US Patent 5,543,150: Progesterone Vaginal Delivery Claims, Expiration, and Patent Landscape

US Patent 5,543,150 protects a method of delivering progesterone to the endometrium through a vaginal drug-delivery system while keeping systemic progesterone concentrations below defined serum thresholds. The patent is directed primarily to therapeutic use, pharmacokinetic outcomes, and use of a cross-linked polycarboxylic polymer, particularly polycarbophil.

The patent issued on August 6, 1996. Because it was granted under the pre-Uruguay Round patent-term regime, its ordinary 17-year term ran to August 6, 2013, absent a term extension or adjustment that would alter the calculation.[1] The claims therefore no longer create a current US patent barrier to vaginal progesterone products.

What does US Patent 5,543,150 protect?

The patent covers vaginal administration of progesterone under a defined pharmacodynamic and pharmacokinetic profile:

Progesterone is delivered through the vagina.
The delivery produces secretory transformation of the endometrium.
Serum progesterone remains below 6.0 ng/mL for at least 48 continuous hours.
Certain claims require a serum concentration of 1 to 4 ng/mL.
Certain claims require 10 to 200 mg of progesterone.
Certain claims require a cross-linked polycarboxylic polymer.
Polycarbophil is the principal expressly claimed polymer.
Some claims require vaginal administration of an adjuvant.
Some claims require prior estrogen priming of the vagina.
Some claims cover endometrial targeting without expressly requiring the secretory-transformation limitation.

The patent does not claim progesterone as a chemical compound. It also does not claim every vaginal progesterone product. Its central subject matter is a method of achieving endometrial activity with limited systemic exposure.

What is the claim structure of US 5,543,150?

The claims divide into four functional groups.

Claim group	Claims	Principal limitations
Core vaginal delivery method	1-5	Vaginal progesterone delivery, secretory transformation, serum level below 6 ng/mL for at least 48 hours
Polymer-based delivery	6-7, 23	Cross-linked polycarboxylic polymer, progesterone, polycarbophil, cross-linking level
Endometrial targeting	8-11	Vaginal system containing progesterone and cross-linked carboxylic polymer; 10-200 mg or adjuvant limitations
Serum-level treatment methods	12-22	Secretory transformation while maintaining progesterone between approximately 1 and less than 5, 1-6, 1-4, or 1-2 ng/mL

Claims 1, 8, 11 and 12 are the principal independent-claim concepts. Claims 2-7, 9-10 and 13-23 narrow those concepts by adding dosage, polymer, serum concentration, adjuvant, estradiol priming or cross-linking limitations.

How should the independent claims be analyzed?

Claim 1: vaginal progesterone with sustained low serum exposure

Claim 1 requires proof of each of the following:

A woman receives progesterone.
Administration occurs through a drug-delivery system inserted into the vagina.
The dose is sufficient to cause secretory transformation of the endometrium.
Serum progesterone remains below 6.0 ng/mL.
The serum threshold is maintained continuously for at least 48 hours.

The claim is outcome-dependent. A product may use the same route and active ingredient but avoid infringement if it does not produce the claimed serum profile or does not cause the claimed endometrial transformation. Conversely, a delivery system could fall within the claim even if its formulation differs, provided the claimed clinical results are achieved.

Claims 2 and 3: dose and serum-level limitations

Claim 2 narrows claim 1 to 10-200 mg of vaginal progesterone. Claim 3 narrows it to a serum progesterone concentration of 1-4 ng/mL.

The dosage limitation and serum-level limitation are separate. A product using 10-200 mg may not satisfy claim 3 if the resulting serum concentration exceeds or falls below 1-4 ng/mL. A product producing 1-4 ng/mL may not satisfy claim 2 if it uses a dose outside the 10-200 mg range.

Claims 4 and 5: adjuvants and estradiol priming

Claim 4 covers vaginal administration of one or more adjuvants with progesterone. The claim does not identify a closed list of adjuvants. The scope therefore turns on claim construction and the patent specification's disclosure of compatible excipients or active agents.

Claim 5 requires that the vagina has been primed with estradiol. A progesterone product used without the required estradiol-priming step would not satisfy this limitation.

Claims 6, 7 and 23: polymer-based systems

These claims add formulation-specific limitations:

A cross-linked polycarboxylic polymer.
Progesterone incorporated with that polymer.
Polycarbophil in claim 7.
A cross-linking agent present at approximately 0.1-6.0 weight percent of the polymer in claim 23.

Polycarbophil is a cross-linked polyacrylic-acid-type polymer used for mucoadhesion. The polymer limitations distinguish the patent from simple progesterone suppositories, capsules or non-mucoadhesive vaginal formulations.

Claims 8-11: endometrial targeting

Claims 8-11 focus on targeting progesterone delivery to the endometrium. Claim 8 requires:

Vaginal insertion of a system containing a cross-linked carboxylic polymer and progesterone.
A progesterone amount of 10-200 mg.

Claim 9 adds a 1-4 ng/mL serum-level limitation. Claim 10 specifies polycarbophil. Claim 11 covers the same targeting concept with at least one adjuvant.

These claims do not expressly repeat the 48-hour requirement from claim 1. They also do not expressly require secretory transformation. That makes them structurally different from claims 1-7, although the phrase "targeting" would be interpreted in light of the specification and prosecution history.

Claims 12-22: serum-controlled endometrial transformation

Claim 12 is directed to causing secretory transformation while maintaining progesterone serum levels between approximately 1 and less than 5 ng/mL. Claims 20 and 21 narrow the range to 1-4 ng/mL and 1-2 ng/mL.

Claim 13 combines the treatment outcome with a cross-linked polycarboxylic polymer and progesterone. Claims 14-19 add the principal formulation and administration limitations, including:

10-200 mg of progesterone.
1-4 ng/mL serum concentration.
Polycarbophil.
Adjuvants.
Estradiol priming.
0.1-6.0 weight percent cross-linking agent.

What formulations are protected by US 5,543,150?

The strongest formulation-specific coverage is directed to vaginal systems containing progesterone and polycarbophil or another cross-linked polycarboxylic or carboxylic polymer.

Formulation type	Likely relevance to claim set
Progesterone in polycarbophil vaginal gel	Directly implicated by claims 6, 7, 10, 13 and 16
Progesterone in another cross-linked polycarboxylic polymer	Potentially implicated by claims 6, 8, 11 and 13
Progesterone vaginal insert without cross-linked polymer	More relevant to claims 1-5 and 12, depending on serum and clinical results
Progesterone suppository or capsule	Potential method risk if the claimed pharmacodynamic and serum criteria are met
Oral progesterone	Outside the express vaginal-delivery limitations
Injectable progesterone	Outside the express vaginal-delivery limitations
Vaginal estrogen without progesterone	Outside the patent's progesterone-delivery requirements

The claims do not require a gel in every instance. A non-gel vaginal device could potentially implicate the claims if it satisfies the route, active ingredient, polymer and serum-level limitations.

When did US Patent 5,543,150 lose exclusivity?

The patent's ordinary expiration date was August 6, 2013.[1] The term calculation follows the pre-1995 rule of 17 years from grant rather than the modern 20-year term from the earliest effective nonprovisional filing date.

Event	Date
Patent issued	August 6, 1996
Ordinary patent term	17 years from issue
Ordinary expiration	August 6, 2013
Current enforceability	Expired
Current Paragraph IV threat from this patent	None

A patent that has expired cannot support an injunction against a later entrant. It also cannot support a current patent-based royalty claim for post-expiration conduct, although historical disputes may involve pre-expiration sales, settlement obligations or contractual rights.

What is the Orange Book status of US Patent 5,543,150?

The patent was associated with the older patent estate surrounding progesterone vaginal gel products, including Crinone. Crinone is a progesterone vaginal gel approved by the FDA under NDA 020701.[2]

US Patent 5,543,150 is no longer a live exclusionary patent because its term ended in 2013. Historical Orange Book listings can remain relevant to past ANDA certifications and litigation records, but an expired listing does not prevent FDA approval or commercial launch of a generic product.

The Orange Book issue should be separated from FDA regulatory exclusivity:

Patent protection: expired.
Regulatory approval: remains with the reference product.
New-drug exclusivity: separate from patent term and generally much shorter.
Current generic approval risk: driven by other patents, formulation differences, labeling and regulatory requirements rather than US 5,543,150.

What related patents covered progesterone vaginal products?

The Crinone and vaginal progesterone patent estate included later US patents directed to related delivery systems and formulations. Public patent records commonly associate the following patents with the broader estate:

Patent	General relevance	Approximate term status
US 5,543,150	Vaginal progesterone delivery, serum thresholds and endometrial transformation	Expired August 6, 2013
US 5,756,484	Related vaginal progesterone delivery and formulation subject matter	Expired under its applicable term
US 6,099,853	Related progesterone vaginal delivery technology	Expired under its applicable term

The later patents must be analyzed claim by claim. They should not be treated as interchangeable with US 5,543,150. A product that avoids the 5,543,150 claims may still have faced historical risk from a formulation or delivery patent with different limitations.

Which companies were relevant to the commercial patent landscape?

Columbia Laboratories and Crinone

Columbia Laboratories was closely associated with the development and commercialization of progesterone vaginal gel technology. Crinone used a bioadhesive vaginal gel platform containing progesterone and was approved for assisted reproductive technology-related indications and secondary amenorrhea.[2]

The 5,543,150 claims align closely with the product concept because they address vaginal delivery, endometrial effect, controlled systemic exposure and polycarbophil-based delivery.

Actavis and generic progesterone gel

Actavis became associated with generic competition to progesterone vaginal gel products. Once the relevant patents expired, the commercial barrier shifted from patent validity and infringement to FDA approval, manufacturing capability, product equivalence and market economics.

Ferring Pharmaceuticals and Endometrin

Ferring's Endometrin is a progesterone vaginal insert rather than the same polycarbophil gel platform.[3] It illustrates the distinction between:

Vaginal delivery as a route.
A specific bioadhesive polymer system.
A solid vaginal insert.
Product-specific formulation and manufacturing patents.

A competing insert would require a separate analysis of its own patent estate and would not automatically infringe claims requiring a cross-linked polycarboxylic polymer.

Are there Paragraph IV challenges to US Patent 5,543,150?

A Paragraph IV certification is relevant only while a listed patent remains unexpired. Because US 5,543,150 expired in 2013, it cannot now be the basis for a current Paragraph IV launch dispute.

Historically, generic applicants seeking approval for progesterone vaginal products could have addressed the reference product's patent listings through:

Paragraph III certification, accepting delayed approval until expiration.
Paragraph IV certification, alleging invalidity, unenforceability or noninfringement.
A section viii statement carving out patented methods from the proposed labeling.
A patent certification directed to later formulation or method patents.

The commercial impact of any historical Paragraph IV dispute would depend on the specific ANDA, listed patent and litigation settlement. The expiration of 5,543,150 removes that patent from current launch blocking analysis.

What patent litigation affects progesterone vaginal products?

US 5,543,150 presents no current litigation barrier because it is expired. Historical litigation involving progesterone vaginal products would have centered on:

Whether the accused product used the required vaginal delivery system.
Whether serum progesterone remained within the claimed ranges.
Whether the product achieved secretory transformation.
Whether a polymer qualified as a cross-linked polycarboxylic or carboxylic polymer.
Whether a generic label induced performance of a patented method.
Whether later formulation patents remained unexpired.

Method claims can create difficult infringement questions because infringement may depend on clinical use and measured serum outcomes rather than simply on the product's ingredients. A generic manufacturer may reduce risk by using a different dosage, different polymer, different label or a noninfringing indication, although product conduct and physician use remain material.

What is the manufacturing and intellectual-property barrier?

The expired patent does not prevent manufacture of vaginal progesterone products. Remaining barriers are commercial and regulatory:

Development of a stable progesterone dosage form.
Uniform drug distribution.
Control of release and residence time.
Microbiological quality and preservative control.
Applicator and packaging design.
Scale-up of the polymer system.
FDA demonstration of product quality and therapeutic equivalence.
Manufacturing-site compliance.
Physician and fertility-clinic adoption.

Polycarbophil may have been central to the historical product differentiation, but the polymer itself is not protected indefinitely by this patent. Current protection would depend on later patents, trade secrets, know-how, trademarks, manufacturing controls and regulatory exclusivity.

How strong was the patent estate for US 5,543,150?

The patent had meaningful historical value because it combined three layers of protection:

A therapeutic outcome: secretory transformation of the endometrium.
A pharmacokinetic result: maintaining serum progesterone below specified concentrations.
A delivery technology: vaginal administration using a cross-linked polymer, particularly polycarbophil.

Its weaknesses were equally specific:

Several claims depend on measured serum concentrations.
Some claims require proof of a clinical endometrial result.
The claims do not broadly cover all progesterone products.
Claims limited to polycarbophil or defined cross-linking levels are easier to design around.
Patent-term expiration eliminated prospective enforcement after 2013.

The patent was strongest against a product that used vaginal progesterone in a polycarbophil system, delivered 10-200 mg, produced 1-4 ng/mL serum concentrations and was used to induce secretory transformation. It was weaker against oral products, injectable products, nonpolymeric vaginal systems and products used under labels that did not implicate the claimed methods.

What generic launch scenarios existed?

A generic entrant could have pursued several strategies:

Launch strategy	Patent and regulatory profile
Same or similar vaginal gel after patent expiration	Lowest risk from US 5,543,150, subject to other patents and FDA requirements
Non-polycarbophil vaginal formulation	May avoid polymer-specific claims, but method claims could remain relevant before expiration
Vaginal insert	Potentially outside polymer-specific claims; separate product patents require review
Label carve-out	Could reduce method-of-use exposure where FDA labeling permits omission
Paragraph IV launch before expiration	Required litigation and 30-month-stay analysis if listed patents were challenged
Post-expiration ANDA approval	No current infringement risk from the expired patent

Does US 5,543,150 create biosimilar risk?

No. Progesterone is a small-molecule active ingredient, not a biologic. The relevant FDA pathway is an ANDA or, depending on product characteristics, another small-molecule approval route. Biosimilar procedures under section 351(k) of the Public Health Service Act do not apply to progesterone vaginal products.

Key Takeaways

US Patent 5,543,150 is a method patent covering vaginal progesterone delivery and controlled serum exposure.
Its principal technical focus is endometrial transformation with serum progesterone below 6 ng/mL, often within a 1-4 ng/mL range.
The most specific formulation coverage concerns cross-linked polycarboxylic polymers, particularly polycarbophil.
Claims 1-5 and 12-22 can reach methods based on clinical and pharmacokinetic outcomes even without every polymer limitation.
The patent issued August 6, 1996 and ordinarily expired August 6, 2013.
It no longer blocks generic or competing vaginal progesterone development.
Historical relevance remains for Crinone, progesterone vaginal gel products, ANDA certifications and related patent-family analysis.
Current launch risk must be assessed against later patents, FDA requirements, manufacturing capability and product-specific labeling.
The patent does not create biosimilar risk because progesterone is a small-molecule drug.

FAQs

Can a vaginal progesterone suppository infringe US Patent 5,543,150?

It could have presented historical method-claim risk if it achieved the claimed endometrial transformation and serum progesterone ranges. The polymer-specific claims would be less likely to apply if the suppository did not contain a cross-linked polycarboxylic polymer. The patent's expiration eliminates current infringement risk.

Does claim 12 require a vaginal delivery system?

No. Claim 12, as provided, requires secretory transformation while maintaining serum progesterone between approximately 1 and less than 5 ng/mL. Claim 22 adds vaginal delivery for a subset of the serum-level claims.

Does polycarbophil have to be present in every claim?

No. Polycarbophil is expressly required only in claims that depend on claims 7, 10 or 16. Other claims cover vaginal delivery, serum levels or clinical outcomes without expressly requiring polycarbophil.

Could a product avoid the patent by using more than 200 mg of progesterone?

That approach could avoid claims expressly limited to 10-200 mg, including claims 2, 8 and 14. It would not automatically avoid broader claims that lack the 10-200 mg limitation, such as portions of claims 1 and 12.

Is US 5,543,150 still relevant to FDA approval of a new progesterone product?

It is relevant as historical patent and product-background information, but it is not a current patent barrier. FDA approval now depends on the applicable application pathway, product quality, manufacturing controls, labeling, bioequivalence or clinical requirements and any other unexpired patents.

References

United States Patent and Trademark Office. (1996). U.S. Patent No. 5,543,150, Vaginal delivery of progesterone.
U.S. Food and Drug Administration. (n.d.). Crinone progesterone gel, NDA 020701: Prescribing information.
U.S. Food and Drug Administration. (n.d.). Endometrin progesterone vaginal insert, NDA 022057: Prescribing information.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.
United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation resources.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	174796	⤷ Start Trial
Australia	689133	⤷ Start Trial
Australia	7726194	⤷ Start Trial
Brazil	9407475	⤷ Start Trial
Canada	2171939	⤷ Start Trial
Colombia	4290332	⤷ Start Trial
Germany	69415543	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,543,150

Summary for Patent: 5,543,150