Details for Patent: 6,225,474

Summary for Patent: 6,225,474

Title:	Polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid and method of producing the same
Abstract:	The present invention provides a technique of selectively producing a desired polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid.The present invention also provides a method of producing various polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, which comprises crystallizing under the conditions defined by a specific temperature and a composition of a mixed solvent of methanol and water, and polymorphs obtained by the method.The present invention further provides a method of producing the other polymorphs or amorphous compounds by drying a specific polymorph under a reduced pressure with heating, and the other polymorphs or amorphous compounds obtained by the method.
Inventor(s):	Koichi Matsumoto, Kenzo Watanabe, Toshiyuki Hiramatsu, Mitsutaka Kitamura
Assignee:	Teijin Pharma Ltd
Application Number:	US09/485,861
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,225,474
Patent Claim Types: see list of patent claims	Use; Composition;

United States Patent 6,225,474: Febuxostat Polymorph Claims, Expiration, Litigation and Patent Landscape

US Patent 6,225,474 protects selected crystalline and amorphous forms of febuxostat, the active ingredient in Uloric. Its independent product claims are defined primarily by X-ray powder diffraction or infrared absorption characteristics. The patent also claims crystallization, drying and conversion processes for producing crystals A, B, C, D and G and an amorphous form.

The patent issued on May 1, 2001, from an application claiming priority to June 18, 1996. Its ordinary 20-year patent term expired on June 18, 2017, absent a term adjustment or extension that materially changes the calculation. The patent is therefore no longer a blocking US patent for febuxostat polymorphs or the claimed manufacturing processes. [1]

What drug and chemical entity does US Patent 6,225,474 cover?

The claimed compound is febuxostat, chemically identified as 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid.

Item	Details
Generic name	Febuxostat
Brand	Uloric
Therapeutic class	Xanthine oxidase inhibitor
Primary use	Chronic management of hyperuricemia in gout
Original patent holder	Teijin Limited
US patent	6,225,474
Patent issue date	May 1, 2001
Earliest claimed priority	June 18, 1996
Ordinary expiration	June 18, 2017
FDA approval	Uloric NDA 021856, February 13, 2009
Regulatory pathway	New drug application for a small-molecule drug
Follow-on competition	ANDA-approved generic febuxostat products

The patent does not claim the basic febuxostat molecule in the broadest chemical sense. Its central subject matter is solid-state form control.

What patents protect febuxostat and Uloric?

The febuxostat estate historically contained several categories of rights:

1. Composition-of-matter protection for febuxostat.
2. Polymorph protection under US 6,225,474.
3. Manufacturing and crystallization protection for particular forms.
4. Method-of-use protection for treating hyperuricemia and gout.
5. Regulatory exclusivity associated with NDA approval.

US 6,225,474 is a solid-form patent. It is distinct from a composition patent covering febuxostat itself and from method-of-use patents directed to dosing or treatment.

Patent category	Typical claim subject	Commercial effect
Composition patent	Febuxostat molecule	Blocks manufacture and sale of the active ingredient
Polymorph patent	Crystal or amorphous form	Can block a specific solid form used in drug substance or tablets
Process patent	Crystallization, drying or conversion	Can block a manufacturing route
Method-of-use patent	Treatment of hyperuricemia or gout	Can create a narrower use-based barrier
Regulatory exclusivity	FDA approval period	Delays ANDA filing or approval independently of patent scope

The patent itself does not establish ownership of every later febuxostat patent, licensing arrangement or Orange Book listing. Those questions require separate patent-family and FDA-record analysis.

What do claims 1 through 11 cover?

Claims 1 through 5 are product claims directed to specific crystalline polymorphs identified by XRPD peak sets. Claims 6 through 10 identify additional polymorphs through infrared spectroscopy. Claim 11 covers an amorphous form.

XRPD polymorph claims

Claims 1 through 5 require the claimed febuxostat form to show the listed diffraction peaks at approximately the specified 2θ values.

Claims	Analytical definition	Scope
1	12 characteristic XRPD peaks	One defined crystalline form
2	20 characteristic XRPD peaks	A second defined crystalline form
3	17 characteristic XRPD peaks	A third defined crystalline form
4	12 characteristic XRPD peaks	A fourth defined crystalline form
5	21 characteristic XRPD peaks	A fifth defined crystalline form

These claims do not require a particular tablet, capsule, dosage strength or excipient. They are directed to the febuxostat solid form itself. A drug substance containing the claimed crystal may therefore create infringement exposure even if the finished dosage form differs from the examples in the specification.

The practical scope depends on how the terms "about" and "characteristic peaks" are construed. An XRPD comparison would normally consider:

• Peak positions and permitted analytical variation.
• Relative peak intensities.
• Instrument calibration.
• Sample preparation.
• Hydration, solvation or residual solvent.
• Whether the accused material is a single phase or a mixture of forms.

A formulation containing a small amount of a claimed polymorph may raise a different infringement question from a drug substance intentionally manufactured as that polymorph. The claims supplied do not include explicit purity, concentration or phase-percentage thresholds.

Infrared polymorph claims

Claims 6 through 10 identify polymorphs through infrared absorptions:

Claim	Infrared limitation
6	About 1678 cm⁻¹
7	About 1715, 1701 and 1682 cm⁻¹
8	About 1703 and 1219 cm⁻¹
9	About 1705 cm⁻¹
10	About 1703 and 1684 cm⁻¹

These claims create an alternative analytical route to infringement. A material need not necessarily be tested only by XRPD if an infrared method can establish the claimed absorption profile.

Their weakness is evidentiary precision. Single-peak claims, particularly claim 6 and claim 9, may be more vulnerable to disputes involving instrument resolution, baseline correction, polymorph mixtures and the meaning of "can be distinguished from that of other polymorphs." Claim 7 and claim 10 require multiple absorptions and may provide a more discriminating fingerprint.

Amorphous-form claim

Claim 11 covers "an amorphous compound" of febuxostat. Unlike the XRPD claims, it does not list a numerical analytical threshold or a detailed amorphousness criterion.

An amorphous-form infringement analysis would normally examine the absence of crystalline diffraction peaks, glass-transition behavior, thermal analysis and the presence of any residual crystalline material. The lack of a stated crystallinity threshold creates potential claim-construction and proof issues.

What do claims 12 through 19 protect?

Claims 12 through 19 are product claims defined by how the febuxostat form is obtained.

Claims	Claimed form or result	Production condition
12	Polymorph from region I	Methanol-water crystallization
13	Polymorph from region II	Methanol-water crystallization
14	Polymorph from region III	Methanol-water crystallization
15	Polymorph	Heated reduced-pressure drying of crystal G
16	Polymorph	Heating in methanol-water with seed crystal C
17	Polymorph	Crystallization from 2-propanol-water
18	Polymorph	Air-drying crystal D
19	Amorphous febuxostat	Heated reduced-pressure drying of crystal D

These claims have product-by-process characteristics. In US patent law, a product claim generally turns on the identity and characteristics of the product, not merely on whether the accused party used the same process. A party may face infringement if it makes the same claimed product through a different process, subject to the specific claim language and controlling case law. [2]

Claims 12 through 19 are less commercially useful if the process condition does not produce a form distinguishable from other febuxostat forms. They are more valuable when the resulting form has a reproducible XRPD or infrared signature.

What do claims 20 through 27 cover?

Claims 20 through 27 are express process claims.

Claims	Process subject
20	Production of crystal A in region I
21	Production of crystal B by heated reduced-pressure drying of crystal G
22	Production of crystal C by seeded heating in methanol-water
23	Production of crystal D in region II
24	Production of crystal G in region III
25	Production of crystal G from 2-propanol-water
26	Production of crystal G by air-drying crystal D
27	Production of amorphous febuxostat by heated reduced-pressure drying of crystal D

Claim 20 defines region I using three equations:

• Y = -0.2X + 85
• Y = 1.0X - 31
• Y = -3.3X + 273

Claim 23 defines region II using the corresponding boundaries, including Y = 20 and X = 100. Claim 24 defines region III using the boundaries and X = 50.

Here, X is the methanol/water composition in U/V percent, and Y is temperature in degrees Celsius. The claim language appears to contain typographical duplication in the supplied equations, including "Y=−−0.2X+85." The issued patent and prosecution file should control the exact claim text for any legal analysis.

Process claims 20 through 27 are narrower than the product claims because they require specified solvents, temperatures, drying conditions, seeding steps or starting crystals. A manufacturer could potentially avoid literal infringement by using a different solvent system or a different crystallization route, although the doctrine of equivalents could remain relevant.

How strong is the patent estate for febuxostat polymorphs?

The estate was technically meaningful during its enforceable term because it covered several commercially relevant solid-state outcomes rather than one manufacturing route.

Strengths

• Multiple XRPD-defined crystalline forms.
• Separate infrared-defined polymorph claims.
• An amorphous-form claim.
• Product-by-process claims covering forms produced under defined conditions.
• Independent process claims covering crystallization and drying.
• Coverage extending across methanol-water and 2-propanol-water systems.
• Claims directed to drug substance rather than only a finished tablet.

Weaknesses

• The patent expired in 2017.
• Several claims depend on analytical terms such as "about" and "characteristic."
• The amorphous-form claim lacks a quantitative definition.
• Process claims are narrow and route-specific.
• Polymorph claims can be challenged through solid-state characterization.
• A generic manufacturer may select a nonclaimed form or use a different manufacturing route.
• A mixed polymorph product may create difficult questions about claim satisfaction and materiality.

The historical strength of the patent was higher against a generic that deliberately selected the same crystal form as the reference product. Its present blocking value is zero because the patent term has ended.

When did US Patent 6,225,474 lose exclusivity?

The patent lost enforceable patent exclusivity on June 18, 2017, based on the 20-year term calculated from the relevant US filing framework and the patent's 1996 priority history. [1]

Event	Date
Earliest priority	June 18, 1996
US patent issue	May 1, 2001
Ordinary patent expiration	June 18, 2017
FDA approval of Uloric	February 13, 2009
Generic febuxostat availability	After expiry and FDA ANDA approvals

Patent expiration did not eliminate FDA regulatory requirements. Generic manufacturers still needed approved ANDAs, bioequivalence data and appropriate certification to listed patents.

What was the Orange Book status of US 6,225,474?

US 6,225,474 was associated with Uloric and its febuxostat solid-state protection. The FDA Orange Book is the controlling source for current patent listing and expiration information, while the patent itself controls claim scope. [3]

An Orange Book listing does not prove that every commercial febuxostat product infringes. It indicates that the NDA holder identified the patent as relevant to the approved drug. The listing also affects ANDA certification and the possibility of a 30-month stay after a Paragraph IV notice and timely patent litigation.

The key distinction is:

• Orange Book status concerns FDA approval and ANDA procedures.
• Patent validity and infringement are judicial questions.
• Expiration ends the patent right even if historical Orange Book records remain available.

Which companies challenged febuxostat patent protection?

Generic manufacturers typically challenge small-molecule patents through ANDA Paragraph IV certifications, asserting that listed claims are invalid, unenforceable or not infringed. Public FDA and court records should be used to identify each filer and litigation docket.

For this patent, the commercial challenge was primarily a generic-entry issue rather than a biosimilar dispute. Febuxostat is a chemically synthesized small molecule, so the relevant competitors are ANDA applicants, not biosimilar sponsors.

Potential generic risk categories included:

1. Use of the same polymorph as Uloric.
2. Use of a different crystalline form.
3. Use of amorphous febuxostat.
4. Manufacture through a different crystallization route.
5. Product-by-process infringement despite a different process.
6. Induced infringement based on the approved labeling.

After the patent expired, the principal barriers shifted from patent enforcement to FDA review, manufacturing scale-up, formulation performance and commercial pricing.

What generic launch scenarios existed for febuxostat?

Same-form launch

A generic using the same reference-product polymorph would face the highest historical solid-state risk. Before expiration, an ANDA applicant would need to assess whether the drug substance matched any XRPD or infrared claim.

Nonclaimed-form launch

A manufacturer could develop a different polymorph or amorphous form. That approach could reduce infringement risk but would introduce solid-state development risks involving dissolution, stability, hygroscopicity and bioequivalence.

Process-around launch

A manufacturer could use a solvent and drying sequence outside claims 20 through 27. This would not necessarily avoid the product claims if the resulting material matched a claimed polymorph.

Post-expiration launch

After June 18, 2017, the patent no longer supported an injunction or damages claim for new US activities. Generic entry then depended primarily on ANDA approval and the status of any separate live febuxostat patents.

Did biosimilar risk apply to Uloric?

No. Febuxostat is a small-molecule active pharmaceutical ingredient. The statutory pathway is an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act, not a biosimilar application under the Public Health Service Act.

The competitive risk therefore came from generic febuxostat products. Solid-form patents could delay or complicate generic entry, but they do not create biologic interchangeability issues.

What FDA regulatory issues affected febuxostat competition?

FDA approved Uloric for chronic management of hyperuricemia in adults with gout. In 2019, FDA required a boxed warning concerning increased risk of cardiovascular death associated with febuxostat compared with allopurinol and limited the approved use to patients who had an inadequate response to or could not tolerate allopurinol. [4]

That regulatory action affected commercial positioning and prescribing, but it did not restore patent exclusivity. Generic febuxostat products remain subject to the approved labeling and any applicable FDA safety requirements.

What manufacturing and IP barriers remain after patent expiration?

The principal barriers are now technical and regulatory:

• Reproducible control of polymorph formation.
• Prevention of unwanted polymorph conversion during drying and milling.
• Control of residual methanol, water or 2-propanol.
• Demonstration of physical and chemical stability.
• Consistent dissolution performance.
• Scale-up of seeded crystallization.
• Validation of XRPD and infrared release tests.
• Compliance with current good manufacturing practice.
• ANDA approval and postapproval manufacturing controls.

A patent expiration does not place every solid-state process in the public domain. Separate later patents, trade secrets, manufacturing know-how and regulatory exclusivities may still affect a particular commercial route.

What licensing deals affected febuxostat commercialization?

US Patent 6,225,474 identifies the patent owner and inventors but does not, by itself, establish the full commercial licensing chain for Uloric. Febuxostat was developed by Teijin and commercialized in the United States through arrangements involving Takeda and its predecessor commercial structures. The patent record should not be treated as a complete record of those agreements.

No license can be inferred solely from assignment data. Commercial diligence should distinguish:

• Patent assignment.
• Exclusive field-of-use license.
• Territory-specific license.
• Supply agreement.
• Co-promotion arrangement.
• Settlement license granted to an ANDA applicant.

What patent litigation and settlement risks applied?

Before expiration, a Paragraph IV certification against a listed febuxostat patent could trigger patent litigation under 35 U.S.C. § 271(e)(2). A timely suit could produce a statutory 30-month stay of FDA approval, subject to statutory exceptions and court action. [5]

Typical settlement terms in this category could include:

• A defined generic launch date.
• A license before patent expiration.
• No-admission provisions.
• Authorized-generic arrangements.
• Restrictions tied to particular polymorphs.
• Covenants concerning manufacturing routes.

The specific enforceability of any settlement depends on the filed agreement, court docket and FTC review. Patent 6,225,474 itself no longer supports a future settlement-based launch restriction because the patent has expired.

How does US 6,225,474 compare with a composition patent?

Issue	Composition patent	US 6,225,474
Subject	Febuxostat molecule	Specific solid forms and processes
Potential scope	Broad across forms	Narrower and form-dependent
Infringement test	Chemical identity	XRPD, IR, amorphousness or process
Design-around	Difficult during term	Often possible through form or route selection
Manufacturing relevance	Broad	High for crystallization and drying
Current status	Depends on separate patent	Expired June 18, 2017
Biosimilar relevance	None	None
Generic relevance	High	High before expiration, limited afterward

Key Takeaways

• US 6,225,474 is a febuxostat polymorph and manufacturing patent, not a broad composition patent.
• Claims 1 through 5 use XRPD peak patterns to define crystalline forms.
• Claims 6 through 10 use infrared absorption profiles.
• Claim 11 covers amorphous febuxostat.
• Claims 12 through 19 use product-by-process language.
• Claims 20 through 27 claim specific crystallization, seeding and drying methods.
• The patent's ordinary term expired on June 18, 2017.
• Febuxostat is subject to generic, not biosimilar, competition.
• Historical Paragraph IV risk centered on whether a generic used a claimed crystal or amorphous form.
• Current commercial risk must be assessed against later febuxostat patents, FDA records and manufacturing know-how, not this expired patent alone.
• Analytical testing should combine XRPD, infrared spectroscopy, thermal analysis and process-history review.

FAQs

Is febuxostat crystal A still patented in the United States?

No. To the extent crystal A is covered by US 6,225,474, that patent expired on June 18, 2017.

Can a generic use the same febuxostat polymorph as Uloric?

Yes, from the standpoint of US 6,225,474 after its expiration. The generic must still satisfy FDA requirements and avoid infringement of any separate unexpired patent.

Does claim 11 cover every amorphous form of febuxostat?

The claim broadly recites an amorphous febuxostat compound, but its enforceability during the patent term would have depended on claim construction and proof that the accused material was genuinely amorphous under the applicable analytical evidence.

Does using a different solvent automatically avoid claims 20 through 27?

No. A different solvent may avoid literal infringement of a process claim, but it does not necessarily avoid product claims if the resulting material is the same claimed polymorph.

Is Uloric subject to biosimilar competition?

No. Uloric contains the small molecule febuxostat. Competition proceeds through generic ANDA products rather than biosimilar applications.

References

1. United States Patent and Trademark Office. (2001). U.S. Patent No. 6,225,474, Polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid.
2. United States Court of Appeals for the Federal Circuit. (2009). Abbott Laboratories v. Sandoz, Inc., 566 F.3d 1282.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, Orange Book.
4. U.S. Food and Drug Administration. (2019). FDA adds boxed warning for increased risk of death with gout medicine Uloric (febuxostat).
5. U.S. Food and Drug Administration. (2024). Abbreviated new drug application approvals and patent certifications.

Drugs Protected by US Patent 6,225,474

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: 6,225,474

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	10-173079	Jun 19, 1998

PCT Information
PCT Filed	June 18, 1999	PCT Application Number:	PCT/JP99/03258
PCT Publication Date:	December 23, 1999	PCT Publication Number:	WO99/65885

International Family Members for US Patent 6,225,474

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1020454		PA2010005	Lithuania
European Patent Office	1020454		C300447	Netherlands
European Patent Office	1020454		CA 2010 00015	Denmark
European Patent Office	1020454		91682	Luxembourg