United States Patent 10,975,046: Odevixibat Crystalline Hydrates, Mixed Solvates and Manufacturing Process
U.S. Patent No. 10,975,046 protects defined solid-state forms of odevixibat, including a channel hydrate, a sesquihydrate, high-crystallinity material, several water-organic-solvent solvates, and a solvent-mediated process for producing crystal modification 1 from crystal modification 2. The patent is composition-focused rather than directed to the odevixibat molecular structure, clinical use, dosage regimen or finished pharmaceutical formulation.
The strongest claim exposure is associated with commercial manufacture or importation of odevixibat in a protected crystalline form. A generic or alternative supplier may avoid literal infringement by using a nonclaimed polymorph, an anhydrous form, a different solvate, or a process that does not isolate the claimed crystal modification 2. Those alternatives remain subject to equivalence, process evidence and other patents in the odevixibat estate.
What does U.S. Patent 10,975,046 protect?
The patent has three principal claim groups:
| Claim group |
Claims |
Protected subject matter |
| Crystalline hydrates |
1-7 |
Odevixibat hydrates, including channel hydrate, sesquihydrate and high-crystallinity material defined by water content and XRPD peaks |
| Mixed solvates |
8-16 |
Odevixibat containing about two moles of water per mole of odevixibat plus a specified organic solvent, including ethanol |
| Manufacturing process |
17-20 |
Preparation of crystal modification 1 by isolating crystal modification 2 from a water-organic solvent mixture |
The claims do not cover every physical form of odevixibat. They require the accused material or process to satisfy the structural, compositional, analytical or process limitations stated in the applicable claim.
How broad are claims 1 through 7 for odevixibat hydrates?
Claims 1 through 7 establish a layered product claim structure.
Claim 1 broadly covers “a crystalline hydrate of odevixibat.” It does not expressly require a particular stoichiometric water content, XRPD pattern or named polymorph. The claim is therefore the principal genus claim for crystalline hydrated odevixibat, subject to the ordinary meaning of “crystalline hydrate” and the patent’s specification.
Claim 2 narrows the product to a channel hydrate. A channel hydrate generally has solvent or water molecules accommodated within channels or voids in the crystal lattice rather than occupying only a fixed molecular coordination site.
Claim 3 covers a hydrate comprising about zero to about two moles of water per mole of odevixibat. Because the range begins at approximately zero, the claim raises an interpretation issue at the boundary between a hydrate and an anhydrous or nearly anhydrous form. The specification, analytical methods and prosecution history would be important in determining whether the claim reaches a material with negligible water content.
Claim 4 specifically identifies the sesquihydrate, corresponding nominally to approximately 1.5 moles of water per mole of odevixibat.
Claims 5 and 6 define the hydrate by powder X-ray diffraction. Claim 5 requires peaks at one or more of 5.6, 6.7 and 12.1 degrees two-theta, each with a tolerance of plus or minus 0.2 degrees. Claim 6 requires all three peaks and one or more additional peaks at 4.1, 4.6, 9.3, 9.4 or 10.7 degrees two-theta.
Claim 7 adds a crystallinity limitation of greater than approximately 99%. This limitation can materially increase the evidentiary burden for enforcement because crystallinity depends on the analytical method, sample preparation, instrument configuration and calculation methodology.
What is the practical scope of the hydrate claims?
The claims can reach:
- Odevixibat sesquihydrate isolated as an active pharmaceutical ingredient.
- A channel hydrate having the specified water association.
- Material exhibiting the claimed XRPD reflections.
- Highly crystalline odevixibat hydrate used in a drug substance manufacturing process.
- Hydrated material that falls within the claimed water-content range even if its commercial name differs.
A product analysis should use Karl Fischer water determination, thermogravimetric analysis, differential scanning calorimetry and XRPD. XRPD alone may not establish the hydration state, while water content alone may not establish the claimed crystal form.
What do claims 8 through 16 protect for odevixibat solvates?
Claims 8 through 16 cover mixed solvates containing approximately two moles of water per mole of odevixibat and an organic solvent.
Claim 8 is the broadest mixed-solvate claim. Claim 9 identifies the permitted organic solvents:
- Methanol
- Ethanol
- 2-propanol
- Acetone
- Acetonitrile
- 1,4-dioxane
- DMF
- DMSO
Claim 10 narrows the solvent to ethanol.
Claims 11 through 16 use XRPD patterns to define several mixed-solvate forms. They appear to cover distinct solid-state forms or form families based on the following peak sets:
| Claims |
Principal XRPD positions, degrees two-theta |
| 11-12 |
5.0, 5.1 and/or 11.8; claim 12 adds 6.4, 6.6 and 9.5 |
| 13-14 |
4.8, 5.1 and/or 11.6; claim 14 adds 6.2, 6.67, 9.5 and 20.3 |
| 15-16 |
5.0, 6.2, 9.4 and/or 23.9; claim 16 adds 11.5, 19.5 and 20.2 |
The peak tolerances are generally plus or minus 0.2 degrees two-theta. Claim 14 contains “20.3±0,” which is materially narrower in wording than the other peak tolerances. Its construction may depend on the patent specification and prosecution record.
How can a mixed-solvate claim be infringed?
A manufacturer could face product-claim exposure if the marketed odevixibat drug substance contains the claimed water and organic-solvent components, even if the solvent is removed later from the final dosage form. The relevant question is generally the composition of the accused drug substance as made, sold or imported, not only the composition of the finished tablet or capsule.
Residual solvent analysis should be performed with gas chromatography or another validated method. A water-organic solvent mixture used during processing does not, by itself, prove that the isolated product is a claimed mixed solvate. The isolated solid must satisfy the relevant composition and, where required, XRPD limitations.
What does the process claim cover?
Claims 17 through 20 cover a conversion process for producing crystal modification 1 of odevixibat.
The process requires:
- A solution of odevixibat.
- A solvent mixture containing water and one listed organic solvent.
- Isolation of crystal modification 2.
- Preparation of crystal modification 1 through that process sequence.
Claim 18 narrows crystal modification 2 to crystal modification 2A. Claim 19 specifies water and ethanol. Claim 20 narrows the ethanol concentration to approximately 55% to 75% by volume.
The process claims are narrower than the hydrate and mixed-solvate product claims because they require a particular sequence and intermediate. A process using a different solvent system, a different concentration, direct crystallization of modification 1, or a different intermediate may avoid literal infringement of claims 17-20. The doctrine of equivalents could still be relevant if the substituted process performs substantially the same function in substantially the same way with substantially the same result.
What evidence is relevant to process infringement?
Key evidence would include:
- Batch records and master manufacturing instructions.
- Solvent composition and concentration.
- Seeding records.
- Crystallization temperature and cooling profile.
- Isolation and drying conditions.
- XRPD or solid-form identification of the isolated intermediate.
- Whether the process isolates modification 2 or modification 2A.
- Whether the final product converts to modification 1 during drying or storage.
The process claims create a manufacturing barrier even where a supplier attempts to sell the same active ingredient in a different final solid form.
When does U.S. Patent 10,975,046 lose exclusivity?
The patent issued on March 30, 2021. Its underlying priority is associated with a 2017 filing date, and the ordinary twenty-year patent-term calculation points to expiration in 2038, subject to the official patent-term adjustment shown in USPTO records and any applicable patent-term extension.[1]
| Event |
Date or status |
| Earliest reported priority period |
2017 |
| U.S. patent issuance |
March 30, 2021 |
| Ordinary statutory expiry window |
2038 |
| Patent-term adjustment |
Must be taken from the USPTO patent record |
| Patent-term extension |
No extension should be assumed without an FDA and USPTO determination |
Patent expiration does not automatically eliminate regulatory exclusivity. Odevixibat products may also benefit from orphan-drug exclusivity, pediatric exclusivity and other FDA protections that operate independently of the patent term.
What is the Orange Book status of U.S. Patent 10,975,046?
BYLVAY, whose active ingredient is odevixibat, was approved by FDA under NDA 214662. FDA approved BYLVAY for cholestatic pruritus associated with Alagille syndrome and for progressive familial intrahepatic cholestasis in relevant pediatric populations.[2][3]
A patent’s inclusion in the FDA Orange Book must be confirmed from the current Approved Drug Products with Therapeutic Equivalence Evaluations database and the NDA patent-listing records. Patent claims directed to a crystalline drug substance, solvate or manufacturing process may face listing questions because Orange Book listing generally focuses on patents that claim the approved drug, a formulation, or an approved method of use. A process claim is not automatically listable merely because it relates to manufacture of the active ingredient.[4]
For litigation and generic-entry analysis, the following distinctions are material:
| Issue |
Relevance |
| Patent listed for NDA 214662 |
Can trigger a Paragraph IV certification and notice process |
| Patent not listed |
Does not eliminate infringement risk, but does not create the same Orange Book certification pathway |
| Product claim |
More likely to affect the drug substance used in an ANDA |
| Process claim |
May support separate patent litigation but may not independently block an ANDA |
| Method-of-use patent |
Can affect labeling and carve-out strategy |
| Orphan exclusivity |
Can block approval for the protected indication regardless of patent status |
Are Paragraph IV challenges likely to target this patent?
A Paragraph IV certification is relevant only if U.S. Patent 10,975,046 is listed for the applicable BYLVAY NDA. If listed, an ANDA applicant could allege that the patent is invalid, unenforceable or not infringed.
The most plausible challenge positions would include:
- Lack of anticipation or obviousness over earlier odevixibat solid-form disclosures.
- Insufficient written description for the breadth of “a crystalline hydrate.”
- Lack of enablement across the full hydrate and solvate scope.
- Ambiguity in the XRPD limitations.
- Failure of the accused material to meet the required water, solvent or peak limitations.
- Noninfringement based on use of an alternative polymorph.
- Invalidity of claims that combine overlapping or poorly distinguished XRPD peak sets.
- Process noninfringement because the supplier does not isolate modification 2 or 2A.
The strongest defense for a well-characterized alternative solid form would be a complete solid-state package showing different XRPD, water content, thermal behavior and solvent content. A generic applicant that uses the patented sesquihydrate or a substantially identical XRPD form would face a materially higher litigation risk.
How strong is the patent estate for odevixibat?
U.S. Patent 10,975,046 is strongest as a solid-state and manufacturing patent. It is not, based on the supplied claims, a basic composition-of-matter patent for odevixibat.
| Patent layer |
What it protects |
Commercial effect |
| Basic molecule |
Odevixibat chemical structure |
Usually the broadest protection, if unexpired |
| Solid-state form |
Hydrates, polymorphs and solvates |
Can block use of the commercially preferred drug substance |
| Manufacturing process |
Crystallization and form conversion |
Can restrict economically practical production routes |
| Formulation |
Dosage form, excipients, release profile |
Can affect finished-product substitution |
| Method of use |
Treatment of cholestatic disorders |
Can limit labeled generic indications |
| Regulatory exclusivity |
Orphan and pediatric protections |
Can delay approval independently of patent claims |
The patent’s commercial value depends on whether BYLVAY uses a claimed hydrate or solvate and whether the claimed form is necessary for stability, purity, dissolution, manufacturability or regulatory consistency. A solid-form patent is more powerful when the approved product relies on that form and alternative forms have inferior process performance.
What generic launch risks exist?
A generic launch could follow several paths:
Launch after patent expiry
This is the lowest patent-risk path, but FDA exclusivity, pediatric exclusivity and orphan exclusivity must also be cleared.
Paragraph IV litigation
If the patent is listed, a first ANDA with a Paragraph IV certification could trigger litigation and a potential 30-month stay under the Hatch-Waxman framework.[5] The litigation would likely focus on whether the ANDA drug substance is the claimed hydrate, mixed solvate or crystal form.
Section viii strategy
A section viii statement may be relevant for method-of-use patents, but it generally does not avoid a product patent covering the drug substance itself.
Alternative solid form
A supplier could develop an anhydrous form, a nonclaimed hydrate, a different polymorph or a form that does not exhibit the claimed XRPD pattern. This route requires comparative solid-state, stability and bioequivalence work.
At-risk launch
An at-risk launch before final resolution would expose the supplier to damages, injunctive relief and possible disruption of commercial supply. The risk is highest where the reference product and proposed product use the same crystalline active ingredient.
What licensing and competitive issues affect odevixibat?
Albireo developed BYLVAY and was acquired by Ipsen in 2023. Ipsen became the commercial owner of Albireo’s odevixibat business and related intellectual property through that transaction.[6] The relevant competitive set includes:
- Ipsen and its BYLVAY product.
- Potential ANDA applicants pursuing generic odevixibat.
- Suppliers developing alternative crystal forms.
- Companies developing other bile-acid transport inhibitors or treatments for cholestatic pruritus.
- Developers of competing therapies for Alagille syndrome and progressive familial intrahepatic cholestasis.
The supplied patent does not establish a license, settlement or covenant-not-to-sue. Those matters must be assessed from SEC filings, court dockets, FDA records and transaction documents. A patent-family ownership review should track Albireo AB, Albireo Pharma, Ipsen and any recorded assignments at the USPTO.
What geographic coverage does the patent family have?
U.S. Patent 10,975,046 has enforceable U.S. rights only. Equivalent protection may exist in national-stage or regional applications derived from the same priority family, potentially including Europe and other major pharmaceutical markets.
Geographic risk should be assessed separately for:
- U.S. manufacture and sale.
- Importation of odevixibat drug substance into the U.S.
- European Union marketing.
- United Kingdom rights.
- Canada, Japan and other regulated markets.
- Countries where only a process patent, but not a product-form patent, is in force.
A supplier can avoid U.S. infringement through offshore manufacturing only if the resulting conduct does not fall within U.S. importation, sale or offer-for-sale provisions. Importing a patented product can itself create infringement exposure under 35 U.S.C. §271.[7]
Key Takeaways
- U.S. Patent 10,975,046 is directed to odevixibat solid forms and a crystallization process.
- Claims 1-7 cover crystalline hydrates, including a channel hydrate, sesquihydrate and XRPD-defined material.
- Claims 8-16 cover water-organic mixed solvates, including ethanol-containing forms.
- Claims 17-20 cover production of crystal modification 1 through isolation of crystal modification 2 or 2A from specified solvent mixtures.
- The patent is more important for drug-substance manufacture than for odevixibat’s molecular composition or clinical use.
- A generic using the same crystalline odevixibat form as BYLVAY would face substantial product-claim risk.
- An alternative polymorph or anhydrous form could provide a design-around, but only after analytical and regulatory confirmation.
- The ordinary patent-term calculation points to expiration in 2038, subject to USPTO patent-term adjustment and any extension.
- Orange Book listing, Paragraph IV exposure and FDA exclusivity must be analyzed separately from the patent claims.
- Ipsen owns the commercial odevixibat business following its acquisition of Albireo.
FAQs About U.S. Patent 10,975,046
Does U.S. Patent 10,975,046 cover all odevixibat products?
No. It covers specified crystalline hydrates, mixed solvates and a defined manufacturing process. It does not, from the supplied claims, cover every chemical form, formulation or use of odevixibat.
Does the patent cover BYLVAY tablets or capsules directly?
The claims supplied are directed primarily to the active ingredient’s solid state and its preparation. Direct coverage of the finished dosage form would require separate formulation claims or a determination that the dosage form contains a claimed protected form.
Can a generic use a different odevixibat polymorph?
Potentially. A different polymorph may avoid literal infringement if it does not meet the claimed water, solvent, XRPD or crystal-modification limitations. The alternative must also satisfy stability, manufacturing and FDA requirements.
Does an expired basic odevixibat patent eliminate this patent’s value?
No. A later-expiring solid-form or process patent can continue to restrict commercial manufacture or sale after an earlier composition-of-matter patent expires.
Is a Paragraph IV certification required for this patent?
Only if U.S. Patent 10,975,046 is listed in the Orange Book for the relevant BYLVAY NDA. If listed, an ANDA applicant would need to address it through the applicable patent certification framework.
References
- United States Patent and Trademark Office. (2021). U.S. Patent No. 10,975,046, crystalline forms of odevixibat.
- U.S. Food and Drug Administration. (2021). FDA approves treatment for rare liver disease in children.
- U.S. Food and Drug Administration. (n.d.). BYLVAY (odevixibat) prescribing information.
- U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations.
- 21 U.S.C. §355(j); 35 U.S.C. §271(e).
- Ipsen. (2023). Ipsen completes acquisition of Albireo.
- 35 U.S.C. §271(a), (g) and (i).
