DETAILED ACTION
Claims 1-15 are pending.
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 .
Priority
This application is a 371 of PCT/NL2022/050042 (01/28/2022) which claims priority to EUROPEAN PATENT OFFICE (EPO) 21154421.8 (01/29/2021) and EUROPEAN PATENT OFFICE (EPO) 21166717.5 (04/01/2021) as reflected in the filing receipt issued 12/22/2023.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 20 2023 and November 8 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."” In the current case, the view numbers for Figures 1-12 are preceded by the word "Figure" instead of the abbreviation "FIG.".
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.” In the current case, the view numbers for the partial views for Figures 3, 4, 6 and 12 that appear on several sheets are followed by "continued" instead of a capital letter such as FIG. 3A, FIG. 3B, etc.
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.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Specifically Figures 1, 3, 4, 6, 7, 8 and 11 recite nucleic acid sequences with more than 10 specifically defined and enumerated nucleotide residues. Figures 5 and 10 recite amino acid sequences with more than 4 specifically defined and enumerated amino acid residues.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 7 is objected to because of the following informalities: an extra comma occurs after nuclease and before or in line 2. Appropriate correction is required.
Claim 15 is objected to because of the following informalities: in line the claim recites “a adenine” but should recite “an adenine”. Appropriate correction is required.
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 1-15 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 1, 10 and 14 as currently written is vague and indefinite. The claim recites the editing system provides A to G editing and/or C to T editing of the complementary strand of the dstna. It isn’t clear what strand applicants are referring to. The abstract states editing of the guide-complementary strand. However, claims 1/10/14 does not make it clear that the complementary strand is the guide-complementary strand. The claims recite complementary strand of the ds target nucleic acid which is not necessarily the same strand as the guide-complementary strand.
Claimed 4 as currently written is vague and definite. The claim recites the Cas nuclease lacks at least part of a recognition lobe, termed Rece1 and Rec2 domain. This recitation is unclear because it isn’t clear if the at least part is modifying all three, specifically a recognition lobe, Rec1 and Rec2. The punctuation and the recitation termed make the scope unclear. Specifically, it isn’t clear if the recitation termed Rec1 and Rec2 are further limiting the recitation recognition lobe or if the at least part means that the nuclease lacks at least part of all three of those things. If it is the former, then this recitation recites the broad recitation recognition lobe, followed by the narrower recitation Rec1 and Rec2 domain. The claim does not limit the Cas nuclease to a particular type. While Cas9 includes a Rec1 and Rec2 domain in the recognition lobe (see Palermo et al., Q Rev Biophys, 2018) not all Cas nucleases include this particular nomenclature. For example Cas13 has a NTD and Helical-1 rec lobe (see Zhang et al., Front Cell Infect Microbiol, 2024, figure 3). Therefore, it isn’t clear what Cas nucleases are being claimed. See MPEP § 2173.05(c).
Claim 4 as currently written is vague and indefinite. The claim recites the Cas nuclease lacks at least part of a recognition lobe when compared to other Cas nucleases. It is unclear what other Cas nuclease the comparison is to. Is the comparison to Cas nucleases (wt, i.e. those that don’t lack at least part of the recognition lobe) or if it is compared to a completely different Cas nucleases. The claim does not make the comparison clear.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 6 recites the broad recitation multimerizes and the claim also recites preferably dimerizes which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 8 as currently written is vague and indefinite. The claim recites “the Cas nuclease” is fused to a deaminase, whereby a loop structure at the C-terminal region of the deaminase is duplicated at the N-terminal region of the deaminase and a C-terminal helix structure is duplicated and inverted as N-terminus of the deaminase. The claim never refers to the particular class of Cas nuclease. While Cas9 and Cas12a use structural loops not all Cas nucleases necessarily possess a loop (see Tsui et al., Annu Rev Biophys, 2016). Therefore, it isn’t clear if merely combining the nuclease with the deaminase necessarily results in a loop structure or if the Cas nuclease is limited to those such as Cas9 and Cas12a. The claim merely refers to “a loop” or “a helix structure” without providing a description of these particular structures.
The term “suitable expression promoter” in claim 11 is a relative term which renders the claim indefinite. The term “suitable” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It isn’t’ clear what makes an expression promoter suitable. Nor does the claim or the specification provide the metes and bounds for determining if a promote is suitable. The recitation does not distinguish the instantly claimed promoter from any known expression promoter.
Claim 15 as currently written is confusion. The claim recites wherein an adenine or cytidine deaminase enzyme is fused to the C-terminus of the Cas nuclease. This recites the adenine and cytidine deamination enzyme in the alternative. But then the claim also recites optionally wherein a cytidine deamination enzyme is fused to the N-terminal end of the Cas nuclease and the adenine deamination enzyme is fused to the C-terminal end. The recitation “the adenine” must be referring back to the earlier recitation of adenine but the cytidine does not. Therefore the scope of the structural arrangement of the deamination enzyme(s) and the Cas nuclease is unclear. The N-terminal end and C-terminal end are two structurally distinct locations on the Cas nuclease.
Claims 2-3, 5, 7, 9, 12-13 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Claim Rejections - 35 USC § 102
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) 1-2, 8, 10-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhou (CN112126637A).
The instant application claims a method for base-editing a double stranded target nucleic acid (dstna) in a cell, comprising providing the cell with a clustered regularly interspaced short palindromic repeat (CRISPR)-based editing system comprising a guide ribonucleic acid (gRNA) of which a part is complementary to a nucleic acid strand of a dstna, and a cleavage-deficient CRISPR-associated (Cas) nuclease that is fused to a deaminase, whereby the editing system provides A to G editing, and/or C to T editing, of the complementary strand of the dstna.
The instant application claims a nucleotide molecule encoding a Cas nuclease that is fused to a deaminase, allowing A to G editing and/or C to T editing of the complementary strand of the ds target nucleic acid
An expression vector comprising the nucleotide under control of a promoter is claimed. A cell is claimed.
The instant application claims an isolated Cas nuclease that is fused to an adenine deaminase and/or cytidine deaminase, allowing A to G editing and/or C to T editing, of the complementary strand of the ds target nucleic acid.
Zhou (wherein a machine translation is utilized and all references are to the translation). Claimed is a fusion protein which is a TadA9-ScCas9, TadA9- SpRY (D10A); TadA9-SpCas9 (D10A) or TadA9-SpCas9-NG (D10A) (claim 7). Claimed is a nucleic acid encoding the fusion protein. An expression cassette containing the nucleic acid molecule (claim 8). The expression cassette is capable of expressing the DNA of the protein in the host cell. The dna comprises the promoter but also the terminator (page 5). A Ubip promoter is taught (page 6). In embodiment 1, the A point mutation in the rice genome is G. The invention provides a method for point A mutation on the plant genome is G, comprising the following steps: introducing the DNA molecule expressing the adenine base editor and sgRNA into the receptor plant to obtain the target plant containing A point mutation of G (page 6).
The instant application teaches that cleavage deficient Cas proteins include dCas9 (D10A and H840A), Cas9(D10A), Cas9(H840A), nCas9. C2c4 nuclease (aka Cas12u1), AsCas12F1, Cas12F (page 12).
Therefore, Zhou reads on the instant claims as it teaches introducing into a cell a nucleotide encoding a gRNA with a cleavage-deficient Cas nuclease (SpCas9 (D10A)) and an adenine deaminase enzyme (TadA9) wherein the point mutation occurs on the plant genome (complementary strand). This reads on claims 1-2, 10 and 14.
Regarding claim 6, Zhou teaches the same Cas nuclease (i.e. cleavage-deficient Cas nuclease) and gRNA.
Regarding claim 8, Zhou teaches fusing the Cas nuclease to a deaminase. The fusion appears to be the same as what is suggested in the instant specification (i.e. same cleavage-deficient Cas nuclease and deaminase enzyme) suggesting the same structure as claimed.
Regarding claims 11-12, Zhou teaches an expression cassette with a promoter.
Claim(s) 1-3 and 8-15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim (USPGPUB No. 20180258418).
The instant claims are set forth above.
Kim is directed to method of identifying genome-wide off-target sites of base editors by detecting single strand breaks in genomic dna. Claimed is introducing into a cell (a) a cytidine deaminase or a gene encoding a cytidine deaminate, (b) an inactivated target specific endonuclease or a gene encoding an inactivated target-specific endonuclease and (c) a guide RNA or a gene encoding a guide RNA wherein the inactivated target-specific endonuclease is a Cas9 protein or Cpf1 protein lacking endonuclease activity (claim 1). The Cas9 has D10, H840 or both D10 and H804 mutations (claim 2). The cytidine deaminase and the inactivated target-specific endonuclease are in fusion protein form (claim 5). Specifically taught is the cytidine deaminase fused to the C-terminus of the inactivated target specific endonuclease (paragraph 0059). A complementary strand to the strand on which a break has been induced in a double-stranded DNA fragment includes base editing (conversion of at least cytosine (C) residue to uracil (U) or thymine (T)) (paragraph 0114).
Regarding claims 1-2, 10, 13 and 14, Kim teaches a gRNA, a cleavage deficient CAS nuclease (i.e. inactivated target specific endonuclease which is a Cas9) and a cytidine deaminase. This combination is provided to a cell.
Regarding claims 3 and 15, the deaminase is fused to the C-terminus of the endonuclease (paragraph 0059).
Regarding claim 8, Kim teaches fusing the Cas nuclease to a deaminase. The fusion appears to be the same as what is suggested in the instant specification (i.e. same cleavage-deficient Cas nuclease and deaminase enzyme) suggesting the same structure as claimed.
Regarding claim 9, Kim teaches a peptide linker can be used to fuse the Cas nuclease to deaminase (paragraph 0059).
Regarding claims 11-13, Fig. 4 shows the cleavage map of the Cas9 expression plasmid vector. The plasmid in which a cytidine deaminase-encoding gene and an inactivated target-specific endonuclease-encoding gene are contained to encode the fusion protein. Included is a promoter and a host cell (paragraph 0059-0060).
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Kim as applied to claims 1-3 and 8-15 above and in view of Liu et al. (USPGPUB No. 20190367891)
Applicant Claims
The instant application claims the Cas nuclease lacks at least part of a recognition lobe, termed Rec and Rec2 domain, when compared to other Cas nucleases.
The instant application claims the Cas nuclease multimerizes upon binding to the gRNA in the CRISPR-based editing system, preferably dimerizes.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Kim are set forth above. Kim teaches an inactivated target-specific endonuclease is a Cas9 protein or Cpf1 protein lacking endonuclease activity.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Kim teaches an inactivated endonuclease, Kim does not expressly teach the Cas nuclease lacks at least part of a recognition lobe when compared to other Cas nuclease or that the Cas nuclease multimerizes. However, these deficiencies are cured by Liu et al.
Liu et al. is directed to programmable cas9-recombinase fusion proteins and uses thereof. Taught are nuclease inactive Cpf1 variants. These proteins do not have the alfa-helical recognition lobe of Cas9 (paragraph 0101). In some embodiments a nuclease protein can bind and cleave a nucleic acid molecule in a monomeric form, while, in other embodiments, a nuclease protein has to dimerize or multimerize in order to cleave a target nucleic acid molecule (paragraph 0067). In the context of proteins that dimerize (or multimerize) such as, for example, fusions between a nuclease-inactivated Cas9 (or a Cas9 gRNA binding domain) and a recombinase (or catalytic domain of a recombinase) (paragraph 0147).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kim and Liu et al. and utilize an inactive Cpf1. One skilled in the art would have been motivated to utilize this inactive endonuclease as Kim suggests the endonuclease can be Cas9 or Cpf1. It would have been obvious to one of ordinary skill in the art to try any of the specifically taught endonucleases as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007). Regarding claim 4, as taught by Liu et al. the Cpf1 lacks the alfa-helical recognition lobe of Cas9 meaning it lacks at least part of a recognition lobe when compared to Cas9.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kim and Liu et al. and utilize an endonuclease which dimerizes. As taught by Liu et al. nuclease protein can bind and cleave a nucleic acid molecule in a monomeric form, while, in other embodiments, a nuclease protein has to dimerize or multimerize in order to cleave a target nucleic acid molecule. Since there are only two options, binding to monomer or dimeric form, one skilled in the art would recognize that use of endonucleases which dimerize which is required for cleavage would be obvious.
Claims 5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Kim as applied to claims 1-3 and 8-15 above and in view of Karvelis et al. (Nucleic Acids Research, 2010, cited on PTO Form 1449).
Applicant Claims
The instant application claims the Cas nuclease is a Cas12F nuclease.
The instant application claims the Cas nuclease comprises at most 800 amino acid residues.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Kim are set forth above. Kim teaches an inactivated target-specific endonuclease.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Kim teaches an inactivated target-specific endonuclease, Kim does not expressly teach a Cas12F nuclease. However, this deficiency is cured by Karvelis et al.
Karvelis et al. is directed to PAM recognition by miniature CRISPR-Cas12f nucleases triggers programmable double-stranded DNA target cleavage. Recently, small CRISPR-associated effector proteins (Cas12f) have been identified (page 5016; Fig 1). The majority of Cas12f proteins are nearly half the size of the smallest Cas9 or Cas12 nucleases which as shown in Figure 1 is 400-700 aa (page 5016). It was found that these compact proteins are programmable enzymes capable of introducing targets dsDNA breaks like larger effectors, Cas9 and Cas12. The data confirms that at least some of the Cas12f effectors function like Cas9 and Cas12 nucleases to recognize, cleave and protect against dsDNA invaders (pages 5022-5023). The more compact versions simplify delivery (abstract).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kim and Karvelis et al. and replace the Cas9 of Kim with Cas12f with a reasonable expectation of success. One skilled in the art would have been motivated to replace the Cas9 with Cas12f as both are nucleases which can recognize and cleave dsDNA as taught by Karvelis et al. Since Cas1f is more compact which would simply delivery as taught by Karvelis et al. one skilled in the art would have been motivated to utilize this substitution.
Regarding claim 7, as taught by Karvelis et al. Cas12f has 400-700 amino acids which is less than the claimed 800.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636