Details for Patent: 8,426,391

Which drugs does patent 8,426,391 protect, and when does it expire?

Patent 8,426,391 protects RAYALDEE and is included in one NDA.

This patent has twenty-nine patent family members in thirteen countries.

Summary for Patent: 8,426,391

Title:	Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
Abstract:	Methods and compositions for treating 25-hydroxyvitamin D insufficiency and deficiency in a patient are described herein. The method includes orally administering to the patient a delayed, sustained release formulation including a first ingredient selected from the group consisting of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, or it includes gradually administering to the patient a sterile intravenous formulation including a first ingredient selected from the group consisting of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3.
Inventor(s):	Charles W. Bishop, Keith H. Crawford, Eric J. Messner
Assignee:	Opko Health Inc , Opko Renal LLC
Application Number:	US12/278,053
Patent Claim Types: see list of patent claims	Use; Formulation;

US Patent 8,426,391: Scope, Claim Construction, Expiration and Patent Landscape for Sustained-Release Calcifediol

US Patent No. 8,426,391 protects methods of treating vitamin D insufficiency or deficiency with orally administered sustained-release 25-hydroxyvitamin D, commonly called calcifediol. The patent is directed primarily to the therapeutic use and pharmacokinetic profile of extended-release calcifediol, rather than to calcifediol as a molecule. Its strongest commercial relevance is to Rayaldee, OPKO Health's extended-release calcifediol product.

The claims cover daily oral dosing, target serum vitamin D levels, reduced peak exposure, avoidance of transient supraphysiologic surges, increased bioavailability, and controlled-release matrices, including wax matrices. The patent's nominal term appears to extend into 2027, subject to any applicable patent-term adjustment and the official USPTO term calculation.

What does US Patent 8,426,391 protect?

The patent protects a treatment method with five core elements:

1. The patient has 25-hydroxyvitamin D insufficiency or deficiency.
2. The active ingredient is 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or both.
3. The product is administered orally.
4. The product is sustained-release or is administered gradually.
5. The treatment produces specified pharmacokinetic or clinical effects.

The patent does not broadly claim all uses of vitamin D, all calcifediol products, or all extended-release formulations. It claims the combination of the active ingredient, patient condition, route of administration, release profile, and, in dependent claims, particular dose or performance limitations.

Claim architecture

Claims	Subject matter	Commercial significance
1	Oral sustained-release treatment of 25-hydroxyvitamin D insufficiency or deficiency	Principal method claim
2	Daily dose of 1 to 100 mcg	Broad dose limitation
3	Increase in serum total 25-hydroxyvitamin D to at least 30 ng/mL	Clinical target
4	Lower Cmax than an equal immediate-release dose	Pharmacokinetic limitation
5	Avoidance of transient supraphysiologic surge	Safety and tolerability limitation
6	No transient increase above 3 ng/mL after a unit dose	Quantitative pharmacokinetic limitation
7	Increased bioavailability compared with immediate release	Relative performance limitation
8	Unit formulation containing 1 to 50 mcg	Formulation dose range
9	Matrix containing a release-controlling constituent	Controlled-release formulation limitation
10	Wax matrix	Narrower formulation limitation
11	Once-daily administration	Dosing schedule
12-13	Daily doses of 1 to 100 mcg and 5 to 50 mcg	More focused dosing claims
14	Gradual administration to avoid a supraphysiologic surge	Separate functional method claim

How broad is independent claim 1?

Claim 1 is broad in active ingredient and dose, but narrower in dosage form and therapeutic context.

It covers:

• 25-hydroxyvitamin D2;
• 25-hydroxyvitamin D3;
• a combination of D2 and D3;
• oral administration;
• sustained-release formulations; and
• treatment of insufficiency or deficiency.

The claim does not require a particular matrix, capsule, tablet, excipient, release percentage, dissolution profile, dose, or serum concentration. A potentially infringing product could therefore use a non-wax controlled-release technology if it satisfies the claim's sustained-release requirement.

The principal claim-construction issue is the meaning of "sustained release." The patent likely depends on the specification's description of release kinetics, dosage forms, dissolution testing, and comparative pharmacokinetic data. A product manufacturer would not avoid claim 1 merely by using a polymer matrix instead of a wax matrix. Claim 10 expressly narrows the claim to wax matrices, but claim 1 is not so limited.

What does "25-hydroxyvitamin D" include?

The claim expressly identifies 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3. It also covers a combination of those compounds. The claims therefore reach calcifediol products based on either vitamin D2 or vitamin D3, as well as combination products.

The claims do not expressly cover:

• cholecalciferol, or vitamin D3, without hydroxylation;
• ergocalciferol, or vitamin D2, without hydroxylation;
• calcitriol;
• paricalcitol;
• doxercalciferol; or
• other vitamin D receptor agonists.

A conventional immediate-release vitamin D product would generally fall outside claim 1 because the claim requires sustained release. A conventional immediate-release calcifediol product could still implicate other patents, but not this claim unless the accused product is legally characterized as sustained release.

What do claims 2, 8, 12 and 13 add?

The dose claims establish overlapping ranges:

• Claim 2: 1 to 100 mcg per day.
• Claim 8: 1 to 50 mcg in the formulation.
• Claim 12: 1 to 100 mcg per day.
• Claim 13: 5 to 50 mcg per day.

The ranges overlap with the 30 mcg and 60 mcg extended-release capsule strengths associated with Rayaldee. A product containing 30 mcg per capsule and administered once daily would fall within the narrower 5-to-50-mcg range of claim 13. A 60 mcg daily dose would fall within claims 2 and 12 but outside claim 13's 5-to-50-mcg limitation.

The dose claims are dependent claims. If claim 1 were held invalid or not infringed, claims 2, 8, 12 and 13 would not independently create liability unless their additional limitations were combined with all limitations of the parent claim and the parent claim remained enforceable.

What do the pharmacokinetic claims require?

Claims 4 through 7 are performance-based claims. They compare sustained-release administration with an equal dose of an immediate-release formulation.

Lower Cmax

Claim 4 requires a lower maximum blood concentration of 25-hydroxyvitamin D than an equal dose of an immediate-release formulation. The comparison must be defined carefully:

• the same active ingredient should generally be compared;
• the administered dose must be equal;
• the blood analyte must be identified;
• the sampling period must be adequate; and
• the immediate-release comparator must be scientifically appropriate.

A generic applicant could challenge the claim by arguing that the comparator is undefined, that the result varies by patient, or that the claimed reduction is not consistently observed.

Avoidance of a supraphysiologic surge

Claim 5 requires avoidance of a transient supraphysiologic surge. "Supraphysiologic" is potentially vulnerable to indefiniteness arguments if the patent does not establish a clear numerical threshold or clinical reference range.

Claim 6 is more quantitative. It requires avoidance of a transient increase greater than 3 ng/mL following a unit dose. The claim still raises measurement questions, including:

• baseline serum concentration;
• timing of the post-dose measurement;
• assay variability;
• whether the increase is measured as total 25-hydroxyvitamin D or one metabolite; and
• whether the result must occur in every patient or only as a population pharmacokinetic outcome.

Claim 7 requires increased bioavailability compared with immediate release. This is unusual because sustained release often lowers or spreads peak exposure while total exposure may remain similar. The patent therefore appears to rely on a specific formulation or absorption profile that improves systemic exposure relative to an immediate-release comparator.

What does claim 9 protect?

Claim 9 covers a formulation in which the active ingredient is dispersed within a matrix containing a release-controlling constituent. The claim is broader than claim 10 because it does not restrict the matrix to wax.

Potentially covered release-controlling materials could include:

• waxes;
• hydrophobic polymers;
• hydrophilic polymers;
• lipid matrices;
• mixtures of wax and polymer;
• coated particles; and
• other excipient systems that control release.

The claim requires the active compound to be dispersed within the matrix. A dosage form in which the active is merely coated, layered, or placed in a separate reservoir could raise a claim-construction issue, depending on the specification and prosecution history.

Claim 10 narrows claim 9 to a wax matrix. Wax-based systems are easier to identify analytically than functional sustained-release systems. A manufacturer may therefore face greater literal-infringement risk under claim 10 if its formulation uses a wax such as a fatty alcohol, glyceride, ester, or related hydrophobic release-control material.

How does claim 14 differ from claim 1?

Claim 14 is a separate independent method claim. It requires gradually administering a formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or both to avoid a transient supraphysiologic surge.

Unlike claim 1, claim 14 does not expressly require the formulation to be "sustained release." The phrase "gradually administering" may capture sustained-release delivery, divided dosing, infusion-like administration, or another method that produces gradual systemic exposure.

This gives claim 14 potentially broader reach than claim 1 with respect to dosage-form terminology. It also creates greater validity and infringement risk because "gradually" and "avoid a transient supraphysiologic surge" may require interpretation from the specification and prosecution record.

What is the patent's relationship to Rayaldee?

Rayaldee is an extended-release calcifediol product approved by the FDA in 2016 for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease and serum 25-hydroxyvitamin D levels below 30 ng/mL. The product is available in 30 mcg and 60 mcg extended-release capsules.[2]

The approved indication overlaps materially with claim 3, which identifies a target serum total 25-hydroxyvitamin D concentration of at least 30 ng/mL. The product's extended-release design also corresponds to claims 1, 4, 5, 6, 7, 11 and 12.

The claims, however, are not limited to chronic kidney disease or secondary hyperparathyroidism. Their literal scope reaches treatment of 25-hydroxyvitamin D insufficiency or deficiency more generally, subject to the other claim limitations.

Rayaldee claim mapping

Rayaldee characteristic	Potentially relevant claims
Oral capsule	Claim 1
Extended-release calcifediol	Claim 1
30 mcg strength	Claims 8, 12 and 13
60 mcg strength	Claims 2 and 12
Once-daily dosing	Claim 11
Targeting vitamin D below 30 ng/mL	Claims 1 and 3
Reduced peak exposure	Claims 4-6
Controlled-release formulation	Claim 9
Possible lipid or wax-based release system	Claim 10, depending on actual formulation

The product label and FDA approval materials identify the regulatory indication, but claim infringement depends on the patented method and the characteristics of the accused product, not solely on the label.[2]

When does US Patent 8,426,391 expire?

The patent appears to have a nominal expiration date in 2027 based on its earliest relevant US filing priority. The expected term should be confirmed against the USPTO patent record, including any patent-term adjustment.

Event	Date or status
Earliest priority	2007, based on the patent family record
US patent grant	April 23, 2013
Patent number	US 8,426,391
Expected nominal expiration	Approximately August 2027
Patent-term adjustment	Must be checked in the USPTO record
Patent-term extension	No conclusion should be drawn without the official Orange Book and USPTO records

The patent term is separate from FDA regulatory exclusivity. FDA approval of Rayaldee occurred in 2016, while the patent term is expected to run later. A generic applicant may therefore face patent-based delay even after regulatory exclusivity has expired.

What is the Orange Book status?

The relevant Orange Book issue is whether US 8,426,391 is listed against an approved calcifediol product and which use code is associated with the listing.

A listed method-of-use patent can support a Paragraph IV certification if a generic applicant's proposed labeling would practice the patented method. The scope of a Paragraph IV dispute would depend on:

• the patent number listed for the reference product;
• the use code;
• the generic label;
• whether the generic seeks a full or abbreviated indication;
• whether a section viii statement is available; and
• whether the proposed product uses the same extended-release characteristics.

The statutory framework is governed by the Hatch-Waxman Act and FDA's Orange Book listing rules.[3][4]

Because the claims are method claims, a generic applicant may seek to omit the patented indication or use a carve-out strategy if the remaining label does not encourage infringement. That approach is more difficult where the claimed method is embedded in the product's core approved use or where the label necessarily instructs once-daily sustained-release calcifediol treatment.

Which companies are challenging the patent?

The claim text does not establish the existence, identity, or current status of a Paragraph IV challenger, ANDA litigation, inter partes review, post-grant review, or settlement agreement. No challenger should be identified without a current FDA, PACER, PTAB, or company filing record.

For competitive diligence, the relevant challenge paths are:

• an ANDA Paragraph IV certification;
• a declaratory-judgment action;
• an inter partes review before the Patent Trial and Appeal Board;
• a post-grant review, if statutory timing permits;
• a patent-term challenge; and
• a carve-out or section viii strategy.

A generic company would likely attack the patent through obviousness, anticipation, indefiniteness, written description, enablement, and lack of infringement. The most exposed limitations are the functional terms "sustained release," "gradually," "supraphysiologic," and "increased bioavailability."

How strong is the patent estate?

The patent has meaningful commercial value because it combines use claims with pharmacokinetic and formulation limitations. Its strength is mixed by claim category.

Claim category	Relative strength	Principal risk
Claim 1 treatment method	Moderate to strong if sustained-release product is clearly covered	Scope and construction of sustained release
Dose claims	Moderate	Prior-art dose ranges and obviousness
Target serum level	Moderate	Inherent result and treatment-target prior art
Cmax and surge claims	Moderate	Measurement, indefiniteness and reproducibility
Bioavailability claim	Vulnerable to proof issues	Comparator and variable patient response
Matrix claim	Stronger for matching formulations	Design-around using non-matrix technology
Wax matrix claim	Strong if formulation composition is known	Non-wax formulation or claim construction
Claim 14	Potentially broad but more vulnerable	Meaning of gradually and supraphysiologic

A competitor using immediate-release calcifediol has a substantial noninfringement argument under claim 1. A competitor using an extended-release capsule with a different formulation may avoid claims 9 and 10 but still face claim 1 and the pharmacokinetic claims.

What generic entry risks exist?

Scenario 1: Immediate-release calcifediol

An immediate-release product is less likely to infringe claim 1 because it lacks sustained release. It may still face other patents or regulatory issues, but US 8,426,391 would be a weaker barrier.

Scenario 2: Extended-release calcifediol with a different matrix

This product could avoid claim 10 and possibly claim 9. It could still implicate claim 1, depending on whether the formulation satisfies the patent's sustained-release construction.

Scenario 3: Extended-release calcifediol at 30 mcg daily

This is the highest overlap scenario. It potentially falls within claims 1, 3, 4, 5, 6, 7, 8, 9, 11, 12 and 13, subject to proof of the claimed pharmacokinetic results.

Scenario 4: Extended-release calcifediol at 60 mcg daily

This product potentially falls within claims 1, 2, 3, 4, 5, 6, 7, 9, 11 and 12. It would not fall within claim 13 solely because of the 60 mcg daily amount.

Scenario 5: Combination calcifediol D2/D3 product

The express combination language creates direct claim coverage if the formulation uses both 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3.

How does this patent compare with competing vitamin D products?

Product or ingredient	Active compound	Release type	Direct overlap with US 8,426,391
Rayaldee	Extended-release calcifediol, 25-hydroxyvitamin D3	Sustained release	High
Immediate-release calcifediol	25-hydroxyvitamin D3	Immediate release	Lower under claim 1
Ergocalciferol	Vitamin D2	Usually immediate release	Low
Cholecalciferol	Vitamin D3	Usually immediate release	Low
Doxercalciferol	1-alpha-hydroxyvitamin D2	Active vitamin D analog	Low
Paricalcitol	Vitamin D receptor agonist	Various	Low
Calcitriol	1,25-dihydroxyvitamin D3	Immediate or conventional formulations	Low

The patent is strongest against products that replicate the extended-release calcifediol concept. It is not a broad blocking patent for the entire vitamin D market.

Key Takeaways

• US 8,426,391 is a method-of-use patent centered on oral sustained-release 25-hydroxyvitamin D.
• It covers calcifediol D2, calcifediol D3 and combinations.
• The principal commercial overlap is with Rayaldee and similar extended-release calcifediol products.
• Claims 4 through 7 add pharmacokinetic limitations involving Cmax, supraphysiologic surges and bioavailability.
• Claims 9 and 10 target controlled-release matrix formulations, including wax matrices.
• Claims 2, 8, 12 and 13 cover overlapping dose ranges from 1 to 100 mcg per day.
• Claim 14 may reach gradual administration without using the express term "sustained release."
• The patent's expected nominal expiration is approximately August 2027, subject to official USPTO term calculations.
• Immediate-release vitamin D products have a stronger noninfringement position than extended-release calcifediol products.
• The principal legal vulnerabilities are functional claim terms, comparator definitions, pharmacokinetic variability, indefiniteness and obviousness.
• Biosimilar risk is not relevant because calcifediol is a small molecule. The principal threat is ANDA-based generic entry.

FAQs

Does US Patent 8,426,391 cover ordinary vitamin D3 supplements?

No. The claims identify 25-hydroxyvitamin D2 or 25-hydroxyvitamin D3, not ordinary cholecalciferol or ergocalciferol. They also require sustained-release or gradual administration.

Would a 60 mcg extended-release calcifediol capsule fall within the patent?

Potentially yes. A 60 mcg once-daily product could meet claims 1, 2, 9, 11 and 12, along with the pharmacokinetic claims if the required results are demonstrated.

Does the patent cover calcifediol as a chemical compound?

No. The claims provided are method claims. They do not claim the isolated molecule, a composition of matter, or every pharmaceutical formulation containing calcifediol.

Can a generic avoid the patent by using a polymer instead of wax?

Possibly for claim 10, but not necessarily for claim 1 or claim 9. Claim 1 is not limited to wax, and claim 9 covers a matrix with a release-controlling constituent without specifying wax.

Is a biosimilar pathway available for Rayaldee?

No. Rayaldee contains a chemically defined small-molecule active ingredient. A competing manufacturer would generally pursue an abbreviated new drug application or a full NDA pathway, not a biosimilar application.

References

1. United States Patent and Trademark Office. (2013). United States Patent No. 8,426,391: Methods for treating vitamin D insufficiency or deficiency.
2. U.S. Food and Drug Administration. (2016). Rayaldee (calcifediol) extended-release capsules: Prescribing information.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
4. Drug Price Competition and Patent Term Restoration Act of 1984, 21 U.S.C. § 355(j).

Drugs Protected by US Patent 8,426,391

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Eirgen	RAYALDEE	calcifediol	CAPSULE, EXTENDED RELEASE;ORAL	208010-001	Jun 17, 2016		RX	Yes	Yes	8,426,391					USE OF SUSTAINED RELEASE 25-HYDROXYVITAMIN D IN TREATING PATIENTS HAVING 25-HYDROXYVITAMIN D INSUFFICIENCY OR DEFICIENCY

Foreign Priority and PCT Information for Patent: 8,426,391

PCT Information
PCT Filed	February 02, 2007	PCT Application Number:	PCT/US2007/061521
PCT Publication Date:	August 16, 2007	PCT Publication Number:	WO2007/092755

International Family Members for US Patent 8,426,391

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2640094
Canada	2882048
Cyprus	1118017
Cyprus	1125077
Denmark	1993559