United States Patent 5,270,181: Claims, Expiration, Patent Scope, and Biologic Manufacturing Landscape

United States Patent 5,270,181 covers recombinant DNA constructs that fuse thioredoxin or a structurally related redox protein to a heterologous eukaryotic protein. Its claims extend to fusion DNA, expression vectors, bacterial and yeast host cells, and production methods using osmotic shock or freeze-thaw recovery. The patent is expired and no longer creates a current U.S. exclusionary right. Its principal commercial relevance is historical: it helped establish thioredoxin fusion technology for soluble expression and recovery of recombinant proteins, including interleukin-11.

What does United States Patent 5,270,181 cover?

Patent 5,270,181 covers a platform for expressing selected eukaryotic proteins as fusions with thioredoxin-like proteins. The patent was granted on December 14, 1993. Its claim architecture has four layers:

Claim category	Claims	Principal subject matter
Fusion DNA	1-11	Thioredoxin or thioredoxin-like DNA fused to eukaryotic protein DNA
Expression vectors	12-17	Vectors containing the claimed fusion constructs
Host cells	18-24	Bacterial or yeast cells containing the vectors
Production methods	25-30	Culturing host cells and recovering recombinant protein

The independent technical concepts are:

A thioredoxin-like fusion partner with a three-dimensional structure substantially similar to E. coli thioredoxin.
An active-site loop functionally and structurally equivalent to the double-cysteine loop of E. coli thioredoxin.
In-frame fusion to a selected eukaryotic protein or peptide.
Optional linker DNA encoding a proteolytic cleavage site.
Expression in bacterial or yeast host cells.
Recovery of the expressed protein by culture, osmotic shock, or freeze-thaw treatment.

The claims are directed to biological production technology rather than to a finished therapeutic formulation.

What are the broadest claims in Patent 5,270,181?

Claims 1 and 2 provide the principal breadth.

Claim 1 covers fusion DNA in four orientations:

R1-R2
R2-R1
R1-L-R2
R2-L-R1

R1 is thioredoxin-like DNA. R2 is eukaryotic DNA encoding the selected protein. L is an optional linker encoding a proteolytic cleavage site and intended to reduce steric interference between the fusion partners.

Claim 2 covers DNA encoding the desired protein fused in frame within the active site of thioredoxin-like DNA. This claim is technically narrower than claim 1 because it requires insertion within the active-site region rather than merely joining the two coding regions.

Claims 4 and 5 define specific thioredoxin-like partners:

Thioredoxin
Glutaredoxin
Thioredoxin-like domains of protein disulfide isomerase
Thioredoxin-like domains of form-1 phosphoinositide-specific phospholipase C
Thioredoxin-like domains of ERp72

Claims 6 and 8 identify specific target proteins:

Interleukin-11
Interleukin-6
Macrophage colony-stimulating factor
MIP-1 alpha
Bone morphogenetic protein-2

Claims 7-11 focus on E. coli thioredoxin. Claim 10 is the most sequence-specific commercial claim because it requires an E. coli thioredoxin-IL-11 fusion containing the linker sequence:

G-S-G-S-G-D-D-D-D-K

Claim 11 narrows the construct further by identifying the IL-11 coding region as nucleotides 2599 through 3132 of Figure 1.

How strong is the patent estate for Patent 5,270,181?

The patent had meaningful historical scope but would have faced substantial validity and claim-construction pressure even during its enforceable term.

Strengths of the claims

The patent's strongest features were its functional definition of thioredoxin-like proteins and its coverage of multiple implementation layers. A competitor could not avoid the patent merely by changing from a plasmid to a different expression vector if the resulting vector still contained the claimed fusion DNA. The host-cell and production-method claims provided additional enforcement theories.

The patent also claimed more than one target protein. Claims directed to IL-6, IL-11, M-CSF, MIP-1 alpha, and BMP-2 created a bridge between platform technology and specific recombinant products.

Claim 10 was comparatively stronger in technical specificity because it identifies:

E. coli thioredoxin;
IL-11;
A defined linker sequence; and
An in-frame fusion arrangement.

Weaknesses and likely validity issues

The broadest claims depend on functional language that could generate disputes over scope and definiteness. The terms "substantially similar," "functionally and structurally equivalent," and "preventing steric hindrance" require scientific interpretation. A challenger could argue that these terms fail to provide a sufficiently objective boundary unless the specification supplies adequate structural and functional tests.

The claims also combine structural and functional limitations. A fusion partner may satisfy the claim only if it both resembles E. coli thioredoxin in three-dimensional structure and has an equivalent active-site loop. That limitation narrows the field, but it also creates fact-intensive infringement questions involving protein structure, sequence identity, redox activity, and assay conditions.

Claim 2 presents a separate technical issue. It requires the desired DNA to be fused within the active site of thioredoxin-like DNA. A construct with the target protein attached at the amino or carboxyl terminus could fall outside claim 2 while remaining within claim 1 or claim 7.

When did United States Patent 5,270,181 expire?

Patent 5,270,181 expired on December 14, 2010, based on the 17-year term applicable to a pre-Uruguay Round patent issued before the transition to the modern 20-year term. The patent therefore has no enforceable U.S. patent term today.

Event	Date or status
U.S. patent grant	December 14, 1993
Applicable historical term	17 years from grant
Expected U.S. expiration	December 14, 2010
Current enforceability	Expired
Current Paragraph IV threat	None based on this patent
Current patent royalty leverage	None based solely on this patent

The expiration date eliminates infringement risk from practicing the issued claims in the United States. It does not eliminate risk from later patents covering particular sequences, vectors, host-cell systems, purification methods, formulations, manufacturing processes, or therapeutic uses.

What patents protect thioredoxin fusion expression technology after Patent 5,270,181?

Patent 5,270,181 should be treated as an expired foundational patent, not as the entire patent estate for thioredoxin fusion technology.

Later patent families may claim:

Particular thioredoxin sequences or engineered variants;
Specific linker sequences;
Protease-cleavable fusion designs;
Proprietary expression vectors;
Periplasmic or cytoplasmic secretion systems;
Codon-optimized nucleic acids;
Fusion constructs with defined therapeutic proteins;
Improved solubility or refolding methods;
Purification processes;
Use of thioredoxin tags in screening or assay systems.

A freedom-to-operate review must therefore distinguish between the expired platform claims and later patent rights. Using a commercially available thioredoxin vector, such as a vector sold for recombinant protein expression, may implicate supplier licensing terms or later patents even though Patent 5,270,181 itself is expired.

The patent is also not a blanket right over every protein expressed with a thioredoxin tag. A later construct must be assessed against the specific claim limitations, including the active-site requirement, fusion orientation, linker sequence, target protein, and host-cell or production-method limitations.

What formulations are protected by Patent 5,270,181?

Patent 5,270,181 does not claim a finished pharmaceutical formulation. The claims do not recite:

A liquid or lyophilized dosage form;
Excipients;
Buffer systems;
Stabilizers;
Container-closure systems;
Route of administration;
Therapeutic dosing;
A purified active pharmaceutical ingredient as such.

The patent claims recombinant DNA, vectors, host cells, and production methods. It may have been relevant to manufacture of a recombinant therapeutic protein, but it does not independently protect the drug product, label, dosage regimen, or formulation.

How does the patent relate to recombinant interleukin-11?

The patent has unusually direct relevance to recombinant IL-11 because claims 8-11 identify IL-11 expressly.

The most specific claim is claim 10, which covers a fusion DNA having:

E. coli thioredoxin DNA;
In-frame IL-11 DNA; and
The linker sequence G-S-G-S-G-D-D-D-D-K.

Claim 11 narrows the IL-11 sequence to the nucleotide segment identified in Figure 1. Claims 28-30 extend the IL-11 subject matter into production methods.

The IL-11 claims appear designed to protect a soluble-expression and recovery strategy rather than the natural IL-11 protein itself. The commercial significance was likely connected to recombinant IL-11 development, including oprelvekin, marketed in the United States as Neumega.

FDA approved Neumega on November 22, 1997, for prevention of severe thrombocytopenia in certain patients receiving myelosuppressive chemotherapy. The product received orphan-drug exclusivity, which is separate from patent protection. Orphan exclusivity did not extend the life of Patent 5,270,181 and ended independently of the patent term. FDA later identified Neumega as discontinued from marketing in the United States, a regulatory status distinct from patent expiration. [2]

What is the Orange Book status of Patent 5,270,181?

Patent 5,270,181 is not an Orange Book product patent.

The Orange Book principally lists patents submitted for approved small-molecule drug products under the Hatch-Waxman framework. Patent 5,270,181 claims recombinant DNA technology, expression vectors, host cells, and manufacturing methods. It does not claim a conventional drug composition or dosage form.

The relevant FDA framework for a recombinant therapeutic protein is generally the biologics framework, including the Purple Book and the biosimilar pathway under the Public Health Service Act. Patent 5,270,181 is therefore not a current Orange Book barrier to generic or follow-on competition. [3,4]

Which companies challenged Patent 5,270,181?

No current Paragraph IV challenge can be maintained against Patent 5,270,181 because the patent expired in 2010. A Paragraph IV certification is relevant to an unexpired patent listed in the Orange Book, not to an expired recombinant-DNA platform patent.

Publicly available patent records should be reviewed for historical litigation involving the patent, but the issued claims do not create a present litigation barrier. The commercial disputes most likely to matter now involve later patents, trade secrets, platform licenses, or product-specific patents rather than this expired patent.

What litigation status affects commercial use of the patent?

The current litigation position is straightforward:

Issue	Current position
Direct infringement of issued claims	No enforceable U.S. liability after expiration
Injunction risk under Patent 5,270,181	None based on current expiration
Damages for new conduct	Unavailable for post-expiration activity
Paragraph IV litigation	Not applicable
Patent-term extension	No current extension changes the expired status
Trade-secret exposure	Possible only if separate confidential information is used
Later-patent exposure	Must be assessed independently

Expired patent claims can remain relevant as prior art and as evidence of the technical history of a platform. They cannot be asserted to stop current practice of the claimed technology.

What generic or biosimilar entry risks exist for IL-11 products?

Patent 5,270,181 creates no current entry risk for an IL-11 developer. The more relevant risks are regulatory, clinical, manufacturing, and later-patent risks.

Regulatory pathway

A follow-on IL-11 product would likely require a biologics pathway rather than an abbreviated new drug application. The applicable route depends on the reference product's regulatory status and the sponsor's product strategy. A biosimilar sponsor would need to address analytical similarity, residual uncertainty, immunogenicity, and any clinical or pharmacologic requirements imposed by FDA.

Manufacturing barriers

The expired patent does not remove manufacturing complexity. IL-11 production may require control of:

Fusion-protein expression;
Proteolytic cleavage;
Misfolding and aggregation;
Host-cell impurities;
Endotoxin;
Product-related variants;
Refolding or recovery conditions;
Comparability after process changes.

These issues may create practical barriers even when no blocking patent remains.

Commercial barriers

Neumega's discontinued U.S. marketing status reduces the value of a direct follow-on strategy unless a sponsor identifies a current clinical or commercial use. The relevant market may instead involve research reagents, specialty biologics, regional products, or new therapeutic applications.

How does Patent 5,270,181 compare with modern fusion-protein patents?

Attribute	Patent 5,270,181	Modern fusion-protein patent strategy
Core technology	Thioredoxin-like fusion partner	Engineered sequence, vector, linker, host, or process
Claim style	Broad functional and platform claims	More sequence-defined and implementation-specific
Targets	IL-11, IL-6, M-CSF, MIP-1 alpha, BMP-2	Often one product or defined protein class
Host cells	Bacterial and yeast cells	May specify strain, compartment, or engineered host
Recovery	Osmotic shock and freeze-thaw	Chromatography, secretion, refolding, or continuous processes
Current legal status	Expired	Depends on filing date, continuations, and patent-term adjustment
Main business value	Historical platform disclosure and prior art	Potentially active FTO constraint

The patent's broad functional language was useful for platform coverage but could be vulnerable to enablement, written-description, definiteness, and claim-construction challenges. Modern portfolios tend to divide protection across narrower families, which can make individual claims easier to defend while increasing the number of rights requiring review.

What geographic coverage remains?

The U.S. patent right has expired. Foreign counterparts, if any, would have expired under their respective national terms. Patent protection should not be assumed to have ended simultaneously worldwide because foreign applications may have had different filing dates, prosecution outcomes, lapse events, or claim scope.

A current international FTO review should separately examine:

European Patent Office family members;
Canada;
Japan;
Australia;
China;
South Korea;
Brazil;
India;
Countries where IL-11 products or manufacturing may be commercialized.

No foreign right can be inferred solely from the U.S. grant. The United States expiration does not establish the status of every family member.

Key Takeaways

Patent 5,270,181 covers thioredoxin and thioredoxin-like fusion DNA, expression vectors, host cells, and recombinant-protein production methods.
Claims 1 and 2 are the principal platform claims; claims 7-11 focus on E. coli thioredoxin and IL-11.
Claim 10 specifically covers an E. coli thioredoxin-IL-11 fusion containing the G-S-G-S-G-D-D-D-D-K linker.
The patent expired on December 14, 2010.
The patent is not an active Orange Book patent and does not create a current Paragraph IV barrier.
It does not claim a pharmaceutical formulation, dosage regimen, or finished therapeutic product.
Current risk must be assessed against later patents, licensing restrictions, trade secrets, biologics regulation, and manufacturing know-how.
For IL-11, the principal present barriers are likely clinical demand, regulatory requirements, process development, and commercial viability rather than Patent 5,270,181.

FAQs

Does Patent 5,270,181 block use of thioredoxin fusion tags today?

No. The U.S. patent expired in 2010. Later patents covering specific vectors, sequences, linkers, host cells, or processes may still require review.

Does the patent cover all recombinant IL-11 products?

No. It covers specified fusion-DNA arrangements and related production methods. It does not claim every IL-11 molecule, formulation, therapeutic use, or manufacturing process.

Can a biosimilar sponsor rely on expiration of Patent 5,270,181?

The sponsor can treat the patent as expired in the United States. That does not establish freedom from later patents or satisfy FDA biosimilar requirements.

Is the G-S-G-S-G-D-D-D-D-K linker independently protected today?

Not by Patent 5,270,181. Claim 10 is expired. A separate later patent could claim the same or a similar linker in a different technical context.

Does the patent provide freedom to operate for commercial expression vectors?

No. Expiration removes this patent as a U.S. barrier, but commercial vectors may be subject to later patents, material-transfer terms, supplier licenses, or restrictions on use.

References

United States Patent No. 5,270,181. (1993). Fusion DNA, expression vectors, host cells, and methods for producing recombinant proteins. U.S. Patent and Trademark Office.
U.S. Food and Drug Administration. (1997). Neumega (oprelvekin) prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products. FDA.
35 U.S.C. § 154. Patent term.
42 U.S.C. § 262. Licensure of biological products as biosimilar or interchangeable.

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Wyeth Pharmaceuticals Inc.	NEUMEGA	oprelvekin	For Injection	103694	November 25, 1997	⤷ Start Trial	2011-08-14
>Applicant	>Tradename	>Biologic Ingredient	>Dosage Form	>BLA	>Approval Date	>Patent No.	>Expiredate

Country	Patent Number	Estimated Expiration
Austria	E237692	⤷ Start Trial
Austria	E456661	⤷ Start Trial
Australia	1399495	⤷ Start Trial
Australia	1467192	⤷ Start Trial
Australia	4781493	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration

Patent: 5,270,181

Summary for Patent: 5,270,181