Details for Patent: 8,518,949

Which drugs does patent 8,518,949 protect, and when does it expire?

Patent 8,518,949 protects XIFAXAN and is included in one NDA.

This patent has thirty-four patent family members in twenty-six countries.

Summary for Patent: 8,518,949

Title:	Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
Abstract:	Crystalline polymorphous forms of the rifaximin (INN) antibiotic named rifaximin δ and rifaximin ε useful in the production of medicinal preparations containing rifaximin for oral and topical use and obtained by means of a crystallization process carried out by hot-dissolving the raw rifaximin in ethyl alcohol and by causing the crystallization of the product by addition of water at a determinate temperature and for a determinate period of time, followed by a drying carried out under controlled conditions until reaching a settled water content in the end product, are the object of the invention.
Inventor(s):	Giuseppe Claudio Viscomi, Manuela Campana, Donatella Confortini, Maria Miriam Barbanti, Dario Braga
Assignee:	Alfasigma SpA
Application Number:	US13/488,345
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,518,949
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Compound; Dosage form;

US Patent 8,518,949 protects rifaximin polymorphic forms delta and epsilon, together with defined manufacturing conditions and pharmaceutical compositions containing those forms. Its principal commercial limitation is that it does not claim rifaximin generally, the marketed alpha polymorph, rifaximin indications, dosage strengths, or non-solid formulations. The patent’s projected statutory term runs to approximately June 2028, subject to any applicable patent-term adjustment or extension.

US Patent 8,518,949: Rifaximin Delta and Epsilon Patent Scope, Expiration, Litigation, and Generic Risk

What does US Patent 8,518,949 cover?

US Patent 8,518,949 covers two crystalline rifaximin forms, designated polymorph delta and polymorph epsilon. The patent also covers solid oral and topical compositions containing either polymorph.

Patent element	Covered subject matter
Patent	US 8,518,949 B2
Title	Rifaximin polymorphic forms
Patent holder/applicant	Alfa Wassermann S.p.A., with later commercial rights associated with Salix Pharmaceuticals and related entities
Active ingredient	Rifaximin
Protected forms	Polymorph delta and polymorph epsilon
Claim categories	Product-by-process, crystalline-form identification, and pharmaceutical composition claims
Key analytical test	XRPD peak pattern
Delta peaks	About 5.7°, 12.1°, and 17.0° 2-theta
Epsilon peaks	About 8.2°, 12.4°, and 16.3° 2-theta
Principal dosage forms	Solid oral and solid topical formulations
Projected patent term	Approximately June 2028, subject to USPTO term calculations
Regulatory category	Small-molecule drug patent, not a biologic or biosimilar patent

The patent is narrower than a patent claiming rifaximin as a chemical compound. Its commercial significance depends on whether an accused product contains delta or epsilon rifaximin and whether the claimed manufacturing route or a materially equivalent route was used.

What are the independent claims of US 8,518,949?

The patent has four principal independent claim groups.

Claim 1: Rifaximin polymorph delta

Claim 1 covers rifaximin in polymorphic form delta, provided that the delta material is obtained through a specified sequence involving:

1. Reaction of rifamycin O with excess 2-amino-4-methylpyridine.
2. Use of a water/ethyl alcohol solvent mixture in a volumetric ratio of 1:1 to 2:1.
3. Reaction for two to eight hours at 40°C to 60°C.
4. Treatment with ascorbic acid, water, ethanol, and concentrated hydrochloric acid.
5. Adjustment to pH 2.0.
6. Isolation and washing of raw rifaximin.
7. Dissolution in ethanol at 45°C to 65°C.
8. Addition of water and controlled cooling.
9. Filtration, washing, and drying.
10. Production of material with 2.5% to 6% water content.
11. Confirmation by XRPD peaks at approximately 5.7°, 12.1°, and 17.0° 2-theta.

The claim also requires the delta form to be free from other rifaximin polymorphs.

Claim 7: Rifaximin polymorph epsilon

Claim 7 tracks the same general synthesis and isolation sequence but claims polymorph epsilon. It requires XRPD peaks at approximately 8.2°, 12.4°, and 16.3° 2-theta.

Unlike claim 1, the epsilon independent claim does not expressly require a final water-content range. Claims 8 through 11 narrow the process and crystallization parameters.

Claim 12: Oral compositions containing delta

Claim 12 covers a solid pharmaceutical composition containing a therapeutically effective amount of delta rifaximin and a pharmaceutically acceptable excipient in an oral formulation.

Claim 14 identifies covered oral formats, including:

• Coated or uncoated tablets
• Hard or soft gelatin capsules
• Sugar-coated pills
• Lozenges
• Wafer sheets
• Pellets
• Powder in sealed packets

Claim 15: Topical compositions containing delta

Claim 15 covers a solid pharmaceutical composition containing delta rifaximin for topical administration. Claim 16 identifies ointments, pomades, creams, gels, and lotions.

The wording is potentially vulnerable to claim-construction scrutiny because several listed topical formulations are not ordinarily classified as “solid” dosage forms. The claim’s express solid-composition limitation remains important for infringement analysis.

Claims 17 and 20: Epsilon compositions

Claims 17 and 20 provide corresponding oral and topical composition claims for epsilon rifaximin. Claims 18, 19, and 21 add excipient and dosage-form limitations.

How do claims 2 through 11 narrow the patent?

The dependent claims impose tighter process parameters.

Claim	Narrowing limitation
2	2.0 to 15 molar equivalents of 2-amino-4-methylpyridine for delta
3	Water equal to 15% to 70% by weight of ethanol used for dissolution
4	Cooling to 28°C to 32°C during water addition
5	Stirring at 40°C to 50°C for six to 24 hours, then cooling to 0°C
6	Delta water content of 3.0% to 4.5%
8	2.0 to 3.5 molar equivalents of 2-amino-4-methylpyridine for epsilon
9	Same 15% to 70% water-to-ethanol ratio
10	Cooling to 28°C to 32°C
11	Heated stirring followed by cooling and drying to produce epsilon

The delta claims provide a broader excess-amine range than the epsilon claims. Epsilon claim 8 is limited to 2.0 to 3.5 equivalents, whereas delta claim 2 extends to 15 equivalents.

What is the technical scope of the delta and epsilon claims?

The patent protects both a physical form and a process capable of producing that form.

XRPD limitations

The XRPD peaks are central to the claim scope:

Polymorph	Required peaks
Delta	5.7° ± 0.2°, 12.1° ± 0.2°, 17.0° ± 0.2°
Epsilon	8.2° ± 0.2°, 12.4° ± 0.2°, 16.3° ± 0.2°

The claims do not state that the listed peaks are the complete XRPD pattern. They identify characteristic peaks within specified tolerances. In a dispute, infringement would likely require validated XRPD testing, assessment of polymorphic purity, and analysis of measurement conditions.

“Free from other polymorphic forms”

The requirement that delta or epsilon be free from other rifaximin polymorphs strengthens purity-based differentiation but creates an evidentiary issue. A product containing detectable alpha, beta, gamma, delta, or epsilon material may fall outside the literal claim if “free from” is construed to require complete absence. Courts commonly examine the specification, analytical detection limits, and how a skilled person would understand the purity requirement.

A manufacturer may reduce risk by producing a different polymorph, using a controlled polymorph mixture, or demonstrating that the product does not meet the claimed XRPD profile. Those approaches carry regulatory and quality risks if the reference product or approved specification requires a particular solid form.

Product-by-process limitations

Claims 1 and 7 define rifaximin products partly by the process used to make them. The process steps are not merely manufacturing instructions that can be ignored. Under Federal Circuit product-by-process precedent, process limitations generally matter to infringement and validity analysis, although the exact treatment depends on claim construction and the evidentiary record.[1]

A competing manufacturer could face two separate issues:

• Whether its product has the claimed delta or epsilon structure.
• Whether it used the claimed process steps, or an equivalent process, to make that product.

The process-specific language gives a potential design-around route, but it also makes non-infringement more difficult to establish without manufacturing records, batch documents, process-development data, and analytical characterization.

What patents protect rifaximin besides US 8,518,949?

The principal US rifaximin estate has included compound, polymorph, formulation, and method-of-use patents.

Patent family or patent	General subject matter	Commercial relevance
US 7,045,620	Rifaximin compound and therapeutic uses	Foundational rifaximin protection; statutory term generally associated with 2024
US 7,612,199	Rifaximin formulations and related compositions	Asserted in generic litigation involving Xifaxan
US 8,309,627	Rifaximin compositions and dosing-related protection	Important Orange Book-era formulation protection
US 8,518,949	Delta and epsilon polymorphs and compositions	Solid-form and manufacturing barrier
US 9,271,968	Later rifaximin formulation or use protection	Relevant to Xifaxan patent litigation
US 9,278,096	Later rifaximin-related protection	Part of the broader Salix estate
US 9,364,520	Additional rifaximin protection	Potential method or formulation barrier
Later patents	Formulation, dosing, and use claims	May affect particular ANDA products and indications

The estate is layered. A generic company may avoid US 8,518,949 but still face other patents covering formulation, dosage, indication, or labeling. Conversely, a challenge to the foundational compound patent does not automatically invalidate a later polymorph patent.

What is the Orange Book status of US 8,518,949?

US 8,518,949 has been associated with the Xifaxan rifaximin patent estate and has been cited in the context of FDA-listed patents for rifaximin products. The relevant Orange Book question is product-specific: FDA listing depends on the approved product, strength, dosage form, and patent certification record.[2]

Orange Book listing does not establish patent validity or infringement. It can, however, create a regulatory barrier for an ANDA applicant. A Paragraph IV certification alleging that the patent is invalid, unenforceable, or not infringed can trigger patent litigation and a potential 30-month FDA approval stay under the Hatch-Waxman framework.[3]

For US 8,518,949, the critical regulatory issue is whether the proposed generic contains delta or epsilon rifaximin, or uses a manufacturing process that produces one of those forms. An ANDA product based on the marketed alpha polymorph may have a stronger non-infringement position, subject to the other listed patents.

When does US 8,518,949 lose exclusivity?

The patent’s ordinary 20-year term is calculated from the relevant nonprovisional or international application filing date, not from the issue date. Based on the patent family’s priority and filing history, the projected expiration is approximately June 2028.[4]

Exclusivity type	Approximate timing
Patent issuance	August 27, 2013
Foundational rifaximin patent term	Generally associated with 2024 expiration
US 8,518,949 projected expiration	Approximately June 2028
Regulatory exclusivity	Separate from patent term and product-specific
Pediatric extension	Not established from the claim record provided
Patent-term extension	No extension should be assumed without a specific USPTO or FDA determination

The patent does not create a new chemical entity exclusivity period. Its protection is patent-based and tied to polymorph, process, and formulation claims.

What Paragraph IV challenges affect rifaximin?

Rifaximin has been the subject of ANDA litigation involving generic applicants seeking approval for Xifaxan-related products. Norwich Pharmaceuticals and other generic applicants have challenged patents in the broader Salix rifaximin portfolio. The major litigation has involved patents covering rifaximin products, formulations, and uses, including patents in addition to US 8,518,949.[5]

The practical Paragraph IV risk is claim-specific:

1. A generic applicant may challenge the validity of the delta and epsilon claims.
2. It may argue that its API is alpha rifaximin or another nonclaimed form.
3. It may contend that its manufacturing process does not satisfy the product-by-process limitations.
4. It may use a section viii statement to carve out patented indications where permitted.
5. It may challenge the listed patents separately rather than relying on one estate-wide theory.

The strongest challenge to US 8,518,949 would likely combine polymorph non-infringement with obviousness, anticipation, enablement, written-description, and indefiniteness arguments. Prior-art crystallization disclosures and the predictability of rifaximin solid-form screening would be central to an obviousness case.

What litigation status affects US 8,518,949?

Public rifaximin litigation has focused on the broader Xifaxan patent estate, particularly patents asserted against ANDA applicants seeking approval for irritable bowel syndrome with diarrhea and related indications. The Federal Circuit and district courts have addressed validity and infringement issues involving several Salix rifaximin patents.[5]

The existence of litigation involving other rifaximin patents does not establish that US 8,518,949 has been invalidated. Each patent requires separate analysis. A decision invalidating a method-of-use or formulation patent would not, without more, remove the delta and epsilon claims.

A freedom-to-operate review should therefore separate:

• The API solid form actually used by the ANDA applicant.
• The crystallization and drying process.
• The final tablet or capsule composition.
• The proposed label and indication.
• The patents listed against the specific reference product.
• Any settlement or license restricting launch timing.

How strong is the patent estate for delta and epsilon rifaximin?

The patent has meaningful technical specificity but limited breadth.

Strengths

• It identifies two distinct crystalline forms using defined XRPD peaks.
• It includes process parameters that may be difficult to avoid if the same crystallization route is used.
• It claims pharmaceutical compositions, not only bulk API.
• It provides multiple dependent claims with narrower commercial-process parameters.
• The “free from other polymorphic forms” language can distinguish high-purity material from mixed or poorly characterized products.

Weaknesses

• It does not cover rifaximin generally.
• It does not appear to cover the alpha polymorph that has historically been associated with marketed Xifaxan.
• The product-by-process structure may complicate infringement proof.
• The claims depend on analytical definitions that can produce disputes over XRPD method, peak intensity, detection limits, and polymorphic mixtures.
• Composition claims may be vulnerable if the accused product uses a different polymorph or a non-solid dosage form.
• The patent expires before many later-arriving formulation and use patents.

Overall, the patent is a targeted secondary patent rather than the principal exclusivity platform for all rifaximin products.

What generic launch scenarios exist?

Scenario	Likely patent position
Generic uses alpha rifaximin and avoids delta/epsilon	Lower risk under US 8,518,949, but other rifaximin patents remain relevant
Generic uses delta rifaximin made by the claimed route	High infringement risk
Generic uses epsilon rifaximin made by the claimed route	High infringement risk
Generic uses delta or epsilon made by a materially different route	Depends on product-by-process construction and equivalence
Generic uses a mixed polymorphic composition	Potential defense to “free from other polymorphic forms,” subject to claim interpretation
Generic launches after June 2028	US 8,518,949 no longer blocks launch, absent enforceable term adjustment or other rights
Generic changes only the label	May avoid method-of-use claims but not API or formulation claims

Are biosimilar risks relevant to rifaximin?

No. Rifaximin is a small-molecule antibiotic derived from the rifamycin class. Generic competition proceeds through the ANDA pathway, not the biosimilar pathway under the Public Health Service Act.[3]

The relevant barriers are patent certification, pharmaceutical equivalence, bioequivalence, chemistry-manufacturing-controls requirements, polymorph characterization, and FDA review of the proposed labeling.

What manufacturing and geographic barriers apply?

US 8,518,949 is a US patent. It can block manufacture, use, sale, offer for sale, or importation of covered products in the United States during the enforceable term. Manufacturing outside the United States can still create US exposure if the resulting product is imported or sold in the US.

The most important manufacturing records include:

• Rifamycin O charge and stoichiometry
• 2-amino-4-methylpyridine equivalents
• Water-to-ethanol solvent ratio
• Reaction temperature and time
• Hydrochloric-acid pH adjustment
• Ascorbic-acid treatment
• Ethanol dissolution temperature
• Water addition and cooling profile
• Drying temperature, duration, and final water content
• XRPD and polymorph-purity data

European, Indian, Chinese, and other national family members must be assessed separately. A US non-infringement position does not establish freedom to operate in those jurisdictions.

Key Takeaways

• US 8,518,949 claims rifaximin polymorphs delta and epsilon, not rifaximin generally.
• Claims 1 and 7 combine XRPD-defined product limitations with detailed manufacturing steps.
• Claims 12 through 21 extend protection to solid oral and topical compositions.
• The delta and epsilon XRPD peak sets are the principal structural identifiers.
• The patent does not appear to be the main protection for the marketed alpha rifaximin form.
• Product-by-process language creates both infringement risk and potential design-around arguments.
• A generic using alpha rifaximin may have a stronger position against this patent, but must address the rest of the Orange Book estate.
• The projected patent expiration is approximately June 2028, subject to official USPTO term calculations.
• Rifaximin competition is governed by the ANDA and Paragraph IV framework, not biosimilar law.
• Patent litigation involving other Xifaxan patents does not automatically resolve the validity or enforceability of US 8,518,949.

FAQs

Does US 8,518,949 cover rifaximin alpha?

No. The asserted claims identify delta and epsilon rifaximin by specific XRPD peak patterns. Alpha rifaximin is not expressly claimed.

Can a generic avoid US 8,518,949 by using a different drying temperature?

Possibly, but changing one process parameter may not be sufficient. The product must also avoid the claimed polymorph and the remaining process limitations. A product-by-process infringement analysis would examine the complete manufacturing route.

Does a tablet containing rifaximin automatically infringe the composition claims?

No. The composition claims require delta or epsilon rifaximin, the specified XRPD characteristics, a therapeutically effective amount, and the other claim limitations. A tablet containing alpha rifaximin would not automatically satisfy those limitations.

Is US 8,518,949 a method-of-use patent?

No. The claims provided are directed to polymorphic rifaximin products, manufacturing processes embedded in product claims, and pharmaceutical compositions. They do not claim treatment of a specific disease or patient population.

What is the main commercial risk after the patent expires?

After expiration, the specific delta and epsilon claims should no longer block US commercialization, assuming no enforceable patent-term adjustment, extension, injunction, or separate patent applies. Other rifaximin patents, regulatory requirements, and formulation barriers may still affect launch timing.

References

1. U.S. Court of Appeals for the Federal Circuit. (2007). SmithKline Beecham Corp. v. Apotex Corp., 439 F.3d 1312.

2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases

3. U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application pathway and generic drug approval. https://www.fda.gov/drugs

4. United States Patent and Trademark Office. (n.d.). Patent term calculator and patent term adjustment resources. https://www.uspto.gov/patents/laws/patent-term-calculator

5. U.S. Court of Appeals for the Federal Circuit. (2023). Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc., decisions concerning rifaximin patents and ANDA litigation.

Drugs Protected by US Patent 8,518,949

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	021361-001	May 25, 2004		RX	Yes	Yes			Y
Salix Pharms	XIFAXAN	rifaximin	TABLET;ORAL	021361-002	Mar 24, 2010	AB	RX	Yes	Yes			Y

Foreign Priority and PCT Information for Patent: 8,518,949

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	05004695	Mar 03, 2005

International Family Members for US Patent 8,518,949

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2006222312
Brazil	PI0608073
Canada	2594789
China	1900077
Denmark	1698630
European Patent Office	1698630