Details for Patent: 7,045,620

Summary for Patent: 7,045,620

Title:	Polymorphous forms of rifaximin, processes for their production and use thereof in medicinal preparations
Abstract:	Crystalline polymorphous forms of the rifaximin (INN) antibiotic named rifaximin α and rifaximin β, and a poorly crystalline form named rifaximin γ have been discovered. These forms are useful in the production of medicinal preparations for oral and topical use and can be 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 the addition of water at a determinate temperature and for a determinate period of time. The crystallization is followed by drying carried out under controlled conditions until a specific water content is reached in the end product.
Inventor(s):	Giuseppe C. Viscomi, Manuela Campana, Dario Braga, Donatella Confortini, Vincenzo Cannata, Denis Severini, Paolo Righi, Goffredo Rosini
Assignee:	Alfasigma SpA
Application Number:	US10/728,090
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,045,620
Patent Claim Types: see list of patent claims	Use; Compound;

US Patent 7,045,620: Rifaximin Polymorph Claims, Patent Scope, Expiration and Generic Entry Risk

US Patent 7,045,620 protects three crystalline or partially amorphous forms of rifaximin, identified as rifaximin alpha, beta and gamma, together with manufacturing and interconversion processes. The patent was assigned to Alfa Wassermann S.p.A. and issued on May 16, 2006. Its listed patent term expired on October 2, 2024, based on the October 2, 2002 priority date.[1]

The patent was commercially important because rifaximin's solid-state form affects water content, crystallinity, dissolution, stability and manufacturing reproducibility. The patent does not claim rifaximin as a chemical molecule generally. It claims defined physical forms of rifaximin and processes that produce or convert those forms.

Because the patent has expired, it no longer creates a standalone US patent barrier. Generic and follow-on manufacturers must still evaluate later rifaximin patents, FDA regulatory exclusivity, Orange Book listings and litigation settlements.

What does US Patent 7,045,620 cover?

The patent covers:

1. Purified rifaximin alpha with specified water content and XRPD peaks.
2. Purified rifaximin beta with higher water content and a different XRPD profile.
3. Purified rifaximin gamma with 1% to 2% water and a mainly amorphous XRPD profile.
4. A multistep rifaximin synthesis and purification process.
5. Solid-state conversion processes between alpha, beta and gamma forms.
6. Humidity-driven conversion of rifaximin alpha to beta.
7. Drying-driven conversion of rifaximin beta to alpha.

The claims divide into product claims, manufacturing-process claims and polymorph-conversion claims.

Claim group	Claims	Subject matter	Key limitation
Rifaximin alpha	1-2	Purified alpha polymorph	Water content of 3% or less; specified XRPD peaks
Rifaximin beta	3-4	Purified beta polymorph	Water content above 4.5%; specified XRPD peaks
Rifaximin gamma	5	Purified gamma form	Water content of 1%-2%; mainly amorphous XRPD
Core synthesis and purification	6-8	Production of alpha, beta or gamma	Rifamycin O, 2-amino-4-methylpyridine, aqueous ethanol, ascorbic acid, pH 2
Alpha production	9-10	Controlled crystallization and drying	2%-3% water in the dependent claim
Beta production	11-12	Controlled crystallization and hydration state	5%-6% water in the dependent claim
Gamma production	13	Low-temperature precipitation and drying	1%-2% water
Gamma-to-alpha conversion	14-15	Conversion in 7:3 ethanol/water	Heating at 38°C-50°C
Gamma-to-beta conversion	16-17	Conversion in 7:3 ethanol/water	Heating at 38°C-50°C
Alpha- or beta-to-gamma conversion	18	Recrystallization into gamma	Cooling and strong stirring
Alpha-to-beta conversion	19	Humidity conversion	Relative humidity above 50%
Beta-to-alpha conversion	20	Dehydration conversion	Drying up to 105°C

What are the strongest product claims in US Patent 7,045,620?

Claims 1, 3 and 5 are the principal product claims. They require a rifaximin material to satisfy both a water-content limitation and an XRPD limitation.

Rifaximin alpha claim scope

Claim 1 requires:

• A purified rifaximin alpha polymorph.
• Water content of 3% or less.
• XRPD peaks at 14 specified 2θ values, including 6.6°, 7.4°, 7.9°, 8.8°, 10.5°, 11.1°, 11.8°, 12.9°, 17.6°, 18.5°, 19.7°, 21.0°, 21.4° and 22.1°.

Claim 2 narrows the water content to 2.0%-3.0%.

A commercial batch could infringe claim 1 if it contains rifaximin alpha with the claimed diffraction pattern and water content, even if the manufacturer uses a different synthesis route. Product claims generally do not depend on how the product was made unless the claim expressly includes a process limitation.

Rifaximin beta claim scope

Claim 3 requires:

• Purified rifaximin beta.
• Water content higher than 4.5%.
• XRPD peaks at 12 specified angles, including 5.4°, 6.4°, 7.0°, 7.8°, 9.0°, 10.4°, 13.1°, 14.4°, 17.1°, 17.9°, 18.3° and 20.9°.

Claim 4 narrows the water content to 5.0%-6.0%.

The beta claims are sensitive to humidity control and residual or bound water. A manufacturer could avoid the narrower claim 4 while still facing claim 3 if the product has more than 4.5% water and the required beta XRPD profile.

Rifaximin gamma claim scope

Claim 5 covers a gamma form having:

• Water content between 1.0% and 2.0%.
• A mainly amorphous XRPD profile.
• Few significant peaks at 5.0°, 7.1° and 8.4°.

This claim is materially different from claims 1 and 3 because it protects a mainly amorphous material rather than a strongly crystalline profile. The words "mainly amorphous" create an analytical characterization issue. In an enforcement dispute, the parties would likely contest the significance threshold for the observed peaks and the test conditions used to classify a batch.

How do the process claims operate?

Claim 6 is the broadest process platform in the patent. It requires a specific reaction, acid treatment, purification and drying sequence.

The process begins by reacting rifamycin O with excess 2-amino-4-methylpyridine in water and ethanol. The solvent mixture must have a water-to-ethanol volumetric ratio between 1:1 and 2:1. The reaction must run for 2-8 hours at 40°C-60°C.

The process then requires:

• Treatment with ascorbic acid in water, ethanol and concentrated aqueous hydrochloric acid.
• Adjustment to pH 2.0.
• Filtration and washing.
• Dissolution of raw rifaximin in ethanol at 45°C-65°C.
• Water addition to precipitate rifaximin.
• Cooling to 0°C-50°C while stirring for 4-36 hours.
• Filtration, washing and drying.
• Drying at room temperature to 105°C for 2-72 hours.

Claim 7 narrows the 2-amino-4-methylpyridine amount to 2.0-3.5 molar equivalents. Claim 8 narrows the water addition to 15%-70% by weight relative to the ethanol used for dissolution.

The process claims are narrower than a general rifaximin manufacturing claim because they require multiple parameters in combination. A process that changes the starting material, solvent ratio, acid treatment, pH, precipitation conditions or drying sequence may avoid literal infringement. The doctrine of equivalents could still be relevant, but the numerous numerical limitations make substantial variation more defensible.

What polymorph conversion processes are protected?

Claims 14-20 address interconversion rather than initial rifaximin synthesis.

Alpha and beta production from gamma

Claims 14-17 require suspending gamma rifaximin in a 7:3 ethanol/water mixture and heating it at 38°C-50°C for 6-36 hours. The resulting material is filtered, washed and dried to the targeted water content.

The alpha route requires a final water content below 4.5%, with claim 15 narrowing that range to 2.0%-3.0%. The beta route requires a water content above 4.5%, with claim 17 narrowing it to 5.0%-6.0%.

Gamma production from alpha or beta

Claim 18 requires dissolving alpha or beta rifaximin in ethanol at 50°C-60°C, adding demineralized water to a 7:3 ethanol/water ratio, cooling to 30°C under strong stirring, then cooling to 0°C for 6-24 hours. The solid is filtered, washed and dried to a water content below 2.0%.

Humidity conversion from alpha to beta

Claim 19 covers keeping alpha rifaximin at relative humidity above 50% for 12-48 hours until conversion to beta occurs.

This claim is directed to a controlled environmental treatment. It would not necessarily cover ordinary storage unless the required humidity, time and conversion result were established.

Drying conversion from beta to alpha

Claim 20 covers drying beta rifaximin at atmospheric pressure, under vacuum or with a drying agent, at room temperature to 105°C for 2-72 hours until conversion to alpha occurs.

The claim does not require a particular drying apparatus. It covers multiple drying modes, but it requires the specified conversion result.

How strong are the product claims compared with the process claims?

The product claims were commercially stronger during their term because they could reach a product regardless of the manufacturing route. The process claims required proof that the accused process used the claimed sequence and operating ranges.

Issue	Product claims 1, 3, 5	Process claims 6-20
Infringement focus	Physical identity of the rifaximin batch	Steps and parameters used in manufacture
Typical evidence	XRPD, water-content testing, solid-state characterization	Batch records, process validation, equipment records, analytical data
Alternative manufacturing route	Usually does not avoid infringement	May avoid infringement if material steps differ
Claim breadth	Defined by form and analytical properties	Defined by cumulative process limitations
Main vulnerability	Variability in XRPD and water testing	Design-around through changed conditions
Commercial relevance	High for finished API and tablets	High for API suppliers and contract manufacturers

The product claims have a potential divided-infringement advantage because possession, sale or importation of a conforming rifaximin form can be sufficient. The process claims depend on conduct by the manufacturer or importer and can be harder to prove without discovery.

When did US Patent 7,045,620 expire?

The patent's listed expiration date was October 2, 2024.[1] The date corresponds to the earliest claimed priority date, October 2, 2002, under the post-1995 US patent-term regime.

Milestone	Date
Earliest priority date	October 2, 2002
US patent application filing	September 26, 2003
Patent issued	May 16, 2006
Listed patent expiration	October 2, 2024
Current status	Expired by term

The patent's expiration removes the direct patent bar created by claims 1-20. It does not invalidate later patents covering rifaximin dosage forms, therapeutic indications, formulations, manufacturing improvements or other solid-state characteristics.

What was the Orange Book status of US Patent 7,045,620?

US Patent 7,045,620 was listed in the FDA Orange Book for Xifaxan, rifaximin, under Salix Pharmaceuticals' NDA 021361.[2] Xifaxan was initially approved as a 200 mg tablet in 2004. The 550 mg tablet was later approved for reduction in risk of overt hepatic encephalopathy recurrence and for irritable bowel syndrome with diarrhea.[3]

The patent listing connected a commercial rifaximin product to the alpha polymorph technology. A generic applicant addressing the listing could have used a Paragraph IV certification before expiration, asserting that the patent was invalid, unenforceable or not infringed. After October 2, 2024, the patent no longer supports a new exclusion period based on its own claims.

Orange Book status must be reviewed by product and NDA supplement. A patent can be listed for one strength, formulation or approved use while having different practical relevance to another product presentation.

What FDA exclusivity protected Xifaxan?

Rifaximin did not receive new chemical entity exclusivity for the 2004 approval because rifaximin had previously been marketed outside the United States. The principal FDA protections were approval-related exclusivities and patent rights.

The 550 mg Xifaxan product received FDA approval for hepatic encephalopathy in 2010 and IBS-D in 2015.[3] The IBS-D approval carried a period of regulatory exclusivity associated with the new clinical investigation supporting that indication. That regulatory exclusivity did not extend the term of US Patent 7,045,620.

FDA exclusivity and patent exclusivity are separate:

• Patent expiry is controlled by the patent term.
• Three-year exclusivity is tied to the approved change or clinical investigation.
• Five-year NCE exclusivity applies only to qualifying new chemical entities.
• Orphan-drug exclusivity can apply to a qualifying orphan indication, but it does not convert a polymorph patent into a permanent barrier.

Which later patents affect rifaximin generic entry?

The most important commercial issue is that 7,045,620 was only one part of the Xifaxan patent estate. Later patents have addressed therapeutic uses, dosage strengths, formulations, crystalline forms and product-specific commercial presentations.

Representative estate categories include:

Patent category	Typical subject matter	Generic-entry effect
Polymorph patents	Alpha, beta, gamma or later solid-state forms	May require XRPD and water-content design-around
Hepatic encephalopathy patents	Reduction of recurrence and related dosing	May block labeled use or create skinny-label issues
IBS-D patents	Treatment of diarrhea-predominant IBS	Can affect label carve-outs and inducement risk
Formulation patents	Tablet composition, excipients, dissolution and release	Can block a formulation even after API patent expiry
Manufacturing patents	Improved yield, purification or crystallization	May restrict API suppliers
Product-specific patents	550 mg tablets or commercial dosage systems	May extend effective market protection

Norwich Pharmaceuticals' abbreviated new drug application and Salix-related litigation demonstrate the risk of treating the 620 patent as the entire barrier. The principal disputes in later litigation involved other rifaximin patents, including patents asserted against proposed generic Xifaxan products.[4]

What generic launch scenarios exist after expiration?

Scenario 1: Non-infringing API and formulation

A generic manufacturer uses rifaximin that does not fall within an unexpired solid-state claim, uses a non-claimed formulation and files certifications or label carve-outs for protected indications. This is the lowest-risk pathway.

Scenario 2: Alpha-form API with later-patent exposure

A manufacturer uses rifaximin alpha because it is the commercially established form. The expired 620 claims do not block the product, but a later patent may claim a specific alpha form, water range, particle-size distribution, formulation or dissolution profile.

Scenario 3: Product approval with a skinny label

A generic may omit a still-protected method of use from its labeling. This can reduce induced-infringement exposure, but it does not eliminate risk if the product is actively promoted for the omitted use or if the patented use is the only practical use.

Scenario 4: Paragraph IV litigation and settlement

A generic applicant can challenge listed patents through Paragraph IV certifications. The resulting litigation may end in a negotiated launch date, license, authorized-generic arrangement or other settlement terms. The expiration of 7,045,620 alone does not determine settlement economics.

What manufacturing and IP barriers remain?

The principal technical barrier is solid-state control. Rifaximin can change polymorphic form as water activity, temperature, solvent composition and drying conditions change. This creates three risks:

1. A nominally non-infringing process may produce a claimed form unintentionally.
2. A generic product may fail bioequivalence or quality specifications if its solid form differs from the reference product.
3. A process design-around may create a new patent risk under a later manufacturing patent.

A defensible freedom-to-operate program should compare the proposed API against:

• XRPD pattern.
• Water content and water activity.
• Thermal analysis.
• Residual solvents.
• Particle-size distribution.
• Dissolution profile.
• Tablet composition.
• Approved labeling.
• Manufacturing-site process parameters.

The relevant geographic scope of 7,045,620 was the United States. Parallel European and other national patents required separate validity and expiration analysis. US expiration did not terminate foreign rights.

How does US Patent 7,045,620 compare with later rifaximin patents?

US 7,045,620 is a foundational solid-state patent. Its claims are structurally broad within the alpha, beta and gamma forms but technically narrow because they require particular XRPD and water-content characteristics.

Later rifaximin patents generally have greater relevance to current launch timing because they may expire later and target:

• The 550 mg commercial presentation.
• IBS-D and hepatic encephalopathy treatment methods.
• Tablet formulations.
• Dissolution or release properties.
• Alternative crystalline or amorphous forms.
• Manufacturing improvements.

The 620 patent is therefore historically central but no longer the controlling US exclusivity asset after October 2, 2024.

Key Takeaways

• US Patent 7,045,620 claims rifaximin alpha, beta and gamma forms and processes for producing or interconverting them.
• Claims 1, 3 and 5 are product claims defined by XRPD patterns and water content.
• Claims 6-20 cover synthesis, crystallization, humidity conversion and drying processes.
• The listed US expiration date was October 2, 2024.
• The patent's expiration removes its direct US blocking effect.
• Xifaxan generic entry remains dependent on later patents, Orange Book listings, FDA exclusivity, formulation claims and settlement agreements.
• Rifaximin solid-state characterization remains important for API qualification and freedom-to-operate analysis.
• A generic that avoids the expired 620 claims can still face infringement risk from later method-of-use, formulation or manufacturing patents.

FAQs About US Patent 7,045,620 and Rifaximin

Does US Patent 7,045,620 cover all rifaximin?

No. It covers specified alpha, beta and gamma solid forms, defined by XRPD and water content, plus specified processes. It does not claim every physical or chemical form of rifaximin.

Can a generic use rifaximin alpha after October 2, 2024?

Yes, the expired patent no longer blocks use of the claimed alpha form. The manufacturer must still assess unexpired patents covering the same form, formulations, methods of use or manufacturing process.

Is rifaximin beta the same as rifaximin alpha?

No. The patent distinguishes them by XRPD pattern and water content. Alpha has 3% or less water under claim 1, while beta has more than 4.5% water under claim 3.

Can a manufacturer avoid the patent by changing the drying temperature?

A changed drying temperature may avoid a process claim if another required limitation is also absent. It will not necessarily avoid a product claim if the resulting batch still has the claimed polymorph, XRPD profile and water content.

Does patent expiration automatically authorize FDA generic approval?

No. FDA approval requires compliance with the ANDA pathway, including pharmaceutical equivalence, bioequivalence, quality requirements and applicable exclusivity rules. Patent expiry removes one legal barrier but does not replace FDA approval requirements.

References

1. US Patent and Trademark Office. (2006). Polymorphic forms of rifaximin and processes for their preparation, U.S. Patent No. 7,045,620 B2.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (2015). Xifaxan (rifaximin) prescribing information. Salix Pharmaceuticals.
4. United States Court of Appeals for the Federal Circuit. (2023). Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc., decisions concerning rifaximin patents and proposed generic Xifaxan products.

Drugs Protected by US Patent 7,045,620

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 7,045,620

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Italy	MI2003A2144	Nov 07, 2003

International Family Members for US Patent 7,045,620

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	043547
Argentina	081991
Argentina	081992
Austria	361927
Austria	421965
Austria	421966
Australia	2004200964