United States Patent 5,739,152: Emulsion IV Formulations of Short-Acting Dihydropyridines

United States Patent 5,739,152 claims an intravenous emulsion formulation defined by (i) a short-acting dihydropyridine active with plasma half-life under 30 minutes, (ii) a lipid phase (preferably triglycerides), (iii) an emulsifier (preferably phospholipid), and (iv) an aqueous phase (water or buffer). The patent also claims therapeutic use for short-term blood pressure lowering during surgery and postoperatively via intravenous administration of the claimed formulation.

Below is a claim-scope deconstruction, then a US patent landscape view focused on design-arounds, likely invalidity angles, and freedom-to-operate (FTO) fault lines implied by the claim structure.

What is the claim scope in US 5,739,152?

Independent claim backbone (Claim 1)

Claim 1 defines a “pharmaceutical formulation” that “is an emulsion for intravenous administration” and requires all of the following elements:

1) Active: “a short-acting dihydropyridine compound having a half-life in plasma of less than 30 minutes”
2) Lipid phase: present
3) Emulsifier: present
4) Aqueous phase: “water or a buffer”

This is a classic formulation combination claim: it is not limited to a single chemical entity for the active (the active is defined by class + pharmacokinetic half-life constraint), and it is not limited to a single lipid or emulsifier species (those are narrowed in dependent claims).

Method/use (Claims 9 and 10)

Claim 9 is a method claim: “short-term lowering of the blood pressure during surgery and postoperatively” by IV administration of a therapeutically active amount of a Claim 1 formulation.
Claim 10 is a use claim: “for use in the short-term lowering of blood pressure” in a patient in need thereof, with the same formulation elements as Claim 1.

Legal implication: If Claim 1 is avoided, Claims 9 and 10 are typically avoided as well because they depend on administration/use of “a formulation according to claim 1.”

How does Claim 2 narrow the active ingredient class?

Dihydropyridine structure filter

Claim 2 narrows “short-acting dihydropyridine compound” to dihydropyridines of a defined formula (Formula I), where substituents are constrained:

R1 and R2: independently selected from hydrogen, chloro, bromo, nitro, cyano, trifluoromethyl
R3 and R4: independently selected from straight or branched lower alkyl groups (1–5 carbons)

Exclusion rules that matter for design-around

Claim 2 includes explicit “provided that” exclusion combinations that bar certain specific substituent patterns:

If R3 is methyl and R4 is tert.-butyl, then R1/R2 are not:
- hydrogen/hydrogen
- hydrogen/2’-trifluoromethyl
- 2’-chloro/3’-chloro
If R3 is methyl and R1/R2 are hydrogen/3’-nitro, then R4 is not:
- methyl, ethyl, propyl, iso-propyl, tert.-butyl

Legal implication: The exclusion language reduces the covered chemical space within the broader “dihydropyridine” family.

Which specific actives are explicitly claimed (Claim 3)?

Claim 3 enumerates specific esterified dihydropyridine species. The list includes:

Acetoxymethyl methyl 4-(2’,3’-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
Propionoxymethyl methyl 4-(2’,3’-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
Butyroxymethyl methyl 4-(2’,3’-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
(4S)-Butyroxymethyl methyl ...
(4R)-Butyroxymethyl methyl ...
iso-Butyroxymethyl methyl 4-(2’,3’-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

Scope effect: Claim 3 gives strong evidentiary anchoring that the patent’s core dihydropyridine portfolio is not generic; it is tied to particular substituted dihydropyridine esters likely intended to yield short-acting pharmacokinetics when administered IV.

What quantitative formulation ranges are required?

Active amount (Claim 4)

Claim 4 requires the short-acting dihydropyridine compound present at:

0.001 to 20% by weight of the entire emulsion weight.

This is a wide envelope, but it still can be a design-arithmetic gate (especially for concentrated vs dilute dosing).

Lipid phase: triglycerides (Claim 5)

Claim 5 specifies:

lipid phase selected from the group consisting of triglycerides.

If Claim 5 applies, only triglyceride-type lipid phases are covered. Claim 1 itself is broader (it just says “lipid phase”), but many accused products will be structured to fall into triglyceride platforms, making Claim 5 an important dependent hook.

Lipid percentage (Claim 6)

Claim 6 sets:

lipid phase present at 1 to 35% by weight of the entire emulsion weight.

Emulsifier type and loading (Claims 7 and 8)

Claim 7: emulsifier is a phospholipid.
Claim 8: emulsifier present in amount of 0.01 to 2 times by weight of the lipid phase.

Practical scope effect: The emulsifier ratio is a wide band, but it can still be avoided by using a non-phospholipid emulsifier system or an emulsifier amount outside the ratio window.

What does the patent cover that competitors must avoid?

Hard “must-have” elements that are claim-limiting

To infringe at least Claim 1, a product must satisfy all four elements:

1) IV emulsion
2) Contains a dihydropyridine with plasma half-life < 30 min
3) Has lipid phase
4) Has emulsifier and water/buffer

Key dependent-claim design tripwires

Even if a competitor includes the right active class, infringement risk increases if their formulation also satisfies:

active matches Claim 2 and/or enumerated species in Claim 3
active concentration fits Claim 4 (0.001 to 20% w/w)
lipid is triglyceride and at 1 to 35% w/w (Claims 5 and 6)
emulsifier is a phospholipid and at 0.01 to 2x lipid by weight (Claims 7 and 8)

How can this be attacked or narrowed (patent landscape implications)?

Patent landscape assessment for this US patent hinges on two technical levers encoded in the claims: (i) the pharmacokinetic half-life threshold and (ii) the specific formulation class (IV lipid emulsion with phospholipid emulsifier).

1) Half-life < 30 minutes as a litigation and FTO fault line

The “half-life in plasma” requirement is likely the central differentiator for prior art and also an enforcement pivot. In infringement, the patentee must link the claimed active(s) in the specific formulation to a plasma half-life below 30 minutes.

Landscape implication: If other emulsion formulations exist using related dihydropyridines but produce a half-life above 30 minutes in IV plasma, they can fall outside Claim 1 even if the chemistry overlaps.

2) Chemical coverage is constrained but not exhaustive

Claim 2 uses a structure formula plus exclusion rules. Claim 3 enumerates specific compounds. That reduces the literal scope versus a broad “any short-acting dihydropyridine” claim.

Landscape implication: Dihydropyridines outside Formula I, or those excluded by the provided-that rules, can be outside literal coverage even if pharmacologically similar.

3) Formulation coverage depends on emulsion mechanics

Claim 1 requires an emulsion “for intravenous administration.” If a product is a solution, micellar system, nanoemulsion with substantially different characterization, or a different dosage form not meeting the emulsion definition used by courts, Claim 1 may be avoided.

Landscape implication: Competitors in the same therapeutic space often differentiate using carrier systems (solubilizers, cyclodextrins, polymeric micelles). A non-emulsion IV system can move the product outside Claim 1 even with the correct active and half-life.

Competitive design-arounds mapped to claim elements

Avoid Claim 1 by changing the formulation category

Switch away from an IV emulsion (change dosage form to a non-emulsion IV system).
Remove one of the required components (e.g., omit a lipid phase or emulsifier) if the product concept can still deliver IV dosing.

Avoid dependent claim hooks while keeping the same therapeutic intent

Use a non-phospholipid emulsifier to avoid Claims 7 and 8.
Use lipid type other than triglycerides to avoid Claim 5.
Adjust lipid content outside 1 to 35% w/w to avoid Claim 6.
Adjust active loading outside 0.001 to 20% w/w to avoid Claim 4.

Avoid dependent chemical hooks

Select a dihydropyridine whose structure does not fall under Formula I exclusions in Claim 2.
Avoid the enumerated actives in Claim 3 even if within Formula I.

What is the US patent landscape likely to look like around this family?

Even without enumerating all citing or overlapping US publications here, the claim architecture implies the adjacent patent landscape typically clusters into four layers:

1) Dihydropyridine chemistry patents (structure, synthesis, stereochemistry)

To cover specific ester prodrugs/derivatives intended for short plasma half-life. 2) Formulation patents (IV emulsion platforms)
To cover lipid carriers, emulsifier selection, and concentration ranges. 3) Pharmacokinetic and performance patents
To support the <30-minute half-life requirement and justify therapeutic windows. 4) Medical use patents
To cover perioperative blood pressure control and postoperative dosing protocols.

In that structure, 5,739,152 sits primarily in layers 2 and 4, while still reaching into layer 1 via the active constraint (Claims 2 and 3).

Business read-across for portfolios: A company entering this space typically needs a multi-layer clearance strategy: not only for IV emulsion formulation patents, but also for the specific short-acting dihydropyridine active entities and their prodrug conversions that create the half-life profile.

Freedom-to-operate risk checklist (US 5,739,152-specific)

1) Product profile matching

Does the product deliver the dihydropyridine as an IV emulsion?
Is the administered active a dihydropyridine “having a half-life in plasma of less than 30 minutes” when delivered in the formulation?

2) Formulation composition alignment

Is there a lipid phase (and is it triglycerides)?
Is there a phospholipid emulsifier?
Are the concentrations within the quoted ranges:
- active 0.001 to 20% w/w
- lipid 1 to 35% w/w
- emulsifier ratio 0.01 to 2x lipid by weight

3) Chemical coverage alignment

Does the active match Formula I constraints in Claim 2, including exclusions?
Does it match any enumerated compound in Claim 3?

4) Use alignment

Is the product indicated or used for “short-term lowering of blood pressure during surgery and postoperatively”?

Claim-by-claim scope table (what must be present)

Claim	Scope element(s) required	Narrowing effect
1	IV emulsion; short-acting dihydropyridine (plasma half-life <30 min); lipid phase; emulsifier; water/buffer	Core combination definition
2	Active must fit Formula I; R1/R2 set; R3/R4 alkyl set; explicit exclusion combos	Chemical narrowing inside active class
3	Active is one of listed dihydropyridine ester stereoisomers	Explicit chemical list
4	Active amount is 0.001 to 20% w/w of emulsion	Quantitative envelope
5	Lipid phase is triglycerides	Lipid type narrowing
6	Lipid phase is 1 to 35% w/w	Quantitative envelope
7	Emulsifier is phospholipid	Emulsifier type narrowing
8	Emulsifier present at 0.01 to 2x by weight of lipid	Loading ratio envelope
9	Method: IV administration for short-term BP lowering during surgery and postoperatively	Use narrowing to perioperative period
10	Use: formulation for short-term BP lowering in patients needing it	Use claim with same formulation elements as Claim 1

Key Takeaways

1) US 5,739,152’s enforceable core is Claim 1: an IV emulsion containing a short-acting dihydropyridine defined by plasma half-life < 30 minutes, plus lipid, emulsifier, and aqueous phase.
2) Dependent claims materially increase infringement risk when the formulation uses triglyceride lipid (1 to 35% w/w) and phospholipid emulsifier within the 0.01 to 2x lipid-by-weight window, with active load 0.001 to 20% w/w.
3) The chemical scope tightens via Formula I constraints and explicit exclusion pairs, with additional certainty provided by the enumerated ester prodrugs and stereoisomers in Claim 3.
4) The landscape around this patent is likely layered: chemistry patents for short-acting dihydropyridines, formulation patents for lipid emulsion delivery, and medical-use patents for perioperative blood pressure control; portfolio clearance should cover all layers because Claim 1 cross-links chemistry and formulation.

FAQs

1) Does the patent require a specific dihydropyridine concentration to infringe Claim 1?

No. Claim 1 does not set an active concentration range. The 0.001 to 20% w/w range appears in Claim 4 as a dependent limitation.

2) What is the main non-chemical gating requirement in Claim 1?

The dosage form and carrier system: it must be “an emulsion for intravenous administration” with lipid phase, emulsifier, and water or buffer.

3) Can a competitor avoid infringement by using a non-phospholipid emulsifier?

Yes for the dependent claims that specify emulsifier identity (Claims 7 and 8). Claim 1 still requires an “emulsifier,” but it does not restrict type.

4) How does Claim 2’s “provided that” language affect coverage?

It creates explicit excluded substituent combinations within Formula I, narrowing which dihydropyridines qualify as “short-acting” actives under the claim’s structural definition.

5) What’s the practical linkage between Claims 9/10 and Claim 1?

Claims 9 and 10 require administration or use of “a formulation according to claim 1,” so avoiding Claim 1 typically avoids the method/use claims.

References (APA)

[1] United States Patent 5,739,152. (n.d.). Emulsion for intravenous administration containing short-acting dihydropyridines.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Sweden	9303744	Nov 12, 1993

PCT Information
PCT Filed	November 03, 1994	PCT Application Number:	PCT/SE94/01032
PCT Publication Date:	May 18, 1995	PCT Publication Number:	WO95/13066

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	213158	⤷ Start Trial
Australia	1037195	⤷ Start Trial
Australia	678650	⤷ Start Trial
Canada	2176360	⤷ Start Trial
China	1072934	⤷ Start Trial
China	1136774	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 5,739,152