United States Patent 6,235,756: Scope, Claims, Expiration, and Thalidomide Patent Landscape

U.S. Patent No. 6,235,756 covered methods of treating tumor-associated angiogenesis with thalidomide. Its central claim extended across human and animal tumors, including solid tumors, blood-borne tumors, leukemia, Kaposi's sarcoma, breast cancer, and several pediatric and vascular tumors. The patent also claimed dosage ranges, dosage forms, and administration routes.

The patent issued on May 22, 2001, to Children’s Medical Center Corporation. Its statutory term ran to approximately December 3, 2019, based on the December 3, 1999 nonprovisional filing date, subject to any applicable patent-term adjustment. It is therefore expired and does not create a current U.S. blocking right against generic thalidomide, new drug applications, or biosimilar products. [1]

What does U.S. Patent 6,235,756 protect?

The patent protects the use of thalidomide as an antiangiogenic treatment for a tumor-bearing human or animal. Claim 1 is the controlling independent claim:

“A method of treating undesired angiogenesis in a human or animal having a tumor comprising administering to the human or animal in need thereof an angiogenesis inhibiting amount of thalidomide.”

The claim has four principal limitations:

The subject must be a human or animal.
The subject must have a tumor.
The treatment must address “undesired angiogenesis.”
The administered substance must be thalidomide in an angiogenesis-inhibiting amount.

The patent does not claim thalidomide as a composition of matter. It claims a medical-use method. It also does not claim every use of thalidomide for cancer. A potential infringement analysis would require evidence that the accused treatment satisfies the angiogenesis-related limitations.

What tumor types are covered?

Claims 2 through 13 identify specific tumor categories or diseases:

Claim	Tumor or disease category
2	Kaposi’s sarcoma
3	Hemangioma
4	Solid tumor
5	Blood-borne tumors
6	Rhabdomyosarcoma
7	Retinoblastoma
8	Ewing’s sarcoma
9	Neuroblastoma
10	Osteosarcoma
11	Neurofibroma
12	Pyogenic granulomas
13	Breast cancer
24	Leukemia

Claims 2 through 13 depend on claim 1. They narrow the tumor population but remain subject to the requirement that treatment be directed to undesired angiogenesis using an angiogenesis-inhibiting amount of thalidomide.

Claim 24 is independently drafted around leukemia. It does not depend on claim 1, although it repeats substantially the same treatment concept.

How broad is claim 1?

Claim 1 is broad in disease coverage but narrower than a general claim to treating cancer with thalidomide. Its operative limitation is angiogenesis.

A product or treatment would not necessarily fall within claim 1 merely because:

thalidomide is administered to a cancer patient;
the patient has a tumor;
thalidomide has immunomodulatory or anti-inflammatory effects; or
the treatment is used for multiple myeloma.

The patent requires an angiogenesis-inhibiting treatment. In a method-of-use enforcement case, relevant evidence could include the prescribing information, clinical protocol, promotional statements, physician instructions, dosage, disease indication, and scientific evidence linking the treatment to angiogenesis inhibition.

The claim uses “an angiogenesis inhibiting amount,” which is a functional amount limitation. The quantity need not be fixed in the independent claim, but the administered amount must perform the claimed antiangiogenic function in the relevant treatment context.

Does claim 1 cover all thalidomide cancer treatment?

No. The claim is not a composition claim and does not expressly cover every oncologic use. It requires:

a tumor;
undesired angiogenesis; and
administration for an angiogenesis-inhibiting purpose.

A thalidomide regimen prescribed solely for an immunomodulatory indication could present a different infringement analysis. The distinction would depend on the treatment instructions and evidence of the intended therapeutic mechanism.

What dosage ranges are protected?

Claims 14 through 16 define nested dosage ranges:

Claim	Dose
14	Approximately 0.1 to approximately 300 mg/kg/day
15	Approximately 0.5 to approximately 50 mg/kg/day
16	Approximately 1 to approximately 10 mg/kg/day

These ranges are dependent on the preceding treatment claims. They do not stand alone as claims to a thalidomide dose. The dose must be administered for the claimed antiangiogenic tumor treatment.

The ranges are extremely broad when converted to absolute daily doses. For a 70-kilogram adult, claim 14 corresponds approximately to 7 to 21,000 mg per day, while claim 16 corresponds approximately to 70 to 700 mg per day. Conventional clinical thalidomide dosing is generally much lower than the upper end of claim 14, although the claim language covers the full stated range.

The words “approximately” create an infringement and claim-construction issue around the boundaries. The specification, prosecution history, clinical examples, and technical meaning of the dose ranges would be relevant to determining the permissible range.

What dosage forms and administration routes are protected?

Claims 17 through 19 cover dosage forms. Claims 20 through 23 cover routes of administration.

Dosage-form claims

Claim	Claimed form
17	Tablet
18	Capsule
19	Lozenge, cachet, solution, suspension, emulsion, powder, aerosol, suppository, spray, pastille, ointment, cream, paste, foam, gel, tampon, or pessary

Claim 19 is unusually expansive. It reaches oral, topical, mucosal, rectal, vaginal, and other dosage-form concepts. The claim remains limited by the underlying antiangiogenic tumor-treatment method.

Administration-route claims

Claim	Route
20	Oral
21	Sublingual, buccal, rectal, vaginal, or nasal
22	Parenteral
23	Transdermal or topical

Claims 20 through 23 depend on claims 1, 4, 5, or 14. They therefore concentrate on treatment of tumors, solid tumors, blood-borne tumors, or the specified dosage range, depending on the dependency path.

For commercial products, the most relevant historical embodiments were oral tablets and capsules. The patent’s coverage of topical, transdermal, parenteral, and mucosal forms did not by itself establish commercial use or FDA approval for those routes.

When did U.S. Patent 6,235,756 expire?

The patent was filed on December 3, 1999, and issued on May 22, 2001. The record identifies an earlier provisional filing dated December 3, 1998. For a U.S. application filed after June 8, 1995, the ordinary patent term is generally 20 years from the earliest effective nonprovisional U.S. filing date, not from the provisional filing date. [1,2]

Event	Date
Provisional priority filing	December 3, 1998
U.S. nonprovisional filing	December 3, 1999
Patent issuance	May 22, 2001
Approximate statutory expiration	December 3, 2019

The patent is expired. Any patent-term adjustment would need to be checked against the USPTO patent-term record, but it would not change the present conclusion that the patent no longer provides enforceable U.S. exclusivity.

What is the FDA and Orange Book status of the patent?

Thalidomide is an FDA-approved active ingredient, but U.S. approval is tied to specific products and indications. FDA approved THALOMID for erythema nodosum leprosum in 1998 and later approved it, in combination with dexamethasone, for newly diagnosed multiple myeloma. [3]

The FDA approval does not establish approval of thalidomide for the broad tumor and angiogenesis indications described in Patent 6,235,756. In particular:

the patent claims are broader than the labeled indications;
antiangiogenic treatment of the listed tumors is not established as a general FDA-approved indication;
the patent’s expiration removes the patent-based barrier to off-patent competition; and
the THALOMID risk-management framework remains relevant because thalidomide is teratogenic.

Thalidomide products are distributed under a restricted program, historically known as the THALOMID REMS. The program controls prescribing, dispensing, pregnancy testing, contraception, and handling requirements. [3]

Patent 6,235,756 is not a current enforceable Orange Book barrier. Historical Orange Book listings, if any, would not restore exclusivity after expiration. Orange Book listing also does not convert a method-of-use patent into a composition-of-matter patent.

What Paragraph IV challenges affect thalidomide?

A Paragraph IV certification is relevant when an ANDA applicant seeks approval before expiration of an Orange Book-listed patent and asserts that the patent is invalid, unenforceable, or not infringed. [4]

For Patent 6,235,756, the practical Paragraph IV issue has ended because the patent expired in 2019. A current generic applicant does not need to defeat this patent to obtain approval or commercialize thalidomide, subject to other applicable FDA requirements.

Historically, a Paragraph IV challenge could have focused on:

lack of infringement because the proposed labeling did not direct angiogenesis treatment;
invalidity based on prior use of thalidomide or prior antiangiogenic research;
written-description or enablement issues arising from the broad tumor list;
indefiniteness surrounding “angiogenesis inhibiting amount”; and
obviousness based on known thalidomide pharmacology and antiangiogenic research.

Those arguments are now primarily historical. They could matter only in disputes involving pre-expiration conduct, damages, licensing obligations, or historical ANDA litigation.

Which companies challenged or commercialized thalidomide rights?

Celgene commercialized THALOMID in the United States and developed the product for oncology use. Bristol Myers Squibb later acquired Celgene. [5] Generic thalidomide products have also been approved, subject to the FDA’s controlled-distribution and safety requirements.

Patent 6,235,756 was assigned to Children’s Medical Center Corporation. Commercial rights, licensing arrangements, and product rights involving thalidomide may have been separate from ownership of the patent. Patent assignment does not establish the terms of a license, royalty, field-of-use restriction, or settlement agreement.

No current license or settlement can preserve the expired patent’s exclusionary effect against third parties. Contractual obligations may survive expiration, but they are distinct from patent enforcement.

What patent litigation affects Patent 6,235,756?

The principal litigation risk associated with this patent would have arisen before its 2019 expiration. The claim structure would have supported a method-of-use dispute involving:

a thalidomide product label;
oncology prescribing instructions;
clinical-trial protocols;
promotion of thalidomide as an antiangiogenic treatment; or
a generic label that expressly directed use for one of the claimed tumor types.

A generic capsule manufacturer would face a stronger pre-expiration risk if its labeling expressly instructed treatment of Kaposi’s sarcoma, leukemia, solid tumors, or another claimed tumor through angiogenesis inhibition. A simple label for an approved non-angiogenic indication would present a narrower case.

After expiration, direct patent litigation based solely on future use of thalidomide under these claims is no longer commercially significant. Litigation may still arise over pre-expiration sales, damages, license audits, or unrelated patents.

How strong was the patent estate?

Strengths

The patent had several strengths during its enforceable term:

Claim 1 covered a broad range of tumors.
The patent claimed both human and animal treatment.
The claim was directed to a therapeutic use rather than a narrow formulation.
Dependent claims added specific tumor types, doses, dosage forms, and routes.
Oral tablet and capsule coverage aligned with commercially practical formulations.

Weaknesses

The estate also had material limitations:

It did not claim thalidomide itself.
It did not claim lenalidomide or pomalidomide.
It required proof of angiogenesis inhibition.
Several tumor categories were broad, including “solid tumor” and “blood borne tumors.”
The dosage claims used approximate boundaries.
The extensive route and formulation claims may have raised enablement and written-description questions across forms not shown in clinical practice.
The patent term ended before the modern expansion of immunomodulatory-drug oncology products.

The patent was therefore a foundational use patent, not a durable platform estate.

How does Patent 6,235,756 compare with later thalidomide and IMiD patents?

Patent 6,235,756 is distinct from later patent families directed to:

multiple myeloma treatment;
thalidomide combinations with corticosteroids or chemotherapy;
lenalidomide and pomalidomide;
specific crystalline forms;
controlled-release or modified-release formulations;
dosing schedules and adverse-event management;
teratogenicity risk controls; and
manufacturing processes and intermediates.

Later IMiD products such as lenalidomide and pomalidomide are chemically related to thalidomide but are not covered by the literal term “thalidomide.” Patent 6,235,756 therefore does not provide a direct patent basis for blocking Revlimid or Pomalyst. Their patent estates depended on separate compound, formulation, method-of-use, and dosing patents.

The patent also does not create biosimilar risk in the conventional sense. Thalidomide is a small molecule, so competing products proceed through generic-drug pathways rather than the biosimilar pathway under the Public Health Service Act. [4]

What generic launch risks existed?

Before expiration, the principal generic-entry scenarios were:

Scenario	Risk profile
Generic label limited to an approved non-angiogenic indication	Lower risk under Patent 6,235,756
Label expressly covering cancer treatment	Higher risk, depending on indication language
Label referring to angiogenesis inhibition	Direct claim exposure
Off-label physician use without manufacturer direction	More difficult inducement case
Generic capsule with no patented formulation limitation	Limited formulation risk
Launch after December 3, 2019	Patent 6,235,756 no longer blocks entry

The main remaining barriers to generic commercialization are regulatory compliance, restricted distribution, manufacturing controls, commercial demand, and any separate unexpired patents associated with a specific product or indication.

What manufacturing and geographic barriers remain?

Patent 6,235,756 was a U.S. patent. It did not itself establish protection in Europe, Japan, Canada, or other jurisdictions. Foreign protection would depend on national counterparts and their individual filing, prosecution, maintenance, and expiration records.

The patent also did not claim a thalidomide manufacturing process. A manufacturer could therefore avoid this patent through an independently developed process, provided that no separate process, polymorph, formulation, or impurity-control patent applied.

Current commercial barriers are more likely to involve:

validated manufacture of a high-risk active ingredient;
contamination and cross-contamination controls;
pregnancy-prevention systems;
FDA restricted-distribution obligations;
supply-chain qualification;
controlled-substance and pharmacovigilance procedures; and
separate product-specific patents.

Key Takeaways

U.S. Patent 6,235,756 covered thalidomide treatment of tumor-associated angiogenesis.
Claim 1 was broad across tumor types but required an angiogenesis-inhibiting treatment purpose.
Dependent claims covered leukemia, Kaposi’s sarcoma, solid tumors, blood-borne tumors, breast cancer, pediatric tumors, dosage ranges, formulations, and administration routes.
The patent was a method-of-use patent, not a composition patent.
The approximate statutory expiration date was December 3, 2019.
It is no longer a current U.S. blocking patent.
It did not cover lenalidomide, pomalidomide, or biologic products.
Current thalidomide competition is governed primarily by FDA approval requirements, restricted distribution, manufacturing capability, and separate patent rights.
Paragraph IV and pre-expiration litigation issues are now historical unless tied to earlier conduct or contractual disputes.

FAQs About U.S. Patent 6,235,756

Did Patent 6,235,756 cover multiple myeloma?

Not expressly. The claims refer to tumors, blood-borne tumors, leukemia, and angiogenesis. Multiple myeloma could raise a claim issue under broader language, but the patent did not specifically name multiple myeloma in the claims provided.

Did Patent 6,235,756 cover generic thalidomide capsules?

It claimed methods using thalidomide in capsule form, not capsules as a composition independent of use. A generic capsule would implicate the patent only if used or labeled for the claimed antiangiogenic tumor treatment during the enforceable term.

Is thalidomide a biologic subject to biosimilar competition?

No. Thalidomide is a small-molecule drug. Competing products use the ANDA generic-drug pathway rather than the biosimilar pathway.

Could the patent block topical or injectable thalidomide?

During its term, claims 21 through 23 reached several nonoral routes, including parenteral, topical, transdermal, nasal, rectal, vaginal, sublingual, and buccal administration. The patent’s expiration removes that current blocking effect.

Does the patent still affect Revlimid or Pomalyst?

No direct patent effect follows from this patent. Revlimid contains lenalidomide and Pomalyst contains pomalidomide. Those compounds require analysis of their own patent estates and are not thalidomide for purposes of literal claim scope.

References

U.S. Patent No. 6,235,756. (2001). Inhibition of angiogenesis by thalidomide. U.S. Patent and Trademark Office.
U.S. Patent and Trademark Office. (2024). Patent term adjustment and patent term calculation guidance.
U.S. Food and Drug Administration. (2024). THALOMID (thalidomide) prescribing information.
U.S. Food and Drug Administration. (2024). Abbreviated new drug application regulations and patent certifications.
Bristol Myers Squibb. (2019). Bristol Myers Squibb completes acquisition of Celgene.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0688211	⤷ Start Trial	91471	Luxembourg	⤷ Start Trial
European Patent Office	0688211	⤷ Start Trial	CA 2008 00034	Denmark	⤷ Start Trial
European Patent Office	0688211	⤷ Start Trial	300358	Netherlands	⤷ Start Trial
European Patent Office	0688211	⤷ Start Trial	SPC025/2008	Ireland	⤷ Start Trial
European Patent Office	0688211	⤷ Start Trial	SPC/GB08/039	United Kingdom	⤷ Start Trial
European Patent Office	0688211	⤷ Start Trial	C300358	Netherlands	⤷ Start Trial
European Patent Office	0688211	⤷ Start Trial	08C0036	France	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,235,756

Summary for Patent: 6,235,756