Details for Patent: 8,921,326

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Which drugs does patent 8,921,326 protect, and when does it expire?

Patent 8,921,326 protects LUPRON DEPOT and LUPRON DEPOT-PED KIT and is included in two NDAs.

This patent has thirty-five patent family members in twenty-eight countries.

Summary for Patent: 8,921,326

Title:	Sustained-release composition and method for producing the same
Abstract:	Sustained-release compositions wherein a water-soluble physiologically active peptide is substantially uniformly dispersed in a microcapsule comprised of a lactic acid polymer or a salt thereof, and the physiologically active substance is contained in an amount of 15 to 35 wt/wt % to the total microcapsules and weight-average molecular weight (Mw) of the lactic acid polymer is about 11,000 to about 27,000, which is characterized by having a high content of the physiologically active substance, and suppression of the initial excessive release within one day after the administration and a stable drug sustained-release over a long period of time, and method for producing the same.
Inventor(s):	Tomomichi Futo, Kazuhiro Saito, Tetsuo Hoshino, Masuhisa Hori
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US12/312,751
Patent Claim Types: see list of patent claims	Composition; Formulation; Dosage form;

United States Drug Patent 8,921,326: Claim Scope, Exclusivity, Litigation Risk, and Patent Landscape

U.S. Patent No. 8,921,326 protects a sustained-release leuprorelin acetate microsphere formulation using a lactic-acid-based polymer matrix and stearic acid. The independent claim is composition-based and requires a specific combination of peptide loading, polymer molecular weight, stearic-acid inclusion, and substantially uniform dispersion. Dependent claims add manufacturing parameters that narrow the protected process and product structure.

The patent is most relevant to long-acting injectable leuprorelin products for prostate cancer, endometriosis, uterine fibroids, precocious puberty, breast cancer, and contraception. It does not broadly cover leuprorelin, all depot formulations, or all polylactic-co-glycolic acid formulations. A competing product can avoid literal infringement by changing one required feature, although the doctrine of equivalents and process evidence remain relevant.

What drug and formulation does U.S. Patent 8,921,326 protect?

The claimed active substance is leuprorelin, also called leuprolide, specifically the peptide:

5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C2H5

The claims cover the peptide itself and its acetate salt when incorporated into sustained-release microcapsules. The formulation is structurally defined by the following elements:

Required feature	Claim requirement
Active ingredient	Leuprorelin peptide or leuprorelin acetate
Dosage form	Sustained-release microcapsule composition
Matrix	Lactic acid polymer or salt
Distribution	Active substantially uniformly dispersed in the microcapsule
Active loading	15% to 35% by weight of total microcapsules
Polymer molecular weight	Mw about 11,000 to 27,000
Release modifier	Stearic acid
Pharmaceutical use	Pharmaceutical, prophylactic, therapeutic, or contraceptive use

Independent claim 1 is the principal composition claim. Claim 30 covers a pharmaceutical composition containing the claimed sustained-release composition. Claims 31 and 32 cover specified therapeutic and prophylactic uses.

How broad is claim 1 of U.S. Patent 8,921,326?

Claim 1 is narrower than a generic claim to a leuprorelin depot injection. It requires all of the following limitations:

1. A physiologically active substance that is the specified leuprorelin peptide or acetate.
2. Substantial uniform dispersion within a microcapsule.
3. A lactic acid polymer or salt as the encapsulating material.
4. Active loading of 15% to 35% by weight.
5. Polymer Mw of about 11,000 to about 27,000.
6. Stearic acid in the sustained-release composition.

The claim does not require a particular injection volume, particle-size distribution, release duration, route of administration, vial configuration, or named commercial product. It also does not expressly require poly-DL-lactic acid, PLGA, dichloromethane, alcohol, or the specific emulsion process. Those limitations appear in dependent claims.

The phrase “about” creates a potentially material claim-construction issue. A court would assess the scope of the numerical ranges in light of the specification, prosecution history, measurement method, and ordinary pharmaceutical formulation practice. Polymer Mw and loading percentage are therefore likely to become central infringement and validity issues.

What dependent claims add to the protected formulation?

The dependent claims create several nested claim groups.

Polymer molecular-weight claims

Claims 2, 21, 22, and 27-29 narrow the polymer range:

Claim	Polymer Mw limitation
2	About 11,600-20,000 or about 19,000-27,000
21	11,600-20,000 and Mw/Mn greater than 1.9
22	19,000-27,000 and Mw/Mn greater than 1.5
27	12,000-19,000
28	13,000-18,000
29	19,500-26,500

These claims target polymer populations with defined molecular-weight distributions, not merely a nominal average. The Mw/Mn limitations may be useful in distinguishing the claimed formulation from a polymer with similar Mw but a narrower molecular-weight distribution.

Polymer identity and composition

Claims 23-26 cover:

• Polylactic acid.
• Poly-DL-lactic acid.
• Lactic acid-glycolic acid polymer.
• A lactic-acid-to-glycolic-acid ratio of 60/40 to 99.9/0.1.

A PLGA formulation falls within these claims only if its lactic-acid content, molecular weight, active loading, stearic-acid content, and other claim limitations also satisfy the relevant claim.

Stearic-acid limitations

Claim 19 requires stearic acid at about 0.01% to about 50% by weight of the total microcapsules. Claim 20 requires 0.1 to 10 moles of stearic acid per mole of peptide or acetate. Claim 33 narrows that ratio to 0.25 to 2 moles per mole of peptide or acetate.

Claim 34 excludes hydroxynaphthoic acid. This negative limitation may distinguish the claimed formulation from earlier depot compositions using hydroxynaphthoic acid or related hydrophobic release modifiers.

Manufacturing claims

Claims 4-18 cover an oil-in-water emulsion and in-water drying process. The process requires:

1. Dissolving the lactic acid polymer in a volatile water-immiscible solvent.
2. Dissolving leuprorelin or its acetate in a water-miscible solvent.
3. Mixing the two solutions into a uniform third solution.
4. Dispersing that solution in an aqueous emulsifier solution.
5. Removing the solvents from the resulting microcapsules.

The dependent process limitations include dichloromethane as the first solvent, methanol, ethanol, or propanol as the lower alcohol, a water-immiscible-to-water-miscible solvent ratio of 35:65 to 55:45, polymer concentration of about 33% to 45% by weight, and controlled temperatures of about 15°C to 35°C.

What formulations are protected by U.S. Patent 8,921,326?

The strongest literal coverage applies to a formulation with the following profile:

Formulation parameter	Claim-supported range
Active	Leuprorelin acetate
Polymer	Poly-DL-lactic acid or PLGA
Polymer Mw	12,000-19,000, 13,000-18,000, or 19,500-26,500 depending on claim
Active loading	17%-26% under narrower claims
Stearic acid	0.01%-50% by weight or 0.25-2 moles per mole of peptide
Organic solvent	Dichloromethane plus a lower alcohol
Emulsion	O/W emulsion
Drying	In-water drying
Temperature	Approximately 15°C-35°C
Acid modifier exclusion	No hydroxynaphthoic acid under claim 34

The claims are directed to a high-drug-loading microsphere system. A formulation with less than 15% leuprorelin, more than 35% loading, no stearic acid, or a polymer Mw materially outside the claimed range may avoid claim 1. It may still require analysis under narrower claims, continuation patents, or other members of the patent family.

When does U.S. Patent 8,921,326 lose exclusivity?

The patent was granted on December 30, 2014. Its ordinary U.S. patent term is measured from the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension, terminal disclaimers, and any applicable disclaimer recorded in the patent file.[1]

The patent’s priority and term data should be read from the issued patent, its continuity data, and USPTO Patent Center rather than inferred solely from the grant date. The grant date does not itself establish the expiration date.[1] Based on the apparent 2011 priority-era filing history, the ordinary expiration window is in the early 2030s, but the operative date is the USPTO-calculated expiration date.

Exclusivity timeline

Event	Date or status
Earliest priority	Japanese priority claim associated with the patent family
U.S. application	Filed before grant; continuity information is recorded by USPTO
U.S. patent publication	Published before grant
U.S. grant	December 30, 2014
Patent term	Twenty years from the applicable earliest nonprovisional filing date, subject to adjustment
Regulatory exclusivity	Separate from patent term and dependent on the approved product
Orange Book exclusivity	Must be assessed against the specific reference-listed drug and listed patent

A patent expiration date cannot be equated with FDA market exclusivity. FDA exclusivity may expire earlier or later, and a patent may remain enforceable after regulatory exclusivity ends.

What is the Orange Book status of U.S. Patent 8,921,326?

Orange Book listing is product-specific. A patent is not automatically listed because it covers a formulation or method of use. FDA generally lists patents submitted by the NDA holder and accepted for listing against a particular approved drug and dosage form.[2]

Leuprolide products include depot injections marketed under different products and sponsors, including Lupron Depot and Eligard. Those products use different formulation platforms and are not interchangeable for patent analysis. Lupron Depot is a leuprolide acetate microsphere product, while Eligard uses the Atrigel delivery system.[3,4]

The practical Orange Book questions are:

• Whether U.S. Patent 8,921,326 was submitted for a particular leuprolide NDA.
• Whether FDA accepted the patent for listing.
• Which strengths and dosage forms it covers.
• Whether the listing is a drug-substance, drug-product, or method-of-use patent.
• Whether the listed claims correspond to the approved product.

A patent can create substantial freedom-to-operate risk without appearing in the Orange Book, particularly for injectable products, 505(b)(2) applications, manufacturing processes, or non-NDA commercial uses.

Which companies could face paragraph IV risk?

A generic or 505(b)(2) applicant seeking approval for a leuprorelin acetate depot product would face potential paragraph IV issues if the reference product’s patent listing includes this patent or related family members. A paragraph IV certification would require an assertion that the patent is invalid, unenforceable, or not infringed.

Potential challengers would likely include:

• Generic injectable manufacturers.
• Specialty pharmaceutical companies developing long-acting GnRH agonist products.
• 505(b)(2) applicants relying on published clinical or safety data.
• Contract manufacturers supplying microsphere products.
• Sponsors developing alternative leuprorelin depot technologies.

A formulation applicant can reduce claim risk by using a different polymer molecular-weight profile, omitting stearic acid, adopting a different release modifier, changing active loading, or using a different encapsulation process. Those design choices must be validated against all claims, including claims 30-34 and any related patents.

What generic launch risks exist?

The principal launch risks are technical, regulatory, and litigation-related.

Technical risk

The most important parameters are polymer Mw, Mw/Mn, active loading, stearic-acid quantity, solvent composition, and temperature. These parameters are measurable in development and batch-release records. A patent owner could seek production records, analytical data, development reports, and supplier specifications in discovery.

Regulatory risk

Injectable microsphere products require close control of particle size, residual solvents, sterility, release profile, peptide integrity, and batch consistency. A design-around that avoids a patent limitation may create a separate FDA comparability or bioequivalence problem.

Litigation risk

A Paragraph IV notice could trigger a Hatch-Waxman action and a 30-month stay if the patent is properly listed and the statutory requirements are met.[2] If the patent is not listed, the sponsor may still pursue a conventional infringement action, but the Orange Book stay mechanism would not apply.

How strong is the patent estate?

The patent has meaningful formulation strength but limited molecule-level breadth.

Strength factor	Assessment
Active ingredient	Narrow to leuprorelin or its acetate
Core composition	Strong if all loading, Mw, and stearic-acid limits are met
Process coverage	Detailed and potentially difficult to prove without manufacturing records
Design-around exposure	Moderate to high
Polymer coverage	Broad across PLA, poly-DL-lactic acid, and specified PLGA
Numerical limitations	Useful for commercial targeting but vulnerable to measurement and claim-construction disputes
Therapeutic-use coverage	Broad list of indications, but dependent on composition claim validity
Product blocking power	Product-specific; depends on formulation overlap and patent listing

The patent is stronger against an identical or closely matched high-loading microsphere formulation than against a conventional leuprorelin depot using a different polymer system or release modifier.

How does this patent compare with competing leuprorelin delivery technologies?

Technology	Representative product or approach	Relationship to U.S. 8,921,326
Lactic-acid microspheres with stearic acid	Claimed platform	Directly targeted
PLGA microspheres without stearic acid	Alternative microsphere design	May avoid claim 1, subject to other claims
Atrigel in situ depot	Eligard	Different delivery architecture
Conventional leuprolide microspheres	Lupron Depot and related products	Requires product-specific formulation comparison
Implant or other long-acting depot	Alternative delivery system	Generally outside the claimed microcapsule structure

The key competitive distinction is that U.S. Patent 8,921,326 claims a specific microsphere composition and preparation route, not every long-acting leuprorelin product.

What patent litigation and settlement issues affect the patent?

The relevant litigation questions are whether:

• The patent was asserted against a leuprorelin applicant.
• A generic applicant filed a Paragraph IV certification.
• The patent owner entered a launch-date or license settlement.
• A terminal disclaimer or post-grant proceeding affected enforceability.
• Related family patents were asserted instead of, or together with, U.S. 8,921,326.

A complete litigation conclusion requires current USPTO Patent Center, PACER, FDA Orange Book, and FDA Paragraph IV records. The patent number alone does not establish a litigation history, settlement, or commercial license.

Are biosimilar risks relevant?

No. Leuprorelin is a chemically synthesized peptide drug, not a biologic subject to the biosimilar pathway under the Public Health Service Act. The relevant regulatory routes are an ANDA or, depending on the product and reliance strategy, a 505(b)(2) application. FDA’s biosimilar framework does not govern a generic leuprorelin acetate microsphere product.[5]

What licensing and manufacturing barriers matter?

The most significant manufacturing barrier is reproducibility. The claimed process combines high polymer concentration, mixed solvents, controlled emulsification temperature, and in-water drying. Small changes can affect particle morphology, encapsulation efficiency, residual solvent content, and release kinetics.

Commercial risk may also arise from:

• Access to controlled-release peptide manufacturing capacity.
• Supply of pharmaceutical-grade PLA or PLGA with the required Mw/Mn profile.
• Scale-up of dichloromethane and alcohol solvent removal.
• Sterile filling of microsphere suspensions.
• Analytical methods for polymer molecular-weight distribution.
• Control of stearic-acid content and distribution.

No licensing right should be inferred from the patent’s assignment or ownership record. A license, covenant not to sue, or settlement would require documentary evidence from the patent owner or litigation record.

Key Takeaways

• U.S. Patent 8,921,326 targets high-loading leuprorelin acetate microcapsules.
• Claim 1 requires lactic acid polymer, 15%-35% active loading, polymer Mw of about 11,000-27,000, stearic acid, and substantially uniform dispersion.
• Dependent claims add narrower polymer ranges, Mw/Mn ratios, solvent systems, temperature controls, emulsion conditions, and stearic-acid ratios.
• The patent does not broadly block all leuprorelin depot products.
• A PLGA or PLA product must be compared against every limitation, not merely the active ingredient.
• Orange Book listing must be confirmed against the specific leuprorelin NDA and dosage form.
• Generic risk is highest for a microsphere product using the claimed molecular-weight and stearic-acid profile.
• Biosimilar analysis is not applicable; ANDA and 505(b)(2) pathways are the relevant FDA routes.
• The operative expiration date depends on the patent’s continuity, patent-term adjustment, and any recorded disclaimer or extension.

Frequently Asked Questions

Does U.S. Patent 8,921,326 cover Lupron Depot?

It may be relevant to a Lupron Depot-type leuprorelin microsphere only if the commercial formulation satisfies the claimed polymer, molecular-weight, active-loading, stearic-acid, and dispersion limitations. Product branding alone does not establish infringement.

Does U.S. Patent 8,921,326 cover Eligard?

Eligard uses the Atrigel delivery system. Because the patent claims lactic-acid-based microcapsules, an Eligard product would require a separate formulation comparison and would not be presumed to infringe.

Can a generic avoid the patent by removing stearic acid?

Removing stearic acid can avoid a literal limitation of claim 1, but the complete claim set and related patent family must also be reviewed. The design change may affect drug release and FDA approval requirements.

Is a formulation with PLGA automatically covered?

No. PLGA is covered only when the formulation also meets the applicable active-loading, polymer molecular-weight, stearic-acid, dispersion, and other limitations. Claim 25 alone does not eliminate the limitations inherited from claim 1.

Is the patent relevant to a leuprorelin implant?

Generally, the claims are directed to microcapsules and an O/W emulsion process. An implant using a materially different delivery architecture would require separate analysis and may fall outside the literal scope of these claims.

References

1. United States Patent and Trademark Office. (2014). U.S. Patent No. 8,921,326, sustained-release composition.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
3. U.S. Food and Drug Administration. (2024). Drugs@FDA: Lupron Depot leuprolide acetate.
4. U.S. Food and Drug Administration. (2024). Drugs@FDA: Eligard leuprolide acetate.
5. U.S. Food and Drug Administration. (2024). Biosimilar and interchangeable biologic products.

Drugs Protected by US Patent 8,921,326

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Abbvie Endocrine Inc	LUPRON DEPOT	leuprolide acetate	INJECTABLE;INJECTION	020517-003	Jun 17, 2011		RX	Yes	Yes	8,921,326		Y			PALLIATIVE TREATMENT OF PROSTATE CANCER
Abbvie Endocrine Inc	LUPRON DEPOT-PED KIT	leuprolide acetate	POWDER;INTRAMUSCULAR	020263-009	Apr 14, 2023		RX	Yes	Yes	8,921,326		Y

Foreign Priority and PCT Information for Patent: 8,921,326

PCT Information
PCT Filed	December 17, 2007	PCT Application Number:	PCT/JP2007/074617
PCT Publication Date:	June 26, 2008	PCT Publication Number:	WO2008/075762

International Family Members for US Patent 8,921,326

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	064381
Australia	2007335406
Brazil	PI0720582
Canada	2671670