United States Patent 5,635,517: Scope, Claims, Expiration, and Patent Landscape for Lenalidomide and Pomalidomide

U.S. Patent No. 5,635,517 is a foundational Celgene patent covering amino-substituted isoindolinone and isoindoline-dione compounds related to lenalidomide and pomalidomide. It includes method claims for reducing tumor necrosis factor alpha, or TNFα, and one composition claim directed to four mono-oxo amino compounds. The patent issued June 3, 1997, and its 17-year pre-URAA term expired June 3, 2014.[1]

The most commercially important covered compounds are:

Lenalidomide, corresponding to the 4-amino mono-oxo compound in claim 4.
Pomalidomide, corresponding to the 4-amino dioxo compound in claim 8 for method-of-treatment purposes.

The patent no longer creates an enforceable U.S. exclusionary right. Later patents covering specific indications, formulations, dosing schedules, manufacturing processes, and regulatory-use restrictions became more important to generic-entry analysis.

What does U.S. Patent 5,635,517 cover?

The patent covers a chemical class built around an isoindoline or isoindoline-dione core linked to a 2,6-dioxopiperidin-3-yl group. The claims distinguish the compounds by the oxidation state of the fused aromatic nitrogen-containing ring.

Claim group	Structural limitation	Principal legal subject matter
Claim 1	One ring position is C=O and the other is C=O or CH2	Method of reducing undesirable TNFα
Claims 2-6	X=C=O and Y=CH2	Methods using four amino-substituted mono-oxo compounds
Claims 7-9	X=Y=C=O	Methods using amino-substituted dioxo compounds
Claim 10	Four specified mono-oxo amino compounds	Composition claim

The claim set has two distinct protection layers:

Therapeutic-use protection for reducing TNFα.
Product protection for four specified mono-oxo compounds.

The patent does not provide a standalone composition claim for the dioxo compounds in claims 8 and 9. Those compounds are claimed only through methods of reducing TNFα.

Which commercial drugs correspond to Patent 5,635,517?

Lenalidomide and claim 4

Lenalidomide is the 4-amino mono-oxo compound:

3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione.

That structure corresponds to claim 4:

1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline.

Lenalidomide was commercialized by Celgene as Revlimid. The FDA approved Revlimid in combination with dexamethasone for multiple myeloma in 2006 and later approved it for several hematologic indications, including transfusion-dependent anemia associated with low- or intermediate-1-risk myelodysplastic syndromes with a 5q deletion.[2]

Pomalidomide and claim 8

Pomalidomide is the 4-amino dioxo compound:

4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

That structure corresponds to the compound identified in claim 8:

1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline.

Pomalidomide was commercialized by Celgene as Pomalyst. The FDA approved Pomalyst in 2013 for multiple myeloma after at least two prior therapies, including lenalidomide and bortezomib, followed by disease progression.[3]

Commercial relevance of the remaining compounds

Claims 3, 5, and 6 cover positional mono-oxo amino isomers. The patent does not establish that those compounds became approved products. Their inclusion broadens the original chemical and pharmacological disclosure, but their commercial value is materially lower than the claims corresponding to lenalidomide and pomalidomide.

How are the claims structured?

Claim 1: Broad TNFα method claim

Claim 1 covers administering an effective amount of a compound within the stated structural formula to a mammal to reduce undesirable TNFα levels.

Its important limitations are:

The use must be therapeutic or pharmacological.
The target is undesirable TNFα.
The subject is a mammal.
The administered compound must fall within the defined X/Y oxidation-state relationship.
The dose must be an effective amount.

The claim is not a general claim to every use of the compounds. It is limited to reducing undesirable TNFα. A claim-construction dispute would likely focus on the meaning of “reducing,” “undesirable levels,” and “effective amount,” as well as whether the accused compound falls within the chemical formula.

Claims 2-6: Mono-oxo amino compounds

Claim 2 narrows claim 1 by requiring X to be C=O and Y to be CH2. Claims 3 through 6 then identify the amino substitution position:

Claim	Covered compound
3	5-amino mono-oxo isoindoline
4	4-amino mono-oxo isoindoline, lenalidomide
5	6-amino mono-oxo isoindoline
6	7-amino mono-oxo isoindoline

Claim 4 is the key commercial claim for lenalidomide. Because claim 10 separately recites the four compounds as compositions, the patent contains both method and product protection for the mono-oxo isomer set.

Claims 7-9: Dioxo compounds

Claim 7 requires both X and Y to be C=O. Claims 8 and 9 specify the 4-amino and 5-amino dioxo isomers.

Claim 8 is commercially significant because it corresponds to pomalidomide. Its protection is narrower than a composition claim because it requires use of the compound in the claimed TNFα-reduction method.

Claim 10: Composition claim

Claim 10 covers the following four compounds as a group:

1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline
1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline
1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline
1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline

This is a product claim rather than a treatment claim. It does not require proof of TNFα reduction. An accused product containing one of the listed compounds would fall within the literal scope of claim 10, subject to claim construction and other infringement requirements.

When did Patent 5,635,517 expire?

The patent issued June 3, 1997. Because its underlying application was filed before the Uruguay Round Agreements Act patent-term transition, its term was generally 17 years from issuance rather than 20 years from the earliest effective nonprovisional filing date.[1]

Event	Date
Patent issuance	June 3, 1997
Statutory term basis	17 years from issuance
Scheduled expiration	June 3, 2014
Current status	Expired

No current U.S. exclusivity should be attributed to Patent 5,635,517. A later patent, regulatory exclusivity period, settlement term, or restricted distribution arrangement could have delayed actual generic commercialization, but those mechanisms did not extend the enforceable term of this patent itself.

What was the Orange Book status of Patent 5,635,517?

The Orange Book analysis must distinguish patent listing from current enforceability.

A patent may appear in historical FDA listing data for an approved product even after its patent term has expired. Listing does not extend patent life. For Revlimid and Pomalyst, the relevant commercial protection shifted over time from foundational compound patents to later patents covering:

Specific therapeutic indications.
Dosing schedules.
Combination therapies.
Formulations.
Risk-management and distribution procedures.
Methods of treating multiple myeloma or myelodysplastic syndromes.

The FDA Orange Book identifies patents and exclusivity associated with approved small-molecule products, but it is not a complete register of every patent that may affect commercial launch. Patents outside the Orange Book, including process patents and certain method-of-use patents, can remain relevant.[4]

What exclusivity did Revlimid and Pomalyst receive?

Patent expiry and FDA regulatory exclusivity were separate constraints.

Revlimid

Revlimid received orphan-drug and other regulatory protections tied to particular indications. FDA exclusivity applied by indication and approval date, not as a permanent product-wide monopoly. The principal commercial barrier after Patent 5,635,517 expired was the later patent estate and Celgene’s agreements with generic applicants, not the expired foundational patent.[2]

Pomalyst

Pomalyst received FDA orphan-drug exclusivity associated with its multiple myeloma indication. That exclusivity restricted approval of the same drug for the same orphan indication for a defined period, but it did not prevent all competing products or all uses. Later patents and regulatory protections were more relevant to commercial timing.[3]

Which later patents mattered to lenalidomide and pomalidomide?

The post-1997 landscape generally divided into five categories.

Later compound and pharmaceutical-composition patents

Later patents addressed specific compounds, stereochemical forms, salts, pharmaceutical compositions, and related analogs. These patents could overlap commercially with the original patent while having different claim scope and expiration dates.

Method-of-use patents

Celgene and related entities obtained patents directed to:

Multiple myeloma treatment.
Myelodysplastic syndromes.
Mantle-cell lymphoma and other hematologic cancers.
Combination treatment with dexamethasone or other agents.
Maintenance treatment.
Relapsed or refractory disease.
Specific patient populations.

A generic applicant could avoid some method-of-use claims through a skinny-label strategy under the FDA’s section viii pathway, but that strategy did not eliminate exposure to composition claims or non-carved-out indications.[5]

Formulation and dosage-regimen patents

Later patents addressed:

Oral capsule formulations.
Specific dose strengths.
Administration schedules.
Treatment cycles.
Reduced-dose regimens.
Combination regimens.
Patient-management protocols.

These claims were commercially relevant because lenalidomide and pomalidomide are administered orally and marketed in multiple strengths. A generic launch could avoid certain method claims by carving out protected uses, but formulation or product claims could be harder to avoid.

Risk-management and distribution patents

Celgene’s restricted-distribution systems, including the RevAssist and Pomalyst REMS programs, became part of the market-access framework. A REMS program is not itself a patent right, but patents could cover aspects of controlled distribution, patient authorization, or administration procedures. FDA approval of a generic product depends on compliance with applicable REMS requirements, not ownership of Celgene’s commercial system.[6]

Manufacturing and process patents

Process patents can protect intermediates, reaction sequences, purification procedures, and solid-state forms. These rights may affect supply economics even when the active ingredient composition patent has expired. A generic manufacturer can reduce risk by using an independent process, obtaining a license, or challenging the asserted process patent.

What Paragraph IV challenges affected the market?

Generic lenalidomide applicants filed ANDAs with Paragraph IV certifications against listed patents. These challenges generated litigation involving Celgene and generic manufacturers, including Natco, Teva, Mylan, and other applicants.

The strategic outcome was a series of settlements and launch arrangements that allowed generic entry on negotiated dates, often before complete expiry of every later-listed patent. The settlements were commercially important because they controlled the timing and scale of generic supply even after the foundational Patent 5,635,517 expired.

The principal legal points are:

Patent 5,635,517 itself could no longer block launch after June 3, 2014.
Later listed patents could support infringement litigation.
A Paragraph IV certification could trigger a 30-month FDA approval stay under the Hatch-Waxman framework, subject to statutory conditions.[5]
Settlement terms could provide delayed entry, limited-volume entry, or authorized-generic arrangements.
A generic applicant could use section viii statements to omit protected indications where permitted.

For pomalidomide, the market was protected by a later product-specific patent and regulatory estate associated with Pomalyst. Patent 5,635,517 was historically relevant but was not the principal long-term barrier once it expired.

How strong was the patent estate for lenalidomide?

The original patent was strong during its term because claim 10 directly covered the lenalidomide compound and claims 1 and 2-6 covered therapeutic uses of the disclosed isomer class. The combination of composition and method claims reduced design-around options during the patent term.

Its present strength is zero as an enforceable patent because it expired. The continuing strength of the broader lenalidomide estate depended on later patents, including indication, regimen, formulation, and manufacturing rights.

Factor	Assessment
Historical compound coverage	Strong for the listed mono-oxo isomers
Historical use coverage	Broad within the TNFα-reduction limitation
Lenalidomide relevance	Direct, through claim 4 and claim 10
Current enforceability	None for this patent
Design-around opportunity during term	Limited for lenalidomide itself
Post-expiry commercial relevance	Background only; later patents control

How does Patent 5,635,517 compare with later lenalidomide patents?

Issue	Patent 5,635,517	Later lenalidomide patents
Primary focus	Foundational compound and TNFα method	Indications, dosing, formulation, manufacturing
Lenalidomide coverage	Direct	Often narrower or use-specific
Pomalidomide coverage	Method claim through claim 8	Product-specific and indication-specific rights
Expiration	June 3, 2014	Varied by patent and term adjustment
Orange Book impact	Historical	More important to later generic-entry timing
Paragraph IV relevance	Historical litigation target	Main post-2014 litigation exposure
Current blocking power	None	Depends on individual patent status

What generic-entry risks remain after expiry?

After expiry of Patent 5,635,517, the principal risks were:

Later composition patents covering the same active ingredient or pharmaceutical form.
Method-of-use patents covering commercially important indications.
Formulation or dosage-regimen patents.
REMS implementation and distribution requirements.
Manufacturing-process patents.
Settlement restrictions agreed with Celgene.
Patent-listing and 30-month-stay consequences under Hatch-Waxman.
Commercial supply limitations for controlled or restricted products.

For lenalidomide, generic entry eventually occurred through negotiated arrangements and staged launches. For pomalidomide, the later product-specific estate and orphan-drug framework created a different entry timeline.

Does Patent 5,635,517 create biosimilar risk?

No. Lenalidomide and pomalidomide are chemically synthesized small molecules, not biologics. The relevant competitors are generic manufacturers filing ANDAs, not biosimilar applicants filing under the Biologics Price Competition and Innovation Act.

The principal regulatory pathway is the Hatch-Waxman ANDA process. Generic applicants must demonstrate pharmaceutical equivalence and bioequivalence, comply with labeling requirements, and address listed patents through Paragraph IV certifications or section viii statements.[5]

Key Takeaways

U.S. Patent 5,635,517 is a foundational Celgene patent for amino-substituted isoindolinone and isoindoline-dione compounds.
Claim 4 and claim 10 directly cover lenalidomide as the 4-amino mono-oxo compound.
Claim 8 covers the pomalidomide structure as a TNFα-reduction method, but the patent does not claim pomalidomide as a standalone composition.
The patent issued June 3, 1997, and expired June 3, 2014.
It has no current blocking power in the United States.
Later patents covering indications, formulations, dosing regimens, manufacturing, and distribution controlled much of the post-2014 market-access analysis.
Generic competition proceeded through ANDA litigation, Paragraph IV certifications, settlements, and negotiated launch arrangements.
Biosimilar analysis is not applicable because lenalidomide and pomalidomide are small-molecule drugs.

FAQs

Is lenalidomide covered by U.S. Patent 5,635,517?

Yes. Lenalidomide corresponds to the 4-amino mono-oxo compound identified in claim 4 and is also within the composition group in claim 10.

Is pomalidomide claimed as a compound in Patent 5,635,517?

No. The pomalidomide structure corresponds to claim 8, which is a method claim requiring use to reduce TNFα. Claim 10 covers only the four mono-oxo compounds and does not include the dioxo pomalidomide structure.

Can an expired patent still appear in the Orange Book?

Yes. Historical listing data may include an expired patent. Orange Book listing does not extend the patent term or restore enforceability.

Did Patent 5,635,517 prevent generic lenalidomide after 2014?

No. The patent expired June 3, 2014. Later patents, FDA exclusivity, Paragraph IV litigation, settlement agreements, and REMS requirements determined the practical timing of generic entry.

Are generic lenalidomide applicants biosimilar applicants?

No. Lenalidomide is a small molecule. Applicants use the ANDA pathway, with Paragraph IV certifications and section viii statements where applicable.

References

United States Patent and Trademark Office. (1997). U.S. Patent No. 5,635,517: Methods of reducing levels of TNF-alpha.
U.S. Food and Drug Administration. (2023). Revlimid (lenalidomide) prescribing information.
U.S. Food and Drug Administration. (2023). Pomalyst (pomalidomide) prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
U.S. Food and Drug Administration. (2024). Abbreviated new drug application submissions: Patent certifications and approval requirements.
U.S. Food and Drug Administration. (2024). Risk evaluation and mitigation strategies.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0925294	⤷ Start Trial	91359	Luxembourg	⤷ Start Trial
European Patent Office	0925294	⤷ Start Trial	CA 2007 00054	Denmark	⤷ Start Trial
European Patent Office	0925294	⤷ Start Trial	07C0056	France	⤷ Start Trial
European Patent Office	0925294	⤷ Start Trial	SPC033/2007	Ireland	⤷ Start Trial
European Patent Office	0925294	⤷ Start Trial	SPC/GB07/047	United Kingdom	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,635,517

Summary for Patent: 5,635,517