United States Patent 10,335,397: Claim Scope, Xifaxan Exclusivity, and Hepatic Encephalopathy Patent Landscape

United States Patent No. 10,335,397 protects a rifaximin regimen for reducing the risk of recurrent overt hepatic encephalopathy in a defined patient population. Its core limitations are: oral rifaximin at approximately 1,000 to 1,200 mg per day, treatment for at least about 12 months, baseline Conn score of 0 or 1, and, in the narrowest claim, MELD score of 1 to 24 plus at least two prior overt HE episodes within six months.

The patent is a method-of-use patent. It does not claim rifaximin as a chemical compound, tablet composition, manufacturing process, or formulation. Its commercial importance comes from overlap with the FDA-approved Xifaxan 550 mg twice-daily regimen for reducing overt HE recurrence.

What does U.S. Patent 10,335,397 cover?

The patent covers administration of rifaximin to a clinically defined hepatic encephalopathy population. Claim 1 establishes the principal combination of limitations:

Limitation	Claim requirement
Disease	Overt hepatic encephalopathy risk
Objective	Reduce risk of a breakthrough overt HE episode
Dose	About 1,000 to about 1,200 mg rifaximin daily
Duration	About 12 months or longer
Baseline neurological status	Conn score of 0 or 1

The claims are cumulative. A potentially infringing use must satisfy all limitations of the asserted claim, subject to claim construction and the facts of the treatment record.

The patent does not cover every rifaximin use. It is directed to recurrence prevention in patients who are relatively stable at treatment initiation, rather than treatment of an active acute HE episode.

How do the individual claims narrow patent protection?

Claim 1: Core regimen and patient population

Claim 1 requires:

A subject at risk of a breakthrough overt HE episode.
Rifaximin administration.
A daily dose of approximately 1,000 to 1,200 mg.
Treatment for approximately 12 months or longer.
A baseline Conn score of 0 or 1.

The use of "about" creates potential scope for reasonable variation around the stated dose and duration. The precise boundaries would depend on claim construction, prosecution history, clinical practice, and the evidence concerning how the treating physician implemented the regimen.

A 550 mg tablet administered twice daily produces a total daily dose of 1,100 mg and falls within the stated range.

Claims 2 and 3: Definition of breakthrough HE

Claim 2 defines a breakthrough overt HE episode as an increase in Conn score to Grade 2 or higher.

Claim 3 addresses a patient with a baseline Conn score of 0. For that patient, a breakthrough episode is defined by a one-grade increase in both Conn and Asterixis scores.

These claims convert clinical outcome definitions into claim limitations. They may create factual disputes concerning baseline scoring, the consistency of neurological assessments, and whether an observed deterioration qualifies under the patent’s definitions.

Claim 4: Prior recurrence history

Claim 4 requires at least two overt HE episodes within the six months before rifaximin administration.

This is an important narrowing limitation. A patient who has had only one prior overt HE episode, or whose two episodes occurred outside the six-month period, would not fall within claim 4 unless another asserted claim independently captures that treatment.

Claims 5 through 8: MELD score limitations

Claims 5 through 8 add MELD-score requirements:

Claim	MELD limitation
5	MELD score from 1 to 24
6	MELD score of 10 or less
7	MELD score from 11 to 18
8	MELD score from 19 to 24

Claims 6, 7, and 8 are alternative subranges within the broader range in claim 5. They are useful fallback positions because they preserve protection for specific disease-severity bands if a broader range is challenged.

Claims 9 through 11: Oral dosing

Claim 9 requires oral administration.

Claim 10 narrows the daily dose to 1,100 mg. Claim 11 further specifies 550 mg twice daily. The supplied text states "method of claims 10"; that language appears to be a drafting error, and the intended dependency is likely claim 11 depending from claim 10.

The 550 mg twice-daily limitation is commercially significant because it corresponds to the marketed Xifaxan HE regimen and the FDA-approved product strength.

Claim 12: Combination with lactulose

Claim 12 adds concurrent administration of lactulose.

This claim protects a combination-treatment scenario. It may be relevant where the patient receives the standard rifaximin regimen while continuing lactulose, which is commonly used in the management of recurrent HE.

Claim 13: Narrowest commercially relevant combination

Claim 13 requires all of the following:

Oral administration.
Rifaximin 550 mg twice daily.
Treatment for about 12 months or longer.
Baseline Conn score of 0 or 1.
MELD score of 1 to 24.
At least two overt HE episodes during the preceding six months.

Claim 13 is narrower than claim 1 but closely tracks the patient profile and dosing regimen associated with recurrent overt HE prevention. It is likely to be the most directly relevant claim for an ANDA applicant seeking approval of the same 550 mg twice-daily regimen.

What FDA-approved product does the patent overlap?

The patent overlaps with Xifaxan, the rifaximin product marketed by Salix Pharmaceuticals, a division of Bausch Health Companies Inc. The FDA-approved HE indication is reduction in risk of overt HE recurrence in adults.[1]

The marketed regimen is 550 mg orally twice daily, or 1,100 mg daily. That regimen falls within claim 1 and is expressly recited in claims 10 and 11. The approved indication therefore creates substantial practical overlap with the patent, although regulatory-label overlap does not by itself establish infringement.

The patent’s additional patient-selection limitations are narrower than the broad FDA indication. The approved label does not necessarily require every patient to have:

A Conn score of 0 or 1 at treatment initiation.
A MELD score of 1 to 24.
Two or more overt HE episodes within the prior six months.
Treatment for at least 12 months.

Those limitations can materially affect infringement analysis.

What is the Orange Book status of U.S. Patent 10,335,397?

U.S. Patent 10,335,397 has been associated with Xifaxan’s Orange Book patent estate for the hepatic encephalopathy indication. Orange Book listing is important because it can trigger statutory notification and litigation procedures when an ANDA applicant seeks approval for a product that could be used under a listed method.[2]

The relevant regulatory distinction is:

Issue	Effect
Orange Book listing	Identifies a patent that the NDA holder asserts is relevant to the approved drug
Paragraph IV certification	Applicant alleges the listed patent is invalid, unenforceable, or not infringed
30-month stay	May delay approval if the NDA holder timely files an infringement action
Section viii statement	Applicant may seek approval while carving out a patented method from its labeling, where legally and commercially feasible

A method-of-use patent is more vulnerable to a section viii strategy than a composition patent if the applicant can remove the patented indication from its proposed labeling. That strategy becomes more difficult where the product’s principal commercial use is the patented indication or where the remaining label still encourages the patented method.

When does U.S. Patent 10,335,397 expire?

Public patent records identify a March 2033 expiration date for U.S. Patent 10,335,397, subject to any applicable patent-term adjustment or other statutory adjustment shown in the official USPTO record.[3]

The patent’s expected term is materially longer than the principal early rifaximin composition patent. That distinction is central to Xifaxan generic-entry analysis. Even after earlier composition or formulation protection expires, a later-issued method patent can continue to create litigation and labeling risk for the recurrent-HE indication.

The effective commercial date may differ from the nominal expiration date because of:

Patent-term adjustment.
Patent-term extension.
Pediatric exclusivity.
Litigation-related injunctions.
Settlement agreements.
The scope of the ANDA applicant’s proposed labeling.

How does Patent 10,335,397 compare with earlier Xifaxan patents?

Xifaxan’s patent estate has included composition, formulation, method-of-use, and later clinical-use patents. The major categories are summarized below.

Patent category	Typical protection	Commercial relevance
Composition patent	Rifaximin compound or rifamycin derivative	Broadest product-level barrier, generally expiring earlier
Formulation patent	Tablet composition, dissolution, excipients, dosage form	Can block or complicate generic formulation substitution
HE method patent	Rifaximin use to reduce recurrence of overt HE	Directly relevant to the 550 mg twice-daily indication
Patient-selection patent	Treatment of defined Conn, MELD, or recurrence subgroups	Narrower but potentially later-expiring protection
Manufacturing patent	Process or intermediate production	May create supply-chain barriers without necessarily blocking sale of a non-infringing product

Earlier Xifaxan patents have included U.S. Patent Nos. 7,045,620, 8,309,569, and 8,642,573, which have been associated with rifaximin composition or hepatic encephalopathy use protection in public patent and litigation records.[4][5]

Patent 10,335,397 differs because its claims are highly dependent on clinical characteristics and duration. A generic company may be able to challenge it by arguing that:

The claimed patient subgroup was obvious from the prior art.
The clinical endpoint lacks sufficient written-description support.
The terms "about 12 months" or "breakthrough overt HE episode" are indefinite.
The claimed results are inherent in the known rifaximin regimen.
The claims are not infringed by the proposed label or actual prescribing practices.

Which companies have challenged the Xifaxan patent estate?

Norwich Pharmaceuticals challenged Xifaxan patents in ANDA litigation against Salix Pharmaceuticals. The litigation concerned multiple Xifaxan patents and the legal barriers to approval of a generic rifaximin product.[5][6]

The dispute illustrates the principal generic-entry issue: a company may challenge the patents covering the product and the HE indication at the same time, rather than waiting for each patent to expire. The court’s treatment of validity, infringement, and approved-label scope can determine whether a generic launches:

Before all listed patents expire.
Only after a settlement date.
With a carved-out label.
At risk after a non-infringement or invalidity decision.

Patent 10,335,397 should be analyzed separately from earlier patents even where the same ANDA litigation includes multiple patent numbers. A favorable decision against one patent does not automatically eliminate liability under another patent with different claim limitations.

What Paragraph IV risks apply to Patent 10,335,397?

A Paragraph IV challenger would likely attack the patent on four principal grounds.

Obviousness

The applicant may argue that the 550 mg twice-daily regimen, long-term treatment, and recurrent-HE population were already known from the rifaximin clinical-development program and FDA labeling. The challenge would focus on whether the specific Conn and MELD subgroup selection produced an unexpected clinical result or merely described patients already treated in the prior art.

The patent holder would likely rely on:

Clinical efficacy data.
Reduced HE recurrence rates.
The defined baseline Conn-score population.
The claimed relationship between disease severity and treatment benefit.
The duration of therapy.

Written description and enablement

The challenger may contend that the specification does not support the full range of patients and MELD subgroups recited in claims 1 and 5 through 8. The patent holder would respond that the clinical data and statistical analysis support the claimed patient population and dosing regimen.

Indefiniteness

Potential terms for dispute include:

"About 1,000 mg to about 1,200 mg."
"About 12 months or longer."
"Breakthrough overt HE episode."
Conn and Asterixis score changes.

Clinical terms can be sufficiently definite when used in the art, but the parties may dispute scoring methodology and the boundaries of the claimed ranges.

Infringement

A generic applicant may contend that its proposed label does not require treatment of patients with the claimed baseline scores, MELD values, or prior-episode history. The patent holder may argue that the labeling, promotional materials, dosing instructions, or routine clinical use would encourage administration to the claimed population.

The most exposed claims are likely claims 10, 11, and 13 because they track the commercial 550 mg twice-daily regimen. The added patient-selection limitations may make claim 13 harder to prove infringed on an individual-patient basis, but they may also reduce the prior-art exposure.

What generic launch scenarios exist?

Scenario 1: Launch after patent expiry

This is the lowest litigation-risk path if the relevant patents have expired and no enforceable settlement restriction remains.

Scenario 2: Label carve-out

An ANDA applicant may remove the patented HE method from its label if the remaining indications and labeling do not encourage the claimed use. This approach is difficult where the HE indication is the principal commercial use of the product.

Scenario 3: At-risk launch

A generic may launch after prevailing on invalidity or non-infringement arguments, or before final resolution. This creates potential damages and injunction exposure if the patent is later upheld.

Scenario 4: Settlement-based entry

A settlement may establish a future launch date, authorized-generic arrangement, license, or other commercial terms. Publicly available settlement terms should be reviewed against FTC reporting and court filings before assigning a firm entry date.

How strong is the patent estate for Xifaxan?

Patent 10,335,397 is strategically meaningful but narrower than a composition patent.

Strength factor	Assessment
Direct overlap with marketed regimen	Strong
Chemical product coverage	None
Formulation coverage	None based on supplied claims
Patient-selection specificity	High
Dependence on clinical records	High
Potential label-carve-out exposure	Material
Expiration relative to early rifaximin patents	Later
Risk of obviousness challenge	Material
Risk of direct infringement proof	Fact-dependent

Its principal strength is commercial alignment with 550 mg twice-daily Xifaxan treatment. Its principal weakness is that infringement depends on multiple clinical facts that may not appear in a generic label or may vary from patient to patient.

What revenue is exposed to this patent?

Xifaxan is one of Bausch Health’s major prescription products, with annual sales around the low-single-digit billions of dollars in recent reporting periods.[7] The HE indication is a major component of demand, although Xifaxan is also approved for travelers’ diarrhea caused by noninvasive strains of E. coli.

Patent 10,335,397 therefore has greater commercial relevance than its narrow claim language might suggest. A generic company may be able to enter with a restricted label or pursue other indications, but a fully substitutable product for recurrent HE could face litigation and regulatory barriers through the expected patent term.

What manufacturing and formulation barriers remain?

The supplied claims do not cover:

Rifaximin polymorphs.
Tablet excipients.
Dissolution profiles.
Coating systems.
Granulation processes.
Crystalline forms.
Manufacturing intermediates.
Purification methods.

A generic applicant may still face separate patents directed to those subjects. Manufacturing patents can also affect cost and supply reliability without directly preventing sale of a product made through a different process.

The absence of formulation language in Patent 10,335,397 means that a validity or non-infringement decision concerning this patent would not necessarily resolve the broader Xifaxan patent estate.

Key Takeaways

U.S. Patent 10,335,397 is a clinical method-of-use patent for reducing recurrent overt HE risk with long-term rifaximin therapy.
The commercial core is 550 mg orally twice daily, equivalent to 1,100 mg daily.
The most important added limitations are baseline Conn score of 0 or 1, MELD score of 1 to 24, and at least two prior overt HE episodes within six months.
Claim 13 is the narrowest and most commercially targeted claim.
The patent does not claim rifaximin itself, a tablet formulation, or a manufacturing process.
Public patent records identify an expected expiration in March 2033, subject to the official USPTO term calculation.
Paragraph IV disputes are likely to focus on obviousness, clinical subgroup support, indefiniteness, and whether a generic label encourages the claimed use.
The patent creates meaningful risk for a fully substitutable HE generic, but its patient-specific limitations may support label-carve-out or non-infringement arguments.
Patent 10,335,397 must be evaluated alongside earlier Xifaxan composition, formulation, and HE method patents.

FAQs

Does Patent 10,335,397 cover all use of rifaximin for hepatic encephalopathy?

No. The claims require specific dose, duration, baseline Conn score, and, for narrower claims, MELD score and prior HE recurrence criteria.

Can a generic sell rifaximin after the early Xifaxan patents expire?

Potentially, but expiration of an earlier composition patent does not eliminate later method-of-use, formulation, or manufacturing patents.

Is 550 mg twice daily within the scope of Patent 10,335,397?

Yes. It equals 1,100 mg per day and is expressly recited in the dependent claims.

Does concurrent lactulose use increase infringement risk?

It can. Claim 12 specifically adds lactulose administration, but infringement still requires satisfaction of the underlying claim 1 limitations.

Does an Orange Book listing prove that the patent is valid?

No. Listing identifies the patent as relevant to the approved drug. Validity, enforceability, and infringement remain subject to litigation or other legal determination.

References

U.S. Food and Drug Administration. (2024). Xifaxan (rifaximin) prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
United States Patent and Trademark Office. (2019). U.S. Patent No. 10,335,397, methods of treating hepatic encephalopathy.
United States Patent and Trademark Office. (2006). U.S. Patent No. 7,045,620.
United States Patent and Trademark Office. (2012). U.S. Patent No. 8,309,569.
United States Court of Appeals for the Federal Circuit. (2024). Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc.
Bausch Health Companies Inc. (2024). Annual report on Form 10-K.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Salix Pharms	XIFAXAN	rifaximin	TABLET;ORAL	021361-002	Mar 24, 2010	AB	RX	Yes	Yes	10,335,397	⤷ Start Trial				REDUCTION IN A SUBJECT'S RISK OF EXPERIENCING A BREAKTHROUGH OVERT HEPATIC ENCEPHALOPATHY (HE) EPISODE	⤷ 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
Australia	2009298389	⤷ Start Trial
Australia	2010260089	⤷ Start Trial
Australia	2010271070	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 10,335,397