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, filed 05/01/2024 is a Continuation of 17731831, filed 04/28/2022.
17731831 is a Continuation of 17034419, filed 09/28/2020.
17034419 is a Continuation of 16591927, filed 10/03/2019, now U.S. Patent # 10821099.
16591927 is a Continuation of PCT/US19/53107, filed 09/26/2019.
PCT/US19/53107 Claims Priority from Provisional Application 62874927, filed 07/16/2019.
PCT/US19/53107 Claims Priority from Provisional Application 62737992, filed 09/28/2018.
Status of Claims
Claims 1-20 are currently pending.
Claims 1-20 were examined and are rejected.
Claim Rejections-35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 5-9, 12-18, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ottoboni et. al., WO 2014093907 A1, publ. 6/19/2014.
Ottoboni teaches pharmaceutical compositions for providing sustained release of a 5-HT3 receptor antagonist and a neurokinin-1 (NK-1) receptor antagonist to a subject in need thereof (title & abstract; para [0002], [0006]). Ottoboni teaches an embodiment wherein the combination is administered for treating nausea and vomiting (para [0006]), as well as the treatment of motion sickness (para [0041], [0103]). Administration of a therapeutically effective amount of each of a 5-HT3 receptor antagonist and NK-1 receptor antagonist is taught (para [0007], [0072]). Ottoboni teaches suitable NK-1 receptor antagonists for the treatment to include LY686017, also known as (2-chloro-phenyl)-{2-[5-pyridin-4-yl-1-(3,5-bistrifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-methanone, or tradipitant (para [0108]). Ottoboni teaches the active agents can be administered by a variety of routes, including in solid oral dosage forms (para [0050]). Ottoboni teaches examples of different amounts of NK-1 receptor antagonists, including 375 mg. (para [0092]), 750 mg. (para [0093]), and 150 mg (para [0094]). Treatment is taught to encompass prophylactic treatment, wherein the subject doesn’t yet experience or exhibit symptoms of the condition, as well as providing relief from symptoms as they are experienced (para [0073]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims, to have treated or prevented a symptom of motion sickness in a subject comprising administering a therapeutically effective amount of tradipitant prior to the commencement of motion sickness activity, in consideration of Ottoboni. As discussed above, Ottoboni teaches treatment of symptoms of nausea and vomiting, in conditions such as motion sickness, by administering a sustained release combination of a 5-HT3 receptor antagonist and a NK-1 receptor antagonist, with tradipitant included as a suitable NK-1 receptor antagonist. Ottoboni also teaches prophylactic treatment, and administration of the active agents in solid oral dosage forms. As such, one of ordinary skill in the art would have arrived at the method of the instant claims in view of Ottoboni, and have had a reasonable expectation of success.
Regarding the doses of tradipitant recited in claims 5-8 and 14-17, Ottoboni teaches a therapeutically effective amount of the NK-1 receptor antagonist, and teaches exemplary doses of such an agent to include 375 mg., 750 mg., and 150 mg. Therefore, one of ordinary skill in the art would have understood adjustment of the therapeutically effective dose of NK-1 receptor antagonist, and have arrived at the doses of tradipitant recited in the claims, based on the guidance of Ottoboni, and have had a reasonable expectation of success.
Claims 1, 5-10, and 12-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bös et al., USP 6297375 B1 (patented 10/2/2001, cited in an IDS), in view of Borghese et. al., USP 7381826 B2 (patented 6/3/2008, cited in an IDS).
Bös teaches 4-phenyl-pyridine derivatives having activity as neurokinin-1 (NK1) receptor antagonists (title & abstract; col. 2, lines 1-65). Bös further teaches the use of the compounds in the control or prevention of symptoms associated with certain conditions or diseases (col. 2, line 66-col. 3, line 4). Bös teaches NK1 antagonists are known in the art to be useful for the treatment of motion sickness (col. 1, lines 59-67), and teaches the 4-phenyl-pyridine derivatives for treating motion sickness and emesis (col. 4, lines 13-14; col. 13, lines 61-62; col. 19, lines 21-25). Oral administration of the NK1 receptor antagonists, in the form of tablets or capsules with one or more pharmaceutical excipients, is taught (col. 40, line 53-col. 41, line 12). Bös doesn’t teach the tablets or capsules for sustained release, therefore Bös is interpreted as teaching immediate release tablets or capsules. The oral daily dose is taught to range from about 10-1000 mg (col. 42, lines 5-11).
Bös doesn’t teach tradipitant.
Borghese teaches crystalline forms of the compound {2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, which is structurally identical to tradipitant, as a NK1 receptor antagonist for treating disorders associated with an excess of tachykinins (title & abstract; col. 1, lines 1-28). Borghese teaches the compound to be suitable for oral administration, and that this route of delivery is preferred (col. 17, line 65-col. 18, line 9). Tablet or capsule dosage forms with suitable excipients are taught (col. 18, lines 26-64). Borghese doesn’t teach the tablets or capsules for sustained release therefore Borghese is interpreted as teaching immediate release tablets or capsules. Borghese teaches the amount of compound to be administered ranges from about 0.001-100 mg/kg body weight per day, and that effective amounts can be readily determined by one skilled in the art (col. 21, lines 18-22).
It would have been prima facie obvious to one of ordinary skill in the art, at the time of the invention, to have treated a subject about to engage in an activity involving sickness inducing motion comprising administering tradipitant to the subject, prior to the commencement of the activity, in an amount effective to prevent motion sickness or at least one symptom of motion sickness in view of the combined teachings of Bös and Borghese. Bös teaches NK1 receptor antagonists were known to be useful for treating motion sickness, and further teaches administration of another subgenus of NK1 receptor antagonists to treat motion sickness or symptoms thereof, wherein treating is taught to encompass prevention of symptoms. As Borghese teaches tradipitant as therapeutic NK1 receptor antagonist, it would have been prima facie obvious to one of ordinary skill in the art to have practiced the method taught by Bös, using tradipitant as the NK1 receptor antagonist to be administered, with a reasonable expectation of success. Bös further teaches NK1 receptor antagonists for treating emesis; therefore, it would have been prima facie obvious to have treated a symptom of motion sickness, emesis or nausea, comprising administering to a subject in need thereof an effective amount of tradipitant prior to the subject participating in motion sickness inducing activity, with a reasonable expectation of success. Bös teaches the NK1 receptor antagonists to be orally administered, and Borghese also teaches tradipitant to be orally administered; moreover, the effective amount of NK1 receptor antagonist administered as taught by Bös, from 10-1000 mg., overlaps with the ranges recited by instant claims 5-8 and 14-17. Therefore, one of ordinary skill in the art would have been motivated to have administered an effective amount of tradipitant within the dosage range taught by Bös, including in an immediate release tablet or capsule for inhibiting motion sickness or nausea associated with motion sickness, prior to the subject participating in motion sickness inducing activity, with a reasonable expectation of success.
Claims 2-4 and 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bös et al., USP 6297375 B1 (patented 10/2/2001, cited in an IDS), in view of Borghese et. al., USP 7381826 (patented 6/3/2008, cited in an IDS), as applied to claims 1, 5-10, and 12-20 as discussed previously, further in view of Tattersall, USP 6140324 (patented 10/31/00, cited in an IDS).
Bös and Borghese teach as discussed previously, but they don’t teach wherein the activity is vehicle travel, and administration occurs about 30 minutes prior to entering a vehicle or commencement of vehicle travel.
Tattersall teaches treatment or prevention of motion sickness comprising administering a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine (title & abstract; col. 1, lines 8-12). Tattersall teaches motion sickness can be produced by numerous situations, including travel by sea, car, air, swing, camel, or space, and that subjects can develop symptoms of motion sickness without being in motion, such as by watching a cinema film taken from a moving vehicle (col. 1, lines 13-22; col. 3, lines 1-5). Tattersall teaches the combination of a tachykinin antagonist, a muscarinic antagonist, and/or an antihistamine is useful for treating or preventing motion sickness caused by any provocative stimuli, and that preferably the tachykinin antagonist is a NK-1 receptor antagonist (col. 3, lines 1-26). Tattersall teaches administering a composition comprising a tachykinin antagonist, a muscarinic antagonist, and/or an antihistamine preferably between 2 hours to 30 minutes before the subject is exposed to the provocative stimuli (col. 28, lines 29-34).
It would have been prima facie obvious to one of ordinary skill in the art, at the time of the invention, to have arrived at the instantly claimed method of treating motion sickness or at least one symptom thereof, comprising administering an effective amount of tradipitant to a subject at least 30 minutes prior to the subject commencing motion sickness inducing activity, including vehicle travel, in view of the teachings of Bös, Borghese, and Tattersall, with a reasonable expectation of success. Bös teaches NK1 receptor antagonists were known in the art to be useful for treating motion sickness and emesis, while Borghese teaches tradipitant as a therapeutic NK1 receptor antagonist. Tattersall teaches treatment or prevention of motion sickness comprising administering a tachykinin, e.g., NK1 antagonist and a muscarinic antagonist and/or an antihistamine. Tattersall further teaches motion sickness can be induced by travel by sea, car, air, swing, camel, or space, and administering a composition comprising a NK1 antagonist, a muscarinic antagonist, and/or an antihistamine preferably between 2 hours to 30 minutes before the subject is exposed to the provocative stimuli. As such, one of ordinary skill in the art would have been motivated to have administered the NK1 receptor antagonist, tradipitant, to a subject prior to commencement of motion sickness inducing activity, such as vehicle travel, wherein tradipitant is administered between 2 hours to 30 minutes prior to commencement of vehicle travel, in view of the teachings of Tattersall, with a reasonable expectation of success.
Claim(s) 13-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Borghese et. al., WO 2005042515 A1, publ. 5/12/2005.
The claims are drawn to a method of treating a subject with at least one symptom of motion sickness comprising administering tradipitant to said subject in an amount effective to treat a symptom of motion sickness.
Borghese teaches crystalline forms of the compound {2-[1-(3,5-bis-trifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, i.e., tradipitant, and methods of treating a disorder associated with an excess of tachykinins (title & abstract; p. 1, lines 5-11). Borghese teaches the compound to be useful for treating a variety of disorders, such as emesis, i.e., vomiting (p. 1, line 13-p. 2, line 5). Particularly, emesis is included within a list of conditions as a particularly preferred disorder to be treated (p. 30, lines 24-28). Borghese teaches administration of an effective amount of the compound (p. 25, lines 1-2), administration of the compound in a pharmaceutical composition with a pharmaceutical excipient (p. 25, lines 3-7), as well as oral administration in dosage forms such as tablets or capsules (p. 25, lines 10-18 and 24-30). Borghese teaches an effective amount of the compound to range from about 0.001-100 mg/kg of body weight/day, but preferred amounts can be readily determined by one skilled in the art (p. 30, lines 21-23). Borghese provides an example of a capsule formulation comprising 100 mg. of the compound (p. 28, formulation 1). Borghese doesn’t teach the tablets or capsules for sustained release therefore Borghese is interpreted as teaching immediate release tablets or capsules. As such, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have treated a symptom of motion sickness, vomiting, comprising administering an effective amount of tradipitant, and have had a reasonable expectation of success, wherein an effective amount includes 100 mg. Regarding the limitation of claim 17, wherein the effective amount is about 170 mg., although this amount is not explicitly taught by Borghese, it is taught that an effective amount can be readily determined by one skilled in the art. Therefore, it would have been prima facie obvious to have arrived at an amount of about 170 mg. by routine experimentation, in the absence of evidence indicating the criticality of this amount. See MPEP 2144.05(II): “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical”. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claim Rejections-Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10821099. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to treating a subject about to engage in motion sickness inducing activity by administering an effective amount of tradipitant, prior to the commencement of motion sickness inducing activity. Both sets of claims further recite vehicle travel (claim 2), administering tradipitant about 30 minutes prior to vehicle travel (claim 4), oral administration (claim 9), and overlapping amounts of tradipitant (claims 5-8). The instant claims and method claimed in US ‘099 are therefore not patentably distinct.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of USP 10772880 in view of Tattersall, USP 6140324 (patented 10/31/2000, cited in an IDS), in view of Borghese et. al., USP 7381826 (patented 6/3/2008, cited in an IDS). The instant claims are drawn to a method of treating a subject about to engage in an activity involving sickness-inducing motion comprising administering tradipitant to the subject, prior to commencement of said activity, in an amount effective to prevent motion sickness or at least one symptom of motion sickness in the subject. The claims of US ‘880 are drawn to a method of treating an individual in need of treatment with tradipitant comprising administering about 170 mg/day of tradipitant; or from 150-400 mg/day to the individual for such time as required to achieve and maintain a tradipitant plasma concentration of at least about 175 ng/mL during treatment wherein the disease or condition includes nausea or vomiting, including oral administration (see claims 2 & 9), tradipitant in an immediate release form of a capsule or tablet (see claims 4 & 5). Both sets of claims encompass oral administration of tradipitant at a dose of 170 mg/day or 150-400 mg, as well as an immediate release dosage form as tablets or capsules. Although the claims of US ‘880 do not explicitly recite treatment of motion sickness or a symptom of motion sickness, it would have been prima facie obvious to have applied the method claimed in US ‘880 to treat motion sickness and symptoms thereof in view of Tattersall and Borghese. Tattersall teaches treatment or prevention of motion sickness comprising administering a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine (Abstract; col. 1, lines 8-12). Tattersall teaches motion sickness can be produced by numerous situations, including travel by sea, car, air, swing, or space, and that subjects can develop symptoms of motion sickness without being in motion (col. 1, lines 13-22). Tattersall teaches the combination of a tachykinin antagonist, a muscarinic antagonist, and/or an antihistamine is useful for treating or preventing motion sickness caused by any provocative stimuli, and that preferably the tachykinin antagonists is a NK-1 receptor antagonist (col. 3, lines 1-26). Tattersall teaches administering a composition comprising a tachykinin antagonist, a muscarinic antagonist, and/or an antihistamine preferably between 2 hours to 30 minutes before the subject is exposed to the provocative stimuli (col. 28, lines 29-34). Oral administration is taught in dosage forms such as pills, tablets, and capsules, wherein the dosage form further comprises a pharmaceutical carrier and/or excipient (col. 26, lines 24-51). Tattersall further teaches that optionally the tablets or pills can be coated to provided prolonged or delayed action (col. 26, lines 51-63); as this is not required, it would have been prima facie obvious to one of ordinary skill in the art that Tattersall also encompasses immediate release oral dosage forms, including tablets or capsules. Tattersall an effective amount of the tachykinin antagonist to range from about 0.001-25 mg/kg per day (col. 28, lines 8-11); it is calculated that for an individual of about 50 kg, this dosage range would correspond to about 0.05-1250 mg per day. Tattersall further teaches nausea and vomiting as symptoms of motion sickness, and that emesis can be blocked by administration of a NK-1 receptor antagonist (col. 1, lines 23-56; col. 2, lines 31-40). Borghese teaches {2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, also known as tradipitant, as an NK1 subtype tachykinin receptor antagonist useful for treatment of disorders associated with an excess of tachykinins (col. 1, lines 20-52). Therefore, it would have been prima facie obvious to have arrived at the instantly claimed method of treatment, and to have applied this method of treatment to method claimed in US ‘880, in view of Tattersall and Borghese, with a reasonable expectation of success. The instant and method claimed in US ‘880 are therefore not patentably distinct.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of US Patent 11324735 B2 in view of Tattersall, USP 6140324 (patented 10/31/2000, cited in an IDS), in view of Borghese et. al., USP 7381826 (patented 6/3/2008, cited in an IDS). The instant claims are drawn to a method of treating a subject about to engage in an activity involving sickness-inducing motion comprising administering tradipitant to the subject, prior to commencement of said activity, in an amount effective to prevent motion sickness or at least one symptom of motion sickness in the subject. The claims of US ‘735 are drawn to a method of treating an individual in need of treatment with tradipitant comprising orally administering about 100-200 mg/day of tradipitant in a solid immediate release form to the individual wherein the disease or condition includes nausea or vomiting (claims 1 & 8), tradipitant in an immediate release form of a capsule or tablet (see claim 2), wherein the individual is afflicted with one or more disorders ameliorated by tradipitant. Both sets of claims encompass oral administration of tradipitant at overlapping doses, as well as an immediate release dosage form as tablets or capsules. Although the claims of US ‘735 do not explicitly recite treatment of motion sickness or a symptom of motion sickness, it would have been prima facie obvious to have applied the method claimed in US ‘735 to treat motion sickness and symptoms thereof in view of Tattersall and Borghese. Tattersall teaches treatment or prevention of motion sickness comprising administering a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine (Abstract; col. 1, lines 8-12). Tattersall teaches motion sickness can be produced by numerous situations, including travel by sea, car, air, swing, or space, and that subjects can develop symptoms of motion sickness without being in motion (col. 1, lines 13-22). Tattersall teaches the combination of a tachykinin antagonist, a muscarinic antagonist, and/or an antihistamine is useful for treating or preventing motion sickness caused by any provocative stimuli, and that preferably the tachykinin antagonists is a NK-1 receptor antagonist (col. 3, lines 1-26). Tattersall teaches administering a composition comprising a tachykinin antagonist, a muscarinic antagonist, and/or an antihistamine preferably between 2 hours to 30 minutes before the subject is exposed to the provocative stimuli (col. 28, lines 29-34). Oral administration is taught in dosage forms such as pills, tablets, and capsules, wherein the dosage form further comprises a pharmaceutical carrier and/or excipient (col. 26, lines 24-51). Tattersall further teaches that optionally the tablets or pills can be coated to provided prolonged or delayed action (col. 26, lines 51-63); as this is not required, it would have been prima facie obvious to one of ordinary skill in the art that Tattersall also encompasses immediate release oral dosage forms, including tablets or capsules. Tattersall an effective amount of the tachykinin antagonist to range from about 0.001-25 mg/kg per day (col. 28, lines 8-11); it is calculated that for an individual of about 50 kg, this dosage range would correspond to about 0.05-1250 mg per day. Tattersall further teaches nausea and vomiting as symptoms of motion sickness, and that emesis can be blocked by administration of a NK-1 receptor antagonist (col. 1, lines 23-56; col. 2, lines 31-40). Borghese teaches {2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, also known as tradipitant, as an NK1 subtype tachykinin receptor antagonist useful for treatment of disorders associated with an excess of tachykinins (col. 1, lines 20-52). Therefore, it would have been prima facie obvious to have arrived at the instantly claimed method of treatment, and to have applied this method of treatment to method claimed in US ‘735 in view of Tattersall and Borghese, with a reasonable expectation of success. The instant and method claimed in US ‘735 are therefore not patentably distinct.
Information Disclosure Statements
The IDS filed on 5/1/24, 10/17/24, and 10/8/25 have been considered.
Correspondence
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SARAH . PIHONAK
Primary Examiner
Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627