US Patent 5,763,454: Scope, Claims, Expiration, and Trovafloxacin Mesylate Patent Landscape

US Patent 5,763,454 protects a specific crystalline form of trovafloxacin mesylate, the methanesulfonic acid salt of the fluoroquinolone antibiotic trovafloxacin. The patent covers the solid form by its X-ray powder diffraction pattern, a process for producing it, pharmaceutical compositions containing it, and its use to treat bacterial infections. The patent issued on June 9, 1998, and its ordinary term expired on November 8, 2015, assuming the recorded filing and term data without a relevant patent-term adjustment or extension.[1]

The patent is no longer an enforceable barrier to generic manufacture, formulation, or sale. Its commercial importance was historically significant because it protected a drug substance form used in Trovan and related trovafloxacin products. The protection was narrower than a basic compound patent and depended on the claimed crystalline form.

What drug does US Patent 5,763,454 protect?

US 5,763,454 protects crystalline trovafloxacin mesylate. Trovafloxacin is a fluoroquinolone antibacterial formerly marketed by Pfizer under the Trovan brand. The claimed chemical entity is:

The trovafloxacin core: a 1,8-naphthyridone-3-carboxylic acid fluoroquinolone
A 2,4-difluorophenyl substituent at the N-1 position
A 6-fluoro substituent
A 3-azabicyclo[3.1.0]hex-3-yl substituent at position 7
A 6-amino substituent on the bicyclic ring
Methanesulfonic acid, producing the mesylate salt
A defined crystalline solid form identified by powder X-ray diffraction

The patent does not claim every physical form of trovafloxacin mesylate. It claims a particular crystalline form identified through eight major diffraction peaks.

Trovafloxacin mesylate is distinct from trovafloxacin free acid and from other possible salts, solvates, hydrates, amorphous forms, or polymorphs unless those forms also satisfy the claim limitations.

What are the claims of US Patent 5,763,454?

The four claims divide into product, manufacturing process, composition, and method-of-treatment categories.

Claim	Claim category	Principal subject matter	Scope
1	Product-by-characterization	Crystalline trovafloxacin mesylate defined by XRPD peaks	Core patent claim
2	Process	Heating the salt or monohydrate in an alcohol with an aprotic co-solvent	Manufacturing route to the claimed form
3	Pharmaceutical composition	Composition containing the claimed crystalline trovafloxacin mesylate	Product formulation claim
4	Method of treatment	Administering the claimed crystalline form to treat bacterial infection	Medical-use claim

What does claim 1 cover?

Claim 1 covers crystalline trovafloxacin mesylate characterized by the following major Cu Kα X-ray powder diffraction peaks:

Peak	2θ, degrees	d-spacing, angstroms
1	4.5	19.5
2	7.7	11.5
3	9.1	9.7
4	13.6	6.5
5	15.0	5.9
6	18.2	4.9
7	18.6	4.8
8	22.8	3.9

This is a product-by-process-independent characterization claim. The product is defined by its chemical identity and physical diffraction profile, not by the method used to make it.

A party could infringe claim 1 even if it used a different crystallization process, provided the resulting material is trovafloxacin mesylate and has the claimed crystalline pattern. Conversely, a process that produces trovafloxacin mesylate in a different polymorphic or amorphous form would not necessarily fall within claim 1.

The claim contains no expressly stated numerical tolerance for the peak positions. In an infringement analysis, the relevant questions would include the XRPD measurement conditions, instrument calibration, sample preparation, peak-shift tolerance, and whether the accused material contains the claimed set of major peaks as a matter of pharmaceutical solid-state identification.

What does claim 2 cover?

Claim 2 covers a process for preparing the crystalline form by heating:

Trovafloxacin mesylate, or its derived monohydrate;
In the presence of an alcohol or alcohol mixture; and
With an aprotic co-solvent.

The process claim is narrower than the product claim. It requires the specified starting material, solvent environment, and heating operation. A manufacturer could avoid claim 2 by using a different conversion route, such as:

Direct crystallization under a different solvent system
Cooling crystallization without the claimed heating step
Antisolvent precipitation
Seeded crystallization using a different solvent combination
Solid-state conversion under conditions outside the claim

Avoiding claim 2 would not avoid claim 1 if the resulting product were still the claimed crystalline trovafloxacin mesylate.

What does claim 3 cover?

Claim 3 covers a pharmaceutical composition having antibacterial activity that contains the claimed crystalline trovafloxacin mesylate.

The use of “comprises” generally makes the composition claim open-ended. A formulation may contain excipients, fillers, binders, disintegrants, coatings, buffers, or other ingredients and still fall within the claim if it contains the claimed crystalline active ingredient.

The claim does not appear limited to a particular:

Dose
Route of administration
Tablet or capsule configuration
Excipient
Dissolution profile
Particle size
Release mechanism
Packaging system

The central limitation is the presence of the specified crystalline salt.

What does claim 4 cover?

Claim 4 covers treating a bacterial infection by administering an antibacterial amount of the claimed crystalline trovafloxacin mesylate to a subject in need of treatment.

The claim requires:

A bacterial infection
Administration to a subject needing treatment
An antibacterial amount
The claimed crystalline trovafloxacin mesylate

The claim is not a broad claim to treating infection with any trovafloxacin product. It is tied to the specified crystalline mesylate form.

How strong is the patent estate for crystalline trovafloxacin mesylate?

The patent was technically narrow but commercially useful. Its strength came from product-form protection rather than broad chemical coverage.

Factor	Assessment
Chemical scope	Narrow; limited to trovafloxacin mesylate
Solid-form scope	Focused on one XRPD-defined crystalline form
Process scope	Narrow and condition-dependent
Formulation scope	Potentially broad because of open composition language
Method-of-use scope	Limited to administration of the claimed solid form
Design-around potential	Moderate to high before expiry
Current enforceability	None; patent expired in 2015
Historical commercial value	Material for protecting the marketed drug substance form

The patent did not independently control all trovafloxacin products. A competing manufacturer could have examined alternative forms, including a different polymorph, amorphous material, another salt, or a formulation that did not contain the claimed crystalline form. The practical value of such a design-around would have depended on stability, dissolution, bioavailability, manufacturability, and regulatory comparability.

When did US Patent 5,763,454 expire?

The patent expired on November 8, 2015, based on its November 8, 1995 filing date and the 20-year patent term applicable to the application.[1]

Event	Date
Patent application filing	November 8, 1995
Patent issued	June 9, 1998
Patent term expiration	November 8, 2015
FDA approval of Trovan/trovafloxacin	December 18, 1997
U.S. commercial withdrawal of Trovan	2005

The patent issued before the modern 20-year term framework was fully implemented, but its term was governed by the application filing date rather than the issue date. The patent therefore did not run until 2018, despite issuing in 1998.

No continuing enforceable exclusion is created by the patent today. A patent expiration also removes the need to design around the patent for U.S. commercial purposes, although regulatory, product-liability, manufacturing, and other intellectual-property issues may remain relevant.

What was the FDA and Orange Book status of trovafloxacin?

The FDA approved trovafloxacin for specified bacterial infections in adults under NDA 20-780 on December 18, 1997.[2] Trovan was marketed in oral and injectable forms. The FDA later imposed strong safety restrictions after reports of serious liver injury, including liver failure and deaths.

Pfizer withdrew Trovan from the U.S. market in 2005. The product’s withdrawal was associated with hepatotoxicity concerns rather than patent expiry. The FDA has treated the product as discontinued for commercial purposes, while the product’s historical approval and labeling remain relevant to patent and regulatory analysis.[2][3]

Was there FDA exclusivity?

The key regulatory exclusivity was the original approval exclusivity associated with the 1997 NDA. That period ended long before the 2015 patent expiration. There is no current regulatory exclusivity that blocks an ANDA or other U.S. application on the basis of Trovan’s historical approval.

Trovafloxacin is a small-molecule drug. Biosimilar legislation under the Public Health Service Act does not apply. Any follow-on product would be evaluated through a small-molecule pathway, principally an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act, or potentially an NDA under section 505(b)(2).

Were there Paragraph IV challenges to US 5,763,454?

A Paragraph IV certification would have been the relevant mechanism for an ANDA applicant seeking approval before the patent expired. A generic applicant could have alleged that the patent was invalid, unenforceable, or not infringed.

The most likely Paragraph IV positions against this patent would have involved:

Non-infringement based on a different polymorph or amorphous form.
Non-infringement based on a different salt or solvate.
Invalidity based on anticipation or obviousness of the claimed crystalline form.
Lack of adequate written description or enablement for the XRPD-defined form.
Process non-infringement under claim 2.
Lack of infringement of claim 4 where the marketed product did not contain the claimed form.

Because the patent expired in 2015, any historical Paragraph IV dispute no longer creates a current launch bar. Public FDA Orange Book records and the patent record should be used to confirm any particular ANDA notice, litigation case, or 30-month stay. No current Paragraph IV restraint arises from US 5,763,454.[3][4]

What patent litigation and settlements affected trovafloxacin?

The primary commercial risk was historically associated with the broader trovafloxacin compound and product estate, not only the crystalline-form patent. A complete litigation review would ordinarily separate:

Compound patents
Salt and polymorph patents
Formulation patents
Method-of-use patents
Process and manufacturing patents
Orange Book-listed patents
ANDA litigation and settlement agreements

US 5,763,454 should not be treated as a proxy for the entire trovafloxacin estate. Its claims are directed to one crystalline mesylate form and related uses. Any historical generic challenge would have needed to address the full set of live, listed patents, not only this patent.

The patent’s expiration eliminates present infringement exposure under its claims. Historical settlement provisions, supply agreements, or confidential commercial terms do not revive an expired patent monopoly.

What manufacturing and formulation barriers existed?

Before expiration, the principal barrier was reproducing a stable, pharmaceutically acceptable trovafloxacin mesylate form without falling within the XRPD definition.

Manufacturing issues likely included:

Controlling hydration and dehydration
Preventing conversion between crystalline forms
Maintaining consistent XRPD peak positions
Controlling residual solvents
Managing particle size and flow properties
Maintaining dissolution and bioavailability
Scaling the alcohol/aprotic co-solvent crystallization process
Preventing amorphous-content variability

Claim 2 specifically identifies a conversion process involving an alcohol and an aprotic co-solvent. That limitation could have been important in process diligence, but it did not prevent alternative routes to the same product if those routes avoided the claim language.

Claim 3 increased formulation risk because it was not limited to a particular dosage form or excipient system. A tablet, capsule, suspension, or other antibacterial composition containing the claimed crystalline form could potentially have implicated the claim while the patent remained in force.

How does this patent compare with a core compound patent?

Issue	US 5,763,454	Core trovafloxacin compound patent
Protected subject	Crystalline mesylate form	Chemical compound or compound class
Scope	Narrow physical form	Generally broader chemical scope
Design-around	Alternative polymorph, salt, solvate, or form	More difficult if the active compound itself is claimed
Formulation impact	Directly relevant to compositions containing the form	Usually indirect
Process protection	Specific solvent-and-heating route	May include synthesis intermediates or reaction steps
Current status	Expired November 8, 2015	Historical patents also expired based on their individual terms
Relevance to modern launch	No current patent bar	No current barrier from ordinary expired patents

The crystalline-form patent would ordinarily be classified as a secondary patent. Such patents can extend practical exclusivity beyond a core compound patent, but only if the protected form is commercially necessary and the patent remains enforceable.

What is the current generic launch risk for trovafloxacin?

The patent risk from US 5,763,454 is zero as an active patent constraint because the patent expired in 2015. A generic manufacturer would not need to avoid the claimed crystalline form on account of this patent.

Current commercial obstacles are different:

Historical safety concerns involving severe hepatotoxicity
Lack of active U.S. market demand
Discontinued branded marketing
Need for a viable regulatory pathway
Potential clinical and pharmacovigilance burdens
Limited commercial opportunity relative to currently used antibacterials

The product is not a biosimilar opportunity. It is a discontinued small-molecule antibacterial opportunity with limited apparent revenue exposure from the former originator product.

What licensing or partnership issues are associated with the patent?

The patent record identifies the originator-side Pfizer estate for trovafloxacin mesylate. The patent itself does not establish a continuing license obligation after expiration. A patent assignment, license, or settlement agreement could have affected commercialization during the patent term, but such private arrangements do not extend the patent’s statutory exclusion.

There is no current patent-license payment attributable solely to US 5,763,454 after its expiration.

Key Takeaways

US 5,763,454 covers crystalline trovafloxacin mesylate, not every trovafloxacin product.
Claim 1 is the principal claim and defines the product by eight major XRPD peaks.
Claim 2 protects a specific heat-based solvent conversion process.
Claim 3 covers antibacterial pharmaceutical compositions containing the claimed crystal form.
Claim 4 covers treatment of bacterial infection using that form.
The patent issued June 9, 1998, and expired November 8, 2015.
The patent is no longer an enforceable U.S. barrier to generic manufacture or launch.
Trovafloxacin was FDA-approved in 1997 and later withdrawn from the U.S. market because of serious liver-safety concerns.
Biosimilar risk is not applicable because trovafloxacin is a small molecule.
The historic estate should be analyzed separately from broader compound, formulation, process, and method-of-use patents.
Current commercial risk is driven more by safety, regulatory, and market factors than by patent exclusivity.

FAQs

Is US 5,763,454 a polymorph patent?

Yes. It is a crystalline-form patent. The claimed form is identified by its chemical identity as trovafloxacin mesylate and by a defined XRPD pattern.

Does the patent cover trovafloxacin hydrochloride?

No. The claims identify the methanesulfonic acid salt, or mesylate. A hydrochloride salt is chemically different and would not satisfy the salt limitation.

Could a generic use a different trovafloxacin polymorph?

During the patent term, a different polymorph could have avoided claim 1 if it did not exhibit the claimed XRPD pattern. That design-around is no longer necessary because the patent expired.

Does the patent cover injectable trovafloxacin?

Potentially, if the injectable composition contained the claimed crystalline trovafloxacin mesylate and satisfied claim 3. The claim does not expressly limit the composition to tablets or oral dosage forms.

Is Trovan still protected by U.S. patent rights?

US 5,763,454 no longer provides protection because it expired in 2015. Trovan was also withdrawn from the U.S. market, and the current commercial issue is not active exclusivity under this patent.

References

United States Patent and Trademark Office. (1998). U.S. Patent No. 5,763,454: Crystalline form of trovafloxacin mesylate.
U.S. Food and Drug Administration. (1997). Trovan (trovafloxacin mesylate) approval and prescribing information.
U.S. Food and Drug Administration. (2005). FDA public health advisory: Trovan safety and market withdrawal information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.

PCT Information
PCT Filed	June 06, 1995	PCT Application Number:	PCT/US95/07211
PCT Publication Date:	December 12, 1996	PCT Publication Number:	WO96/39406

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	002753	⤷ Start Trial
Australia	5474996	⤷ Start Trial
Australia	703634	⤷ Start Trial
Bulgaria	100639	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,763,454

Summary for Patent: 5,763,454