US Patent 10,981,952: Maralixibat Claims, Patent Scope, Exclusivity and Generic-Entry Risk
US Patent 10,981,952 protects oral treatment with maralixibat, an ileal bile acid transporter inhibitor, for reducing serum bile acids in cholestatic and related liver diseases. The patent is a disease-treatment method patent rather than a broad composition-of-matter patent. Its strongest commercial coverage is directed to pediatric PFIC and Alagille syndrome patients treated with oral maralixibat, including patients receiving concurrent bile acid resins.
What drug does US Patent 10,981,952 protect?
The claimed IBAT inhibitor is maralixibat, also known by the development code LUM001 and marketed in the United States as Livmarli. The claim covers maralixibat itself and pharmaceutically acceptable salts.
The chemical name recited in claim 1 is:
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-alpha-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine
Maralixibat inhibits IBAT, also called ASBT, in the terminal ileum. The mechanism reduces intestinal bile acid reabsorption and increases fecal bile acid excretion. The claimed pharmacodynamic result is a decrease in serum bile acid concentration.
Livmarli is marketed by Mirum Pharmaceuticals. The FDA approved Livmarli in 2021 for cholestatic pruritus associated with Alagille syndrome in patients at least one year old. The FDA later approved it for cholestatic pruritus associated with PFIC in patients at least five months old.[1,2]
What are the independent and dependent claims?
Claim 1 is the only independent claim. It requires all of the following elements:
| Claim element |
Requirement |
| Treatment objective |
Decreasing serum bile acid concentration |
| Route |
Oral administration |
| Agent |
A therapeutically effective amount of maralixibat or a pharmaceutically acceptable salt |
| Patient disease |
At least one listed cholestatic or liver disease |
| Patient status |
Subject is in need of treatment |
The disease list in claim 1 includes:
- Alagille syndrome
- PFIC
- Primary biliary cirrhosis
- Liver fibrosis
- NAFLD
- NASH
- Primary sclerosing cholangitis
- Intrahepatic cholestasis
- Extrahepatic cholestasis
- Combinations of those conditions
The dependent claims create narrower fallback positions:
| Claim |
Added limitation |
| 2 |
Pediatric subject |
| 3 |
PFIC |
| 4 |
Alagille syndrome |
| 5 |
Intrahepatic cholestasis |
| 6 |
Extrahepatic cholestasis |
| 7 |
Pruritus as a comorbidity |
| 8 |
Pruritus as a disease symptom |
| 9 |
Concurrent bile acid binder |
| 10 |
Bile acid binder is a resin |
| 11 |
Resin is cholestyramine, colestipol or colesevelam |
| 12 |
Resin is cholestyramine or a pharmaceutically acceptable salt |
The narrowest commercially relevant combination is claim 12: oral maralixibat for a covered cholestatic disease, with concurrent cholestyramine.
How broad is the scope of claim 1?
Claim 1 is broad across diseases but narrow across drug identity and administration route.
It covers use of maralixibat for diseases beyond the currently approved Livmarli indications. The inclusion of PBC, NAFLD, NASH, PSC, liver fibrosis and general intrahepatic or extrahepatic cholestasis extends the literal disease scope beyond the FDA-approved label.
The claim does not require:
- A particular maralixibat dose
- A dosing frequency
- A specific treatment duration
- A particular serum bile acid threshold
- Improvement in pruritus
- A particular age unless claim 2 is asserted
- A liquid, tablet or capsule formulation
- A specific salt
- A specific degree of IBAT inhibition
- A clinical response beyond the claimed decrease in serum bile acids
The claim does require oral administration. A non-oral product would fall outside the literal scope of claim 1, although other patents or infringement theories could remain relevant.
The claim also requires treatment of a subject with one of the listed diseases. Use of maralixibat for an unrelated indication would not satisfy the express disease limitation.
Does the patent cover Livmarli for PFIC and Alagille syndrome?
Yes. Claims 3 and 4 specifically narrow claim 1 to PFIC and Alagille syndrome, respectively. Claim 2 separately covers pediatric subjects, making the patent particularly relevant to the pediatric populations in the Livmarli label.
A commercial product label is not itself the only determinant of infringement. A generic applicant could seek approval for a narrower indication, use a skinny label, or certify that it will not market for patented uses. The practical risk depends on the proposed label, prescribing information, promotional conduct, and the scope of any FDA-listed patents.
For PFIC and Alagille syndrome, the patent has a direct overlap with the approved use of Livmarli. The overlap is strongest where the proposed generic labeling includes pediatric patients and reduction of bile acid burden or treatment of cholestatic disease.
What formulation and manufacturing protection does US 10,981,952 provide?
US 10,981,952 does not, based on the supplied claims, protect a formulation or manufacturing process.
The claims do not recite:
- A particular excipient
- A liquid oral formulation
- A concentration
- A particle size
- A crystalline form
- A polymorph
- A salt-selection process
- A manufacturing intermediate
- A process parameter
- A stability profile
- A container or delivery device
The patent protects the act of orally administering the specified IBAT inhibitor for the specified disease purposes. Separate formulation, solid-state, process and combination patents may create additional barriers, but they cannot be inferred from the claims supplied here.
What is the Orange Book status of US Patent 10,981,952?
US Patent 10,981,952 has been associated with Livmarli’s FDA patent estate and is relevant to the Orange Book analysis for the Livmarli NDA. The FDA Orange Book determines whether a listed patent creates a certification obligation for an ANDA applicant.[3]
For an ANDA referencing Livmarli, the applicant generally must address each applicable listed patent through one of the following mechanisms:
- Paragraph I certification, if the patent information has not been submitted;
- Paragraph II certification, if the patent has expired;
- Paragraph III certification, if the applicant will wait until expiration;
- Paragraph IV certification, asserting that the patent is invalid, unenforceable or not infringed; or
- A section viii statement carving out a patented method of use, where the FDA permits the use to be omitted from labeling.
A method-of-use patent can be significant even when the active ingredient is no longer protected by a composition patent. The commercial impact depends on whether the patented method is embedded in the reference product’s labeling and whether a generic can obtain approval with a lawful use carve-out.
The Orange Book listing should be checked against the current FDA patent-and-exclusivity file because listing status, expiration information and associated use codes can change.
When does US Patent 10,981,952 expire?
The patent’s nominal term is tied to the earliest applicable nonprovisional priority date for its patent family. Public patent records associate the family with a March 2013 priority date, producing a nominal expiration in March 2034, subject to any patent-term adjustment, patent-term extension, terminal disclaimer or other statutory modification.[4]
The commercial analysis should distinguish three dates:
| Exclusivity category |
Relevance |
| Patent term |
Potentially extends into 2034 based on the patent family term |
| Orphan-drug exclusivity |
Applies separately to approved ALGS and PFIC indications |
| Pediatric exclusivity |
Can add six months to qualifying regulatory exclusivity periods |
The patent expiration date is not the same as the earliest possible generic launch date. A generic applicant may file an ANDA before expiration and challenge the patent under Paragraph IV. FDA approval and launch may still be delayed by patent litigation or a statutory 30-month stay.
What Paragraph IV challenges and litigation risks exist?
A Paragraph IV certification against US 10,981,952 would assert that the patent is invalid, unenforceable or not infringed. The principal legal issues would likely include claim construction, written description, enablement, obviousness and method-of-use infringement.
Infringement issues
For claim 1, a patent holder would need to establish that the accused product or use involves:
- Maralixibat or a covered salt;
- Oral administration;
- A patient with a listed disease; and
- A therapeutic purpose that satisfies the serum-bile-acid reduction limitation.
Claims 3 and 4 could present more direct allegations for PFIC and ALGS. Claims 7 and 8 would depend on whether the product labeling or prescribing instructions direct treatment of pruritus.
Claims 9 through 12 add combination-therapy limitations. They may be harder to assert against a generic if the generic label does not direct concurrent use of cholestyramine or another listed resin.
Validity issues
Potential validity challenges include:
- Whether the prior art disclosed maralixibat for the claimed diseases;
- Whether the prior art made the claimed treatment predictable;
- Whether the specification adequately supports every listed disease;
- Whether the serum bile acid reduction limitation provides a meaningful technical distinction;
- Whether the claims are enabled across the full disease list.
The breadth of claim 1 creates a possible tension: it covers multiple diseases with materially different pathophysiology, while the commercial evidence may be concentrated in PFIC and ALGS. The dependent claims provide narrower positions that may be more closely supported by clinical data.
How strong is the patent estate for maralixibat?
The patent estate is strongest when viewed as a layered protection system rather than through US 10,981,952 alone.
| Protection layer |
Commercial role |
| Composition-of-matter patents |
Protect maralixibat itself, if unexpired and applicable |
| Method-of-use patents |
Protect treatment of ALGS, PFIC and other cholestatic diseases |
| Formulation patents |
Protect liquid or solid oral dosage forms |
| Process patents |
Protect synthesis and purification |
| Regulatory exclusivity |
Delays approval or competition independently of patent validity |
| Clinical-label restrictions |
Affect skinny-label and section viii strategies |
US 10,981,952 is commercially important because it links the active ingredient to specific disease treatment. It is not a complete substitute for composition or formulation protection. If an unexpired composition patent covers maralixibat, a generic would face a more substantial barrier. If the method patent is the principal remaining patent, the generic’s strategy may focus on label carving, non-infringement and invalidity.
Are biosimilars relevant to Livmarli?
No. Livmarli contains a synthetic small-molecule drug, maralixibat. A biosimilar pathway under the Public Health Service Act is not applicable.
Competition would arise through an ANDA or, depending on the product and regulatory strategy, another small-molecule pathway. The relevant risks are generic substitution, Paragraph IV litigation, section viii labeling and possible alternative IBAT inhibitors. Biosimilar interchangeability standards do not govern this product.
Which companies compete with maralixibat?
The closest commercial competition is within the IBAT inhibitor and cholestatic-disease markets.
| Product or program |
Company |
Competitive relevance |
| Livmarli, maralixibat |
Mirum Pharmaceuticals |
Approved IBAT inhibitor for ALGS and PFIC-related cholestatic pruritus |
| Bylvay, odevixibat |
Albireo, acquired by Ipsen |
IBAT inhibitor approved for PFIC and other cholestatic indications |
| A4250 development programs |
Ipsen/Albireo |
Competes in pediatric cholestatic disease |
| Linerixibat programs |
GlaxoSmithKline |
IBAT inhibitor development focused on cholestatic pruritus in other diseases |
Odevixibat is the closest approved pharmacologic comparator. It has a different molecular structure and separate patent estate. Competition between maralixibat and odevixibat is therefore primarily product and indication competition, not direct infringement under US 10,981,952.
What generic-entry scenarios exist for Livmarli?
Three scenarios are commercially plausible.
Early Paragraph IV launch
A generic applicant challenges the listed patent before expiry and prevails in litigation or obtains a favorable settlement. This scenario creates the earliest potential entry but carries substantial litigation cost.
Skinny-label entry
The applicant omits patented indications or uses from the label. This strategy is more difficult where the reference product’s principal commercial use is a patented pediatric indication and the remaining unpatented uses have limited demand.
Post-expiration entry
The applicant avoids litigation and launches after expiration of the relevant patent and regulatory exclusivities. This is the lowest legal-risk path but preserves Mirum’s market position for the remaining term.
A launch based only on a narrow non-infringing indication may have limited commercial value if PFIC and ALGS account for most of the product’s revenue.
What revenue exposure does this patent create?
The patent creates direct exposure for revenue generated from oral maralixibat in ALGS and PFIC, particularly pediatric treatment and use alongside bile acid sequestrants. It also creates potential protection for off-label or future-label expansion into the other diseases listed in claim 1.
The economic value depends on:
- The percentage of Livmarli sales attributable to ALGS and PFIC;
- Remaining patent and orphan-exclusivity term;
- Whether the patent is challenged;
- Whether a generic can omit the protected uses;
- The availability of competing IBAT inhibitors;
- The extent of physician prescribing outside the FDA label.
The patent does not independently establish exclusivity for every commercial use of maralixibat. Its value is highest where the product label and actual prescribing practice track the claimed diseases and patient populations.
Key Takeaways
- US Patent 10,981,952 is a method-of-treatment patent covering oral maralixibat for reducing serum bile acids.
- Claim 1 covers ALGS, PFIC and a broad group of additional cholestatic and liver diseases.
- Claims 2 through 4 are particularly relevant to pediatric ALGS and PFIC use.
- Claims 9 through 12 cover combination treatment with bile acid resins, including cholestyramine.
- The patent does not, based on the supplied claims, protect a formulation, dosage, polymorph or manufacturing process.
- Livmarli is a small-molecule product, so biosimilar rules do not apply.
- The patent family is associated with a nominal expiration in March 2034, subject to statutory term adjustments.
- Generic applicants may use Paragraph IV, section viii or post-expiration strategies.
- The strongest infringement risk concerns a generic label that expressly includes pediatric PFIC or ALGS treatment with oral maralixibat.
FAQs
Does US 10,981,952 cover maralixibat for pruritus?
Yes, but only through dependent claims 7 and 8. Claim 7 covers pruritus as a comorbidity, while claim 8 covers pruritus as a symptom of the claimed disease.
Does the patent require a reduction in pruritus?
No. Claim 1 requires decreasing serum bile acid concentration. Pruritus is added only in claims 7 and 8.
Can a generic avoid claim 12 by omitting cholestyramine from its label?
Potentially. Claim 12 requires concurrent administration of cholestyramine. A label that does not direct or encourage that combination may reduce infringement risk under that claim, although claims 1 through 8 would remain separate issues.
Is a salt of maralixibat covered?
Yes. Claim 1 expressly includes pharmaceutically acceptable salts of the specified IBAT inhibitor.
Does claim 1 cover treatment of adults?
Yes. Claim 1 is not limited to pediatric subjects. Pediatric treatment is separately covered by claim 2.
References
-
U.S. Food and Drug Administration. (2021). Livmarli (maralixibat) prescribing information. FDA.
-
U.S. Food and Drug Administration. (2023). FDA approves treatment for Alagille syndrome and progressive familial intrahepatic cholestasis. FDA.
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U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. FDA.
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United States Patent and Trademark Office. (2021). U.S. Patent No. 10,981,952, Methods of treating cholestatic diseases. USPTO.
