Details for Patent: 5,342,625

Summary for Patent: 5,342,625

Title:	Pharmaceutical compositions comprising cyclosporins
Abstract:	Pharmaceutical compositions comprising a cyclosporin, e.g. Ciclosporin or [Nva]2-Ciclosporin, in "microemulsion pre-concentrate" and microemulsion form. The compositions typically comprise (1.1) a C1-5alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkane diol, e.g. Transcutol or Glycofurol, as hydrophilic component. Compositions are also provided comprising a cyclosporin and (1.1) and, suitably, also a saccharide monoester, e.g. raffinose or saccharose monolaurate. Dosage forms include topical formulations and, in particular, oral dosage forms.
Inventor(s):	Birgit Hauer, Armin Meinzer, Ulrich Posanski, Friedrich Richter
Assignee:	Novartis AG
Application Number:	US07/990,734
Patent Claim Types: see list of patent claims	Composition; Compound; Dosage form;

Patent 5,342,625 (US5342625) Scope, Claims, and U.S. Patent Landscape for Cyclosporin Microemulsion Pre-Concetrates

US Patent 5,342,625 claims a cyclosporin pharmaceutical microemulsion pre-concentrate that, on dilution with water, forms an oil-in-water microemulsion with average particle size < about 1,000 Å. The core claim scope is defined by (1) a specific hydrophilic phase system (notably ether-type di/partial ethers or 1,2-propylene glycol), (2) a lipophilic phase (notably fatty acid triglycerides), and (3) a surfactant system (polyoxyethylene glycolated natural or hydrogenated vegetable oils plus optional co-surfactant such as monoglyceride). Downstream dependent claims narrow to oral and capsule formats, explicit loading ranges for cyclosporin and 1,2-propylene glycol, and topical compositions.

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What does US 5,342,625 claim about cyclosporin microemulsion pre-concentrates and particle size?

Answer: Claim 1 covers a pharmaceutical composition that is a microemulsion pre-concentrate containing cyclosporin, a hydrophilic phase component, a lipophilic phase component, and a surfactant, where dilution with water to at least 1:1 (pre-concentrate:water by weight) yields an oil-in-water microemulsion with average particle size < ~1,000 Å.

Core system requirement in Claim 1

Claim 1 is a “composition-of-part” claim with a performance definition:

• Active ingredient: “a cyclosporin as active ingredient”
• Hydrophilic phase component: either
  • ether-type di- or partial-ether:
    • general structure: R1–[O–(CH2)2]x–OR2
    • R1: C1–5 alkyl or tetrahydrofurfuryl
    • R2: hydrogen, C1–5 alkyl, or tetrahydrofurfuryl
    • X: integer 1 to 6
  • or 1,2-propylene glycol
• Lipophilic phase component: present (Claim 6 gives an exemplary narrowing: fatty acid triglyceride)
• Surfactant: present (Claim 7 gives an exemplary narrowing: polyoxyethylene glycolated natural or hydrogenated vegetable oil)
• Critical functional limitation: after dilution with water at ≥ 1:1 by weight, the mixture forms an oil-in-water microemulsion with average particle size < about 1,000 Å

Claim 1 is not limited to oral dosing

Claim 1 is written broadly as a “pharmaceutical composition.” Oral and topical are handled through dependent claims (Claims 11–14 and 21–22).

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How broad are the hydrophilic phase claims in US 5,342,625 (ether di/partial-ethers vs 1,2-propylene glycol)?

Answer: Claim 1 gives two alternative hydrophilic phase paths: a defined ether scaffold or 1,2-propylene glycol. This makes Claim 1 comparatively flexible in excipient selection while keeping the microemulsion performance criterion.

Claim 1.1: ether di- or partial-ethers (structural scope)

The ether option is defined by:

• ether backbone: R1–[O–(CH2)2]x–OR2
• R1: C1–5 alkyl or tetrahydrofurfuryl
• R2: hydrogen, C1–5 alkyl, or tetrahydrofurfuryl
• x: 1–6

This means Claim 1 covers a family of ethylene glycol-like ether linkers (–O–(CH2)2– units) with terminal groups that can vary within those constraints.

Claim 3 and Claim 15–16 narrow to 1,2-propylene glycol

• Claim 3: hydrophilic phase comprises 1,2-propylene glycol
• Claim 15: 1,2-propylene glycol in 3–45% by weight
• Claim 16: ratio cyclosporin : 1,2-propylene glycol from 1:0.5 to 1:3 (parts by weight)

Claim 4–5 add an additional alkanol (ethanol)

• Claim 4: C1–5 alkanol as additional hydrophilic phase component
• Claim 5: C1–5 alkanol is ethanol

Practical scope inference for freedom-to-operate (FTO)

• If a product uses propylene glycol as the hydrophilic phase (alone or plus a C1–5 alkanol), it is plausibly within Claim 1 if other elements match and the particle-size performance is met.
• If a product uses a different hydrophilic cosolvent system (e.g., glycerol, PEG-only, alcohol blends outside C1–5), it may avoid the explicit hydrophilic component definition, though any resulting microemulsion pre-concentrate would still need to evade the “hydrophilic phase component comprising” language.

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What do the lipophilic phase and surfactant claims cover in US 5,342,625 (fatty acid triglycerides, PEG-glycolated oils, monoglyceride)?

Answer: Claim 6 and Claim 7 define representative and likely essential embodiments: fatty acid triglycerides as the lipophilic phase and polyoxyethylene glycolated natural/hydrogenated vegetable oils as surfactants, with optional co-surfactant such as monoglyceride.

Lipophilic phase

• Claim 6: lipophilic phase comprises a fatty acid triglyceride
• Claim 17: lipophilic phase in 2–45% by weight

Claim 1 itself only says “a lipophilic phase component,” so Claim 6 is an additional limitation that can narrow specific embodiments.

Surfactant system

• Claim 7: surfactant comprises polyoxyethylene glycolated natural or hydrogenated vegetable oil

• Claim 8: surfactant comprises an additional co-surfactant

• Claim 9: surfactant comprises:

  • PEG-glycolated natural/hydrogenated vegetable oil (surfactant) and
  • monoglyceride (co-surfactant)

• Claim 19: surfactant present in 20–90% by weight (as a dependent claim tied to Claim 11’s oral adaptation)

Surfactant and co-surfactant composition risk

If a formulation uses PEGylated oils and monoglycerides in similar proportions, the dependent claims increase infringement risk beyond Claim 1.

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When does US 5,342,625 require dilution with water, and how much water triggers the particle-size limitation?

Answer: Claim 1 requires that the pre-concentrate diluted with water at 1:1 by weight or more yields an oil-in-water microemulsion with average particle size < about 1,000 Å. Claim 2 tightens the dilution ratio for one embodiment.

• Claim 1: water dilution ratio ≥ 1:1 (pre-concentrate:water by weight)
• Claim 2: embodiment where ratio is 1:5 (pre-concentrate:water by weight or more of the said water, per the claim text)

Why this matters for scope

A product that only forms <1,000 Å at much higher dilution than 1:1, or only under specific mixing conditions not covered by the claim, can be argued outside the performance limitation. However, Claim 1 reads broadly on “upon dilution with water” and “capable of providing” microemulsion <1,000 Å, so formulation capability is the key.

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Which dosage forms are covered: oral capsule and topical cyclosporin microemulsion?

Answer: The patent covers oral unit dosage forms (gelatin capsules) and also includes topical-ready microemulsion compositions.

Oral administration (Claims 11–14)

• Claim 11: adapted for oral administration
• Claim 12: in unit dosage form
• Claim 13: in gelatin capsule
• Claim 14: cyclosporin 5–20% by weight of total composition

Topical application (Claims 21–22)

• Claim 21: topical application form with cyclosporin 0.05–15% by weight
• Claim 22: cyclosporin 0.1–10% by weight

Interpreting the portfolio of use cases

• Oral and topical coverage are explicit. If a product is positioned as topical (skin/ocular/etc.), it can still fall within Claim 1 if it is a microemulsion pre-concentrate that meets the particle-size threshold on dilution with water.
• If a company has an oral microemulsion concentrate approach, Claim 11–14 add strong narrowing hooks that can be used in infringement/invalidity arguments.

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How much cyclosporin and how much 1,2-propylene glycol are required in the dependent claims?

Answer: Dependent claims give defined ranges that materially constrain specific embodiments.

Cyclosporin loading ranges

• Claim 14 (oral): 5–20% by weight
• Claim 21 (topical): 0.05–15%
• Claim 22 (topical): 0.1–10%
• Claim 20 (oral): cyclosporin : surfactant ratio 1:1 to 1:10 (parts by weight)

1,2-propylene glycol ranges (Claim 3 pathway)

• Claim 15: 1,2-propylene glycol 3–45% by weight
• Claim 16: cyclosporin : 1,2-propylene glycol 1:0.5 to 1:3
• Claim 18 (oral + propylene glycol dependent): lipophilic phase : 1,2-propylene glycol 1:0.15 to 1:6

Lipophilic phase

• Claim 17: lipophilic phase 2–45% by weight

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Which cyclosporin forms are named: ciclosporin and [Nva]2-ciclosporin?

Answer: The claims include generic “cyclosporin” in Claim 1 and then explicitly name:

• Claim 24: Ciclosporin
• Claim 25: [Nva]2-ciclosporin

Claim 26’s presence (as you provided) is an additional dependent claim expanding specific cyclosporin species into the oral microemulsion context.

Scope implication

• A product using a cyclosporin analog outside the named “ciclosporin” and “[Nva]2-ciclosporin” may still fall under Claim 1 if it qualifies as “a cyclosporin.” The explicit naming supports breadth and can be used to argue the intended enzyme/biologic identity.

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What does the patent landscape around US 5,342,625 typically look like for cyclosporin microemulsions?

Answer: The claim architecture (microemulsion pre-concentrate + oil-in-water microemulsion particle-size criterion + cyclosporin + defined excipient classes) is characteristic of a formulation patent strategy used for cyclosporin delivery systems. In practice, the landscape tends to cluster into:

1. Microemulsion concentrate formulations (same core strategy as this patent)
2. Self-emulsifying systems (different mechanistic language but overlapping ingredients)
3. Surfactant/oil system patents (specific PEGylated oils, monoglycerides, triglycerides)
4. Particle size / dispersion performance patents (performance-defined limits)
5. Oral unit dose packaging patents (capsules vs liquid)
6. Topical microemulsion patents (different end-use and loading)

Within that cluster, US 5,342,625 is most directly positioned against competitors using:

• cyclosporin
• a microemulsion pre-concentrate intended to generate an oil-in-water microemulsion upon dilution
• PEGylated vegetable-oil surfactants and monoglyceride co-surfactants
• triglyceride oils and propylene glycol (or ether-type hydrophilic agents)
• particle size < ~1,000 Å

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How strong is the patent estate around US 5,342,625’s key limitations (particle size, ingredient scaffolds, and dilution ratio)?

Answer: The strength of US 5,342,625 is driven by how defensible the performance and compositional limitations are.

Claim elements with the highest “enforcement leverage”

1. Performance limitation: average particle size < ~1,000 Å after dilution at ≥ 1:1
2. Composition partitioning: hydrophilic phase + lipophilic phase + surfactant, not just “microemulsion”
3. Hydrophilic scaffold: specific ether-type or 1,2-propylene glycol
4. Surfactant chemistry: PEGylated natural/hydrogenated vegetable oils; optional monoglyceride co-surfactant
5. Dose form hooks: oral unit dose gelatin capsule; topical-ready compositions

Claim elements that competitors can attack more easily

• If they can show their system does not form <1,000 Å under comparable dilution conditions, they can aim at the performance limitation.
• If their hydrophilic phase avoids the explicitly claimed ether structure and avoids propylene glycol, they can attack Claim 1’s “comprising” hydrophilic phase definition.
• If they omit monoglyceride or use a different class of surfactant, they can attack dependent claims (7–9).

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What generic entry risks exist for products that use cyclosporin microemulsion concentrates?

Answer: The risk is highest when an ANDA or 505(b)(2) applicant relies on a cyclosporin oral microemulsion concentrate that is compositionally similar and achieves the same dilution-to-particle-size performance.

Where the risk is most acute

• Oral microemulsion pre-concentrates intended to form oil-in-water microemulsions <1,000 Å at dilution ratios comparable to Claim 1/2
• Formulations using PEGylated vegetable oils and triglyceride oils with monoglyceride co-surfactants
• Formulations using propylene glycol at 3–45% and meeting ratio constraints

Where risk can drop

• Formulations that avoid the explicit hydrophilic phase definitions (ether scaffold in Claim 1.1 or propylene glycol in Claim 1 alternative)
• Systems that do not meet <1,000 Å on water dilution at ≥1:1 by weight
• Topical or oral formats that are outside the dependent claim constraints (capsule/unit dose and/or loading ranges)

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Claim map (US 5,342,625) to accelerate FTO and litigation scoping

Claim	What it adds beyond Claim 1	Key quantitative / structural limit
1	Baseline microemulsion pre-concentrate composition + performance	water dilution ≥1:1; oil-in-water microemulsion avg particle size < ~1,000 Å; hydrophilic ether scaffold or propylene glycol
2	Tightens dilution scenario	dilution ratio 1:5 (pre-concentrate:water by weight or more of said water)
3	Hydrophilic phase narrowing	hydrophilic phase = 1,2-propylene glycol
4–5	Additional hydrophilic component	C1–5 alkanol; e.g., ethanol
6	Lipophilic phase narrowing	lipophilic phase = fatty acid triglyceride
7	Surfactant narrowing	surfactant = polyoxyethylene glycolated natural or hydrogenated vegetable oil
8–9	Co-surfactant narrowing	additional co-surfactant; e.g., monoglyceride
10	Process/formulation add-on	thickening agent
11–13	Oral unit dose and capsule	oral; unit dose; gelatin capsule
14	Cyclosporin loading (oral)	5–20% cyclosporin by weight
15–16	Propylene glycol amounts and ratios	3–45% propylene glycol; cyclosporin:propylene glycol 1:0.5 to 1:3
17	Lipophilic phase amount	2–45% by weight
18	Ratio constraint	lipophilic phase : propylene glycol = 1:0.15 to 1:6
19–20	Surfactant amount and ratios	surfactant 20–90% (oral); cyclosporin:surfactant = 1:1 to 1:10
21–22	Topical embodiment	0.05–15% (and 0.1–10%) cyclosporin for topical application
23	Microemulsion composition claim	water + Claim 1 composition
24–25	Named cyclosporin species	ciclosporin; [Nva]2-ciclosporin
26	Oral microemulsion composition restatement	cyclesporin or [Nva]2-ciclosporin + hydrophilic ether/propylene glycol + triglyceride + surfactant system; forms <1,000 Å microemulsion

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Key Takeaways

• US 5,342,625 is centered on a cyclosporin microemulsion pre-concentrate that generates an oil-in-water microemulsion with average particle size < ~1,000 Å after water dilution at ≥ 1:1 by weight.
• Claim scope is compositionally segmented: specific hydrophilic phase definitions (ether scaffold or 1,2-propylene glycol) plus lipophilic phase (notably triglycerides) plus PEG-glycolated vegetable oil surfactants with optional monoglyceride co-surfactant.
• Dependent claims materially narrow to oral unit dose gelatin capsules and to topical compositions, with defined loading ranges and ratio constraints for cyclosporin, propylene glycol, lipophilic phase, and surfactant.
• The strongest infringement leverage is the combination of (a) microemulsion particle-size performance and (b) the specific excipient classes that characterize the formulation.

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FAQs

1) What part of US 5,342,625 is most likely to be dispositive in an infringement dispute?

The performance limitation requiring an oil-in-water microemulsion avg particle size < ~1,000 Å after dilution with water at ≥1:1 by weight, combined with whether the accused product uses the claimed hydrophilic phase and surfactant systems.

2) Do the dependent claims on dilution ratio (Claim 2) matter if Claim 1 is already met?

Yes, Claim 2 provides a narrower embodiment, but meeting Claim 1 is sufficient for baseline coverage. Claim 2 can increase leverage for formulations that only reliably achieve performance at 1:5 dilution.

3) Can a product avoid the patent by changing the cyclosporin species?

Claim 1 covers “a cyclosporin,” while Claims 24–25 explicitly name ciclosporin and [Nva]2-ciclosporin. Changing to a cyclosporin not clearly within the “cyclosporin” term would be a key design direction.

4) If the formulation is topical, is it automatically outside US 5,342,625?

No. Claim 21–22 include topical application embodiments, and Claim 1 is not limited to oral use.

5) Which excipient substitution is most likely to reduce claim coverage?

Substituting away from 1,2-propylene glycol and away from the specific ether di/partial-ether scaffold in Claim 1.1 reduces coverage risk for the hydrophilic phase limitation; substituting away from PEGylated vegetable-oil surfactants and monoglyceride reduces risk for the surfactant/co-surfactant dependent claims.

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References

1. United States Patent 5,342,625. “Pharmaceutical composition comprising cyclosporin as active ingredient…” (as provided via the user-provided claim text).

Drugs Protected by US Patent 5,342,625

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 5,342,625

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8821754	Sep 16, 1988
United Kingdom	8902900	Feb 09, 1989
United Kingdom	8902903	Feb 09, 1989

International Family Members for US Patent 5,342,625

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	403435
Austria	A214289
Australia	4140089
Australia	627220
Belgium	1003105
Bulgaria	60525
Canada	1332150