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 .
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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 4, 2025 has been entered.
The amendment filed November 4, 2025 has been entered. Claims 1 and 113 have been amended, claims 2, 4-7, 9, 11, 13, 17, 19-23, 25-26, 32, 35-42, and 44-112, are cancelled and claim 115 has been added.
Applicant’s arguments filed November 4, 2025 were fully considered but they were not persuasive. Rejections and response to arguments are addressed below.
Claims 1, 3, 8, 10, 12, 14-16, 18, 24, 27-31, 33-34, 43, and 113-115 are pending in this application.
Priority
This application is a 371 National Stage of PCT/US20/17951, filed February 12, 2020 which claims the benefit under 35 U.S.C.§119(e) of U.S. Provisional Application Nos. 62/804,523, filed February 12, 2019, 62/863,904, filed June 20, 2019, 62/908,431, filed September 30, 2019, and 62/932,015, filed November 7, 2019.
Specification
The disclosure is objected to because of the following informalities: The structures on pages 2, 7, and 46 of the instant specification are blurry, rendering them illegible. On pages 2 and 7 see the structures of maralixibat, volixibat, odevixibat. On page 46 see para. 00299 (“MeO” group is unclear).
Appropriate correction is required.
Claim Rejections - 35 USC § 112 (b)
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, 4, 8, 10, 12, 14-16, 18, 24, 27-31, 33-34, 43, and 113-114 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.
Regarding claims 1, 4, 8, 10, 12, 14-16, 18, 24, 27-31, 33-34, 43, and 113-114: The term “(maralixibat)” in claims 1 and 113 is used by the claim to mean “
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,” while instant specification defines the term “(maralixibat)” to mean
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(pg. 2, para. 0006). Given that the phrase in the claim differs from what is defined in the instant specification, the scope of the claim is unclear and thus indefinite. Claims 4, 8, 10-12, 14-16, 18, 24, 27-31, 33-34, 43, and 114 which depend from claims 1 and 113 are similarly 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.
Claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43 and 113-115 are rejected under 35 U.S.C. 103 as being unpatentable over Mirum Pharmaceuticals (US Clinical Trial NCT03353454), hereinafter referred to as Mirum, in view of Malatack (Pediatrics, 2018, IDS filed January 11, 2024) and Stieger (Current Drug Targets, 2011, cited on PTO-892) and as evidenced by Amer (Gastroenterology Research, 2014, cited in previous action), Betts (Love to Know, 2024, cited in previous action), and Mayo (Hepatology Communications, 2019, IDS filed November 21, 2023).
Regarding claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29, and 113-115: Mirum teaches a method for treating progressive familial intrahepatic cholestasis (PFIC) comprising administering to the subject maralixibat (SHP625) (pg. 3, title). According to Mayo, SHP625 is equivalent to maralixibat chloride (pg. 2, last para.). The method comprises administering an oral solution of maralixibat containing up to 600 µg/kg twice daily (1200 ug/kg total) for 26 weeks (pg. 6, arms and interventions). The method comprises measuring treatment response as measured by the observer itch reported outcome (ITCHRO(Obs)), which compares severity from baseline (pgs. 6-7, primary outcome measures). The method comprises measuring normalization or reduction from baseline in serum bile acids (sBA) and disappearance of pruritus ( pg. 7, secondary outcome measures). The subjects comprise people less than 18 years of age (i.e. pediatric), with a body weight greater than or equal to 5 kg (pg. 9, criteria). The subjects include participants with 2 documented mutant alleles in ABCB11 (PFIC2) (i.e. genotype is determined), but exclude participants with truncating mutations (i.e. non-truncating mutations are included) that result in nonfunctioning bile salt export pump (BSEP, pg. 10, criteria a). According to the instant specification, “in various embodiments, the BSEP deficiency is PFIC2.” (pgs. 102, para. 00640). According to Amer, PFIC 2 is an autosomal recessive disease is caused by mutation in ABCB11 gene on chromosome 2q24, which encodes the canalicular bile salt export protein (BSEP, pg. 41, col. 1, para. 4). Defective BSEP leads to impaired bile salt secretion (i.e. impaired bile flow, pg. 41, col. 1, para. 4). Wherein the method is directed towards treating PFIC 2, the method encompasses describes treating a patient with a mutation in the ABCB11 gene with impaired bile secretion as recited by instant claim 10.
Mirum does not teach wherein an ABCB11 gene of the subject specifically comprises a missense mutation that is not selected from the group consisting of c.470A>G and c,3892G>A.
However, Malatack teaches a method for treating pediatric subjects with PFIC2 comprising administering maralixibat once daily for two years (abstract, pg. 3, col. 2, para. 1). The patients remained symptom free, including improvement in pruritis (pg. 3, col. 2, para. 1). The pruritis symptom after treatment was compared to typical pruritis symptoms in the patient (i.e. baseline, pg. 2, figure 1). The patients were DNA tested and found to have heterozygous missense variants in ABCB11: c.470A>G (p.Y157C) and c.3892G>A (p.G1298R) (i.e. alternative missense mutations, pg. 2, col. 1, para. 2). Malatack establishes that a composition comprising maralixibat controlled symptoms in 2 siblings with partial loss of BSEP activity (abstract).
Additionally, Stieger teaches additional known BSEP mutations in PFIC2 that result in residual transport activity (i.e. partial loss of activity), p.E297G, p.R432T and D482G (pg. 666, col. 2, para. 1). According to the instant specification, D482G and p.E297G are non-truncating missense mutations (i.e. classified as moderate/mild PFIC2, pgs. 148-150, tables 2-33)
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to apply the method of Mirum to patients with missense mutations, such as those described by Stieger (p.E297G, p.R432T and D482G), as taught by Malatack and Stieger. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as maralixibat is known in the art to be beneficial to patients suffering from cholestatic liver disease with these mutation types that result in partial loss of BSEP activity.
Regarding claim 28: As discussed above, the prior art render obvious the method of claim 27. Mirum teaches administration of the ASBTI twice daily, but does not teach once daily administration. However, Malatack teaches a method for treating pediatric subjects with PFIC2 comprising administering maralixibat once daily for two years (abstract, pg. 3, col. 2, para. 1).
Taken together it would have been prima facie obvious to modify the method of Mirum by administering the ASBTI once daily instead of twice daily. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success for the purpose of simplifying the method further and once daily administration of maralixibat is a known practice in the art.
Regarding claim 30: Mirum does not explicitly teach a method comprising administering the ASBTI maralixibat at a daily dose of from about 10mg/day to about 100 mg/day as recited by instant claim 30.
However, as discussed above the method comprises administering to subjects comprising people less than 18 years of age (i.e. pediatric), with a body weight greater than or equal to 5 kg (pg. 9, criteria). The method comprises administering an oral solution of maralixibat containing up to 600 µg/kg twice daily for 26 weeks (pg. 6, arms and interventions). wherein Mirum teaches a maximum dose of 600 µg/kg twice per day (1200 µg/kg = 1.2 mg/kg) twice per day wherein patients can at the very least weigh 5 kg, this equates to a daily dose of 6mg/day (1.2mg/kg*5kg). Betts discloses the average teen weight can range between approximately 46 kg to 71 kg (pg. 3, Weight Table). For example, with a teen weighing 60 kg, this equates to a daily dose of 72 mg/day (1.2 mg/kg*60kg). In the case where the claimed ranges, 10 mg/day to 100 mg/day, overlap or lie inside ranges disclosed by the prior art 6 mg/day to 72 mg/day a prima facie case of obviousness exists (See MPEP 2144.05 (I)).
Regarding claim 31: As discussed above, Mirum and Malatack render obvious the method of claim 1. Mirum teaches administration for 26 weeks, but does not teach administration for a period of at least one year. However, Malatack teaches a method for treating pediatric subjects with PFIC2 comprising administering maralixibat once daily for two years (abstract, pg. 3, col. 2, para. 1).
Taken together it would have been prima facie obvious to modify the method of Mirum by continuing administration for a period of at least one year as taught by Malatack. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order to continue to treat the underlying condition and the art establishes administration of ASBTI for longer than a year are known in the art.
Regarding claims 33-34 and 43: As discussed above, the prior art render obvious the method of claim 1. Mirum teaches the method comprises measuring treatment response as measured by the observer itch reported outcome (ITCHRO(Obs)), which compares severity from baseline (pgs. 6-7, primary outcome measures). The method comprises measuring disappearance of pruritus (pgs. 7, secondary outcome measures). Mirum does not explicitly state wherein the administration of the ASBTI results in a reduction in severity of pruritus that is maintained for at least one year. However, Malatack teaches following ASBTI administration for two years, the patients remained symptom free, including improvement in pruritis (pg. 3, col. 2, para. 1). The pruritis symptom after treatment was compared to typical pruritis symptoms in the patient (i.e. baseline, pg. 2, figure 1). The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer (See MPEP 2112 (I)). Wherein the method of the prior art is comparable to the instantly claimed in effective doses and measurement of pruritus is a known measurable symptom of the underlying disorder, the obtained reduction in pruritus are expected properties of practicing the method.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Mirum (US Clinical Trial NCT03353454), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011), Amer (Gastroenterology Research, 2014), Betts (Love to Know, 2024), and Mayo (Hepatology Communications, 2019, IDS filed November 21, 2023) as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29-31, 33-34, 43 and 113-115 above, in view of Waisbourd-Zinman (Annals of Hepatology, 2017, cited on PTO-892).
Regarding claim 14: As discussed above, the prior art renders obvious the methods of claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29-31, 33-34, 43 and 113-115, wherein the mutation can be a E297G, D482G, or R432T missense mutation that exhibit residual BSEP activity.
The prior art relied upon did not disclose a patient wherein the ABCB11 gene comprises a missense mutation that is not an E297G or D482G or Y157C or G1298R mutation as excluded by claim 14.
However, Waisbourd-Zinman teaches additional missense mutations of the ABCB11 gene, p.C68Y and p.R832H, in pediatric patients with mild PFIC2 (abstract). According to the instant specification, R832H is a non-truncating missense mutation (pg. 149 table 3).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to apply the method of the prior art to the mutations that lead to mild forms of PFIC2 as taught by Waisbourd-Zinman. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes compositions comprising maralixibat are an effective treatment for PFIC2 in patients with missense mutations with residual BSEP activity. To summarize, it would have been obvious to apply the method to the treatment of PFIC2 patients with the following mutations, E297G, D482G, R432T, C68Y and R832H. Although the art does not establish C68Y as a non-truncating missense mutation, as discussed previously, the art establishes R432T as a possible non-truncating mutation, thus it would be obvious to treat a patient that is heterozygous R432T/ C68Y, as these a non-truncating mutations that lead to mild forms of PFIC2.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Mirum (US Clinical Trial NCT03353454), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), Amer (Gastroenterology Research, 2014, cited in previous action), Betts (Love to Know, 2024, cited in previous action), Mayo (Hepatology Communications, 2019, IDS filed November 21, 2023) as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29-31, 33-34, 43 and 113-115 above, in view of Thompson (Phase 2 open-label efficacy and safety study of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with progressive familial intrahepatic cholestasis: 48-week interim efficacy analysis, October 2017, IDS filed November 3, 2023) and Camilleri (Neurogastroenterol Motil, 2009, cited in previous action).
Regarding claim 18: As discussed above, the prior art renders obvious the method of claim 1. Mirum teaches the method comprises measuring normalization or reduction from baseline in serum bile acids (sBA, pg. 7, secondary outcome measures).
Mirum does not teach wherein the ratio of 7αC4:sBA is determined prior to administering the ASBTI at a first dose level and determining the ratio after ASBTI administration wherein the ratio is about 2-fold greater or higher.
However, Thompson teaches a method for treating PFIC2 in children comprising administering 280 µg/kg/day maralixibat (slides 7 and 9). The method comprises measuring sBA changes in comparison to a baseline measurement (slide 9). The method comprises determining sBA and 7αC4 levels in serum and comparing to baseline (slides 6 and 8). The method comprises dose escalation of maralixibat (slide 5). Camilleri teaches that 7αC4 is related as an indirect measurement of bile acid synthesis (pg. 1, abstract). Utilizing the values of Thompson (slide 8) the ratio of 7aC4:sBA changed from approximately 0.012 at baseline (4.2:352) to about 0.03 (10:320) (i.e. greater than 2-fold).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to further modify the method of Mirum such that the measured sBA and 7αC4 levels are compared as a ratio. A person of ordinary skill in the art would have the motivation to do so as the art establishes these metrics are obtainable through routine practice for evaluating treatment of PFIC, and comparing ratios would allow for an overall assessment of the effect of the drug on bile acid synthesis. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer (See MPEP 2112 (I)). Wherein the method of the prior art is comparable to the instantly claimed in effective doses, the obtained ratios are expected properties of practicing the method.
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, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43 and 113-115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/382,636 (US 2024/0173317, cited in previous action) in view of Malatack (Pediatrics, 2018, IDS filed January 11, 2024) and Stieger (Current Drug Targets, 2011, cited on PTO-892) as evidenced by Amer (Gastroenterology Research, 2014, cited in previous action), Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29, 43 and 113-115: The copending application teaches a method for treating PFIC in a subject in need thereof comprising administering maralixibat in an amount from about 600 µg/kg/day to about 1200 µg/kg/day (claim 1). The copending claims teach wherein maralixibat chloride is an alternative (claim 3). The maralixibat chloride can be administered twice daily (claim 29). The PFIC can be PFIC 2 (claim 9). According to Amer, PFIC 2 is an autosomal recessive disease is caused by mutation in ABCB11 gene on chromosome 2q24, which encodes the canalicular bile salt export protein (BSEP, pg. 41, col. 1, para. 4). Defective BSEP leads to impaired bile salt secretion (i.e. impaired bile flow, pg. 41, col. 1, para. 4). Wherein the method is directed towards treating PFIC 2, the method encompasses describes treating a patient with a mutation in the ABCB11 gene with impaired bile secretion as recited by instant claim 10. The subject can be a pediatric subject (claim 21). The subject has a mutation in ABCB11, which encompasses a method comprising determining genotype of a subject (claim 24). The mutation can be selected from a non-truncating mutation and a truncating mutation (claim 25). The administration results in a reduction of intensity of pruritus as measured by an ItchRO(Obs) score (claim 37 wherein the score is reduced by at least 1.0 points relative to a baseline (claim 37).
They do not teach wherein the genotype of the subject has alternative missense mutations in the ABCB11 gene.
However, Malatack teaches a method for treating pediatric subjects with PFIC2 comprising administering maralixibat once daily for two years (abstract, pg. 3, col. 2, para. 1). The patients remained symptom free, including improvement in pruritis (pg. 3, col. 2, para. 1). The pruritis symptom after treatment was compared to typical pruritis symptoms in the patient (i.e. baseline, pg. 2, figure 1) The patients were DNA tested and found to have heterozygous missense variants in ABCB11: c.470A>G (p.Y157C) and c.3892G>A (p.G1298R) (i.e. alternative missense mutations, pg. 2, col. 1, para. 2). Malatack establishes that a composition comprising maralixibat controlled symptoms in 2 siblings with partial loss of BSEP activity (abstract).
Additionally, Stieger teaches additional known BSEP mutations in PFIC2 that result in residual transport activity (i.e. partial loss of activity), p.E297G, p.R432T and D482G (pg. 666, col. 2, para. 1). According to the instant specification, D482G and p.E297G are non-truncating missense mutations (i.e. classified as moderate/mild PFIC2, pgs. 148-150, tables 2-33)
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to apply the method to patients with missense mutations, such as those described by Stieger (p.E297G, p.R432T and D482G), as taught by Malatack and Stieger. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as maralixibat is known in the art to be beneficial to patients suffering from cholestatic liver disease with these mutation types that result in partial loss of BSEP activity.
Regarding claim 28: As discussed above, the copending claims teach administering maralixibat chloride twice daily. They do not explicitly teach administering once daily. However, it would have been prima facie obvious to do so in order to simplify the administration process. A person of ordinary skill in the art would have a reasonable expectation to do so as the claims require 600 µg/kg/day to about 1200 µg/kg/day could be accomplished with a single dose.
Regarding claim 30: As discussed above the copending claims render obvious the method of claim 1. The copending claims teach administering maralixibat in an amount from about 600 µg/kg/day to about 1200 µg/kg/day (claim 1). They do not explicitly teach wherein the daily dose is between about 5mg/day to about 100 mg/day.
However, according to Reagan-Shaw the average weight of an adult human is 60 kg, and a child is 20 kg (pg. 660, col. 2, table 1).
Wherein the method can be directed towards the treatment of pediatric subjects with a dose of 600 µg/kg to about 1200 µg/kg, corresponding to 12 mg to 24 mg (600 µg/kg*20kg=12000 µg =12mg) in an average weight child, claim 30 is encompassed.
Regarding claims 31 and 33-35: As discussed above, the copending claims teach wherein the severity of pruritus is reduced. They do not teach wherein the reduction is maintained for at least one year. However, given that the copending method teaches administration of maralixibat in comparable doses to the instantly claimed method, this is an expected property of the method, absent evidence to the contrary. Additionally a person of ordinary skill in the art would have had the motivation to do so in order to maintain reduction in pruritus.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/382,636 (US 2024/0173317), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), and Stieger (Current Drug Targets, 2011, cited on PTO-892), Amer (Gastroenterology Research, 2014, cited in previous action), and Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024) as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43 and 113-115 in view of Waisbourd-Zinman (Annals of Hepatology, 2017, cited on PTO-892).
Regarding claim 14: As discussed above, the copending claims in view of the prior art render obvious the methods of claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29-31, 33-34, 43 and 113-115, wherein the mutation can be a E297G, D482G, or R432T missense mutation that exhibit residual BSEP activity.
The prior art relied upon did not disclose a patient wherein the ABCB11 gene comprises a missense mutation that is not an E297G or D482G or Y157C or G1298R mutation as excluded by claim 14.
However, Waisbourd-Zinman teaches additional missense mutations of the ABCB11 gene, p.C68Y and p.R832H, in pediatric patients with mild PFIC2 (abstract). According to the instant specification, R832H is a non-truncating missense mutation (pg. 149 table 3).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to apply the method of the copending claims and prior art to the mutations that lead to mild forms of PFIC2 as taught by Waisbourd-Zinman. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes compositions comprising maralixibat are an effective treatment for PFIC2 in patients with missense mutations with residual BSEP activity. To summarize, it would have been obvious to apply the method to the treatment of PFIC2 patients with the following mutations, E297G, D482G, R432T, C68Y and R832H. Although the art does not establish C68Y as a non-truncating missense mutation, as discussed previously, the art establishes R432T as a possible non-truncating mutation, thus it would be obvious to treat a patient that is heterozygous R432T/ C68Y, as these a non-truncating mutations that lead to mild forms of PFIC2.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/382,636 (US 2024/0173317), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), and Stieger (Current Drug Targets, 2011, cited on PTO-892), Amer (Gastroenterology Research, 2014, cited in previous action), and Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024) as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 27-30, 31, 33-34, 43 and 113-115 in view of Thompson (Phase 2 open-label efficacy and safety study of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with progressive familial intrahepatic cholestasis: 48-week interim efficacy analysis, October 2017, IDS filed November 3, 2023) and Camilleri (Neurogastroenterol Motil, 2009, cited in previous action).
Regarding claim 18: As discussed above, the copending claims teach the method of claim 1.
They do not teach wherein the 7aC4:sBA ratios are compared before and after dosing, and wherein after the ASBTI administration the ratio is 2-fold or greater higher than the baseline ratio.
However, Thompson teaches a method for treating PFIC2 in children comprising administering 280 µg/kg/day maralixibat (slides 7 and 9). The method comprises determining sBA and 7αC4 levels in serum and comparing to baseline (slides 6 and 8). The method comprises dose escalation of maralixibat (slide 5). Camilleri teaches that 7αC4 is related as an indirect measurement of bile acid synthesis (pg. 1, abstract).
Taken together, it would have been prima facie obvious to modify the copending method by measuring the 7aC4:sBA ratios before and after treatment with the ASBTI and obtain the ratios as recited by instant claim 18. A person of ordinary skill in the art would have the motivation to do so as the art establishes these metrics are obtainable through routine practice for evaluating treatment of PFIC, and comparing ratios would allow for an overall assessment of the effect of the drug on bile acid synthesis. Wherein the method of the copending claims is comparable to the instantly claimed in effective doses, the obtained ratios are expected properties of practicing the method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43 and 113-115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/417,725 (US 2024/0189308, cited in previous action) in view of Malatack (Pediatrics, 2018, IDS filed January 11, 2024) and Stieger (Current Drug Targets, 2011, cited on PTO-892) as evidenced by Amer (Gastroenterology Research, 2014, cited in previous action). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, and 113-115: The copending claims teach a method for treating PFIC in a subject comprising maralixibat in an amount of about 560 µg/kg/day to about 1400 µg/kg/day (claim 103). According to the copending specification maralixibat is maralixibat chloride (pg. 2, para. 0007). The PFIC can be PFIC2 (claim 111). According to Amer, PFIC 2 is an autosomal recessive disease is caused by mutation in ABCB11 gene on chromosome 2q24, which encodes the canalicular bile salt export protein (BSEP, pg. 41, col. 1, para. 4). Defective BSEP leads to impaired bile salt secretion (i.e. impaired bile flow, pg. 41, col. 1, para. 4). Wherein the method is directed towards treating PFIC 2, the method encompasses describes treating a patient with a mutation in the ABCB11 gene with impaired bile secretion as recited by instant claim 10. The maralixibat can be administered in an amount of about 10mg/day to about 100 mg/day (claim 107). The maralixibat can be administered once daily (claim 113). The maralixibat can be administered twice daily (claim 114). The administration can carry on for at least 2 years (claim 116). The subject can be a pediatric subject (claim 120). The subject experiences pruritus prior to the administration of maralixibat (claim 119).
They do not teach wherein the genotype of the subject is determined and wherein the subject has alternative missense mutations in the ABCB11 gene.
However, Malatack teaches a method for treating pediatric subjects with PFIC2 comprising administering maralixibat once daily for two years (abstract, pg. 3, col. 2, para. 1). The patients remained symptom free, including improvement in pruritis (pg. 3, col. 2, para. 1). The pruritis symptom after treatment was compared to typical pruritis symptoms in the patient (i.e. baseline, pg. 2, figure 1) The patients were DNA tested and found to have heterozygous missense variants in ABCB11: c.470A>G (p.Y157C) and c.3892G>A (p.G1298R) (i.e. alternative missense mutations, pg. 2, col. 1, para. 2). Malatack establishes that a composition comprising maralixibat controlled symptoms in 2 siblings with partial loss of BSEP activity (abstract).
Additionally, Stieger teaches additional known BSEP mutations in PFIC2 that result in residual transport activity (i.e. partial loss of activity), p.E297G, p.R432T and D482G (pg. 666, col. 2, para. 1). According to the instant specification, D482G and p.E297G are non-truncating missense mutations (i.e. classified as moderate/mild PFIC2, pgs. 148-150, tables 2-33)
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to apply the method to patients with missense mutations, such as those described by Stieger (p.E297G, p.R432T and D482G), as taught by Malatack and Stieger. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as maralixibat is known in the art to be beneficial to patients suffering from cholestatic liver disease with these mutation types that result in partial loss of BSEP activity. Wherein the mutations are determined, the method of determining them is encompassed by the prior art.
Regarding claims 33-34 and 43: The copending claims do not state wherein the reduction in symptoms or pruritus are measured. However, wherein the method teaches the administration of maralixibat in comparable doses as instantly claimed for at least two years specifically to patients with pruritus, these are expected properties of practicing the method, absent evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application 18/417,725 (US 2024/0189308, cited in previous action), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), and Amer (Gastroenterology Research, 2014, cited in previous action) as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43 and 113-115 in view of Waisbourd-Zinman (Annals of Hepatology, 2017, cited on PTO-892).
Regarding claim 14: As discussed above, the copending claims in view of the prior art render obvious the methods of claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29-31, 33-34, 43 and 113-115, wherein the mutation can be a E297G, D482G, or R432T missense mutation that exhibit residual BSEP activity.
The prior art relied upon did not disclose a patient wherein the ABCB11 gene comprises a missense mutation that is not an E297G or D482G or Y157C or G1298R mutation as excluded by claim 14.
However, Waisbourd-Zinman teaches additional missense mutations of the ABCB11 gene, p.C68Y and p.R832H, in pediatric patients with mild PFIC2 (abstract). According to the instant specification, R832H is a non-truncating missense mutation (pg. 149 table 3).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to apply the method of the copending claims and prior art to the mutations that lead to mild forms of PFIC2 as taught by Waisbourd-Zinman. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes compositions comprising maralixibat are an effective treatment for PFIC2 in patients with missense mutations with residual BSEP activity. To summarize, it would have been obvious to apply the method to the treatment of PFIC2 patients with the following mutations, E297G, D482G, R432T, C68Y and R832H. Although the art does not establish C68Y as a non-truncating missense mutation, as discussed previously, the art establishes R432T as a possible non-truncating mutation, thus it would be obvious to treat a patient that is heterozygous R432T/ C68Y, as these a non-truncating mutations that lead to mild forms of PFIC2.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/417,725 (US 2024/0189308), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), and Amer (Gastroenterology Research, 2014, cited in previous action) as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 27-30, 31, 33-34, 43 and 113-115 above in view of Thompson (Phase 2 open-label efficacy and safety study of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with progressive familial intrahepatic cholestasis: 48-week interim efficacy analysis, October 2017, IDS filed November 3, 2023) and Camilleri (Neurogastroenterol Motil, 2009).
Regarding claim 18: As discussed above, the copending claims teach the method of claim 1.
They do not teach wherein the 7aC4:sBA ratios are compared before and after dosing, and wherein after the ASBTI administration the ratio is 2-fold or greater higher than the baseline ratio.
However, Thompson teaches a method for treating PFIC2 in children comprising administering 280 µg/kg/day maralixibat (slides 7 and 9). The method comprises determining sBA and 7αC4 levels in serum and comparing to baseline (slides 6 and 8). The method comprises dose escalation of maralixibat (slide 5). Camilleri teaches that 7αC4 is related as an indirect measurement of bile acid synthesis (pg. 1, abstract).
Taken together, it would have been prima facie obvious to modify the copending method by measuring the 7aC4:sBA ratios before and after treatment with the ASBTI and obtain the ratios as recited by instant claim 18. A person of ordinary skill in the art would have the motivation to do so as the art establishes these metrics are obtainable through routine practice for evaluating treatment of PFIC, and comparing ratios would allow for an overall assessment of the effect of the drug on bile acid synthesis. Wherein the method of the copending claims is comparable to the instantly claimed in effective doses, the obtained ratios are expected properties of practicing the method.
Claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43 and 113-115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/430,210 (US 2022/0160726, IDS filed August 8, 2024) in view of Malatack (Pediatrics, 2018, IDS filed January 11, 2024) and Stieger (Current Drug Targets, 2011, cited on PTO-892) as evidenced by Amer (Gastroenterology Research, 2014, cited in previous action) and Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claims 1, 3, 8, 10, 12, 15-16, 24, 27-29, 31, 33-34, 43 and 113-115: The copending claims teach a method for treating PFIC in a subject comprising administering to a subject an ASBTI selected from maralixibat chloride and volixibat, wherein the ASBTI is administered in amount of about 280 µg/kg/day to about 1400 µg/kg/day (claim 1). The PFIC can be PFIC2 (claim 16). According to Amer, PFIC 2 is an autosomal recessive disease is caused by mutation in ABCB11 gene on chromosome 2q24, which encodes the canalicular bile salt export protein (BSEP, pg. 41, col. 1, para. 4). Defective BSEP leads to impaired bile salt secretion (i.e. impaired bile flow, pg. 41, col. 1, para. 4). Wherein the method is directed towards treating PFIC 2, the method encompasses describes treating a patient with a mutation in the ABCB11 gene with impaired bile secretion as recited by instant claim 10. The subject has a non-truncating mutation in the ABCB11 gene (claim 17). The subject can be a pediatric subject (claim 18). The ASBTI can be administered once daily (claim 48). The subject can be a pediatric subject (claim 18). The ASBTI can be administered twice daily (claim 49). The administration reduces a symptom or disease relevant laboratory measure that is maintained for at least 6 months (claim 52). The reduction in a symptom comprises a reduction in sBA concentration or increase in serum 7aC4 concentration (claim 53). The reduction in symptom is determined relative to a baseline level (claim 54). The administration reduces intensity of pruritus (claim 58).
The copending claims do not teach wherein the reduction in symptoms is maintained for at least one year. However, wherein the copending claims teach the administration reduces symptoms for at least 6 months, and the copending method encompasses the claimed method in comparable doses, these are expected properties of practicing the method, absent evidence to the contrary.
They do not teach wherein the genotype of the subject has alternative missense mutations in the ABCB11 gene.
However, Malatack teaches a method for treating pediatric subjects with PFIC2 comprising administering maralixibat once daily for two years (abstract, pg. 3, col. 2, para. 1). The patients remained symptom free, including improvement in pruritis (pg. 3, col. 2, para. 1). The pruritis symptom after treatment was compared to typical pruritis symptoms in the patient (i.e. baseline, pg. 2, figure 1) The patients were DNA tested and found to have heterozygous missense variants in ABCB11: c.470A>G (p.Y157C) and c.3892G>A (p.G1298R) (i.e. alternative missense mutations, pg. 2, col. 1, para. 2). Malatack establishes that a composition comprising maralixibat controlled symptoms in 2 siblings with partial loss of BSEP activity (abstract).
Additionally, Stieger teaches additional known BSEP mutations in PFIC2 that result in residual transport activity (i.e. partial loss of activity), p.E297G, p.R432T and D482G (pg. 666, col. 2, para. 1). According to the instant specification, D482G and p.E297G are non-truncating missense mutations (i.e. classified as moderate/mild PFIC2, pgs. 148-150, tables 2-33)
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to apply the method to patients with missense mutations, such as those described by Stieger (p.E297G, p.R432T and D482G), as taught by Malatack and Stieger. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as maralixibat is known in the art to be beneficial to patients suffering from cholestatic liver disease with these mutation types that result in partial loss of BSEP activity. Wherein the mutations are determined, the method of determining them is encompassed by the prior art.
Regarding claim 30: As discussed above the copending claims render obvious the method of claim 1. The copending claims teach administering maralixibat in an amount from about 600 µg/kg/day to about 1200 µg/kg/day (claim 1). They do not explicitly teach wherein the daily dose is between about 5mg/day to about 100 mg/day.
However, according to Reagan-Shaw the average weight of an adult human is 60 kg, and a child is 20 kg (pg. 660, col. 2, table 1).
Wherein the method can be directed towards the treatment of pediatric subjects with a dose of 600 µg/kg to about 1200 µg/kg, corresponding to 12 mg to 24 mg (600 µg/kg*20kg=12000 µg =12mg) in an average weight child, claim 30 is encompassed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application 17/430,210 (US 2022/0160726, IDS filed August 8, 2024), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), Amer (Gastroenterology Research, 2014, cited in previous action), and Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024) as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43 and 113-115 in view of Waisbourd-Zinman (Annals of Hepatology, 2017, cited on PTO-892).
Regarding claim 14: As discussed above, the copending claims in view of the prior art render obvious the methods of claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29-31, 33-34, 43 and 113-115, wherein the mutation can be a E297G, D482G, or R432T missense mutation that exhibit residual BSEP activity.
The prior art relied upon did not disclose a patient wherein the ABCB11 gene comprises a missense mutation that is not an E297G or D482G or Y157C or G1298R mutation as excluded by claim 14.
However, Waisbourd-Zinman teaches additional missense mutations of the ABCB11 gene, p.C68Y and p.R832H, in pediatric patients with mild PFIC2 (abstract). According to the instant specification, R832H is a non-truncating missense mutation (pg. 149 table 3).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to apply the method of the copending claims and prior art to the mutations that lead to mild forms of PFIC2 as taught by Waisbourd-Zinman. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes compositions comprising maralixibat are an effective treatment for PFIC2 in patients with missense mutations with residual BSEP activity. To summarize, it would have been obvious to apply the method to the treatment of PFIC2 patients with the following mutations, E297G, D482G, R432T, C68Y and R832H. Although the art does not establish C68Y as a non-truncating missense mutation, as discussed previously, the art establishes R432T as a possible non-truncating mutation, thus it would be obvious to treat a patient that is heterozygous R432T/ C68Y, as these a non-truncating mutations that lead to mild forms of PFIC2.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/430,210 (US 2022/0160726, IDS filed August 8, 2024), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), Amer (Gastroenterology Research, 2014, cited in previous action), and Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024) as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43 and 113-115 above in view of Thompson (Phase 2 open-label efficacy and safety study of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with progressive familial intrahepatic cholestasis: 48-week interim efficacy analysis, October 2017, IDS filed November 3, 2023) and Camilleri (Neurogastroenterol Motil, 2009).
Regarding claim 18: As discussed above, the copending claims teach the method of claim 1.
They do not teach wherein the 7aC4:sBA ratios are compared before and after dosing, and wherein after the ASBTI administration the ratio is 2-fold or greater higher than the baseline ratio.
However, Thompson teaches a method for treating PFIC2 in children comprising administering 280 µg/kg/day maralixibat (slides 7 and 9). The method comprises determining sBA and 7αC4 levels in serum and comparing to baseline (slides 6 and 8). The method comprises dose escalation of maralixibat (slide 5). Camilleri teaches that 7αC4 is related as an indirect measurement of bile acid synthesis (pg. 1, abstract).
Taken together, it would have been prima facie obvious to modify the copending method by measuring the 7aC4:sBA ratios before and after treatment with the ASBTI and obtain the ratios as recited by instant claim 18. A person of ordinary skill in the art would have the motivation to do so as the art establishes these metrics are obtainable through routine practice for evaluating treatment of PFIC, and comparing ratios would allow for an overall assessment of the effect of the drug on bile acid synthesis. Wherein the method of the copending claims is comparable to the instantly claimed in effective doses, the obtained ratios are expected properties of practicing the method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43 and 113-115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/430,168 (US 2022/0160726, IDS filed August 8, 2024) in view of Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), Amer (Gastroenterology Research, 2014, cited in previous action), and Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43, and 113-115: The copending claims teach a method for increasing growth in a pediatric subject having a cholestatic liver disease comprising administering an effective amount of an ASBTI, wherein the ASBTI can be maralixibat or volixibat (claim 1). The copending claims teach wherein the liver disease is PFIC 2 (claim 12). According to Amer, PFIC 2 is an autosomal recessive disease is caused by mutation in ABCB11 gene on chromosome 2q24, which encodes the canalicular bile salt export protein (BSEP, pg. 41, col. 1, para. 4). Defective BSEP leads to impaired bile salt secretion (i.e. impaired bile flow, pg. 41, col. 1, para. 4). Wherein the method is directed towards treating PFIC 2, the method encompasses describes treating a patient with a mutation in the ABCB11 gene with impaired bile secretion as recited by instant claim 10. The subject has an ABCB11 gene with a missense gene and no truncating mutation (claim 13). The ASBTI can be maralixibat chloride (claim 3). The ASBTI can be administered once daily (claim 16). The ASBTI can administered twice daily (claim 18). The ASBTI can be administered in an amount of about 70 µg/kg to 700 µg/kg per dose (claim 19). The increase in growth is maintained over a period of up to 2 years (i.e. reduction in symptom for at least one year) (claim 25). The increase in growth is measured relative to baseline (claims 20-22).
They do not teach wherein the genotype of the subject has alternative missense mutations in the ABCB11 gene or wherein the method results in a reduction in severity of pruritus.
However, Malatack teaches a method for treating pediatric subjects with PFIC2 comprising administering maralixibat once daily for two years (abstract, pg. 3, col. 2, para. 1). The patients remained symptom free, including improvement in pruritis (pg. 3, col. 2, para. 1). The pruritis symptom after treatment was compared to typical pruritis symptoms in the patient (i.e. baseline, pg. 2, figure 1) The patients were DNA tested and found to have heterozygous missense variants in ABCB11: c.470A>G (p.Y157C) and c.3892G>A (p.G1298R) (i.e. alternative missense mutations, pg. 2, col. 1, para. 2). Malatack establishes that a composition comprising maralixibat controlled symptoms in 2 siblings with partial loss of BSEP activity (abstract).
Additionally, Stieger teaches additional known BSEP mutations in PFIC2 that result in residual transport activity (i.e. partial loss of activity), p.E297G, p.R432T and D482G (pg. 666, col. 2, para. 1). According to the instant specification, D482G and p.E297G are non-truncating missense mutations (i.e. classified as moderate/mild PFIC2, pgs. 148-150, tables 2-33)
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to apply the method to patients with missense mutations, such as those described by Stieger (p.E297G, p.R432T and D482G), as taught by Malatack and Stieger. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as maralixibat is known in the art to be beneficial to patients suffering from cholestatic liver disease with these mutation types that result in partial loss of BSEP activity. Wherein the method of the prior art is comparable to the instantly claimed in effective doses and measurement of pruritus is a known measurable symptom of the underlying disorder, the obtained reduction in pruritus are expected properties of practicing the method.
Regarding claim 30: As discussed above the copending claims render obvious the method of claim 1. The copending claims teach administering maralixibat in an amount from about 600 µg/kg/day to about 1200 µg/kg/day (claim 1). They do not explicitly teach wherein the daily dose is between about 5mg/day to about 100 mg/day.
However, according to Reagan-Shaw the average weight of an adult human is 60 kg, and a child is 20 kg (pg. 660, col. 2, table 1).
Wherein the method can be directed towards the treatment of pediatric subjects with a dose of 600 µg/kg to about 1200 µg/kg, corresponding to 12 mg to 24 mg (600 µg/kg*20kg=12000 µg =12mg) in an average weight child, claim 30 is encompassed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/430,168 (US 2022/0160726, IDS filed August 8, 2024), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), Amer (Gastroenterology Research, 2014, cited in previous action), and Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024) as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 27-31, 33-34, 43 and 113-115 in view of Waisbourd-Zinman (Annals of Hepatology, 2017, cited on PTO-892).
Regarding claim 14: As discussed above, the copending claims in view of the prior art render obvious the methods of claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29-31, 33-34, 43 and 113-115, wherein the mutation can be a E297G, D482G, or R432T missense mutation that exhibit residual BSEP activity.
The prior art relied upon did not disclose a patient wherein the ABCB11 gene comprises a missense mutation that is not an E297G or D482G or Y157C or G1298R mutation as excluded by claim 14.
However, Waisbourd-Zinman teaches additional missense mutations of the ABCB11 gene, p.C68Y and p.R832H, in pediatric patients with mild PFIC2 (abstract). According to the instant specification, R832H is a non-truncating missense mutation (pg. 149 table 3).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to apply the method of the copending claims and prior art to the mutations that lead to mild forms of PFIC2 as taught by Waisbourd-Zinman. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes compositions comprising maralixibat are an effective treatment for PFIC2 in patients with missense mutations with residual BSEP activity. To summarize, it would have been obvious to apply the method to the treatment of PFIC2 patients with the following mutations, E297G, D482G, R432T, C68Y and R832H. Although the art does not establish C68Y as a non-truncating missense mutation, as discussed previously, the art establishes R432T as a possible non-truncating mutation, thus it would be obvious to treat a patient that is heterozygous R432T/ C68Y, as these a non-truncating mutations that lead to mild forms of PFIC2.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/430,168 (US 2022/0160726, IDS filed August 8, 2024), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), Amer (Gastroenterology Research, 2014, cited in previous action), and Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024) as applied to claims 1, 3, 8, 10, 12, 14-16, 24, 27-31, 33-34, 43 and 113-114 above in view of Thompson (Phase 2 open-label efficacy and safety study of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with progressive familial intrahepatic cholestasis: 48-week interim efficacy analysis, October 2017, IDS filed November 3, 2023) and Camilleri (Neurogastroenterol Motil, 2009).
Regarding claim 18: As discussed above, the copending claims and the prior art render obvious the method of claim 1.
They do not teach wherein the 7aC4:sBA ratios are compared before and after dosing, and wherein after the ASBTI administration the ratio is 2-fold or greater higher than the baseline ratio.
However, Thompson teaches a method for treating PFIC2 in children comprising administering 280 µg/kg/day maralixibat (slides 7 and 9). The method comprises determining sBA and 7αC4 levels in serum and comparing to baseline (slides 6 and 8). The method comprises dose escalation of maralixibat (slide 5). Camilleri teaches that 7αC4 is related as an indirect measurement of bile acid synthesis (pg. 1, abstract).
Taken together, it would have been prima facie obvious to modify the copending method by measuring the 7aC4:sBA ratios before and after treatment with the ASBTI and obtain the ratios as recited by instant claim 18. A person of ordinary skill in the art would have the motivation to do so as the art establishes these metrics are obtainable through routine practice for evaluating treatment of PFIC, and comparing ratios would allow for an overall assessment of the effect of the drug on bile acid synthesis. Wherein the method of the copending claims is comparable to the instantly claimed in effective doses, the obtained ratios are expected properties of practicing the method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 8, 10, 12, 15-16, 24, 28-31, 33-34, 43 and 113-115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/119,132 (US 2021/0113585) in view of Al-Dury (Frontiers in Pharmacology, 2018, IDS filed August 11, 2021), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), and Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024), as evidenced by Amer (Gastroenterology Research, 2014, cited in previous action). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claims 1, 3, 8, 10, 12, 15-16, 24, 28-31, 33-34, 43 and 113-115: The copending claims teach a method for treating cholestatic liver disease in a subject comprising administering to the subject an apical sodium-dependent Bile Acid Transport, wherein the ASBTI is volixibat, and wherein the volixibat administered in an amount about 40 mg/day to about 200 mg/day (claim 1). The cholestatic liver disease can be PFIC or biliary atresia (claim 9). The subject can be a pediatric subject (claim 18). The ASBTI can be administered once daily (claim 48). The ASBTI can be administered twice daily (claim 49). The administration of the ASBTI reduces a symptom or changes in a disease relevant laboratory measure of the liver disease for at least 6 months (claim 52). The reduction in symptom comprises a reduction in pruritus (claim 53). The symptom is determined relative to a baseline level (claim 54).
The copending claims do not teach wherein the reduction in symptoms is maintained for at least one year. However, wherein the copending claims teach the administration reduces symptoms for at least 6 months, and the copending method encompasses the claimed method in comparable doses, these are expected properties of practicing the method, absent evidence to the contrary.
The copending claims teach wherein the cholestatic liver disease is PFIC (claim 9). They do not teach wherein the compound is maralixibat chloride. They do not specifically teach wherein the subject has a BSEP deficiency.
However, Al-Dury teaches that volixibat and maralixibat are both recognized in the art as ASBTI useful for the treatment of cholestatic liver disease (abstract, pg. 5, col. 2, para. 4., pg. 2, col. 1, last para.). Malatack teaches a method for treating pediatric subjects with PFIC2 comprising administering maralixibat once daily for two years (abstract, pg. 3, col. 2, para. 1). According to Amer, PFIC 2 is an autosomal recessive disease is caused by mutation in ABCB11 gene on chromosome 2q24, which encodes the canalicular bile salt export protein (BSEP, pg. 41, col. 1, para. 4). Defective BSEP leads to impaired bile salt secretion (i.e. impaired bile flow, pg. 41, col. 1, para. 4). Wherein the method is directed towards treating PFIC 2, the method encompasses describes treating a patient with a mutation in the ABCB11 gene with impaired bile secretion as recited by instant claim 10. Wherein both volixibat and maralixibat are recognized as ASBTI and the copending claims teach the use of ASBTI for the treatment of cholestatic liver disease, it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)). According to the instant specification, BSEP deficiency is PFIC2 (pgs. 102, para. 00640).
Taken together it would have been prima facie obvious to modify the method of the copending claims by administering maralixibat or volixibat for treatment of PFIC2. A person of ordinary skill in the art would have the motivation to do so with a reasonable expectation of success as volixibat and maralixibat are known in the art as ASBTI that are useful in treating cholestatic liver diseases such as PFIC2. Wherein it would have been obvious to treat PFIC2 which is equivalent to BSEP deficiency according to the instant specification, instant claim 10 is encompassed.
As discussed above, the copending claims render obvious the method of claim 1. They do not teach wherein the genotype of the subject is determined wherein the subject has alternative missense mutations in the ABCB11 gene.
However, Malatack teaches a method for treating pediatric subjects with PFIC2 comprising administering maralixibat once daily for two years (abstract, pg. 3, col. 2, para. 1). The patients remained symptom free, including improvement in pruritis (pg. 3, col. 2, para. 1). The pruritis symptom after treatment was compared to typical pruritis symptoms in the patient (i.e. baseline, pg. 2, figure 1) The patients were DNA tested and found to have heterozygous missense variants in ABCB11: c.470A>G (p.Y157C) and c.3892G>A (p.G1298R) (i.e. alternative missense mutations, pg. 2, col. 1, para. 2). Malatack establishes that a composition comprising maralixibat controlled symptoms in 2 siblings with partial loss of BSEP activity (abstract).
Additionally, Stieger teaches additional known BSEP mutations in PFIC2 that result in residual transport activity (i.e. partial loss of activity), p.E297G, p.R432T and D482G (pg. 666, col. 2, para. 1). According to the instant specification, D482G and p.E297G are non-truncating missense mutations (i.e. classified as moderate/mild PFIC2, pgs. 148-150, tables 2-33).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to apply the method to patients with missense mutations, such as those described by Stieger (p.E297G, p.R432T and D482G), as taught by Malatack and Stieger. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as maralixibat is known in the art to be beneficial to patients suffering from cholestatic liver disease with these mutation types that result in partial loss of BSEP activity.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/119,132 (US 2021/0113585), Al-Dury (Frontiers in Pharmacology, 2018, IDS filed August 11, 2021), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024), and Amer (Gastroenterology Research, 2014, cited in previous action) as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 28-31, 33-34, 43 and 113-115 above in view of Waisbourd-Zinman (Annals of Hepatology, 2017, cited on PTO-892).
Regarding claim 14: As discussed above, the copending claims in view of the prior art render obvious the methods of claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29-31, 33-34, 43 and 113-115, wherein the mutation can be a E297G, D482G, or R432T missense mutation that exhibit residual BSEP activity.
The prior art relied upon did not disclose a patient wherein the ABCB11 gene comprises a missense mutation that is not an E297G or D482G or Y157C or G1298R mutation as excluded by claim 14.
However, Waisbourd-Zinman teaches additional missense mutations of the ABCB11 gene, p.C68Y and p.R832H, in pediatric patients with mild PFIC2 (abstract). According to the instant specification, R832H is a non-truncating missense mutation (pg. 149 table 3).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to apply the method of the copending claims and prior art to the mutations that lead to mild forms of PFIC2 as taught by Waisbourd-Zinman. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes compositions comprising maralixibat are an effective treatment for PFIC2 in patients with missense mutations with residual BSEP activity. To summarize, it would have been obvious to apply the method to the treatment of PFIC2 patients with the following mutations, E297G, D482G, R432T, C68Y and R832H. Although the art does not establish C68Y as a non-truncating missense mutation, as discussed previously, the art establishes R432T as a possible non-truncating mutation, thus it would be obvious to treat a patient that is heterozygous R432T/ C68Y, as these a non-truncating mutations that lead to mild forms of PFIC2.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/119,132 (US 2021/0113585), Al-Dury (Frontiers in Pharmacology, 2018, IDS filed August 11, 2021), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024), Amer (Gastroenterology Research, 2014, cited in previous action), as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 28-31, 33-34, 43 and 113-115 above in view of Thompson (Phase 2 open-label efficacy and safety study of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with progressive familial intrahepatic cholestasis: 48-week interim efficacy analysis, October 2017, IDS filed November 3, 2023) and Camilleri (Neurogastroenterol Motil, 2009).
Regarding claim 18: As discussed above, the copending claims teach the method of claim 1.
They do not teach wherein the 7aC4:sBA ratios are compared before and after dosing, and wherein after the ASBTI administration the ratio is 2-fold or greater higher than the baseline ratio.
However, Thompson teaches a method for treating PFIC2 in children comprising administering 280 µg/kg/day maralixibat (slides 7 and 9). The method comprises determining sBA and 7αC4 levels in serum and comparing to baseline (slides 6 and 8). The method comprises dose escalation of maralixibat (slide 5). Camilleri teaches that 7αC4 is related as an indirect measurement of bile acid synthesis (pg. 1, abstract).
Taken together, it would have been prima facie obvious to modify the copending method by measuring the 7aC4:sBA ratios before and after treatment with the ASBTI and obtain the ratios as recited by instant claim 18. A person of ordinary skill in the art would have the motivation to do so as the art establishes these metrics are obtainable through routine practice for evaluating treatment of PFIC, and comparing ratios would allow for an overall assessment of the effect of the drug on bile acid synthesis. Wherein the method of the copending claims is comparable to the instantly claimed in effective doses, the obtained ratios are expected properties of practicing the method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 27 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/119,132 (US 2021/0113585), Al-Dury (Frontiers in Pharmacology, 2018, IDS filed August 11, 2021), Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), Reagan-Shaw (FASEB J., 2007, IDS filed August 8, 2024), Amer (Gastroenterology Research, 2014, cited in previous action), as applied to claims 1, 3, 8, 10, 12, 15-16, 24, 28-31, 33-34, 43 and 113-115 above in view of Mirum (US Clinical Trial NCT03353454). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claim 27: As discussed above maralixibat and volixibat are established equivalents for the purpose of treating PFIC. The copending claims do not teach wherein the ASBTI is administered at a daily dose of 1200 µg/kg
However, Mirum teaches a method for treating progressive familial intrahepatic cholestasis (PFIC) comprising administering to the subject maralixibat (pg. 3, title). The method comprises administering an oral solution of maralixibat containing up to 600 µg/kg twice daily for 26 weeks (pg. 6, arms and interventions).
As discussed above maralixibat and volixibat are established equivalents for the purpose of treating PFIC. Taken together it would have been prima facie obvious to administer the compound in the claimed doses as suggested by Mirum. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as these doses are known in the art to be useful for the treatment of PFIC with an ASBTI.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3, 8, 10, 12, 15-16, 18, 24, 27-31, 33-34, 43 and 113-115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/271,591 (unpublished, cited on PTO-892) in view of Malatack (Pediatrics, 2018, IDS filed January 11, 2024) and Stieger (Current Drug Targets, 2011, cited on PTO-892) as evidenced by Amer (Gastroenterology Research, 2014, cited in previous action). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claims 1, 3, 8, 10, 12, 15-16, 18, 24, 27-31, 33-34, 43 and 113-115: The copending claims teach a method for treating cholestatic liver disease in a subject comprising administering to the subject an ASBTI, wherein the ASBTI is administered in an amount of from about 10 ug/kg/day to about 1400 ug/kg/day (claim 1). The copending claims teach the ASBTI can be maralixibat chloride (claim 2). The compound can be administered once daily (claim 19). The compound can be administered twice daily (claim 20). The PFIC can be PFIC 2 (claim 16). According to Amer, PFIC 2 is an autosomal recessive disease is caused by mutation in ABCB11 gene on chromosome 2q24, which encodes the canalicular bile salt export protein (BSEP, pg. 41, col. 1, para. 4). Defective BSEP leads to impaired bile salt secretion (i.e. impaired bile flow, pg. 41, col. 1, para. 4). Wherein the method is directed towards treating PFIC 2, the method encompasses describes treating a patient with a mutation in the ABCB11 gene with impaired bile secretion as recited by instant claim 10. The subject can be a pediatric subject (claim 18). The subject has a non-truncating mutation in ABCB11, which encompasses a method comprising determining genotype of a subject (claim 17). The administration of the ASBTI reduces a symptom or changes in a disease relevant laboratory measure of the liver disease for at least one year (claim 23). The reduction in symptom comprises a reduction in pruritus (claim 24). The symptom is determined relative to a baseline level (claim 25). The administration of the ASBTI results in an increase in a ratio of serum 7aC4 concentration to sBA concentration (claim 31). The increase of ratio is increased by about 2 fold (claim 32).
They do not teach wherein the subject has missense mutations in the ABCB11 gene.
However, Malatack teaches a method for treating pediatric subjects with PFIC2 comprising administering maralixibat once daily for two years (abstract, pg. 3, col. 2, para. 1). The patients remained symptom free, including improvement in pruritis (pg. 3, col. 2, para. 1). The pruritis symptom after treatment was compared to typical pruritis symptoms in the patient (i.e. baseline, pg. 2, figure 1) The patients were DNA tested and found to have heterozygous missense variants in ABCB11: c.470A>G (p.Y157C) and c.3892G>A (p.G1298R) (i.e. alternative missense mutations, pg. 2, col. 1, para. 2). Malatack establishes that a composition comprising maralixibat controlled symptoms in 2 siblings with partial loss of BSEP activity (abstract).
Additionally, Stieger teaches additional known BSEP mutations in PFIC2 that result in residual transport activity (i.e. partial loss of activity), p.E297G, p.R432T and D482G (pg. 666, col. 2, para. 1). According to the instant specification, D482G and p.E297G are non-truncating missense mutations (i.e. classified as moderate/mild PFIC2, pgs. 148-150, tables 2-33).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to apply the method to patients with missense mutations, such as those described by Stieger (p.E297G, p.R432T and D482G), as taught by Malatack and Stieger. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as maralixibat is known in the art to be beneficial to patients suffering from cholestatic liver disease with these mutation types that result in partial loss of BSEP activity.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/271,591 (unpublished, cited on PTO-892) in view of Malatack (Pediatrics, 2018, IDS filed January 11, 2024), Stieger (Current Drug Targets, 2011, cited on PTO-892), and Amer (Gastroenterology Research, 2014, cited in previous action) as applied to claims 1, 3, 8, 10, 12, 15-16, 18, 24, 27-31, 33-34, 43 and 113-115 above in view of Waisbourd-Zinman (Annals of Hepatology, 2017, cited on PTO-892).
Regarding claim 14: As discussed above, the copending claims in view of the prior art render obvious the methods of claims 1, 3, 8, 10, 12, 15-16, 24, 27, 29-31, 33-34, 43 and 113-115, wherein the mutation can be a E297G, D482G, or R432T missense mutation that exhibit residual BSEP activity.
The prior art relied upon did not disclose a patient wherein the ABCB11 gene comprises a missense mutation that is not an E297G or D482G or Y157C or G1298R mutation as excluded by claim 14.
However, Waisbourd-Zinman teaches additional missense mutations of the ABCB11 gene, p.C68Y and p.R832H, in pediatric patients with mild PFIC2 (abstract). According to the instant specification, R832H is a non-truncating missense mutation (pg. 149 table 3).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to apply the method of the copending claims and prior art to the mutations that lead to mild forms of PFIC2 as taught by Waisbourd-Zinman. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes compositions comprising maralixibat are an effective treatment for PFIC2 in patients with missense mutations with residual BSEP activity. To summarize, it would have been obvious to apply the method to the treatment of PFIC2 patients with the following mutations, E297G, D482G, R432T, C68Y and R832H. Although the art does not establish C68Y as a non-truncating missense mutation, as discussed previously, the art establishes R432T as a possible non-truncating mutation, thus it would be obvious to treat a patient that is heterozygous R432T/ C68Y, as these a non-truncating mutations that lead to mild forms of PFIC2.
Response to Arguments
Applicant’s arguments filed November 4, 2025 have been fully considered but they are not persuasive.
On page 6 of Applicant’s response, Applicant argues that the newly amended claims which exclude the mutations taught by Malatack render the instant claims allowable over the prior art.
However, see 103 rejections above, wherein:
Malatack establishes that a composition comprising maralixibat controlled symptoms in 2 siblings with partial loss of BSEP activity (abstract).
Stieger teaches additional known BSEP mutations in PFIC2 that result in residual transport activity (i.e. partial loss of activity), p.E297G, p.R432T and D482G (pg. 666, col. 2, para. 1). According to the instant specification, D482G and p.E297G are non-truncating missense mutations (i.e. classified as moderate/mild PFIC2, pgs. 148-150, tables 2-33)
Waisbourd-Zinman teaches additional missense mutations of the ABCB11 gene, p.C68Y and p.R832H, in pediatric patients with mild PFIC2 (abstract). According to the instant specification, R832H is a non-truncating missense mutation (pg. 149 table 3).
Given that the art establishes ASBTI treatment of missense mutations, it would have been prima facie obvious to apply the method to other missense mutations with a reasonable expectation of success, absent a showing of unexpected results. The art teaches that missense mutations that result in residual BSEP function are treatable with maralixibat, which is a common property across the missense mutations cited above. Thus, a person of ordinary skill in the art would recognize the therapeutic potential in applying the method to other missense mutations, which are known in the art and thus those patients are in need of treatment.
Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 103 rejections are maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this action.
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/S.L.G./Examiner, Art Unit 1693
/ERIC OLSON/Primary Examiner, Art Unit 1693
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