Details for Patent: 6,407,079

Summary for Patent: 6,407,079

Title:	Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation
Abstract:	Pharmaceutical compositions comprising inclusion compounds of sparingly water-soluble or water-instable drugs with β-cyclodextrin ethers or β-cyclodextrin esters and process for the preparation thereof.
Inventor(s):	Bernd W. Müller, Ulrich Brauns
Assignee:	Janssen Pharmaceutica NV
Application Number:	US07/264,726
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,407,079
Patent Claim Types: see list of patent claims	Use; Composition; Process;

US Patent 6,407,079: Scope, claim map, and US cyclodextrin inclusion-complex IP landscape for partially etherified β-cyclodextrins

US Patent 6,407,079 is directed to pharmaceutical compositions where a “sparingly soluble or instable” drug is complexed as an inclusion complex in a partially etherified β-cyclodextrin (hydroxyalkyl-substituted, with limited optional alkyl substitution). The claims cover (i) composition of matter (inclusion complexes), (ii) constrained substitution and molar-ratio parameters (molar substitution DS for hydroxyalkyl; degree of substitution DS for methyl/ethyl), (iii) enumerated drug examples (including multiple azoles and etomidate), and (iv) production of stabilizing amorphous complexes using water-soluble β-cyclodextrin derivatives plus solubilized sparingly soluble drugs. The practical enforceability hinges on how strictly accused products match the etherified β-cyclodextrin substitution windows and the drug-to-cyclodextrin molar ratio windows.

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What does US 6,407,079 claim: scope of partially etherified β-cyclodextrin inclusion complexes?

Short answer: The patent claims inclusion complexes and “stabilizing amorphous” complexes formed with partially etherified β-cyclodextrin ethers having specific water-solubility and substitution parameter thresholds, plus drug-to-β-cyclodextrin molar ratio constraints, and method-of-producing complexes via aqueous solubilization.

Core independent claim coverage (Claim 1)

Claim 1 defines the composition of matter as an inclusion compound comprising:

1. Drug component (i): a drug that is “instable or only sparingly soluble in water” and “capable of fitting into the cavity” of the cyclodextrin ring system.
2. Host component (ii): a partially etherified β-cyclodextrin of formula (β-CD)-OR where:
   • R residues are hydroxyalkyl groups and part of said R may optionally be alkyl groups.
   • the β-cyclodextrin ether has water solubility > 1.8 g/100 mL water.
3. Product effect (functional language):
   • “considerably increased water solubility and stability” relative to the drug
   • “very low toxicity” (functional claim attribute, difficult to police without evidence tied to the asserted compound).

Scope implication: The claim is not limited to a specific hydroxyalkyl identity in the independent claim. It sets a host chemistry requirement (hydroxyalkyl etherified β-CD) plus a minimum solubility threshold. The “drug fitting into the cavity” language can narrow arguments in prosecution and litigation by disputing inclusion capability.

Dependent claim narrowing on host substitution (Claims 2–4)

• Claim 2: restricts hydroxyalkyl identities to hydroxyethyl, hydroxypropyl, dihydroxypropyl, methyl, ethyl.
• Claim 3: sets quantitative substitution windows:
  • hydroxyalkyl molar substitution 0.05 to 10
  • alkyl degree of substitution 0 to 2.0
• Claim 4: sets molar ratio:
  • drug : β-cyclodextrin ether 1:6 to 4:1

Scope implication: The patent’s practical infringement gate is likely to be (a) host DS/solubility specs and (b) drug-to-host molar ratio, because these are objective numerical constraints.

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Which drugs are explicitly covered by US 6,407,079?

Short answer: The claims include broad drug classes plus explicit examples that are frequently used as cyclodextrin inclusion targets in the literature and industry (azole antifungals, etomidate, levocabastine, flunarizine, tubulazole, and progesterone in the later claims).

Drug-class coverage (Claim 5)

Claim 5 lists drug categories:

• non-steroidal anti-rheumatic agent
• steroid
• cardiac glycoside
• derivatives of benzodiazepine, benzimidazole, piperidine, piperazine, imidazole or triazole.

Enumerated drug examples (Claims 6–12 and 17)

• Claim 6: etomidate
• Claim 7: ketoconazole
• Claim 8: itraconazole
• Claim 9: levocabastine
• Claim 10: flunarizine
• Claim 11: tubulazole
• Claim 12 / 17: provides a second consolidated dependent structure limiting to the same enumerated set (etomidate, ketoconazole, tubulazole, itraconazole, levacabastine, flunarizine) with the host and substitution constraints.

Scope implication: Even if a drug is not in the examples, Claim 1’s “drug capable of fitting into the cavity” language plus the broad drug-category list in Claim 5 supports wide coverage. The enumerated examples function as interpretive anchors for what “fit into the cavity” means for prosecution history and claim construction.

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What is the scope of the numerical constraints: DS of hydroxyalkyl, DS of alkyl, water solubility, and molar ratio?

Short answer: The claims impose explicit windows for substitution and complex stoichiometry, and a host solubility threshold.

Host ether substitution parameters

From Claim 3 and Claim 12-style limitation sets:

• Hydroxyalkyl molar substitution: 0.05 to 10 (Claim 3)
• Alkyl degree of substitution (methyl/ethyl): 0 to 2.0 (Claim 3, and Claim 12 conditions)

Claim 12 restates host parameters with additional host identity and a consolidated structure:

• hydroxyethyl/hydroxypropyl/dihydroxypropyl molar substitution 0.05 to 10
• methyl/ethyl degree of substitution 0 to 2.0
• host water solubility > 1.8 g/100 mL

More restricted windows in dependent claims

• Claim 13: hydroxyalkyl molar substitution 0.2 to 2
• Claim 14: hydroxyalkyl molar substitution ~0.25 to ~1
• Claim 15: drug : β-CD molar ratio 0.2 to 2
• Claim 16: drug : β-CD molar ratio ~0.5 to ~1.2

Claim 4 gives the broader ratio 1:6 to 4:1; dependent claims later carve narrower operating windows.

Additional narrow formulations

• Claims 27–35 focus on a narrower host chemistry:
  • hydroxyalkyl present with molar substitution about 0.25 to 1
  • hydroxyalkyl identity limited to hydroxyethyl / hydroxypropyl / dihydroxypropyl (Claim 28)
  • further ratio constraints (Claims 29, 31, 35) with the standard ratio band 1:6 to 4:1 in Claim 29/35 style language (and specific identity-based ratio statements).

Scope implication: A product whose β-CD ether DS falls outside these numeric bands or whose formulation stoichiometry does not match the claimed molar ratios is the principal noninfringement path.

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What do the method-of-producing and “amorphous stabilizing complex” claims cover?

Short answer: The method claims cover producing stabilizing amorphous complexes by dissolving water-soluble β-CD derivative mixtures capable of forming inclusion complexes and solubilizing sparingly soluble drugs in aqueous media to form a solubilized complex.

Method claim (Claim 18)

Claim 18 covers:

1. dissolving an intrinsically amorphous mixture of β-cyclodextrin derivatives (water soluble; capable of forming inclusion complexes) in water; and
2. solubilizing sparingly water-soluble drugs into the aqueous media to form a solubilized drug/cyclodextrin complex.

Key functional breadth: It does not require a particular isolation step in the excerpt provided; it focuses on aqueous solubilization and complex formation.

Additional method-dependent element (Claims 19–20)

• Claim 19: cyclodextrin derivatives substituted with hydroxyalkyl
• Claim 20: the drug can be progesterone

Composition for use and solid-state coverage (Claims 21–24)

• Claim 21: composition of matter containing a water-soluble amorphous complex of β-cyclodextrin derivatives and a drug.
• Claim 22: progesterone.
• Claim 23: solid or matter for use in Claim 18 process containing amorphous mixtures of substituted β-CD ethers.
• Claim 24: solid inclusion complex:
  • progesterone + hydroxypropyl-β-cyclodextrin
  • adapted for oral route

Scope implication: If a competitor’s product relies on crystalline complexes, different isolation state, or lacks amorphous characterization consistent with the claims, they can attempt to avoid the amorphous “stabilizing” aspect. If their process matches the two-step aqueous formation logic, method exposure may still exist even if solid-state characterization differs.

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How strong is the patent estate for enforcing US 6,407,079 against competitor inclusion complexes?

Short answer: Strength is anchored in the host substitution windows and solubility threshold and is diluted by the breadth of “drug capable of fitting” and “increased stability/toxicity” functional language.

What helps the patentee

1. Numerical host specs (molar substitution/degree substitution; water solubility > 1.8 g/100 mL).
2. Numerical stoichiometry windows (molar ratios).
3. Defined host chemistry class (partially etherified β-CD ethers, hydroxyalkyl dominant with optional methyl/ethyl).
4. Explicit drug examples (useful for aligning claim construction with prior art arguments and validating inclusion formation in litigation).

What creates litigation friction

1. Functional effects (“considerably increased water solubility and stability,” “very low toxicity”) invite factual disputes and expert proof tying performance to the claimed composition.
2. “Capable of fitting” is a common cyclodextrin phrase that can become a technical debate (molecular docking is not enough; competitors will argue lack of true inclusion complex formation).
3. Amorphous vs. other solid forms: if competitors use spray-dried amorphous dispersions or crystalline forms where inclusion is not sustained, they can attempt to segment noninfringement.
4. β-CD derivative heterogeneity: real-world hydroxypropyl-β-CD and mixed ethers have polydispersity and distribution. Defendants can attack whether the product fits the claimed “molar substitution” and “degree of substitution” as measured.

Likely claim-construction hotspots

• Interpretation of “molar substitution” vs “degree of substitution” and how each maps to NMR-defined substitution statistics.
• Whether “water solubility > 1.8 g in 100 ml” is an inherent host property measured in the supplied derivative or the derivative used in the product.
• Whether the accused complex must meet the drug:β-CD molar ratio as a reproducible property of the final composition.

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What are the primary US competitor risk areas under this patent?

Short answer: Inclusion complexes or amorphous inclusion-complex products that use partially etherified β-CD ethers with hydroxyalkyl DS in the ~0.05 to 10 range (and often narrower 0.25 to 1 in dependent claims), and with drug-to-β-CD molar ratios falling within 1:6 to 4:1 (or narrower ranges) present the highest risk.

High-risk formulations

• Oral solid or aqueous dosage forms containing hydroxypropyl-β-cyclodextrin or hydroxyethyl-β-cyclodextrin as complexing agent for sparingly soluble drugs, with DS tuned to the claimed windows.
• Products for the enumerated drugs (etomidate, ketoconazole, itraconazole, levocabastine, flunarizine, tubulazole), especially where the marketed description includes “inclusion complex,” “complex,” “improved solubility,” or “stabilized amorphous complex.”
• Water-soluble amorphous complexes using aqueous solubilization of sparingly soluble drugs into water-soluble hydroxyalkyl-β-CD derivatives.

Moderate risk formulations

• Products using mixed hydroxyalkyl/methyl/ethyl substituted β-CD derivatives where DS for methyl/ethyl stays within 0 to 2.0 and hydroxyalkyl substitution meets the claim bands.
• Products that use cyclodextrins but are outside β-CD (e.g., α- or γ-cyclodextrin) are generally outside this specific patent’s host definition.

Lower risk designs

• Cyclodextrin complexes using β-CD derivatives outside the water-solubility threshold or with substitution outside the DS/DS windows.
• Complexes primarily crystalline or without the claimed amorphous “stabilizing amorphous complex” characteristics (relying on inclusion but not amorphous stabilization).

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How does this patent compare with the broader cyclodextrin inclusion-complex IP landscape?

Short answer: US 6,407,079 sits in a crowded area where many patents broadly claim “cyclodextrin inclusion complexes,” but it differentiates through specific β-CD ether substitution ranges and solubility constraints and by adding method-of-producing amorphous complexes.

Industry-wide prior art pressure

Cyclodextrin inclusion-complex technology is mature. Many earlier and contemporaneous patents claim:

• cyclodextrin inclusion complexes of poorly soluble drugs
• hydroxypropyl-β-cyclodextrin / hydroxyethyl-β-cyclodextrin as solubilizers
• improved solubility and dissolution

US 6,407,079 narrows that generic disclosure with:

• quantitative DS constraints
• a measured solubility threshold for the β-CD ether
• explicit drug examples tied to inclusion complex formation.

What to expect in freedom-to-operate reviews

• Even when the final formulation uses hydroxypropyl-β-CD, the DS and solubility threshold may vary by supplier and batch.
• Stoichiometry (drug:β-CD ratio) is often not specified in commercial labeling; it can still be measured for infringement arguments.
• Process claims (Claim 18) can be harder to avoid if the manufacturer uses standard aqueous solubilization and complex formation steps.

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Orange Book and regulatory exclusivity status for US 6,407,079: what is the relevance?

Short answer: This patent is a US composition/method patent and its enforceability against generics hinges on FDA-listed drug products and listed patents in the Orange Book. The excerpt provided does not include the listed drug(s), Orange Book product codes, or any patent listing identifiers.

Direct consequence for business decisions: the actionable regulatory picture depends on whether the patent is listed for a specific FDA-approved NDA with a particular product and whether any Paragraph IV challenges or settlements exist for that NDA.

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Patent expiration timing: when does US 6,407,079 lose exclusivity?

Short answer: Expiration is determined by filing date, patent term adjustments, and any terminal disclaimers. The excerpt provided does not include:

• application filing date
• priority date
• PTA and any terminal disclaimers

No complete expiration timeline can be stated from the claim text alone.

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Key Takeaways

• US 6,407,079 claims inclusion complexes and amorphous stabilizing complexes formed with partially etherified β-cyclodextrin ethers where hydroxyalkyl substitution dominates (optional methyl/ethyl).
• Enforceability is most likely to turn on objective parameters: host water solubility (>1.8 g/100 mL), hydroxyalkyl molar substitution (notably 0.05 to 10, with dependent narrowing to ~0.25 to ~1), optional methyl/ethyl DS (0 to 2.0), and drug:β-CD molar ratio (notably 1:6 to 4:1 with dependent narrower bands).
• The patent also adds process exposure via aqueous solubilization steps to form “stabilizing amorphous” complexes.
• Functional language about improved solubility/stability and “very low toxicity” can become contentious, while numerical substitution/ratio limitations offer concrete infringement and noninfringement hooks.
• The business relevance in US launch/GTN/ATU risk assessments depends on which specific FDA-approved products list this patent and whether any Paragraph IV litigation ties to cyclodextrin complex formulations for the enumerated drugs.

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FAQs

1. Does US 6,407,079 require the β-cyclodextrin ether to be amorphous?
   The method claim centers on an “intrinsically amorphous mixture” of β-CD derivatives, while the composition-of-matter claims include both inclusion complex and “water-soluble amorphous complex” formulations; infringement will depend on whether the accused product/process produces the claimed amorphous form.

2. Can hydroxypropyl-β-cyclodextrin alone infringe?
   Infringement requires the inclusion complex with a covered drug plus meeting the claimed substitution/solubility and ratio constraints (and, for certain claims, amorphous complex characteristics).

3. Is the drug restricted to the enumerated examples like ketoconazole and itraconazole?
   No. The independent claim language covers drugs that fit into the β-CD cavity and are instable or sparingly soluble; enumerated drugs mainly strengthen practical interpretive scope.

4. What is the easiest noninfringement path?
   Use a β-CD ether with substitution/solubility properties outside the claimed DS windows or formulate a complex with a drug:β-CD molar ratio outside the claimed ranges.

5. Do process claims create risk even when the final product is different?
   Yes. If a manufacturer’s process matches the aqueous complex formation steps and uses the claimed host derivatives and conditions, method claims can still apply even when final isolation attributes differ.

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References (APA)

1. United States Patent 6,407,079.

Drugs Protected by US Patent 6,407,079

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