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 .
Claims Status
Claims 1-2 and 14-20 are pending.
Claims 1 and 14 are amended.
Claims 3-13 are canceled.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-13 and 17-18) in the reply filed on 05/01/2026 is acknowledged.
Applicant’s election without traverse of:
Species Group 1: (for the first peptide fragment), SEQ ID NO: 3
Species Group 2: (for the second peptide fragment), SEQ ID NO: 4
Species Group 3: (for the pharmaceutically acceptable adjuvant), buffer in the reply filed on 05/01/2026 is acknowledged.
Claims 14-16 and 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/01/2026.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/10/2026, 07/30/2025, and 03/22/2024 is acknowledged. The submission is in compliance with the provision of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show the associated SEQ ID NO. for the sequences listed in Figure 9 as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
With regards to claim 2, claim 2 recites “a cysteine position 454 in the second peptide sequence”. It is unclear in the reference sequence numbering what position 454 is in the second peptide fragment (SEQ ID NO: 4 in claim 1), therefore the claim is rendered indefinite.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Thanongsaksrikul et al. (Toxins, Vol. 3, pg. 469-488; published May 13, 2011; PMID: 22069720), hereinafter referred to as Thanongsaksrikul, in view of Atassi et al. (US Patent No: US 7,341,843 B2; published Mar. 11, 2008), hereinafter referred to as Atassi, and in further view of Smith et al. (US Patent No: US 7,214,787 B1; published May 8, 2007), hereinafter referred to as Smith.
With regards to claim 1-2, Thanongsaksrikul teaches a gene coding for a BoNT/A (bont/A) that synthesizes a single polypeptide which is then nicked to form a di-chain active BoNT/A consisting of a BoNT/A light chain (residues 1-437) and a BoNT/A heavy chain (residues 448-1295). Thanongsaksrikul further teaches that a disulfide bond is formed by cysteine residues 430 and 454 between the two chains (see pg. 471, Figure 1).
PNG
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504
553
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Greyscale
Thanongsaksrikul does not teach the sequence of either chain fragment has an amino acid sequence as set forth in SEQ ID NO: 3 and SEQ ID NO: 4.
However, Atassi teaches a Botulinum Toxin A mutant sequence that has an amino acid sequence as set forth in SEQ ID NO: 3 (residues 1-448) of the current instant application and a cysteine residue at position 430, (see sequence alignment below):
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
39 2326 99.0 1296 US-10-821-669-1 2004-04-09 9 Botulinum Toxin A Peptides and Methods of Predicting and Reducing Immunoresistan
ALIGNMENT:
Query Match 99.0%; Score 2326; Length 1296;
Best Local Similarity 99.3%;
Matches 445; Conservative 0; Mismatches 3; Indels 0; Gaps 0;
Qy 1 MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN 60
|||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||
Db 1 MPFVNKQFNYKDPVNGVDIAYIKIPNVGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN 60
Qy 61 PPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGG 120
Qy 121 STIDTELKVIDTNGINVIQPDGSYRSEELNLVIIGPSADIIQFEPKSFGHEVLNLTRNGY 180
||||||||||||| |||||||||||||||||||||||||||||| |||||||||||||||
Db 121 STIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGY 180
Qy 181 GSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPN 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPN 240
Qy 241 RVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 RVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKA 300
Qy 301 KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV 360
Qy 361 LNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 LNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFT 420
Qy 421 GLFEFYKLLCVRGIITSKTKSLDKGYNK 448
||||||||||||||||||||||||||||
Db 421 GLFEFYKLLCVRGIITSKTKSLDKGYNK 448
Atassi does not teach a peptide fragment of BoNT/A that has an amino acid sequence as set forth in SEQ ID NO: 4 and has a cysteine residue at position 454.
However, Smith teaches a botulinum toxin sequence that has an amino acid sequence (SEQ ID NO:41, heavy chain; see Column 9, lines 1-6) as set forth in SEQ ID NO: 4 (residues 1-848) of the current instant application, (see sequence alignment below) and a cysteine residue at position 454. Note: The examiner is interpreting the cysteine in position 6 of the sequence alignment as the cysteine 454 (see underlined cysteine in sequence alignment) as supported and described by Figure 9 and paragraph 0011 of the specification of the current instant application.
RESULT 1
US-09-611-419B-41
(NOTE: this sequence has 2 duplicates in the database searched.
See complete list at the end of this report)
Sequence 41, US/09611419B
Patent No. 7214787
GENERAL INFORMATION
APPLICANT: Smith, Leonard A.
APPLICANT: Byrne, Michael P.
APPLICANT: Middlebrook, John L.
APPLICANT: Lapenotiere, Hugh
APPLICANT: Clayton, Michael A.
APPLICANT: Brown, Douglas R.
TITLE OF INVENTION: RECOMBINANT VACCINE AGAINST BOTULINUM
TITLE OF INVENTION: NEUROTOXIN
FILE REFERENCE: A33626 067252.0105
CURRENT APPLICATION NUMBER: US/09/611,419B
CURRENT FILING DATE: 2000-07-06
PRIOR APPLICATION NUMBER: PCT/US00/12890
PRIOR FILING DATE: 2000-05-12
PRIOR APPLICATION NUMBER: 60/133,865
PRIOR FILING DATE: 1999-05-12
PRIOR APPLICATION NUMBER: 60/133,866
PRIOR FILING DATE: 1999-05-12
PRIOR APPLICATION NUMBER: 60/133,867
PRIOR FILING DATE: 1999-05-12
PRIOR APPLICATION NUMBER: 60/133,868
PRIOR FILING DATE: 1999-05-12
PRIOR APPLICATION NUMBER: 60/133,869
PRIOR FILING DATE: 1999-05-12
PRIOR APPLICATION NUMBER: 60/146,192
PRIOR FILING DATE: 1999-07-29
PRIOR APPLICATION NUMBER: 08/123,975
PRIOR FILING DATE: 1993-09-21
NUMBER OF SEQ ID NOS: 44
SEQ ID NO 41
LENGTH: 848
TYPE: PRT
ORGANISM: Clostridium botulinum
Query Match 99.6%; Score 4389; Length 848;
Best Local Similarity 99.6%;
Matches 845; Conservative 0; Mismatches 3; Indels 0; Gaps 0;
Qy 1 ALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNF 60
Qy 61 DNEPENISIENLSSDIIGQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIAL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DNEPENISIENLSSDIIGQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIAL 120
Qy 121 TNSVNEALLNPSRVYTFFSSDYVKKVNKATEAAMFLGWVEQLVYDFTDETSEVSTTDKIA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TNSVNEALLNPSRVYTFFSSDYVKKVNKATEAAMFLGWVEQLVYDFTDETSEVSTTDKIA 180
Qy 181 DITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFIPEIAIPVLGTFALVSYIANK 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFIPEIAIPVLGTFALVSYIANK 240
Qy 241 VLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEATKAIIN 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 VLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEATKAIIN 300
Qy 301 YQYNQYTEEEKNNINFNIDDLSSKLNESINKAMININKFLNQASVSYLMNSMIPYGVKRL 360
|||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||
Db 301 YQYNQYTEEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRL 360
Qy 361 EDFDASLKDALLKYIYDNRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTE 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 EDFDASLKDALLKYIYDNRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTE 420
Qy 421 YIKNIINTSILNLRYESNHLIDLSRYASKINIGSKVNFDPIDKNQIQLFNLESSKIEVIL 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 YIKNIINTSILNLRYESNHLIDLSRYASKINIGSKVNFDPIDKNQIQLFNLESSKIEVIL 480
Qy 481 KNAIVYNSMYENFSTSFWIRIPKYFNSISLNNEYTIINAMENNSGWKVSLNYGEIIWTLQ 540
|||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||
Db 481 KNAIVYNSMYENFSTSFWIRIPKYFNSISLNNEYTIINCMENNSGWKVSLNYGEIIWTLQ 540
Qy 541 DTQEIKQRVVFKYSQMINISDYINRWIFVTITNNRLNNSKIYINGRLIDQKPISNLGNIH 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 DTQEIKQRVVFKYSQMINISDYINRWIFVTITNNRLNNSKIYINGRLIDQKPISNLGNIH 600
Qy 601 ASNNIMFKLDGERDTHRYIWIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYD 660
||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 ASNNIMFKLDGCRDTHRYIWIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYD 660
Qy 661 KPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPRGSVMTTNIYLNSSLYRGTKFIIKKYASG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 KPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPRGSVMTTNIYLNSSLYRGTKFIIKKYASG 720
Qy 721 NKDNIVRNNDRVYINVVVKNKEYRLATNASQAGVEKILSALEIPDVGNLSQVVVMKSKND 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 NKDNIVRNNDRVYINVVVKNKEYRLATNASQAGVEKILSALEIPDVGNLSQVVVMKSKND 780
Qy 781 QGITNKCKMNLQDNNGNDIGFIGFHQFNNIAKLVASNWYNRQIERSSRTLGCSWEFIPVD 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 QGITNKCKMNLQDNNGNDIGFIGFHQFNNIAKLVASNWYNRQIERSSRTLGCSWEFIPVD 840
It would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to modify the di-chain active BoNT/A taught by Thanongsaksrikul by substituting the light chain (residues 1-437) with the BoNT/A fragment sequence taught by Atassi and the heavy chain (residues 448-1295) with the botulinum fragment sequence (heavy chain) taught by Smith. One of ordinary skill in the art of protein engineering would be motivated to do so in order to identify additional BoNT/A variants with alternative properties and functionalities that can be used for various treatments. One of ordinary skill in the art of protein engineering would be motivated to do so as an option to identify additional BoNT/A variants with alternative properties and functionalities by creating a BoNT/A mutant comprising a first peptide fragment and a second peptide fragment linked through an interchain disulfide bond where the first peptide fragment of the BoNT/A mutant has an amino acid sequence as set forth in SEQ ID NO:3 of the current instant application and the second peptide fragment of the BoNT/A mutant has an amino acid sequence as set forth in SEQ ID NO: 4 as Atassi and Smith provide the necessary teachings and descriptions of the fragment sequences. One would also be motivated by the combined teachings of Thanongsaksrikul, Atassi, and Smith where Thanongsaksrikul provides the template dichain BoNT/A that can be modified by the fragment sequences as taught by Atassi and Smith. In addition, one would be motivated to arrive at such a substitution since Thanongsaksrikul teaches that the two fragments are joined by a disulfide bond formed by cysteine residues 430 and 454 and Atassi teaches a fragment sequence that has a cysteine at position 430 and furthermore, Smith teaches a fragment sequence that has a cysteine at position 454.
One of ordinary skill in the art of protein engineering would have expectations of success in doing so as Thanongsaksrikul, Atassi, and Smith provide all the teachings and guidance necessary to arrive at such a di-chain BoNT/A.
With regards to claims 17-18, Atassi teaches a pharmaceutical composition containing a BoNT/A peptide in which the pharmaceutical composition includes a pharmaceutically acceptable carrier such as a buffer (see Column 34, lines 5-40).
It would have therefore been obvious to one of ordinary skill in the art before the effective filing date of the current instant application to substitute the BoNT/A peptide in the pharmaceutical composition taught by Atassi with the di-chain BoNT/A arrived at by the combined teachings of Thanongsaksrikul, Atassi, and Smith. One of ordinary skill in the art of protein engineering would be motivated by the combined teachings of Thanongsaksrikul, Atassi, and Smith to incorporate the di-chain BoNT/A into a pharmaceutical composition as a potential route of administration of the di-chain peptide for therapeutic use. One of ordinary skill in the art of protein engineering would have expectations of success in do so as Thanongsaksrikul, Atassi, and Smith provide all the teachings and methods to do so.
Therefore, claims 1-2 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Thanongsaksrikul et al. (Toxins, Vol. 3, pg. 469-488; published May 13, 2011; PMID: 22069720) in view of Atassi et al. (US Patent No: US 7,341,843 B2; published Mar. 11, 2008) and in further view of Smith et al. (US Patent No: US 7,214,787 B1; published May 8, 2007).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGE T LOUNTOS whose telephone number is (571)272-0502. The examiner can normally be reached Monday-Friday 8:00 am - 5:00 pm.
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/GEORGE THEMISTOCLIS LOUNTOS/ Examiner, Art Unit 1652
/ROBERT B MONDESI/ Supervisory Patent Examiner, Art Unit 1652
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