Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment filed 10/10/2025 has been entered. Claims 1-65, 67-90, 92-95, 99-104, and 106b are cancelled. Claims 66, 91, 96-98, and 105-118 are pending. Claims 91, and 96-98 are withdrawn. Claim 118 is newly added. Claims 66 and 105-118 are under examination.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/10/2025 has been entered.
Response to Arguments
With respect to the rejection of claim 110 under 35 USC 112(a), and the rejection of claims 66, 105-109, 112-114, 116 and 117 under 35 USC 103, Applicant's arguments filed 10/10/2025 have been fully considered but they are not persuasive.
Applicant argues against the rejection under 35 U.S.C. §112(a) by stating that the skilled person could readily envision all the amino acid sequences that are 95% identical to the SEQ ID NO’s in claim 110 by comparing any given sequence to the SEQ ID NOs in claim 110. The Examiner respectfully disagrees. An amino acid sequence with at least 95% sequence identity to the SEQ ID NOs in claim 110 could have up to 75 amino acid residues that differ from the residues of the recited sequences. MPEP 2163.05 II states “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A ‘representative number of species’ means that the species which are adequately described are representative of the entire genus.” The species disclosed by Applicant do not demonstrate the claimed function in all species that have up to 5% divergence with the SEQ ID NOs recited in claim 110. The specification discloses that the BoNT polypeptides of the invention function by acting as delivery vehicles of therapeutic agents (Paragraph spanning pages 18 and 19), but does not disclose what amino acids are required to maintain this function. Applicant has not reduced into practice all possible sequences with up to 5% sequence divergence with each of the claimed sequences, therefore, one of ordinary skill in the art cannot reasonably predict which residues may be further modified to generate a BoNT/X that functions as a delivery vehicle.
Applicant argues against the rejection under 35 USC 103 by stating that one of ordinary skill could not have predicted the ability of the claimed complex to achieve 90% survival rate after exposure to a ~4 LD50 value BoNT. However, said ability of the complex is not a claim limitation. Therefore, Applicant’s arguments are not considered persuasive.
Applicant argues against the Double Patenting by stating that the claims of the ‘473 patent do not disclose an antibody or antigen binding fragment. However, as stated in the rejection, Ichtchenko teaches a Clostridium botulinum neurotoxin comprising an antibody (Abstract). It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have added an antibody, as taught by Ichtchenko, to the modified Clostridium botulinum neurotoxin of serotype X (BoNT/X), claimed in U.S. Patent No. 11,286,473.
Claim Objections
Claim 117 is objected to because of the following informalities: the claim contains grammatical errors and may be amended to recite: wherein the receptor binding domain is or BoNT/X.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 66, 105-110, and 112-118 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 claims contain 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.
MPEP 2163.05 II states “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. 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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that ‘only describe[d] one type of structurally similar antibodies’ that ‘are not representative of the full variety or scope of the genus.’). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us].’”
Claim 66 is drawn to a complex comprising: a catalytically inactive botulinum neurotoxin-like toxin from Clostridium botulinum (BoNT/X) comprising an inactive protease domain and a translocation domain, and an antibody or antigen binding fragment thereof. The broadest reasonable interpretation of an inactive protease domain from BoNT/X is any mutant protease domain that lacks enzymatic activity, i.e., the genus encompasses numerous amino acid sequences comprising any mutation and/or deletion that results in an inactive protease domain. The claim also encompasses a broad genus of any possible antibody or antigen binding fragment thereof as the claim does not recite what antigen the antibody/antigen binding fragment is specific against. The broadest reasonable interpretation of “antigen binding fragment thereof” is any antibody fragment that retains binding activity.
Claim 105, which depends from claim 66, recites types of antibodies and antigen binding fragments but does not recite what the antigens the antibodies/antigen binding fragments are specific against, and does not recite an amino acid sequence of the inactive protease domain.
Claim 106, which depends from claim 66, recites that the antibody/antigen binding fragment is a VHH but does not recite what antigen the VHH is specific against, and does not recite an amino acid sequence of the inactive protease domain.
Claim 108, which depends from claim 66, recites that the antibody or antigen binding fragment thereof is against a BoNT light chain but does not recite a specific BoNT serotype, and does not recite an amino acid sequence of the inactive protease domain.
Claim 109 recites: the complex of claim 66, wherein the antibody or antigen binding fragment thereof comprises the amino acid sequence of any one of SEQ ID NO: 57, SEQ ID NO:58, SEQ ID NO: 67, SEQ ID NO: 113, and SEQ ID NO: 114. Claim 109 does not recite an amino acid sequence of the inactive protease domain.
Claim 110, which depends from claim 66, is drawn to complex comprising a catalytically inactive BoNT/X comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 65, 66, 71, 75, 76, 119, 128, 129, 133, 134, 137, 138, and 142-150. The amino acid sequences recited in instant claim 110 are at least 1500 amino acid sequences in length, therefore, an amino acid sequence with at least 95% sequence identity could have up to 75 amino acid residues that differ from the residues of the recited sequences. Claim 110 also does not recite what antigen the antibody/antigen binding fragment is specific against.
Claim 112, which depends from claim 66, recites that the complex further comprises an additional antibody or antigen binding fragment thereof but does not recite what antigen the antibody/antigen binding fragments is specific against, and does not recite an amino acid sequence of the inactive protease domain.
Claim 113 recites: the complex of claim 112, wherein the antibody or antigen binding fragment thereof is against BoNT/A and the additional antibody or antigen binding fragment thereof is against BoNT/B. Claim 113 does not recite the sequence of the inactive protease domain recited in claim 66.
Claim 114 recites: the complex of claim 66, wherein the inactive protease domain comprises one or more substitution mutations at a position corresponding to H227, E228, H231, R360, or Y363 of SEQ ID NO: 1, but does not recite what antigen the antibody/antigen binding fragment is specific against.
Claim 115 recites: the complex of claim 114, wherein the inactive protease domain comprises amino acid substitutions corresponding to E228Q, R360A, and Y363F in SEQ ID NO: 1, but does not recite what antigen the antibody/antigen binding fragment is specific against.
Claim 116, which depends from claim 66, recites that the toxin further comprises a receptor binding domain but does not recite a specific type of receptor binding domain, does not recite what antigen the antibody/antigen binding fragment is specific against, and does not recite an amino acid sequence of the inactive protease domain.
Claim 117 recites: the complex of claim 116, wherein the receptor binding domain is a receptor binding from a BoNT/A, BoNT/B, BoNT/C, BoNT/D, BoNT/E, BoNT/F, BoNT/G, BoNT/H, BoNT/X, but does not recite a sequence of the inactive protease domain or recite what antigen the antibody/antigen binding fragment is specific against.
Claim 118, which depends from claim 66, recites that the antibody/antigen binding fragment thereof is against a BoNT but does not recite a specific BoNT serotype, and does not recite a sequence of the inactive protease domain.
Claim 107 recites: the complex of claim 118, wherein the BoNT is a BoNT/A or BoNT/B, but does not recite a sequence of the inactive protease domain.
Therefore, the claims are drawn to a broad genus of polypeptide complexes and amino acid sequences. The dependent claims do not resolve the issue of lack of written description to support each genus as recited in claim 66. The person of ordinary skill in the art would not have recognized that the inventors were in possession of all species within the claimed genus.
The specification discloses that the invention provides catalytically inactive botulinum neurotoxin-like toxins BoNT/X, BoNT/En, and BoNT/PMP1 and their uses as delivery vehicles to deliver agents (e.g., therapeutic agents) to a cell (e.g., neurons) (Paragraph spanning pages 18 and 19). The specification has only reduced to practice the activity of VHH (A8)-ciBoNT/XA, (Figures 2-5, 7, 14, and 15), VHH B8-B10-ciBoNT/XA (Figure 6), A8-J10-ciBoNT/XA (Figures 10, 16, and 20), and A8-ciBoNT/PMP1-A (Figure 21), and discloses that they neutralize botulinum toxins (BoNT) in vitro and in vivo via the delivery of a therapeutic antibody against BoNT. It is unclear what SEQ ID NOs correspond to the VHH (A8)-ciBoNT/XA, VHH B8-B10-ciBoNT/XA, A8-J10-ciBoNT/XA, and A8-ciBoNT/PMP1-A chimeras, as the names recited in Table 2 differ from the names recited in the figures. The specification does not disclose the entire genus of claimed BoNT/X species.
Applicant has not demonstrated possession of all possible polypeptide complexes comprising an inactive BoNT/X protease domain, a translocation domain, an antibody or antigen binding fragment thereof. One of ordinary skill in the art cannot reasonably predict all domains and antibodies/antigen binding fragments that may be combined to generate a BoNT/X that functions as a delivery vehicle.
Applicant has not reduced into practice all possible sequences with up to 5% sequence divergence with each of the claimed sequences, therefore, one of ordinary skill in the art cannot reasonably predict which residues may be further modified to generate a BoNT/X that functions as a delivery vehicle.
Kupinski et al., (Pub. No. 2022/0211823 A1) teaches methods of proteolytically processing a single-chain Clostridial neurotoxin into a corresponding di-chain Clostridial neurotoxin (Paragraph 0010) and is the only prior art reference that teaches a sequence with at least 85% sequence identity to any of the SEQ ID NOs recited in instant claim 84. SEQ ID NO:7 of Kupinski shares 88.1% sequence similarity to instant SEQ ID NO:33 (recited in instant claim 84). Kupinski teaches that SEQ ID NO:7 is a BoNT/XA chimera containing the light chain and translocation domain of BoNT/X, the binding domain of BoNT/A1, and the BoNT/C1 activation loop (Paragraph 0450). However, Kupinski is silent as to whether or not said chimera can act as a delivery vehicle. Therefore, neither the specification, nor the prior art, disclose a structure-function relationship between the ability of an engineered BoNT/X to act as a delivery vehicle and its amino acid sequence.
Based on the above analysis, the specification does not identify the conserved amino acid residues, or the core structure that is present in any of the claimed complexes or sequences, correlated with the claimed delivery function. Neither is this structure-function relationship disclosed in the art. One of ordinary skill in the art would not conclude that the applicant was in possession of the entire genus of claimed species.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 66, 105-109, 112-114, and 116-118 are rejected under 35 U.S.C. 103 as being unpatentable over Dong et al. (WO2018/009903 A2) in view of Ichtchenko et al., (US2016/0159866 A1).
Regarding claim 66, Dong teaches a modified BoNT/X polypeptide comprising an inactive protease domain and a translocation domain (Page 7, lines 25-27)
Dong does not teach that the modified BoNT/X polypeptide comprises an antibody or antigen binding fragment thereof.
However, Ichtchenko teaches a fusion protein comprising a light chain region of a Clostridial neurotoxin, a heavy chain region of a Clostridial neurotoxin, and a single chain antibody positioned upstream of the light chain region (Abstract).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have added an antibody or antigen binding fragment thereof, as taught by Ichtchenko, to the modified BoNT/X polypeptide taught by Dong, to generate fusion protein (i.e., a protein complex). One of ordinary skill in the art would have been motivated to do so because Ichtchenko teaches that, by fusing an antibody to an atoxic Clostridal neurotoxin derivative, the fusion protein is able to direct a single chain antibody to neurons, translocate the antibody from an internalized endosome into the cytoplasm, potentially deliver the antibody by retrograde transport to distal neuronal cell bodies and to other neurons, and provide a means of administering a therapeutic agent by multiple routes (Paragraph 0032). One of ordinary skill in the art would have had a reasonable expectation of success because Dong and Ichtchenko are in the same field of endeavor of BoNT protein engineering.
Regarding claim 105 and 106, Ichtchenko teaches that the antibody in the fusion protein is the single-chain antibody VHH (Abstract; Paragraph 0166).
Regarding claim 107, Figure 19 (Page 80) of Ichtchenko and Example 2 (Paragraph 0242) teach an antibody against the light chain of BoNT/B.
Regarding claims 118 and 108, Ichtchenko teaches that the single-chain antibody is specific against the light chain of a wild-type Clostridium botulinum neurotoxin (Paragraph 0129).
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Regarding claim 109, Itchtenko teaches that the fusion protein comprises a sequence with 100% sequence identity to SEQ ID NO:67 (see alignment below).
Regarding claim 112, although Ichtchenko teaches a fusion protein comprising only one antibody or antigen binding fragment against the light chain of a BoNT, Ichtchenko teaches that VHH single-chain antibodies can be easily engineered into multivalent and multispecific formats (Paragraph 0114), which suggests that they can be engineered to include more than one antigen-binding fragment. Therefore, one of ordinary skill in the art would be reasonably expected to understand that additional antigen-binding fragments may added to a BoNT fusion protein based on the teachings of Ichtchenko.
Regarding claim 113, as stated above, Ichtchenko teaches that the single-chain VHH antibody can be easily engineered into multivalent or multispecific formats. Ichtchenko also teaches that a proteasome-targeting sequence to an anti-BoNT, serotype A VHH could accelerate recovery from intoxication with wt BoNT/A (Paragraph 0114) and teaches a fusion protein comprising an antibody against BoNT/B (Paragraph 0242). Therefore, one of ordinary skill in the art would be reasonably expected to understand that the single-chain antibody of Ichtchenko may be engineered to have multiple antigen binding sites specific to both BoNT/A and BoNT/B.
Regarding claim 114, Ichtchenko does not teach that the fusion protein comprises a substitution mutation corresponding to position H227, E228, H231, R360, or Y363 of SEQ ID NO:1 (which is the full length BoNT/X amino acid sequence), however, Ichtenko does teach that early work reported that the heavy chain and light chain of wild type BoNTs could be separated, and that the wild-type heavy chain could be reconstituted in vitro with a recombinant light chain which could carry point mutations such as H227Y, which rendered the light chain protease domain atoxic (Paragraph 0009). Therefore, it would be obvious to one of ordinary skill in the art that H227 of any BoNT could be mutated to generate a light-chain protease domain that is atoxic (i.e., catalytically inactive against SNAP-25).
Regarding claim 116, Figure 55 of Itchtenko teaches an amino acid sequence of the fusion protein of the invention (Paragraph 0089). Figure 55N-55P teaches that the sequence comprises a receptor binding domain (Pages 329-331).
Regarding claim 117, Figure 55N-55P of Itchtenko teaches that the receptor binding domain is BoNT/C (Pages 329-331).
Allowable Subject Matter
Claims 111 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claim 111, there are no prior art references that teach a sequence with 100% sequence identity to any of SEQ ID NOs: 65, 66, 71, 75, 76, 119, 128, 129, 133, 134, 137, 138, or 142-150 as required for the claimed complex.
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 66, 114, and 116 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12-14 of U.S. Patent No. 11,286,473 in view of Ichtchenko et al., (US2016/0159866 A1).
Claim 12 of ‘473 recites a modified Clostridium botulinum neurotoxin, serotype X (BoNT/X) polypeptide comprising an inactive protease domain, a linker region, and a translocation domain.
Claim 12 of ‘473 does not recite that the modified C. botulinum neurotoxin, serotype X (BoNT/X) comprises an antibody or antigen binding fragment thereof.
However, Ichtchenko teaches a Clostridium botulinum neurotoxin comprising an antibody (Abstract).
Instant claim 66 is unpatentable over claim 12 of ‘473 in view of Ichtchenko because both claims require an inactive protease domain and a translocation domain of Clostridium botulinum BoNT/X, while Ichtchenko teaches a Clostridium botulinum neurotoxin comprising an antibody.
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have added an antibody, as taught by Ichtchenko, to the modified Clostridium botulinum neurotoxin of serotype X (BoNT/X), claimed in U.S. Patent No. 11,286,473.
Claim 13 of ‘473 recites the modified BoNT/X of claim 12, wherein the modified BoNT/X further comprises a receptor binding domain.
Claim 14 of ‘473 recites the modified BoNT/X of claim 12, wherein the inactive protease domain comprises one or more substitution mutations at position R360, Y363, H227, E228, or H231 of SEQ ID NO: 1.
Instant claim 116 is unpatentable over claim 13 of ‘473 because both claims require that the catalytically inactive BoNT/X further comprises a receptor binding domain.
Instant claim 114 is unpatentable over claim 14 of ‘473 because both claims require that the inactive protease domain comprises one or more substitution mutations at a position corresponding to H227, E228, H231, R360, or Y363 of SEQ ID NO:1.
Instant SEQ ID NO:1 and SEQ ID NO:1 of ‘473 share 100% sequence identity (see alignment attached to this Office action).
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/RACHEL EMILY MARTIN/Examiner, Art Unit 1657