US Patent 4,594,358: Scope, Claims, Expiration, and Patent Landscape

US Patent 4,594,358 covers the use of fluoxetine or norfluoxetine to potentiate dextropropoxyphene analgesia and pharmaceutical combinations containing both agents. The patent was granted to Eli Lilly and Company in 1986 and expired in 2003 under the pre-1995 patent-term rule. It does not create a current US exclusivity barrier for fluoxetine, dextropropoxyphene, or a combination product.

The patent’s commercial relevance is now historical. Dextropropoxyphene products were withdrawn from the US market in 2010 because of cardiac toxicity concerns, and no current US market opportunity remains for an FDA-approved product relying on these claims.[1]

What does US Patent 4,594,358 cover?

The patent covers two distinct subject-matter categories:

A method of increasing or potentiating dextropropoxyphene analgesia by administering fluoxetine or norfluoxetine within a defined time window.
A pharmaceutical formulation containing fluoxetine or norfluoxetine, dextropropoxyphene, and an acceptable carrier, diluent, or excipient.

The independent claims are claims 1 and 5.

Claim	Claim type	Principal limitation
1	Method of treatment	Fluoxetine or norfluoxetine administered to a mammal from 24 hours before to 2 hours after dextropropoxyphene
5	Pharmaceutical formulation	Fluoxetine or norfluoxetine plus dextropropoxyphene in a 4:1 to 1:4 ratio
2-4	Method dependents	Simultaneous administration, fluoxetine hydrochloride, and specified dose ranges
6-9	Formulation dependents	Fluoxetine hydrochloride, approximately 1:2 ratio, specified doses, and oral delivery

The claims are combination claims. They do not broadly cover fluoxetine alone, nor do they broadly cover dextropropoxyphene alone.

How broad is claim 1?

Claim 1 is the broadest therapeutic-use claim. It requires:

Administration to a mammal.
Fluoxetine or norfluoxetine.
Dextropropoxyphene analgesia.
An effective amount of the serotonergic compound.
Administration between 24 hours before and 2 hours after dextropropoxyphene.
Potentiation of the analgesic effect.

The claim is not limited to humans, oral dosing, fluoxetine hydrochloride, a particular dosage, or a particular formulation. It therefore reaches veterinary use in principle, provided the claimed analgesic potentiation and timing requirements are met.

Claim 1 limitation analysis

Limitation	Scope consequence
"Mammals"	Includes humans and nonhuman mammals
"Fluoxetine or norfluoxetine"	Covers either named active compound; the claim does not require both
"Effective amount"	Functional limitation tied to potentiating analgesia
"Dextropropoxyphene analgesia"	Requires use of dextropropoxyphene as the analgesic agent
"Between 24 hours before and 2 hours after"	Creates a defined temporal relationship
"Potentiating"	Requires an increased analgesic effect, not merely co-administration

The timing language is commercially important. A product that contains both agents but is administered outside the stated time relationship would not meet claim 1 literally. The formulation claims may still be relevant if the product falls within their composition and ratio limitations.

What do claims 2 through 4 add?

Claims 2 through 4 narrow the method claim progressively.

Claim 2: simultaneous administration

Claim 2 requires the fluoxetine or norfluoxetine and dextropropoxyphene to be administered simultaneously. A single combination tablet, capsule, or other co-administered dosage form would be a natural target of this claim.

Claim 2 is narrower than claim 1 because simultaneous dosing is only one point within the broader 26-hour timing window in claim 1.

Claim 3: fluoxetine hydrochloride

Claim 3 limits the method to fluoxetine hydrochloride. It excludes a method relying only on norfluoxetine and narrows the salt form of fluoxetine.

Claim 4: dose ranges

Claim 4 specifies approximately:

10 to 80 mg fluoxetine hydrochloride; and
30 to 100 mg dextropropoxyphene napsylate.

The use of "about" creates a potential range of equivalent values around the stated endpoints. The scope would depend on ordinary claim construction, prosecution history, and the actual formulation or dosing regimen.

Claim 4 is directed to a clinically recognizable co-dosing range rather than a single fixed strength. It does not require the 1:2 ratio recited in formulation claim 7, although the stated ranges can overlap that ratio.

What does formulation claim 5 cover?

Claim 5 covers a pharmaceutical formulation containing:

Fluoxetine or norfluoxetine;
Dextropropoxyphene;
A pharmaceutically acceptable carrier, diluent, or excipient;
A ratio of fluoxetine or norfluoxetine to dextropropoxyphene of approximately 4:1 to 1:4; and
An effective amount of the active ingredients.

This claim is composition-oriented and does not require simultaneous administration as an express limitation. A finished combination dosage form could fall within claim 5 even if the product labeling did not expressly describe a potentiation mechanism, provided the formulation satisfies the claim limitations.

Ratio scope

The stated ratio is broad:

Fluoxetine or norfluoxetine : dextropropoxyphene	Covered status
4:1	Nominal boundary
2:1	Within range
1:1	Within range
1:2	Within range and expressly targeted by claim 7
1:4	Nominal boundary

The claim does not specify whether the ratio is measured by free-base molecular weight, salt weight, molar amount, or another basis. That issue could have affected infringement analysis and would ordinarily be addressed using the specification, prosecution history, and technical evidence.

What formulations are protected by claims 6 through 9?

Claims 6 through 9 narrow the formulation coverage.

Claim	Additional limitation
6	Fluoxetine hydrochloride
7	Approximately 1:2 fluoxetine hydrochloride to dextropropoxyphene ratio
8	10-80 mg fluoxetine hydrochloride and 30-100 mg dextropropoxyphene napsylate
9	Oral administration

Claim 9 is the narrowest issued claim listed in the question. It requires the limitations of claims 5 through 8 plus oral delivery.

A tablet or capsule containing approximately 10-80 mg fluoxetine hydrochloride and 30-100 mg dextropropoxyphene napsylate, at approximately a 1:2 ratio, would be the clearest commercial embodiment within the dependent formulation claims.

Salt-form considerations

The claims distinguish between:

Fluoxetine or norfluoxetine in claim 1;
Fluoxetine hydrochloride in claims 3, 4, 6, 7, and 8;
Dextropropoxyphene generally in claim 5; and
Dextropropoxyphene napsylate in claims 4 and 8.

This structure creates a layered salt-form strategy. The broad claims may reach the active moiety, while the dependent claims target the hydrochloride and napsylate forms used in the specified embodiments.

When did US Patent 4,594,358 expire?

US Patent 4,594,358 was granted on June 10, 1986. Because it predates the change to a patent term measured from the earliest effective nonprovisional filing date, its ordinary term was 17 years from grant under the law then in effect.

Event	Date
US patent grant	June 10, 1986
Ordinary 17-year expiration	June 10, 2003
Current status	Expired

The patent is therefore no longer enforceable in the United States. There is no current patent infringement exposure under US Patent 4,594,358.

The patent’s expiration also means that a new product cannot be blocked today by the patent itself, although separate patents, regulatory restrictions, controlled-substance rules, or product-safety requirements could independently affect development.

What is the Orange Book status of US Patent 4,594,358?

US Patent 4,594,358 is not a current Orange Book barrier.

The Orange Book lists patents associated with approved drug products and identifies relevant patent certifications for abbreviated new drug applications. A patent covering a combination that was not approved and marketed as an FDA product would not normally operate as an Orange Book-listed barrier for the individual ingredients.[2]

The patent is also expired. Even if it had historically been associated with a product submission, it would not create a current period of FDA approval exclusivity or delay generic approval.

Relation to fluoxetine products

Fluoxetine products, including Prozac and later generic products, were approved for indications such as major depressive disorder, obsessive-compulsive disorder, bulimia nervosa, and panic disorder. The 4,594,358 claims are directed to potentiating dextropropoxyphene analgesia, not to those stand-alone fluoxetine indications.

Accordingly:

A fluoxetine product does not infringe merely because it contains fluoxetine.
A dextropropoxyphene product does not infringe merely because it contains dextropropoxyphene.
A combination product could historically have implicated the patent if it met the method, ratio, dose, and formulation limitations.

Did the patent create Paragraph IV risk?

Historically, a Paragraph IV certification could have been relevant only to an ANDA seeking approval for a product that referenced an approved combination product associated with the patent.

That pathway has no current practical significance for US Patent 4,594,358 because:

The patent expired in 2003.
Dextropropoxyphene products were withdrawn from the US market.
There is no current FDA-approved dextropropoxyphene-fluoxetine reference product.
An expired patent cannot support a 30-month stay under the Hatch-Waxman framework.

A modern applicant would not face a meaningful Paragraph IV launch delay based on this patent.

What patent landscape surrounded fluoxetine and dextropropoxyphene?

The relevant landscape had three layers.

Fluoxetine compound and therapeutic patents

Eli Lilly held the principal early US patent position around fluoxetine. The foundational fluoxetine patent, US 4,314,081, covered fluoxetine-related compounds and pharmaceutical use. Its original term also expired long before the present date.[3]

The 4,594,358 patent was narrower. It did not attempt to re-monopolize fluoxetine generally. It focused on a specific pharmacodynamic combination with dextropropoxyphene.

Dextropropoxyphene product patents

Dextropropoxyphene was marketed in the United States under products including Darvon and Darvocet. These products involved dextropropoxyphene alone or in combination with acetaminophen, not fluoxetine.

The major commercial issue for dextropropoxyphene was product safety, not patent life. FDA requested withdrawal of propoxyphene products in 2010 after data showed serious cardiac risks, including changes in cardiac electrical activity and potentially fatal arrhythmias.[1]

Combination patent

US 4,594,358 occupied a narrow combination position:

It linked an SSRI-related compound to an opioid analgesic.
It claimed a defined dosing sequence.
It claimed a ratio-controlled pharmaceutical composition.
It targeted potentiation rather than a new analgesic molecule.

No current US patent right remains from this combination patent.

Was there an FDA-approved fluoxetine-dextropropoxyphene combination?

The patent does not establish FDA approval. Patentability and FDA approval are separate issues.

The claims describe a proposed therapeutic combination and dosage range. The public FDA product record for propoxyphene products does not establish an approved fluoxetine-dextropropoxyphene product. The principal US propoxyphene products were Darvon and Darvocet, with Darvocet combining propoxyphene and acetaminophen rather than fluoxetine.[1]

The practical commercial implication is important: the patent appears to have protected a development concept rather than a continuing approved-product franchise.

Does biosimilar law apply?

No. Biosimilar law is not relevant to this patent.

Fluoxetine and dextropropoxyphene are small-molecule active pharmaceutical ingredients. They are regulated through small-molecule drug pathways, including NDAs and ANDAs, rather than the biologics license application and biosimilar framework under the Public Health Service Act.

There is therefore no biosimilar interchangeability, reference-biologic, or biologic patent dance issue associated with US Patent 4,594,358.

What litigation and settlement issues affect the patent?

The patent is expired and does not present a live US litigation risk. Its age and narrow subject matter make current Hatch-Waxman litigation or settlement activity unlikely.

There is no current commercial settlement consequence that can extend the patent’s expired term. A private license could historically have governed development or commercialization, but a license cannot revive an expired US patent right.

No material current litigation exposure should be assigned to:

Fluoxetine generic manufacturers;
Former dextropropoxyphene manufacturers;
Developers of unrelated analgesic combinations; or
Companies selling approved fluoxetine products for labeled psychiatric indications.

How strong was the patent estate?

The patent estate was narrow but technically coherent.

Strength factor	Assessment
Claim differentiation	Strong distinction between method and formulation claims
Chemical scope	Limited to fluoxetine, norfluoxetine, and dextropropoxyphene
Timing limitation	Clear and commercially relevant in claim 1
Formulation limitation	Ratio and dose restrictions provide identifiable boundaries
Product blocking power	Limited because the patent did not cover either ingredient alone
FDA linkage	Weak because no continuing approved combination product is established
Current enforceability	None; patent expired
Geographic coverage	US only for this patent

The strongest historical claim would likely have been a commercially marketed oral combination meeting the claimed dose and ratio, especially the embodiment in claims 7 through 9. Claim 1 was broader in administration timing but required proof that the fluoxetine or norfluoxetine actually potentiated dextropropoxyphene analgesia.

What generic launch scenarios exist today?

There is no meaningful generic launch constraint from this patent.

Scenario	Effect of US 4,594,358
Generic fluoxetine alone	No blocking effect
Generic dextropropoxyphene alone	No blocking effect, although FDA withdrawal is independently decisive
Fluoxetine plus another analgesic	Outside the claim unless dextropropoxyphene is present
Fluoxetine-dextropropoxyphene combination	Patent expired; no patent-based launch block
Veterinary combination	No patent block in the US because the patent expired
Reformulated oral combination	No patent block from this patent

A modern developer would face safety, regulatory, clinical, and commercial barriers rather than exclusivity barriers. The FDA withdrawal of propoxyphene products is the dominant regulatory issue.

What are the geographic limitations?

US Patent 4,594,358 provides only US patent rights. It does not establish protection in Canada, Europe, Japan, or other jurisdictions.

Any international analysis would require review of corresponding foreign applications, national grants, expiration dates, maintenance records, and local regulatory status. The US expiration does not automatically determine foreign expiry, although corresponding patents from the same 1980s family would generally also be expired or near expiration.

Key Takeaways

US Patent 4,594,358 covers fluoxetine or norfluoxetine used to potentiate dextropropoxyphene analgesia.
Claim 1 covers administration from 24 hours before to 2 hours after dextropropoxyphene.
Claims 5 through 9 cover combination formulations with a 4:1 to 1:4 active-ingredient ratio, including an approximately 1:2 embodiment.
The principal specified dose range is 10-80 mg fluoxetine hydrochloride and 30-100 mg dextropropoxyphene napsylate.
The patent was granted June 10, 1986, and expired June 10, 2003.
It is not a current Orange Book or Paragraph IV barrier.
Biosimilar law does not apply.
No current US litigation, settlement, or licensing issue creates enforceable rights under this patent.
Dextropropoxyphene’s 2010 FDA withdrawal is more significant than the expired patent for any present commercial assessment.
The patent’s historical strength was its combination-specific method and formulation coverage, not broad control of either active ingredient.

FAQs

Can fluoxetine alone infringe US Patent 4,594,358?

No. The claims require dextropropoxyphene as part of the claimed method or formulation.

Does dextropropoxyphene napsylate fall within the patent claims?

Yes. Dextropropoxyphene napsylate is expressly identified in claims 4 and 8, subject to the stated dose limitations.

Does claim 1 require a single combination tablet?

No. Claim 1 covers administration within the specified time window and does not require a single dosage form. The formulation claims address products containing both active ingredients.

Can a company obtain FDA approval for a fluoxetine-dextropropoxyphene product based on this patent?

The patent does not provide FDA approval rights. Any current application would face separate safety and regulatory issues, including the FDA withdrawal of propoxyphene products.

Is US Patent 4,594,358 relevant to current fluoxetine generic products?

No. Current fluoxetine products do not infringe merely by containing fluoxetine, and the patent expired in 2003.

References

U.S. Food and Drug Administration. (2010, November 19). FDA recommends against continued use of propoxyphene. https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-against-continued-use-propoxyphene
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, 44th edition. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files
United States Patent and Trademark Office. (1982). U.S. Patent No. 4,314,081: N-substituted-3-phenyl-3-(4-substituted phenoxy) propylamines. https://patents.google.com/patent/US4314081
United States Patent and Trademark Office. (1986). U.S. Patent No. 4,594,358: Potentiation of dextropropoxyphene analgesia. https://patents.google.com/patent/US4594358

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	5390086	⤷ Start Trial
Australia	584678	⤷ Start Trial
Canada	1268120	⤷ Start Trial
European Patent Office	0193354	⤷ Start Trial
Japan	S61200912	⤷ Start Trial
South Africa	8601212	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,594,358

Summary for Patent: 4,594,358