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 .
Claim Status
Claims 1, 3-11, and 13-19 have been amended and claims 20-25 have been newly added, as requested in the preliminary amendment filed on 04/07/2023. Following the amendment, claims 1-25 are pending in the instant application.
Claims 1-25 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, it is noted that the claim to foreign priority has not been perfected as no English translation of the foreign priority document has been provided.
Claims 1-25 have an effective filing date of October 14, 2021 corresponding to PCT/CN2021/123731 because the claim to foreign priority has not been perfected.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/07/2023 and 10/02/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The use of the terms FACS, Trizol, PrimeScript, GraphPad PRISM, Varioskan, for example, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Art-Free Subject Matter
It is noted that the 9 antibody species of the instant claims comprising HCDRs 1-3 and LCDRs 1-3 corresponding to instant SEQ ID NOs: 4/43/6 and 7/8/9, respectively, have been thoroughly searched and are free of the prior art. Additionally, the corresponding heavy chain variable, light chain variable, full heavy chain, and full light chain sequences have also been searched and are free of the prior art.
The closest prior art made of record but not relied upon is US 2021/0130496 A1 (herein after referred to as “Chang”). Chang teaches multispecific binding proteins that bind the NKG2D receptor, CD16 and a tumor-associated antigen wherein said tumor-associated antigen may be TROP2. More specifically, Chang discloses that the TROP2 antigen binding domain may comprise a heavy chain carriable region of SEQ ID NO: 190 and a light chain variable region of SEQ ID NO: 191; it is noted that Chang SEQ ID NO: 191 residues 1-107 are an 87.5% match to instant SEQ ID NO: 11 and Chang SEQ ID NO: 191 comprises 100% matches to instant SEQ ID NOs: 7 and 8 and an 88.9% match to instant SEQ ID NO: 9. However, it is noted that Chang instant SEQ ID NO: 191 does not comprise exact matches to all three of instant SEQ ID NOs: 7-9, nor does the corresponding heavy chain variable sequence corresponding to Chang SEQ ID NO: 190 comprise exact matches to any of the HCDR 1-3 combinations represented by instant SEQ ID NOs: 4/43/6. As such, Chang does not teach nor render obvious the instantly claimed anti-TROP2 antibody species.
Claim Rejections - 35 USC § 112
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 2, 17, 19, and 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for murine, chimeric, and/or humanized anti-TROP2 antibodies and the therapeutic treatment of a TROP2-mediated disease or condition, does not reasonably provide enablement for fully human antibodies nor the prophylactic treatment/prevention of TROP2-mediated diseases or conditions. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The Breadth of the Claims
Claim 2 is drawn to the anti-TROP2 antibody, antigen binding fragment thereof or mutant thereof of claim 1, wherein the antibody is a murine antibody, chimeric antibody, human antibody, or a humanized antibody. It is noted that the definition of “human antibody” as provided at Page 12 of the instant specification indicates that human antibodies include variable and constant regions of human germline immunoglobulin sequences, and does not include humanized antibodies. It is specifically noted that the CDRs recited in instant claim 1 from which claim 2 depends are murine CDRs, as supported at Pages 18-19 of the instant specification. Thus, the instantly claimed antibodies cannot be fully human antibodies and therefore the full scope of claim 2 is not enabled.
Claim 17 is drawn to a method of treating or preventing a TROP2-mediated disease or condition comprising administering the anti-TROP-2 antibody, antigen-binding fragment thereof or mutant thereof according to claim 1, or the pharmaceutical composition according to claim 15. It is noted that at Page 9 of the instant specification, it is indicated that a TROP2-mediated disease or condition includes cancer (e.g., breast cancer, non-small cell lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, liver cancer, gastric cancer, colon cancer, bladder cancer, esophageal cancer, cervical cancer, gallbladder cancer, glioblastoma and melanoma). It also noted that claims 19 and 25, which depend from claim 17, also disclose that a TROP2-mediated disease or condition is cancer. Furthermore, it is noted that “treatment” is specifically defined, in reference to a human subject as in claim 17, as therapeutic treatment, preventative or prophylactic measures. Thus, claims 17, 19, and 25 are drawn to the therapeutic treatment, or prophylactic treatment/prevention of cancer, the full scope of which is not enabled.
The State of the Prior Art/Level of Predictability in the Art
No material has been found to date that has been shown to or would be expected to prevent cancer, and there is no working example, prior art, or any evidence that would provide the skilled artisan with any predictable guidance to use the claimed invention. It would be reasonable to conclude the full scope of the claimed invention is not enabled.
Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations that have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, or family histories. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Further, a preventive administration also must assume that the therapeutic will be safe and tolerable for anyone susceptible to the disease.
The vaccine art teaches that compositions comprising some tumor associated antigens are effective in treatment of cancer through generation of immunogenic response to the tumor antigen (see for example, Komenaka et al., Clinics in Dermatology, 2004, Vol. 22, Pg. 251-265, specifically page 257). However, nowhere in the art does it show that tumor antigens are effective at preventing cancer. Evans et al. (Q. J. Med 1999: 92: 299-307) teach that vaccines against cancer are not fully established, and it is stated that adjuvant therapy to prevent or delay disease still needs experimentation. Evans et Al. further state that such cancer vaccines are at best used as a therapeutic and not as a prophylactic and that “the notion that cancer vaccines will replace standard therapeutic strategies in malignant disease still belongs to the realm of fiction” (see page 303 last paragraph).
In some cases, it is known that certain cancers arise from a single cause. This cause can be viral as in the case of cervical cancer, caused predominantly by persistent cervical infection with human papillomavirus (HPV) (Schiffman et al., The New England Journal of Medicine, Vo. 353, No. 20, Pg. 2101-2104, 2005). Schiffman et al. teach that primary prevention through vaccination against HPV might be possible in young women (Pg. 2101, Column 3, Paragraph, first partial). However, they also teach that vaccine evaluations are ongoing (Pg. 2103, Column 3, Paragraph, first full). In addition, the most promising vaccines designed against HPV types 16 and 18 would only prevent 70 percent of cervical cancer cases at best (Pg. 2103, Column 2, Paragraph, first full). Therefore, there is still no vaccine that can definitively prevent a cancer. Current evidence points only to the potential of future prophylactic agents.
The art of small molecule chemotherapeutics teach that some molecules successful at treating cancers can also reduce risk. Cuzick et al. (The Lancet, Vol. 361, Pg. 296-300, 2003) teach that tamoxifen can reduce the risk of ER-positive breast cancer but cannot be recommended as a preventive agent (Pg. 299, Column 2, Paragraph, first). The reason it cannot be recommended centers around the need for continued research into specific subgroups of high-risk but healthy women for whom the risk-benefit ratio is sufficiently positive to recommend prophylactic tamoxifen treatment (Pg. 299, Column 2, Paragraph, first).
With respect to peptide-based cancer prevention agents, the art currently does not recognize a definitive example though promising candidates are present. Hernandez-Ledesma (Peptides, Vol. 30, Pg. 426-430, 2009) teaches that lunasin, a peptide discovered in soy has demonstrated cancer-preventative capacity in vitro and mouse models (Abstract). The authors define it as a perfect candidate to exert an in vivo cancer-preventive activity but more research is required to establish it in this role (Pg. 429, Column 2, Paragraph, first partial).
Therefore, the art has only recognized the treatment of a cancer.
The Amount of Direction Provided the Inventor/Existence of Working Examples
With regard to the antibodies of claim 2, Example 2 (Pages 18-19) of the instant specification discloses mouse immunization programs and hybridoma preparation, subsequent screening, subcloning, and sequencing of murine antibody molecules. Examples 4-5 further disclose humanization of the murine antibodies and variant design. Thus, all antibodies of the instant specification are based on murine sequences, and the instant specification provides no description/working examples of fully human antibodies.
With regard to claims 17, 19, and 25 it is noted that there are no working examples provided that demonstrate successful prophylactic treatment/preventative measures regarding TROP2-mediated diseases or conditions (e.g., cancer).
Double Patenting
Claims 1-11, 15, 17, 19-22, and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 14-16 of copending Application No. 18/694,370 (herein after referred to as “reference application”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Reference application claim 1 is generally drawn to an antibody-drug conjugate (ADC) which comprises an anti-TROP2 antibody or antigen binding fragment thereof which comprises HCDR1 as shown in SEQ ID NO: 3, HCDR2 as shown in RIDPXDSETHYNQKFKD and HCDR3 as shown in SEQ ID NO: 5; and LCDR1 as shown in SEQ ID NO: 6, LCDR2 as shown in SEQ ID NO: 7 and LCDR3 as shown in SEQ ID NO: 8, and X is an amino acid residue selected from the group consisting of R, Y, Q, L, T, I, F, E and A. It is specifically noted that reference application SEQ ID NOs: 3, 5, 6, 7, and 8 are exact matches to instant SEQ ID NOs: 4, 6, 7, 8, and 9, respectively. It is further noted that reference application HCDR2 corresponding to RIDPXDSETHYNQKFKD wherein X is an amino acid residue selected from the group consisting of R, Y, Q, L, T, I, F, E and A is an exact match for instant HCDR2 represented by instant SEQ ID NO: 43. Reference application claim 2 further recites the possible HCDR1-3 and LCDR1-3 combinations, wherein it is noted that the CDR combinations recited by reference application claim 2 are exact matches for the CDR combinations recited by instant claim 20. More specifically, it is noted that reference application HCDR2 SEQ ID NOs: 9-17 are exact matched to instant HCDR2 SEQ ID NOs: 26-30 and 39-42, respectively. Reference application claim 3 recites that the anti-TROP2 antibody or antigen binding fragment thereof may be selected from the group consisting of a murine antibody or an antigen binding fragment thereof, a chimeric antibody or an antigen binding fragment thereof, a human antibody or an antigen binding fragment thereof, and a humanized antibody or an antigen binding fragment thereof. Reference application claim 4 recites that the anti-TROP-2 antibody or the antigen binding fragment thereof further comprises a heavy chain constant region of human IgGI, IgG2, IgG3 or IgG4 or a variant thereof, preferably, the anti-TROP-2 antibody or the antigen binding fragment thereof further comprises a heavy chain constant region of human IgG1, IgG2 or IgG4;and more preferably, the anti-TROP-2 antibody or the antigen binding fragment thereof further comprises a heavy chain constant region as shown in SEQ ID NO: 48, or as shown in SEQ ID NO: 1. It is specifically noted that reference application SEQ ID NO: 1 is an exact match to instant SEQ ID NO: 12. Reference application claim 5 recites that the anti-TROP-2 antibody or the antigen binding fragment thereof further comprises a light chain constant region of a human antibody kappa chain, lambda chain or a variant thereof; preferably, the anti-TROP-2 antibody or the antigen binding fragment thereof further comprises a light chain constant region of a human antibody kappa chain; and more preferably, the anti-TROP-2 antibody or the antigen binding fragment thereof further comprises a light chain constant region as shown in SEQ ID NO: 2. It is specifically noted that reference application SEQ ID NO: 2 is an exact match to instant SEQ ID NO: 13. Reference application claim 6 recites the anti-TROP-2 antibody or the antigen binding fragment thereof comprises a heavy chain variable region selected from the group consisting of the following sequence, or a heavy chain variable region having at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identity to the following sequence: SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or SEQ ID NO: 27; and/or, a light chain variable region of or having at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identity to SEQ ID NO: 19 and reference application claim 7 recites heavy chain variable/light chain variable region combinations comprising 100% matches to the recited sequences of claim 6. It is specifically noted that reference application SEQ ID NOs: 18, 20-27, and 19 are exact matches to instant SEQ ID NOs: 16-20, 31-34, and 11, respectively. Reference application claim 8 recites the anti-TROP-2 antibody or the antigen binding fragment thereof comprises a heavy chain selected from the group consisting of the following sequence, or a heavy chain having at least 80%, 85%, 90%, 95% or 99% identity to the following sequence: SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36 or SEQ ID NO: 37; and/or, a light chain as shown in or having at least 80%, 85%, 90%, 95% or 99% identity to SEQ ID NO: 29 and reference application claim 9 recites heavy chain variable/light chain variable region combinations comprising 100% matches to the recited sequences of claim 8. It is specifically noted that reference application SEQ ID NOs: 28, 30-37, and 29 are exact matches to instant SEQ ID NOs: 21-25, 35-38, and 15, respectively. Reference application claims 14-16 are drawn to, respectively: (i) a pharmaceutical composition comprising the ADC of any one of claims 1-9, for example, and one or more pharmaceutically acceptable excipients, diluents, or carriers; (ii) the use of the ADC of any one of claims 1-9, for example, or the pharmaceutical composition of claim 14 in the treatment of a TROP2 related disease or condition; and (iii) the use of claim 15 wherein the TROP2 related disease or condition is a cancer with high TROP2 expression, wherein the cancer is selected from the recited group. As such, the reference application reads on the anti-TROP2 antibody, antigen binding fragment thereof, or mutant thereof of instant claims 1-10 and 20-22, the pharmaceutical composition of instant claim 15, and the method of treatment of instant claims 17, 19, and 25. It is further noted that a polynucleotide that encodes such an antibody, as in instant claim 11, is also rendered obvious by the antibody of the reference application, as the nucleic acid sequence of the polynucleotide is obvious over the recited amino acid sequences.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 12-14, 16, 18, and 23-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 14-16 of copending Application No. 18/694,370 (herein after referred to as “reference application”) in view of WO 2020/191092 A1 (herein after referred to as "Shan").
With regard to claims 12-14 and 23-24, the reference application reads on the instantly claimed anti-TROP2 antibody of claim 1 and renders obvious a polynucleotide thereof as detailed above. However, the reference application does not explicitly disclose an expression vector comprising such a polynucleotide, host cells comprising said expression vector, nor methods of producing the antibody. This deficiency is remedied by Shan.
Shan teaches anti-Trophoblast cell surface antigen2 (TROP2) antibodies and fragments thereof as well as isolated nucleic acid molecules that encode anti-TROP2 antibodies, vectors comprising such nucleic acids, host cells comprising such vectors or nucleic acids, and methods of making anti-TROP2 antibodies. More specifically, Shan discloses that an antibody of the present disclosure can be produced recombinantly as a fusion polypeptide with a heterologous polypeptide, e.g., a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide (Paragraph 0157). Expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells, e.g., to allow the vector to replicate independently of the host chromosomal DNA; this sequence can include origins of replication or autonomously replicating sequences and such sequences are well known for a variety of bacteria, yeast, and viruses (Paragraph 0158). Suitable host cells for cloning or expressing the DNA in the vectors herein are the prokaryote, yeast, or higher eukaryote cells; suitable prokaryotes for this purpose include eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, etc. (Paragraph 0164) and suitable vertebrate cells for use as host cells include, for example, human embryonic kidney (HEK) 293 cells and Chinese hamster ovary (CHO) cells (Paragraph 0167). Host cells may be cultured in a variety of media, and if the antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed fragments, are removed, for example, by centrifugation or ultrafiltration prior to isolating the antibody, and the antibody composition prepared from the cells can be purified using, for example, hydroxylapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being among one of the typically preferred purification steps (Paragraphs 0168-0170). Thus, Shan teaches expression vectors comprising polynucleotides that encode anti-TROP2 antibodies, host cells (e.g., HEK293 or CHO cells) that comprise said expression vectors, and methods of producing anti-TROP2 antibodies comprising culturing said host cells, isolating the antibodies, and purifying the antibodies using chromatographic methods.
The reference application and Shan are analogous to the present invention as they are in the same field of anti-TROP2 antibodies. Thus, it would have been obvious to one of ordinary skill in the art that the anti-TROP2 antibody of the reference application could be produced using the method of Shan, using expression vectors that comprise a polynucleotide encoding the antibody (the polynucleotide is rendered obvious by the reference application), culturing host cells comprising said expression vectors, isolating the antibody, and purifying the antibody using chromatographic methods. Combining prior art elements according to known methods to yield predictable results; one of ordinary skill would recognize that the methods/compositions of Shan (expression vectors, host cells, and method of making antibodies) could be applied to produce any anti-TROP2, including the anti-TROP2 antibodies with the sequences disclosed by the reference application, with a reasonable expectation of success.
With regard to claims 16 and 18, Shan further teaches a method of detecting a TROP2 protein in sample from an individual comprising contacting an anti-TROP antibody or antigen binding fragment thereof according to the invention, or a conjugate according to the invention to the sample and detecting the anti-TROP2 antibody bound to the TROP2 protein; for example, the anti-TROP2 antibody or antigen binding fragment thereof is used an immunohistochemistry assay (IH C) or in an ELISA assay (Paragraph 0026). The antibodies provided by the invention can be used diagnostic methods, e.g., in detecting TROP2 in patients or patient samples by, e.g., administering an anti-TROP2 antibody to a patient and detecting the anti-TROP2 antibody bound to TROP2 (e.g., using in vivo or ex vivo methods), or, e.g., by contacting a sample (e.g., ex vivo sample) from a patient with an anti-TROP2 antibody and qualitatively or quantitatively detecting the anti- TROP2 antibody bound to the TROP2 protein in the sample (Paragraph 0080). The antibodies of the invention may be conjugated to a label for detecting TROP2 in patient samples or in vivo by imaging wherein the label may be a radioisotope, fluorescent dye or enzyme (i.e., such a conjugate comprising an anti-TROP2 antibody and a label is a detection reagent) (Paragraph 0123). Labeled anti-TROP2 antibodies, fragments thereof, and derivatives and analogs thereof, which specifically bind to a TROP2 polypeptide can be used for diagnostic purposes (i.e., as diagnostic reagents) to detect, diagnose, or monitor diseases and/or disorders associated with the expression, aberrant expression and/or activity of TROP2 (Paragraph 0216). More specifically, diagnosis comprises: (a) administering an effective amount of a labeled anti-TROP2 antibody (or fragment thereof) to a mammal (b) waiting for an interval of time following the administration step to permit the labeled anti-TROP2 antibody (or fragment thereof) to preferentially concentrate at sites in the subject where TROP2 is expressed (and/or for unbound labeled molecule to be cleared to background level); (d) detecting an amount or level of labeled anti-TROP2 antibody in the subject, and (e) comparing the amount or level of labeled anti-TROP2 antibody in the subject to a level or amount of anti-TROP2 antibody in a healthy control subject wherein if the amount or level of the labeled anti-TROP2 antibody in the subject exceeds the amount or level of anti-TROP2 antibody in a healthy control subject, this may indicate that the subject has a disease or disorder associated with expression or aberrant expression of TROP2 (Paragraph 0217). Thus, Shan discloses detection/diagnostic reagents comprising anti-TROP2 antibodies (e.g., the antibodies conjugated to a label) and methods of detecting/diagnosing TROP2-mediated diseases or conditions in a sample using said antibodies and/or conjugates thereof. Thus, it would have been obvious to one of ordinary skill in the art that the anti-TROP2 ADC of the reference application could modified such that a label is conjugated to the antibody instead of a drug, and the labeled antibody could be used to detect aberrant TROP2 expression in samples in order to diagnose a TROP2-mediated disease or condition, as suggested by Shan. Combining prior art elements according to known methods to yield predictable results; one of ordinary skill would expect that labeling the anti-TROP2 antibody of the reference application with a label, as suggested by Shan, could be used to detect aberrant TROP2 expression in samples in order to diagnose a TROP2-mediated disease or condition according to the methods of Shan with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-25 are pending. Claims 1-25 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/
Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642