DETAILED ACTION
Claims 21-29 were pending; Applicant have amended claim 1 and canceled claim 28 in the reply mailed 12/11/2025.
Claims 21-27 and 29 are pending.
Priority
The instant application, filed 1/29/2022 Claims Priority from Provisional Application 63/144355, filed 2/1/2021.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 12/11/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the Information Disclosure Statement is being considered by the Examiner.
Claim Rejections - 35 USC § 103
(NEW Rejection)
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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 21-28 are rejected under 35 U.S.C. 103 as being unpatentable over Jones et al. “Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study,” Lancet Gastroenterol Hepatol. 2017; 2: 716–26 published Online August 14, 2017; Corpechot et al. “A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis,” New England J. Med. 378;23 published June 7, 2018 2171; Silveira et al. “Investigational drugs in phase II clinical trials for primary biliary cholangitis ,” EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2017, VOL. 26, NO. 10, 1115–1121; Study Protocol CB8025-31735, “Protocol Reference” CymaBay Therapeutics, Inc Protocol published July 2018; Boudes US 20190038581 A1 published February 7, 2019; Hirchfield et al. “Efficacy of Obeticholic Acid in Patients With Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid,” Gastroenterology 2015;148:751–761; and Markham et al. “Obeticholic Acid: First Global Approval,” Drugs (2016) 76:1221–1226.
Claim 21 is directed towards a method of treating primary biliary cholangitis in a subject who is intolerant of, or who has an inadequate response to, at least one of obeticholic acid and a fibrate, comprising administration of a compound selected from seladelpar or a salt thereof, in an amount equivalent to 5 mg/day or 10 mg/day of seladelpar.
Primary biliary cholangitis is PBC.
Jones teaches some background information of the treatment of Primary Biliary Cholangitis (PBC), the treatment modalities, and the known side effects. Jones discusses the use of Ursodeoxycholic acid, Obeticholic acid, Fibrates, and Seladelpar.
“Primary biliary cholangitis occurs predominantly in women and is often first suspected by persistent elevations of serum alkaline phosphatase on routine blood tests. Patients progress at varying rates, although a diagnosis at a younger age appears to negatively affect prognosis. Inadequate medical treatment puts patients at risk of liver death and the need for liver transplantation. Two drugs, ursodeoxycholic acid and obeticholic acid, have been approved to medically treat primary biliary cholangitis.
Ursodeoxycholic acid, a non-cytotoxic bile acid, has been the mainstay of therapy for more than 20 years. However, up to 40% of patients have persistent elevation of alkaline phosphatase or bilirubin or both despite treatment with ursodeoxycholic acid and are considered inadequate responders. These patients have a worse hepatic transplant free survival rate compared with ursodeoxycholic acid responders. Consequently, alkaline phosphatase, when combined with total bilirubin, are now considered surrogate markers of primary biliary cholangitis severity that predict the progression of the disease.
Obeticholic acid, a synthetic analogue of chenodeoxycholic acid, was recently conditionally approved based on its ability to decrease alkaline phosphatase concentrations when used as an add-on therapy in patients with primary biliary cholangitis who are inadequate responders to ursodeoxycholic acid. It is also approved for patients who cannot tolerate ursodeoxycholic acid (around 5% of patients). By contrast with ursodeoxycholic acid, obeticholic acid activates the farnesoid X receptor and exerts its effects through a distinct mechanism of action. However, about 50% of patients with primary biliary cholangitis still lack an adequate response to a combination of ursodeoxycholic acid and obeticholic acid. Also, obeticholic acid has been associated with inducing or worsening pruritus, a characteristic symptom of primary biliary cholangitis, which can require treatment interruption.4 Accordingly, there is still a substantial medical need to develop new therapies for primary biliary cholangitis.
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that direct the transcription of genes involved in bile acids or sterols, lipids, and glucose metabolism, as well as inflammation. Three PPAR subtypes—α, γ, and δ—are known, each of which have their own distinct but overlapping cellular expression, target genes, pathway regulation, and biological functions. Fenofibrate, a PPAR-α agonist, and bezafibrate, a pan-PPAR agonist, have shown promising activity in decreasing markers of cholestasis in patients with primary biliary cholangitis, although there are concerns about potential toxic effects. Their primary effects result from decreasing hepatocellular bile acid concentrations by regulation of genes responsible for bile acid synthesis and transport. Seladelpar (MBX-8025) is an oral, once-daily, potent, and selective PPAR-δ agonist. Like PPAR-α, PPAR-δ is also expressed in hepatocytes, where it controls genes involved in bile acid homoeostasis. Seladelpar downregulates the expression of cyp7a1 which encodes cholesterol 7α-hydroxylase (appendix p 10), the enzyme that hydroxylates cholesterol in the first step in the synthesis of bile acids. Unlike PPAR-α, for which liver expression is mainly restricted to hepatocytes, PPAR-δ is also expressed in cholangiocytes, Kupffer cells, and hepatic stellate cells, and its activation in these cells has implications for modifying progression of primary biliary cholangitis. Cholangiocytes use PPAR-δ to regulate transporters involved in the absorption and secretion of bile components. Seladelpar regulates the cholesterol transporter ABCG5/ABCG8 in mouse liver (appendix p 11) and another PPAR-δ agonist was shown to increase bile flow three-fold in mice. Activation of PPAR-δ also results in anti-inflammatory effects in macrophages, including Kupffer cells. Seladelpar, in a mouse model, reduces markers of liver inflammation, including reductions in macrophage numbers, reductions in fibrosis, and reduction of other markers of stellate cell activity. Thus, the rationale for assessing PPAR-δ as a target for cholestatic diseases includes the impact on bile acid retention, cholangiocyte function, and anti-inflammatory and anti-fibrotic effects on Kupffer and stellate cells.”
The key takeaway, from Jones is that mainstay treatment, Ursodeoxycholic acid, is not a cure and there is an unmet need to modify the disease with other drugs in a vast majority of patients. Those patients could be put on Obeticholic acid with Ursodeoxycholic acid, as the two are used together. Yet, the drug cocktail is still problematic, showing 50% of patients with primary biliary cholangitis still lack an adequate response to a combination. This patient population is still in need of a treatment. This patient population is then one in which Fibrates and Seladelpar would be an ideal match. These drugs have overlapping mechanism of action, as they both target PPAR. Jones is teaching Seladelpar as a new therapeutic for PBC that should be used in patients in need, this reference makes clear that the drug is used in all cases of PBC.
Corpechot teaches the treatment of PBC with bezafibrate (a fibrate) in combination with ursodeoxycholic acid. Corpechot states, among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. Corpechot however still shows a large group of patients with an inadequate response to this fibrate combination treatment, showing in Figure 1 that only around 30% of patients had a complete biochemical response, indicating a need for additional therapy in these patients. Therefore Corpechot teaches the patient population of claim 1, though not the use of Seladelpar in the patient population.
Silveira teaches some background information about cholangitis and the first line therapy for the treatment of PBC. Silveira also discusses the treatments that are in the clinic and their mechanisms and use. In the introduction, page 1115, primary biliary cholangitis (PBC) is a slowly progressive immune-mediated liver disease characterized by damage to and destruction of the biliary epithelial cells in the small- and medium-sized intrahepatic bile ducts, leading to progressive cholestasis, biliary fibrosis, and eventually cirrhosis.
Silveira states, ursodeoxycholic acid (UDCA), a naturally occurring hydrophilic bile acid (BA), in the dosage of 13–15 mg/kg/day, is the recommended first-line therapy for patients with PBC. This is a known treatment for the disease, around 2010 to present. Silveira teaches however, not all patients benefit equally from treatment with UDCA; biochemical response to therapy over prolonged periods of time has been consistently demonstrated to have a major effect on outcomes. Up to 40% of patients have an inadequate biochemical response to UDCA and, though data are lacking, it is estimated that up to 5% of patients cannot tolerate UDCA, mostly due to gastrointestinal (GI) symptoms and weight gain.
Silveira goes on to state, at present (the reference is 2017), the only therapy approved for patients who cannot tolerate UDCA or have inadequate response to UDCA is obeticholic acid (OCA), an epimer of the primary BA chenodeoxycholic acid, which has a potent farnesoid-X-receptor (FXR) agonist effect. Applicant requires the patient either be intolerant to, or have an inadequate response to OCA, the newer treatment that is used when UDCA fails. Silveira notes that the FDA approved OCA in 2016 in an accelerated fashion for clinical data indicating effect in a life-threatening disease.
Silveira continues to note, that improvement in long-term outcomes has not yet been demonstrated and the use of OCA is associated with pruritus in some patients, which can be ameliorated with the employment of a titration strategy. A confirmatory trial to determine the effects of OCA on progression of disease, survival, and disease-related symptoms is ongoing (COBALT trial).
Silveira then goes on to discuss “Novel Treatments.” One of the novel treatments is MBX-8025 (seladelpar), the compound instantly claimed. Seladelpar is a is a potent, selective agonist for the PPAR-δ. In preclinical studies, PPAR-δ agonism demonstrated a variety of beneficial effects on the lipid profile and other metabolic parameters, including increased peripheral oxidation of fatty acids leading to reduced levels of triglycerides and LDL cholesterol, while raising HDL cholesterol. Seladelpar (MBX-8025) decreased ALP in patients with dyslipidemia and appears well tolerated in these populations.
Silveira discusses the clinical trial of Seladelpar in patients with PBC. A small 12-week phase II study recently evaluated the anticholestatic effects and safety of MBX-8025 in patients with PBC who had an inadequate response to UDCA (clinicaltrials.gov, NCT 02609048). The dose of the drug was 50 and 200 mg, and this dose was determined to be too high as indicated by muscle adverse effect and increases in transaminases without hyperbilirubinemia. This effect was not seen in other populations and appeared to be dose related. The authors postulated that because MBX-8025 is predominantly excreted in bile, and PBC impairs bile flow, these patients may have experienced higher hepatic drug exposure. Interestingly, Seladelpar, was not associated with pruritus (OCA was associated with pruritus).
This reference, as a whole, teaches that patients with PBC are primarily treated with UDCA, if that failed the only available FDA approved option in the USA is OCA. OCA is associated with pruritus, and in PBC still not all patients are cured and have complete response to the approved methods. This reference makes clear that Seladelpar is used for PBC, that the drug is promising at doses of 50 and 200mg (though too high of a dose based on toxicity), and that the treatment is not associated with pruritus.
This reference makes clear, that patients might be treated with UDCA, have an undesirable response, then tried on OCA. OCA also fails or the patient could have an unmitigated pruritus to treatment. This patient would than need other treatments, one of which is Seladelpar. This treatment is not associated with pruritus, and would be used at a dose less than 50 mg, as this dose was found to have some toxicity in some patients. This refence doesn’t teach the lysine salt specifically (claims 22-23), and doesn’t teach a lower dose (5 or 10 mg, required by claim 21).
To discuss the dose lowering, from 50 and 200 mg taught by Silveira, to 5 and 10 mg, the Protocol Reference is brought in. This refence shows the oral administration of Seladelpar at 5 and 10 mg in patients with PBC. Meeting the limitation of claim 24.
To discuss the lysine salt dihydrate, other indications for the drug, and the dose in general. Boudes is brought in. Boudes teaches, claim 1, a method of treating an intrahepatic cholestatic disease by administering a therapeutically effective amount of a compound that is seladelpar or a salt thereof, where the amount is between 0.5 mg/day and 2 mg/day [25 mg/day] when the dose is calculated as seladelpar. Claim 2, the method of claim 1 where the compound is seladelpar L-lysine dihydrate salt. Meeting the instant limitations to claims 2-3. Boudes teaches the diseases of instant claim 21 (see claim 13 to “disease is primary biliary cholangitis, primary sclerosing cholangitis, progressive familial intrahepatic cholestasis, or Alagille syndrome.”)
The question of patentability of the instant claims revolves around the claim requiring, “a subject who is intolerant of, or who has an inadequate response to, at least one of obeticholic acid (OCA) and a fibrate,”
Silveira and Jones however show that OCA is not perfect. Hirschfield is brought in to show this specifically. As well as Corpechot above showing additional fibrate is also not adequate.
The non-response is seen in the reference, (see Table 2, Hirschfield). OCA even in the lowest dose tested still had an incidence of pruritus, see conclusions page 751 col 2. These patients would be ripe for treating with Seladelpar, a drug not associated with pruritus and of a different mechanism of action.
This meets the limitations of claims 26-27, that note an inadequate response to UDCA or OCA.
The last thing to discuss is claim 28 which requires and inadequate response to a fibrate. Going back to Silveira, we have a discussion of Fibrates.
“Data on the potentially beneficial effects of fibrates in the treatment of PBC, which are mainly PPAR-α agonists, have been reported over the last several years [44–46]; systematic meta-analysis studies have shown that in patients with suboptimal response to UDCA, fibrates significantly improve liver biochemistries compared to UDCA alone and might offer survival benefit [47–49]. A phase III, randomized, controlled trial of bezafibrate 400 mg versus placebo in addition to UDCA for 2 years including 100 patients was recently completed (clinicaltrials.gov, NCT 01654731) [50]. The primary end point of normal total bilirubin, ALP, transaminases, albumin, and prothrombin time was achieved in 30% of patients who received bezafibrate compared to 0% of those who received placebo (p < 0.0001). Normalization of ALP was observed in 67% of patients who received bezafibrate compared to 0% placebo (p < 0.0001).”
Again, we see that the diseases to be treated with these drugs are notoriously hard to treat and have patient populations that do not respond. Again leaving the patients ripe for treating with Seladelpar.
The art of record clearly demonstrates that Seladelpar is known in the art as a treatment for all the diseases claimed. The drug is oral, one a day and dosed in the ranges claimed. The diseases claimed are hard to treat and many of the known treatments produce inadequate response, and those patients would be ripe for treating with Seladelpar. As such Applicant’s claims are obvious at the time of filing.
In regards to claim 29, which requires where the subject is intolerant to obeticholic acid (OCA) a new refence has been added, Markham is brough in to show how OCA was approved and how it is used in patients with PBC. This is pertinent because the process is identical to what is instantly claimed. OCA was first tried in patients with poor response to UDCA in combination with UDCA, and as a monotherapy when the patient was intolerant to UDCA. One would see this process, and find it obvious to use the same process when introducing a new drug in this indication. Markham teaches:
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This process outlines the known method of introducing new drugs in this indication.
Now looking to Section 2.5 one sees that OCA has Adverse Events. Markham shows:
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This Section outlines the known adverse events with OCA, and indicates the fact that there are many patients who have intolerance and poor response to OCA. This again indicated a patient population ripe for treating with the drug Seladelpar.
A person of ordinary skill would realize PBC is hard to treat and in need of new modalities including the drug, Seladelpar. One would know that the introduction of drugs in this category are introduce to patients in combination with older methods, and as monotherapies in patients intolerant to the current drugs. As such the use of Seladelpar in patients intolerant to OCA is obvious at the time of filing.
Response to Arguments: Applicant has amended the claims to a scope directed to lack or response or intolerance to fibrate. This embodiment was not previously rejected, as such the arguments are not directed to the NEW rejection above.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL J SCHMITT whose telephone number is (571)270-7047. The examiner can normally be reached M-F 8-6 MidDay Flex.
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/MICHAEL J SCHMITT/ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629