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 14-17, 21, 23-39 are cancelled. Claim 22 is amended.
Claims 1-13, 18-20, 22, 40-42 are pending examination on the merits.
Election/Restrictions
Claim 7 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/02/2025.
Applicant elects species (a) antisense oligonucleotide, small interfering RNA (siRNA) or short hairpin RNA (shRNA), for prosecution at this time. Claims 1-6, 8-13, 18-20, 22, and 40-42 read on the elected species.
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62891124, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The application fails to provide support for the claims under examination, since there is no disclosure therein of SEQ ID NOS: 1, 3-7, 9-21, 23-28, 30-35, 37, 39, 41, 43, 45-52, 54, 56-59, 61, 63-64, 66, 68-69, 71, 73-74, 76, 78-79, 81, 83-84. Therefore, the filing date of claims 6, 13, 22, 42 are deemed to have a priority date of 08/24/2020, which is the filing date of Application No. PCT/US2020/047640, because this application includes the first disclosure of SEQ ID NOS: 3-7, 9-21, 23-28, 30-35, 37, 39, 41, 43, 45-52, 54, 56-59, 61, 63-64, 66, 68-69, 71, 73-74, 76, 78-79, 81, 83-84.
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 1-5 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 inhibition of nucleoside reverse transcriptase, does not reasonably provide enablement for preventing a disease disorder or condition associated with NLRC4 inflammasome. 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404: Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The instant claim 1 is drawn to a method for treating and/or preventing a disease, disorder, or condition associated with an NLR family CARD domain containing 4 (NLRC4) inflammasome biological activity, the method comprising administering to a subject in need thereof a composition comprising, consisting essentially of, or consisting of a nucleoside reverse transcriptase inhibitor (NRTI), wherein the administering is via an route and in an amount effective for reducing the NLRC4 inflammasome biological activity, thereby treating and/or preventing the disease, disorder, or condition associated with the NLRC4 inflammasome biological activity. The nature of the claim is complicated, because the claim requires the outcome of “preventing” a disease condition associated with an NLR family CARD domain containing 4 (NLRC4) inflammasome biological activity, yet the claim is drawn to administering a nucleoside reverse transcriptase inhibitor as the only step.
Breadth of the claim: The claims encompass the use of nucleoside reverse transcriptase inhibitor to prevent or treat condition associated with an NLR family CARD domain containing 4 (NLRC4) inflammasome, wherein the administering is via a route and in an amount effective for reducing the NLRC4 inflammasome biological activity. The breadth of the claim far exceeds the limited disclosure in the specification. The word preventing a disease requires an understanding of the disease etiology, identify appropriate subjects for prophylactic administration, determining the timing of the administration prior to the disease offset, or predict efficacy in preventing the disease initiation. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification envisions a compositions for use in treating and/or preventing diseases, disorders, and/or conditions associated with NLRC4
inflammasome biological activities. In some embodiments, the compositions comprise, consist essentially of, or consist of a nucleoside reverse transcriptase inhibitor (NRTI) (e.g., paragraph , page 8). The specification envisions composition further comprises, consists essentially of, or consists of an inhibitor of a biological activity of at least one molecule or complex selected from the group consisting of NLRC4, NLRP3, caspase-1, cyclic GMP-AMP synthase (cGAS), caspase- 4, stimulator of interferon genes (STING), peptidyl-prolyl cis-trans isomerase F (PPIF),
mitochondrial permeability transition pore (MPTP), Gasdermin D (GSDMD), interferon-beta (IFN-3), and interferon-a/3 receptor (IFNAR). In some embodiments, the inhibitor is a small interfering RNA (siRNA) or short hairpin RNA (shRNA) that targets a transcription product of a gene selected from the group consisting of NLRC4, NLRP3, caspase-1, cGAS, caspase-4, STING,PPIF, MPTP, GSDMD, IFN-3, and IFNAR, optionally wherein the transcription product (e.g., paragraph , page 8).
The working examples of the specification teach DDX17-mediated Non-canonical NLRC4-NLRP3 inflammasome as a therapeutic target for age related macular degeneration using mice models with SINE RNA-induced RPE degeneration, however the specification does not teach prevention of age-related macular degeneration by targeting NLRC4 inflammasome.
Predictability and state of the art: The state of the art with respect to using nucleoside reverse transcriptase inhibitors for treating and/or preventing a disease, disorder, or condition associated with an NLR family CARD domain containing 4 (NLRC4) inflammasome biological activity is under developed and unpredictable. Fowler et al. (Science, 2014) teaches that NRTIs blocked NLRP3 inflammasome activation by lipopolysaccharide/
adenosine 5´-triphosphate (LPS/ATP). d4T inhibits NLRP3 inflammasome activation via P2X7, d4T did not prevent caspase-1 activation in primary mouse BMDMs treated with nigericin or crystalline monosodium urate, NLRP3 agonists that do not signal via P2X7. Furthermore, d4T did not inhibit AIM2 inflammasome activation by poly(dA:dT) or NLRC4 inflammasome activation by flagellin (e.g., paragraph 2nd, column left, page 4; Fig. S18 c-d). Huang et al. (IOVS, 2023) teaches rhegmatogenous retinal detachment (RRD) induced retinal inflammasome activation and photoreceptor death in mice. Systemic administration of K-9, 3TC, or AZT inhibited retinal inflammasome activation and photoreceptor death. In the RRD/SRR model, K-9 protected retinal electrical function during the time of RRD and induced an improvement following retinal reattachment. This novel RRD/SRR model may facilitate experimental evaluation of functional outcomes relevant to RRD (e.g., paragraph 3rd, page 1). Huang teaches that dual NLRC4–NLRP3 inflammasome that is critical in models of retinal
pigmented epithelium degeneration that are responsive to K-9 treatment (e.g., paragraph 2nd, column right, page 8). Alehashemi (Front. Immunol, 2020) teaches that novel findings in inflammasome biology and genetics that altered the diagnosis and management of patients with autoinflammatory syndromes caused by NLRP3-, Pyrin-, NLRP1-, and NLRC4-inflammasomes and spurred the development of novel treatments (e.g., abstract). Alehashemi teaches that despite these data, the efficacy of inflammasome modulators as adjuvant therapy in the comprehensive treatment of human malignancies, metabolic and degenerative diseases is yet to be established in clinical settings (e.g. paragraph 1st, column right, page 8).
Thus, the teachings of the post-filing art are consistent with the prior art demonstrating the underdeveloped and unpredictable nature of the invention.
Neither the specification nor prior art teaches about prevention, neither teaches the implications and long-term effects of continuous administration of nucleoside reverse transcriptase inhibitor in normal tissues.
Amount of experimentation necessary: Treating or preventing a disease associated with NLRC4 inflammasome are still in development stages. It would require a large amount of experimentation to make use of nucleoside reverse transcriptase inhibitors for treatment of disease associated with NLRC4 inflammasome. Preventing a disease requires an understanding of the disease etiology. The specification is silent as to how one of ordinary skill in the art would identify appropriate subjects for prophylactic administration, determining the timing of the administration prior to the disease offset, or predict efficacy in preventing the disease initiation. Absent of such guidance, undue experimentation would be required to practice the full scope of the claimed method, particularly, “preventing” embodiments.
In view as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1-5 are not considered to be enabled by the instant disclosure.
In view of the breadth of the claims, the lack of guidance provided by the specification, the lack of the predictability of the art to which the invention pertains, undue amount of experimentation would be required to make and use the claimed invention to prevent or treat disease associated with NLRC4 inflammasome, with a reasonable expectation of success. Because the specification does not contain a detailed description of how to make and use the method based on nucleoside reverse transcriptase inhibitors for treatment or prevention of disease associated with NLRC4 inflammasome, according to the invention, and absent working examples that provide evidence that is reasonably predictive of the ability of preventing, disease associated with NLRC4 inflammasome, the claims are not enabled commensurate in scope with the claimed invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 1-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ambati et al. (“Ambati”, US 2015/0038446 A1).
Regarding claims 1, 3, Ambati teaches methods for treating degradation of the retinal pigment epithelium (RPE) by administering compositions comprising a nucleoside and/or a nucleoside or nucleotide reverse transcriptase inhibitor (e.g., paragraph 0002). Ambati teaches the methods of the present disclosure may further comprise the steps of (i) inhibiting inflammasome activation by Alu RNA; (ii) reducing ATP-induced permeability of a cell; (iii) reducing an amount of mitochondrial reactive oxygen species in a cell; and/or (iv) inhibiting activation of at least one inflammasome in a subject's eye (e.g., paragraph 0008). Ambati teaches treating retinal damage and/or retinal degeneration, some methods of the present disclosure comprise administering to a subject in need thereof an effective amount of a composition for treating
retinal damage and/or degradation (e.g., paragraph 0081). Ambati teaches that d4T and AZT prevent RPE degeneration in the Alu RNA induced
mouse model of dry AMD (e.g., paragraph 0114).
The claimed methods differ only in that the claim recites inhibition of NLRC4 inflammasome rather than NLRP3 or IL1-beta inflammasome disclosed by Ambati. However, the claim as drafted in terms of intended use “wherein the administering is via an route and in an amount effective for reducing the NLRC4 inflammasome biological activity, thereby treating and/or preventing the disease” rather than reciting structural or method steps that would distinguish the claimed method from the method taught by the prior art; see MPEP 2111.4, a statement of intended use or result does not serve to distinguish a claim from the prior art if the prior art discloses the same process or composition. Accordingly, Ambati teaches the administration of the same class of nucleoside reverse transcriptase inhibitors to a subject for the purpose of inhibiting inflammasome activity to treat a disease.
Regarding claim 2, Ambati teaches administered composition is a
composition comprising a nucleoside and/or NRTI. Thus, exemplary compositions are comprised of compounds including, but not limited to, stavudine (d4T), lamivudine (3TC), cordycepin, azidothymidine (AZT), abacavir (ABC), chemical derivatives thereof (e.g., paragraph 0083).
Regarding claims 4-5, Ambati teaches a method comprising inhibiting the activation of at least one inflammasome. In certain embodiments, the at least one inflammasome is selected from an NLRP3 inflammasome, an IL-1 beta inflammasome, and a combination thereof. In some embodiments, the inhibiting one or more inflammasomes of a cell includes administering an inhibitor (composition) to the cell and/or to a subject, wherein the cell is the cell of a subject. For compositions comprising an inhibitor, an inhibitor as described herein can be, for example, a polypeptide inhibitor (including an oligonucleotide inhibitor), a small molecule inhibitor, and/or an siRNA inhibitor (e.g., paragraph 0085).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Ambati et al. (“Ambati”, US 2015/0038446 A1) in view of Khvorova et al. (“Khvorova”, US 8,090,542 B2).
The teachings of Ambati are discussed above.
Ambati does not teach RNA interference that targets a transcription product of NLCR4 as required by instant claim 6. However, this is cured by Khvorova.
Khvorova teaches provides a kit for gene silencing, wherein said kit is comprised of a pool of at least two siRNA duplexes, each of which is comprised of a sequence that is complementary to a portion of the sequence of one or more target messenger RNA (e.g., paragraph 3rd, column 3). Khvorova teaches a siRNA oligonucleotide SEQ ID NO 1162266 with 100% homology to SEQ ID NO 4, (it corresponds to NLCR4 mRNA [NCBI Blast Search] see below).
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Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to use the siRNA oligonucleotide SEQ ID NO 1162266 taught by Khvorova and integrate in the method comprising inhibiting the activation of NLRC4 inflammasome taught by Ambati, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method comprising inhibiting the activation NLRC4 inflammasome.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a method comprising inhibiting the activation of at least one inflammasome by siRNA.
Claim 8-12, 18-20, 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Ambati et al. (“Ambati”, US 2015/0038446 A1) in view of Ambati et al (“226”, US 9,453,226 B2) and Wu et al. (“Wu”, J Clin Immunol. 2010).
Regarding claims 8-9, 11-12, 19-20, Ambati teaches methods for treating degradation of the retinal pigment epithelium (RPE) by administering compositions comprising a nucleoside and/or a nucleoside or nucleotide reverse transcriptase inhibitor (e.g., paragraph 0002). Ambati teaches the methods of the present disclosure may further comprise the steps of (i) inhibiting inflammasome activation by Alu RNA; (ii) reducing ATP-induced permeability of a cell; (iii) reducing an amount of mitochondrial reactive oxygen species in a cell; and/or (iv) inhibiting activation of at least one inflammasome in a subject's eye (e.g., paragraph 0008). Ambati teaches administered composition is a composition comprising a nucleoside and/or NRTI. Thus, exemplary compositions are comprised of compounds including, but not limited to, stavudine (d4T), lamivudine (3TC), cordycepin, azidothymidine (AZT), abacavir (ABC), chemical derivatives thereof (e.g., paragraph 0083). Ambati teaches treating retinal damage and/or retinal degeneration, some methods of the present disclosure comprise administering to a subject in need thereof an effective amount of a composition for treating retinal damage and/or degradation (e.g., paragraph 0081). Ambati teaches that d4T and AZT prevent RPE degeneration in the Alu RNA induced mouse model of dry AMD (e.g., paragraph 0114).
Regarding claim 10, Ambati teaches terms "subject" or "subject in need thereof' refer to a target of administration, which optionally displays
symptoms related to a particular disease, condition, disorder, or the like. The subject( s) of the herein disclosed methods can be human (e.g., paragraph 0079).
Regarding claims 40-41, Ambati teaches a method comprising inhibiting the activation of at least one inflammasome. In certain embodiments, the at least one inflammasome is selected from an NLRP3 inflammasome, an IL-1 beta inflammasome, and a combination thereof. In some embodiments, the inhibiting one or more inflammasomes of a cell includes administering an inhibitor (composition) to the cell and/or to a subject, wherein the cell is the cell of a subject. For compositions comprising an inhibitor, an inhibitor as described herein can be, for example, a polypeptide inhibitor (including an oligonucleotide inhibitor), a small molecule inhibitor, and/or an siRNA inhibitor (e.g., paragraph 0085).
Ambati does not teach inhibition of NLRC4-induced caspase-1 as required by claim 8, 18. Ambati does not teach NRTI inhibiting NLRC4 and NLRP3 as required by claim 8, 12. However, this is cured by “226” and Wu.
“226” teaches method of protecting a cell, comprising: inhibiting an inflammasome of the cell. The method of any one of the prior claims, wherein the inflammasome is selected from NLRP3 inflammasome, NLRP1 inflammasome, NLRC4 inflammasome, AIM2 inflammasome, and IFI16 inflammasome (e.g., paragraph 2nd, column 14). “226” teaches methods including inhibiting one or more of MyD88, IL-18, VDACl, VDAC2, NFKB, caspase-8, caspase-1, NLRP-3, PYCARD, and an inflammasome, including a component of an inflammasome (e.g., caspase 1, NLRP-3, PYCARD) of a cell (e.g., paragraph 3rd, column 2).
Wu teaches AIM2, NLRC4, and NLRP3 inflammasomes as well as
the adaptor protein ASC all contribute to activation of caspase-1 in Listeria-infected macrophages (e.g., abstract). Wu teaches that NLRC4 is required for WT Listeria-Induced Caspase-1 Activation in Nonprimed Macrophages (e.g., paragraph 2nd, title, page 695). Wu teaches that NLRC4-KO macrophages were also resistant to WT and flaA Listeria-induced cell death as most NLRC4-KO macrophages were viable after a 5-h infection with the two Listeria strains (e.g., paragraph 1st, page 696; Fig. 2a-b, see below)
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Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to use the nucleotide reverse transcriptase inhibitors taught by Ambati to inhibit the NLRC4-induced caspase-1 taught by Wu and integrate in the method comprising inhibiting of NLRC4 or NLPR3 inflammasome taught by “226”, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method comprising inhibiting the NLRC4-induced caspase-1 or NLRP3 inflammasomes.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a method comprising inhibiting the activation of at least one inflammasome with an effective amount of nucleotide reverse transcriptase inhibitors.
Claims 13, 22, 42 are rejected under 35 U.S.C. 103 as being unpatentable over Ambati et al. (“Ambati”, US 2015/0038446 A1), Ambati et al (“226”, US 9,453,226 B2) and Wu et al. (“Wu”, J Clin Immunol. 2010) as applied to claims 8-12, 18-20, 40-41 above, and further in view of Khvorova et al. (“Khvorova”, US 8,090,542 B2).
Ambati “226” and Wu do not teach RNA interference that targets a transcription product of NLCR4 as required by instant claim 13, 22, 42. However, this is cured by Khvorova.
Khvorova teaches provides a kit for gene silencing, wherein said kit is comprised of a pool of at least two siRNA duplexes, each of which is comprised of a sequence that is complementary to a portion of the sequence of one or more target messenger RNA (e.g., paragraph 3rd, column 3). Khvorova teaches a siRNA oligonucleotide SEQ ID NO 1162266 with 100% homology to SEQ ID NO 4, (it corresponds to NLCR4 mRNA, see below).
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Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to use the siRNA oligonucleotide SEQ ID NO 1162266 taught by Khvorova and integrate in the method comprising inhibiting the activation of NLRC4 inflammasome taught by Ambati, “226” and Wu, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method comprising inhibiting the activation NLRC4 inflammasome.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a method comprising inhibiting the activation of at least one inflammasome by siRNA.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIO GOMEZ RODRIGUEZ whose telephone number is (571)270-0991. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/J. E. ANGELL, Ph.D./Primary Examiner, Art Unit 1637