Details for Patent: 10,300,078

Which drugs does patent 10,300,078 protect, and when does it expire?

Patent 10,300,078 protects RAYALDEE and is included in one NDA.

This patent has eighty-five patent family members in thirty-seven countries.

Summary for Patent: 10,300,078

Title:	Stabilized modified release vitamin D formulation and method of administering same
Abstract:	A stabilized formulation for controlled release of a vitamin D compound is disclosed. The formulation comprises one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 and a cellulosic compound. The stabilized formulations exhibit a stable dissolution profile following exposure to storage conditions and demonstrate improved pharmacokinetic parameters compared to unstabilized formulations.
Inventor(s):	Jay A. White, Samir P. Tabash, Sammy A. Agudoawu, Joel Z. Melnick
Assignee:	Opko IP Holdings II Inc , Eirgen Pharma Ltd
Application Number:	US15/990,354
Patent Claim Types: see list of patent claims	Formulation; Compound; Dosage form;

United States Patent 10,300,078: Claim Scope, Patent Strength, Orange Book Status and Generic Entry Risk for Extended-Release Calcifediol

U.S. Patent No. 10,300,078 protects stabilized extended-release formulations containing 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or both. The core invention combines a lipophilic release matrix with 5% to 30% cellulose ether, particularly hydroxypropyl methylcellulose, and ties the formulation to in vivo pharmacokinetic performance in humans. The patent is directed primarily to Rayaldee-type extended-release calcifediol formulations rather than to calcifediol as a chemical substance.

The strongest commercial coverage is concentrated in claims 1, 12, 13, 17, 20, and 25-28. Claims 1 and 17-19 use pharmacokinetic limitations that may complicate infringement analysis but can materially narrow design-around options when an accused product uses the same excipient architecture and achieves the claimed exposure profile.

What does U.S. Patent 10,300,078 protect?

The patent protects a formulation with five required elements:

1. A vitamin D compound consisting of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or both.
2. An extended-release lipophilic matrix.
3. A cellulose ether stabilizing agent.
4. Cellulose ether at approximately 5 wt% to 30 wt% of the formulation.
5. A specified human pharmacokinetic or stability profile.

The independent claims are formulation claims. They do not claim the calcifediol molecule itself, treatment of vitamin D insufficiency in general, or every extended-release vitamin D product.

Claim group	Principal subject matter	Key limitation
Claim 1	Broad stabilized extended-release formulation	Cmax of approximately 0.0133-0.04 ng/mL per microgram administered
Claim 2	Stability-performance formulation	Post-storage Cmax within 80%-125% of pre-storage mean
Claims 3-4	Wax-containing matrix	Wax, including paraffin wax
Claims 5-6	Emulsifier-containing matrix	Glycerol monostearate
Claims 7-8	Absorption-enhanced formulation	Lauroyl macrogolglycerides and lauroyl polyoxylglycerides
Claims 9-10	Oil-containing matrix	Mineral oil
Claims 11-12	Defined multi-excipient formulation	Wax, oil, emulsifier, absorption enhancer and HPMC
Claims 13-15	Vitamin D and cellulose ether limitations	25-hydroxyvitamin D3 and HPMC
Claim 16	Dosage-form coverage	Capsule, tablet, sachet or dragee
Claims 17-19	Clinical pharmacokinetic formulations	AUC0-6 weeks at 30, 60 or 90 mcg daily
Claims 20-28	Dependent clinical formulations	25-hydroxyvitamin D3, paraffin wax, HPMC and defined excipient ranges

The patent therefore has a layered structure. Claim 1 establishes the broad formulation platform. Claims 3-16 narrow the platform by excipient, composition and dosage form. Claims 17-19 create separate independent claim categories based on clinical exposure.

How broad is claim 1 of Patent 10,300,078?

Claim 1 is broad in ingredient selection but narrow in performance requirements. It covers either 25-hydroxyvitamin D2 or 25-hydroxyvitamin D3, including formulations containing both. It does not require a specific capsule shell, manufacturing process, particle size or tablet geometry.

The claim does require a lipophilic matrix and a cellulose ether in the 5 wt% to 30 wt% range. A formulation using a hydrophilic matrix without a lipophilic phase would fall outside the literal scope of claim 1. The same is true for a lipophilic matrix using a non-cellulosic stabilizer, unless another patent claim applies.

The Cmax limitation is important. The formulation must provide a mean baseline-adjusted in vivo Cmax per microgram of vitamin D administered to humans of approximately 0.0133 ng/mL to 0.04 ng/mL. This limitation introduces several potential claim-construction issues:

• The meaning of “mean” depends on the study population and statistical treatment.
• “Baseline-adjusted” requires subtraction or adjustment for pre-dose endogenous vitamin D levels.
• The unit-normalized Cmax depends on the administered dose.
• The claim does not specify a particular assay, sampling schedule or number of subjects.
• “About” creates a range boundary that may require expert and industry evidence.

For a generic manufacturer, failure to use the same matrix does not automatically eliminate risk if the alternative formulation produces the claimed pharmacokinetic profile. Conversely, a formulation with the same excipients may avoid claim 1 if its measured Cmax falls outside the claimed range, although reliance on pharmacokinetic non-infringement creates testing and litigation risk.

What formulations are protected by the dependent claims?

The dependent claims identify the commercial formulation architecture most closely associated with the patent.

Wax, oil and emulsifier matrix

Claims 3 and 4 cover a lipophilic matrix containing a wax, specifically including paraffin wax. Claims 9 and 10 cover an oily vehicle, including mineral oil. Claims 5 and 6 cover emulsifiers, with glycerol monostearate expressly identified.

Claim 11 combines the main functional excipient categories:

• Wax
• Oil
• Emulsifier
• Absorption enhancer

This claim is narrower than claim 1 but captures a formulation design that is difficult to avoid without changing several excipient classes.

Absorption-enhancer coverage

Claims 7 and 8 cover a mixture of lauroyl macrogolglycerides and lauroyl polyoxylglycerides. This type of excipient combination can improve dispersion, solubilization or absorption of the lipophilic vitamin D compound.

A generic product using a different absorption enhancer may avoid claims 7, 8, 11 and 12, but it would remain exposed to claim 1 if it uses a cellulose ether-stabilized lipophilic matrix and meets the claimed pharmacokinetic range.

Defined composition in claim 12

Claim 12 is the most commercially specific composition claim. It requires approximately:

Component	Claimed amount
Paraffin	About 20 wt%
Glycerol monostearate	About 20 wt% to 25 wt%
Lauroyl macrogolglycerides and lauroyl polyoxylglycerides	About 10 wt%
Mineral oil	About 30 wt% to 35 wt%
Hydroxypropyl methylcellulose	About 10 wt% to 15 wt%

The listed ranges total approximately 90 wt% to 105 wt%, leaving room for active ingredient, capsule contents, processing aids and rounding. Because the claim uses “about,” minor deviations may remain within the literal scope depending on the specification, prosecution history and accepted formulation tolerances.

Claim 13 narrows claim 12 to 25-hydroxyvitamin D3. Claims 14 and 15 define the cellulose ether class and identify hydroxypropyl methylcellulose, commonly abbreviated HPMC, as the preferred member.

How do claims 17-19 protect clinical formulations?

Claims 17-19 are independent formulation claims that incorporate clinical-use pharmacokinetics without being drafted as conventional method-of-treatment claims.

Claim	Patient population	Daily dose	Claimed baseline-adjusted AUC0-6 weeks
17	Adults with CKD Stage 3, secondary hyperparathyroidism and vitamin D insufficiency	30 mcg	Mean of about 700 ng·day/mL
18	Same	60 mcg	Mean of about 1,500 ng·day/mL
19	Same	90 mcg	Mean of about 2,100 ng·day/mL

These claims require the same basic formulation architecture as claim 1, including a lipophilic matrix and 5% to 30% cellulose ether. They then add a dose-specific AUC result in a defined CKD population.

Claims 17-19 can be commercially significant because they track the dosing logic used for extended-release calcifediol in chronic kidney disease. They also create evidentiary complications. An infringement case would likely require:

• Product composition testing.
• Dose confirmation.
• Clinical or comparative pharmacokinetic evidence.
• Interpretation of the CKD Stage 3 population.
• A determination of whether the accused formulation produces the claimed mean AUC.

A product may avoid claims 17-19 by using a different dose, a different patient population, or a materially different exposure profile. It may still infringe claim 1 or other related patents.

What is the scope of the dosage-form claim?

Claim 16 covers an extended-release dosage form in the form of a capsule, tablet, sachet or dragee that contains the stabilized formulation of claim 1.

The claim does not require a capsule specifically. A competing product in a tablet or sachet could fall within claim 16 if it contains the claimed formulation. Conversely, a dosage form using a formulation that lacks the required cellulose ether concentration or lipophilic matrix would not meet claim 16 through literal incorporation of claim 1.

The claim creates broad dosage-form coverage, but its reach remains dependent on all limitations of claim 1.

How strong is the patent estate for Rayaldee and extended-release calcifediol?

U.S. Patent 10,300,078 is one part of a broader Rayaldee-related patent estate. Rayaldee is an extended-release oral formulation of calcifediol, also known as 25-hydroxyvitamin D3. The FDA approved Rayaldee in 2016 for adults with chronic kidney disease Stage 3 or 4, not on dialysis, who have secondary hyperparathyroidism and vitamin D insufficiency [2].

The estate has several potential protection layers:

Protection layer	Relevance to generic entry
Active ingredient	Limited for calcifediol because the molecule is established and chemically known
Extended-release formulation	High relevance; covers release architecture and excipient selection
Stabilization technology	High relevance to products using cellulose ethers in lipophilic matrices
Pharmacokinetic performance	Relevant where the generic reproduces Rayaldee exposure
Method of use	May cover CKD, secondary hyperparathyroidism and vitamin D insufficiency
Dosage form	Relevant to capsules and other oral extended-release presentations
Manufacturing process	Potentially relevant if the process uses protected mixing, melting, coating or encapsulation steps

The patent is strongest against a product that copies the composition disclosed in claim 12, particularly paraffin, glycerol monostearate, mineral oil, the specified lauroyl excipient mixture and HPMC.

Its strength is lower against a product that uses:

• A hydrophilic polymer matrix.
• A non-cellulosic stabilizer.
• A different vitamin D analog.
• A different release mechanism.
• A composition outside the claimed cellulose ether range.
• A dose or patient population that does not generate the claimed clinical AUC.

The estate should be evaluated as a portfolio. Avoiding this patent does not establish freedom to operate if a separate formulation, method-of-use or dosage-form patent remains enforceable.

When does U.S. Patent 10,300,078 lose exclusivity?

The patent issued on June 11, 2019. Its term is generally calculated from the earliest effective nonprovisional filing date in its priority chain, subject to patent-term adjustment and any applicable terminal disclaimer [1, 5].

The patent family is associated with a 2034 expiration horizon. The relevant term date is approximately June 2034, subject to the USPTO-recorded patent-term calculation. A generic launch assessment must use the official USPTO term data and any terminal-disclaimer information rather than the issue date alone.

FDA regulatory exclusivity is separate from patent exclusivity. Rayaldee received FDA approval in 2016. Any new chemical entity exclusivity associated with the approval would have expired before the patent term. The commercial barrier therefore depends primarily on listed patents, formulation claims and related patent-family members.

What is the Orange Book status of Patent 10,300,078?

Rayaldee is listed in the FDA Orange Book as an approved prescription product, and the Orange Book provides the principal FDA source for approved-product patent and exclusivity information [3]. U.S. Patent 10,300,078 is associated with the Rayaldee patent estate and is relevant to ANDA certification analysis.

An ANDA applicant seeking approval before the relevant patent expiration dates generally must address listed patents through one of the statutory certifications under the Hatch-Waxman framework:

• Paragraph I: no patent information is listed.
• Paragraph II: the listed patent has expired.
• Paragraph III: approval is sought after patent expiration.
• Paragraph IV: the patent is invalid, unenforceable or will not be infringed.

A Paragraph IV certification can trigger a patent-infringement action within the statutory period. A timely action can impose a 30-month stay of FDA approval, subject to statutory exceptions and court developments [4].

The Orange Book listing does not itself establish infringement. It identifies patents that an ANDA applicant must address. The decisive issues remain claim construction, product composition, pharmacokinetic evidence and patent validity.

Which companies are challenging Rayaldee patents?

Public FDA Orange Book records identify the listed patents but generally do not provide a complete real-time record of every ANDA applicant, certification, litigation settlement or commercial launch strategy. No confirmed Paragraph IV challenger or final settlement involving U.S. Patent 10,300,078 is established by the claim information supplied here.

The relevant competitive set includes:

• Generic manufacturers pursuing an ANDA for extended-release calcifediol.
• Manufacturers of immediate-release calcifediol products.
• Sponsors of vitamin D analogs such as paricalcitol, doxercalciferol and calcitriol.
• Companies developing oral formulations for CKD-associated secondary hyperparathyroidism.

Immediate-release vitamin D products are not direct substitutes for purposes of literal infringement because they do not necessarily contain the patented extended-release lipophilic matrix. They can still compete clinically and commercially if physicians use them for vitamin D repletion.

What Paragraph IV risks exist for a generic Rayaldee product?

A generic applicant could challenge Patent 10,300,078 on three principal grounds.

Non-infringement

The applicant could design around one or more limitations by using:

• No cellulose ether.
• Less than 5 wt% or more than 30 wt% cellulose ether.
• A non-lipophilic release matrix.
• A different active ingredient.
• A formulation that does not produce the claimed Cmax or AUC.
• A different excipient system from claim 12.

A non-infringement position based on pharmacokinetic results can be difficult because the applicant may need comparative human data. A formulation that is bioequivalent for FDA purposes may still produce data relevant to infringement under a performance-limited claim.

Invalidity

Potential validity arguments would focus on anticipation, obviousness, written description, enablement and indefiniteness. The most vulnerable features for challenge could include:

• Combining known lipophilic matrix excipients with known cellulose ethers.
• Selecting the 5 wt% to 30 wt% concentration range.
• Claiming a pharmacokinetic result that may arise from routine formulation optimization.
• Defining clinical AUC values without extensive formulation-specific structural limitations.

The patent’s counterargument would be that the cellulose ether stabilizes dissolution behavior over time in a difficult lipophilic system and that the claimed composition produces predictable, reproducible human exposure.

Unenforceability

Potential unenforceability theories would depend on prosecution conduct, inventorship, disclosure obligations and patent-term documents. No such determination follows from the issued claims alone.

What manufacturing and formulation barriers affect generic entry?

The principal technical barrier is not synthesis of calcifediol. It is reproducible manufacture of a stable extended-release lipid matrix.

A manufacturer attempting to reproduce the claimed architecture would need to control:

• Wax melting and solidification.
• Uniform dispersion of HPMC through the lipophilic phase.
• Distribution of the active ingredient.
• Viscosity and particle-size effects.
• Capsule fill weight.
• Dissolution profiles across storage conditions.
• Stability at 25°C and 60% relative humidity.
• Lot-to-lot Cmax and AUC behavior.

Claim 2 is commercially important because it requires post-storage Cmax within 80% to 125% of the pre-storage product mean after three months at 25°C and 60% relative humidity. A generic manufacturer may need to demonstrate stable dissolution and exposure even if it avoids the exact claim 12 composition.

The formulation’s use of both lipid components and HPMC creates a manufacturing design problem. Changing one excipient may alter release rate, dispersion, absorption and stability simultaneously. That interaction can raise development cost and increase the risk that a nominally different formulation remains within the functional scope of claim 1.

How does Patent 10,300,078 compare with competing vitamin D products?

Product or category	Active ingredient	Release profile	CKD-focused indication	Direct exposure to Patent 10,300,078
Rayaldee	Extended-release calcifediol	Extended release	Yes	Core product
Immediate-release calcifediol	Calcifediol	Immediate release	Variable	Generally lower
Calcitriol products	Calcitriol	Usually immediate release	Secondary hyperparathyroidism and related uses	Low for this formulation patent
Doxercalciferol products	Doxercalciferol	Immediate release	Secondary hyperparathyroidism	Low
Paricalcitol products	Paricalcitol	Immediate or injectable formulations	Secondary hyperparathyroidism	Low
A future generic ER calcifediol	Calcifediol	Extended release	Potentially yes	High if matrix and PK overlap

The patent is narrower than a patent on all calcifediol treatment but more relevant to a direct generic of Rayaldee than patents covering unrelated vitamin D analogs.

What revenue exposure does the patent create?

The patent’s revenue exposure is concentrated in the market for prescription extended-release calcifediol used in adults with CKD and vitamin D insufficiency. The risk is highest if:

• Rayaldee remains the principal approved extended-release calcifediol product.
• The patent and related family members remain enforceable through the 2034 period.
• No non-infringing generic formulation secures approval and launch.
• Related method-of-use and formulation patents provide overlapping protection.

A generic launch could reduce price and volume for the branded product. The magnitude depends on the number of entrants, the timing of any authorized generic, payer substitution rules, and whether the generic can use the same labeling and dosing claims.

For investors and licensors, Patent 10,300,078 should be valued as a formulation barrier with significant product-specific relevance but limited blocking power over the broader vitamin D market.

Key Takeaways

• U.S. Patent 10,300,078 covers stabilized extended-release formulations of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3.
• The core technical requirement is a lipophilic matrix containing 5 wt% to 30 wt% cellulose ether.
• HPMC, paraffin wax, mineral oil, glycerol monostearate and lauroyl-based absorption enhancers receive specific dependent-claim protection.
• Claim 12 is the strongest composition claim against a Rayaldee-like formulation.
• Claims 17-19 add CKD Stage 3, dose-specific and AUC-based limitations.
• Claim 2 protects a defined post-storage Cmax stability result.
• The patent is associated with a 2034 U.S. expiration horizon, subject to the official USPTO term calculation.
• Generic risk is highest for an ANDA product that copies the claimed lipid/HPMC architecture and reproduces Rayaldee-like pharmacokinetics.
• A non-lipophilic matrix, non-cellulosic stabilizer or materially different exposure profile may provide a design-around route.
• Patent 10,300,078 does not cover calcifediol as a molecule or all vitamin D therapies for CKD.
• Orange Book and related family patents must be assessed together before making a launch or licensing decision.

FAQs About U.S. Patent 10,300,078

Does Patent 10,300,078 cover ordinary vitamin D3 supplements?

No. The claims require 25-hydroxyvitamin D2 or 25-hydroxyvitamin D3 in an extended-release lipophilic matrix with a cellulose ether. Ordinary cholecalciferol supplements generally do not meet those limitations.

Can a generic use hydroxypropyl methylcellulose and avoid the patent?

Not necessarily. HPMC is expressly identified in claims 14, 15, 27 and 28. A product using HPMC at 5 wt% to 30 wt% in a qualifying lipophilic matrix may remain exposed to claim 1 even if it avoids the narrower claim 12 composition.

Does a capsule automatically infringe claim 16?

No. The capsule must contain the stabilized formulation of claim 1. Capsule format alone is insufficient.

Are the AUC values in claims 17-19 treatment claims?

They are independent formulation claims that include patient population, dose and pharmacokinetic limitations. Their enforcement would require analysis of both the formulation and the claimed clinical exposure.

Does FDA approval establish that a generic product infringes Patent 10,300,078?

No. FDA approval and patent infringement are separate legal questions. An ANDA applicant must address listed patents, but approval does not determine whether the marketed formulation meets the patent claims.

References

1. United States Patent and Trademark Office. (2019). U.S. Patent No. 10,300,078, stabilized extended release formulations of vitamin D compounds.
2. U.S. Food and Drug Administration. (2016). Rayaldee (calcifediol) extended-release capsules: Prescribing information.
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. Hatch-Waxman Act, 21 U.S.C. § 355(j).
5. United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation guidance.

Drugs Protected by US Patent 10,300,078

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	10,300,078		Y

International Family Members for US Patent 10,300,078

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2968172		122021000009	Germany
European Patent Office	2968172		301095	Netherlands
European Patent Office	2968172		CA 2021 00005	Denmark
European Patent Office	2968172		132021000000074	Italy