DETAILED ACTION
Claims 1-14 are currently under examination. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/29/23 is in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statement has been considered by the examiner, and an initialed and signed copy of the 1449 is attached to this action.
37 CFR 1.821-1.825
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below and on the Notice To Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures which is attached to this communication. Specifically, Figure 1 depicts 15 separate amino acid sequences which are not identified by SEQ ID NOS as required by 37 CFR 1.821. It is noted that the Brief Description of the Drawings in the specification further fails to provide the requisite SEQ ID NO: for each sequence presented in Figure 1.
If these sequences are present in the sequence listing filed on 8/29/23, then applicant may comply with the 37 CFR 1.821-1.825 by amending either the drawings or the Brief Description of the drawings in the specification, or both, to incorporate the correct SEQ ID NOS for each sequence listed. Instructions for filing an amendment to the drawings may be found in 37 CFR 1.121(d). See also 37 CFR 1.84. Instructions for amending the specification may be found in 37 CFR 1.121(b).
If one or more of these sequences is not present in the as filed sequence listing, a new sequence listing is required. See the attached Notice to Comply for details.
APPLICANT IS GIVEN A THREE MONTH EXTENDABLE PERIOD WITHIN WHICH TO COMPLY WITH THE SEQUENCE RULES, 37 CFR 1.821-1.825. Failure to comply with these requirements will result in ABANDONMENT of this application under 37 CFR 1.821 (g). Extension of time may be obtained by filing a petition accompanied by the extension fee under the provisions of 37 CFR 1.136. In no case may an applicant extend the period for response beyond the six month statutory period. Applicant is requested to return a copy of the attached Notice To Comply with the response.
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.
Claims 9-12 are 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.
Claims 9-12 all depend on independent claim 1, which is a method for treating a medical condition by administering to a subject a nucleic acid construct or expression vector encoding one of SEQ ID NOS: 1, 2, or 9-15. Claims 9-12 each further recite a functional property of the proton pump. However, claims 9-12 are confusing as following the recitation of the functional property, each of the claims recite, “if measured in” followed by a recitation of a proteo-nanodisc or a rat hippocampal cell under particular conditions. The phrase “if measured in” renders the claims confusing as it is unclear whether the functional property recited only occurs in proteo-nanodiscs or rat hippocampal cells under those conditions, or whether the functional property is also occurring in vivo in the subject. Further, the conditions listed after the phrase “if measured in” appear to be in vitro conditions involving the use of specific cell media, patch-clamps, and patch pipettes, and not in vivo conditions. Claim 9 is further indefinite in the recitation “if measured in proteo-nanodiscs exhibiting a molar ratio of DMPC:MSP1 E3:light-driven inward directed proton pump of 100:2:3 at 20oC and pH 7.5, providing pulses of 5 ns duration at 532 nm wavelength and energy of 3 mJ/pulse”. The phrase “providing pulses of 5 ns duration at 532 nm wavelength and energy of 3 mJ/pulse” is confusing as it is unclear what types of pulses are provided, how they are provided, and if, as they written in the present tense, the “providing pulses” is meant to be an active method step. Thus, the metes and bounds of claims 9-12 cannot be determined.
In the interests of compact prosecution, claims 9-12 have been given their broadest reasonable interpretation as reading on a proton pump with the sequence of one of SEQ ID NOS 1, 2, or 9-15, and the functional property as claimed whether it occurs in vivo or in vitro.
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 1-14 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are broadly drawn to methods of medical treatment comprising the administration to a patient of a nucleic acid construct or an expression vector comprising a nucleotide sequence coding for a light-driven inward directed proton pump, wherein the light-driven inward directed proton pump comprising or consisting of an amino acid sequence selected from SEQ ID NO:1 (NsXeR), SEQ ID NO:2 (HrvXeR1), SEQ ID NO:9 (HrvXeR), SEQ ID NO:10 (AIkXeR), SEQ ID NO:11 (AIkXeR1), SEQ ID NO:12 (AIkXeR2), SEQ ID NO:13 (AIkXeR3), SEQ ID NO:14 (AIkXeR4) and SEQ ID NO:15 (AIkXeR5). The specification does not provide an enabling disclosure for treating any medical condition in a patient by administering using any route of administration any nucleic acid construct or expression vector encoding a nucleic acid which encodes any of the XeR inward directed proton pumps set forth in SEQ ID NOS 1, 2, or 9-15. The broadest claims read on the treatment of any medical condition which includes any genetic disease, any infectious disease, any autoimmune disease, any neurological disease, any hyperproliferative disease, any inflammatory disease, any blunt force trauma, etc. Claim 13 limits treating a medical condition to restoring auditory activity, recovery of vision, treating or alleviating alkalosis, treating or alleviating neurological injury, treating or alleviating brain damage, treating or alleviating seizure, and treating or alleviating a degenerative neurological disorder. Claim 14 limits the treatment to treatment of Parkinson's disease or Alzheimer's disease. The broadest claims further read on the use of a nucleic acid construct or expression vector which may or may not comprise a promoter or other regulatory sequences. It is also noted that while claims 5 and 6 do include the limitation that the nucleotide sequence encoding the proton pump is under the control of a neuronal cell specific promoter, or more specifically a human synapsin promoter, the method of these claims continues to read on the treatment of any medical condition. The claims also read broadly on the use of any nucleic acid construct, or any expression vector including linear nucleic acids, RNA, plasmids, and bacterial or viral vectors.
The specification discloses that NsXeR, HrvXeR, and AlkXeR belong to a relatively new family of Nanohaloarchaea bacteria. The specification notes that rhodopsin proteins from each of these species had been reported in the prior art and designated as xenorhodopsins, but that these xenorhodopsins had not been characterized in terms of their ability to transport any specific ion across a cell membrane. The specification teaches that these three xenorhodopsins are in fact inward directed proton pumps, in contrast to all previously known bacterial rhodopsin proton pumps which are outward proton pumps. The specification provides a disclosure of the amino acid sequence of NsXeR (SEQ ID NO:1) , HrvXeR (SEQ ID NO:9), and AlkXeR (SEQ ID NO:10), and further discloses the HrvXeR1 mutant (SEQ ID NO:2) of HrvXeR, and the five mutants of AlkXeR referred to as ALKXe1-5 (SEQ ID NOS 11-15) respectively. The specification also discloses a single human codon optimized nucleotide sequence for NsXeR (SEQ ID NO:16). The specification generally discloses properties for these inward directed proton pumps, including the functional properties recited in claims 7-12.
The specification also provides several working examples. The first working example disclose that the nucleotide sequences of three previously reported xenorhodopsins, NsXeR, HrvXeR, and AlkXeR, were codon optimized for E. coli expression, incorporated into an expression vector and expressed in transfected E. coli cells. Each of the three sequences were capable of affecting the increase in the pH of the transfected cell suspension following illumination with a halogen lamp emitting light of undisclosed wavelength(s) (specification pages 32-33). The working examples teach the purification of at least NsXeR and AlkXeR from E.coli and incorporation of the proteins in liposomes or nanodiscs. The working examples disclose that NsXeR also exhibited the ability to increase the pH of NsXeR liposomes in response to halogen lamp illumination. The working examples further disclose that NsXeR exhibits a light absorption maximum of 565 nm which was unaffected by pH. In contrast, AlkXeR is red-shifted with an absorption maximum of 577 nm (specification, pages 35-36). The working examples also disclose the crystal structure of NsXeR, which differs significantly from other known microbial retinal proton pumps such as bacteriorhodopsin (BR). The specification provides a Table on page 39 which further discloses the negative effects of mutations in a number of residues present in NsXeR on either protein folding, stability, or proton pump activity. In fact, of the 15 mutants tested, only two were fully functional. The specification states that based on their analysis, “ a unique and unusual set of key residues in NsXeR results in inwardly directed proton pumping” (specification page 42). Finally, the working examples teach the generation of a human codon optimized NsXeR nucleotide sequence, a plasmid vector encoding the optimized NsXeR sequence operably linked a sequence encoding a heterologous membrane trafficking signal under transcriptional control of the CMV promoter, and a recombinant AAV vector encoding the optimized NsXeR sequence linked to a Kir trafficking signal under transcriptional control of a neuron specific human synapsin promoter. The examples demonstrate transfection of a human embryonic kidney cell line and a neuronal neuroblastoma cell line in vitro with the plasmid vector, and transduction of rat hippocampal neurons in vitro with the AAV vector, and reports light induced photocurrent generation in the cell membranes of all three cells in vitro under specific conditions, which include laser light exposure with a wavelength of 532 nm. The example further shows light induced depolarization of the rat neuroblastoma cells expressing NsXeR, with some neurons requiring longer pulse widths for light-triggered spiking. The working example provide a prophetic description of the use of their disclosed inwardly directed proton pumps for the treatment of deafness or for vision recovery, but provide no in vivo data resulting from the delivery of any nucleic acid construct or vector encoding SEQ ID NO1, 2, or 9-15 to any location in a subject or demonstrate any effect on any medical condition resulting from the administration of the nucleic acid construct or vector. It is also noted that the working examples did not test any of the mutants identified as SEQ ID NOS 2, or 11-15.
As discussed above, the specification provides a specific description of the amino acid sequence of three specific xenorhodopsin proteins, NsXeR, AlkXeR, and HrvXeR, which were previously reported in the art and derived from three different bacteria respectively, 1 variant of HrvXeR, and 4 variants of AlkXeR. Of these, only unmutated NsXeR, AlkXeR, and HrvXeR were shown to be capable of affecting pH in bacteria, and only NsXeR was fully characterized for crystal structure, and expressed in mammalian cells. Functional properties and activity of the disclosed variants (SEQ ID NOS 2, and 11-15) is not provided. Further, while each of these three sequences were shown to respond to light and act as inwardly directed proton pumps in bacterial cells, only NsXeR was tested for activity in mammalian cells. The specification does not provide an enabling disclosure for the use of any of SEQ ID NOS 2, or 9-15 in mammalian cells for affecting membrane potential or for membrane depolarization upon exposure to any light source of any wavelength. Figure 1 shows sequence homology between NsXeR, AlkXeR, and HrvXeR. Although a number of the residues identified in the specification as important to NsXeR protein folding, stability, and proton pump activity are conserved between NsXeR, AlkXeR, and HrvXeR, the sequences do show significant differences that clearly translate into functional differences. For example, as seen in Figure 2, whereas the expression of NsXeR in bacteria resulted in a greater than 1.5 increase in pH following exposure to a halogen light, the expression of AlkXeR and HrvXeR resulted in at most a 0.5 increase in pH with a slower increase rate. AlkXeR is also described as being redshifted compared to NsXeR with a max absorbance of 577. Furthermore, while the specification does provide the crystal structure of NsXeR, and discloses the effects of several mutations on protein folding, stability, and proton pump activity, the specification does not disclose the crystal structure of any other inward directed proton pump, or teach that the crystal structures of inward directed proton pumps are similar, or disclose any specific functional motif responsible for inward directed proton pump activity which is conserved between all three proteins. The specification also does not disclose additional motifs or residues which may be required in light driven inward directed proton pump proteins other than NsXeR for proper protein folding, protein stability, proton pump activity, and/or light activation. In addition, dependent claims 7-12 recite more specific functional properties for the light driven inward directed proton pump protein including specific activity in proteo nanodiscs, or in rat hippocampal neurons. However, the activities recited in claims 9-12 in particular are activities which were reported in the working examples for a specific modified NsXeR (SEQ ID NO:1) expressed from human codon optimized NsXeR sequence where the NsXeR is a C-terminal fusion protein with a Kir2.1 membrane trafficking signal in proteo-nanodiscs or in rat hippocampal cells following exposure to a specific wavelength of light- 532 nm. There is no evidence provided that any light driven inward directed proton pump protein other than NsXeR would share the exact same properties exhibited by NsXeR in proteonanodiscs or in rat hippocampal neurons, or even that an NsXeR in the absence of the membrane trafficking signal would be capable of exhibiting these same properties when expressed in rat hippocampal cells and exposed to 532 nm wavelength light under the conditions recited in the claims. In fact, as NsXeR was shown in the specification to have different effects on pH than AlkXeR, and HrvXeR, and has a different max absorbance wavelength than the other two rhodopsins, the skilled artisan would not have predicted that either AlkXeR or HrvXeR would exhibit the same functional properties as NsXeR in proteonanodiscs or in rat hippocampal neurons. Further, in regards to NsXeR, the specification provides no guidance that this proton pump can be expressed in any cell from a nucleic acid construct or vector which lacks a promoter. The specification also clearly teaches that the inwardly directed proton pump activity of NsXeR requires exposure to a specific wavelength of light. It is noted that the claimed method only include a single active step of administering the nucleic acid construct or vector and do not include exposure of the subject to light. In addition, as discussed above, the specification does not provide specific guidance for administering a nucleic acid construct or expression vector encoding NsXeR to any subject using any means of administration where any medical condition is treated. Applicant’s prophetic examples of the use of the claimed constructs/vectors for treating deafness or vision disorders were based on prior art reports exploring the activity of channel rhodopsins, which the specification clearly discloses are substantially unrelated in structure, sequence, and function. Applicant’s working examples, while showing that exposure of rat hippocampal cells expressing a modified NsXeR protein in vitro to 532nm wavelength light can induce membrane depolarization, does not correlate the depolarization to any functional effect on the rat hippocampal cells. Note that the specification states that a light-driven inward proton pump protein taught by Inoue et al., while capable of depolarizing mouse neurons, is insufficient for activation of neuronal cells (specification page 3). Thus, the specification itself acknowledges a lack of correlation between the triggering of depolarization in neurons and the activation of neurons. Thus, as a whole, the specification, including the working examples, does not provide an enabling disclosure for affecting any cells, including any neurons, in vivo, with or without exposure to light, by expression of any one of SEQ ID NOS 1, 2, or 9-15 in the cells, or that such expression can result in any therapeutic effect on any symptom of any medical condition in the subject.
Turning to the prior art at the time of filing, while the prior art, as acknowledged by the specification, taught several xenorhodopsins, including a xenorhodopsin with more than 90% sequence identity to SEQ ID NO:1, the prior art at the time of filing did not teach that these xenorhodopsins exhibited light driven inward directed proton pump activity. Narasingarao et al. disclosed the genomes of two archaea bacteria found in the surface water of Lake Tyrrell, which they describe as highly unusual in both genomic and amino acid composition compared to previously sequenced archaeal and bacterial genomes (Narasingarao et al. (2012) ISME J., Vol. 6, 81-93). Narasingarao et al. teaches that the two archaea, while phylogenically related, are different species that each encode one rhodopsin-like protein (Narasingarao et al., pages 86-87, and Figure 1). It is noted that Uniprot Accession Number G0QG75 shows that the amino acid sequence of the J07AB43 strain rhodopsin-like protein is 100% identical to SEQ ID NO:1 (Uniprot Accession Number G0QG75 (October 19, 2011)). Ugalde et al. teaches that the two archaea species discovered by Narasingarao, Nanosalina sp. J07AB43 and Nanosalinarum sp. J07AB56, are the first representatives of a major new lineage of Achaea referred to as Nanohaloarchaea, and are highly similar to each other (89% amino acid identity), but substantially dissimilar to other rhodopsins, with the highest similarity to Anabaena (Nostoc) sp. PCC 7120 at 34% (Ugalde et al. (2011) Biology Direct, Vol. 6:52, 1-8, see pages 1-2). Ugalde et al. refers to these two new rhodopsins and rhodopsins from several other novel phylogenically related bacteria as xenorhodopsins and further teaches that the amino acid sequences of these xenorhodopsins appear to be inconsistent with known proton or chloride transporting rhodopsins (Ugalde et al., pages 2-3). Ugalde et al. teaches that xenorhodopsins may be sensory rhodopsins, but emphasizes that it is impossible to the predict functional activity of these proteins based on sequence alignment, particularly since microbial rhodopsin protein as a whole are structurally and functionally sensitive to even single amino acid substitutions (Ugalde et al., page 3). As examples, Ugalde et al. teaches that a single amino acid substitution can confer inward proton pumping activity of the ASR protein, and that a single amino acid substitution can convert a bacteriorhodopsin proton pump into a chloride pump (Ugalde et al.., page 3). Ugalde et al. concludes that no sensory or ion transport function has been determined for any xenorhodopsin (Ugalde et al., page 6). Inoue et al. does teach a single light-driven inward proton pump protein from a deep sea marine bacterium, but this protein does not appear to be even 59% similar to SEQ ID NO:1 (Inoue et al. (2016) Nat. Commun., 7:13415, pages 1-10.DOI:10.1038/ncomms13415).Further, as noted above, the instant specification states that this specific light-driven inward proton pump protein taught by Inoue et al., while capable of depolarizing mouse neurons is insufficient for activation of neuronal cells (specification page 3). Thus, the prior art at the time of filing does not teach a genus of rhodopsins which are light driven inward directed proton pumps, and does not teach that Nanosalina sp. J07AB43, with a sequence 100% identical to SEQ ID NO:1, is an inward directed proton pump or provide any teaching that it could be used as such. In addition, the prior art at the time of filing teaches that J07AB43 is unusual in its amino acid sequence and that the rhodopsin family as a whole are functionally sensitive to even single amino acid substitutions. Therefore, the state of the prior art with regards to light driven inward directed proton pumps was largely undeveloped as the function of proteins referred to as xenorhodopsins had yet to be established. Further, due to the art-recognized sensitive nature of rhodopsins to amino acid alterations, the limited disclosure in the specification regarding the activity of a light driven inward directed proton pump other than SEQ ID NO:1, the lack of sufficient guidance for the motifs required for inward directed proton pump activity, protein folding, and protein stability, and the teachings of the specification that the single light-driven inward proton pump protein from a deep sea marine bacterium reported in the prior art (Inoue et al.), while capable of depolarizing mouse neurons, is insufficient for activation of neuronal cells, the skilled artisan at the time of filing would not have found the use of any one of SEQ ID NOS 1, 2, or 9-15, for treating any medical condition based on solely on their identification as an inwardly directed proton pump as predictable.
Further in regards to the use of a light driven inward directed proton pump protein as claimed to treat a medical condition, it is noted that the specification provides no working examples demonstrating the delivery of any vector encoding a light driven inward directed proton pump protein to cells in vivo, where the protein is taken up and incorporated into the cell membrane of any cell in a subject, is functional as a light driven inward directed proton pump protein, and has a therapeutic effect on any medical condition. The specification is primarily focused on optogenetic methods, where a vector encoding a light driven inward directed proton pump protein is used to transfect/transduce cells and express the encoded proton pump in the cell. However, the specification does not teach specific target cells for expressing the light driven inward directed proton pump protein, or how a light driven inward directed proton pump protein may treat or ameliorate any disease or disorder in a subject. In addition, though the specification does teach optogenetic therapy of neurological diseases, where a vector is delivered directly to target cells in the brain followed by targeted light induction of rhodopsin activity, the specification does not teach how to target any particular neuron with a light driven inward directed proton pump protein as claimed. It is also noted that the specification clearly teaches the need for light at a specific wavelength to activate the light driven inward directed proton pump protein. The claimed methods lack a step wherein light is the subject to activate the light driven inward directed proton pump protein for any treatment effect.
Turning to the state of the prior art for treatment of diseases using rhodopsins, the prior art does not teach the treatment of any disease using a light driven inward directed proton pump protein. In addition, it is noted that even optogenetic methods using outward directed proton pumps such as bacteriorhodopsin, or other types of optogenetic methods using channel rhodopsins for medical therapy are neither well established nor routine. Ordaz et al., in a recent review of optogenetics and its application in neural degeneration and regeneration, teaches that even though application of optogenetics in understanding brain functional organization and complex behavior states has seen some progress, the potential for optogenetic treatment of neurodegeneration and regeneration is still being established (Ordaz et al. (2017) Neural Regeneration Research, Vol. 12(8), 1197-1209, see page 1197 and 1206). Ordaz et al. teaches that major obstacles for therapeutic application of optogenetics include the invasive nature of the treatment which requires not only delivery of a vector to target cells but the implantation of an optic fiber into brain tissue to apply light to active the opsins in deep regions which can induce tissue damage and scarring (Ordaz et al., page 1206). Thus, the state of the prior art for therapeutic delivery of a light driven inward directed proton pump protein for the treatment of any disease was highly unpredictable.
Therefore, in view of the undeveloped state of the art for xenorhodopsins and more specifically for light driven inward directed proton pump proteins, the undeveloped state of the art for treating any disease including a neurological disease by administering a vector encoding a xenorhodopsin or any light driven inward directed proton pump protein, the lack of guidance in the specification for the functional effects of the putative light driven inward directed proton pumps with the sequence of SEQ ID NOS 2, or 9-15 in any type of cell, the lack of correlation between the activity of SEQ ID NO:1 fused to a Kir2.1 membrane trafficking signal in depolarizing a rat hippocampal cell and activation of the hippocampal cell, the lack of any in vivo working examples demonstrating a therapeutic effect on any medical condition, and the breadth of the claims, it would have required under experimentation to practice the methods of treatment as claimed.
Prior Art
The closest prior art is considered to be Uniprot Accession Number G0QG75 shows that the amino acid sequence of the J07AB43 strain rhodopsin-like protein is 100% identical to SEQ ID NO:1 (Uniprot Accession Number G0QG75 (October 19, 2011)). However, the prior art did not recognize this sequence or other sequences referred to as xenorhodopsins as being inwardly direct proton pumps, or provide any teaching or motivation to introduce nucleic acid sequence encoding SEQ ID NO:1 to any subject for the treatment of any medical condition.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634