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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/16/2026 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/16/2026 has been considered by the examiner and initialed copies of the IDS are included with the mailing of this office action.
Status of the Claims
This action is in response to papers filed 03/16/2026 in which claims 1-104, 106-107, 109-114, and 116-117 were canceled; claims 105, 115, 128, and 130 were amended; claim 131 was newly added. All the amendments have been thoroughly reviewed and entered.
Claims 105, 108, 115, and 118-131 are under examination.
Withdrawn Objection/Rejection
The Examiner has re-weighted all the evidence of record. Any rejection and/or objection not specifically addressed below is hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
New Rejection
Necessitated by Applicant’s Claim Amendments
Claim Rejections - 35 USC § 112 – NEW MATTER
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 105, 108, 115, and 118-131 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 105 introduces new matter as the claim recite the limitation: administering to the subject an amount of a calcium ion chelator effective to treat the bile acid diarrhea. There is no support in the specification for this limitation.
Applicant asserted that support the amendments can be found in paragraph [0237] of the published application (US20220280514).
However, after a review of said paragraph [0237] of the published application, as well as, throughout the specification (the published application), there is no support or disclosure for the genus of calcium ion chelator, much less the support for the active step of “administering to the subject an amount of a calcium ion chelator effective to treat the bile acid diarrhea.”
It is noted that paragraph [0237] is drawn to disclosing “[t]he CDCA-induced increase in short-circuit current in T84 cells is largely blocked by pretreatment with the Ca2+ chelator BAPTA-AM.” There is nothing in paragraph [0237] which disclosed a subject was administered an amount of a calcium ion chelator effective to treat the bile acid diarrhea. Paragraph [0237] is describing experiments showing the involvement of Ca2+ signaling in the prosecretory response to CDCA in T84 cells, which is not support for “administering to the subject an amount of a calcium ion chelator effective to treat the bile acid diarrhea,” as no indication that an effective amount of a calcium ion chelator was administered to subject to treat bile acid diarrhea. In addition, nowhere in the specification does it describe a combination therapy of BPO-27 and a calcium ion chelator in the treatment of bile acid diarrhea. Thus, Applicant does not have possession of the claimed active step of “administering to the subject an amount of a calcium ion chelator effective to treat the bile acid diarrhea.”
Furthermore, paragraph [0237] particularly used BAPTA-AM as the specific Ca2+ chelator. One species of Ca2+ chelator (BAPTA-AM) is not support for the entire genus of “calcium ion chelator” as claimed because calcium ion chelators encompassed a multitudes of chelators including calcium citrate, EDTA, citric acid, and calcium Disodium EDTA, to name a few, which are not supported by Applicant’s specification. Thus, Applicant does not have possession of the claimed genus of “calcium ion chelator.”
Claims 108, 115, and 118-131 are also rejected as they depend directly or indirectly from claim 105, thereby also containing the new matter material.
As such, the disclosure does not reasonably convey that the inventor had possession of the subject matter of the amendments at the time of filing of the instant application.
Modified Rejections
Necessitated by Applicant’s Claim Amendments
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) 105, 108, 115, 118-125, and 131 is/are rejected under 35 U.S.C. 103 as being unpatentable over Verkman et al (US 2014/0080821 A1) in view of Camilleri (Gut and Liver, May 2015, 9(3): 332-339), Beigel et al (Journal of Crohn’s Colitis, 2014, 8: 1471-1479), and Vidyasagar et al (US 2014/0377374 A1).
Regarding claim 105, Verkman teaches a method of treating diseases and disorders associated with aberrantly increased CFTR chloride channel activity such as secretory diarrhea, the method comprising administering to a subject in need thereof, a composition comprising an effective amount of CFTR chloride channel inhibitor, particularly, (R)-BPO-27 (Abstract; [0014] . [0142]-[0160], [0164], [0232], [0388]-[0389], [0393], [0394], [0415], [0434]-[0435], [0455]-[0461], [0546], [0549]; Example 33; claims, 1, 43-46 and 51-55).
While Verkman does not expressly teach that bile acid diarrhea, it would have been obvious that the method of Verkman would also be effective in treating bile acid diarrhea, as bile acid diarrhea is a type of secretory diarrhea per Camilleri and Beigel. Camilleri teaches the mechanism of bile acid diarrhea include water secretion through activation of CFTR via adenylate cyclase (Camilleri: pages 333-338). Furthermore, Beigel also established that bile acid diarrhea is characterized as watery diarrhea (Abstract; pages 1472). Additionally, Camilleri and Beigel teaches bile acid diarrhea is usually seen in patients ileal Crohn’s disease or ileal resection (Camilleri: pages 333-334 and 336-337; Beigel: Abstract and page 1472).
Given that Verkman established that one of the cause of bile acid diarrhea is due to the activation of CFTR via adenylate cyclase, it would have been obvious to one of ordinary skill in the art that the use of a CFTR chloride channel inhibitor such as (R)-BPO-27 would be effective in treating bile acid diarrhea, as the treatment of bile acid diarrhea per Beigel is to reducing liquid stool (Beigel: Abstract; pages: pages 1472-1478), and such inhibition of CFTR using (R)-BPO-27 would reduce water secretion, as the activation of CFTR of has been blocked.
One of ordinary skill in the art would have reasonable predictably and expectation of success of using (R)-BPO-27 in effective treatment of bile acid diarrhea because Verkman indicated that diarrhea that is a condition of, or is related to inflammatory gastrointestinal disorders such as inflammatory bowel disease (IBD) and Crohn’s disease can be treated using a CFTR chloride channel inhibitor such as (R)-BPO-27 (Verkman: [0394]), and the bile acid diarrhea as taught in Verkman and Beigel is within the scope of such “diarrhea that is a condition of, or is related to inflammatory gastrointestinal disorders such as inflammatory bowel disease (IBD) and Crohn’s disease,” as both Camilleri and Beigel teach bile acid diarrhea is usually seen in patients with IBD or Crohn’s disease (Camilleri: pages 333-334 and 336-337; Beigel: Abstract and page 1472).
With respect to the claimed “administering to the subject an amount of a calcium ion chelator effective to treat the bile acid diarrhea” of claim 105, Vidyasagar teaches a method of treating diarrhea including secretory diarrhea mediated via CFTR channels and/or CaCC channels using an active ingredient that decrease Cl- and/or HCO3- secretion and/or improve fluid absorption (Abstract; [0003]-[0017], [0065]-[0070], [0085] and [0123]-[0126]; Example 11). Vidyasagar teaches increase in intracellular cAMP ([cAMP]i) and Ca2+ ([Ca2+]i are known to mediate Cl and/or HCO3 − secretion in diarrhea associated with both infective as well as inflammatory conditions ([0004]). Vidyasagar teaches glucose increase intracellular Ca2+ levels in Caco-2-cells showed that in cells and in pre-incubated with BAPTA-AM (a calcium chelator), glucose fails to stimulate any increase in intracellular Ca2+ levels, thereby glucose-stimulated Ca2+ oscillation is abolished by pre-incubating the cells with intracellular Ca2+ chelator BAPTA-AM, and indicates that intracellular Ca2+ is involved in glucose-induced anionic secretion ([0017], [0085] and [0123]-[0126]; Example 11).
It would have been obvious to one of ordinary skill in the art to further administer to the subject of Verkman in view of Camilleri and Beigel in the treatment of bile acid diarrhea a calcium chelator such as BAPTA-AM, and produce the claimed invention. One of ordinary skill in the art would have been motivate do to do because Vidyasagar showed that BAPTA-AM was effective in blocking intracellular Ca2+ levels, which are known to mediate chloride (Cl-) section in diarrhea including secretory diarrhea mediated via CFTR channels and/or CaCC channels (Vidyasagar: [0017], [0085] and [0123]-[0126]; Example 11). As discussed above, Verkman in view of Camilleri and Beigel established that bile acid diarrhea is a secretory diarrhea that is caused by aberrantly increased CFTR chloride channel activity and thus it would have been reasonably obvious to further use a calcium chelator such as BAPTA-AM in combination with (R)-BPO-27 to provide at least an additive effect of treating bile acid diarrhea, and achieve Applicant’s claimed invention with reasonable expectation of success.
Regarding claim 108, as discussed above, Verkman teaches the CFTR chloride channel inhibitor is (R)-BPO-27.
Regarding claim 115, Verkman teaches the composition contains a racemic mixture of BPO-27 ([0016], [0074], [0457], [0548]; claim 1), thereby the composition of Verkman also contains (S)-BPO-27.
Regarding claims 118 and 119, Beigel teaches the bile acid sequestrants including colesevalam is a standard treatment for bile acid diarrhea (Beigel: Abstract; pages: pages 1472-1478). It would have been obvious to use a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27, with bile acid sequestrant such as colesevalam in the treatment of bile acid diarrhea because this combination would at least provide an additive effect in the treatment of bile acid diarrhea. One of ordinary skill in the art would have reasonable expectation of success in using a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27, with bile acid sequestrant such as colesevalam because Verkman teaches that the CFTR chloride channel inhibitor can be used in combination with other pharmaceutically active compounds in the treatment of secretory diarrhea (Verkman: [0416]), and as discussed above, Camilleri and Beigel established that bile acid diarrhea is a secretory diarrhea.
Regarding claim 120, Verkman teaches the subject is a human ([0398]).
Regarding claims 121 and 122, Verkman teaches diarrhea that is a condition of, or is related to inflammatory gastrointestinal disorders such as inflammatory bowel disease (IBD) and Crohn’s disease can be treated using a CFTR chloride channel inhibitor such as (R)-BPO-27 (Verkman: [0394]). Camilleri and Beigel teach bile acid diarrhea is usually seen in patients with IBD or Crohn’s disease (Camilleri: pages 333-334 and 336-337; Beigel: Abstract and page 1472). Thus, it would have been reasonably obvious that the patient population for treating bile acid diarrhea would include patients having Crohn’s disease and IBS-D.
Regarding claim 123, Camilleri teaches patients with functional diarrhea also have evidence of bile acid diarrhea (Camilleri: pages 332-334). Thus, it would have been reasonably obvious that the patient population for treating bile acid diarrhea would include patients having functional diarrhea.
Regarding claim 124, Verkman teaches the administration of the CFTR chloride channel inhibitor reduce intestinal fluid secretion (Verkman: [0014], [0144], [0145], [0160], [0392]-[0394]; claims 50-51). Camilleri and Beigel teaches treatment of bile acid diarrhea includes reducing liquid stool (Camilleri: pages 332-334 and 336; Beigel: Abstract; pages: pages 1472-1478). Thus, it would have been reasonably obvious that the administration of the CFTR chloride channel inhibitor to a patient having bile acid diarrhea of Camilleri and Beigel would implicitly result in a reduction in the water content of the subject’s stool, as claimed.
Regarding claim 125, Beigel teaches the standard tool for measuring the water content in a patent’s stool is the Bristol Stool Form Scale, and effective treatment of bile acid diarrhea would result in a reduction of frequency of liquid stool or improvement of at least one level in the Bristol stool chart (Beigel: Abstract; pages: pages 1472-1478).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claim(s) 126 is/are rejected under 35 U.S.C. 103 as being unpatentable over Verkman et al (US 2014/0080821 A1) in view of Camilleri (Gut and Liver, May 2015, 9(3): 332-339), Beigel et al (Journal of Crohn’s Colitis, 2014, 8: 1471-1479), and Vidyasagar et al (US 2014/0377374 A1), as applied to claims 105 and 118 above, and further in view of Hvas et al (World Journal of Gastroenterology, 7 June 2018, 24(21): 2320-2326).
The methods of claims 105 and 118 are discussed above, said discussion being incorporated herein in its entirety.
Regarding claim 126, Hvas teaches the use of farnesoid X receptor agonist, obeticholic acid in treating patients having bile acid diarrhea, especially in patients having refractory bile acid diarrhea (Abstract; pages 2321-2324).
It would have been obvious to one of ordinary skill in the art to further administered a farnesoid X receptor agonist such as obeticholic acid in the treatment of bile acid diarrhea of Verkman in view of Camilleri, Beigel, and Vidyasagar, or in other words, use a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with a farnesoid X receptor agonist such as obeticholic acid in the treatment of bile acid diarrhea, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because this combination would at least provide an additive effect in the treatment of bile acid diarrhea, especially in patients whom have refractory bile acid diarrhea. One of ordinary skill in the art would have reasonable expectation of success in using a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with a farnesoid X receptor agonist such as obeticholic acid to treat bile acid diarrhea because Verkman teaches that the CFTR chloride channel inhibitor can be used in combination with other pharmaceutically active compounds in the treatment of secretory diarrhea (Verkman: [0416]), and as discussed above, Camilleri and Beigel established that bile acid diarrhea is a secretory diarrhea. Thus, an ordinary artisan would have looked to other useful active ingredients in the treatment of bile acid diarrhea including obeticholic acid so as to provide a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with a farnesoid X receptor agonist such as obeticholic acid that is effective in treating bile acid diarrhea, especially refractory bile acid diarrhea, and achieve Applicant’s claimed invention with reasonable expectation of success.
Regarding claim 131, as discussed above, Vidyasagar teaches BAPTA-AM as the calcium chelator.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claim(s) 127 is/are rejected under 35 U.S.C. 103 as being unpatentable over Verkman et al (US 2014/0080821 A1) in view of Camilleri (Gut and Liver, May 2015, 9(3): 332-339), Beigel et al (Journal of Crohn’s Colitis, 2014, 8: 1471-1479), and Vidyasagar et al (US 2014/0377374 A1), as applied to claims 105 and 118 above, and further in view of Lembo et al (Clinical Gastroenterology and Hepatology, 2004, 2: 675-682; hereafter as “Lembo 2004”).
The methods of claims 105 and 118 are discussed above, said discussion being incorporated herein in its entirety.
Regarding claim 127, Lembo 2004 teaches the use of 5-HT3 antagonist such as alosetron in the treating patients having diarrhea predominant irritable bowel syndrome (D-IBS) (Background & Aims; pages 675 and 680-681). Lembo 2004 teaches alosetron provides improvement in stool frequency, stool consistency, and percentage of days with incomplete evacuation, thereby effectively manage bowel urgency (Background & Aims; pages 675 and 680-681).
It would have been obvious to one of ordinary skill in the art to further administered a 5-HT3 antagonist such as alosetron in the treatment of bile acid diarrhea of Verkman in view of Camilleri, Beigel, and Vidyasagar, or in other words, use a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with a 5-HT3 antagonist such as alosetron in the treatment of bile acid diarrhea, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because this combination would at least provide an additive effect in the treatment of bile acid diarrhea, especially in patients with diarrhea predominant irritable bowel syndrome (D-IBS). One of ordinary skill in the art would have reasonable expectation of success in using a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with a 5-HT3 antagonist such as alosetron to treat bile acid diarrhea because Verkman teaches that the CFTR chloride channel inhibitor can be used in combination with other pharmaceutically active compounds in the treatment of secretory diarrhea (Verkman: [0416]), and Verkman further established that secretory diarrhea is a sequelae of irritable bowel syndrome (IBS) (Verkman: [0143]). Additionally, as discussed above, Camilleri and Beigel established that bile acid diarrhea is a secretory diarrhea, and per Camilleri, 25% to 50% of patients with diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of bile acid diarrhea (BAD) (Camilleri: pages 332-335). Thus, an ordinary artisan would have looked to other useful active ingredients in the treatment of bile acid diarrhea including alosetron acid so as to provide a combination therapy of CFTR chloride channel inhibitor such as (R)-BPO-27 with a 5-HT3 antagonist such as alosetron that is effective in treating bile acid diarrhea, especially in patients having diarrhea predominant irritable bowel syndrome (D-IBS), and achieve Applicant’s claimed invention with reasonable expectation of success.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claim(s) 128 is/are rejected under 35 U.S.C. 103 as being unpatentable over Verkman et al (US 2014/0080821 A1) in view of Camilleri (Gut and Liver, May 2015, 9(3): 332-339), Beigel et al (Journal of Crohn’s Colitis, 2014, 8: 1471-1479), and Vidyasagar et al (US 2014/0377374 A1), as applied to claims 105 and 118 above, and further in view of Ahmed et al (US 2015/0336986 A1)
The methods of claims 105 and 118 are discussed above, said discussion being incorporated herein in its entirety.
Regarding claim 128, Ahmed teaches the use of a combination of an inhibitor of CFTR chloride channel with loperamide in the treatment of all forms of diarrhea including secretory diarrhea and diarrhea predominant irritable bowel syndrome (IBS) ([0005]-[0006] and [0400]-[0401]).
It would have been obvious to one of ordinary skill in the art to further administered loperamide in the treatment of bile acid diarrhea of Verkman in view of Camilleri, Beigel, and Vidyasagar, or in other words, use a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with loperamide in the treatment of bile acid diarrhea, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because this combination would at least provide an additive effect in the treatment of bile acid diarrhea, especially in patients with diarrhea predominant irritable bowel syndrome (D-IBS). One of ordinary skill in the art would have reasonable expectation of success in using a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with loperamide to treat bile acid diarrhea because as discussed above, Ahmed teaches that loperamide is used in combination with a CFTR chloride channel inhibitor to treat all forms of diarrhea including secretory diarrhea and diarrhea predominant irritable bowel syndrome (IBS) and likewise, Verkman teaches that the CFTR chloride channel inhibitor can be used in combination with other pharmaceutically active compounds in the treatment of secretory diarrhea (Verkman: [0416]), and Verkman further established that secretory diarrhea is a sequelae of irritable bowel syndrome (IBS) (Verkman: [0143]). Additionally, as discussed above, Camilleri and Beigel established that bile acid diarrhea is a secretory diarrhea, and per Camilleri, 25% to 50% of patients with diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of bile acid diarrhea (BAD) (Camilleri: pages 332-335). Thus, an ordinary artisan would have looked to other useful active ingredients in the treatment of bile acid diarrhea including loperamide so as to provide a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with loperamide that is effective in treating bile acid diarrhea, especially in patients having diarrhea predominant irritable bowel syndrome (D-IBS), and achieve Applicant’s claimed invention with reasonable expectation of success.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claim(s) 129 is/are rejected under 35 U.S.C. 103 as being unpatentable over Verkman et al (US 2014/0080821 A1) in view of Camilleri (Gut and Liver, May 2015, 9(3): 332-339), Beigel et al (Journal of Crohn’s Colitis, 2014, 8: 1471-1479), and Vidyasagar et al (US 2014/0377374 A1), as applied to claims 105 and 118 above, and further in view of Ozdener et al (Drug Design, Development and Therapy, 2017, 11: 2827-2840).
The methods of claims 105 and 118 are discussed above, said discussion being incorporated herein in its entirety.
Regarding claim 129, Ozdener teaches the use of eluxadoline in the treatment of diarrhea-predominant irritable bowel syndrome (Abstract; Introduction; pages 2827-2828).
It would have been obvious to one of ordinary skill in the art to further administered eluxadoline in the treatment of bile acid diarrhea of Verkman in view of Camilleri, Beigel, and Vidyasagar, or in other words, use a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with eluxadoline in the treatment of bile acid diarrhea, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because this combination would at least provide an additive effect in the treatment of bile acid diarrhea, especially in patients with diarrhea predominant irritable bowel syndrome (D-IBS). One of ordinary skill in the art would have reasonable expectation of success in using a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with eluxadoline to treat bile acid diarrhea because Verkman teaches that the CFTR chloride channel inhibitor can be used in combination with other pharmaceutically active compounds in the treatment of secretory diarrhea (Verkman: [0416]), and Verkman further established that secretory diarrhea is a sequelae of irritable bowel syndrome (IBS) (Verkman: [0143]). Additionally, as discussed above, Camilleri and Beigel established that bile acid diarrhea is a secretory diarrhea, and per Camilleri, 25% to 50% of patients with diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of bile acid diarrhea (BAD) (Camilleri: pages 332-335). Thus, an ordinary artisan would have looked to other useful active ingredients in the treatment of bile acid diarrhea including eluxadoline so as to provide a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with eluxadoline that is effective in treating bile acid diarrhea, especially in patients having diarrhea predominant irritable bowel syndrome (D-IBS), and achieve Applicant’s claimed invention with reasonable expectation of success.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the reference, especially in the absence of evidence to the contrary.
Claim(s) 130 is/are rejected under 35 U.S.C. 103 as being unpatentable over Verkman et al (US 2014/0080821 A1) in view of Camilleri (Gut and Liver, May 2015, 9(3): 332-339), Beigel et al (Journal of Crohn’s Colitis, 2014, 8: 1471-1479), and Vidyasagar et al (US 2014/0377374 A1), as applied to claims 105 and 118 above, and further in view of Lembo et al (Gastroenterology, 2016, 151: 1113-1121; hereafter as “Lembo 2016”).
The methods of claims 105 and 118 are discussed above, said discussion being incorporated herein in its entirety.
Regarding claim 130, Lembo 2016 teaches the use of rifaximin in the treatment of diarrhea-predominant irritable bowel syndrome (Background & Aims; pages 1113 and 1119-1120).
It would have been obvious to one of ordinary skill in the art to further administered rifaximin in the treatment of bile acid diarrhea of Verkman in view of Camilleri, Beigel, and Vidyasagar, or in other words, use a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with rifaximin in the treatment of bile acid diarrhea, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because this combination would at least provide an additive effect in the treatment of bile acid diarrhea, especially in patients with diarrhea predominant irritable bowel syndrome (D-IBS). One of ordinary skill in the art would have reasonable expectation of success in using a combination therapy of the CFTR chloride channel inhibitor such as (R)-BPO-27 with rifaximin to treat bile acid diarrhea because Verkman teaches that the CFTR chloride channel inhibitor can be used in combination with other pharmaceutically active compounds in the treatment of secretory diarrhea (Verkman: [0416]), and Verkman further established that secretory diarrhea is a sequelae of irritable bowel syndrome (IBS) (Verkman: [0143]). Additionally, as discussed above, Camilleri and Beigel established that bile acid diarrhea is a secretory diarrhea, and per Camilleri, 25% to 50% of patients with diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of bile acid diarrhea (BAD) (Camilleri: pages 332-335). Thus, an ordinary artisan would have looked to other useful active ingredients in the treatment of bile acid diarrhea including eluxadoline so as to provide a combination therapy of CFTR chloride channel inhibitor such as (R)-BPO-27 with rifaximin that is effective in treating bile acid diarrhea, especially in patients having diarrhea predominant irritable bowel syndrome (D-IBS), and achieve Applicant’s claimed invention with reasonable expectation of success.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the reference, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 03/16/2026 have been fully considered but they are not persuasive.
Below is the Examiner’s response to Applicant’s arguments as they pertain to the pending 103 rejections.
Applicant argues that the involvement of calcium ion signaling in the prosecretory response to bile acid was unexpected, and thus, “none of the cited references recognizes the role of Ca2+ signaling in conjunction with the chloride channel response to bile acid, much less the claimed combination therapy for the resulting diarrhea.” (Remarks, page 6).
In response, the Examiner disagrees. As discussed above in the pending 103 rejection, Vidyasagar showed that BAPTA-AM was effective in blocking intracellular Ca2+ levels, which are known to mediate chloride (Cl-) section in diarrhea including secretory diarrhea mediated via CFTR channels and/or CaCC channels. Thus, Applicant’s alleged unexpected results shown in paragraph [0237] of the published application is not unexpected, but rather reasonably expected by the teachings from Vidyasagar.
Furthermore, as discussed above in the pending 103 rejection, it would have been obvious to one of ordinary skill in the art to further administer to the subject of Verkman in view of Camilleri and Beigel in the treatment of bile acid diarrhea a calcium chelator such as BAPTA-AM, and produce the claimed invention. One of ordinary skill in the art would have been motivate do to do because Vidyasagar showed that BAPTA-AM was effective in blocking intracellular Ca2+ levels, which are known to mediate chloride (Cl-) section in diarrhea including secretory diarrhea mediated via CFTR channels and/or CaCC channels (Vidyasagar: [0017], [0085] and [0123]-[0126]; Example 11). As discussed above, Verkman in view of Camilleri and Beigel established that bile acid diarrhea is a secretory diarrhea that is caused by aberrantly increased CFTR chloride channel activity and thus it would have been reasonably obvious to further use a calcium chelator such as BAPTA-AM in combination with (R)-BPO-27 to provide at least an additive effect of treating bile acid diarrhea, and achieve Applicant’s claimed invention with reasonable expectation of success.
As a result, for at least the reasons discussed above, claims 105, 108, 115, and 118-131 remain rejected as being obvious and unpatentable over the combined teachings of the cited prior arts in the pending 103 rejections as set forth in this office action.
Conclusion
No claim is allowed.
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/DOAN T PHAN/ Primary Examiner, Art Unit 1613
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