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 .
Election/Restrictions
Applicant’s election of Group I (claims 1, 2, 5, 34, 36, 38, 51-53, 80-83, 86 and 88) and species of K11 (sing modification), SEQ ID NO: 88, SEQ ID NO: 206 in the reply filed on 04/16/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 54, 55, 89 and 90 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/16/2026.
Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/16/2026.
In the interest of compact prosecution, claim 84 is not withdrawn and is examined herein. Applicant states that claims 1-2, 34, 36, 38, 51-53, 80-83, 86 and 88 read on the elected species, which does not include claim 5.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 34, 36, 38, 51-53, 80-84, 86 and 88 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Frevert et al. (U.S. 2020/0131494 A1).
Frevert, abstract, teaches:
This invention relates to novel recombinant botulinum neurotoxins serotype A exhibiting both (i) an increased duration of effect and (ii) a high specific biological activity. These novel recombinant botulinum neurotoxins comprise at least two additional domains consisting of proline, alanine and an additional amino acid residue and at least one amino acid modification which is located at the alpha-exosite or at the beta-exosite of the light chain of the neurotoxin. The invention further relates to novel recombinant single-chain precursor botulinum neurotoxins and compositions comprising the recombinant botulinum neurotoxin with an increased duration of effect and a high specific biological activity.
“In particular embodiments, the recombinant botulinum neurotoxin serotype A according to the invention comprises at least one amino acid modification which is located at the alpha-exosite at at least one position selected from D102, T109, K340, I348, N353, K356.” Frevert, para. [0050].
Frevert, Example 1 and Table 1, provides for 1: Generation and Purification of a PASylated Botulinum Toxin Type A (PAS100-BoNT/A (D102F T109R K340M I348L N353M K356R)-PAS100) having SEQ ID NO: 4 of Frevert. An alignment between recited SEQ ID NO: 1 and SEQ ID NO: 4 (translation of nucleotide sequence) of Frevert is as follows:
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574
651
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500
665
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570
665
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From the alignment above, the protein encoded by SEQ ID NO: 4 of Frevert is a modified clostridial botulinum neurotoxin serotype A1 (BoNT/A1) having an arginine substitution at K356 (as aligned with recited SEQ ID NO: 1, Qy sequence) as recited in claim 1.
Regarding claims 34, 36 and 38, the same protein encoded by SEQ ID NO: 4 of Frevert has a sequence with over 80% identity to recited SEQ ID NOS: 2, 45 and 88.
Regarding claims 51-53, “Botulinum and tetanus neurotoxins have highly homologous amino acid sequences and show a similar domain structure. Their biologically active form comprises two peptide chains, a light chain of about 50 kDa and a heavy chain of about 100 kDa, linked by a disulfide bond. A linker or loop region, whose length varies among different clostridial toxins, is located between the two cysteine residues forming the disulfide bond. This loop region is proteolytically cleaved by an unknown clostridial endoprotease to obtain the biologically active toxin.” Frevert, para. [0006]. “In particular embodiments, the recombinant single-chain precursor botulinum neurotoxin comprises a protease cleavage site in said loop region.” Frevert, para. [0090]. “In particular embodiments, the protease cleavage site is a site that is cleaved by a protease selected from the list of: thrombin.” Frevert, para. [0092]. The same protein encoded by SEQ ID NO: 4 has recited SEQ ID NO: 206 (LPVR) as indicated as follows (highlighted by arrow):
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106
639
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The sequence LPVR (SEQ ID NO: 206, Qy sequence) is understood to be a thrombin cleavage site. The specification, page 144, describes the linker region under discussion as associated with positions 430-454 of BoNT polypeptides (number of recited SEQ ID NO: 1, Qy sequence), which is consistent with the location of LPVR (SEQ ID NO: 206) in the protein encoded by SEQ ID NO: 4 of Frevert. The same is understood as a description by Frevert of a BoNT protein having a modified linker comprising a protease cleavage site of recited SEQ ID NO: 206 as recited.
Regarding claims 80-83, claims 12-16 and corresponding supporting disclosure of Frevert show that any BoNT polypeptide of Frevert can appropriately be encoded by a nucleic acid molecule (SEQ ID NO: 4 of Frevert is a nucleic acid molecule) present in a vector and transformed into a recombinant host cell, which meets the features of claims 80-83.
Regarding claim 86, “In another aspect, the present invention relates to a composition, in particular to a pharmaceutical composition comprising the recombinant botulinum neurotoxin of the present invention.” Frevert, para. [p0024].
Regarding claim 87, Frevert, para. [0113], describes that BoNT polypeptides as shown by Frevert are produced by culturing an E. coli host having a vector encoding such BoNT polypeptide under conditions wherein the BoNT polypeptide is produced.
Regarding claim 88, “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art.” MPEP 2112.02(III). Here, the printed matter (i.e. text) of “directions” do not functionally change a pharmaceutical composition such that the content of the printed matter will not distinguish the claimed product from the prior art, which is Frevert. Further, the nature and actual text of such “directions” are not disclosed by the specification. Frevert, para. [0080], describes “the pharmaceutical composition of the present invention is for use in the treatment of a disease or condition taken from the list of: cervical dystonia (spasmodic torticollis), blepharospasm, severe primary axillary hyperhidrosis, achalasia, lower back pain, benign prostate hypertrophy, chronic focal painful neuropathies, migraine and other headache disorders,” which constitutes “direction” for use of such pharmaceutical compositions. That is, a pharmaceutical composition of Frevert with the disclosure of Frevert constitutes a kit comprising such pharmaceutical composition and directions for therapeutic administration thereof.
Claim(s) 1, 2, 34 and 80-84 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dyer et al. (Reengineering the Specificity of the Highly Selective Clostridium botulinum Protease via Directed Evolution, bioRxiv preprint, Sept. 2020, doi.org/10.1101/2020.09.29.319145) as evidenced by GenBank, PDB 1XTG_A, 2018, www.ncbi.nlm.nih.gov.
Dyer, abstract, states:
The botulinum neurotoxin serotype A (BoNT/A) cuts a single peptide bond inSNAP25, an activity used to treat a wide range of diseases. Reengineering the substrate specificity of BoNT/A’s protease domain (LC/A) could expand its therapeutic applications; however, LC/A’s extended substrate recognition (≈60 residues) challenges conventional approaches. We report a directed evolution method for retargeting LC/A’s substrate and retaining its exquisite specificity. The resultant eight-mutation LC/A (omLC/A) has improved cleavage specificity and catalytic efficiency (1300- and 120-fold, respectively) for SNAP23 versus SNAP25 compared to a previously reported LC/A variant. Importantly, the BoNT/A holotoxin equipped with omLC/A infiltrates neurons and retains its SNAP23 activity. The identification of 5 substrate control loops outside BoNT/A’s active site could guide the design of improved BoNT proteases and inhibitors.
Fig. 1 of Dyer states that the identity of the light-chain of BoNT/A under discussion is as in PDB 1XTG. Cited GenBank 1XTG shows that the same has 414 amino acid residues and is over 99% (3 substitutions) identical to the first 414 amino acid residues of recited SEQ ID NO: 1 and has over 80% identity to recited SEQ ID NO: 88.
“The qmLC/A encoding plasmid served as a template for the first round of mutagenesis, and the qmLC/A provided a positive control and standard for each screen of SNAP23/25 specificity.” “In Rounds 3 to 6 and part of Round 7, iterative saturation mutagenesis using an NDT codon (encoding Cys, Asp, Phe, Gly, His, Ile, Leu, Asn, Arg, Ser, Val, and Tyr) was employed at residues N26, A27, G28, Q29, M30, T52, N53, E55, E56, E171, S143, Q162, M253, T327, and K337).” Dyer, page S4.
Although substitution at K337 may not affect for SNAP23/25, the above is nevertheless a description that BoNT/A polypeptide with K337R substitution was made as part of a library, such BoNT polypeptide having the features recited in claims 1, 2 and 34 with a substitution K337R.
Regarding claims 80-84, Dyer, page S3, describes production and purification of LC/A variants by cloning an encoding nucleic acid sequence into a vector, transforming such vector into an E. coli host cell and producing such variants by culturing the transformed host cell under conditions wherein the LC/A variant (BoNT polypeptide) is produced.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TODD M EPSTEIN whose telephone number is (571)272-5141. The examiner can normally be reached Mon-Fri 9:00a-5:30p.
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652
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