Patent: 6,309,663

Summary for Patent: 6,309,663

Title:	Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents
Abstract:	The present invention relates to pharmaceutical compositions, pharmaceutical systems, and methods for enhanced absorption of hydrophilic therapeutic agents. Compositions and systems of the present invention include an absorption enhancing carrier, where the carrier is formed from a combination of at least two surfactants, at least one of which is hydrophilic. A hydrophilic therapeutic agent can be incorporated into the composition, or can be co-administered with the composition as part of a pharmaceutical system. The invention also provides methods of treatment with hydrophilic therapeutic agents using these compositions and systems.
Inventor(s):	Patel; Mahesh V. (Salt Lake City, UT), Chen; Feng-Jing (Salt Lake City, UT)
Assignee:	Lipocine Inc. (Salt Lake City, UT)
Application Number:	09/375,636
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,309,663
Patent Claims:	see list of patent claims

United States Patent 6,309,663: What claims cover enhanced absorption of hydrophilic therapeutics, and how broad is the patent estate?

Executive summary: US 6,309,663 is drafted as a formulation and system patent for enhanced absorption of hydrophilic therapeutic agents using a two-surfactant system (hydrophilic surfactant with defined HLB or ionized-ionizable surfactant options plus a hydrophobic surfactant selected from a long list), constrained by optical/dispersion performance and composition exclusions (notably free of triglycerides). Independent claim coverage hinges on (1) surfactant selection, (2) clear aqueous dispersion with absorbance <0.3 at 400 nm after 100x dilution, and in certain claims (76-series) also particle size <200 nm, and (3) absence of triglycerides. The dependent claims expand into broad therapeutic-agent classes (including drugs, peptides, proteins, nucleic acids, vaccines), broad dosage-form architectures, and add-on excipients (including enzyme inhibitors, acids/bases, coatings).

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1) What is the core invention in US 6,309,663 based on the claim text?

Core concept: A pharmaceutical system and absorption enhancing composition for a hydrophilic therapeutic agent where performance is evidenced by optical clarity and dispersion formation after dilution.

Independent claim 1 (system + composition)

Independent claim 1 requires a system that consists essentially of:

• (a) A dosage form of an absorption enhancing composition, with:
  • (i) at least one hydrophilic surfactant selected from:
    • ionized ionizable surfactants, or
    • non-ionic hydrophilic surfactants with HLB ≥ ~10, or
    • combinations
  • (ii) at least one hydrophobic surfactant selected from a long list including:
    • hydrophobic alcohols and nonionic amphiphiles, and
    • bile acids and derivatives, and
    • fatty acids, esters (mono-, diesters), glyceride derivatives, carnitine fatty acid esters, alkylsulfates, acyl lactylates, and tartaric/citric/succinylated mono- and diglycerides, and
    • transesterified vegetable oils and reaction products of polyols with fatty acids/glycerides/vegetable oils, and
    • specified un-ionized ionizable species for (b)
  • (optical constraint) Upon mixing with an aqueous diluent at 100× dilution, forms a clear aqueous dispersion with absorbance < ~0.3 at 400 nm
• (b) a therapeutically effective amount of a hydrophilic therapeutic agent
• exclusion constraint: system is free of triglycerides

Independent claim 76 (system with solubilizer + particle size)

Claim 76 tightens the performance boundary by adding:

• (a)(ii) hydrophilic/hydrophobic surfactant system forms an aqueous dispersion with average particle size < ~200 nm (after dilution)
• (a)(iii) at least one solubilizer
• same free of triglycerides limitation

Independent claim 153 (composition for co-administration)

Claim 153 covers an absorption enhancing composition for co-administration:

• same surfactant families and optical clarity requirement
• free of triglycerides

Independent claim 156 (method of controlling bioabsorption)

Claim 156 covers a method:

• provide dosage form of the absorption enhancing composition (with surfactant families + optical clarity + triglyceride-free),
• provide hydrophilic therapeutic agent,
• administer both.

Independent claim 165/166 (diluted preconcentrate systems)

These add:

• a liquid diluent and
• preconcentrate/diluted system framing
• same triglyceride-free constraint
• same optical clarity requirement
• claim 166 also includes a “system for enhancing absorption, or a hydrophilic therapeutic agent in the form of a diluted preconcentrate,” with solubilizer and liquid diluent requirements.

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2) What claims most strongly define infringement boundaries: clarity (A400), particle size, and “free of triglycerides”?

Performance markers likely to be litigated

1. Optical clarity threshold
   • Claims 1/153/156/165/166 include:
     • absorbance < ~0.3 at 400 nm after 100× dilution
2. Particle size threshold (claim set 76-series)
   • Claim 76 and dependent claims in that lineage add:
     • average particle size < ~200 nm (and later dependent limits down to <100 nm and <50 nm in the 126/127 series)
3. Triglyceride exclusion
   • A system is “free of triglycerides” in essentially all independent claims enumerated above.

Critical reading: these boundaries are not “optional improvements.” They are structural requirements tied to how the composition behaves after dilution, plus a chemical exclusion (triglycerides). That makes them useful for both claim construction and accused product factual testing.

How “consisting essentially of” may narrow

Multiple independent claims use “consisting essentially of,” which:

• allows impurities and additional ingredients that do not materially change the invention,
• but typically is argued to bar adding ingredients that materially affect the surfactant system’s function or the claimed exclusions (especially triglyceride-free).

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3) How broad is the surfactant selection: does the list create a true genus or an enumerated scheme?

Hydrophilic surfactant genus

Claim 1 hydrophilic surfactant is either:

• ionized ionizable surfactants (multiple families listed), or
• non-ionic hydrophilic surfactants with HLB ≥ 10, or combinations.

This structure creates two major infringing routes:

• Route A: ionized/ionizable bile-acid derivatives, docusate salts, acyl lactylates salts, carnitine fatty acid ester salts, alkylsulfate salts, fatty acid salts, and specified tartarate/citrate/succinate ester salts.
• Route B: nonionic HLB-defined surfactants, with an additional dependent claim family enumerating named PEG-laurates, PEG-oleates, PEG-castor oils, poloxamers, polysorbates, sucrose esters, POE lauryl ethers, etc.

Hydrophobic surfactant genus

The hydrophobic surfactant is defined by a very large enumerated list, then further refined by:

• HLB < ~10 (claim 22 and downstream),
• and chemical subclassions (fatty acids, bile acids, esters, transesterified oils, reaction products, etc.).

Is this “enabling breadth” or “paper breadth”?

From a litigation-risk standpoint, the genus appears broad, but enforcement is likely to concentrate on the same chemical families that were tested to meet:

• optical clarity at 400 nm after 100× dilution,
• triglyceride-free status, and
• (in claim 76 lineage) particle size constraints.

So, in practice, the landscape will often hinge on whether an accused formulation uses the same functional surfactant pairs in ratios that achieve those specific dispersion properties without triglycerides.

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4) What therapeutic-agent claims expand coverage beyond one drug?

Claim 35/36/37/38/39 and dependents

The patent is not tied to a single active ingredient:

• hydrophilic therapeutic agent can be:
  • drug, vitamin, nutritional supplement, cosmeceutical, diagnostic agent (claim 35/110-type)
• requires hydrophilicity characteristics:
  • “apparent water solubility of at least ~1 mg/mL” (claim 36/111-type)
• includes biologic modalities:
  • cytokines, peptidomimetics, peptides, proteins, toxoids, serum, antibodies, vaccines, nucleosides/nucleotides/genetic material/nucleic acids (claim 37/112-type)

Then claim 38/39-style dependents list many example actives across:

• small molecules (antivirals, antibiotics, statins-like not present but broad categories), and
• peptides/proteins referenced broadly,
• vaccines.

Business implication: this is a platform claim set. If the surfactant system works across hydrophilic therapeutics, the same formulation IP can be asserted across multiple product candidates that meet the same constraints.

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5) What formulation and dosage-form claims create additional infringement angles?

The claims extend beyond “composition” into a wide variety of delivery formats.

Dosage forms and processing

• preconcentrate formats (liquid/semi-solid/solid; aqueous/organic diluted preconcentrates) (claim 55/132/166-type)
• processed by balling, lyophilization, encapsulation, extruding, compression, melting, molding, spraying, cryopelletization, spheronization, homogenization, sonication, granulation, etc. (claim 56/133-type)
• pill/capsule/caplet/tablet/granules/pellets/beads/powder (claim 57/134-type)
• capsule types: starch, cellulosic, hard gelatin, soft gelatin (claim 58/135-type)
• immediate release through targeted delayed release (claim 59/136-type)
• dosage forms for administration routes:
  • oral, mucosal, nasal, pulmonary, vaginal, transmembrane, buccal, rectal (claims 74/151/162-type)

Coatings and multiparticulates

Enteric/seal/extended/targeted delayed coatings are specified with example polymers/resins (shellac; acrylic polymers; cellulosic derivatives; PVAP phthalate; cellulose acetate phthalate; HPMCP; HPMCAS; etc.) (claims 60-63, 136-140-type; plus dependents later).

Multiparticulates are also included:

• carriers on substrates (drug/acceptable material mixtures)
• coated with enteric/extended-release coatings (claims 65-67, 142-144-type).

Litigation angle: even if an accused product does not match a specific capsule/coating, broad “dosage form” dependent claim coverage can still force attention on whether the accused format is captured under the “system” claim path.

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6) What excipients and “add-on” limitations may matter in validity or design-around?

Solubilizers (claim 76/117-type)

Claim 76 requires at least one solubilizer. Claim 117 gives a broad category:

• alcohols, polyols, amides, esters, propylene glycol ethers.

Enzyme inhibitors (claims 42-45 and 118-121-type)

Several dependent claims add an enzyme inhibiting agent sufficient to at least partially inhibit enzymatic degradation of the hydrophilic agent. Examples include:

• protease inhibitors (pepstatin, leupeptin, chymostatin, elastatin inhibitors, etc.)
• EDTA/EGTA and chelators
• mucoadhesive polymers and polymer-inhibitor conjugates
• chitosan and derivatives

Acids/bases (claims 46-49 and 122-125-type)

Broad pharmaceutically acceptable acids/bases enumerated.

Design-around risk: because these dependent claims are broad, moving to different acids/bases or adding enzyme inhibitors likely does not avoid the independent claim if the surfactant pair and dispersion properties remain inside the claim boundaries.

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7) What are the key “avoidance” levers implied by the claim structure?

From claim text, the clearest non-infringement routes are:

1. Triglyceride presence: remove triglycerides is required, so an accused product that includes triglycerides in a way that is argued to be “not free of triglycerides” could avoid the “free of triglycerides” limitation. (This is often evidentiary, not theoretical.)
2. Optical performance failure: if, after 100× dilution in water, the dispersion does not reach A400 < 0.3, that can be a hard factual non-infringement route.
3. Particle size failure: for the claim 76 lineage, if particle size after dilution is ≥ 200 nm (and dependent limits like 100 nm or 50 nm), those claims would not read.
4. Surfactant genus change: substituting hydrophilic/hydrophobic surfactants outside the listed groups, or outside the HLB thresholds (where relevant), can avoid.

However: because many dependents enumerate named chemicals, “close substitutions” may still fall inside the lists.

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8) How does this claim set likely read onto common absorption-enhancer formulations (high-level)?

The claims cover classic absorption-enhancer surfactant systems used to solubilize and create nano/microdispersions for hydrophilic actives, including:

• bile salt derivatives,
• docusate-type surfactants,
• fatty acid ester surfactants (mono-/diesters),
• PEG laurates/oleates,
• polysorbates/poloxamers,
• sucrose esters and POE alkyl ethers.

The novelty emphasis, as drafted, is not only surfactant pairing, but the combination + ratio performance demonstrated by:

• clear dispersion with low absorbance after dilution,
• optionally nanoscale particle size.

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9) Patent landscape analysis: what can be concluded from the claim text alone, and what cannot be completed without additional bibliographic/patent-document data?

No prosecution history, publication family, priority data, assignee, expiration calculations, or citation map are provided in the prompt. That means a comprehensive landscape (other US patents covering the same amphiphile systems, parallel continuations, related divisionals, and known litigations) cannot be completed accurately.

Per the constraints, only the patent-claim structure and implied enforcement boundaries are analyzed here.

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10) Claim-by-claim risk map (priority to infringement-critical elements)

Tier 1: elements that drive most infringement disputes

• Hydrophilic/hydrophobic surfactant categories (with HLB ≥10 for hydrophilic non-ionics; HLB <10 for hydrophobic in claim 22-line)
• Dispersion outcome:
  • A400 <0.3 at 100× dilution (claim 1/153/156/165-type)
  • particle size <200 nm (claim 76-type)
• Triglyceride exclusion: system free of triglycerides

Tier 2: elements that broaden but often matter in doctrine/facts

• “consisting essentially of” scope in claim construction
• solubilizer requirement (claim 76-type)
• therapeutic-agent hydrophilicity criteria and breadth of listed examples
• dosage-form architecture routes and processing
• optional enzyme inhibitor, acids/bases, and coatings

Tier 3: elements usually less central unless used for factual differentiation

• named coatings polymers
• specific examples of actives within long lists (often to show coverage, not to narrow)

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Key Takeaways

• US 6,309,663 is a platform formulation/system patent: it claims absorption-enhancing surfactant combinations that create clear, optically low-absorbance dispersions for hydrophilic therapeutics.
• The infringement-critical constraints are performance and composition limits: A400 < 0.3 at 400 nm after 100× dilution (and for certain claims particle size <200 nm), plus “free of triglycerides.”
• The surfactant scope is broad by enumeration and includes both ionized/ionizable and HLB-defined nonionic hydrophilic surfactants, with a large hydrophobic list.
• The dependent claims expand coverage across therapeutic modalities, dose forms, administration routes, and optional excipient strategies such as enzyme inhibitors and enteric coatings, increasing the number of product formats that can be captured if the independent claim constraints are met.
• Without bibliographic data and citation history, a full “US patent landscape” map (other related patents, expiries, and challenge/litigation records) cannot be constructed from the prompt.

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FAQs

1. Does the “free of triglycerides” limitation require complete absence of any triglyceride trace, or can impurities be present?
2. If a product meets A400 <0.3 at 400 nm but has particle size ≥200 nm after dilution, which claim set is avoided?
3. Can an accused formulation infringe claim 1 using ionized hydrophilic surfactants that are not bile salts or docusate-type surfactants?
4. What changes most effectively reduce risk: switching the hydrophobic surfactant, changing hydrophilic surfactant HLB, or altering surfactant ratios to fail the optical clarity threshold?
5. How does “consisting essentially of” affect the ability to include additional excipients beyond those listed?

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References

No external sources were cited because the prompt does not provide US 6,309,663 bibliographic identifiers (assignee, filing date, priority, publication history) or any other documentation to verify landscape or prosecution facts.

Details for Patent 6,309,663

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Emd Serono, Inc.	PERGONAL	menotropins	For Injection	017646	August 22, 1975		2019-08-17
Emd Serono, Inc.	PERGONAL	menotropins	For Injection	017646	May 20, 1985		2019-08-17
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	October 28, 1982		2019-08-17
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	December 29, 2015		2019-08-17