US Patent 10,052,337: Obeticholic Acid Formulation Claims, Scope, Expiration and Patent Landscape

US Patent No. 10,052,337 covers particle-size-controlled obeticholic acid compositions, jet-milled obeticholic acid, and tablet formulations with defined intra-granular and extra-granular architecture. Its strongest commercial relevance is to orally administered obeticholic acid tablets, including formulations corresponding to Ocaliva, rather than to obeticholic acid as a chemical compound generally.

The patent creates potential infringement exposure where a product combines:

Obeticholic acid or a covered derivative;
A particle-size distribution meeting the claimed thresholds;
Jet milling;
Low-alcohol excipients;
A tablet containing intra-granular and extra-granular excipient portions; and
The claimed microcrystalline-cellulose-to-obeticholic-acid ratio.

The broadest composition claim is claim 1. The most commercially specific claims are claims 11, 14, 15, 17, 18 and 19.

What does US Patent 10,052,337 protect?

US 10,052,337 protects pharmaceutical compositions and tablets containing obeticholic acid in controlled particle-size forms. The patent is assigned to Intercept Pharmaceuticals, Inc., the original developer of Ocaliva. The patent’s claim set is directed primarily to formulation and manufacturing characteristics, not to the molecular structure of obeticholic acid itself.[1]

Patent	Subject matter	Principal commercial relevance
US 10,052,337	Particle-size-controlled obeticholic acid, jet milling and tablet architecture	Ocaliva-type tablets and competing oral formulations
Claims 1-10	Obeticholic acid particle-size distributions and low-alcohol excipients	Powder and composition claims
Claims 11-12	Intra-granular and extra-granular tablet portions	Direct-compression or wet-granulation tablet manufacture
Claims 13-15	Jet-milling process and jet-milled tablet formulations	Manufacturing-process and product-by-process exposure
Claims 16-19	Unit-dose tablets and microcrystalline-cellulose ratios	Finished dosage-form claims

The patent does not require obeticholic acid to be present in its free-acid form. Claim 1 expressly covers obeticholic acid and a pharmaceutically acceptable salt, ester or amino acid conjugate.

How broad are the particle-size claims?

Claim 1 requires that at least 50% of the obeticholic acid particles have a diameter of 200 micrometers or less. This is a median-type limitation. It does not require every particle to be 200 micrometers or smaller.

The dependent claims progressively tighten the particle-size requirement.

Claim	Particle-size requirement
1	At least 50% at 200 μm or less
2	At least 50% at 100 μm or less
3	At least 50% at 50 μm or less
4	At least 50% at 10 μm or less
5	At least 50% at 5 μm or less
6	At least 90% at 200 μm or less
7	At least 90% at 100 μm or less
8	At least 90% at 25 μm or less

A formulation satisfying claim 5 would also satisfy claims 1 through 4, assuming the other limitations are met. A formulation satisfying claim 8 would also satisfy claims 1, 6 and 7.

Why particle-size measurement matters

Particle-size claims can turn on the analytical method used. Laser diffraction, sieve analysis, microscopy and dynamic image analysis can generate different results, especially for irregular or agglomerated particles.

The patent claims refer to particle diameter but, in the quoted claims, do not specify a single measurement technique. A dispute would likely focus on:

Whether agglomerates are measured as single particles;
Whether the reported value is volume-based, number-based or surface-area-based;
Whether the test measures the active ingredient before or after granulation;
Whether dissolution or dispersion breaks up agglomerates;
The sampling procedure and batch uniformity; and
Whether “at least 50%” means a D50 value under the relevant analytical convention.

A generic applicant using a particle-size distribution outside the claimed thresholds could reduce literal-infringement risk. The risk is higher where the product specification routinely produces a median particle size below 200 μm, even if the regulatory dossier does not emphasize micronization.

What formulations are protected by claims 9 through 12?

Claim 9 adds an excipient limitation. The composition must contain at least one pharmaceutically acceptable excipient with an alcohol content of less than approximately 6% by weight.

Claim 10 narrows claim 9 to sodium starch glycolate. This limitation is relevant to solid oral formulations because sodium starch glycolate is commonly used as a disintegrant.

Claims 11 and 12 shift from particle-size distribution to tablet structure:

The intra-granular portion contains obeticholic acid, microcrystalline cellulose and one or more additional excipients.
The extra-granular portion contains one or more pharmaceutical excipients.
Claim 12 requires microcrystalline cellulose in the extra-granular portion as well.

The claim therefore distinguishes between excipients incorporated into granules and excipients added after granulation. A tablet may fall within claim 11 even if it does not meet the particle-size limitations of claim 1, because claim 11 is an independent tablet claim with its own structural requirements.

Claim 11 infringement risk

A competing tablet is more exposed under claim 11 if its manufacturing records show:

Obeticholic acid incorporated into a granulated intra-granular blend;
Microcrystalline cellulose in that blend;
At least one additional intra-granular excipient; and
A separate extra-granular excipient phase.

The claim does not, on its face, require a specific granulation method. Wet granulation, dry granulation or another process could potentially satisfy the claim if the final tablet has the claimed portions.

A formulation using direct compression without a technically distinct intra-granular portion may present a stronger non-infringement position. That position depends on whether the manufacturing process and final dosage form establish separate portions under the claim construction applied by a court.

How do the jet-milling claims operate?

Claim 13 covers a method of preparing a composition with the claim 1 particle-size threshold by forming the particles through jet milling.

Claims 14 and 15 apply the jet-milling limitation to the tablet claims. Claim 14 requires that the obeticholic acid in the tablet be jet-milled. Claim 15 further requires the particle-size threshold of claim 1.

This creates two different enforcement paths:

Claim 13 is a process claim directed to making the composition.
Claims 14 and 15 are product or tablet claims incorporating jet-milled obeticholic acid.

A finished product claim can create commercial exposure even where the generic manufacturer performs the actual jet milling through a contract manufacturer. Manufacturing records, supplier specifications, batch documents and regulatory submissions may be relevant to proving the process and product limitations.

A generic applicant could seek to avoid claims 13-15 by using an alternative size-reduction process, such as hammer milling, pin milling or controlled crystallization. That strategy would not necessarily avoid claims 1-12 if the resulting particle-size distribution and tablet structure remain within those claims.

What does claim 19 add?

Claim 19 requires the intra-granular portion to contain microcrystalline cellulose and obeticholic acid in a ratio of approximately 20:1 to 1:5.

The ratio appears to be a weight ratio of microcrystalline cellulose to obeticholic acid, although the claim language should be read with the specification and prosecution history. The range is broad:

Ratio boundary	Practical implication
20:1	Highly excipient-rich intra-granular formulation
1:1	Equal weight of microcrystalline cellulose and obeticholic acid
1:5	Active-rich formulation relative to microcrystalline cellulose

Claim 19 is commercially important because it can capture formulation optimization around tablet manufacturability, flow, compressibility and dose uniformity. It also narrows the claim to a quantifiable formulation parameter that can be tested from batch records and composition data.

When does US Patent 10,052,337 lose exclusivity?

The patent was granted on August 21, 2018. Its effective expiration date depends on the earliest nonprovisional priority date, patent-term adjustment, terminal disclaimers and any applicable patent-term extension.[1]

Public patent records commonly associate the patent with an expiration in the 2033-2034 period. The critical business point is that the patent extends materially beyond the earliest obeticholic-acid composition patents and may remain relevant after basic compound protection has expired.

Exclusivity category	Expected timing
Original obeticholic-acid compound protection	Earlier expiration, generally in the 2020s
US 10,052,337 formulation protection	Approximately 2033-2034, subject to official PTA and term records
FDA small-molecule regulatory exclusivity	Separate from patent term and indication-specific
Generic launch date	Potentially before patent expiration through Paragraph IV litigation or settlement

The exact enforceable expiration date must be taken from the USPTO patent-term record and the FDA Orange Book listing applicable to the approved product and patent code. Patent expiration does not automatically establish a generic launch date because litigation, settlements, pediatric exclusivity, regulatory review and other listed patents may control entry.

What is the Orange Book status of US 10,052,337?

US 10,052,337 has been associated with the Ocaliva patent estate and is relevant to the FDA-listed product, subject to the current Orange Book entry and any use-code limitations.[2] The Orange Book distinguishes listed patents from the scope of the approved labeling and does not determine whether every claim would be infringed by every generic formulation.

For an ANDA applicant, the relevant certification could include:

Paragraph I, if no patent information is listed;
Paragraph II, if the listed patent has expired;
Paragraph III, if the applicant will wait until patent expiration; or
Paragraph IV, if the applicant asserts that the patent is invalid, unenforceable or will not be infringed.

A Paragraph IV certification directed to US 10,052,337 could trigger patent litigation if the NDA holder or patent owner files suit within the statutory period. A successful Paragraph IV challenge could support an earlier launch, while a failed challenge could delay entry until patent expiration or settlement terms permit launch.

Are there Paragraph IV challenges to this patent?

No publicly established Paragraph IV outcome should be inferred solely from the patent’s Orange Book listing. A challenge may exist at the ANDA level without immediately producing a published district-court decision naming the patent.

The most likely challenge theories would be:

Invalidity theories

Lack of written description for broad particle-size ranges;
Lack of enablement across all salts, esters and amino acid conjugates;
Obviousness based on routine micronization and conventional tablet excipients;
Obviousness of separating intra-granular and extra-granular excipients;
Indefiniteness of particle diameter or the claimed alcohol-content limitation;
Indefiniteness or ambiguity in the microcrystalline-cellulose-to-active ratio.

Non-infringement theories

The product has a particle distribution above the claimed threshold;
The formulation uses a non-jet-milled active;
The tablet lacks distinct intra-granular and extra-granular portions;
Microcrystalline cellulose is present only in one portion;
The excipient alcohol content is outside the claimed range;
The ratio in claim 19 falls outside 20:1 to 1:5.

A product-by-process challenge to claims 13-15 could argue that the final product is not necessarily distinguishable from material produced by another milling process. The strength of that argument depends on whether the claims are construed to require the process itself or only product characteristics attributable to jet milling.

How strong is the patent estate for obeticholic acid?

The estate is layered rather than dependent on a single patent. Its commercial strength comes from the combination of compound, method-of-use, formulation and manufacturing protection.

Protection layer	Representative relevance
Compound protection	Obeticholic acid chemical entity
Formulation protection	Particle size, excipients and tablet structure
Manufacturing protection	Jet milling and granulation architecture
Method-of-use protection	PBC and other therapeutic indications
Regulatory protection	FDA exclusivity tied to approved indications

US 10,052,337 is stronger against a conventional copy of the branded tablet than against a genuinely redesigned oral formulation. Its broadest claim covers a relatively low particle-size threshold of 200 μm for at least half of the particles. Many solid oral development programs could meet that threshold unintentionally through ordinary milling. Claims 2 through 8 become narrower but may correspond more closely to commercial micronized material.

The patent is less powerful against:

Non-tablet dosage forms;
Formulations using a different active form and a different particle distribution;
Direct-compression tablets without distinct intra-granular and extra-granular portions;
Products manufactured without jet milling;
Products using an alternative disintegrant and no covered low-alcohol excipient.

What other patents affect obeticholic acid generic entry?

Obeticholic acid generic entry is governed by the full Orange Book and patent-family landscape, not US 10,052,337 alone. The principal categories include the original composition patent, therapeutic-use patents and later formulation patents.

Patent category	Entry risk
Original composition patents	May have expired or approach expiration before formulation patents
PBC method-of-use patents	Relevant if the ANDA label includes the patented indication
NASH or other-use patents	Relevant only if the indication and labeling overlap
Formulation patents	Can block an otherwise non-infringing active ingredient
Process patents	More difficult to detect from the finished product alone
Regulatory exclusivity	Can delay approval independently of patent validity

Method-of-use patents can be addressed through a section viii statement or a skinny label where permitted. Formulation claims are more difficult to avoid when the generic must demonstrate pharmaceutical equivalence and comparable dissolution to the reference product.

What is the biosimilar risk for obeticholic acid?

Biosimilar risk is not applicable in the conventional statutory sense. Obeticholic acid is a chemically synthesized small molecule, so a competing product would generally proceed through the abbreviated new drug application pathway rather than the biologics license application and biosimilar pathway.

The competitive threat is therefore from:

ANDA-approved generic tablets;
Potential 505(b)(2) products with modified formulations;
Alternative dosage forms;
Licensed or authorized generic arrangements; and
Products entering after patent settlement dates.

The key regulatory question is pharmaceutical equivalence and bioequivalence, not biosimilarity.

Which companies are challenging the obeticholic acid patent estate?

Publicly visible competition is likely to come from generic manufacturers with ANDA programs rather than biosimilar developers. The identity of an ANDA filer may remain confidential until litigation is filed, a settlement is disclosed, or FDA approval becomes public.

No specific challenger should be treated as having defeated US 10,052,337 without a filed court decision, a settlement announcement or an FDA approval record tied to the patent certification. Patent litigation involving other Ocaliva patents does not automatically resolve the validity or enforceability of this patent.

What licensing deals affect the patent?

Intercept transferred its commercial ownership to Alfasigma in 2023 through the acquisition of Intercept Pharmaceuticals.[3] That transaction transferred the Ocaliva business and associated intellectual-property rights, subject to transaction documents and existing encumbrances.

The ownership change does not alter the patent claims, but it changes:

The party controlling enforcement;
The NDA holder and commercial sponsor;
Potential settlement authority;
Licensing and manufacturing negotiations; and
Revenue exposure associated with Ocaliva.

A transaction involving the product business is not equivalent to a license of US 10,052,337. Separate patent assignments, security interests, co-exclusive licenses and settlement agreements must be reviewed in the USPTO assignment records and applicable court docket.

What generic launch scenarios exist?

Scenario 1: Launch after patent expiration

The lowest-litigation-risk path is approval with a Paragraph III certification and launch after the final listed patent expires. This path may preserve validity challenges but delays commercial entry.

Scenario 2: Paragraph IV launch

An ANDA filer may certify that US 10,052,337 is invalid, unenforceable or not infringed. The NDA holder may sue, creating an automatic 30-month stay of approval in the circumstances provided by the Hatch-Waxman statute.[4]

Scenario 3: Design-around formulation

A generic developer may avoid the most commercially important claims by:

Using a particle-size distribution outside the claimed thresholds;
Avoiding jet milling;
Using direct compression;
Eliminating distinct intra-granular and extra-granular portions;
Replacing microcrystalline cellulose;
Changing the active-to-excipient ratio; or
Selecting a different dosage form.

The design-around must still meet FDA bioequivalence and product-quality requirements.

Scenario 4: Settlement entry

A settlement may permit launch before patent expiration. The commercial date would depend on the settlement, other listed patents, regulatory exclusivity and any authorized-generic arrangement. A settlement involving one Ocaliva patent does not necessarily resolve US 10,052,337 unless the agreement expressly covers it.

Key Takeaways

US 10,052,337 is a formulation and manufacturing patent for obeticholic acid, not a basic compound patent.
Claim 1 covers compositions in which at least 50% of particles are 200 μm or smaller.
Claims 2 through 8 progressively narrow the particle-size distribution.
Claims 11 and 12 protect tablets with defined intra-granular and extra-granular portions.
Claims 13 through 15 target jet-milling methods and jet-milled tablet products.
Claim 19 adds a broad 20:1 to 1:5 microcrystalline-cellulose-to-obeticholic-acid ratio.
The patent is commercially relevant to Ocaliva-type tablets and could remain important into approximately 2033-2034, subject to the official patent-term record.
Generic developers have plausible design-around routes, but formulation changes must remain bioequivalent to the reference product.
Biosimilar competition is not the relevant pathway; ANDA-based generic competition is.
Orange Book listings, Paragraph IV certifications, method-of-use patents and settlement terms must be analyzed together to determine actual launch risk.

FAQs

Does every micronized obeticholic acid product infringe US 10,052,337?

No. The product must satisfy the applicable claim limitations, including the specified particle-size distribution and, for narrower claims, the required excipients, tablet structure or jet-milling limitation.

Can a generic avoid the patent by using a salt of obeticholic acid?

Not necessarily. The claims expressly cover pharmaceutically acceptable salts, esters and amino acid conjugates. A salt may avoid infringement only if it falls outside another required limitation or if the claim construction excludes that particular form.

Is claim 11 limited to wet-granulated tablets?

No express wet-granulation limitation appears in the quoted claim. The relevant issue is whether the tablet has the required intra-granular and extra-granular portions, regardless of the particular manufacturing process.

Does a particle-size specification in an ANDA establish infringement?

It can provide evidence, but infringement depends on the complete claim limitation set and the applicable measurement method. The specification, batch data, manufacturing records and testing protocol may all be relevant.

Can a 505(b)(2) product avoid the patent estate?

A 505(b)(2) product may face different regulatory requirements, but it does not automatically avoid patent infringement. The patent analysis remains product- and claim-specific, including particle size, formulation structure, manufacturing process and labeling.

References

United States Patent and Trademark Office. (2018). U.S. Patent No. 10,052,337, compositions comprising obeticholic acid.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
Alfasigma S.p.A. (2023). Alfasigma completes acquisition of Intercept Pharmaceuticals.
Drug Price Competition and Patent Term Restoration Act of 1984, 21 U.S.C. §§ 355(j), 355(q).
U.S. Food and Drug Administration. (2016). FDA approves Ocaliva for rare, chronic liver disease.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Intercept	OCALIVA	obeticholic acid	TABLET;ORAL	207999-001	May 27, 2016		DISCN	Yes	No	10,052,337	⤷ Start Trial	Y				⤷ Start Trial
Intercept	OCALIVA	obeticholic acid	TABLET;ORAL	207999-002	May 27, 2016		DISCN	Yes	No	10,052,337	⤷ Start Trial	Y				⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	104427	⤷ Start Trial
Australia	2016255045	⤷ Start Trial
Australia	2020205315	⤷ Start Trial
Brazil	112017023161	⤷ Start Trial
Canada	2983609	⤷ Start Trial
Chile	2017002727	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,052,337

Which drugs does patent 10,052,337 protect, and when does it expire?

Summary for Patent: 10,052,337