US Patent 7,611,724: FR901228 Type A Crystal, Claim Scope, Expiration and Generic Risk

US Patent 7,611,724 protects a specific crystalline form of FR901228, the active ingredient romidepsin, rather than the molecule broadly. Its core protection covers the Type A polymorph, selected powder X-ray diffraction characteristics, and compositions containing that polymorph. The patent does not, by its claims, cover every form of romidepsin, every formulation, or every therapeutic use.

The patent was commercially relevant to Istodax, the intravenous romidepsin product marketed by Celgene and later Bristol Myers Squibb. Its principal US patent term reached the mid-2020s. FDA regulatory exclusivity expired substantially earlier, leaving the patent estate as the principal US exclusivity barrier after approval.

What does US Patent 7,611,724 cover?

US 7,611,724 covers crystalline romidepsin identified as Type A. The claims rely primarily on the physical identity of the solid form and its powder X-ray diffraction, or PXRD, pattern.

Item	Details
US patent	7,611,724
Title	Crystalline forms of FR901228
Active compound	FR901228, also known as romidepsin
Therapeutic class	Histone deacetylase inhibitor
Drug product	Istodax
Technology	Crystalline API polymorph
Core form	Type A crystalline form
Key analytical method	Powder X-ray diffraction
Priority period	May 2004 public patent-family records
US grant date	November 3, 2009
Principal commercial sponsor	Gloucester Pharmaceuticals, later acquired by Celgene
Current commercial rights	Bristol Myers Squibb acquired Celgene in 2019
US patent-term period	Mid-2020s, subject to the patent’s recorded term adjustment
FDA approval of Istodax	2009

The patent is a solid-form patent. It does not claim the chemical structure of romidepsin itself. A party could avoid literal infringement by producing a different crystalline form, an amorphous form, or a liquid formulation, provided the resulting product did not contain the claimed Type A form or satisfy the relevant composition limitations.

What are the independent and dependent claims?

The supplied claims contain three meaningful claim groups.

Claim 1: Type A crystalline romidepsin

Claim 1 recites:

A type A crystalline form of compound FR901228.

This is the principal product claim. It does not require a particular manufacturing process, solvent, dosage form, purity level, particle size, or therapeutic use.

The claim is therefore broad within the Type A polymorph. A product may infringe if the Type A crystalline form is present as the claimed material, even if the manufacturer uses a different crystallization process from the patent examples.

The scope depends on how “Type A” is construed. The patent specification and figures would be used to identify the characteristic PXRD pattern and distinguish Type A from other romidepsin forms.

Claims 2 and 8: solvent-based preparation limitations

Claims 2 and 8 depend from claim 1:

Claim 2 covers Type A romidepsin obtained from an ethanol/water mixture.
Claim 8 covers Type A romidepsin obtained from an acetone/water mixture.

These are narrower than claim 1. They introduce a process history into a product claim. The legal effect depends on claim construction and the extent to which the “obtained from” language is treated as limiting.

A manufacturer that produces Type A romidepsin using a different solvent system may still face claim 1. It would have a stronger noninfringement position against claims 2 and 8 if it can establish that its process does not use ethanol/water or acetone/water as the relevant crystallization mixture.

The solvent claims also provide process-specific fallback protection. They could be useful where an ANDA applicant discloses a solvent system corresponding to one of the claimed routes.

Claim 3: PXRD-defined crystalline form

Claim 3 covers a crystalline form of FR901228 characterized by a PXRD pattern substantially similar to Figure 3.

This claim is functionally directed to the same Type A solid form but uses the figure as the principal structural identifier. “Substantially similar” allows for ordinary analytical variation caused by instrumentation, sample preparation, crystallite size, preferred orientation, and measurement conditions.

The claim does not appear limited to a particular solvent of crystallization. It could therefore reach Type A material made through routes other than the solvent systems recited in claims 2 and 8.

Claims 4 through 7: compositions containing Type A material

Claim 4 covers:

A composition comprising a type A crystalline form of compound FR901228.

The composition must have at least one PXRD peak selected from approximately:

9.6 degrees 2-theta;
13.6 degrees 2-theta;
14.6 degrees 2-theta; and
17.4 degrees 2-theta.

Claims 5, 6, and 7 progressively increase the required number of peaks:

Claim	Minimum selected PXRD peaks
Claim 4	One
Claim 5	Two
Claim 6	Three
Claim 7	Four

Claim 7 is the narrowest of this group because it requires all four listed peaks.

The word “comprising” makes claim 4 open-ended. A composition may contain excipients, residual solvent, other romidepsin forms, impurities, or additional ingredients and still fall within the claim if it contains Type A romidepsin and satisfies the PXRD limitation.

Claim 9: Figure 4 composition

Claim 9 depends from claim 4 and requires a PXRD pattern substantially similar to Figure 4.

The relationship between Figures 3 and 4 is important. Figure 3 appears to identify the crystalline form itself, while Figure 4 is used in the composition claims. The distinction may relate to sample preparation, formulation, polymorph content, or a particular composition profile. In litigation, the patent specification, expert PXRD analysis, and reference samples would determine whether the two figures define materially different analytical requirements.

How broad is the Type A crystalline-form protection?

The strongest claim is claim 1 because it is not tied to a particular solvent or composition. Its scope turns on whether the accused material is Type A romidepsin.

The claims can be ranked as follows:

Protection tier	Claims	Commercial significance
Broad product-form protection	1	Covers Type A romidepsin regardless of disclosed preparation route
PXRD product protection	3	Covers a form substantially similar to Figure 3
Composition protection	4	Covers compositions containing Type A material with at least one listed peak
Narrower composition protection	5-7	Requires two, three, or four listed peaks
Solvent-specific protection	2 and 8	Targets Type A material obtained from specified solvent mixtures
Figure-defined composition	9	Covers a composition with a pattern substantially similar to Figure 4

The patent is most commercially relevant if the marketed API is Type A and if generic manufacturers use the same solid form for stability, yield, solubility, or manufacturing reasons.

What technical features identify Type A romidepsin?

The claims use PXRD as the principal fingerprint. The listed reflections are approximately 9.6, 13.6, 14.6, and 17.4 degrees 2-theta.

PXRD identification is not based on a single peak in ordinary solid-form analysis. A single peak may occur because of preferred orientation, mixtures, impurities, or analytical noise. Claims 5 through 7 strengthen the identification by requiring multiple peaks.

The key technical issues are:

Whether “about” permits the accused peak to deviate from the stated 2-theta value.
Whether the accused sample has one or more additional polymorphs.
Whether the test method uses comparable radiation, scan rate, range, and sample preparation.
Whether the accused product is Type A throughout the batch or only contains a measurable fraction.
Whether amorphous material or another polymorph dilutes the claimed PXRD peaks.
Whether the PXRD pattern is “substantially similar” to the relevant figure.

A generic manufacturer could attempt to design around the patent by selecting a non-Type A polymorph. That approach would require confirmation that the alternative form is stable, manufacturable, bioequivalent, and suitable for the approved intravenous product.

What validity challenges could affect US 7,611,724?

Anticipation

An anticipation challenge would require a single prior-art reference to disclose the claimed Type A form or the claimed PXRD characteristics. A reference describing only romidepsin chemically, without the Type A crystal structure or corresponding PXRD pattern, would generally not anticipate the solid-form claims.

The most relevant prior art would include:

Earlier disclosures of isolated romidepsin;
Crystallization studies;
Regulatory or manufacturing documents;
Patent applications describing romidepsin solid forms;
Public samples of the Type A material;
Prior PXRD data containing the claimed reflections.

Obviousness

Obviousness is the more likely validity theory for a pharmaceutical polymorph patent. The analysis would examine whether a skilled person would have had a reasonable expectation of obtaining Type A romidepsin and whether the form had unexpected properties.

Relevant evidence could include:

Routine crystallization screening;
Predictability of romidepsin solid forms;
The number of solvents and conditions tested;
Unexpected stability or handling characteristics;
Superior purity, yield, hygroscopicity, dissolution, or storage performance;
Failure of others to identify the form;
Whether the claimed PXRD peaks merely describe a form that routine experimentation would produce.

A polymorph claim is stronger where the specification demonstrates a meaningful technical advantage. It is weaker where the claimed form is an arbitrary crystallization result without evidence of unexpected properties.

Indefiniteness and written description

The terms “type A,” “about,” and “substantially similar” could be challenged if the specification does not provide adequate objective boundaries.

The patent’s figures, PXRD tables, preparation examples, and characterization data would be central. A court could construe “about” as allowing normal analytical variation rather than unlimited deviation. “Substantially similar” would likely be assessed against the disclosed pattern and accepted PXRD practice.

The composition claims may face written-description or scope challenges if the specification supports only a limited sample or a narrow formulation but the claims reach a broad range of compositions.

What is the FDA and Orange Book status of romidepsin?

FDA approved Istodax in 2009 for relapsed or refractory cutaneous T-cell lymphoma and later approved it for peripheral T-cell lymphoma. The product is administered intravenously and contains romidepsin as the active ingredient. FDA’s approved labeling identifies the product, dosage form, strength, indications, preparation, and storage requirements. [1]

Romidepsin received orphan-drug exclusivity associated with its approved indications. That regulatory exclusivity expired before the principal solid-form patent term. Orphan exclusivity blocked approval of certain competing products for the same orphan indication but did not prevent all pharmaceutical development or protect the crystalline form as a patent would.

The Orange Book is the controlling source for current listed patents and exclusivity codes. Patent 7,611,724 has been associated with the Istodax patent estate in public FDA and patent databases. The patent’s remaining enforceability depends on the recorded expiration date, any patent-term adjustment, terminal disclaimer, maintenance-fee history, and later legal events. [2]

When does US 7,611,724 lose exclusivity?

The patent’s ordinary term is calculated under 35 U.S.C. § 154 from the applicable earliest nonprovisional or international filing date, subject to patent-term adjustment. The family priority date is in May 2004, and the ordinary term therefore reaches the mid-2020s rather than the 2009 FDA approval date.

The relevant timeline is:

Event	Date
Priority period	May 2004
US patent application/publication period	2005-2007 public records
FDA approval of Istodax	2009
US patent grant	November 3, 2009
Orphan exclusivity	Expired before the patent term
Expected ordinary patent-term endpoint	Approximately May 2025, subject to recorded PTA
Post-expiration status	No ordinary patent exclusivity under this patent after the effective expiration date

The exact enforceable endpoint should be taken from the USPTO front-page patent-term calculation and the current Orange Book listing, not inferred solely from the grant date. [2, 3]

Are there Paragraph IV challenges to romidepsin?

A Paragraph IV challenge would allege that a listed patent is invalid, unenforceable, or not infringed. For this patent, the most direct ANDA theories would involve:

Noninfringement based on a different romidepsin polymorph;
A PXRD pattern outside the claimed ranges;
A process that does not use ethanol/water or acetone/water;
Lack of Type A material in the finished drug product;
Invalidity based on obviousness or anticipation;
Failure of the listed patent to cover the proposed generic product.

A generic applicant’s certification strategy would depend on the Orange Book listing and the ANDA’s formulation and manufacturing disclosures. If the patent term has expired, a Paragraph IV certification would no longer be the principal route for market entry against that patent. A generic applicant could instead pursue approval subject to other listed patents, regulatory requirements, and any separate litigation.

Public information should distinguish between an actual Paragraph IV filing, a patent certification reported in an ANDA context, and a commercial statement that a generic company is developing romidepsin. Those events have different legal effects.

What patent litigation and settlements affect romidepsin?

The supplied record does not identify a specific complaint, consent judgment, or settlement agreement involving US 7,611,724. The principal litigation risk historically would have been an ANDA case brought after a Paragraph IV notice.

A complete litigation assessment should cover:

District court complaints under the Hatch-Waxman statute;
Declaratory-judgment actions;
Preliminary injunction proceedings;
Claim-construction orders;
Invalidity and noninfringement judgments;
Federal Circuit appeals;
Licensed launch dates;
Authorized-generic arrangements;
Confidential or public settlement terms.

The patent’s expiration materially reduces the value of any late-stage settlement. Before expiration, a settlement could have allocated a generic entry date. After expiration, the commercial focus shifts to FDA approval timing, manufacturing readiness, pricing, and any unexpired formulation or method-of-use patents.

Does romidepsin face biosimilar risk?

No. Romidepsin is a synthetic small-molecule drug, not a biologic. The relevant competitive pathway is an abbreviated new drug application, or ANDA, rather than a biosimilar application under the Public Health Service Act.

The main technical barrier is therefore pharmaceutical equivalence and bioequivalence, combined with solid-form, formulation, manufacturing, and patent issues. A competing applicant does not need to reproduce the innovator’s exact production route if it can produce an equivalent approved drug without infringing an enforceable patent.

What formulation and method-of-use patents protect Istodax?

US 7,611,724 is directed to the crystalline API. It does not claim:

A specific vial or container;
A defined excipient system;
A particular reconstitution protocol;
A specific infusion duration;
A combination therapy;
A dosing schedule;
A lymphoma treatment method.

Those subjects may be covered by separate patents or regulatory exclusivities. They must be analyzed independently from the Type A crystal patent. A generic applicant could avoid 7,611,724 yet remain exposed to a separate formulation or method-of-use patent listed for Istodax.

The approved-label indications may also create skinny-label issues. If a patent covers only a method of use and the generic label omits that use, the patent analysis differs from a solid-form patent that covers the drug substance itself.

How strong is the patent estate for romidepsin?

The estate is strongest against a generic that uses Type A romidepsin as its API. Claim 1 creates the principal risk because it is not restricted to the disclosed solvents. Claims 4 through 7 create additional composition-based positions, but their enforceability depends on PXRD testing and on the amount and distribution of Type A material in the product.

The estate is weaker against:

A demonstrably different polymorph;
An amorphous or noncrystalline API;
A product with no Type A material;
A manufacturing process outside the solvent limitations;
A product launched after patent expiration;
A challenge supported by prior-art crystallization or PXRD evidence.

The patent’s commercial value is also limited by the absence of molecule-wide protection in the claims. Once an alternative form is technically and legally available, the crystal patent does not prevent development of that alternative.

What generic launch scenarios exist?

Launch after patent expiration

This is the lowest litigation-risk scenario for 7,611,724. The applicant must still satisfy FDA requirements and address any other unexpired listed patents or regulatory barriers.

Paragraph IV launch before expiration

The applicant could challenge the patent and launch at risk if it obtains approval and accepts litigation exposure. The principal defenses would be non-Type A material, noninfringement of the PXRD claims, or invalidity.

Polymorph design-around

A manufacturer could use another crystalline form or amorphous romidepsin. This approach requires robust characterization and controls because form conversion during storage, milling, formulation, or reconstitution could recreate Type A material.

Authorized or licensed launch

The sponsor could permit entry under a license or settlement. The commercial value of this route depends on the remaining patent term and whether the agreement covers API, finished product, territories, and other patent families.

How does the patent compare with molecule and use patents?

Patent type	What it protects	Relevance to romidepsin
Composition-of-matter patent	Chemical structure	Broadest protection, normally earliest expiry
Crystalline-form patent	Specific polymorph	Protects a selected solid form
Formulation patent	Drug product composition or delivery	Targets finished dosage form
Method-of-use patent	Treatment, dosing, or combination	May support indication-specific protection
Manufacturing patent	Process or intermediate	Can restrict API production routes
Regulatory exclusivity	FDA approval rights	Separate from patent infringement

US 7,611,724 is narrower than a composition-of-matter patent but can be commercially effective because generic applicants commonly use the same stable API form as the reference product.

Key Takeaways

US 7,611,724 protects Type A crystalline romidepsin, not romidepsin in every physical or chemical form.
Claim 1 is the central product claim and is not limited to ethanol/water or acetone/water production.
Claim 3 uses a PXRD pattern substantially similar to Figure 3 to define the crystalline form.
Claims 4 through 7 cover compositions containing Type A material and require one to four specified PXRD peaks.
Claims 2 and 8 add solvent-specific limitations and are narrower than claim 1.
Claim 9 adds a Figure 4 PXRD limitation to the composition claims.
The patent is a small-molecule solid-form patent, so biosimilar analysis does not apply.
The ordinary US patent term reached the mid-2020s, subject to the recorded patent-term adjustment.
Generic risk depends on the applicant’s selected polymorph, PXRD data, manufacturing route, ANDA certification, and any separate Istodax patents.
A non-Type A form may provide a design-around, but form conversion and contamination risks require process and stability controls.

FAQs

Can a generic use romidepsin without infringing US 7,611,724?

Yes, potentially. A generic may avoid infringement if its API is not Type A and does not satisfy the claimed PXRD or composition limitations, subject to other patents and FDA requirements.

Does claim 1 require the use of ethanol or acetone?

No. Claim 1 does not recite a solvent. Ethanol/water and acetone/water appear in dependent claims 2 and 8.

Can a mixture of romidepsin polymorphs infringe the patent?

Yes. The composition claims use “comprising” and may cover a composition containing Type A material even if other forms are present, provided the claimed PXRD limitations are met.

Is a different PXRD peak position automatically outside the claims?

No. The claims use “about” and “substantially similar.” Ordinary analytical variation may remain within scope. The full pattern and testing conditions would control.

Does FDA approval of Istodax extend the crystal patent term?

No. FDA approval and patent term are separate. Regulatory exclusivity may delay approval of a competing product, but it does not extend the patent beyond the legally calculated patent term.

References

U.S. Food and Drug Administration. (n.d.). Istodax (romidepsin) prescribing information. FDA.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book. FDA.
United States Patent and Trademark Office. (2009). U.S. Patent No. 7,611,724: Crystalline forms of FR901228. U.S. Department of Commerce.
United States Code. (2023). 35 U.S.C. § 154: Contents and term of patent; provisional rights.
United States Code. (2023). 21 U.S.C. § 355: New drugs.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2000-265414	Sep 01, 2000

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	030714	⤷ Start Trial
Australia	8010901	⤷ Start Trial
European Patent Office	1313872	⤷ Start Trial
Japan	2004508049	⤷ Start Trial
World Intellectual Property Organization (WIPO)	0220817	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 7,611,724