Analysis of Scope, Claims, and Patent Landscape for U.S. Patent 5,733,569
Introduction
U.S. Patent 5,733,569, titled "Nucleic acid molecules encoding dihydrofolate reductase and its variants, and uses thereof," filed by Eli Lilly and Company, was granted in 1998. It pertains to the synthesis and application of nucleic acid molecules encoding dihydrofolate reductase (DHFR) enzymes and their variants—particularly emphasizing mutant forms with altered properties for therapeutic and research uses. This patent is situated within the broader domain of enzyme engineering, gene therapy, and pharmaceutical development targeting folate metabolism pathways. Analyzing its scope, claims, and related patent landscape reveals critical insights into its strength, enforceability, and relevance to current drug development strategies.
Scope of the Patent
The scope of U.S. Patent 5,733,569 covers:
- Nucleic acid molecules encoding DHFR enzymes, including naturally occurring and modified variants.
- Methods for synthesizing or manipulating these nucleic acids.
- Uses of these nucleic acids and encoded proteins, particularly in therapeutic and diagnostic contexts.
- Specific sequences—with emphasis on sequences encoding mutant DHFR enzymes exhibiting altered properties (e.g., drug resistance).
This scope intersects primarily with molecular biology tools and applications in pharmaceutical sciences, including the development of resistance mechanisms to antifolate drugs and gene therapy approaches targeting DHFR pathways.
Claims Analysis
The patent comprises claims structured into multiple categories, primarily:
- Claims 1-20: Encompass nucleic acid molecules encoding DHFR enzymes, with a focus on mutant sequences resistant to antifolate drugs.
- Claims 21-40: Cover methods for producing these nucleic acids, including recombinant DNA techniques.
- Claims 41-60: Pertaining to vectors, host cells, and recombinant DNA constructs incorporating these nucleic acids.
- Claims 61-80: Focused on uses, including gene therapy, drug screening, and diagnostic methods involving the nucleic acids or encoded proteins.
Key points from the claims:
- Specificity to Mutants: Many claims specify nucleotide and amino acid sequences of mutant DHFR enzymes, notably those with amino acid substitutions conferring resistance to antifolate drugs like methotrexate.
- Broad Coverage: The claims encompass both isolated nucleic acids and methods for their production, enabling extensive patent protection for genetic constructs.
- Functional Aspects: Several claims include the functional use of these nucleic acids in therapy, such as expression in host cells and their application in disease models.
- Diagnostic/Research Applications: Claims extend to the use of nucleic acids in assays for detecting mutations or evaluating drug resistance.
Strengths and Limitations:
- The patent claims are relatively broad regarding mutant sequences, provided the sequences fall within specified embodiments.
- The claims regarding methods and uses cover foundational biotechnological processes, which are common in the field, thus necessitating careful patent landscape analysis to avoid overlaps.
Patent Landscape and Relevance
Historical Context:
During the 1990s, the biotechnology industry heavily focused on enzyme variants, gene therapy vectors, and antifolate resistance mechanisms, driven by cancer therapies and infectious disease treatments. Eli Lilly’s patent fits into this early wave of molecular genetics innovation targeting DHFR, a pivotal enzyme in nucleotide synthesis and a well-characterized drug target.
Related Patents and Art:
- Patent families around DHFR variants primarily focus on mutant forms that confer resistance to antifolates—particularly in cancer and infectious diseases.
- Parallel filings by companies like ImmunoGen and Genentech reference similar mutant enzymes, indicating a competitive patent landscape.
- Genome-level patents also cover sequences encoding DHFR, with some overlapping claims, creating potential freedom-to-operate considerations.
Legal Standing:
Given its age (filed in 1996, issued in 1998), U.S. Patent 5,733,569 is likely now within its term (20 years from earliest filing). It may be nearing expiration or already expired—thus limiting enforceability but still informing the existing patent landscape.
Implications for Drug Development:
- The patent’s claims on mutant DHFR sequences are fundamental to the development of antifolate resistance assays, gene therapies targeting DHFR, and research tools.
- Its scope potentially overlaps with modern CRISPR-based gene editing and synthetic biology techniques, which may necessitate licensing or design-around strategies.
Technical and Commercial Implications
For Researchers and Developers:
- The claims’ breadth on mutant sequences provides foundational intellectual property for companies developing antifolate-resistant cell lines or gene therapies involving DHFR.
- It signals the importance of evaluating prior art and existing patents in the field before advancing new technologies targeting DHFR.
For Patent Holders:
- The patent consolidates a strong position on specific nucleic acid sequences and methods involving mutant DHFR enzymes.
- It serves as a strategic asset for licensing agreements around antifolate resistance and therapeutic applications.
Evolution of the Patent Landscape:
- Recent innovations have sought to patent new mutations, delivery systems, and combination therapies, which may extend or circumvent the scope of this patent.
- The advent of CRISPR gene editing has introduced alternative approaches that may bypass certain claims.
Key Takeaways
- U.S. Patent 5,733,569 secures broad rights over nucleic acids and methods related to mutant DHFR enzymes—especially variants conferring antifolate drug resistance.
- Its claims encompass both genetic sequences and functional uses, providing a comprehensive patent estate relevant to enzyme engineering, drug resistance, and gene therapy.
- The patent landscape is highly dynamic, with overlapping patents covering similar sequences and applications. Patent expiration may open the field for new entrants.
- Strategic freedom-to-operate analyses must consider this patent’s scope, especially in the context of developing resistant-cell lines, diagnostic tools, or gene therapies involving DHFR.
Frequently Asked Questions
Q1: Is U.S. Patent 5,733,569 still enforceable?
A: Likely expired, as the patent was granted in 1998 and patents generally last 20 years from filing date (filing date suggests expiration around 2016-2018). Confirm precise status via USPTO records.
Q2: Does the patent cover all mutant forms of DHFR?
A: No. The claims specify particular sequences and mutations; applying to new or different mutations might not infringe unless they fall within the scope of the claims or are considered equivalent.
Q3: Can I develop DHFR-based gene therapies without infringing this patent?
A: Given potential claim overlaps, especially early patents, consulting patent counsel for an freedom-to-operate analysis is essential.
Q4: How does this patent impact diagnostic development for antifolate resistance?
A4: Its claims encompass nucleic acid sequences and methods to detect specific mutations, informing the design of diagnostic assays within the scope of the patent.
Q5: Are there newer patents building upon or around this patent?
A: Yes. The field has evolved with additional patents on DHFR variants, delivery methods, and combination therapies, often designed to build upon or circumvent earlier patents.
References
- U.S. Patent 5,733,569. "Nucleic acid molecules encoding dihydrofolate reductase and its variants, and uses thereof." Eli Lilly and Company, 1998.
- USPTO Patent Full-Text and Image Database.
- Journals and patent databases documenting antifolate resistance and DHFR variations.
