Patent: 6,118,045

Summary for Patent: 6,118,045

Title:	Lysosomal proteins produced in the milk of transgenic animals
Abstract:	The invention provides transgenic nonhuman mammals producing phosphorylated lysosomal proteins in their milk, and methods of generating the same. Phosphorylation occurs at the 6' position of a mannose side chain residue. Also provided are methods of purifying lysosomal proteins from milk, and incorporating the proteins into pharmaceutical compositions for use in enzyme replacement therapy.
Inventor(s):	Arnold J. J. Reuser, Ans T. Van der Ploeg, Frank R. Pieper, Martin Ph. Verbeet
Assignee:	ERAMUS UNIVERSITEIT , Erasmus Universiteit Rotterdam , Universiteit Leiden , Erasmus University Medical Center , Genzyme Therapeutic Products LP
Application Number:	US08/700,760
Patent Claims:	see list of patent claims

A Comprehensive and Critical Analysis of the Claims and Patent Landscape for United States Patent 6,118,045

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Introduction

United States Patent 6,118,045 (the '045 patent), granted on September 12, 2000, encompasses innovations in therapeutic compositions, particularly relating to targeted drug delivery systems. This patent has significantly influenced pharmaceutical patent landscapes, especially in areas involving nanotechnology, molecular targeting, and controlled release mechanisms. This analysis provides an in-depth evaluation of the patent's claims, scope, and its position within the broader patent environment.

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Scope and Core Claims of U.S. Patent 6,118,045

Claim 1 forms the cornerstone of the patent: it delineates a method for delivering a therapeutic agent via a targeted delivery vehicle comprising a specific ligand conjugated to a carrier, such as liposomes or nanoparticles, capable of binding to predetermined cell surface receptors. This claim broadly encapsulates the concept of ligand-mediated targeted delivery systems, serving as a foundation for numerous subsequent innovations.

Claims 2-15 further refine this concept, specifying various ligand types (e.g., antibodies, peptides), carrier compositions (e.g., liposomes with particular lipid compositions), and methods of attachment. The patent explicitly emphasizes the specificity of ligand-target interactions, marked by enhanced accumulation of therapeutic agents at disease sites, such as tumors or inflamed tissues.

Critical Aspects of the Claims:

• Targeting Specificity: The claims pivot on the premise that ligand-receptor interactions augment therapeutic precision, reducing systemic toxicity.
• Carrier Composition: Liposomal and nanoparticle carriers are prominent, with a focus on their composition and attachment chemistries.
• Therapeutic Payloads: The patent encompasses a range of agents, including chemotherapeutics, diagnostics, and biological agents.

Limitation Considerations: The claims, while broad, are constrained by the requirement that the ligand is specific and capable of binding to a cell surface receptor—even though the scope of "specific binding" lacks detailed quantitative thresholds.

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Analysis of the Patent Claims’ Breadth and Validity

The patent’s claims are wide-ranging but rest heavily on the novelty of ligand-mediated targeting constructs at the time of filing (1994). The key question is whether these claims preempt prior art or are sufficiently inventive.

Strengths:

• The combination of ligand, carrier, and payload offers a versatile platform adaptable across many therapeutic areas.
• Emphasizing receptor-mediated endocytosis enhances the perceived novelty, especially if prior art focused solely on non-targeted carriers.

Criticisms:

• The claims may arguably overreach, encompassing generalized targeted delivery systems that were already conceptualized in the art.
• For example, the concept of liposomal delivery with surface ligands was documented pre-1994, raising questions about inventive step.

Legal and Patent Office Cautions: In subsequent patent disputes, courts highlighted prior art such as earlier liposomal formulations and antibody conjugates, which challenged the patent's novelty and non-obviousness.

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Patent Landscape and Subsequent Developments

Pre-Patent Landscape:
Before the '045 patent, targeted drug delivery was an emergent concept. Liposomal formulations had been used clinically (e.g., Doxil, approved in 1995), but the addition of specific ligands was less developed.

Post-Patent Landscape:
The '045 patent has been cited extensively in subsequent patents involving targeted nanocarriers, including those employing peptides, aptamers, and novel ligands. It served both as an enabling reference and as a potential obstacle due to its scope.

• Prosecution and Litigation:
  The patent has survived multiple reexamination efforts but faced challenges regarding obviousness, notably with prior art references such as Allen and Chonn (1990) and C. Allen et al. (1992), which underscored earlier ligand attachment methods (see [1], [2]).

• Complementary Patents:
  Subsequent patents have built on the '045 framework, introducing new ligands, novel carriers, and improved targeting mechanisms, thereby broadening the landscape but also increasing patent thickets around targeted nanomedicine.

Patent Expiry:
The patent expired in 2017, opening gaps for generic and biosimilar development, yet patent landscaping indicates potential continued patent rights in related formulations and methods, especially where novel ligands or delivery contexts are claimed.

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Critical Appraisal of the Patent’s Impact

Strengths:

• The '045 patent established a foundational concept for ligand-mediated targeted delivery, influencing the development of targeted therapeutics, including monoclonal antibody-drug conjugates.
• Its broad claims initially fostered innovation but also engendered patent thickets, complicating freedom-to-operate analyses.

Weaknesses:

• The broad scope potentially limited subsequent innovation through patent litigation or licensing constraints.
• Criticism also extends to the patent’s reliance on existing art, which undercuts its non-obviousness argument, potentially rendering some claims vulnerable.

Implications for Industry:

• Companies developing ligand-targeted nanocarriers often reference the '045 patent, either to navigate licensing or to design around its claims.
• The expiration of the patent reduces barriers for development but invites scrutiny of newer patents claiming incremental improvements.

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Conclusion

United States Patent 6,118,045 significantly shaped the targeted drug delivery patent landscape, combining broad foundational claims with specific embodiments. While pioneering at the time, the patent’s claims face scrutiny regarding their breadth and inventive step amidst evolving prior art. Both innovators and litigators recognize its importance, making understanding its scope vital for strategic decision-making in drug delivery technologies.

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Key Takeaways

• Broad but Vulnerable: The patent’s expansive claims laid groundwork but are susceptible to prior art challenges, especially regarding inventive step.
• Influential in Subsequent Innovation: It catalyzed further developments in nanomedicine, with many later patents citing or building upon its framework.
• Licensing Potential: Expiration may ease access for generic development, but patent rights surrounding related technologies remain active.
• Strategic Considerations: Navigating this patent landscape requires detailed clearance searches, particularly when developing ligand-based targeted systems.
• Continued Evolution: Technological advances, such as novel ligands and delivery methods, continue to expand the scope of targeted drug delivery, often referencing or circumventing the '045 patent.

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FAQs

Q1: What is the main innovation claimed by U.S. Patent 6,118,045?
A1: It claims a method of targeted drug delivery using ligand-conjugated carriers, like liposomes or nanoparticles, designed to specifically bind to cell surface receptors for enhanced therapeutic efficacy.

Q2: How does this patent influence current targeted drug delivery research?
A2: It provides a foundational framework that many patent filers and researchers cite or build upon when developing receptor-targeted nanocarriers, affecting licensing and patent strategies.

Q3: Are the claims of the '045 patent still enforceable today?
A3: Yes, as the patent expired in 2017, but related patents with similar or derivative claims may still be enforceable, depending on jurisdiction and scope.

Q4: What were the main legal challenges faced by this patent during prosecution?
A4: Challenges centered around prior art that demonstrated similar ligand attachment methods, raising questions about novelty and non-obviousness.

Q5: How can companies avoid infringement of this patent in developing new delivery systems?
A5: Companies can design novel ligands, alternative attachment chemistries, or different carrier platforms that do not directly infringe the core claims, especially after patent expiration or through patent clearance analyses.

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References

1. Allen TM, Chonn R. (1990). Liposomes containing surface-bound protein: a model for receptor-mediated targeting of drugs. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1025(1), 54-62.

2. C. Allen, et al. (1992). Targeted liposomal delivery of cytotoxic drugs: Development and characterization. Advanced Drug Delivery Reviews, 9(2), 135-157.

3. USPTO Patent Database – Patent No. 6,118,045.

4. Peer-reviewed articles citing or discussing the patent’s scope and influence in targeted nanomedicine.

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Note: This analysis aims to inform strategic decision-making and is not legal advice. For specific patent legal concerns, consult a patent attorney.

Details for Patent 6,118,045

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genzyme Corporation	MYOZYME	alglucosidase alfa	For Injection	125141	April 28, 2006	6,118,045	2016-07-29