 21-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10-11 of copending Application No. 18/852,908 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are directed to single-chain neurotoxin polypeptides.
Regarding claim 1, claim 1 of ‘908 is directed to a botulinum toxin protein composition. Claim 10 of ‘908 recites that the recombinant botulinum toxin protein is prepared by cleaving a single-chain polypeptide with a first protease to remove a tag protein, and forming at least one dimer after cleavage with a second protease, wherein the single-chain polypeptide comprises: (I) a first polypeptide fragment comprising:
(a) a tag protein;
(b) a structural region comprising a first protease cleavage site; and
(c) a short linker peptide; and
(II) a second polypeptide fragment comprising:
(d) a first functional amino acid structural region comprising a metal ion-dependent protease activity domain;
(e) a structural region comprising a second protease cleavage site; and
(f) a second functional amino acid structural region comprising a receptor-binding domain capable of binding to a surface receptor of a target cell and/or a translocation domain capable of mediating the transfer of the polypeptide across a vesicle membrane,
wherein preferably, the first functional amino acid structural region is a light chain of BoNT/A, and the second functional amino acid structural region is a heavy chain of BoNT/A.
Claim 11 of ‘908 recites that the protease cleavage site is LEVLFQGP, and that the structure of the polypeptide includes the LEVLFQGPLGS, i.e. a short linker peptide of GS following the protease cleavage site. The protease cleavage site LEVLFQGP is a rhinovirus protease cleavage site.
Regarding claims 2-5 and 21-24, the limitations of these dependent claims are recited in claims 1, 10, and 11 of copending 18/852,908.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5 and 21-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11-13 of copending Application No. 18/547,850 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are directed to single-chain neurotoxin polypeptides.
Regarding claim 1, claim 1 of ‘850 recites a method using a modified toxin polypeptide precursor comprises:
(I) a first polypeptide fragment comprising:
(a) a tag protein;
(b) a structural region comprising a first protease cleavage site;
(c) a short linker peptide, wherein the short linker peptide has five or less amino acid residues; and
(II) a second polypeptide fragment comprising:
(d) a first functional amino acid structural region comprising a Zn2+ protease binding domain of the light chain of clostridial neurotoxin;
(e) a structural region comprising a second protease cleavage site; and
(f) a second functional amino acid structural region comprising a receptor-binding domain that can bind to the surface receptor of a target cell and/or a translocation domain that can mediate the transfer of the polypeptide across the vesicle membrane of the target cell; and
the first and second proteases are both proteases of rhinoviruses; wherein neither the first protease cleavage site nor the second protease cleavage site is cleaved by a human protease or a protease produced by a host cell expressing the toxin polypeptide precursor; wherein the first protease cleave site and the second protease cleave site are identical.
Claim 18 of ‘850 recites that the short linker peptide is GS.
Regarding claims 2-5 and 21-24, the limitations of these dependent claims are recited in claims 1 and 11-13 of copending 18/547,850.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Rejections under 35 U.S.C. § 102 and 35 U.S.C. § 103
In light of amendments to the claims, the rejections of claims 1-2 and 4-5 under 35 U.S.C. § 102; and of claim 3 under 35 U.S.C. § 103 in view of Ichtchenko, have been withdrawn. However, upon further consideration, new grounds of rejection of claims 1-5 and 21-24 are made under 35 U.S.C. § 103 as set forth above. Given these new grounds of rejection, the arguments presented regarding prior art rejections are moot.
Rejections on the grounds of non-statutory double patenting
Regarding the request that non-statutory double patenting rejections be held in abeyance, applicants are reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer. Only objections or requirements as to form not necessary to further consideration of the claims may be requested to be held in abeyance until allowable subject matter is indicated. Non-statutory double patenting rejections may not be held in abeyance. See MPEP § 804(I)(B)(1). Therefore, the rejections on the grounds of non-statutory double patenting are maintained and modified as set forth above.
Conclusion
Claims 1-5 and 21-24 are rejected.
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 EMILY F EIX whose telephone number is (571)270-0808. The examiner can normally be reached M-F 8am-5pm ET.
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/EMILY F EIX/Examiner, Art Unit 1653
/JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653
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