US Patent 7,566,462: Scope, Claims, Expiration, and Sapropterin Patent Landscape

US Patent 7,566,462 protects a stable tablet formulation of sapropterin dihydrochloride containing crystalline polymorph B, an antioxidant, and excipients. Its independent claim is narrow because it requires a specific solid form, antioxidant-to-drug ratio, tablet dosage form, and measured stability performance. The patent was issued on July 28, 2009, and its ordinary 20-year term appears to have ended in October 2024, subject to any patent-term adjustment recorded by the USPTO. The patent does not broadly claim sapropterin, all sapropterin formulations, or methods of treating phenylketonuria.

What does US Patent 7,566,462 protect?

The patent protects a formulation platform for (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, commonly known as sapropterin dihydrochloride, the active ingredient in Kuvan.

The central claim requires all of the following elements:

Required element	Claim limitation
Active ingredient	(6R)-L-erythro-tetrahydrobiopterin dihydrochloride
Solid form	Crystalline polymorph B
Dosage form	Tablet
Antioxidant	Present in a ratio of about 1:5 to about 1:30 relative to the drug
Stability	At least about 95% of the initial drug retained after six months
Storage condition	Container, room temperature, and about 60% humidity
Polymorph identification	Specified powder X-ray diffraction peaks

The claim is therefore a product-by-process-like formulation claim with structural, compositional, dosage-form, and performance limitations. A competing product would generally need to satisfy each required limitation to infringe literally.

How narrow is independent claim 1?

Claim 1 is materially narrower than a claim to sapropterin tablets generally.

A formulation would fall outside the literal scope of claim 1 if it used:

A different crystalline form of sapropterin;
Amorphous sapropterin;
A non-tablet dosage form;
No antioxidant;
An antioxidant outside the stated ratio;
A different active ingredient form that does not correspond to the claimed dihydrochloride;
A formulation that fails the claimed six-month retention threshold; or
A material whose powder X-ray diffraction pattern does not meet the polymorph B limitation.

The “about” language introduces ordinary claim-construction flexibility around the ratio and stability values. It does not eliminate the requirement for a formulation within the claimed technical range.

The stability requirement is particularly important. It is not merely a statement of intended use. The claim expressly requires retention of at least about 95% of the initial drug amount under specified storage conditions. In an infringement dispute, analytical testing, storage protocol, assay method, container configuration, humidity, and temperature control would be central evidence.

What polymorph of sapropterin is claimed?

Claims 1 and 2 require crystalline polymorph B of sapropterin dihydrochloride.

Claim 1 identifies seven characteristic powder X-ray diffraction peaks:

d-value in angstroms	Relative intensity
8.7	Very strong
5.63	Medium
4.76	Medium
4.40	Medium
4.00	Strong
3.23	Strong
3.11	Very strong

Claim 2 adds 19 further characteristic peaks, including d-values at 6.9, 5.07, 4.15, 3.95, 3.52, 3.32, 2.94, 2.84, and 2.82 angstroms.

Claim 2 is narrower than claim 1 because it requires the additional diffraction pattern. Claims 3 through 5 do not add a new ingredient or dosage form. They add longer-term stability performance.

What dosage strengths and compositions are protected?

Claims 6 through 8 cover specified drug loading levels and tablet strengths.

Claim	Limitation
6	Active ingredient at about 30 wt% to about 40 wt%
7	100 mg, 200 mg, or 300 mg per tablet
8	400 mg per tablet

Claim 7 is drafted as an alternative-strength limitation. Claim 8 separately protects a 400 mg tablet. These claims do not protect every tablet strength, and a formulation outside the stated strengths would need to be evaluated against claim 1 and any other asserted claim.

The commercial relevance is strongest for 100 mg, 200 mg, and 300 mg sapropterin tablets, which correspond to established Kuvan dosage presentations. The 400 mg limitation is separately significant because it captures a higher-dose tablet architecture.

What excipients and manufacturing components are covered?

The dependent claims identify formulation components that narrow the patent’s coverage:

Claim	Component
9	A disintegration agent
10	Crospovidone
11	A lubricant
12	Stearyl fumarate
13	Sodium stearyl fumarate
14	Lubricant at about 1.0 wt% to about 1.8 wt%
15	Microcrystalline cellulose
16	About 400 mg drug, 3 wt% to 5 wt% crospovidone, and 1 wt% to 1.7 wt% stearyl fumarate
17	32 wt% to 35 wt% drug, 3 wt% to 5 wt% crospovidone, 1.5 wt% to 3 wt% anhydrous dibasic calcium phosphate, and 0.5 wt% to 2 wt% stearyl fumarate
18	An acidic antioxidant
19	Ascorbic acid
20	Ascorbic acid-to-drug ratio of about 1:20

Claim 16 is directed to a relatively specific high-dose formulation. Claim 17 covers a particular formulation window based on drug loading and excipient concentrations. Claim 20 is the narrowest antioxidant-ratio claim and may be relevant to products using ascorbic acid as the stabilizing agent.

The claims do not require every excipient identified in the specification. A formulation using different binders, fillers, lubricants, or disintegrants may avoid the narrower dependent claims while still raising issues under claim 1.

How does the patent protect against formulation design-arounds?

The principal design-around routes are structural and compositional:

Use a different polymorph or a noncrystalline form.
Remove the antioxidant or substitute a different stabilizing mechanism.
Use an antioxidant ratio outside the claimed range.
Market a capsule, powder, liquid, or orally disintegrating form rather than the claimed tablet.
Use a different active ingredient salt or solid-state form.
Use a formulation that does not meet the claimed retention threshold.

The most difficult design-around issue is polymorph control. A manufacturer using a different input material may still generate polymorph B during granulation, compression, storage, or exposure to humidity. Solid-state characterization would therefore need to examine both the starting active pharmaceutical ingredient and the finished tablet.

A product that intentionally avoids polymorph B may face manufacturing challenges if polymorph B is the most stable or commercially practical form. That is a technical barrier, but it is not equivalent to continued legal protection after patent expiration.

When did US Patent 7,566,462 expire?

The patent issued on July 28, 2009. Its term is governed principally by the 20-year period measured from the relevant nonprovisional or international application filing date, rather than by the issue date.[1]

The public patent record identifies a 2003 priority date and an October 2004 U.S. or international filing chronology. On that basis, the ordinary patent term ended in October 2024, subject to any patent-term adjustment. The USPTO Patent Center record is controlling for the exact adjustment and expiration calculation.

Event	Date
Earliest identified priority	October 31, 2003
U.S. or international filing chronology	October 2004
Patent issued	July 28, 2009
Ordinary 20-year term endpoint	October 2024
Patent status for current generic strategy	Expired ordinary term, subject to USPTO term calculation

An expired patent generally cannot support an injunction against post-expiration commercial activity. It may remain relevant to historical Paragraph IV litigation, settlement dates, damages periods, and freedom-to-operate analysis for conduct occurring before expiration.

What was the FDA exclusivity status of Kuvan?

The FDA approved Kuvan tablets containing sapropterin dihydrochloride on December 13, 2007, for certain patients with phenylketonuria, in combination with a phenylalanine-restricted diet.[2]

Relevant regulatory protections included:

Protection	General endpoint
New chemical entity exclusivity	Five years from approval, subject to Paragraph IV rules
Orphan-drug exclusivity	Seven years from approval
Pediatric exclusivity	Six-month extension if awarded

Regulatory exclusivity and patent term are separate. FDA exclusivity does not extend the life of US Patent 7,566,462. Conversely, expiration of the formulation patent did not itself authorize approval of a generic before applicable FDA exclusivity had ended.

Kuvan is a small-molecule drug. Biosimilar regulation under the Public Health Service Act does not apply. Competitive products would proceed through an abbreviated new drug application, a 505(b)(2) application, or a full new drug application depending on the product and regulatory strategy.[3]

What is the Orange Book status of US Patent 7,566,462?

US Patent 7,566,462 was associated with the Kuvan regulatory patent estate and addressed the tablet formulation rather than a treatment method or broad active-ingredient composition. Orange Book listing status is assessed by the FDA and can change through patent expiration, delisting, or product-specific regulatory updates.[4]

For generic applicants, the practical consequences were:

A Paragraph IV certification could challenge the patent before expiration.
A Paragraph III certification could defer approval until patent expiration.
A non-infringement or invalidity position could support a Paragraph IV notice.
The patent’s expiry in 2024 removed its forward-looking exclusivity value, assuming no later enforceable term or related patent applied.

The patent’s presence in the Orange Book did not establish validity. It identified a patent asserted by the listed drug sponsor as potentially relevant to an approved drug product.

Which related patents matter in the sapropterin landscape?

The commercial estate around sapropterin has included separate patent families directed to solid forms, formulations, methods of treatment, and regulatory protection. US Patent 7,566,462 should not be treated as the entire Kuvan estate.

Patent category	Principal risk
Crystalline-form patents	Claims to polymorph identity or solid-state characteristics
Formulation patents	Claims to tablets, excipients, antioxidants, stability, or release
Method-of-use patents	Claims to treating phenylketonuria or dosing selected patients
Manufacturing patents	Claims to preparation, crystallization, purification, or processing
Regulatory exclusivity	FDA approval-based barriers independent of patent validity

US Patent 8,357,795 is an example of a later sapropterin patent directed to crystalline-form subject matter.[5] Its relevance depends on the specific polymorph, claims, expiration, and whether the proposed generic product contains the claimed form. A formulation design-around that avoids US 7,566,462 could still encounter a separate solid-form patent.

A complete freedom-to-operate review must therefore assess the complete patent family, continuations, divisionals, terminal disclaimers, Orange Book listings, and patent-term adjustments rather than relying on the expiration of US 7,566,462 alone.

What Paragraph IV and litigation risks affected generic entry?

The principal litigation risk before October 2024 was a patent challenge directed to the formulation and related sapropterin claims. A Paragraph IV case would likely focus on:

Whether the proposed generic contains polymorph B;
Whether the finished tablet has the claimed X-ray diffraction profile;
Whether the antioxidant ratio falls within the claim;
Whether the stability data satisfy the claim;
Whether the claims are anticipated or obvious over prior sapropterin solid forms and antioxidant formulations;
Whether the stability limitation is definite and reproducible; and
Whether the asserted claims are enabled across their full scope.

The strongest invalidity theories would likely be obviousness and anticipation based on prior disclosures of sapropterin polymorphs, antioxidant-stabilized tablets, excipient combinations, and routine stability testing. The strongest infringement theories would rely on finished-product testing rather than the supplier’s declared formulation alone.

Settlement agreements could restrict launch timing before patent expiry. Their commercial terms are often confidential, while FDA approval timing, court docket events, and authorized-generic arrangements may be public. Patent expiration substantially reduces the value of any settlement provision tied solely to this patent, although separate patents or contractual restrictions can remain relevant.

How strong is the patent estate for US 7,566,462?

The patent was technically specific but commercially relevant. Its strengths were:

A defined crystalline polymorph;
A measurable powder diffraction profile;
A quantified antioxidant ratio;
Tablet-specific coverage;
Stability limitations tied to real storage conditions; and
Dependent claims covering commercial strengths and excipients.

Its weaknesses were:

Narrow dependence on polymorph B;
Reliance on “about” ranges and functional stability limitations;
Potential prior-art overlap between antioxidant stabilization and solid-form selection;
Possible design-around options using another polymorph or dosage form; and
Term expiration in 2024.

The patent had meaningful pre-expiration blocking value for products that copied the commercial tablet architecture. It has limited current exclusionary value after expiration, but it remains relevant to historical litigation, prior launch timing, and technical design analysis.

What generic launch scenarios exist after patent expiration?

A generic manufacturer could pursue several routes:

Scenario	Commercial implication
AB-rated tablet using polymorph B	Potential exposure to other unexpired solid-form or method patents
Tablet using another polymorph	May avoid literal claim 1 but requires solid-state and stability validation
Different antioxidant system	May avoid claims 18-20 and potentially claim 1
Capsule or oral powder	May avoid the tablet limitation but requires a different regulatory product strategy
505(b)(2) product	May support formulation or dosing differentiation but may face listed patent certifications
Authorized generic	May reduce litigation risk but depends on sponsor arrangements

The relevant market includes generic sapropterin tablets and oral powder products, patient access programs, and any successor or alternative tetrahydrobiopterin therapies. Revenue exposure is concentrated in the Kuvan franchise and related sapropterin products rather than in a broad class of tetrahydrobiopterin medicines.

Key Takeaways

US Patent 7,566,462 claims a specific stable tablet formulation of sapropterin dihydrochloride.
Claim 1 requires polymorph B, an antioxidant ratio of about 1:5 to about 1:30, a tablet, and defined six-month stability.
Claims 2 through 20 narrow the scope through additional X-ray peaks, stability periods, tablet strengths, excipients, and ascorbic acid ratios.
The patent does not broadly cover sapropterin, all sapropterin dosage forms, or methods of treating phenylketonuria.
The ordinary patent term appears to have ended in October 2024, subject to the USPTO’s final patent-term calculation.
Biosimilar risk does not apply because sapropterin is a small-molecule drug.
Post-expiration generic risk depends mainly on other unexpired crystalline-form, formulation, method-of-use, manufacturing, and regulatory protections.
A complete competitive analysis must review the broader Kuvan patent family and current Orange Book records, not this patent in isolation.

FAQs

Does US Patent 7,566,462 claim the active ingredient sapropterin itself?

No. It claims a tablet formulation containing a specified crystalline polymorph of sapropterin dihydrochloride, together with an antioxidant and excipients.

Can a generic use sapropterin polymorph B after the patent expires?

Yes, assuming no other enforceable patent or regulatory exclusivity prevents approval or marketing. This patent alone does not create post-expiration exclusivity.

Does changing ascorbic acid to another antioxidant avoid the patent?

Not necessarily. Claim 1 covers an antioxidant generally within the stated ratio. Claims 18 through 20 specifically narrow the antioxidant to acidic antioxidants and ascorbic acid.

Are 100 mg, 200 mg, 300 mg, and 400 mg tablets all covered?

Claims 7 and 8 specifically identify those strengths. Claim 1 may cover other strengths if all of its formulation, polymorph, ratio, and stability limitations are met.

Is an oral powder version covered by the claims?

The claims supplied require a tablet. An oral powder product would not literally satisfy the dosage-form limitation, although other patents or regulatory protections could apply.

References

United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation. https://www.uspto.gov/patents/laws/patent-term-calculation
U.S. Food and Drug Administration. (2007). Kuvan approval history and prescribing information. https://www.accessdata.fda.gov
U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application and 505(b)(2) application pathways. https://www.fda.gov/drugs
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.fda.gov/drugsatfda
United States Patent No. 8,357,795. (2013). United States Patent and Trademark Office patent record. https://patents.google.com/patent/US8357795B2

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Biomarin Pharm	KUVAN	sapropterin dihydrochloride	TABLET;ORAL	022181-001	Dec 13, 2007	AB	RX	Yes	Yes	⤷ Start Trial	⤷ 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	052238	⤷ Start Trial
Australia	2005306686	⤷ Start Trial
Brazil	PI0517088	⤷ Start Trial
Canada	2581814	⤷ Start Trial
China	101132776	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 7,566,462

Which drugs does patent 7,566,462 protect, and when does it expire?

Summary for Patent: 7,566,462