United States Drug Patent 5,591,731: Claim Scope, Expiration, and Amifostine Patent Landscape

U.S. Patent No. 5,591,731 protects a stable crystalline dosage form of amifostine, particularly crystalline amifostine trihydrate with a specified crystallographic structure, thermal-stability profile, sterile injectable presentation, and reconstitution capability. The patent does not broadly claim the amifostine molecule, all amifostine formulations, or methods of treating patients.

The patent’s practical exclusionary value has ended because its statutory patent term expired no later than 2015, subject to any patent-term adjustment or extension reflected in the official prosecution record. The principal current risks for an amifostine competitor are therefore regulatory, manufacturing, quality, supply, and trade-secret risks rather than infringement of U.S. Patent 5,591,731.

What does U.S. Patent 5,591,731 protect?

The patent protects a pharmaceutical dosage form containing crystalline amifostine that is suitable for reconstitution into a particulate-free injectable product for parenteral administration. The strongest and most technically specific protection is in claim 1.

Claim 1 requires all of the following:

A dosage form of crystalline amifostine.
Thermally stable, sterile, crystalline amifostine trihydrate.
A crystal structure substantially corresponding to space group P21 21 21.
Unit-cell dimensions of approximately:
- a = 8.46 Å;
- b = 21.55 Å; and
- c = 6.76 Å.
Suitability for reconstitution with a pharmaceutically acceptable vehicle.
Formation of an injectable, particulate-free drug product.
Parenteral administration to a subject.

This is a solid-state and pharmaceutical-presentation patent. It is not principally a compound patent.

Claim group	Subject matter	Principal limitation
Claim 1	Crystalline amifostine trihydrate dosage form	Specific crystal structure and injectable reconstitution use
Claims 2-5	Stability characteristics	Less than 2% degradation product or stability for two years
Claims 6-8	Excipients	Salts, sugars, glycine, dextrose, sucrose, and mannitol
Claim 9	Reconstitution vehicle	Water for Injection, USP, or normal saline
Claims 10-12	Presentation and processing	Single-dose formulation, quantity range, vacuum drying
Claim 13	Container	Sealed container supporting sterile reconstitution
Claim 14	Broader crystalline dosage form	Thermally stable, sterile crystalline amifostine without the express trihydrate structure
Claims 15-37	Container and formulation subcombinations	Sealed-container versions of claims 14 and its dependent claims

The commercial target was a dry, stable, sterile dosage form that could be reconstituted before injection. The claims address the known instability and degradation concerns associated with amifostine formulations.

How broad is claim 1 of U.S. Patent 5,591,731?

Claim 1 is narrow in chemical and crystallographic terms but broad in certain presentation terms.

Narrow limitations

The claim is limited to crystalline amifostine trihydrate having a crystal structure substantially matching the identified orthorhombic space group and approximate unit-cell dimensions. A competing product using a different polymorph, amorphous amifostine, a different hydrate or solvate, or a liquid formulation would have a potential non-infringement position if it did not meet the claim’s structural limitations.

The phrase “substantially the crystal structure” creates an infringement and claim-construction issue. The relevant question would be whether the accused solid has the claimed crystallographic structure despite normal analytical variation in powder X-ray diffraction, unit-cell measurements, hydration state, or manufacturing conditions.

Broad presentation limitations

The claim does not require a particular vial size, dose, excipient, reconstitution volume, or commercial brand. It requires that the dosage form be suitable for reconstitution into an injectable particulate-free product for parenteral administration.

A product could therefore fall within claim 1 even if it used a different vial configuration or a different reconstitution volume, provided the crystalline solid and functional requirements were met.

Product forms potentially implicated

Subject to testing and claim construction, the following forms could present claim 1 issues:

Sterile crystalline amifostine trihydrate powder in a vial.
Vacuum-dried crystalline amifostine trihydrate.
A single-dose crystalline amifostine formulation reconstituted with saline.
A formulation containing crystalline amifostine trihydrate and mannitol.
A lyophilized or otherwise dried injectable product retaining the claimed crystal structure.

A liquid amifostine solution would generally face a stronger design-around argument because the claim is directed to a crystalline dosage form that is reconstituted before administration.

What is the scope of claim 14?

Claim 14 is the broadest independent dosage-form claim in the patent. It covers:

“a dosage form of crystalline amifostine comprising thermally-stable, sterile, crystalline amifostine” suitable for reconstitution into an injectable particulate-free product for parenteral administration.

Unlike claim 1, claim 14 does not expressly require:

Amifostine trihydrate;
Space group P21 21 21;
The stated unit-cell dimensions;
A specific hydrate or solvate;
A particular excipient;
A specific reconstitution vehicle; or
A stated dose.

Claim 14 therefore attempts to cover a broader genus of sterile, thermally stable crystalline amifostine dosage forms. Its scope is constrained by the terms “thermally-stable,” “sterile,” “suitable for reconstitution,” “injectable particulate-free,” and “parenteral administration.”

The principal validity questions for claim 14 would include written description, enablement, indefiniteness, and anticipation. The claim may be vulnerable if the patent specification does not adequately support crystalline forms beyond the specifically disclosed trihydrate or if “thermally stable” lacks an objective boundary. The claim’s validity cannot be determined from the claim text alone.

What do claims 2 through 5 protect?

Claims 2 and 3 define thermal degradation performance using a specific accelerated-storage test. The dosage form must form less than approximately 2% of 2-[(3-aminopropyl)amino]ethane thiol after storage in a nitrogen-filled vial at 40°C for either:

One week under claim 2; or
Four weeks under claim 3.

Claims 4 and 5 require thermal stability:

At approximately 4°C for at least two years; or
At approximately ambient temperature for at least two years.

These claims are dependent on claim 1 and therefore inherit its crystal-structure, sterility, reconstitution, injectable, and parenteral-use limitations.

A product does not avoid these claims merely because its label does not make a stability representation. Infringement would turn on the actual characteristics of the product and the meaning of the claim terms, not solely on labeling.

The accelerated degradation claims may be comparatively easier to test than the two-year stability claims. The two-year limitations raise questions concerning storage conditions, analytical methods, lot-to-lot variation, and what constitutes “thermal stability.”

What formulations are protected by the patent?

Claims 6 through 12 add specific formulation and presentation limitations.

Claim	Added limitation
6	Pharmaceutically acceptable excipient
7	Sodium chloride, glycine, dextrose, sucrose, or mannitol
8	Mannitol
9	Water for Injection, USP, or normal saline
10	Sterile single-dose formulation
11	Approximately 10 to 10,000 mg amifostine trihydrate, with optional excipient in the same range
12	Vacuum-dried crystalline amifostine

Claim 7 contains a grammatical issue in the supplied text: “sodium chloride glycine” appears to omit punctuation between sodium chloride and glycine. The intended Markush group is presumably sodium chloride, glycine, dextrose, sucrose, and mannitol.

Claim 11 covers a very broad quantity range. It does not require a specific clinical dose and could encompass small-dose and high-dose parenteral presentations, assuming all other limitations are met.

Claim 12 is directed to vacuum-dried material. It does not expressly require a particular drying temperature, pressure, cycle, residual moisture level, or container closure system.

Are claims 14 through 37 legally coherent?

Claims 14 through 37 repeat the structure of claims 1 through 13 but use the broader crystalline-amifostine language of claim 14.

The supplied text contains an apparent dependency defect in claim 21:

“The dosage form of claim 21 in which said excipient is selected…”

A claim cannot ordinarily depend on itself. The intended dependency was likely claim 20. The official issued patent and prosecution history should control whether this is a transcription error, an issued-claim defect, or an issue addressed through a certificate of correction or other USPTO record.

Claims 27 through 37 are sealed-container claims that depend on particular claims in the second claim set. They cover a container holding the relevant dosage form, with enough volume for reconstitution and a sealing mechanism that maintains sterility while permitting entry of the reconstitution vehicle.

The container claims are not directed to a vial in isolation. They require the vial or other sealed container to contain a qualifying crystalline amifostine dosage form.

What patent-expiration date applies to U.S. Patent 5,591,731?

U.S. Patent 5,591,731 was issued on January 7, 1997. For a U.S. application filed after June 8, 1995, the ordinary term is generally 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension, terminal disclaimers, or other statutory modifications.[1]

On the available patent chronology, the enforceable term ended no later than approximately 2015. The patent is therefore expired and cannot presently block a new U.S. generic or branded entrant through ordinary patent enforcement.

Event	Date or period
Patent issued	January 7, 1997
Ordinary post-1995 U.S. term framework	20 years from earliest effective nonprovisional filing
Expected statutory expiration window	Approximately 2015
Current status for ordinary enforcement	Expired by term

Patent expiration does not erase historical infringement liability incurred while the patent was in force. It does eliminate prospective exclusionary rights after expiration.

What is the Orange Book status of U.S. Patent 5,591,731?

The Orange Book lists patents submitted by NDA sponsors for approved drug products when the patents meet FDA listing requirements.[2] Patent listing is separate from patent validity and enforceability.

U.S. Patent 5,591,731 should not be treated as a currently blocking Orange Book patent solely because it once covered a commercial amifostine formulation. Its term has expired. Any present Orange Book assessment must be based on the FDA’s current patent listing for the relevant NDA and product, not on the historical existence of the patent.

The patent claims dosage forms and containers rather than a method of using amifostine. If listed historically, it would have been relevant primarily to a drug product containing the claimed crystalline form, not to every product containing amifostine.

Does the patent create Paragraph IV risk for generic amifostine?

A new Paragraph IV certification against U.S. Patent 5,591,731 would have no practical effect after expiration. Paragraph IV procedures address patents listed for an approved drug that have not expired. A generic applicant instead would ordinarily make a certification reflecting that the patent has expired or will expire before commercial marketing, depending on the applicable Orange Book and ANDA circumstances.[3]

Historically, a Paragraph IV challenge could have focused on several grounds:

The proposed product does not contain the claimed P21 21 21 trihydrate.
The product is not a crystalline dosage form.
The product is not sterile.
The product is not supplied for reconstitution.
The product does not produce a particulate-free injectable product.
The patent claims are anticipated by earlier amifostine formulations or crystal disclosures.
The claims are indefinite or inadequately supported.
The claims are invalid for obviousness.

Today, the principal commercial question is whether the generic product can obtain FDA approval and meet injectable-product quality requirements, not whether it must overcome this expired patent.

What generic entry risks exist for amifostine?

The principal entry risks are regulatory and technical.

FDA pathway

Amifostine is a small-molecule drug. A competing injectable product would generally proceed through the abbreviated new drug application pathway if the reference product and regulatory conditions permit an ANDA.[4] It is not a biologic, so biosimilar approval under the Public Health Service Act’s 351(k) pathway is not the relevant route.

FDA approval would require, among other matters:

Pharmaceutical equivalence;
Appropriate strength and dosage form;
Sterility assurance;
Control of particulate matter;
Suitable container-closure integrity;
Stability data;
Adequate manufacturing controls;
Labeling consistent with the reference product, subject to applicable regulatory rules.

Solid-state and manufacturing risks

A manufacturer using a crystalline amifostine trihydrate process should characterize:

Hydration state;
Powder X-ray diffraction pattern;
Unit-cell parameters;
Thermal behavior;
Residual moisture;
Degradation product formation;
Sterility;
Reconstitution time;
Visible and subvisible particulates;
Container-closure integrity.

Even though the patent has expired, the same technical attributes may remain necessary to produce a stable commercial injectable.

Supply and process risks

Amifostine is an injectable thiol prodrug with storage and degradation sensitivities. Process conditions that can affect commercial viability include:

Crystallization solvent and temperature;
Drying conditions;
Oxygen exposure;
Nitrogen headspace;
Moisture control;
Excipient compatibility;
Vial and stopper selection;
Reconstitution performance.

Those process parameters can be protected through unexpired manufacturing patents, regulatory exclusivity, confidential know-how, or supplier arrangements. None of those rights can be assumed from U.S. Patent 5,591,731.

Are there biosimilar risks for amifostine?

No conventional biosimilar risk applies. Amifostine is a chemically synthesized small molecule, not a therapeutic protein or other biological product subject to the biosimilar framework.

Competitive entry would be evaluated through generic-drug rules, including ANDA requirements, pharmaceutical equivalence, bioequivalence where applicable, and patent certifications. The relevant competitors would be generic injectable manufacturers, not biosimilar developers.

What method-of-use patents cover amifostine?

U.S. Patent 5,591,731 contains dosage-form and container claims. It does not claim:

Use of amifostine for radioprotection;
Use for reducing xerostomia;
Use for cisplatin nephrotoxicity;
A chemotherapy administration protocol;
A radiation-treatment protocol;
A dosing schedule;
A patient-selection method.

Any method-of-use exclusivity would have to arise from separate patents, approved labeling, regulatory exclusivity, or other rights. The patent should not be cited as a method-of-treatment patent.

What licensing deals affect amifostine?

The patent itself does not establish the existence, scope, or current status of a license agreement. Historical commercial rights in amifostine have involved the product sponsor and subsequent commercial owners, but a patent assignment is not the same as a license, and a product acquisition is not necessarily a transfer of every patent right.

A complete licensing analysis would require review of:

USPTO assignment records;
SEC filings;
Product acquisition announcements;
FDA NDA ownership records;
License agreements and amendments;
Settlement agreements;
Sublicense rights;
Territory restrictions.

The expired status of U.S. Patent 5,591,731 limits its value as a current licensing asset, although historical royalty, indemnity, and liability provisions could remain commercially relevant.

Which companies are challenging U.S. Patent 5,591,731?

The patent number and claim set alone do not establish a current Paragraph IV challenger, ANDA filer, patent-litigation defendant, or settlement agreement. Because the patent is expired, a current Paragraph IV campaign directed specifically at this patent would not create the ordinary 30-month stay or launch-blocking effect associated with an unexpired Orange Book patent.[3]

A competitor assessment should distinguish among:

An ANDA filer challenging other listed patents;
A manufacturer relying on a noninfringing crystalline form;
A manufacturer supplying amifostine outside the United States;
A contract manufacturer;
A distributor of an approved product;
A party involved in historical litigation.

Those categories do not establish infringement or a live challenge to this patent.

How strong is the patent estate for crystalline amifostine?

The patent estate represented by U.S. Patent 5,591,731 was technically focused but commercially limited.

Strength factor	Assessment
Compound coverage	Weak; no broad amifostine molecule claim
Specific crystal coverage	Stronger during term if the claimed trihydrate was uniquely identifiable
Formulation coverage	Moderate; limited to sterile, reconstitutable injectable dosage forms
Container coverage	Moderate but derivative of the dosage-form claims
Method-of-use coverage	None apparent
Manufacturing-process coverage	None apparent in the supplied claims
Duration	Expired
Current blocking value	None for prospective U.S. enforcement
Technical relevance	Still relevant to solid-state and stability development

During its term, the patent could have created a meaningful barrier against copying a particular stable crystalline injectable presentation. It did not prevent competitors from developing a different amifostine salt, polymorph, hydrate, amorphous form, liquid formulation, or alternative delivery format unless those alternatives were covered by separate rights.

How does U.S. Patent 5,591,731 compare with a conventional compound patent?

Issue	U.S. Patent 5,591,731	Typical compound patent
Protected subject matter	Crystal form and dosage presentation	Chemical structure
Design-around potential	Relatively high through alternative solid state or formulation	Often lower during term
Proof of infringement	Requires solid-state and product-form analysis	Often based on active ingredient identity
Manufacturing relevance	Strong for crystallization, drying, and sterile filling	Variable
Method-of-use coverage	None apparent	Often included in separate claims
Commercial scope	Specific injectable presentations	Potentially all formulations containing the molecule
Post-expiration value	Technical precedent and process knowledge	Compound becomes generally available, subject to other rights

The patent’s narrowest claims may be analytically strong but are easier to avoid than a composition-of-matter claim. Claim 14 is broader, but its functional limitations create greater validity and claim-construction exposure.

What generic launch scenarios are available after expiration?

Three principal scenarios exist.

Same crystalline form

A generic manufacturer may use the same or substantially the same crystalline amifostine trihydrate, provided the expired patent is the only relevant patent barrier. The commercial focus shifts to reproducible crystallization, sterile filling, stability, and FDA approval.

Alternative crystalline or amorphous form

A manufacturer may develop a different polymorph, hydrate, solvate, or amorphous form. This may reduce overlap with claim 1, although it must still satisfy stability and injectable-product requirements.

Alternative finished dosage form

A liquid or otherwise non-crystalline formulation may avoid the most specific crystal-form claims. It could face separate regulatory, stability, manufacturing, or patent issues not visible in the supplied patent.

What geographic coverage does the patent have?

U.S. Patent 5,591,731 provides rights only in the United States. It does not establish protection in Canada, Europe, Japan, China, or other jurisdictions.

International protection would require corresponding national or regional patents. Foreign counterparts may have:

Different claim scope;
Different expiration dates;
Different prosecution amendments;
Different validity outcomes;
Different assignments or licenses;
Different terminal disclaimers or patent-term adjustments.

The U.S. expiration analysis cannot be transferred automatically to foreign counterparts.

Key Takeaways

U.S. Patent 5,591,731 is a crystal-form and injectable dosage-form patent for stable crystalline amifostine.
Claim 1 is limited to crystalline amifostine trihydrate with a specified P21 21 21 structure and approximate unit-cell dimensions.
Claim 14 is broader because it omits the express trihydrate and crystallographic limitations.
Claims 2 through 5 add degradation and storage-stability limitations.
Claims 6 through 12 cover excipients, vehicles, single-dose presentations, dose ranges, and vacuum drying.
Claims 13 and 15 through 37 cover sealed reconstitution containers containing the claimed dosage forms.
Claim 21, as supplied, contains an apparent self-dependency defect.
The patent does not claim the amifostine molecule, treatment methods, or manufacturing processes in the supplied claims.
The patent’s U.S. term expired approximately in 2015 and no longer presents a prospective U.S. patent barrier.
Amifostine is a small molecule, so generic-drug rules apply; biosimilar rules do not.
Current commercial barriers are more likely to involve FDA approval, sterile injectable manufacturing, stability, supply, know-how, and any separate unexpired patent rights.

FAQs

Can a generic company use crystalline amifostine trihydrate after the patent expired?

Yes. The expiration of the patent removes its prospective exclusionary effect, subject to any separate unexpired patent, regulatory exclusivity, contractual restriction, or applicable foreign right.

Does the patent cover Ethyol as a brand name?

No. Patent claims do not protect the brand name. The patent potentially covered a crystalline amifostine dosage form used in a commercial product, not the trademark or all versions of the branded product.

Would an amifostine liquid injection infringe claim 1?

A liquid injection would have a strong non-infringement position against claim 1 because claim 1 requires a crystalline dosage form suitable for reconstitution. The expired patent has no current U.S. blocking effect in any event.

Can the patent be used to block a foreign amifostine manufacturer?

No, not outside the United States. A separate enforceable patent in the relevant country would be required.

Does expired patent 5,591,731 affect FDA approval of an amifostine ANDA?

Expiration generally removes the patent-based obstacle, but FDA approval still depends on applicable ANDA requirements, pharmaceutical equivalence, product quality, sterility, stability, labeling, and other regulatory criteria.

References

United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term: 35 U.S.C. §§ 154, 156, and 271. https://www.uspto.gov
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book. https://www.fda.gov
U.S. Food and Drug Administration. (n.d.). Hatch-Waxman amendments: Abbreviated new drug applications and patent certifications. https://www.fda.gov
U.S. Food and Drug Administration. (n.d.). Amifostine injection prescribing information. https://www.accessdata.fda.gov
U.S. Patent No. 5,591,731. (1997). Stable crystalline form of amifostine. United States Patent and Trademark Office.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	261729	⤷ Start Trial
Australia	4796693	⤷ Start Trial
Australia	681858	⤷ Start Trial
Canada	2120133	⤷ Start Trial
China	1070370	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 5,591,731