United States Drug Patent 4,977,138: FR901228 Scope, Claims, Expiration and Patent Landscape

U.S. Patent No. 4,977,138 covers FR901228, now known as romidepsin, as a chemical substance and as a pharmaceutical composition containing that substance. The patent is historically important as the foundational composition-of-matter patent for romidepsin, but it is no longer an enforceable U.S. patent. Its statutory term expired in 2009, before FDA approval of Istodax in 2009.

What drug does U.S. Patent 4,977,138 protect?

U.S. Patent 4,977,138 protects FR901228, a cyclic depsipeptide later developed as romidepsin, FK228, and Istodax.

Romidepsin is a histone deacetylase inhibitor. Its molecular formula is C24H36N4O6S2, and its molecular weight is approximately 540.7 daltons. The molecule contains a cyclic depsipeptide structure and a disulfide bond that is reduced intracellularly to generate the active thiol-containing species.

The patent identifies the compound by the structural formula reproduced in the patent. The claim is not limited to a particular indication, dose, route of administration, formulation strength, or patient population.

Field	Patent information
U.S. patent	4,977,138
Patent title	FR901228 substance
Original applicant/assignee	Fujisawa Pharmaceutical Co., Ltd.
Inventive subject matter	FR901228 composition of matter
Active ingredient	FR901228, later named romidepsin
U.S. filing period	1989
Issue date	December 11, 1990
Principal claims	Compound and pharmaceutical composition
FDA product	Istodax
U.S. patent status	Expired
Statutory expiration	2009, based on the pre-1995 patent-term rules
Current blocking value	None as an enforceable U.S. patent

Source: U.S. Patent No. 4,977,138; FDA, Istodax prescribing information.

What does claim 1 of U.S. Patent 4,977,138 cover?

Claim 1 is a product claim to FR901228 itself:

“FR901228 substance of the following formula…”

This is a composition-of-matter claim. It covers the molecule defined by the structural formula, including its claimed stereochemical configuration and the molecular arrangement shown in the patent.

Scope of the chemical claim

Claim 1 potentially reaches:

Romidepsin manufactured by chemical synthesis.
Romidepsin isolated from a biological source.
Romidepsin used as an active pharmaceutical ingredient.
Romidepsin supplied in bulk form.
Romidepsin incorporated into a dosage form.
Romidepsin sold under the generic name romidepsin or the development code FR901228.

The claim is not limited to the original fermentation process. A party could infringe a product claim by making, using, selling, offering to sell, or importing the claimed compound, even if the compound was made by a different process.

What claim 1 does not expressly cover

Claim 1 does not, based on the quoted language, expressly claim:

A method of treating cancer.
A method of inhibiting histone deacetylase.
A specific dosage regimen.
A specific intravenous infusion protocol.
A particular vial, excipient system, or lyophilized formulation.
A manufacturing process.
A salt, ester, prodrug, analog, or derivative that is not the claimed FR901228 molecule.
A metabolite or active reduced form unless it falls within the claimed structure.

The exact treatment of a salt or derivative depends on whether the claimed substance is present as the claimed molecular entity. A chemically distinct derivative is not automatically covered by a narrow compound claim.

What does claim 2 of U.S. Patent 4,977,138 cover?

Claim 2 covers:

“A pharmaceutical composition which comprises, as an active ingredient FR901228 substance as defined in claim 1 and a non-toxic, pharmaceutically acceptable carrier.”

This is a composition claim dependent on the identity of FR901228 in claim 1.

Required elements of claim 2

A composition must contain:

FR901228 as the active ingredient.
A non-toxic, pharmaceutically acceptable carrier.

The carrier limitation can include conventional pharmaceutical excipients, diluents, stabilizers, bulking agents, solvents, buffers, or other formulation materials that make the product suitable for pharmaceutical administration.

The claim is broad as to:

Dosage form.
Route of administration.
Carrier identity.
Excipient concentration.
Drug concentration.
Patient population.
Therapeutic indication.
Combination with other active ingredients, unless another claim limitation excludes the combination.

Dosage forms potentially within claim 2

The claim can potentially read on a broad range of dosage forms containing the claimed molecule, including:

Injectable solutions.
Lyophilized injectable preparations.
Infusion products.
Oral solid dosage forms.
Capsules and tablets.
Liquid preparations.
Pharmaceutical kits containing the active ingredient and carrier components.

The commercial Istodax product is an intravenous formulation supplied as a lyophilized powder for reconstitution and infusion. The commercial product is a specific implementation of the broader composition concept in claim 2. Claim 2 does not appear limited to the commercial excipient system.

When did U.S. Patent 4,977,138 expire?

U.S. Patent 4,977,138 expired in 2009 under the patent-term rules applicable to applications filed before June 8, 1995.

For this patent, the relevant term was governed by the longer of:

17 years from the patent’s issue date; or
20 years from the applicable U.S. filing date.

The patent issued on December 11, 1990. The 17-year period would have ended in December 2007, but the applicable 20-year filing-based period extended the term into 2009.

Event	Date or period
U.S. application	1989
Patent issued	December 11, 1990
17-year issue-based term	December 2007
Applicable filing-based term	2009
Patent expiration	2009
Istodax FDA approval	November 5, 2009

The patent therefore expired before, or approximately at the time of, FDA approval of Istodax. No current generic or innovator company can rely on U.S. Patent 4,977,138 as an enforceable exclusion right.

What was the FDA exclusivity position for romidepsin?

FDA exclusivity and patent protection are separate rights. Romidepsin received regulatory exclusivity even though the foundational compound patent had expired.

The FDA approved Istodax on November 5, 2009, for treatment of cutaneous T-cell lymphoma in patients who had received at least one prior systemic therapy. The product was approved under the orphan-drug framework. FDA later approved romidepsin for peripheral T-cell lymphoma, subject to the regulatory history applicable to that indication.

Protection type	Relevance to romidepsin
Composition-of-matter patent	U.S. 4,977,138; expired in 2009
New chemical entity exclusivity	Applied from the 2009 approval and restricted certain abbreviated applications during the exclusivity period
Orphan-drug exclusivity	Indication-specific and separate from patent protection
Pediatric exclusivity	No broad conclusion should be drawn from the compound patent alone
Biosimilar exclusivity	Not applicable because romidepsin is a small molecule, not a biologic

FDA exclusivity did not recreate the expired compound patent. It restricted certain FDA approvals or marketing actions for the covered indication and period, but it did not prevent all commercial activity involving romidepsin.

What is the Orange Book status of U.S. Patent 4,977,138?

U.S. Patent 4,977,138 should be treated as an expired historical patent rather than a current Orange Book barrier.

The Orange Book records patents submitted by an NDA holder for an approved drug. An expired patent may remain visible in historical or archived records, but it cannot support a current patent-infringement injunction or a valid Paragraph IV enforcement action.

For an abbreviated new drug application, the relevant questions are whether:

The innovator has listed unexpired patents for the approved drug.
The proposed ANDA product falls within any listed formulation or method-of-use claims.
The FDA exclusivity period has ended.
The applicant can obtain adequate product, manufacturing, and clinical information for an injectable oncology product.

The original compound patent alone would not block an ANDA or other generic pathway after expiration.

What patent landscape surrounds romidepsin?

The romidepsin patent landscape has four principal layers.

1. Original composition-of-matter protection

U.S. Patent 4,977,138 is the foundational patent. It claims the molecule and a pharmaceutical composition containing it. This layer has expired.

2. Later process and formulation patents

Later patent families may address:

Fermentation or recovery of FR901228.
Purification of romidepsin.
Control of stereochemical or impurity profiles.
Stabilization of the active ingredient.
Lyophilized injectable formulations.
Reconstitution and infusion systems.
Manufacturing specifications for commercial-grade material.

These patents must be analyzed claim by claim. A process patent does not prevent manufacture by a non-infringing alternative process. A formulation patent does not prevent use of the active ingredient in an unrelated dosage form.

3. Method-of-use patents

Romidepsin has been studied and marketed for hematologic malignancies, including:

Cutaneous T-cell lymphoma.
Peripheral T-cell lymphoma.
Other lymphomas in clinical development.
Combination regimens involving other anticancer agents.

Method-of-use patents may claim a specific disease, treatment line, dosage schedule, combination, biomarker-defined population, or administration protocol. They do not have the same scope as the original compound claim and may be vulnerable to non-infringing use, divided-infringement, written-description, enablement, or obviousness challenges.

4. Regulatory exclusivity

FDA orphan exclusivity can create a commercial barrier even when patent protection is weak or expired. Its scope is indication-specific. It does not generally prevent off-label use, clinical investigation, or approval of a competing product for an unrelated indication.

Are Paragraph IV challenges relevant to romidepsin?

Paragraph IV litigation is relevant only to unexpired patents listed in the Orange Book for the applicable romidepsin reference product.

A Paragraph IV certification asserts that a listed patent is invalid, unenforceable, or not infringed. For U.S. Patent 4,977,138, a Paragraph IV challenge would have no practical current value because the patent has expired.

A later ANDA applicant could still face litigation based on:

Unexpired formulation patents.
Manufacturing patents if the ANDA manufacturing process falls within the claims.
Method-of-use patents.
Patents covering a particular commercial presentation.

The ANDA applicant could use a section viii statement to carve out a patented method of use if the labeling can omit the protected indication while retaining approval for an unpatented use.

Is romidepsin exposed to biosimilar competition?

No. Romidepsin is a synthetic or fermentation-derived small-molecule drug regulated through the conventional drug approval system. It is not a biologic subject to the biosimilar pathway under the Public Health Service Act.

The relevant competitive pathways are:

ANDA approval for a therapeutically equivalent generic.
A 505(b)(2) application for a product with formulation, route, or clinical differences.
Potential authorized generic or licensed generic arrangements.
Hospital and specialty-pharmacy contracting.

The principal commercial barriers are the complexity of producing a highly potent oncology injectable, establishing pharmaceutical equivalence, controlling impurities, demonstrating stability, and meeting sterile manufacturing requirements.

How strong is the patent estate for romidepsin?

The foundational patent estate is weak from a current enforcement perspective because the principal compound patent expired in 2009.

Estate component	Current strength
Original compound claim	None; expired
Broad pharmaceutical composition claim	None under the expired patent
Method-of-use protection	Depends on the specific patent, indication, and expiration date
Formulation protection	Depends on claim scope and remaining term
Manufacturing protection	Potentially meaningful if the process is difficult to design around
Regulatory exclusivity	Historical and indication-specific
Biosimilar barrier	Not applicable
Generic entry barrier	Manufacturing, formulation, regulatory, and market access issues

The strongest remaining barriers are likely to be technical and regulatory rather than the expired composition claim. Romidepsin is a specialty oncology injectable with a relatively constrained market, which can reduce the commercial incentive for generic entry even after patent expiration.

What generic launch scenarios exist for romidepsin?

Three scenarios are commercially relevant.

Immediate conventional generic entry

A company could pursue an ANDA if it can demonstrate pharmaceutical equivalence, bioequivalence or applicable equivalence requirements, sterility, stability, and manufacturing compliance. The expired composition patent would not prevent approval.

505(b)(2) entry

A 505(b)(2) applicant could pursue a modified formulation, administration method, or presentation. This route may be relevant if the product differs materially from the reference injectable formulation.

Delayed or limited entry

Entry may remain delayed by:

Unexpired listed formulation or use patents.
Difficulty manufacturing the active ingredient.
High-cost sterile injectable production.
Limited oncology demand.
Need for reliable supply of a potent cytotoxic product.
Hospital formulary and contracting barriers.
Commercial concentration around a single manufacturer.

What licensing and commercial relationships affected romidepsin?

Fujisawa developed FR901228 before the product was later commercialized through successor and license relationships involving the romidepsin development program. The commercial history includes Fujisawa, Astellas, Gloucester Pharmaceuticals, and Celgene-related commercialization activities.

Licensing analysis should distinguish among:

Rights to the original compound.
Rights to clinical development.
Rights to manufacturing technology.
Rights to specific indications.
Rights to commercialize Istodax in particular territories.

The expired U.S. patent does not eliminate contractual restrictions in private licenses, but a license cannot extend the statutory exclusionary term of an expired patent against unrelated third parties.

What geographic protection did U.S. Patent 4,977,138 provide?

U.S. Patent 4,977,138 provided protection only under U.S. patent law. Foreign protection required separate national or regional patents.

The relevant geographic review should include:

Japan, where the originating research was conducted.
Europe, through applicable national or European patent filings.
Canada.
Australia.
South Korea.
China.
Other major oncology markets.

Expiration dates can differ because of national filing dates, patent-term rules, supplementary protection certificates, regulatory extensions, and prosecution history. The U.S. expiration date cannot be used as a proxy for worldwide freedom to operate.

Key Takeaways

U.S. Patent 4,977,138 claims FR901228, now known as romidepsin.
Claim 1 is a broad chemical composition-of-matter claim to the molecule shown in the patent.
Claim 2 covers pharmaceutical compositions containing FR901228 and a pharmaceutically acceptable carrier.
The patent does not expressly claim a cancer-treatment method, dose, route, formulation specification, or manufacturing process.
The patent expired in 2009 and is no longer an enforceable U.S. barrier.
FDA regulatory exclusivity was separate from the patent and applied for defined periods and indications.
Romidepsin is a small molecule, so biosimilar analysis is not applicable.
Current entry risk depends on later formulation, manufacturing, and method-of-use patents, together with sterile injectable manufacturing economics.
Any current freedom-to-operate conclusion requires review of the live Orange Book listings and later patent families, not the expired U.S. 4,977,138 alone.

FAQs About U.S. Patent 4,977,138 and Romidepsin

Is U.S. Patent 4,977,138 still enforceable?

No. The patent expired in 2009 under the applicable pre-1995 patent-term rules.

Does the patent cover Istodax by brand name?

The patent does not claim the brand name Istodax. Its claims cover the active compound FR901228 and pharmaceutical compositions containing that compound.

Does the patent cover romidepsin salts?

Not automatically. A salt or derivative must be evaluated against the precise structural scope of the compound claim. A chemically distinct derivative is not necessarily the claimed FR901228 substance.

Can a generic company sell romidepsin after the patent expiration?

The expired patent does not prevent sale. A generic applicant must still satisfy FDA approval requirements and avoid any unexpired formulation, process, or method-of-use patents.

Does romidepsin qualify for a biosimilar application?

No. Romidepsin is a small-molecule drug. The relevant regulatory pathways are an ANDA or, where appropriate, a 505(b)(2) application.

References

U.S. Patent No. 4,977,138. (1990). FR901228 substance. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2009). Istodax (romidepsin) prescribing information. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs database. FDA.
National Library of Medicine. (2024). Romidepsin: PubChem compound summary. PubChem.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8817743	Jul 26, 1988

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	94561	⤷ Start Trial
Australia	3829089	⤷ Start Trial
Canada	1335083	⤷ Start Trial
China	1040054	⤷ Start Trial
Germany	68909139	⤷ Start Trial
Denmark	366889	⤷ Start Trial
European Patent Office	0352646	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,977,138

Summary for Patent: 4,977,138