Details for Patent: 9,617,303

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Which drugs does patent 9,617,303 protect, and when does it expire?

Patent 9,617,303 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: 9,617,303

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:	US14/547,467
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

US Patent 9,617,303: Leuprolide Depot Formulation Claims, Patent Scope, and Generic Entry Risk

US Patent 9,617,303 protects selected sustained-release leuprolide formulations rather than leuprolide itself. The claims require a specific combination of leuprolide acetate, a lactic-acid polymer microcapsule, stearic acid, drug loading, polymer molecular weight, and release-performance characteristics. The broadest independent claims are method-of-treatment claims directed to prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids, precocious puberty, dysmenorrhea, breast cancer, contraception, and postoperative recurrence of premenopausal breast cancer.

The patent is strategically relevant to long-acting leuprolide products, including products using biodegradable polylactic acid or polylactic-co-glycolic acid microspheres. It does not broadly monopolize all leuprolide injections, all GnRH agonists, or all sustained-release peptide products.

What drug and formulation does US Patent 9,617,303 cover?

The claimed peptide is leuprolide, also known as leuprorelin:

Element	Claimed requirement
Active ingredient	5-oxo-Pro-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NH-C2H5, or an acetate salt
Drug class	Gonadotropin-releasing hormone, or GnRH, agonist
Dosage technology	Sustained-release microcapsule
Polymer	Lactic acid polymer or salt
Polymer molecular weight	About 11,000 to about 27,000 Mw
Drug loading	15% to 35% by weight of total microcapsules
Additional excipient	Stearic acid
Administration	Administration to a mammal
Claimed results	Sustained blood levels for approximately 60 to 400 days, depending on polymer molecular weight

Leuprolide suppresses pituitary gonadotropin release after an initial stimulation phase. Approved uses include advanced prostate cancer, endometriosis, uterine fibroids, and central precocious puberty. Product-specific indications and dosage schedules vary by formulation and sponsor. FDA product labeling identifies leuprolide acetate as the active ingredient in Lupron Depot and related depot products. (FDA, 2024a)

The patent focuses on the delivery system. The inventive distinction is the use of polymer molecular weight, molecular-weight distribution, stearic acid, and peptide loading to control the initial release peak and the duration of release.

What are the independent claims of US 9,617,303?

The patent has two principal independent method claims.

Claim 1: broad sustained-release treatment method

Claim 1 requires all of the following:

1. Treatment of one of the listed diseases or use as contraception.
2. Administration to a mammal.
3. A sustained-release composition.
4. Leuprolide or leuprolide acetate.
5. Substantially uniform dispersion of the active ingredient in a microcapsule.
6. A lactic acid polymer or salt.
7. Leuprolide content of 15% to 35% by weight.
8. Polymer Mw of approximately 11,000 to 27,000.
9. Stearic acid in the sustained-release composition.

Each limitation is material. A competing product that uses leuprolide in a non-microcapsule delivery system, omits stearic acid, falls outside the specified loading range, or uses a polymer outside the claimed molecular-weight range could avoid literal infringement of claim 1.

The claim is broad as to the disease indication but narrow as to formulation architecture.

Claim 27: postoperative breast-cancer recurrence

Claim 27 covers reducing postoperative recurrence of premenopausal breast cancer using substantially the same formulation limitations as claim 1.

This claim has a narrower therapeutic indication but may have commercial significance where adjuvant ovarian suppression is used after surgery in premenopausal patients. It also creates a potential method-of-use issue for products whose labeling includes breast-cancer treatment or recurrence-related use.

How do the dependent claims narrow the patent scope?

The dependent claims divide the technology into two release-duration platforms.

Claim group	Polymer Mw	Claimed release period
Claims 2, 3, 9, 18, 19, 21-23	About 11,600 to 20,000	About 60 to 130 days
Claims 2, 4, 10, 20, 24-26	About 19,000 to 27,000	About 120 to 400 days

The lower-Mw range is directed principally to approximately two- to four-month release. The higher-Mw range is directed to approximately four- to thirteen-month release.

Claims 18, 19, and 20 narrow the polymer ranges further:

• 12,000 to 19,000 Mw;
• 13,000 to 18,000 Mw; and
• 19,500 to 26,500 Mw.

These narrower ranges may be more difficult to invalidate for lack of written description if the specification contains formulation examples concentrated in those windows. They may also be easier for a generic or follow-on manufacturer to design around.

What formulation features are protected?

Drug loading

Claims 1 and 27 require leuprolide to represent 15% to 35% of total microcapsule weight. Claim 1 does not cover a formulation with 10% loading or 40% loading unless the product otherwise falls within a legally equivalent range. The loading requirement is likely important because peptide loading affects particle structure, burst release, manufacturing yield, and depot duration.

Stearic acid

Claims 1, 5, and 6 require stearic acid. The dependent claims specify:

• 0.01% to 50% by weight of total microcapsules; or
• 0.1 to 10 moles of stearic acid per mole of leuprolide or leuprolide salt.

This limitation distinguishes the patent from a formulation using only a lactic-acid polymer and leuprolide. A formulation using another fatty acid may avoid literal infringement, although the doctrine of equivalents could become relevant if the substitute performs substantially the same function in substantially the same way.

Polymer type

Claims 11 through 14 cover:

• Polylactic acid;
• Poly-DL-lactic acid; and
• Lactic acid-glycolic acid polymers.

For lactic acid-glycolic acid polymers, claim 14 requires a lactic-acid-to-glycolic-acid ratio of 60/40 to 99.9/0.1.

The claims therefore encompass both PLA and selected PLGA systems. They do not cover every PLGA composition without regard to drug loading, stearic acid, molecular weight, and the other limitations.

Low-molecular-weight fraction

Claims 15 through 17 impose limits on polymer fractions below specified molecular weights:

Claim	Polymer fraction limitation
15	Polymer having Mw of 5,000 or less is about 5.0% or less
16	Polymer having Mw of 3,000 or less is about 1.5% or less
17	Polymer having Mw of 1,000 or less is about 0.1% or less

These limitations address polymer quality and the relationship between low-molecular-weight species and early release. They may be particularly relevant to manufacturing controls, polymer supplier qualification, and batch-release testing.

What release-profile characteristics are claimed?

Claims 21 through 26 do not merely define formulation composition. They claim pharmacokinetic performance.

For the lower-Mw platform, the patent claims:

• A ratio of maximum blood concentration within 24 hours to average concentration from 24 hours to one month of 2 to 50;
• A ratio of maximum concentration within 24 hours to average concentration from one to three months of 20 to 350; and
• An initial 24-hour AUC equal to 3% to 30% of total AUC.

For the higher-Mw platform, the claims require:

• A 24-hour maximum-to-average concentration ratio of 10 to 90 for the first month;
• A ratio of 20 to 500 when compared with average concentration from one to six months; and
• An initial 24-hour AUC equal to 1% to 20% of total AUC.

These claims create enforcement complexity. A patent holder would need reliable pharmacokinetic data, a defined sampling protocol, and a defensible method for calculating average blood concentration and total AUC. Testing a commercial product may require clinical or in vivo comparative studies rather than simple chemical analysis.

How strong is the patent estate for leuprolide depot products?

The patent has meaningful but limited strength.

Strengths

The patent combines multiple technical limitations that are difficult to assess from a label alone:

• Polymer molecular weight;
• Molecular-weight distribution;
• Drug loading;
• Stearic acid content;
• Polymer identity;
• Release duration;
• Peak-to-average blood-level ratios; and
• Initial-versus-total AUC.

A generic sponsor may not be able to establish noninfringement solely from public labeling. It may need access to formulation-development records, polymer specifications, manufacturing data, and pharmacokinetic studies.

The claims also cover both shorter-duration and longer-duration release platforms. That broadens the technical reach across two- to thirteen-month depot products.

Weaknesses

The patent does not claim:

• Leuprolide as a molecule;
• Leuprolide acetate as a pharmaceutical ingredient generally;
• All sustained-release leuprolide products;
• All PLA or PLGA leuprolide microspheres;
• All prostate-cancer uses of leuprolide; or
• All formulations containing stearic acid.

The claims use terms such as "about," "substantially uniformly dispersed," "effective amount," "easily dispersible," and "stable for 24 hours or more." Those terms may create claim-construction disputes, especially for claims 7 and 8.

The claims also depend on analytical methods. Different methods for measuring Mw, Mn, low-molecular-weight fractions, blood concentration, or AUC could produce different results. The patent's enforceability will depend heavily on the specification's definitions, examples, and analytical protocols.

When does US Patent 9,617,303 lose exclusivity?

US Patent 9,617,303 issued on April 11, 2017. Its term is governed by the 20-year term measured from the earliest effective nonprovisional filing date, subject to patent-term adjustment and any applicable patent-term extension. The family priority structure, rather than the issue date, controls the ordinary expiration calculation. (USPTO, 2024)

Based on the patent-family timing associated with this technology, the ordinary expiration is expected to fall in approximately 2028 or 2029, before any patent-term adjustment. The precise enforceable expiration must be confirmed from the USPTO Patent Center term calculation and the patent's certificate data.

The patent does not create a new regulatory exclusivity period. Any FDA exclusivity would arise separately under the Federal Food, Drug, and Cosmetic Act and would depend on the relevant approved product and regulatory pathway. Patent expiration and FDA exclusivity are separate events.

What is the Orange Book status of US 9,617,303?

The Orange Book is product-specific. A patent appears in the Orange Book only when the NDA holder submits it and FDA accepts it as claiming the approved drug, formulation, or method of use under applicable listing rules. A patent document alone does not establish Orange Book listing.

For leuprolide depot products, Orange Book relevance depends on the specific NDA, sponsor, dosage form, and approved labeling. Lupron Depot is associated with AbbVie-related commercial operations, while leuprolide products have historically involved other manufacturers and license arrangements. FDA's Orange Book identifies listed patents by NDA and product rather than by therapeutic class alone. (FDA, 2024b)

US 9,617,303 should therefore be treated as a formulation and method-of-use patent requiring product-specific Orange Book verification. Its existence does not establish that every leuprolide product is blocked by the patent or that the patent is listed against every leuprolide NDA.

Which companies could challenge the patent through Paragraph IV?

Potential Paragraph IV challengers would be companies seeking approval for a generic or follow-on leuprolide depot product under an ANDA or other abbreviated pathway. The relevant competitive group includes:

• Generic injectable manufacturers;
• Specialty injectable companies;
• Companies with PLA or PLGA microsphere manufacturing capabilities;
• Existing suppliers of leuprolide acetate;
• Developers of long-acting GnRH agonist depots.

A Paragraph IV certification would require a challenger to address the patent claims identified in the relevant Orange Book listing. Possible positions include:

1. The patent is invalid for anticipation or obviousness.
2. The claims lack written description or enablement.
3. The proposed product does not contain stearic acid.
4. The product uses a polymer outside the claimed Mw range.
5. Drug loading falls outside 15% to 35%.
6. The product is not a substantially uniform microcapsule dispersion.
7. The proposed label does not induce infringement of a claimed method.
8. The patent has expired or is unenforceable.

If the patent is listed and a Paragraph IV notice is served, the NDA holder may obtain a statutory 30-month stay under applicable conditions. The stay would affect FDA approval timing, not necessarily the challenger's ability to manufacture or litigate.

What generic launch scenarios exist?

Scenario	Commercial result
Product falls within all composition limitations	High infringement exposure if claims are enforceable
Same active ingredient, non-microsphere delivery system	Potential design-around
PLA or PLGA microspheres without stearic acid	Potential design-around, subject to equivalents
Polymer Mw below or above claimed ranges	Potential design-around
Drug loading below 15% or above 35%	Potential design-around
Different release mechanism, such as in situ gel	Lower literal infringement risk
Product uses same composition but different indication label	Method-of-use risk remains if the label encourages a claimed use
Product launched after patent expiration	Patent-based blocking risk ends, subject to other valid rights

The principal commercial barrier is manufacturing reproducibility. A competitor may design around the claims but still face development risk associated with peptide stability, microsphere morphology, injection-site tolerability, burst release, residual solvent, scale-up, and batch consistency.

What manufacturing and intellectual-property barriers remain?

The patent claims implicate several process variables:

• Polymer synthesis and purification;
• Control of Mw and Mn;
• Removal of low-molecular-weight polymer fractions;
• Uniform peptide dispersion;
• Stearic-acid incorporation;
• Microsphere particle-size distribution;
• Aseptic processing;
• Sterilization compatibility;
• Reconstitution and syringeability; and
• Long-term release testing.

These controls may be protected by separate process, manufacturing, device, or formulation patents that are not resolved by analyzing US 9,617,303 alone. A freedom-to-operate review should separate this patent into four categories: formulation composition, manufacturing process, delivery device, and approved method of use.

How does this patent compare with competing leuprolide delivery technologies?

Technology	Delivery approach	Relationship to US 9,617,303
PLA or PLGA microsphere depot	Biodegradable polymer microcapsules	Directly relevant if all claim limitations are met
In situ polymer depot	Polymer precipitates or gels after injection	Potentially outside the microcapsule limitation
Conventional aqueous injection	Immediate or short-duration release	Generally outside the sustained-release microcapsule claims
Implantable depot	Solid implant or rod	Generally outside the microcapsule claims
Alternative GnRH agonist	Goserelin, histrelin, triptorelin, or nafarelin	Different active ingredient; no literal leuprolide claim coverage
Nonpeptide endocrine therapy	Androgen-receptor or estrogen-pathway drugs	Outside the claimed peptide composition

The closest competitive products are other long-acting leuprolide depots, not oral endocrine therapies or other GnRH agonists. A competitor using a different active ingredient does not need to avoid this patent but may compete clinically in the same therapeutic market.

What litigation and settlement issues affect the patent?

The supplied claims establish the scope of US 9,617,303 but do not establish a current infringement action, Paragraph IV notice, settlement agreement, or consent judgment. Those matters must be verified separately through PACER, USPTO Patent Center, FDA Orange Book records, and company disclosures.

The most likely litigation issues are:

• Whether a product contains stearic acid within the claimed amount;
• Whether the polymer Mw is measured by a comparable method;
• Whether the product has a substantially uniform dispersion;
• Whether a proposed label induces a claimed method of treatment;
• Whether the release duration limitation is a claim limitation or an intended result;
• Whether the patent's ranges are anticipated by earlier leuprolide microsphere publications; and
• Whether the claims are obvious combinations of known leuprolide depots, PLA or PLGA polymers, fatty acids, and release-control techniques.

Settlement terms in injectable-generic litigation often include delayed launch dates, licenses, authorized-generic arrangements, or covenants not to sue. No such term should be inferred from the patent's issuance or from the existence of a generic leuprolide product.

Key Takeaways

• US 9,617,303 is a formulation and method-of-treatment patent for sustained-release leuprolide microcapsules.
• The core limitations are 15% to 35% leuprolide loading, lactic-acid polymer Mw of approximately 11,000 to 27,000, and stearic acid.
• The patent covers both shorter-duration depots of approximately 60 to 130 days and longer-duration depots of approximately 120 to 400 days.
• PLA, poly-DL-lactic acid, and selected PLGA formulations are expressly covered by dependent claims.
• Claims 21 through 26 add pharmacokinetic limitations involving peak concentration and AUC.
• The patent does not claim leuprolide itself or every long-acting leuprolide product.
• Generic design-around opportunities include changing the delivery system, omitting stearic acid, altering polymer molecular weight, or moving outside the claimed drug-loading range.
• The ordinary patent term likely ends in approximately 2028 or 2029, subject to USPTO patent-term adjustment.
• Orange Book impact is product-specific and cannot be determined solely from the patent number.
• The commercial risk is highest for PLA or PLGA leuprolide microspheres that reproduce the claimed loading, stearic-acid content, polymer Mw, and release profile.

FAQs

Does US 9,617,303 cover Lupron Depot?

It may be relevant to Lupron Depot or another leuprolide microsphere product if the product satisfies every limitation of an enforceable claim. The patent number alone does not establish infringement or Orange Book listing.

Is leuprolide acetate itself patented by US 9,617,303?

No. The patent claims methods using leuprolide acetate in a specified sustained-release microcapsule formulation. It does not claim the active molecule in all forms.

Can a generic leuprolide product avoid the patent by using PLGA?

Not necessarily. PLGA is expressly covered by claims 13 and 14 when the polymer composition, molecular weight, loading, stearic acid, and other limitations are satisfied. PLGA alone is not a safe harbor.

Does a different leuprolide dosage schedule avoid infringement?

A different schedule may reduce exposure to claims requiring specified release periods, but it does not automatically avoid claim 1 or claim 27. The formulation and method limitations must be analyzed together.

Are biosimilars relevant to this patent?

No. Leuprolide is a chemically synthesized peptide drug, not a biological product typically challenged through the biosimilar pathway under the Public Health Service Act. Competition would generally arise through generic or other abbreviated regulatory pathways, subject to the applicable product classification.

References

1. AbbVie Inc. (2024). Lupron Depot prescribing information. U.S. Food and Drug Administration.

2. U.S. Food and Drug Administration. (2024a). Drugs@FDA: Lupron Depot and leuprolide acetate products. https://www.accessdata.fda.gov/scripts/cder/daf/

3. U.S. Food and Drug Administration. (2024b). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book

4. U.S. Patent and Trademark Office. (2017). U.S. Patent No. 9,617,303, Sustained-release composition.

5. U.S. Patent and Trademark Office. (2024). Patent term adjustment and patent term information. https://www.uspto.gov/patents/laws/patent-term-adjustment-patent-term-extension-priority

Drugs Protected by US Patent 9,617,303

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	9,617,303					TREATMENT OF ADVANCED PROSTATIC CANCER
Abbvie Endocrine Inc	LUPRON DEPOT-PED KIT	leuprolide acetate	POWDER;INTRAMUSCULAR	020263-009	Apr 14, 2023		RX	Yes	Yes	9,617,303					TREATMENT OF PEDIATRIC PATIENTS WITH CENTRAL PRECOCIOUS PUBERTY

International Family Members for US Patent 9,617,303

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	064381
Australia	2007335406
Brazil	PI0720582
Canada	2671670
Chile	2007003658
China	101563068