The patent is no longer enforceable. U.S. Patent No. 4,472,382 issued on September 18, 1984, and its ordinary 17-year term expired on September 18, 2001. Its commercial importance was historically tied to combined androgen deprivation using a long-acting luteinizing hormone-releasing hormone, or LH-RH, agonist, and a nonsteroidal antiandrogen. The principal peptide is buserelin, and the two named antiandrogens are nilutamide and flutamide. The claims do not cover those products individually, all prostate-cancer treatments, or later GnRH antagonists.
U.S. Patent 4,472,382: Scope, Claims, Expiration, and Patent Landscape
What does U.S. Patent 4,472,382 protect?
U.S. Patent 4,472,382 protects treatment methods using an association of:
- An antiandrogen; and
- A specified LH-RH peptide analog;
for prostate adenocarcinoma or benign prostatic hypertrophy.
The patent is a combination-treatment patent. Its central technical concept is the suppression of androgen signaling at two levels:
- The peptide suppresses testicular androgen production through LH-RH receptor activity.
- The antiandrogen blocks androgen-receptor signaling.
The broadest independent claim, claim 1, requires the administration of both components. A product containing only buserelin, only flutamide, or only nilutamide would not practice claim 1.
The claim is also limited to the enumerated peptide structures. It does not claim every LH-RH agonist or every GnRH analog.
What drugs and peptides are covered by the claims?
The principal peptide identified in the dependent claims is:
[D-Ser(tBu)6, des-Gly-NH2 10]-LH-RH ethylamide
This compound is buserelin, also known as buserelin acetate when formulated as a salt. Buserelin is a potent synthetic LH-RH or GnRH agonist.
The patent also identifies two antiandrogens.
| Patent reference |
Chemical compound |
Modern or common name |
| Claim 2 |
5,5-Dimethyl-3-[4-nitro-3-trifluoromethylphenyl]-2,4-imidazolidinedione |
Nilutamide |
| Claim 3 |
2-Methyl-N-[4-nitro-3-trifluoromethylphenyl]propanamide |
Flutamide |
| Claims 5, 9, 10, 17, 18 |
[D-Ser(tBu)6, des-Gly-NH2 10]-LH-RH ethylamide |
Buserelin |
Nilutamide and flutamide are chemically distinct nonsteroidal antiandrogens. Neither compound alone falls within the combination requirement of the independent claims.
How broad is claim 1?
Claim 1 has substantial chemical breadth but is narrower than a generic “GnRH agonist plus antiandrogen” claim.
It covers multiple substitutions at positions corresponding to X, Y, and Z in the peptide structure:
pGlu-His-Trp-Ser-Tyr-X-Y-Arg-Pro-Z
The listed alternatives include:
- Glycine, D-amino acids, L-amino acids, N-methyl amino acids and protected amino acids at X;
- Leucine, serine, cysteine, aspartic acid, glutamic acid, ornithine, lysine and related residues at Y;
- Gly-NH2, alkylamides, hydroxyalkylamides and cyclopropylamide groups at Z.
The claim therefore covers a genus of LH-RH analogs rather than only buserelin. However, the enumerated nature of the substitutions creates meaningful limits. A peptide analog outside the claimed X/Y/Z combinations would not literally satisfy claim 1.
The claim also requires use for one of two stated conditions:
- Prostate adenocarcinoma; or
- Prostate benign hypertrophy, commonly termed benign prostatic hyperplasia, or BPH.
The phrase “effective amount” is functional. It requires an amount capable of treating the specified prostate condition. It does not establish a single mandatory dose, route, or schedule unless a dependent claim is being asserted.
Which claims are directed specifically to buserelin?
Claims 5 and 9 through 14 are directed to buserelin, with route, dose and scheduling limitations.
| Claim |
Limitation |
| 5 |
Buserelin peptide specified by the D-Ser(tBu)6 and des-Gly-NH2 10 structure |
| 9 |
Parenteral administration at 10 to 200 micrograms per day |
| 10 |
Intranasal administration at 100 to 2,000 micrograms per day |
| 11 |
Once or twice daily, every day |
| 12 |
Once or twice daily, every day, for intranasal administration |
| 13 |
Once or twice daily with intervals of several days, parenterally |
| 14 |
Once or twice daily with intervals of several days, intranasally |
Claims 9 through 14 are narrower than claim 1. They may be easier to practice but are also easier to design around by changing the peptide, dose, route, or schedule.
What does claim 17 cover?
Claim 17 is the most commercially focused claim. It requires administration to male humans of:
- Buserelin; and
- Nilutamide.
The claim is limited to treatment of prostate adenocarcinoma and BPH.
It is narrower than claim 1 because it selects a particular peptide and a particular antiandrogen. It is also narrower because it expressly refers to male humans rather than the broader category of male warm-blooded animals.
Claim 18 adds daily dosing limitations. The supplied text states a nilutamide dose of 10 mg to 1 g per day and a peptide dose of 10 to 100,000 mg per day. The peptide range is chemically and clinically implausible when expressed in milligrams and conflicts with the microgram ranges elsewhere in the claim set. The official issued patent text and file history control whether this reflects an original claim limitation, a transcription error, or an OCR error. On the supplied wording alone, claim 18 should be treated as containing the stated milligram unit.
When did U.S. Patent 4,472,382 lose exclusivity?
The patent expired on September 18, 2001, based on the pre-Uruguay Round Agreements Act rule providing a 17-year term from grant for patents of this vintage.
| Event |
Date or status |
| Patent issued |
September 18, 1984 |
| Ordinary term |
17 years from issue |
| Expiration |
September 18, 2001 |
| Current enforceability |
Expired |
| Current Paragraph IV risk |
None for this patent |
| Current Orange Book value |
None based on this expired patent |
Patent term adjustment and patent term extension regimes applicable to newer patents do not revive an expired 1984 patent. The patent cannot support a present-day injunction against a generic, branded product, or biosimilar.
What is the Orange Book status of the patent?
U.S. Patent 4,472,382 should not be treated as a current Orange Book barrier.
The Orange Book lists patents submitted by sponsors for approved drug products. Buserelin has not been a major U.S. FDA-approved prostate-cancer product, and the patent’s expiration independently removes any current exclusivity value. Flutamide and nilutamide have had separate FDA regulatory histories and product-specific patent records rather than relying on this expired combination patent. The FDA-approved labeling for flutamide identifies it for use with a GnRH agonist in metastatic prostate cancer, but that regulatory indication does not restore exclusivity under U.S. Patent 4,472,382.[2]
Nilutamide was approved in the United States under the Nilandron brand for use with surgical castration in metastatic prostate cancer. Its product-specific regulatory history is distinct from the claims of Patent 4,472,382.[3]
Does the patent cover flutamide or nilutamide by themselves?
No. Claims 2 and 3 depend from claim 1 and specify the antiandrogen component. They still require the peptide component and the prostate-treatment method.
This distinction matters in infringement analysis:
| Product or regimen |
Likely relationship to Patent 4,472,382 |
| Flutamide alone |
Outside the combination claims |
| Nilutamide alone |
Outside the combination claims |
| Buserelin alone |
Outside the combination claims |
| Buserelin plus flutamide |
Within the relevant chemical combination if other claim elements are met |
| Buserelin plus nilutamide |
Specifically addressed by claim 17 |
| Leuprolide plus flutamide |
Not literally within the buserelin-specific claims; claim 1 requires a listed peptide structure |
| Degarelix plus an antiandrogen |
Generally outside the claims because degarelix is a GnRH antagonist and structurally different |
| Relugolix plus an antiandrogen |
Generally outside the claims because relugolix is a nonpeptide GnRH antagonist |
What formulation patents are protected by the patent?
Patent 4,472,382 is primarily a treatment-method patent. The claims supplied do not claim:
- A depot polymer;
- A specific injectable formulation;
- A nasal spray device;
- A particular salt;
- A pharmaceutical excipient;
- A manufacturing process;
- A sustained-release implant; or
- A specific package or delivery system.
Claims 7, 8, 9 and 10 create route and dosing limitations, but they do not independently claim a formulation. A later formulation patent could have protected a depot, implant, microsphere, nasal composition or delivery device even if the underlying combination-treatment claims had expired.
For buserelin, formulation and delivery rights historically could have been more commercially important than the broad combination method because peptide delivery is constrained by poor oral bioavailability and the need for parenteral or intranasal administration.
What manufacturing and intellectual-property barriers exist?
The patent does not create a current manufacturing barrier. Its term has ended.
The principal technical barriers for buserelin products are:
- Peptide synthesis and impurity control;
- Control of stereochemistry and protected amino-acid intermediates;
- Stability in aqueous and nasal formulations;
- Delivery across nasal mucosa;
- Sterility for injectable products;
- Consistent pharmacokinetic exposure; and
- Development of sustained-release dosage forms.
These barriers may affect regulatory and commercial entry without creating infringement risk under Patent 4,472,382.
Flutamide and nilutamide are small molecules with materially lower synthesis complexity than buserelin. Their commercial barriers are more likely to involve safety labeling, market demand, manufacturing economics and regulatory compliance than peptide production.
What patent litigation affects U.S. Patent 4,472,382?
The patent’s expiration eliminates current litigation exposure under this patent. A new Paragraph IV certification, infringement action or settlement agreement concerning this patent would have no practical exclusivity effect because the patent is no longer enforceable.
The patent may still appear in historical patent assignments, prosecution records, freedom-to-operate analyses or litigation histories. It cannot block a present-day launch.
No current biosimilar dispute is relevant to this patent. Buserelin is a peptide drug rather than a modern FDA biologic subject to the principal biosimilar pathway under the Public Health Service Act. A follow-on buserelin product would be analyzed through the applicable drug regulatory pathway, not as a biosimilar to a reference biologic.[4]
Which companies challenged or licensed the patent?
The supplied patent claims do not establish a current challenger, Paragraph IV filing, or settlement agreement. Because the patent expired in 2001, any historical challenge would now have limited commercial relevance.
No present licensing transaction can create enforceable exclusivity under the expired patent. A license may still have historical value for know-how, trademarks, manufacturing technology or foreign rights, but it would not restrict U.S. practice of the expired claims.
The commercially relevant companies and products are better analyzed by product class:
| Company or product category |
Relevance |
| Hoechst-associated buserelin development |
Historical GnRH agonist development |
| Flutamide sponsors and generic manufacturers |
Antiandrogen competition |
| AstraZeneca’s Nilandron/nilutamide |
Historical nilutamide competition |
| AbbVie’s Lupron/leuprolide |
Competing GnRH agonist platform |
| Degarelix sponsors |
GnRH antagonist alternative |
| Relugolix sponsors |
Oral GnRH antagonist alternative |
The competitive market moved away from the precise buserelin-nilutamide combination toward other androgen-deprivation regimens, including leuprolide-based therapy, GnRH antagonists and androgen-receptor pathway inhibitors.
How strong is the patent estate for this invention?
The current U.S. patent estate is commercially weak because the only identified patent is expired.
Historically, the patent had moderate claim breadth:
- Claim 1 covered a large set of peptide analogs.
- Claims 2 and 3 identified important antiandrogens.
- Claims 6 through 16 added dosing and administration options.
- Claims 17 and 18 focused on the buserelin-nilutamide combination.
Its main weaknesses were structural and legal specificity. A competitor could potentially design around the claims by:
- Using a different GnRH analog;
- Using a GnRH antagonist;
- Changing the peptide residue at a claimed position;
- Using an antiandrogen not listed in the claims;
- Omitting the antiandrogen;
- Treating a different disease indication; or
- Relying on a formulation or route outside the dependent claims.
Its present weakness is dispositive: expiration.
What generic launch risks exist?
There is no current generic launch risk under Patent 4,472,382. A generic or follow-on entrant would face other issues:
- FDA approval requirements for the selected active ingredient;
- Reference-product availability;
- Bioequivalence or comparative clinical requirements;
- Sterility and stability requirements for injectable products;
- Nasal-device and delivered-dose performance;
- Product-specific Orange Book patents, if any remain; and
- Separate formulation, manufacturing or regulatory exclusivities.
For flutamide, generic competition has existed for many years, subject to safety and market-demand considerations. For nilutamide, the market is smaller and product availability has varied. For buserelin, the key issue is U.S. regulatory and commercial availability rather than this expired patent.
How does this patent compare with competing prostate-cancer patents?
Patent 4,472,382 covers an early form of combined androgen blockade. It differs from later patent estates in three ways.
| Patent category |
Protected subject matter |
Current strategic relevance |
| U.S. 4,472,382 |
Buserelin or related LH-RH analog plus antiandrogen |
Expired |
| Leuprolide patents |
GnRH agonist composition, depot and use claims |
Mostly expired or product-specific historical rights |
| GnRH antagonist patents |
Degarelix or relugolix composition and use claims |
Later and potentially more relevant depending on patent |
| Next-generation androgen-receptor inhibitors |
Enzalutamide, apalutamide, darolutamide and related uses |
Separate, later patent estates |
| Formulation patents |
Depot, implant, injection, nasal or oral delivery |
Product-specific and independent of Patent 4,472,382 |
The patent is therefore relevant as prior technology and historical context, not as a current blocking right.
Key Takeaways
- U.S. Patent 4,472,382 claims prostate treatment using a specified LH-RH peptide analog plus an antiandrogen.
- The key peptide is buserelin.
- The named antiandrogens are flutamide and nilutamide.
- Claim 17 specifically covers buserelin plus nilutamide in male humans.
- The patent does not cover flutamide, nilutamide, buserelin, leuprolide, degarelix or relugolix individually.
- The patent issued on September 18, 1984, and expired on September 18, 2001.
- It has no current Paragraph IV, injunction, Orange Book or biosimilar significance.
- The claims do not materially protect formulations, manufacturing processes or delivery devices.
- Current commercial barriers would arise from regulatory approval, formulation technology, manufacturing quality and separate later patents.
FAQs About U.S. Patent 4,472,382
Does U.S. Patent 4,472,382 still block buserelin products?
No. The patent expired in 2001 and cannot block current U.S. manufacture, sale or use.
Is buserelin the same drug as the peptide in claim 17?
Yes. The peptide designated [D-Ser(tBu)6, des-Gly-NH2 10]-LH-RH ethylamide is buserelin, generally used in salt form for pharmaceutical products.
Does the patent cover leuprolide?
Not literally based on the supplied claims. Leuprolide is a different LH-RH analog and is not the specifically identified buserelin peptide.
Could a company use nilutamide without infringing this patent?
Yes, because the patent claims a combination treatment requiring the specified peptide component as well as the antiandrogen. The patent itself is also expired.
Is claim 18’s peptide dose of 10 to 100,000 mg correct?
That is the unit stated in the supplied text, but it conflicts with the microgram dosing ranges elsewhere in the claims and with the expected dosing scale for buserelin. The issued patent record controls the legally operative wording.
References
- United States Patent No. 4,472,382. (1984). Treatment of prostatic diseases. U.S. Patent and Trademark Office.
- U.S. Food and Drug Administration. (n.d.). Eulexin (flutamide) prescribing information. FDA.
- U.S. Food and Drug Administration. (n.d.). Nilandron (nilutamide) prescribing information. FDA.
- U.S. Food and Drug Administration. (2023). Purple Book: Database of licensed biological products. FDA.
- U.S. Patent and Trademark Office. (n.d.). Patent term calculator and patent term provisions. USPTO.
