United States Patent 5,147,868: Claim Scope, Cilastatin Coverage, Expiration, and Generic Risk

US Patent 5,147,868 covers a broad class of Z-configured substituted 2-amino-2-alkenoic acid derivatives that inhibit dipeptidase, including cilastatin and related compounds. The most commercially important species is the cilastatin acid structure identified in claim 19, together with its sodium, potassium, calcium, or magnesium salts under claim 20. The patent issued September 15, 1992, and, absent a patent-term adjustment, terminal disclaimer, or applicable extension, its 17-year pre-URAA term expired September 15, 2009.[1]

The patent is therefore no longer a current United States exclusivity barrier. Its historical importance was as a composition-of-matter patent for cilastatin-type renal dehydropeptidase inhibitors used with imipenem. Generic entry today is governed primarily by regulatory requirements, manufacturing capability, product quality, and any later patents or regulatory exclusivities, not by US 5,147,868.

What compounds does US Patent 5,147,868 protect?

The claims protect compounds built around a Z-configured unsaturated amino-acid framework with three principal variable regions:

R1, associated with the acid or ester form.
R2, the N-acyl substituent, especially substituted cyclopropyl groups.
R3, the side chain attached to the amino-acid backbone and bearing a terminal polar or basic group.

The broadest independent compound claim is claim 1. It covers a Markush genus rather than one molecule. Its principal limitations are:

Claim element	Scope
Stereochemistry	The compound must have the Z configuration
R1	Hydrogen or a pharmaceutically acceptable cation
R2	Branched or linear C3-C10 alkyl, certain heteroatom-containing chains, or C3-C6 cycloalkyl
R2 substituents	Halogen or cycloalkyl, with carbon-count and substitution limits
R3	C2-C15 alkyl chain, optionally halogenated or containing oxygen, sulfur, or SO2
Terminal R3 group	Basic, acidic, polar, sulfur-containing, cyano, amide, phosphono, amino-acid, or related functionality
Exclusions	Restrictions on tertiary carbon adjacent to the carbonyl, halogen substitution, and certain combinations of short-chain R2 and R3 groups

The central technical concept is a Z-configured dehydropeptide-like structure with a hydrophobic N-acyl group and a terminally functionalized side chain. The terminal functionality gives the compounds the polarity and ionization properties associated with dipeptidase inhibition.

Which claims cover cilastatin?

Cilastatin is most directly covered by claims 19 and 20.

Claim 19 identifies:

7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid.

This corresponds to the cilastatin acid structure, subject to the stereochemical and structural limitations incorporated from claim 9. Claim 20 extends claim 19 to the sodium, potassium, calcium, and magnesium salt forms. Cilastatin sodium is the clinically used form.

Cilastatin-related claim mapping

Claim	Subject matter	Commercial relevance
1	Broad Markush genus of Z-configured dipeptidase inhibitors	Broad platform claim
2	R2 is 2,2-dimethylcyclopropyl	Includes the cilastatin acyl group
9	Narrower compound genus using 2,2-dimethylcyclopropyl or 2,2-dichlorocyclopropyl	More focused genus
19	L-2-amino-2-carboxyethylthio side chain on the dimethylcyclopropyl series	Direct cilastatin-type coverage
20	Salts of the claim 19 compound	Includes cilastatin sodium
23	Pharmaceutical composition containing a claim 1 compound	Formulation and composition coverage
24	Mammalian dipeptidase inhibition method using a claim 1 compound	Therapeutic-use coverage

Claims 10 through 18 cover related analogs. They vary the side-chain length and terminal group, including trimethylammonium, guanidino, amidino, ureido, cyano, acetamido, and amino-acid thioether substituents.

How broad is claim 1?

Claim 1 is structurally broad but heavily constrained by its Markush definitions and provisos. A compound would generally require all of the following for literal infringement:

The claimed core structure.
Z stereochemistry at the relevant alkene.
An R2 group falling within X or Y.
An R3 side chain within the specified carbon range.
A permitted terminal substituent or terminal functional group.
Compliance with the carbon-count and halogen-substitution restrictions.
R1 as hydrogen or a pharmaceutically acceptable cation.

The claim does not cover every dipeptidase inhibitor. It is limited to the disclosed structural class. A compound with E stereochemistry, a different unsaturation pattern, an impermissible R2 group, or a terminal group outside the enumerated categories would present a substantial literal-infringement defense.

R2 limitations

The R2 definition is a major boundary on claim scope. It covers:

Linear or branched C3-C10 alkyl groups.
Certain chains in which a nonterminal methylene is replaced by oxygen, sulfur, or SO2.
C3-C6 cycloalkyl groups.
Cycloalkyl groups substituted with halogen or C1-C4 alkyl.
Specifically, 2,2-dimethylcyclopropyl and 2,2-dichlorocyclopropyl groups through dependent claims.

The claim imposes separate total-carbon limits where cycloalkyl or alkyl substituents are present. Those limits prevent an unrestricted reading of the Markush language.

R3 limitations

R3 is the principal site for analog expansion. The claim reaches C2-C15 chains that may contain:

Oxygen, sulfur, or SO2 in place of a nonterminal methylene.
Halogen substitution, subject to a six-hydrogen limit.
Terminal amino, ureido, amidino, guanidino, alkylamino, ammonium, acylamino, phosphonylamino, hydroxy, carboxy, phosphono, cyano, carbamoyl, thiol, or related groups.
The L-2-amino-2-carboxyethylthio group found in cilastatin.

The broad R3 language creates potential coverage of non-cilastatin analogs, but the terminal-group list, chain-length limits, stereochemical requirements, and structural provisos narrow the practical perimeter.

What formulations are protected by US 5,147,868?

Claim 23 covers a pharmaceutical composition comprising:

A compound within claim 1; and
A pharmaceutically acceptable carrier.

This is a composition claim, not a detailed formulation claim. It does not expressly require:

A specific dosage form.
A specific excipient.
A particular drug-to-carrier ratio.
Combination with imipenem.
Intravenous administration.
A particular pH, buffer, package, or reconstitution method.

The claim could therefore reach pharmaceutical compositions containing a qualifying compound in an amount sufficient to inhibit dipeptidase. Its scope is narrower than a claim directed to all cilastatin formulations because it is expressly tied to claim 1 and does not independently recite every compound in claim 9.

The claim also does not clearly create a standalone formulation monopoly over the marketed imipenem-cilastatin product. A commercial product would need to contain a compound covered by claim 1, and the patent expired in 2009.

What method-of-use patents does US 5,147,868 contain?

Claim 24 covers administering a claim 1 compound to a mammal in a pharmacologically effective amount to inhibit dipeptidase.

This is a functional method claim. Its principal limitations are:

A mammalian subject.
Administration of a compound falling within claim 1.
A pharmacologically effective amount.
The purpose of inhibiting dipeptidase activity.

It is not limited to treatment of a specific disease, infection, organ system, or bacterial species. It also does not expressly require administration with imipenem. The claim could historically have been asserted against use of a qualifying inhibitor for the stated biological purpose, subject to proof of compound identity, administration, and use.

The method claim expired with the patent and does not create a current US enforcement risk.

When did US Patent 5,147,868 lose exclusivity?

Event	Date
Patent issued	September 15, 1992
Standard pre-URAA patent term	17 years from issuance
Expected expiration	September 15, 2009
Current status	Expired by term

US 5,147,868 is a pre-June 8, 1995 patent. Under the applicable pre-URAA framework, the ordinary term was 17 years from issuance, rather than 20 years from the earliest effective filing date.[2]

No current patent-term extension or remaining enforceable term should be attributed to this patent without a specific USPTO record showing otherwise. The patent’s age and the 2009 term date place it outside the period in which it could block a present-day abbreviated new drug application.

What is the Orange Book status of cilastatin and imipenem?

Cilastatin was approved in the United States in combination with imipenem as the antibacterial product marketed as Primaxin. Cilastatin is a dipeptidase inhibitor that protects imipenem from renal degradation. The FDA-approved product is a small-molecule drug, not a biologic.[3]

The relevant regulatory pathway for a generic imipenem-cilastatin product is generally an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act. A 505(b)(2) application could be relevant for a product relying partly on FDA findings while introducing differences in formulation, dosage form, or clinical use.

US 5,147,868 does not presently create an Orange Book patent barrier because its term expired. Historical Orange Book treatment must be distinguished from current enforceability. A patent may have been listed during the product’s protected commercial period, but expiration removes the patent from practical exclusivity analysis.

Regulatory exclusivity

The patent is separate from FDA regulatory exclusivity. Any original new chemical entity or other regulatory exclusivity associated with the imipenem-cilastatin product expired decades ago. Current commercial entry therefore turns on:

ANDA approval.
Bioequivalence.
Sterility and injectable-product controls.
Drug-substance and drug-product manufacturing.
Reference-product availability.
Supply-chain qualification.
Any later, unexpired patents.

There is no biosimilar pathway because imipenem and cilastatin are synthetic small molecules. A competing product would be a generic or an alternative 505(b)(2) product, not a biosimilar.

Which companies are challenging the patent?

The patent no longer presents a live Paragraph IV target. Paragraph IV certifications are used to challenge listed patents in connection with an ANDA. Because US 5,147,868 expired in 2009, a current applicant would not need to challenge it to obtain approval.

Historical Paragraph IV litigation may have involved generic imipenem-cilastatin applicants or other Merck products, but the supplied claim text does not establish a litigation docket, settlement, or party-specific challenge. No current litigation consequence can be assigned to this expired patent from the claims alone.

What patent litigation and settlements affect generic launch?

The patent’s expiration makes a present-day settlement based solely on US 5,147,868 commercially irrelevant. Any historical settlement would not extend the expired statutory term.

For generic imipenem-cilastatin products, launch analysis should separate:

Risk category	Effect of US 5,147,868
Composition-of-matter patent	Expired
Cilastatin sodium claim	Expired
Broad analog claims	Expired
Composition claim	Expired
Method-of-use claim	Expired
FDA exclusivity	Expired for the original product
Biosimilar exposure	Not applicable
Manufacturing barriers	Still potentially relevant
Later formulation or process patents	Must be reviewed separately

The commercial barriers are more likely to involve sterile injectable manufacturing, impurity control, stability, lyophilization or reconstitution performance, and reliable supply of both active ingredients.

How strong was the patent estate?

Historical strength

The estate was strong at issuance because it combined:

A broad Markush composition claim.
Narrower genus claims.
Multiple expressly claimed species.
Salt coverage.
Pharmaceutical composition coverage.
A dipeptidase-inhibition method claim.

Composition-of-matter protection generally provides greater leverage than a narrow formulation or method claim because it can reach the active ingredient across dosage forms and manufacturers. Claims 19 and 20 were particularly important for cilastatin and its pharmaceutical salts.

Current strength

The current legal strength is zero as an exclusionary right because the patent term has expired. The patent remains relevant as prior art and as evidence of historical structure-activity and formulation disclosure, but it cannot support an infringement action for conduct occurring after expiration.

How does this patent compare with competing drug patent estates?

Product or class	Role	Patent position relative to US 5,147,868
Cilastatin	Renal dehydropeptidase inhibitor	Directly covered, but patent expired
Imipenem	Carbapenem antibiotic paired with cilastatin	Protected by separate patent history
Betamipron	Alternative renal dehydropeptidase inhibitor	Separate compound and regulatory estate
Relebactam	Beta-lactamase inhibitor	Different mechanism and structure
Vaborbactam	Beta-lactamase inhibitor	Different chemical class
Avibactam	Beta-lactamase inhibitor	Different mechanism and patent estate

Cilastatin is not a beta-lactamase inhibitor. It inhibits renal dehydropeptidase I and is used to preserve imipenem exposure. Comparisons with relebactam, vaborbactam, and avibactam are therapeutic and commercial rather than claim-overlap comparisons.

What licensing deals are relevant?

The patent claims do not disclose licensing terms. The commercial history of imipenem-cilastatin is associated with Merck’s development and commercialization of Primaxin, but product commercialization, patent ownership, assignment, and license rights are separate legal issues.

No license should be inferred merely from:

A patent assignment.
A co-promotion arrangement.
A generic supply agreement.
A marketing authorization.
A later manufacturer’s ANDA.

For current diligence, the relevant question is not whether a license to US 5,147,868 is required. It is whether a proposed product implicates later unexpired patents, confidential manufacturing know-how, or contractual supply rights.

What geographic coverage did the patent have?

US 5,147,868 provided protection only in the United States. Foreign counterparts, if any, would have had separate national terms and prosecution histories. A US patent does not establish protection in Europe, Japan, Canada, China, or other jurisdictions.

Because the US patent expired in 2009, geographic risk now depends on the status of corresponding foreign patents and any later-filed patents. Foreign patent terms cannot be inferred from the US patent number alone.

What generic launch scenarios exist?

Immediate generic entry

A manufacturer can pursue a conventional ANDA strategy without a Paragraph IV challenge to US 5,147,868. The principal requirements are bioequivalence, injectable-product quality, sterility, and manufacturing validation.

505(b)(2) entry

A 505(b)(2) route may be relevant where the product differs materially in formulation, delivery, concentration, or administration. This pathway may create a separate exclusivity and patent analysis.

Combination-product entry

A competitor may seek approval for imipenem-cilastatin as a fixed combination or co-packaged product. The expired cilastatin patent does not prevent either approach. Product-specific FDA requirements and any later patents remain relevant.

Manufacturing-led competition

The practical barrier may be production rather than patent law. Relevant capabilities include:

Control of cilastatin stereochemistry.
Reproducible formation of the thioether side chain.
Salt conversion and isolation.
Sterile powder or solution manufacture.
Stability through reconstitution.
Compatibility of imipenem and cilastatin.
Control of degradation products.

Key Takeaways

US 5,147,868 covers a broad class of Z-configured dipeptidase inhibitors.
Claims 19 and 20 most directly cover cilastatin-type compounds and their salts, including cilastatin sodium.
Claims 23 and 24 cover compositions and mammalian dipeptidase-inhibition methods tied to claim 1.
The patent issued September 15, 1992, and its ordinary 17-year term expired September 15, 2009.
The patent is no longer a live US composition-of-matter, formulation, method-of-use, or Paragraph IV barrier.
Cilastatin is a synthetic small molecule, so biosimilar analysis does not apply.
Current generic risk is driven by FDA approval, sterile injectable manufacturing, supply, and later patents.
Any foreign patent protection must be analyzed separately by jurisdiction.
No license, settlement, or litigation right can be inferred from the claim text alone.
The patent retains prior-art and historical value but has no current exclusionary force in the United States.

FAQs

Is cilastatin sodium still protected by US Patent 5,147,868?

No. The patent’s ordinary term expired on September 15, 2009.

Does US 5,147,868 cover imipenem?

No. The claims cover cilastatin-type dipeptidase inhibitors and related compounds. Imipenem belongs to a separate carbapenem patent estate.

Can a generic company file Paragraph IV against US 5,147,868?

A current applicant would not need to challenge this patent because it has expired. A Paragraph IV certification is relevant to an unexpired listed patent.

Is a cilastatin generic a biosimilar?

No. Cilastatin is a synthetic small-molecule drug. A competing product would generally use the ANDA or, in some cases, 505(b)(2) pathway.

Does claim 23 cover every imipenem-cilastatin formulation?

No. Claim 23 requires a pharmaceutical composition containing a compound covered by claim 1. It does not expressly claim every combination, excipient system, dosage form, or reconstitution process.

References

United States Patent and Trademark Office. (1992). US Patent No. 5,147,868.
United States Congress. (1994). Uruguay Round Agreements Act, Pub. L. No. 103-465, § 532.
U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drug products and labeling for imipenem and cilastatin.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	244550	⤷ Start Trial
Austria	17472	⤷ Start Trial
Austria	2299	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,147,868

Summary for Patent: 5,147,868