US Patent 8,481,526: Besifloxacin Crystal-Form Claims, Patent Scope, and Generic Risk

US Patent 8,481,526 protects a specific molecular crystal form of besifloxacin and a process for producing it from a soluble besifloxacin salt. The patent does not broadly claim all besifloxacin, besifloxacin hydrochloride, ophthalmic formulations, or every manufacturing route. Its strongest coverage is directed to the claimed free-base crystal form, identified through a combination of XRPD, DSC, carbon-13 NMR, and pKa characteristics, plus a pH-controlled crystallization process.

The patent was issued July 9, 2013, from an application filed December 18, 2009. Its base patent term runs to December 18, 2029, subject to any applicable patent-term adjustment. The original applicant and assignee was InSite Vision Incorporated; commercial rights to Besivance and related assets were later acquired by Bausch + Lomb. [1, 2]

What does US Patent 8,481,526 protect?

The patent claims a particular molecular crystal of the R-enantiomer of besifloxacin and a method for preparing it.

Claim	Subject matter	Primary limitation
1	Besifloxacin molecular crystal	XRPD peaks at 10.6, 15.0, 19.7, 21.1 and 22.0° ±0.2°
2	Besifloxacin molecular crystal	DSC melting peak at 288°C
3	Besifloxacin molecular crystal	Specific ^13C NMR peaks
4	Besifloxacin molecular crystal	pKa values of 5.65 and 9.91
5	Besifloxacin molecular crystal	All four analytical profiles combined
6	Manufacturing process	Solubilizing a soluble salt, adjusting pH to about 6.2-6.8, and allowing crystallization
7	Manufacturing process	Recovering the crystal
8	Manufacturing process	Reducing recovered particles to nanometer or micrometer size

The patent is therefore a crystal-form and process patent. It is not a conventional composition-of-matter patent covering the besifloxacin molecule in every physical or salt form.

What is the chemical subject of the patent?

The claimed compound is the R-(+) enantiomer of besifloxacin:

(R)-(+)-7-(3-amino-2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)-1-cyclopropyl-8-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Besifloxacin is a fourth-generation fluoroquinolone antibacterial. The commercial ophthalmic product Besivance contains besifloxacin hydrochloride in an ophthalmic suspension. The patent claims a molecular crystal of the besifloxacin free-base form, although the process begins with a soluble salt, such as a hydrochloride salt.

That distinction matters. A product containing besifloxacin hydrochloride is not automatically within every claim of the patent. Infringement depends on whether the claimed molecular crystal is present, made, used, imported, or incorporated into the product, and whether the accused material satisfies the analytical limitations in the claims.

How broad are claims 1 through 5?

Claims 1 through 5 are product-by-characterization claims. Each claim defines the crystal through one or more physical or analytical properties rather than through a conventional structural formula alone.

Claim 1: XRPD-defined crystal

Claim 1 requires a crystal having XRPD peaks at:

10.6°
15.0°
19.7°
21.1°
22.0°

Each angle is subject to a ±0.2° tolerance.

The use of “comprises” generally permits additional XRPD peaks. An accused crystal does not necessarily avoid the claim merely because it has additional reflections. The central question is whether the required peaks are present within the stated tolerance and arise from the claimed besifloxacin molecular crystal.

XRPD is usually the most commercially practical test for comparing a generic API or intermediate against the patented form. Testing should compare the accused material against the complete reference pattern, not only the five recited peaks. A partially overlapping XRPD pattern may support infringement, but it may also raise issues involving polymorph mixtures, preferred orientation, hydration, instrument calibration, or peak-shift variability.

Claim 2: DSC-defined crystal

Claim 2 requires a DSC melting peak at 288°C.

This limitation is narrower than a general melting-point range but may create evidentiary issues. DSC results can vary with:

Heating rate
Sample mass
Pan type
Instrument calibration
Purity
Hydration or solvation
Decomposition before or during melting

A materially different thermal event may support a non-infringement position, but an accused party cannot rely solely on a modest numerical difference without controlling test conditions.

Claim 3: ^13C NMR-defined crystal

Claim 3 requires ^13C NMR peaks at 23.3, 27.7, 41.1, 54.5, 116.6, and 153.5 ppm.

NMR peaks generally identify the chemical environment of atoms in the molecule. They may be less effective than XRPD for distinguishing polymorphs because different solid forms of the same compound can have similar solution-state or solid-state NMR signatures. The claim nevertheless uses those peaks as defining characteristics of the crystal.

A material with the same besifloxacin molecular structure but a different crystal arrangement could potentially show similar ^13C NMR peaks while lacking the claimed XRPD or DSC profile. Claim 3 does not require the XRPD peaks listed in claim 1 or the DSC peak in claim 2.

Claim 4: pKa-defined crystal

Claim 4 requires pKa values of 5.65 and 9.91.

pKa is ordinarily a molecular property rather than a uniquely identifying crystal-form property. The two values likely reflect the ionizable carboxylic-acid and amino functionalities of besifloxacin. This creates a potential claim-construction and validity issue: many physical forms, salts, or solution preparations of the same active ingredient may exhibit materially similar pKa values.

Claim 4 is therefore vulnerable to arguments that the limitation does not adequately distinguish the claimed crystal from the known besifloxacin molecule or other forms. Its practical strength depends heavily on how the specification defines the measurement method and how a court interprets “characterized by.”

Claim 5: Combined analytical profile

Claim 5 combines the limitations of claims 1 through 4. It requires the XRPD peaks, 288°C DSC melting peak, six ^13C NMR peaks, and both pKa values.

This is the narrowest product claim and the most difficult to satisfy literally. It is also the claim most likely to survive an attack based on a single analytical property if the complete profile is distinctive and reproducible.

The tradeoff is enforcement difficulty. The patent owner must prove that the accused material satisfies every required characteristic. Minor differences in testing may become material.

What does claim 6 cover?

Claim 6 covers a process with three mandatory steps:

Solubilizing a desired amount of a soluble besifloxacin salt in a solvent, such as water.
Adjusting the solution to a pH from about 6.2 to about 6.8.
Allowing sufficient time for the molecular crystal to form.

Claims 7 and 8 add recovery and particle-size reduction.

The process claim does not require every possible crystallization condition. It does require the pH range and the use of a soluble salt as the starting material. A process using a different pH, a nonsalt starting material, a different crystallization mechanism, or a route that never forms the claimed crystal may avoid literal infringement.

The phrase “about 6.2 to about 6.8” introduces ordinary claim-construction questions concerning the acceptable range. A process at pH 6.1 or 6.9 would not automatically avoid the claim. Courts generally assess the intrinsic evidence, specification, prosecution history, and technical meaning of “about.”

Claim 8 is particularly relevant to nanosuspension or microsuspension manufacturing. It reaches a process that recovers the crystal and then reduces it to nanometer- or micrometer-sized particles. It does not, on its face, claim a finished ophthalmic dosage form or impose a particular excipient system.

Does the patent cover Besivance?

The patent may be relevant to Besivance, but its claims should not be equated with complete product coverage.

Besivance-related subject	Apparent coverage under US 8,481,526
Besifloxacin active ingredient generally	No broad claim
Besifloxacin hydrochloride as a salt	Not expressly claimed as the product
Claimed besifloxacin molecular crystal	Yes
Production from a soluble besifloxacin salt at pH 6.2-6.8	Yes
Ophthalmic suspension generally	No express formulation claim
Specific particle-size reduction process	Yes, under claim 8
All salts, solvates, hydrates, and polymorphs	No

Besivance was approved by the FDA on May 29, 2009, under NDA 022223. The product is a topical ophthalmic suspension containing 0.6% besifloxacin hydrochloride. [3] FDA approval does not establish that every manufacturing step or every physical form used in the product falls within the patent claims.

What is the Orange Book status of US 8,481,526?

US 8,481,526 has been associated with Besivance patent protection and is reported with an expiration date in December 2029. The FDA Orange Book is the controlling public source for listed patents, expiration dates, and regulatory exclusivity information. [2]

The Orange Book listing has two practical consequences:

An ANDA applicant may need to address the patent through a Paragraph III certification, Paragraph IV certification, or another applicable certification.
A Paragraph IV notice can trigger a patent infringement action under the Hatch-Waxman statute and a potential 30-month stay of ANDA approval.

An Orange Book listing does not mean the patent will necessarily be found valid or infringed. It establishes a regulatory patent-certification issue, not the ultimate litigation result.

When does besifloxacin lose exclusivity?

Besifloxacin’s market protection has several separate components.

Protection type	Relevant date or status
NDA approval for Besivance	May 29, 2009
Original regulatory exclusivity	Expired years ago
Core compound-patent protection	Earlier besifloxacin patents have generally reached or approached expiration
Crystal-form patent, US 8,481,526	December 18, 2029 base term
Generic approval pathway	Depends on Orange Book certifications and litigation
Biosimilar pathway	Not applicable

The 2029 date is a patent expiration date, not an automatic generic-launch date. A generic applicant could potentially launch earlier after a successful Paragraph IV challenge, a settlement permitting an earlier date, a finding of non-infringement, invalidity, unenforceability, or a licensing arrangement.

Are there Paragraph IV challenges to Besivance?

A Paragraph IV filing is an ANDA applicant’s assertion that an Orange Book-listed patent is invalid, unenforceable, or will not be infringed by the proposed product.

Public regulatory records should be reviewed for the current applicant-specific certification and litigation position. The key patent issue for an ANDA applicant is whether its API, manufacturing route, and dosage-form supply chain use the claimed molecular crystal or the pH-controlled crystallization process.

A generic applicant can pursue several technical positions:

It uses a different besifloxacin salt or solid form.
It does not produce the claimed XRPD pattern.
Its material lacks the claimed DSC or NMR characteristics.
It uses a crystallization pH outside the claimed range.
It purchases API from a supplier using a non-infringing process.
It uses a route that produces a different polymorph or amorphous material.
The claims are invalid for anticipation, obviousness, indefiniteness, or inadequate written description.

A Paragraph IV strategy based only on changing the final formulation may be insufficient if the API supplier manufactures the claimed crystal using the patented process.

What formulation patents protect besifloxacin ophthalmic products?

US 8,481,526 is not principally a formulation patent. Its claims do not recite the complete Besivance excipient system, preservative system, viscosity profile, container, or ophthalmic suspension composition.

The relevant patent landscape should be divided into four layers:

Layer	Protection target	Relevance
Composition of matter	Besifloxacin chemical structure	Older, generally earlier-expiring protection
Solid form	Free-base molecular crystal	US 8,481,526
Manufacturing process	Salt dissolution, pH adjustment, crystallization	Claims 6-8
Dosage form	Ophthalmic suspension, particle size, excipients, delivery	May involve separate patents or unpatented know-how

The existence of a formulation patent would not automatically extend the scope of US 8,481,526. Conversely, a generic that avoids the crystal-form claims may still face separate formulation claims if listed and enforceable.

How strong is the patent estate?

Strengths

The claims identify a defined solid form rather than merely claiming an intended use.
XRPD provides a practical forensic tool for API comparison.
The process claims identify a commercially plausible salt-to-free-base crystallization route.
Claim 8 reaches particle-size reduction, which may be relevant to ophthalmic suspension production.
The patent term extends materially beyond the original regulatory exclusivity period.

Weaknesses

Claims 2 through 4 rely on analytical or physicochemical characteristics that may not uniquely distinguish the crystal form.
pKa values are potentially weak identifiers of a solid-state form.
Claim 5 is narrow because every listed characteristic must be satisfied.
The product claims may not cover besifloxacin hydrochloride as such.
Process claims can be difficult to enforce when manufacturing occurs outside the United States and evidence of the foreign process is unavailable.
A generic may design around the pH-controlled crystallization step or source a non-infringing API.

The strongest enforcement combination is likely claim 1 plus claim 6 or claim 8, assuming the accused API exhibits the required XRPD profile and the manufacturing route can be established.

What generic launch risks exist?

Scenario 1: Paragraph III certification

The applicant accepts the patent and delays approval or launch until expiration. This produces the lowest litigation risk but postpones entry to December 2029 or another agreed date.

Scenario 2: Paragraph IV certification

The applicant challenges validity or infringement. The patent owner may sue within 45 days, potentially triggering a 30-month approval stay. Litigation risk is high, but an early launch becomes possible if the applicant prevails or reaches a settlement.

Scenario 3: Non-infringing API sourcing

The applicant uses an API supplier that produces a different solid form or follows a different crystallization process. This reduces direct process-claim risk but requires robust analytical and supplier documentation.

Scenario 4: At-risk launch

The applicant launches before final resolution. Exposure can include damages, an injunction, destruction or modification of inventory, and supply-chain disruption.

What litigation or settlement issues matter?

The principal litigation questions are likely to be:

Whether the accused solid is the claimed besifloxacin crystal.
Whether the XRPD peaks fall within the stated tolerances.
Whether the patent claims distinguish a crystal form from the free-base molecule.
Whether the pKa limitation is definite and technically meaningful.
Whether the prior art disclosed the same crystal or made it obvious.
Whether a supplier’s process falls within the pH range.
Whether the patent owner can prove the process used to manufacture imported API.
Whether any Hatch-Waxman settlement permits a launch before December 2029.

No biosimilar litigation analysis is applicable because besifloxacin is a small-molecule fluoroquinolone, not a biologic.

How does US 8,481,526 compare with a typical composition-of-matter patent?

Issue	Composition patent	US 8,481,526
Covers active ingredient generally	Usually yes	No
Covers particular polymorph	Usually no	Yes
Requires analytical testing	Usually limited	Central to claims 1-5
Design-around potential	Lower	Higher
Process enforcement	Usually secondary	Central to claims 6-8
Relevance to API supplier	Moderate	High
Risk from alternate salt or polymorph	Often still covered	Potentially significant

Key Takeaways

US 8,481,526 is a besifloxacin crystal-form and manufacturing-process patent.
Claims 1-5 cover a molecular crystal defined by XRPD, DSC, ^13C NMR, pKa, or combinations of those properties.
Claims 6-8 cover crystallization from a soluble besifloxacin salt at approximately pH 6.2-6.8, followed by recovery and particle-size reduction.
The patent does not broadly claim all besifloxacin, besifloxacin hydrochloride, or every ophthalmic formulation.
The base patent term runs to December 18, 2029.
The patent is relevant to Besivance and could create an ANDA Paragraph IV barrier, but an Orange Book listing does not determine validity or infringement.
The most credible design-around routes involve a different solid form, a different salt-to-crystal route, or a crystallization process outside the claimed pH range.
The principal vulnerability is that pKa and some spectroscopic characteristics may not uniquely identify a crystal form.
Biosimilar risk does not apply; the relevant competitive threat is generic besifloxacin ophthalmic suspension.

FAQs

Can a generic use besifloxacin hydrochloride without infringing US 8,481,526?

Not necessarily. The salt itself is not expressly claimed, but the generic may infringe if its manufacturing process produces the claimed molecular crystal or uses the patented crystallization conditions.

Does changing the excipients avoid the patent?

Usually not if the accused API or manufacturing process satisfies the claims. Excipient changes address formulation issues, while this patent principally concerns the active ingredient’s crystal form and production.

Can XRPD alone prove infringement?

XRPD can provide strong evidence for claim 1, but the result must be interpreted against the full claim language, tolerance range, sample condition, and possible mixtures or polymorphs.

Is a different melting point enough to avoid the patent?

It may be relevant to claim 2, but it does not automatically avoid claims 1, 3, 4, 5, or the process claims. Each asserted claim must be analyzed independently.

Does US 8,481,526 cover a besifloxacin nanosuspension?

It can cover a process for reducing recovered besifloxacin crystals to nanometer- or micrometer-sized particles under claim 8. It does not automatically cover every nanosuspension composition or finished ophthalmic product.

References

United States Patent and Trademark Office. (2013). U.S. Patent No. 8,481,526, Molecular crystal of besifloxacin and method of making same. https://patents.google.com/patent/US8481526B2/en
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm
U.S. Food and Drug Administration. (2009). Besivance prescribing information, NDA 022223. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022223s000lbl.pdf
U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application approvals and patent certifications. https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/anda-approvals

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Bausch And Lomb	BESIVANCE	besifloxacin hydrochloride	SUSPENSION/DROPS;OPHTHALMIC	022308-001	May 28, 2009		RX	Yes	Yes	8,481,526	⤷ Start Trial		Y			⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	075926	⤷ Start Trial
Brazil	PI1009849	⤷ Start Trial
Canada	2756769	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,481,526

Which drugs does patent 8,481,526 protect, and when does it expire?

Summary for Patent: 8,481,526