Details for Patent: 5,364,938

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Summary for Patent: 5,364,938

Title:	Triazole antifungal agents
Abstract:	The invention provides antifungal agents of the formula: (I) and their pharmaceutically acceptable salts, wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and CF3; R1 is C1-C4 alkyl; R2 is H or C1-C4 alkyl; and "Het", which is attached to the adjacent carbon atom by a ring carbon atom, is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, "Het" being optionally substituted by C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, CN, NO2, NH2, -NH(C1-C4 alkanoyl) or -NHCO2(C1-C4 alkyl).
Inventor(s):	Roger P. Dickinson, Kenneth Richardson
Assignee:	Pfizer Corp SRL
Application Number:	US08/026,671
Patent Claim Types: see list of patent claims	Compound;

United States Drug Patent 5,364,938: Claim Scope, Expiration, and Patent Landscape

U.S. Patent No. 5,364,938 is a composition-of-matter patent covering substituted triazole alcohols with a pyrimidinyl group, including stereochemically defined compounds related to the voriconazole chemical class. Based on its November 15, 1994 issue date and the pre-1995 patent-term rules, the patent’s ordinary term expired on November 15, 2011, absent an unusual term adjustment or other extension. The listed claims do not cover formulations, manufacturing methods, or therapeutic methods.

The patent remains relevant as prior art and as part of the historical intellectual-property estate for triazole antifungals. It does not create a current U.S. blocking right by itself.

What compounds does U.S. Patent 5,364,938 cover?

The claims cover a triazole-substituted secondary alcohol with the following principal structural elements:

• A 1,2,4-triazol-1-ylmethyl substituent;
• A substituted phenyl group, limited to chlorophenyl, fluorophenyl, dichlorophenyl, or difluorophenyl;
• An alkyl group, generally C1-C4;
• A second substituent that may be hydrogen or C1-C4 alkyl;
• A pyrimidinyl heteroaryl group, with optional substitution.

Claim 4 identifies one specific compound:

2-(2,4-difluorophenyl)-3-(pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

Claim 8 covers the corresponding defined stereoisomer:

(2R,3S)-2-(2,4-difluorophenyl)-3-(pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

The claim set also reaches pyrimidinyl compounds bearing a fluoro, chloro, bromo, alkyl, alkoxy, trifluoromethyl, nitro, amino, cyano, alkanoylamino, or alkoxycarbonylamino substituent, subject to the positional and structural limitations in the patent’s formula.

How broad is claim 1?

Claim 1 is a Markush composition claim. It defines a chemical genus through independently variable substituents rather than naming one active pharmaceutical ingredient.

Variable	Scope stated in claim 1	Commercial significance
R	Chlorophenyl, fluorophenyl, dichlorophenyl, or difluorophenyl	Controls aromatic lipophilicity and electronic properties
R1	C1-C4 alkyl	Claim 2 narrows this to methyl
R2	Hydrogen or C1-C4 alkyl	Claim 2 narrows this to hydrogen
Het	Pyrimidinyl	Central heteroaryl pharmacophore
Het substitution	Fluoro, chloro, bromo, C1-C4 alkyl, C1-C4 alkoxy, CF3, nitro, amino, cyano, and specified amino-carbonyl groups	Expands the genus across multiple pyrimidine substitution patterns
Salt form	Pharmaceutically acceptable acid addition salts	Captures salt versions of otherwise covered bases

The genus is potentially large because the claim combines multiple aromatic, alkyl, heteroaryl, and stereochemical possibilities. Its practical scope depends on the complete structural formula, the permitted attachment positions on the pyrimidine ring, and whether a proposed compound falls within the ordinary meaning of each substituent.

The claim does not cover every triazole antifungal. A compound must satisfy the complete combination of structural limitations. A triazole-containing compound with a different heteroaryl group, a non-permitted aryl group, or a different carbon skeleton would fall outside claim 1 unless another claim or patent covered it.

What do claims 2 through 8 add?

The dependent claims progressively narrow the genus.

Claim	Limitation	Legal effect
1	Broad Markush genus and acid-addition salts	Principal composition claim
2	R1 is methyl; R2 is hydrogen	Narrows the side chain
3	R is 2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl, or 2,4-difluorophenyl; Het is 4-pyrimidinyl	Narrows both aryl and heteroaryl components
4	Specific non-fluorinated pyrimidinyl compound	Species claim
5	Stereochemical configuration shown in the patent	Creates a stereochemically limited subgenus
6	Claim 5 plus methyl and hydrogen at R1 and R2	Narrow stereochemical subgenus
7	Claim 6 plus specified aryl groups and 4-pyrimidinyl	Narrow stereochemical group
8	Specific (2R,3S) compound	Narrowest expressly listed composition claim

Claims 4 and 8 are important because they provide direct species-level protection. Claim 8 is narrower than claim 1 but is generally more resistant to design-around arguments if the accused compound has the same absolute configuration and substituent pattern.

Does the patent cover voriconazole?

The named compound in claims 4 and 8 is not the marketed active ingredient voriconazole because voriconazole contains a fluorine substituent on the pyrimidine ring. Voriconazole is commonly identified as:

(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

Claim 1, as quoted, permits an optionally fluoro-substituted pyrimidinyl group. That language may encompass a 5-fluoropyrimidin-4-yl embodiment, depending on the complete formula, positional definitions, written description, and claim construction. Claims 3, 4, 7, and 8, however, expressly identify an unsubstituted 4-pyrimidinyl group and should not be treated as direct claims to voriconazole.

Any freedom-to-operate analysis for voriconazole must therefore separate:

1. The broad genus in claim 1;
2. The specific non-fluorinated compound in claims 4 and 8;
3. Later patents directed specifically to voriconazole;
4. Formulation, crystalline-form, manufacturing, and method-of-use patents.

U.S. Patent No. 5,364,938 cannot be treated as the entire voriconazole patent estate.

When did U.S. Patent 5,364,938 lose exclusivity?

The patent issued on November 15, 1994. For an application governed by the pre-June 8, 1995 patent-term regime, the ordinary term was generally 17 years from issuance under 35 U.S.C. § 154(c)(1).

Event	Date or consequence
Patent issued	November 15, 1994
Ordinary statutory term	17 years from issue
Base expiration	November 15, 2011
Current status	Expired
Current enforcement value	No prospective blocking right from this patent alone

The expiration date should be distinguished from the expiration of later patents that may claim a commercial product, a formulation, a manufacturing process, or an approved method of use. A later patent can remain relevant even after this earlier patent has expired.

No patent-term extension should be assumed for this patent. Patent-term extension under 35 U.S.C. § 156 is product-specific and generally applies to qualifying regulatory review periods. The listed claims and the patent’s issue date do not establish such an extension.

What is the Orange Book status of U.S. Patent 5,364,938?

U.S. Patent 5,364,938 is not, by itself, an operative Orange Book barrier for current generic entry.

The Orange Book lists patents submitted by an NDA holder or authorized agent as claiming an approved drug, its formulation or composition, or an approved method of use. A patent may be absent from the Orange Book because it is expired, because it was never submitted, because it does not claim the approved product, or because it does not satisfy Orange Book listing criteria.

For a small-molecule product such as voriconazole, the relevant regulatory pathway is generally an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act. A generic applicant evaluates current unexpired Orange Book patents and submits the applicable certification, including a Paragraph IV certification where appropriate. An expired patent such as U.S. 5,364,938 does not support a current Paragraph IV litigation strategy.

FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations should be reviewed separately from the patent document itself because Orange Book listings can change over time and may include later patents unrelated to this earlier composition patent (FDA, 2024).

Are there Paragraph IV challenges involving this patent?

A current Paragraph IV challenge to U.S. Patent 5,364,938 would have no practical patent-enforcement target because the patent expired in 2011.

Historical ANDA litigation involving a related triazole antifungal would more likely have concerned:

• A later compound patent;
• A patent specifically directed to voriconazole;
• An oral or injectable formulation;
• A crystalline or polymorphic form;
• A method-of-use patent;
• Pediatric or regulatory exclusivity linked to the approved product.

The quoted claims contain no information about ANDA filings, Paragraph IV notices, district-court litigation, settlements, or authorized generic arrangements. Those issues cannot be inferred from the claim language.

What formulations are protected by this patent?

None of the quoted claims expressly cover a formulation.

The claims do not recite:

• Tablets;
• Oral suspensions;
• Intravenous solutions;
• Excipients;
• Particle-size distributions;
• Polymorphs;
• Solid dispersions;
• Liposomal or nanoparticle delivery systems;
• Release profiles;
• Dosage strengths.

A formulation containing a covered compound could have required a separate formulation patent, but the existence of a formulation patent would not expand the scope of U.S. 5,364,938.

Does the patent cover methods of use?

No method-of-use claim is provided. The listed claims are composition claims only.

They do not expressly claim treatment of:

• Invasive aspergillosis;
• Candidiasis;
• Scedosporium infection;
• Fusariosis;
• Other systemic fungal infections.

A patent owner could have pursued separate method claims in a related application or continuation. Such claims would require independent analysis and cannot be read into claims 1 through 8.

Is there biosimilar risk?

There is no biosimilar issue for the claimed compounds. These are chemically synthesized small molecules, not biologics.

The relevant competitive pathway is generic drug entry through an ANDA, or in some cases a 505(b)(2) application. The commercial risk analysis should focus on:

• Active compound identity;
• Salt and polymorph selection;
• Formulation patents;
• Manufacturing-route patents;
• Orange Book listings;
• Regulatory exclusivity;
• Non-infringement and invalidity positions.

For the specific non-fluorinated compound in claims 4 and 8, no approved FDA product is established by the patent itself. The patent therefore has limited direct relevance to current commercial generic competition unless a marketed product contains a compound within claim 1.

How strong is the patent estate?

The patent was structurally significant when unexpired because it combined a broad genus claim with progressively narrower species and stereochemical claims. Its strongest historical features were:

1. A composition-of-matter claim rather than a method claim;
2. Coverage of multiple substituted pyrimidinyl analogs;
3. Explicit protection for selected aryl groups;
4. Stereochemical claims directed to a defined active configuration;
5. Acid-addition salt coverage.

Its current strength is substantially reduced by expiration. The patent cannot support an injunction against future manufacture, sale, or use in the United States. Its remaining value is limited to prior-art analysis, historical patent landscaping, and evaluation of whether later patents contain overlapping or non-obvious improvements.

What generic launch scenarios exist?

Exact compound in claims 4 or 8

A generic launch involving the exact non-fluorinated compound would not be blocked by U.S. 5,364,938 because the patent expired. Commercial viability would depend on whether the compound is an approved product, whether another patent covers it, and whether FDA has an applicable reference product.

Voriconazole or a fluoro-pyrimidinyl analogue

The principal risks would come from later product-specific, formulation, method-of-use, or manufacturing patents. U.S. 5,364,938 should be treated as an expired earlier genus patent, not as the complete product estate.

Salt or formulation variant

The expired patent’s acid-addition-salt language would not create a current barrier. A later patent could still protect a particular salt, polymorph, formulation, or manufacturing process.

What geographic coverage does the patent provide?

The patent provides U.S. rights only. It does not establish protection in Europe, Japan, China, Canada, or other jurisdictions.

A global landscape requires review of:

• The priority application;
• International filings;
• National-phase patents;
• Continuations and divisionals;
• Patent-term differences;
• Local opposition, invalidation, and litigation records.

Expiration in the United States does not establish expiration elsewhere. Conversely, foreign family members may have expired earlier or may never have issued.

Key Takeaways

• U.S. Patent 5,364,938 is a composition-of-matter patent for substituted triazole alcohols containing defined phenyl and pyrimidinyl groups.
• Claims 4 and 8 cover specific non-fluorinated pyrimidinyl compounds, including the defined (2R,3S) stereoisomer.
• Claim 1 is broader and may encompass fluoro-substituted pyrimidinyl embodiments, potentially including compounds related to voriconazole, subject to full claim construction.
• The patent does not expressly claim formulations, manufacturing methods, or therapeutic uses.
• Based on its November 15, 1994 issue date, the ordinary patent term expired on November 15, 2011.
• The patent presents no current standalone Orange Book or Paragraph IV barrier.
• Voriconazole freedom-to-operate analysis must include later product-specific and formulation patents.
• Biosimilar analysis is irrelevant because the claimed products are small molecules.
• Current commercial risk depends on later patents, regulatory listings, approved-product status, and any surviving family members or continuation patents.

Frequently Asked Questions

Is U.S. Patent 5,364,938 still enforceable?

No. Its ordinary U.S. patent term expired on November 15, 2011, based on the patent’s 1994 issue date and the applicable pre-1995 term framework.

Does claim 8 cover voriconazole?

No, not as written. Claim 8 identifies an unsubstituted pyrimidin-4-yl group, while voriconazole contains a fluoro-substituted pyrimidinyl group. Claim 1 is broader and requires separate claim-construction analysis.

Does the patent cover voriconazole salts?

Claim 1 covers pharmaceutically acceptable acid-addition salts of compounds within the claimed genus. That issue is distinct from later patents directed to a specific voriconazole salt, formulation, or dosage form.

Can an expired composition patent support a Paragraph IV lawsuit?

No. An expired patent cannot ordinarily support a current infringement action against an ANDA applicant. Paragraph IV analysis must focus on unexpired listed patents.

Is U.S. Patent 5,364,938 a formulation patent?

No. The quoted claims are composition claims. They do not recite excipients, dosage forms, release characteristics, polymorphs, or delivery systems.

References

1. U.S. Patent No. 5,364,938. (1994). Triazole derivatives. United States Patent and Trademark Office.

2. Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355.

3. U.S. Patent Act, 35 U.S.C. §§ 154, 156.

4. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.

5. U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations, patent and exclusivity information. FDA.

Drugs Protected by US Patent 5,364,938

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 5,364,938

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8819308	Aug 13, 1988

International Family Members for US Patent 5,364,938

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
African Regional IP Organization (ARIPO)	104
African Regional IP Organization (ARIPO)	8900135
Argentina	246963
Austria	101600
Australia	3893089