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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 19, 2026 has been entered.
The amendment filed February 19, 2026 has been entered. Claims 1, 3, 10, 21 and 32 are amended and claims 6, 17-20, 25-29, 31, 34, and 37 are canceled.
Claims 1-5, 7-16, 21-24, 30, 32-33, and 35-36 are pending and are examined on the merits herein.
Priority
The instant application claims domestic benefit to 63/271,916 filed on 10/26/2021, 63/280,470 filed on 11/17/2021, and 63/354,424 filed on 06/22/2022.
Specification
The disclosure is objected to because of the following informalities: The structures in the following paragraphs are blurry rendering them illegible: [0022] maralixibat and volixibat, [00103] maralixibat. In para. [0022] the subscripts in maralixibat are unclear and volixibat is missing bond lines. In para. [00103] the subscripts in maralixibat are unclear.
Appropriate correction is required.
Claim Objections
Claims 1, 3, and 10 are objected to because of the following informalities:
In claims 1, 3, and 10 the structure for maralixibat is blurry, particularly the subscripts, rendering them illegible.
Appropriate correction is required.
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.
Claims 1-5, 7-16, 21-24, 30, 32-33, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Gedulin et al. (WO 2014/144650 A2, hereafter ‘650; cited in previous action), in view of Mayo et al. (Hepatology Communications, 2019; cited in previous action) and Lentz (The AAPS Journal, 2008; cited in previous action).
Regarding claims 1-5, 10-16, 21-24, 30, 32-33, and 35-36: ‘650 discloses methods of treating primary sclerosing cholangitis (PSC) by administering ASBTIs [0003] and discloses the below chloride salt as an ASBTI suitable for this treatment (claim 29). This compound is a chloride salt of maralixibat as defined in instant claim 1.
PNG
media_image1.png
211
319
media_image1.png
Greyscale
‘650 discloses that the methods include treating PSC in pediatric patients [0023, 0038] as well as in adult patients [0024, 0039]. ‘650 discloses that the ASTBI may be administered orally (claim 45). ‘650 teaches that the ASBTI may be administered before, with, or after the ingestion of food [0071]. ‘650 discloses that the ASTBI may be administered, among others, once per day or twice per day [0063]. ‘650 discloses that the dosage comprises 0.1 to 20 mg of the ASBTI (claim 22). ‘650 discloses that less than 10% of the ASBTI may be systemically absorbed (claim 7). ‘650 discloses a clinical study in which LUM001 is administered immediately before the ingestion of food at the morning meal [00451]. ‘650 further discloses administration of LUM001 to patients who had fasted for 12 prior to administration of LUM001 [00459], as well as administration to subjects fasted for 16 hours [00377]. The instant specification defines that LUM001 is the compound maralixibat chloride (Instant Specification, [00105]). Furthermore, ‘650 reports experiments in which 0.2 mg/kg of LUM00l was administered orally 1 hour after feeding, which significantly lowered serum bile acid levels within 30 minutes of dosing and these levels remained significantly lowered for at least 6 hours. This is contrasted with experiments in which a dose of 0.2 mg/kg was required to produce a significant effect that was sustained for at least 2-3 hours after feeding when LUM00l was administered 2 hours prior to feeding [00397]. ‘650 states that these results indicate that the presence of food in the GI tract has a significant impact on the pharmacodynamic activity of maralixibat, most likely by altering the residence time of the drug in the small intestine [00397]. ‘650 teaches formulations of LUM-001 to be administered to pediatric subjects [00379]. ‘650 teaches treatment of pediatric PSC-IBD (i.e. primary sclerosing cholangitis [0002, 0023]. According to the specification, PSC is a cholestatic liver disease [0018].
The teachings of ‘650 differ from that of the instantly claimed invention in that ‘650 does not teach a method for reducing one or more side effects. Although ‘650 exemplifies administration of maralixibat to patients who had fasted for 12 prior to administration of maralixibat, it does not teach administration of maralixibat about 30 minutes prior to the ingestion of food (instant claims 1, 3, and 10).
Mayo describes a study assessing the efficacy and safety of maralixibat in adults with primary biliary cholangitis (abstract). Mayo teaches that gastrointestinal disorders are the most frequently reported adverse effects for maralixibat (abstract) and discloses that the overall incidence of gastrointestinal adverse effects was higher in the maralixibat groups than in the placebo group (page 379, col. 1, paragraph 1). Mayo reports that treatment emergent adverse effects of maralixibat include diarrhea, nausea, and abdominal pain (page 376, cols. 1-2, bridging paragraph).
Lentz discloses the state of the art in understanding the impact of food on the pharmacokinetics of drugs (abstract). Food can impact the pharmacokinetics of a drug product through several mechanisms, such as delay in gastric emptying, stimulation of bile flow, changes in gastrointestinal pH, alterations in luminal metabolism, or interactions of the drug with the food itself (page 282, col. 1, paragraph 1). In addition, factors such as non-specific binding, sequestration, or chemical instability can cause drug–food interactions (page 282, col. 2, paragraph 2). Lentz teaches that several challenges exist in the development of compounds that exhibit food effects. For example, changes in bioavailability due to food effects may produce unwanted side effects. As a result, the clinical plan may require control and/or monitoring of food intake in relation to dosing (page 283, col. 1, paragraph 2). Lentz teaches that the FDA recognized the potential for food to alter the pharmacokinetics of drug products and established standards for the design of clinical food effect studies. It is recommended that trials are run in which drug products are administered to patients under fasted and fed conditions and compared to investigate whether food effects the drug administration (page 283, col. 1, paragraph 2).
One of ordinary skill in the art would have been motivated to optimize the timing of administration of maralixibat relative to eating in the method of ‘650 because Mayo teaches that maralixibat is known to cause gastrointestinal adverse effects, Lentz teaches that the presence of food in a patient has an impact on the pharmacokinetics of drugs and may cause unwanted side effects, and ‘650 teaches that that the presence of food in the GI tract has a significant impact on the pharmacodynamic activity of maralixibat, which suggests that the degree bioavailability and thus pharmacodynamic activity (which encompasses side effects) of maralixibat can be modulated by altering the residence time of the drug in the small intestine through changing the timing in which the maralixibat is administered in relation to feeding times. Furthermore, it would have been obvious to optimize the administration of maralixibat to a patient both with and without the presence of food with the predictable result of reducing the gastrointestinal side effects of maralixibat because Lentz teaches that testing drugs for food effects by comparing administration to patients in fasted and fed conditions is routine in the art and that the presence of food is a result effective variable to alter the side effects of drug administration. One of ordinary skill in the art would have had a reasonable expectation of success because ‘650 teaches that maralixibat may be administered before, after, and during food.
Regarding instant claims 7-9, although the prior art does not expressly teach improving GI tolerability by at least 10%, 20%, or 50%, wherein it would have been obvious to optimize the method and arrive at the claimed method in effective doses as discussed above, these results necessarily flow as a result of practicing the method, absent evidence to the contrary. See instant specification [00286] wherein administration improves GI tolerability by 50% (diarrhea) in the fasted state.
Response to Arguments
Applicant's arguments filed February 19, 2026 have been fully considered but they are not persuasive.
On pages 6-7 of Applicant’s response, Applicant argues the newly amended claims specify that the maralixibat is administered about 30 minutes before ingestion to a subject in a fasted state which is further specified that the subject has not consumed food for at least 4 hours if the subject is 18 or over, or for at least 2 hours if the subject is a pediatric subject (bridging para.). Applicant argues Gedulin specifies administration immediately before the ingestion of food (bridging para.).
However, as discussed above ‘650 (i.e. Gedulin) recognizes the impact of feeding on pharmacodynamic activity, stating that these results indicate that the presence of food in the GI tract has a significant impact on the pharmacodynamic activity of maralixibat, most likely by altering the residence time of the drug in the small intestine [00397]. ‘650 further discloses administration of LUM001 to patients who had fasted for 12 prior to administration of LUM001 [00459], as well as administration to subjects fasted for 16 hours [00377]. While ‘650 discloses an example in which the ASBTI maralixibat is administered immediately before the ingestion of food at the morning meal [00451] , ‘650 additionally teaches wherein LUM001 (i.e. maralixibat chloride) is administered 2 hours prior to feeding [00397], thus establishing the art recognizes administration time with respect to feeding being a result effective variable. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (See MPEP 2123 (II)).
On page 7 of Applicant’s response, Applicant argues Lentz is directed to analyzing PK properties of systemically absorbed drugs and how food alters drugs PK properties in the fed and fasted states (para. 3). Applicant argues that maralixibat is non-systemically absorbed and the teachings of Lentz are unapplicable (para. 3). Applicant argues although Lentz demonstrates the presence of food is a result effective variable to alter side effects of drug administration, it only does so for systemically absorbed drugs (para. 4). On pages 7-8 of Applicant’s response, Applicant argues that since maralixibat is non-systemically absorbed, Lentz cannot be relied upon for any guidance or motivation to optimize the timing of administration of non-systemically absorbed drugs relative to food intake. (bridging para.).
However, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references (See MPEP 2145 (IV)). Lentz establishes generally that exploring drug administration in the presence/absence of food is a known optimizable parameter in the art which is to be viewed in conjunction with ‘650 teachings suggesting administering maralixibat prior to feeding. Additionally, a person of ordinary skill would recognize the teachings of Lentz to be applicable to drug development generally, and does not teach away from determining food effect on non-systemic drugs.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 AM - 5:00 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Y Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMUEL L GALSTER/Examiner, Art Unit 1693
Prosecution Insights