Details for Patent: 6,749,868

Summary for Patent: 6,749,868

Title:	Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
Abstract:	In accordance with the present invention, there are provided compositions and methods useful for the in vivo delivery of substantially water insoluble pharmacologically active agents (such as the anticancer drug paclitaxel) in which the pharmacologically active agent is delivered in the form of suspended particles coated with protein (which acts as a stabilizing agent). In particular, protein and pharmacologically active agent in a biocompatible dispersing medium are subjected to high shear, in the absence of any conventional surfactants, and also in the absence of any polymeric core material for the particles. The procedure yields particles with a diameter of less than about 1 micron. The use of specific composition and preparation conditions (e.g., addition of a polar solvent to the organic phase), and careful election of the proper organic phase and phase fraction, enables the reproducible production of unusually small nanoparticles of less than 200 nm diameter, which can be sterile-filtered. The particulate system produced according to the invention can be converted into a redispersible dry powder comprising nanoparticles of water-insoluble drug coated with a protein, and free protein to which molecules of the pharmacological agent are bound. This results in a unique delivery system, in which part of the pharmacologically active agent is readily bioavailable (in the form of molecules bound to the protein), and part of the agent is present within particles without any polymeric matrix therein.
Inventor(s):	Neil P. Desai, Chunlin Tao, Andrew Yang, Leslie Louie, Zhiwen Yao, Patrick Soon-Shiong, Shlomo Magdassi
Assignee:	Abraxis Bioscience LLC
Application Number:	US09/316,642
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,749,868
Patent Claim Types: see list of patent claims	Compound; Delivery;

United States Patent 6,749,868: Scope, Claim Architecture, and US Landscape

US Drug Patent 6,749,868 claims a protein-coated, water-insoluble drug particle system where “free protein” is associated with the coating, and part of the drug is contained within the protein coating while part is associated with the free protein. The particle size is limited to ≤ 1 micron, with dependent claims tightening to < 200 nm and specifying sterile filtration and amorphous/non-crystalline forms. A central embodiment uses paclitaxel + albumin.

What does US 6,749,868 claim cover?

Claim set structure (independent vs dependent)

• Independent claim
  • Claim 1: Drug delivery system with:
  • Particles comprising a solid or liquid substantially water-insoluble pharmacologically active agent
  • Coated with protein
  • Protein coating has “free protein associated therewith”
  • Drug distribution rule:
    • “portion of said pharmacologically active agent is contained within said protein coating”
    • “portion of said pharmacologically active agent is associated with said free protein”
  • Particle size: average diameter ≤ about 1 micron
• Dependent claims (scope expansion/tightening)
  • Size: Claims 2, 8: < 200 nm
  • Process: Claims 3, 9: sterile filtered
  • Particle morphology: Claims 4, 10: amorphous/crystalline/mixture; Claims 5, 11: substantially amorphous
  • Formulation medium: Claim 6: particles suspended in biocompatible aqueous liquid
  • “Bioprotected particles” alternative language:
  • Claims 7-11 mirror the system of claims 1-5 with “bioprotected particles” framing
  • Drug and protein exemplars:
  • Claim 12: paclitaxel and albumin
  • Drug class selections:
  • Claims 13-16: anti-neoplastic (taxane), anesthetic (propofol), hormone (thyroid hormone)
  • Claims 18-21 mirror those selections for “bioprotected particles” framing
• Net effect: The patent protects a platform composition (protein-coated insoluble drug particles with explicitly defined drug partitioning between coating and free protein), then narrows with particle size, morphology, sterility, and exemplified actives/proteins.

Core technical elements that drive claim breadth

The scope hinges on a few claim-critical phrases:

1. Protein coating + “free protein associated therewith”

   • The system is not merely “drug particles coated with protein.”
   • It requires protein that is both part of the coating and additionally exists as “free protein” associated with the coated particle.

2. Defined drug localization

   • Claim language mandates a split:
     • some drug is contained within the protein coating
     • some drug is associated with the free protein
   • This is a mechanistic/structural limitation that can differentiate from protein-particle systems where drug is only in the coating matrix or only physically adsorbed externally.

3. Size ceiling

   • Claim 1: ≤ 1 micron
   • Claims 2/8: < 200 nm
   • This size limitation is a major practical boundary, especially given common injectable protein-drug colloids that can span broad distributions.

4. Drug particle nature

   • Particles can contain drug that is solid or liquid (Claim 1).
   • Particle drug solid-state options are addressed with amorphous/crystalline/non-crystalline (Claims 4-5, 10-11, 17).

Claim-by-claim scope synopsis (practical)

Claim	What it narrows/defines	Coverage impact
1	Protein-coated insoluble drug particles with free protein; split localization of drug between coating and free protein; ≤1 micron	Breadth: platform + structural rules + size gate
2	Average diameter <200 nm	Medium-narrower: targets nano-range embodiments
3	Sterile filtered system	Adds manufacturing/process constraint
4	Particles are amorphous, crystalline, or mixture	Clarifies physical states for infringement
5	Substantially amorphous	Narrows to amorphous-dominant compositions
6	Suspension in biocompatible aqueous liquid	Typical injectable format; reduces “non-aqueous” alternatives
7	“Bioprotected particles” recast with same structural split + ≤1 micron	Parallel independent coverage language
8	“Bioprotected” particles <200 nm	Nano subset
9	“Bioprotected” particles sterile filtered	Process constraint
10	Amorphous/crystalline/mixture	State clarification
11	Substantially amorphous	Amorphous subset
12	Paclitaxel + albumin	Specific commercial embodiment hook
13-16	Drug class selections: anti-neoplastic/taxane; anesthetic/propofol; hormone/thyroid hormone	Expands platform to specific actives
17	Drug is non-crystalline	State clarification in claim language
18-21	Mirrored drug-class selections for “bioprotected particles” framing	Parallel coverage language

Where is the likely “center of gravity” in the claim set?

The paclitaxel/albumin anchor

• Claim 12 directly recites paclitaxel and albumin.
• If the patent is used to support enforceability against albumin-bound paclitaxel products, claim 12 is the most “direct hit” claim.
• The earlier structural elements (claims 1/7) supply the platform theory: even if a product uses paclitaxel + albumin, the manufacturer must still satisfy:
  • particle size ≤ 1 micron
  • a protein coating with free protein associated
  • and the drug partition into “within the protein coating” vs “associated with free protein.”

Size gating as a non-trivial limitation

• Claim 1 captures up to ~1 micron; dependent claims aim at <200 nm.
• In enforcement, particle sizing and distribution measurement can become dispositive. Products that fall above the size boundary can avoid independent-claim coverage even if protein coating and drug localization concepts are present.

How would this claim language map to product design-around?

The patent’s explicit dependencies create a set of design choices:

1. Eliminate “free protein” as claimed

   • If a formulation uses albumin but prevents albumin from existing as free/associated protein distinct from the coating matrix, it may weaken infringement of claims requiring “free protein associated therewith.”
   • The claims are written so that merely having albumin present is not enough; the claim calls for a specific protein association state and a drug-sharing rule.

2. Change drug localization mechanism

   • If all drug is either:
     • only within the coating layer (no portion “associated with free protein”), or
     • only associated with protein external to the coating with no “contained within the coating,”
   • the split limitation can be a barrier.

3. Avoid the size constraints

   • Avoiding ≤1 micron can steer clear of claim 1/7.
   • Avoiding <200 nm steers away from claims 2/8.

4. Switch from albumin to other protein types

   • The claims do not limit to albumin except in claim 12.
   • Therefore, changing protein type may not avoid claim 1/7, as long as “protein coating + free protein associated + drug split + size” remain met.
   • That said, if the “protein” used in a competitor’s system behaves such that it does not form the required coating/free-protein architecture, it can become a path.

5. Use different amorphous/crystalline profile

   • Claims 4-5/10-11 and claim 17 address solid-state features, but the independent claims do not strictly require amorphous.
   • A crystalline-only formulation could still fall under claim 1/7 if it otherwise meets the coating/free-protein/split/size requirements.

What is the likely patent landscape context for this family concept?

This patent is drafted like a formulation-platform: protein-coated, insoluble drug particles with a specified protein architecture and a drug distribution requirement. In the US, landscape risk typically clusters around:

• albumin-bound / protein-bound nanoparticulate insoluble drugs
• particle size-managed injectable colloids
• albumin and other proteins as stabilizing/distribution media
• claims that attempt to distinguish from traditional excipient-based solubilization via particle engineering rather than only solvent systems

Given the claim’s explicit structural language, the most relevant US landscape points for infringement and validity analysis are typically other patents that claim:

• protein-coated particles for poorly soluble drugs,
• albumin as the protein component,
• and nanoparticle size control in aqueous injectable form,
• especially where claim language includes or avoids “free protein” and drug localization distribution concepts.

However, without the bibliographic data (assignee, filing dates, priority chain) for US 6,749,868 itself and without citing the specific conflicting documents, a complete US landscape map (family members, priority dates, examiner citations, and FTO overlays) cannot be produced accurately from the information provided.

Claim strength analysis: what tends to be most defensible vs most vulnerable?

Strength vectors

• Structural specificity: “free protein associated therewith” and the split of drug location are not generic features. They can create a measurable distinction in product characterization.
• Quantified size limitation: “average diameter no greater than about 1 micron” and the dependent “<200 nm” provide objective thresholds.

Vulnerability vectors

• Interpretation of “associated” and “free protein”
  • If “free protein” is argued broadly to include albumin that is not chemically bound, many products with protein colloids could fall into the claim’s interpretation.
  • Conversely, if a competitor argues for a narrow meaning requiring a specific physical arrangement, the term may become a claim construction battle.
• Localization proof
  • The “contained within the protein coating” vs “associated with free protein” requirement may demand sophisticated characterization. Weak analytical linkage can matter in infringement proofs.
• Medium breadth
  • Claims cover solid or liquid drug particles and do not limit protein to albumin in the independent claims. That breadth can increase invalidity exposure if prior art exists showing similar protein-coated insoluble drug particles with analogous size and protein architecture.

What are the key actionable takeaways for R&D and investment screens?

Practical claim-lens for assessing target competitors

A product is most likely in-scope if it has all of the following:

• Insoluble drug present in particles at ≤ 1 micron average diameter
• Protein architecture consisting of:
  • protein coating on the drug particle, and
  • a population of protein associated as “free protein”
• Drug is physically distributed so that:
  • part is within the protein coating matrix, and
  • part is linked to the free protein fraction
• Aqueous suspension formulation (at least for independent claim pathway through claim 6, though claim 1 does not explicitly require aqueous medium)

Practical avoiders (design-around patterns)

• Maintain protein as a bound/embedded component only (remove free-associated fraction)
• Ensure drug does not partition into both coating-contained and free-protein-associated fractions
• Shift particle size distribution above the “no greater than about 1 micron” threshold

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Key Takeaways

• US 6,749,868 is a protein-coated insoluble drug particle platform with a specific protein architecture requirement: the protein coating has free protein associated with it.
• The claims require a drug partition: part of the drug is contained within the protein coating and part is associated with free protein.
• Particle size is limiting: independent coverage is ≤ about 1 micron; dependent claims cover <200 nm.
• The claim set includes explicit exemplars: paclitaxel + albumin, and lists other actives (taxanes, propofol, thyroid hormone), reinforcing platform breadth.
• Landscape enforcement and validity will most likely turn on claim construction and measurable characterization of “free protein” and drug localization, plus particle size distribution.

FAQs

1. What is the single most important limitation in US 6,749,868?
   The requirement that the protein coating has “free protein associated therewith” and that the drug is split between being contained within the protein coating and associated with the free protein.

2. What particle size range does the independent claim cover?
   Average particle diameter of no greater than about 1 micron (Claim 1) and the parallel “bioprotected particles” independent framing (Claim 7).

3. How do the dependent claims change the scope?
   They tighten particle size to <200 nm (Claims 2 and 8), add sterile filtration (Claims 3 and 9), and narrow morphology to amorphous/substantially amorphous (Claims 5 and 11) or define amorphous/non-crystalline options (Claims 4-5, 17).

4. Is albumin required?
   Not in Claim 1. Albumin is explicitly required only in Claim 12 (paclitaxel + albumin). Independent claims require “protein” generally.

5. Which actives are explicitly listed beyond paclitaxel?
   The claims list anti-neoplastics (taxanes), anesthetics (propofol), and thyroid hormones (thyroid hormone), including mirrored lists for the “bioprotected particles” formulation.

References

[1] User-provided claim text for US Patent 6,749,868 (Claims 1-21).

Drugs Protected by US Patent 6,749,868

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

International Family Members for US Patent 6,749,868

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0961612		CA 2009 00036	Denmark
European Patent Office	0961612		91613	Luxembourg
European Patent Office	0961612		09C0050	France