United States Patent 5,741,523: PGE-1 Lyophilized Formulation Claims, Scope, Expiration, and Patent Landscape
U.S. Patent No. 5,741,523 protects a narrowly defined lyophilized prostaglandin E1 formulation, also known as alprostadil, made through a specified manufacturing sequence. The claims require lactose, tertiary butyl alcohol, an acidic citrate or acetate buffer, a staged freezing cycle, and final limits on residual moisture and tertiary butyl alcohol. The patent issued on April 21, 1998, and its enforceable term has expired under the 20-year U.S. patent-term framework, subject to the patent’s prosecution history and any term adjustment or disclaimer. The claims therefore have historical and freedom-to-operate relevance, but they do not represent a current blocking patent.
What does U.S. Patent 5,741,523 protect?
The patent protects a solid, lyophilized PGE-1 formulation defined by both its composition and its manufacturing process. Claim 1 is the principal claim. Claims 2 and 3 narrow claim 1 by specifying sodium citrate and a PGE-1 concentration range.
The claimed process requires all of the following:
| Claim element |
Required limitation |
| Active ingredient |
PGE-1, or prostaglandin E1/alprostadil |
| Bulking or carrier material |
Lactose |
| Organic solvent |
Tertiary butyl alcohol, also called tert-butanol or TBA |
| TBA concentration before lyophilization |
About 15% to about 33% volume/volume |
| Lactose-to-PGE-1 ratio |
About 40,000:1 to about 10,000:1 weight/weight |
| pH adjustment |
About pH 4 to about pH 5 |
| Buffer |
Citrate or acetate buffer |
| First freezing step |
Approximately -50°C |
| Annealing or warming step |
Approximately -25°C for about two hours |
| Refreezing step |
Approximately -50°C |
| Drying endpoint |
Less than 1% moisture by dry weight |
| Residual TBA endpoint |
Less than 3% TBA by dry weight |
The claim is not directed generally to every lyophilized PGE-1 product. It requires the claimed process and the resulting product characteristics.
How should claim 1 be construed?
Claim 1 is a product-by-process claim. It identifies the product as a “lyophilized formulation of PGE-1 made by” a specified series of manufacturing steps. Under U.S. patent law, process language in a product-by-process claim generally limits the claim to products made by the recited process, even when the final product may be difficult to distinguish structurally from a product made by another process. The Federal Circuit applied this principle in Scripps Research Institute v. Genentech, Inc. and reaffirmed it in later cases.[2]
The claim has four important legal features.
The “consisting of” transition narrows the process
The process is introduced with “consisting of.” That language generally excludes additional process steps or materials that materially alter the claimed sequence, subject to established exceptions for incidental steps and claim construction. A competing manufacturer would face greater infringement risk if it follows the listed sequence and merely adds routine handling steps.
The phrase does not necessarily prohibit every manufacturing operation before or after the listed steps. Packaging, inspection, sterile handling, and ordinary equipment operations would not automatically avoid the claim. The relevant question would be whether an added operation changes a required claim limitation or introduces a material additional process component.
The final formulation must satisfy residual limits
The product must contain less than 1% moisture and less than 3% TBA by dry weight. A process that uses tert-butanol but leaves more than 3% residual TBA does not meet the literal final-product limitation. The same analysis applies to moisture above the claimed level.
These limitations make analytical testing central to any historical infringement analysis. Karl Fischer water analysis, residual-solvent testing, batch records, and lyophilization cycle records would be relevant evidence.
The numerical ranges use “about”
The terms “about 15%,” “about 33%,” “about 40,000:1,” “about 10,000:1,” “about -50°C,” “about -25°C,” and “about two hours” introduce claim-construction issues. “About” does not provide an unlimited range. Its scope depends on the specification, examples, technical precision, and how a person skilled in pharmaceutical formulation would understand the term.
The strongest literal infringement case would involve a process operating inside the stated ranges. A process outside the ranges could still raise an equivalents issue, but prosecution-history estoppel, experimental differences, and the Supreme Court’s all-elements framework limit that route.[3]
What do claims 2 and 3 add?
Claim 2: sodium citrate limitation
Claim 2 requires the formulation of claim 1 to use sodium citrate as the buffer. It excludes acetate-buffer embodiments and citrate salts that do not meet the proper construction of sodium citrate.
The wording refers to “said organic acid buffer,” although claim 1 recites “a citrate or acetate buffer.” That drafting inconsistency does not eliminate the narrowing effect of claim 2. The commercially relevant limitation is the use of sodium citrate within the pH range of approximately 4 to 5.
Claim 3: 25 to 100 ppm PGE-1
Claim 3 requires PGE-1 at approximately 25 to 100 parts per million in lactose. This range corresponds directly to the lactose-to-PGE-1 ratio in claim 1:
| PGE-1 concentration |
Approximate lactose:PGE-1 ratio |
| 25 ppm |
40,000:1 |
| 50 ppm |
20,000:1 |
| 100 ppm |
10,000:1 |
Claim 3 is narrower than claim 1 because it expressly limits PGE-1 concentration. A product containing approximately 25 to 100 ppm PGE-1 would still need to satisfy every other limitation of claim 1, including the TBA concentration, pH, freeze-anneal-refreeze cycle, and final residual limits.
What formulations are outside the literal scope?
The following formulations or processes would generally fall outside the literal wording if the identified difference is material:
- A liquid PGE-1 formulation rather than a lyophilized product.
- A formulation using mannitol, sucrose, trehalose, dextran, or another bulking agent instead of lactose.
- A process using ethanol, isopropanol, acetone, or no organic solvent instead of tertiary butyl alcohol.
- A TBA concentration below approximately 15% or above approximately 33% volume/volume, subject to construction of “about.”
- A pH outside approximately 4 to 5.
- A phosphate, glycine, histidine, or other buffer instead of citrate or acetate.
- A freezing cycle that omits the -25°C warming or annealing period.
- A final product with at least 1% moisture or at least 3% residual TBA.
- A PGE-1 concentration outside approximately 25 to 100 ppm for purposes of claim 3.
- A process that produces the same physical product by a materially different manufacturing route.
A formulation may be commercially similar to the patented product and still avoid literal infringement if one required element is absent. The doctrine of equivalents remains fact-dependent and cannot be assessed solely from the product label or formulation composition.
When did U.S. Patent 5,741,523 lose exclusivity?
U.S. Patent 5,741,523 issued April 21, 1998.[1] Because it was filed after the effective date of the modern U.S. patent-term regime, its basic term is generally 20 years from the earliest effective nonprovisional filing date, not 20 years from the issue date.[4]
The patent’s statutory term therefore expired no later than the applicable 20-year anniversary of its earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimer, or any relevant continuity issue. The patent is now expired and cannot support a new U.S. infringement action based on activities occurring after expiration.
The expiration of this patent does not eliminate other patents covering alprostadil products. A manufacturer must review separate patents directed to dosage forms, delivery systems, manufacturing processes, excipients, devices, and methods of use.
What is the Orange Book status of Patent 5,741,523?
The Orange Book lists patents submitted by sponsors for approved drug products and identifies patent certifications and regulatory exclusivity information.[5] Patent 5,741,523 is not a current enforceable barrier to an FDA-approved generic because the patent term has expired.
Historical Orange Book relevance depends on whether the patent was submitted for a particular alprostadil product and whether FDA retained it in the relevant product-specific listing. An Orange Book appearance would not extend the patent term. It also would not establish infringement. It would affect the regulatory certification pathway while the patent remained listed and unexpired.
For an abbreviated new drug application, a Paragraph IV certification would have been relevant only while an unexpired listed patent raised a patent certification issue. An expired patent generally supports a Paragraph III certification or has no remaining blocking effect, depending on the product’s current listing and application strategy.[6]
What patent litigation and Paragraph IV challenges affect this patent?
No current litigation can be inferred from the patent claims alone. The patent’s age and expiration mean that any active U.S. litigation based solely on Patent 5,741,523 would be unusual and legally constrained.
Historical litigation analysis should distinguish among:
- infringement actions filed before expiration;
- ANDA litigation under the Hatch-Waxman framework;
- declaratory-judgment actions involving alprostadil products;
- disputes over product-by-process claim construction;
- challenges to written description, enablement, anticipation, or obviousness;
- settlements that delayed generic entry without conceding validity or infringement.
A Paragraph IV challenge would have required an ANDA applicant to allege that the patent was invalid, unenforceable, or not infringed. The challenged claims would have been vulnerable to prior-art arguments involving lyophilized prostaglandin formulations, lactose carriers, tert-butanol freeze-drying, pH control, and annealing cycles. The claim’s combination of process parameters may have provided the principal validity distinction over broader formulation references.
How strong was the patent estate?
The patent was narrow but technically focused.
| Strength factor |
Assessment |
| Claim breadth |
Narrow |
| Product coverage |
Limited to products made by the recited process |
| Process specificity |
High |
| Dependence on analytical testing |
High |
| Coverage of liquid products |
None |
| Coverage of non-lactose formulations |
None |
| Coverage of other PGE-1 dosage forms |
None unless the product satisfies every limitation |
| Design-around potential |
High |
| Current enforceability |
None after expiration |
| Historical commercial relevance |
Potentially significant for a matching lyophilized injectable formulation |
The patent’s principal value was process control rather than broad molecule protection. PGE-1 itself was known before this patent. The claimed contribution was the combination of lactose dispersion, tert-butanol concentration, pH adjustment, staged freezing, and stringent drying endpoints.
A competitor could likely design around the patent by changing the carrier, replacing tert-butanol, altering the freeze cycle, using a different buffer, or adopting a liquid, suspension, cyclodextrin-based, urethral, or topical dosage form.
How does this patent compare with the broader alprostadil landscape?
Alprostadil products have used multiple delivery platforms:
| Product category |
Representative form |
Relevance to Patent 5,741,523 |
| Intracavernosal injection |
Lyophilized or reconstituted injectable |
Potentially relevant if every claim element is met |
| Intracavernosal injection |
Liquid injectable |
Outside the literal lyophilized-product requirement |
| Urethral delivery |
Pellet or suppository |
Generally outside claim scope |
| Topical delivery |
Cream or topical system |
Outside the claimed lyophilized formulation |
| Combination products |
Alprostadil with other active ingredients |
Requires separate claim analysis |
| Device-based delivery |
Cartridge, dual-chamber, or injection device |
Not claimed by Patent 5,741,523 |
The key competitive distinction is between the active ingredient and the delivery system. Patent 5,741,523 does not claim alprostadil broadly. It does not claim all injectable alprostadil products, all lyophilized PGE-1 products, or all products containing lactose. Every required process and endpoint must be present.
What manufacturing and IP barriers remain?
Although Patent 5,741,523 is expired, technical barriers may remain. A manufacturer reproducing the claimed process would still need to control:
- PGE-1 dispersion at very low concentration;
- tert-butanol handling and removal;
- sterile filtration or aseptic processing;
- freeze concentration and annealing behavior;
- cake structure and collapse temperature;
- moisture control;
- residual solvent limits;
- PGE-1 degradation and impurity formation;
- reconstitution time and dose uniformity.
These are regulatory and manufacturing barriers, not continuing exclusivity rights under the expired patent. Current freedom-to-operate analysis should search later patents and applications for alprostadil stabilization, cyclodextrin complexes, injection devices, reconstitution systems, topical formulations, and manufacturing controls.
What generic launch risks exist?
Patent 5,741,523 alone does not create a current generic launch delay. The remaining risks are product-specific:
- Other unexpired formulation or device patents.
- FDA requirements for pharmaceutical equivalence and bioequivalence.
- Injectable-product sterility and stability requirements.
- Differences in reconstitution, concentration, and administration device.
- Regulatory exclusivity associated with the reference product, if any remains.
- Trade-secret manufacturing knowledge not disclosed in the patent.
- Separate patents covering methods of treating erectile dysfunction or other PGE-1 indications.
A generic applicant should not assume that expiration of this patent clears the entire alprostadil patent estate. It clears only the claims of Patent 5,741,523.
Key Takeaways
- U.S. Patent 5,741,523 claims a narrowly defined lyophilized PGE-1 formulation made with lactose and tert-butanol.
- Claim 1 requires a specific composition, pH, freeze-anneal-refreeze cycle, moisture endpoint, and residual TBA endpoint.
- Claim 2 narrows the buffer to sodium citrate.
- Claim 3 narrows the PGE-1 concentration to approximately 25 to 100 ppm in lactose.
- The claims are product-by-process claims and require careful comparison of manufacturing records and final-product testing.
- The patent issued April 21, 1998, and its U.S. patent term has expired.
- The patent no longer blocks generic or follow-on activity by itself.
- Current risk may remain from later alprostadil patents covering formulations, devices, methods of use, or manufacturing processes.
- The patent does not broadly cover all PGE-1 products, all injectable alprostadil products, or all lyophilized formulations.
FAQs
Does Patent 5,741,523 cover Caverject?
Not automatically. Caverject or another alprostadil injectable would fall within the claims only if its product and manufacturing process satisfy every limitation, including the lactose-to-PGE-1 ratio, tert-butanol range, pH, freeze cycle, and final residual limits.
Does the patent cover Edex?
The answer depends on the specific Edex formulation and manufacturing process at issue. A product label alone is insufficient because the claims include process limitations that may not appear in the approved composition.
Is tert-butanol the same as tertiary butyl alcohol?
Yes. Tert-butanol, tertiary butyl alcohol, and 2-methyl-2-propanol refer to the same solvent.
Can an expired formulation patent still affect FDA approval?
It can remain relevant to historical patent certifications or product records, but expiration removes its ability to support a current injunction or delay based on patent term. FDA approval still depends on applicable regulatory requirements and any other listed patents or exclusivities.
Does a different freeze-drying cycle avoid the claims?
Potentially, if the alternative process does not meet the required freezing, warming, refreezing, or drying limitations. The complete process and final product must be compared against the claim, and an equivalents analysis may remain fact-specific.
References
- U.S. Patent No. 5,741,523, “Lyophilized prostaglandin E1 formulation” (issued Apr. 21, 1998).
- Scripps Research Institute v. Genentech, Inc., 927 F.2d 1565 (Fed. Cir. 1991).
- Warner-Jenkinson Co. v. Hilton Davis Chemical Co., 520 U.S. 17 (1997).
- 35 U.S.C. § 154(a)(2) (2023).
- U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
- U.S. Food and Drug Administration. (2024). ANDA submissions: Patent certifications and the 30-month stay under Hatch-Waxman.
