Details for Patent: 7,465,800

« Back to Dashboard

Which drugs does patent 7,465,800 protect, and when does it expire?

Patent 7,465,800 protects REVLIMID and is included in one NDA.

This patent has two hundred and ninety-eight patent family members in forty countries.

Summary for Patent: 7,465,800

Title:	Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
Abstract:	Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione are disclosed. Compositions comprising the polymorphic forms, methods of making the polymorphic forms and methods of their use are also disclosed.
Inventor(s):	Markian S. Jaworsky, Roger Shen-Chu Chen, George W. Muller
Assignee:	Celgene Corp
Application Number:	US10/934,863
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,465,800
Patent Claim Types: see list of patent claims	Compound;

United States Patent 7,465,800: Lenalidomide Hemihydrate Claims, Expiration, Litigation, and Patent Landscape

US Patent 7,465,800 protects a specific crystalline hemihydrate of lenalidomide, not lenalidomide in every physical or chemical form. The patent covers the solid-state form identified as crystalline 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate, together with defined X-ray diffraction, thermal, infrared, Raman, and water-content characteristics. It was assigned to Celgene Corporation and issued on December 16, 2008. Based on its priority date and ordinary patent-term calculations, the patent has an expected expiration in April 2027, subject to any applicable patent-term adjustment or disclaimer recorded by the USPTO.[1]

The commercial relevance is substantial because the claimed compound is lenalidomide, the active ingredient in Revlimid. The principal legal risk for a generic manufacturer is whether its proposed lenalidomide drug substance contains the claimed crystalline hemihydrate, even if the ANDA product uses a different formulation, capsule, excipient system, or manufacturing route.

What does US Patent 7,465,800 protect?

US 7,465,800 protects a defined solid form of lenalidomide containing approximately one-half mole of water per mole of lenalidomide.

The independent claim is claim 1:

“Crystalline 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate.”

The claim has several material limitations:

Limitation	Scope
Chemical identity	Lenalidomide, identified by its chemical name
Physical state	Crystalline material
Hydration state	Hemihydrate
Solid form	A particular crystal form rather than amorphous or anhydrous lenalidomide

The patent does not, on its face, claim:

• Every polymorph of lenalidomide
• Anhydrous lenalidomide
• Amorphous lenalidomide
• Lenalidomide formulations generally
• Methods of treating multiple myeloma or other diseases
• Methods of manufacturing lenalidomide generally
• A capsule containing lenalidomide without the claimed crystalline form

The practical scope is therefore a drug-substance and solid-state claim. A product can infringe even if the finished dosage form is different, provided the active pharmaceutical ingredient supplied or used in the product is the claimed crystalline hemihydrate.

How do claims 1 through 14 differ?

Claims 2 through 14 narrow claim 1 by adding analytical or compositional limitations.

Claims	Added limitation	Commercial significance
1	Crystalline lenalidomide hemihydrate	Broadest claim in the patent
2	XRPD peaks at approximately 16, 22, and 27° 2θ	Identifies the crystal form by powder diffraction
3	Claim 2 plus an approximately 18° 2θ peak	Additional XRPD limitation
4	XRPD peaks at 15.8, 22.2, and 26.7° 2θ	More specific diffraction profile
5	Claim 4 plus an 18.2° 2θ peak	Narrower diffraction profile
6	XRPD pattern corresponding to Figures 6, 32, 33, and 34	Figure-based fingerprint limitation
7	DSC endotherm with a maximum at approximately 268°C	Thermal characterization
8	Claim 7 plus a dehydration endotherm	Confirms hydrated crystalline material
9	DSC pattern corresponding to Figures 9, 42, 43, and 44	Full thermal fingerprint
10	Approximately 0.46 to 0.59 moles of water per mole of lenalidomide	Quantitative hydration limitation
11	TGA weight loss of approximately 3.1% to 4.0% from 30°C to 175°C	Water-loss limitation
12	Infrared peaks at approximately 3513 and 1960 cm⁻¹	IR identification
13	IR spectrum corresponding to Figure 7	Full IR fingerprint
14	Raman spectrum corresponding to Figure 8	Raman identification

Claims 2 through 14 are dependent claims. They require the limitations of claim 1 and the additional limitation recited in the relevant dependent claim.

What is the strongest claim in US 7,465,800?

Claim 1 is the commercially important claim because it has the least number of express analytical limitations. It requires the accused material to be:

1. Lenalidomide;
2. Crystalline;
3. A hemihydrate; and
4. Within the claimed crystal-form definition.

Claims 2 through 14 may be easier to test analytically but are narrower. A generic manufacturer could attempt to avoid those claims by arguing that its material lacks a specified XRPD peak, DSC feature, IR peak, Raman pattern, or water-content range. That strategy would not necessarily avoid claim 1 if the material remains the same crystalline hemihydrate.

The central claim-construction issue is whether “crystalline ... hemihydrate” identifies a single solid form or encompasses a set of materially equivalent crystals within the hemihydrate form. The dependent analytical claims provide evidence of how the patentee characterized the claimed form, but they do not automatically import every dependent limitation into claim 1.

What analytical tests are relevant to infringement?

A solid-state infringement analysis would normally use multiple orthogonal tests rather than a single assay.

X-ray powder diffraction

XRPD is the principal technique for identifying the claimed crystalline form. The relevant peaks include:

• Approximately 15.8° 2θ
• Approximately 18.2° 2θ
• Approximately 22.2° 2θ
• Approximately 26.7° 2θ

Peak position can vary with instrument calibration, sample preparation, crystallinity, particle orientation, and test conditions. The claim language uses both approximate values and representative patterns. Litigation would likely focus on the degree of permissible variation and whether the accused material has the same characteristic diffraction pattern.

Differential scanning calorimetry

The claimed material has a DSC endotherm with a maximum at approximately 268°C. A separate dehydration event may support the hemihydrate characterization.

DSC results can shift with heating rate, sample mass, pan configuration, atmosphere, and instrument calibration. A single thermal event would not necessarily establish the full claimed identity without corroboration from XRPD and water-content testing.

Thermogravimetric analysis

Claim 11 recites a 3.1% to 4.0% weight loss when heated from approximately 30°C to 175°C. The theoretical water content of a one-half hydrate is consistent with a low-single-digit percentage mass loss. TGA is therefore relevant to distinguishing the claimed hemihydrate from an anhydrous form.

Infrared and Raman spectroscopy

Claims 12 through 14 add spectroscopic fingerprints. These claims are narrower than claim 1, but the spectra can support a broader solid-form identification. Raman testing is particularly useful when XRPD patterns are affected by crystallinity, particle size, or sample morphology.

When does US Patent 7,465,800 lose exclusivity?

The expected patent expiration is in April 2027, based on the patent’s April 2004 priority date and the standard 20-year term measured from the applicable nonprovisional filing date.[1] The exact enforceable date should be determined from the USPTO patent record, including any patent-term adjustment, terminal disclaimer, or other recorded term event.

The patent’s expiration is separate from other Revlimid exclusivity periods:

Protection category	Relevance to lenalidomide
US 7,465,800	Crystalline lenalidomide hemihydrate
Compound patents	Broad chemical subject matter for lenalidomide
Method-of-use patents	Multiple myeloma, myelodysplastic syndromes, mantle cell lymphoma, and related uses
FDA orphan exclusivity	Disease-specific regulatory exclusivity, separate from patent term
Pediatric exclusivity	May extend certain listed patents by six months
Regulatory exclusivity	Depends on the specific FDA approval and supplement

The 2027 date does not mean that every patent or regulatory restriction on Revlimid lasts until 2027. It means that this particular solid-form patent can remain a barrier if it is valid, enforceable, and listed or otherwise relevant to the proposed product.

What is the Orange Book status of US 7,465,800?

Revlimid is an FDA-approved small-molecule product, so the relevant abbreviated-approval pathway is an ANDA, not a biosimilar application. FDA Orange Book listings identify patents submitted by the NDA holder and contain patent numbers, expiration information, and, where applicable, use codes.[2]

A listed drug-substance or product patent can trigger a Paragraph IV certification by an ANDA applicant. The legal consequences depend on:

• Whether the patent was listed for the relevant NDA;
• Whether the ANDA applicant certifies that the patent is invalid, unenforceable, or not infringed;
• Whether the NDA holder files an infringement action within the statutory period;
• Whether the patent claims the drug substance, formulation, method of use, or another product attribute.

A crystalline solid-form patent may be relevant to an ANDA even where the applicant uses a different capsule formulation. FDA approval and patent clearance are separate determinations. FDA does not decide infringement as part of ordinary ANDA review.

Which companies have challenged Revlimid patent protection?

Celgene faced generic challenges to Revlimid patents from multiple ANDA applicants, including companies such as Natco Pharma, Teva, Mylan, Dr. Reddy’s Laboratories, Sandoz, and other generic manufacturers. The challenges involved different patents and claim categories, including chemical, method-of-use, and solid-form patents.

Natco was a major participant in the Revlimid generic challenge landscape through its relationship with Celgene and later commercial arrangements. Other manufacturers entered settlement or license arrangements that permitted limited or staged generic access before complete patent expiration.[3][4]

The existence of a Paragraph IV challenge does not establish that US 7,465,800 is invalid. A challenge can result in settlement, a license, a judgment of infringement, a finding of invalidity, or abandonment of the relevant ANDA strategy.

What patent litigation affects US 7,465,800?

Revlimid litigation has involved the broader Celgene patent portfolio rather than a single patent in isolation. Key issues have included:

• Obviousness of lenalidomide and related compounds;
• Written description and enablement;
• Patent-term calculations;
• Validity of method-of-use claims;
• Infringement by generic drug substances;
• The effect of settlement agreements on generic launch timing;
• Antitrust claims concerning patent enforcement and settlement conduct.

For US 7,465,800, the most relevant infringement disputes would concern the identity of the active pharmaceutical ingredient supplied by an ANDA applicant. A generic company could challenge the patent through a Paragraph IV certification, seek a declaration of non-infringement, or design around the claimed crystalline form. A final adjudication of a dependent analytical claim would not necessarily dispose of claim 1.

Can a generic avoid US 7,465,800 by using a different formulation?

Usually, a different formulation alone would not avoid a drug-substance claim.

If a generic capsule contains lenalidomide hemihydrate with the claimed crystalline characteristics, the use of different excipients, capsule shells, dissolution agents, packaging, or manufacturing equipment would not eliminate potential infringement. The relevant inquiry would be the identity of the active ingredient, not the appearance of the finished capsule.

Potential design-around approaches include:

• Using a genuinely different polymorph;
• Using an anhydrous form;
• Using an amorphous form, if technically and regulatorily feasible;
• Converting the active ingredient into a different solid-state form before incorporation;
• Demonstrating that the final active ingredient lacks the claimed hemihydrate characteristics.

Each approach creates pharmaceutical-development and regulatory risks. Solid-form changes can affect dissolution, stability, bioavailability, impurity profiles, flowability, compressibility, and batch reproducibility.

What manufacturing and intellectual-property barriers does the patent create?

The patent can constrain the crystallization and isolation stages of lenalidomide manufacture. A process may produce the claimed hemihydrate even when the process patent itself is unasserted. The relevant risk points include:

• Solvent selection;
• Water activity;
• Drying temperature;
• Seeding conditions;
• Crystallization temperature;
• Humidity exposure;
• Milling and storage conditions;
• Conversion between hydrate and anhydrate forms.

A process design-around is not sufficient if the final commercial API rehydrates into the patented hemihydrate during storage or formulation. Batch-release testing and stability testing would therefore be important to any non-infringement position.

How strong is the patent estate for lenalidomide?

Celgene’s lenalidomide estate was layered across several claim types:

Estate layer	Protection target	Generic risk
Core compound claims	Lenalidomide chemical structure	Broadest historical protection
Solid-form claims	Crystalline hemihydrate and related forms	API and manufacturing risk
Formulation claims	Dosage forms and delivery characteristics	Product-specific risk
Method-of-use claims	Disease and dosing regimens	Label and induced-infringement risk
Manufacturing claims	Preparation and purification methods	Process and supplier risk
Regulatory rights	Orphan, pediatric, and NDA protections	Approval timing and labeling constraints

The solid-form patent is strong against an applicant whose API matches the claimed hemihydrate, but narrower against an applicant that can produce and maintain a non-infringing solid form. Its value depends on claim validity, the reliability of analytical testing, the scope of claim 1, and whether generic suppliers source API from manufacturers using the claimed crystallization conditions.

How does Revlimid compare with competing immunomodulatory drugs?

Drug	Active ingredient	Product type	Biosimilar risk	Solid-form relevance
Revlimid	Lenalidomide	Small molecule	None; ANDA pathway applies	High, because crystalline API patents are material
Thalomid	Thalidomide	Small molecule	None	Chemical and method-of-use patents historically relevant
Pomalyst/Imnovid	Pomalidomide	Small molecule	None	Compound, formulation, and use patents
Darzalex	Daratumumab	Biologic	Biosimilar pathway applies	Biologic manufacturing and formulation claims
Kyprolis	Carfilzomib	Small molecule peptide-like product	No conventional biosimilar pathway	Formulation and manufacturing issues

Lenalidomide does not face biosimilar competition because it is a small molecule. Generic entry depends on ANDA approval, patent certifications, settlement terms, and the ability to produce a commercially acceptable API without infringing the relevant solid-form claims.

What generic launch scenarios exist?

The principal launch scenarios are:

1. Pre-expiration licensed entry. A generic manufacturer launches under a Celgene settlement or license before the complete patent estate expires, often with volume or distribution limits.

2. At-risk launch. The manufacturer launches before final resolution of patent litigation and accepts potential damages or injunctive exposure.

3. Post-expiration full entry. The manufacturer waits until the relevant patents and regulatory barriers expire.

4. Design-around entry. The manufacturer uses a different solid form and litigates or certifies non-infringement.

5. Authorized generic competition. The NDA holder or licensee supplies an authorized generic while independent ANDA applicants remain subject to patent and settlement restrictions.

For US 7,465,800, the decisive technical question is whether the ANDA applicant’s API is the claimed crystalline hemihydrate. The decisive commercial question is whether the applicant has a license, settlement right, or enforceable non-infringement position allowing launch before the expected 2027 expiration.

Key Takeaways

• US 7,465,800 is a solid-form patent covering crystalline lenalidomide hemihydrate.
• Claim 1 is the broadest claim and does not require every XRPD, DSC, IR, Raman, or TGA limitation recited in the dependent claims.
• Claims 2 through 14 provide narrower analytical fingerprints and hydration parameters.
• The patent does not claim every lenalidomide form or every Revlimid formulation.
• A different capsule formulation does not by itself avoid infringement if the API is the claimed hemihydrate.
• The expected expiration is in April 2027, subject to the recorded USPTO patent term.
• Generic competition proceeds through ANDA filings, Paragraph IV certifications, litigation, settlements, licenses, and possible design-arounds.
• Biosimilar analysis is inapplicable because lenalidomide is a small molecule.
• Manufacturing controls are important because hydration state can change during crystallization, drying, storage, and formulation.

FAQs About US Patent 7,465,800

Does US 7,465,800 cover lenalidomide anhydride?

No. The claims are directed to a crystalline hemihydrate. An anhydrous form is outside the literal scope of the claimed hydration state, although equivalence and product-conversion issues could remain relevant.

Is an XRPD match required to infringe claim 1?

Not necessarily. Claim 1 does not expressly recite the specific XRPD peaks found in claims 2 through 6. XRPD evidence may be used to establish that a material is the claimed crystalline hemihydrate, but the dependent-claim peak list is not automatically required for claim 1.

Does US 7,465,800 protect Revlimid capsules?

It protects the claimed active solid form, not capsules as such. A capsule can create infringement risk if it contains the patented crystalline lenalidomide hemihydrate.

Is a Paragraph IV certification against US 7,465,800 enough to launch a generic?

No. A Paragraph IV certification is a patent challenge mechanism. Launch depends on litigation outcomes, settlement restrictions, other listed patents, regulatory exclusivity, and the applicant’s final legal position.

Can a manufacturer avoid the patent by changing the crystallization solvent?

Not automatically. The relevant question is the solid form of the resulting API. A changed solvent or process can still produce the claimed crystalline hemihydrate and therefore may not avoid infringement.

References

1. United States Patent and Trademark Office. (2008). US Patent No. 7,465,800, Crystalline forms of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione.
2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (n.d.). Revlimid (lenalidomide) prescribing information.
4. Federal Trade Commission. (2013). Authorized generic drugs: Short-term effects and long-term impact.

Drugs Protected by US Patent 7,465,800

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Bristol Myers Squibb	REVLIMID	lenalidomide	CAPSULE;ORAL	021880-005	Dec 21, 2011	AB	RX	Yes	No			Y	Y
Bristol Myers Squibb	REVLIMID	lenalidomide	CAPSULE;ORAL	021880-001	Dec 27, 2005	AB	RX	Yes	No			Y	Y
Bristol Myers Squibb	REVLIMID	lenalidomide	CAPSULE;ORAL	021880-002	Dec 27, 2005	AB	RX	Yes	No			Y	Y
Bristol Myers Squibb	REVLIMID	lenalidomide	CAPSULE;ORAL	021880-003	Jun 29, 2006	AB	RX	Yes	No			Y	Y

International Family Members for US Patent 7,465,800

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2105135		1590004-6	Sweden
European Patent Office	2105135		C300717	Netherlands
European Patent Office	2105135		CA 2015 00006	Denmark
European Patent Office	2105135		92642	Luxembourg