United States Patent 4,935,507: Cefixime Crystal Form, Claim Scope, Expiration, and Patent Landscape

U.S. Patent 4,935,507 protects a crystalline form of cefixime, the orally active third-generation cephalosporin marketed principally as Suprax. The patent covers the cefixime syn-isomer crystal itself, identified by specified powder X-ray diffraction peaks, and two preparation routes involving acidification of an alkali-metal salt solution or crystallization from an alcohol solution.

The patent issued on June 19, 1990, and its 17-year term from grant expired on June 19, 2007. It no longer creates a U.S. patent barrier to generic cefixime. The claims remain important for historical patent analysis because they illustrate protection of a pharmaceutical solid form rather than the cefixime molecule, antibacterial use, dosage form, or manufacturing process generally.

What compound does U.S. Patent 4,935,507 protect?

The claimed compound is cefixime in a defined crystalline form.

Cefixime is chemically identified in the claims as:

7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid, syn isomer.

The compound has:

Attribute	Description
Active ingredient	Cefixime
Therapeutic class	Third-generation oral cephalosporin
Core structure	3-cephem beta-lactam
Distinguishing substituent	3-vinyl group
Side chain	2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido
Claimed stereochemistry	Syn hydroxyimino isomer
Claimed physical state	Crystalline solid
Patent subject matter	Cefixime crystal form and selected crystallization methods

The patent does not claim every form of cefixime. Its central limitation is the crystalline state of the syn-isomer. A product consisting of amorphous cefixime, a different polymorph, a solvate, a hydrate, or another solid form would require separate analysis against the claim limitations.

The patent was assigned to Fujisawa Pharmaceutical Co., Ltd., the Japanese pharmaceutical company that developed cefixime. Fujisawa later became part of Astellas Pharma.

What are the claims of U.S. Patent 4,935,507?

The patent contains five claims. Claim 1 is the principal product claim. Claims 2 through 5 define alternative or narrower ways to obtain the crystalline material.

Claim structure

Claim	Type	Principal limitation
1	Product-by-characterization	Crystalline cefixime syn-isomer having seven specified powder X-ray diffraction peaks
2	Product-by-process	Crystalline cefixime syn-isomer obtainable by acidifying a solution at room temperature or under warming
3	Dependent product-by-process	The solution in claim 2 is an aqueous solution of an alkali-metal cefixime salt
4	Dependent process limitation	Acidification occurs from room temperature to 40°C at pH 1 to 4
5	Product-by-process	Crystalline cefixime obtained by dissolution in alcohol, warming with slow stirring, cooling, and standing

How does claim 1 define the cefixime crystal?

Claim 1 identifies the crystal by powder X-ray diffraction peaks at approximately:

Diffraction angle, 2θ	Claim status
14.7°	Required
17.8°	Required
21.5°	Required
22.0°	Required
23.4°	Required
24.5°	Required
28.1°	Required

The claim does not provide relative intensities, peak widths, lattice constants, solvent content, water content, particle size, or a complete diffraction pattern. Its literal scope therefore turns on whether the accused cefixime material exhibits the claimed crystal identity at those approximate angles.

Technical significance of the diffraction limitations

The X-ray limitations distinguish the claimed solid form from:

Amorphous cefixime;
A different cefixime polymorph;
A hydrate or solvate with a different lattice;
A cefixime salt;
A material having altered crystallinity or a substantially different diffraction pattern;
Cefixime in a non-crystalline pharmaceutical formulation.

The word "about" gives some tolerance around each diffraction angle. The patent does not specify the numerical tolerance. In an infringement dispute, the analysis would normally compare validated powder X-ray diffraction data from the accused material with the claimed peak positions, taking account of instrument calibration, sample preparation, radiation source, and analytical variability.

The claim does not expressly require that the seven listed peaks be the only peaks present. A cefixime crystal showing the seven claimed peaks could potentially fall within claim 1 even if it also has additional diffraction peaks, provided the other claim limitations are met.

What do claims 2 through 5 protect?

Claims 2 through 5 add crystallization-route limitations.

Claim 2: acidification route

Claim 2 covers crystalline cefixime obtained by acidifying a solution containing cefixime syn-isomer at room temperature or under warming.

The claim does not expressly limit the acid, solvent system, pH, or starting salt in its independent language. Claim 2 is therefore broader than claim 4 regarding temperature and pH, subject to the legal effect of the phrase "obtainable by."

The likely process concept is conversion of a soluble cefixime salt or solution form into the free-acid crystalline cefixime by controlled acidification.

Claim 3: alkali-metal salt solution

Claim 3 narrows claim 2 to an aqueous solution of an alkali-metal salt of cefixime. The relevant salts would ordinarily include sodium or potassium cefixime, although the claim language is not limited to those examples.

A process that begins with a non-alkali-metal salt, a nonaqueous medium, or cefixime free acid may fall outside the literal scope of claim 3, even if it produces the same crystalline product.

Claim 4: temperature and pH

Claim 4 limits the acidification step to:

Temperature from room temperature to 40°C; and
pH from 1 to 4.

The claim is narrower than claim 2 and claim 3. It is directed to controlled precipitation conditions that may improve crystal formation, purity, yield, or reproducibility.

Claim 5: alcohol crystallization route

Claim 5 covers crystalline cefixime obtained by:

Dissolving cefixime syn-isomer in an alcohol;
Continuing slow stirring under warming;
Cooling the solution to room temperature; and
Allowing the solution to stand.

The claim does not identify a single alcohol in the language supplied. The absence of a specific alcohol, concentration, temperature, or standing time creates a broader process description, although infringement would still depend on whether the accused process follows the required sequence and produces the claimed crystalline substance.

Is U.S. Patent 4,935,507 a product patent or a process patent?

The patent is principally a crystal-form product patent with product-by-process claims.

Claim 1 is a product claim defined by chemical identity, stereochemistry, crystalline state, and powder X-ray diffraction characteristics. Claims 2 through 5 use process language to identify the claimed crystalline product.

For product-by-process claims, the central infringement question is generally whether the accused product is the claimed product, not merely whether the accused manufacturer used the identical process. The process language can still limit claim scope, particularly where the claim requires a product "obtainable by" a specified route and the product cannot be distinguished adequately from other forms.

The patent does not expressly claim:

Cefixime as a chemical genus;
The cefixime molecule in every solid form;
Oral suspension formulations;
Tablets or capsules as dosage forms;
A particular dose or dosing regimen;
Treatment of otitis media, pharyngitis, urinary tract infection, or other disease;
A cefixime manufacturing intermediate;
A fermentation process;
A specific pharmaceutical excipient;
A specific package or delivery device.

When did U.S. Patent 4,935,507 expire?

Event	Date
Patent issued	June 19, 1990
Statutory term under pre-1995 patent rules	17 years from issue
Expiration	June 19, 2007
Current status	Expired

U.S. Patent 4,935,507 was granted before the Uruguay Round Agreements Act changed the standard U.S. patent term to 20 years from the earliest effective nonprovisional filing date. For a pre-June 8, 1995 patent, the applicable term generally depended on the earlier of the old 17-year-from-grant term or the newer 20-year-from-filing term. The grant-date term was the relevant limitation here.

The expiration date eliminates current U.S. infringement risk under this patent. A generic manufacturer no longer needs to design around these claims or delay launch because of this patent.

What was the FDA and Orange Book status of cefixime?

Cefixime was approved in the United States as Suprax in 1989. The original product was associated with Lederle Laboratories, while later commercial rights and generic competition involved other companies, including Lupin and multiple abbreviated new drug application sponsors.

The FDA Orange Book historically identified cefixime drug products and listed relevant patent information where applicable. Orange Book patent listings do not extend an expired patent term. Once U.S. Patent 4,935,507 expired in 2007, it ceased to be an enforceable Orange Book barrier to an ANDA applicant.

Regulatory issue	Assessment
FDA pathway for generics	ANDA under section 505(j)
Reference product	Suprax cefixime products
Reference-product approval	1989
Patent at issue	U.S. 4,935,507
Current enforceability	None, expired
Orange Book relevance today	Historical only
Biosimilar pathway	Not applicable
Product category	Small-molecule antibiotic

Cefixime is a chemically synthesized small molecule. Biosimilar regulation under section 351(k) does not apply. Competitors enter through the generic drug pathway rather than through a biosimilar application.

Did U.S. Patent 4,935,507 create a Paragraph IV risk?

During its enforceable term, an ANDA applicant seeking approval for a cefixime product could have addressed the patent through a Paragraph IV certification if the patent was listed for the reference product and the applicant believed the patent was invalid, unenforceable, or not infringed.

A Paragraph IV certification could have raised issues such as:

Whether the proposed generic contained the same claimed crystal form;
Whether the proposed product was amorphous or a different polymorph;
Whether the applicant used the acidification route in claims 2 through 4;
Whether the applicant used the alcohol crystallization route in claim 5;
Whether the listed patent was valid and enforceable;
Whether the patent was properly listed for the relevant dosage form.

The patent’s expiration makes a present-day Paragraph IV strategy unnecessary for this patent. An ANDA applicant can rely on patent expiration rather than challenge the claims.

Historical Paragraph IV litigation cannot be inferred solely from the patent record. The patent record establishes issuance, ownership, claims, and expiration. It does not by itself establish whether a particular generic sponsor sent a Paragraph IV notice, whether the patent owner filed suit, or whether a settlement occurred.

What other intellectual-property barriers affect generic cefixime?

The principal current barriers are regulatory, commercial, and manufacturing-related rather than patent-based.

Formulation patents

Cefixime tablets, capsules, chewable tablets, and oral suspensions may involve separate formulation patents or applications. Those rights would need to be reviewed independently from U.S. Patent 4,935,507.

The 1990 patent does not claim:

A cefixime oral suspension;
A cefixime tablet composition;
A specific excipient system;
Taste masking;
Particle-size control;
A pediatric dosage form;
A reconstitutable powder;
A sustained-release delivery system.

A formulation patent could therefore have presented a distinct barrier even after the crystal-form patent expired. The existence and enforceability of any such barrier depend on the specific Orange Book listing, patent family, and expiration date.

Method-of-use patents

The patent does not claim treatment methods. A later patent could cover a dosing regimen, patient population, indication, combination therapy, or reduced-duration treatment. Such rights are separate from the crystal-form claims and must be evaluated by indication and labeling.

For a standard generic cefixime product, the ANDA applicant would analyze whether the reference labeling contains patented uses and whether a section viii statement or labeling carve-out is available.

Manufacturing and technical barriers

Cefixime production can require control of:

Syn-isomer selectivity;
Beta-lactam stability;
Impurity profiles;
Crystal nucleation;
Solvent and water content;
Particle size;
Powder flow;
Suspension stability;
Microbiological quality;
Residual solvents;
API-to-formulation compatibility.

These factors can create development and regulatory risk without creating patent infringement risk. A manufacturer that uses an alternative crystallization route may avoid claims 2 through 5, but it still must demonstrate that its final cefixime solid does not fall within claim 1. Because claim 1 is product-based, changing the process alone would not necessarily avoid infringement during the patent term if the same claimed crystal form resulted.

How strong was the patent estate for cefixime?

U.S. Patent 4,935,507 was technically narrow but potentially commercially meaningful during its enforceable life.

Strength factor	Assessment
Chemical compound coverage	Weak; does not claim cefixime in all forms
Crystal-form coverage	Strong if the seven diffraction peaks identify the commercial form
Process coverage	Moderate; claims 2 through 5 describe alternative crystallization routes
Formulation coverage	None apparent from the claims
Method-of-use coverage	None apparent from the claims
Generic design-around potential	Possible through a different solid form or process, subject to claim 1
Current legal strength	None; expired
Historical commercial value	Potentially material because the product claim covered the physical API form

The strongest claim was claim 1 because it did not depend on proving that the accused manufacturer used a particular crystallization procedure. If the commercial cefixime API matched the claimed diffraction pattern, the product claim could reach the API regardless of the manufacturing route, subject to claim construction and proof of the crystal identity.

Claims 2 through 5 were narrower and more process-dependent. They offered fallback protection against specified precipitation and alcohol crystallization techniques, but they were less robust against a manufacturer using a materially different process.

Which companies compete in cefixime after patent expiry?

Cefixime is a mature generic antibiotic market. Competition has historically included:

The Suprax branded product;
Authorized or branded-generic suppliers;
Generic API manufacturers;
ANDA sponsors producing tablets, capsules, chewables, and oral suspension products.

The commercial impact of U.S. Patent 4,935,507 is therefore historical. Its expiration in 2007 opened the relevant crystal-form claims to unrestricted generic competition, subject to other patents, FDA approval requirements, supply qualification, and commercial contracting.

Revenue exposure is concentrated in the branded cefixime franchise and does not extend to the entire cephalosporin market. Once the patent expired, price erosion depended on the number of approved ANDA products, payer substitution, distributor access, manufacturing capacity, and the relative demand for pediatric suspension and solid oral products.

What patent litigation and settlement issues remain?

No current enforcement action can arise under U.S. Patent 4,935,507 because the patent expired in 2007. Any historical litigation or settlement involving cefixime would have had to occur before that date or involve other patents.

The patent itself does not establish:

A continuing injunction;
A launch restriction;
A royalty obligation;
A settlement term;
A covenant not to sue;
A licensed generic;
A current Orange Book dispute.

A party evaluating historical launch timing should separate this patent from later formulation, use, or regulatory exclusivity issues. Patent expiration did not automatically eliminate FDA requirements, but it removed this patent as a legal basis for blocking a compliant generic launch.

Key Takeaways

U.S. Patent 4,935,507 covers a crystalline syn-isomer form of cefixime.
Claim 1 is defined by seven powder X-ray diffraction peaks at approximately 14.7°, 17.8°, 21.5°, 22.0°, 23.4°, 24.5°, and 28.1°.
Claims 2 through 5 cover crystal material made through acidification or alcohol-based crystallization routes.
The patent does not claim cefixime in every physical form, a formulation, a method of treatment, or a dosage regimen.
The patent issued June 19, 1990, and expired June 19, 2007.
It has no current blocking effect on U.S. generic cefixime entry.
Cefixime is a small molecule, so biosimilar analysis is not applicable.
Any current patent risk must come from separate formulation, method-of-use, manufacturing, or delivery-system patents.
Claim 1 was historically the strongest claim because it focused on the final crystal form rather than the manufacturing route.

FAQs

Does U.S. Patent 4,935,507 cover cefixime tablets?

No. The claims cover crystalline cefixime and specified preparation routes. They do not expressly claim a tablet, capsule, chewable dosage form, excipient system, or oral suspension.

Can a generic manufacturer use a different cefixime crystallization process?

Yes, but a different process would not by itself avoid claim 1 during the patent term if the resulting API had the claimed crystal form. Claims 2 through 5 are more directly tied to specified preparation conditions.

Is cefixime subject to biosimilar competition?

No. Cefixime is a small-molecule antibiotic. FDA competition proceeds through ANDAs and the Hatch-Waxman framework, not the biosimilar pathway.

What analytical test is most relevant to claim 1?

Powder X-ray diffraction is the principal test because claim 1 identifies the crystal by diffraction angles. Sample preparation, instrument calibration, radiation source, peak tolerance, and comparison methodology are material to the analysis.

Can the expired patent still support a current patent lawsuit?

No. An expired patent cannot support a new claim for ongoing infringement after expiration. Historical damages or litigation issues would depend on events occurring before the expiration date and on applicable limitation and evidentiary rules.

References

U.S. Patent and Trademark Office. (1990). U.S. Patent No. 4,935,507: Crystalline cefixime and processes for preparation. U.S. Department of Commerce.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration. (1989). Suprax (cefixime) prescribing information. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration. (n.d.). Generic drug facts and abbreviated new drug applications. U.S. Department of Health and Human Services.
United States Code, 35 U.S.C. §§ 154, 156, 271, 282.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	62-206199	Aug 19, 1987

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	123221	⤷ Start Trial
Australia	617347	⤷ Start Trial
Canada	1297096	⤷ Start Trial
Germany	3853901	⤷ Start Trial
European Patent Office	0304019	⤷ Start Trial
Spain	2072856	⤷ Start Trial
Hong Kong	18496	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,935,507

Summary for Patent: 4,935,507