United States Patent 6,723,351: Claim Scope, Expiration, Orange Book Status, and Arsenic Trioxide Patent Landscape

U.S. Patent No. 6,723,351 covers a weight-based arsenic trioxide treatment regimen for acute promyelogenous leukemia, now generally called acute promyelocytic leukemia, or APL. Its core limitation is administration of 0.15 mg/kg arsenic trioxide once daily, followed by defined remission, consolidation, and repeat-cycle schedules.

The patent issued on April 20, 2004, from an application claiming priority to August 13, 1998. Its ordinary 20-year patent term ran from the earliest effective nonprovisional filing date and expired in August 2019. The patent is therefore no longer an enforceable barrier to generic or follow-on use of the claimed regimen. The claims remain relevant for historical Orange Book, Paragraph IV, licensing, and product-development analysis.

What patent protects arsenic trioxide treatment for acute promyelocytic leukemia?

U.S. Patent 6,723,351 protects treatment methods rather than a new arsenic compound, formulation, manufacturing process, or delivery device.

Field	Information
U.S. patent	6,723,351
Title	Method of treating acute promyelogenous leukemia with arsenic trioxide
Filing priority	August 13, 1998
Issue date	April 20, 2004
Patent type	Utility, therapeutic method
Active ingredient	Arsenic trioxide, As2O3
Primary disease	Acute promyelogenous leukemia
Related disease terminology	Acute promyelocytic leukemia, or APL; acute myelogenous leukemia, or AML
Core dose	0.15 mg/kg once daily
Core treatment sequence	Induction until bone marrow remission, followed by consolidation
Reported ordinary expiration	August 13, 2019
Current enforceability	Expired

The patent claims are concentrated around the clinical dosing protocol described in the arsenic trioxide clinical literature and later reflected in the Trisenox prescribing information.[1][2]

How many claims are in U.S. Patent 6,723,351?

The patent has 64 claims. The claims form three substantially overlapping families.

Claim family	Claims	Principal subject
Direct APL method claims	1-21	Administration of 0.15 mg/kg once daily to a human with APL
AML and dose-calculation claims	22-43	Determining a weight-based dose for AML, with APL as a dependent species
APL dose-determination claims	44-64	Calculating and administering 0.15 mg/kg based on patient weight

The claims are mostly nested regimen limitations. Claims 2 through 21 narrow claim 1 by adding induction duration, remission, consolidation, dosing frequency, intervals, and repeat cycles. Claims 24 through 43 and 45 through 64 reproduce much of the same regimen through different claim language.

This structure gives the patent multiple paths to a substantially identical treatment protocol, but it does not create independent protection for every clinical use of arsenic trioxide.

What is the scope of independent claim 1?

Claim 1 requires all of the following:

A method of treating acute promyelogenous leukemia.
Treatment of a human.
Administration of arsenic trioxide.
A dose of 0.15 mg/kg.
Administration once per day.

The claim does not expressly require:

A particular formulation;
Intravenous administration;
A specific commercial product;
A particular treatment duration;
Bone marrow remission;
A consolidation phase;
A hospital setting;
A minimum patient age;
A genetic confirmation of the PML-RARA fusion; or
Relapsed or refractory disease.

A treatment course could therefore fall within claim 1 even if it does not follow the complete induction-and-consolidation program in the dependent claims, provided the accused conduct satisfies the disease, patient, drug, dose, and frequency limitations.

The principal claim-construction issue is the meaning of “0.15 mg/kg.” The claim is directed to a patient-weight-based dose, not a fixed vial quantity or a concentration in a manufactured solution. A protocol using a materially different dose, such as a fixed daily dose or a body-surface-area calculation, would present a different literal-infringement analysis.

What treatment schedule is protected by claims 2 through 21?

Claims 2 through 21 cover the more detailed regimen associated with arsenic trioxide induction and consolidation.

Induction phase

Claim 2 requires administration until bone marrow remission. Claims 12 and 34 provide an alternative induction limitation of administration for up to 60 days.

The patent thus contains two principal induction concepts:

Treatment until bone marrow remission; and
Treatment for up to 60 days.

The “up to 60 days” limitation is narrower than the broader daily-dose requirement in claim 1. It may exclude a course that continues beyond 60 days, although such a course could still be evaluated against claim 1 if the other limitations are met.

Consolidation phase

Claims 3 through 11 and 13 through 21 add a second administration consisting of:

0.15 mg/kg arsenic trioxide;
Once daily;
For 25 doses;
Beginning 3 to 6 weeks after the first administration;
Administered over up to five weeks;
At five doses per week.

The claims also cover repeated consolidation cycles every 3 to 6 weeks, with two to ten total cycles.

Limitation	Claim examples
First treatment until remission	2, 24, 45
First treatment for up to 60 days	12, 34, 55
Second treatment for 25 doses	3, 13, 25, 35, 46, 56
Start 3 to 6 weeks later	4, 14, 26, 36, 47, 57
Up to five weeks	5, 15, 27, 37, 48, 58
Five doses per week	6, 16, 28, 38, 49, 59
Repeat consolidation	7, 17, 29, 39, 50, 60
Repeat every 3 to 6 weeks	8, 18, 30, 40, 51, 61
Two to ten cycles	9, 19, 31, 41, 52, 62
Exactly two cycles	10, 20, 32, 42, 53, 63
Exactly ten cycles	11, 21, 33, 43, 54, 64

The claims contain drafting defects, including “end ten cycles” and “once per” omissions. Those errors do not necessarily invalidate the claims, because courts generally interpret claim language in the context of the specification and prosecution history. They can, however, create indefiniteness, construction, and enforcement issues.

How do claims 22 through 64 differ from claims 1 through 21?

Claims 22 through 64 emphasize dose calculation based on body weight.

Claim 22 requires:

Determining a therapeutically effective arsenic trioxide dose;
Using the patient’s weight;
Applying 0.15 mg/kg; and
Administering the resulting dose once per day.

Claim 44 uses similar language for APL but omits the express reference to AML in the independent claim.

These claims seek to capture the act of converting the 0.15 mg/kg instruction into a patient-specific dose. For example, a 70-kg patient would receive 10.5 mg per administration under the claimed calculation.

The practical distinction between the claim families is limited. A protocol that administers a calculated 0.15 mg/kg dose to a patient with APL could implicate claim 1 and one or more of claims 22 and 44, subject to claim construction and the evidence of how the dose was selected and administered.

What FDA-approved regimen overlaps the patent claims?

The Trisenox prescribing information describes an APL regimen that closely tracks the patent:

Induction at 0.15 mg/kg intravenously once daily until bone marrow remission, up to a maximum of 60 days.
Consolidation at 0.15 mg/kg once daily for 25 doses over a five-week period.
Consolidation beginning 3 to 6 weeks after induction, depending on recovery from toxicity.

The label also identifies electrocardiographic monitoring, electrolyte management, and risks including QT prolongation and differentiation syndrome.[2]

That overlap made the patent commercially relevant when it was in force. A generic applicant seeking approval with a label containing the same APL regimen could have faced a method-of-use patent issue if the patent remained enforceable and properly listed.

What was the Orange Book status of U.S. Patent 6,723,351?

The Orange Book is the FDA’s official source for patent and exclusivity information submitted for approved drug products. Patent listing status can change over time through delisting, expiration, corrections, or product-specific updates.[3]

For Trisenox, U.S. Patent 6,723,351 was associated with the product’s arsenic trioxide treatment regimen. The patent’s relevance was primarily method-of-use based. It did not protect the active ingredient as a chemical entity.

The patent’s expiration in August 2019 removed the principal statutory patent barrier associated with these claims. FDA approval of a generic arsenic trioxide injection does not, by itself, establish that every historic patent was invalid. It indicates that the FDA approval pathway addressed the relevant patent certifications and regulatory requirements at the time of approval.

When did arsenic trioxide lose exclusivity?

Arsenic trioxide lost exclusivity in stages.

Exclusivity category	Approximate event
Orphan-drug exclusivity	Trisenox approval for relapsed or refractory APL in 2000; seven-year orphan period ended around 2007
Patent exclusivity	U.S. Patent 6,723,351 expired in August 2019
Generic competition	Generic arsenic trioxide products entered the U.S. market before patent expiration under applicable FDA certifications and labeling strategies
Current position	No enforceable exclusivity remains under Patent 6,723,351

Orphan exclusivity is product- and indication-specific. It does not confer the same rights as a patent and does not prevent all competing uses outside the protected orphan indication.

Which companies challenged the arsenic trioxide patent?

The patent record and FDA materials do not establish a current, active Paragraph IV dispute involving U.S. Patent 6,723,351. Generic arsenic trioxide development has involved companies seeking approval through abbreviated new drug applications, but a generic applicant’s commercial entry does not prove that it prevailed in a litigated patent case.

The commercial challenge was structurally straightforward:

Arsenic trioxide is an old active ingredient.
The patent claims cover a specific dosing method.
A generic applicant could certify that the patent was expired, invalid, unenforceable, or would not be infringed.
A label could be evaluated for carve-outs or for whether it retained the patented APL use.
After expiration, the method claims no longer created a launch restriction.

No current Paragraph IV litigation risk should be assigned to this patent because the patent has expired.

What patent litigation affected U.S. Patent 6,723,351?

The principal present legal fact is that the patent cannot support a new infringement action for post-expiration conduct. Any historical dispute would require review of:

The asserted claim;
The date of the alleged activity;
The product label in effect at that time;
FDA patent certifications;
Assignment and licensing records;
Any settlement or covenant not to sue; and
The applicable statute of limitations.

An expired patent can remain relevant to damages for pre-expiration conduct, settlement interpretation, prosecution history, and market-entry analysis. It cannot support prospective exclusion of a generic product today.

What formulation patents protect arsenic trioxide products?

U.S. Patent 6,723,351 does not claim:

A stable arsenic trioxide formulation;
A specific concentration;
A container or vial;
A preservative system;
A pH range;
An infusion device;
A lyophilized product; or
A manufacturing process.

Its claims are method claims. A separate formulation patent would need to be analyzed independently for claim scope, expiration, listing, and enforceability.

This distinction matters because a generic manufacturer may avoid a formulation patent while still practicing a patented method, or may practice the same method using a noninfringing formulation. Once Patent 6,723,351 expired, its dosing regimen no longer created that method-of-use barrier.

Is there biosimilar risk for arsenic trioxide?

No traditional biosimilar pathway applies. Arsenic trioxide is a small-molecule active pharmaceutical ingredient, not a biologic subject to the Biologics Price Competition and Innovation Act.

The relevant competitive pathways are:

ANDA approval for a generic drug;
505(b)(2) approval for a product relying partly on existing clinical data;
Supplemental applications for changes to an approved product; and
Conventional full NDA development.

The principal regulatory competition is generic rather than biosimilar competition.

How strong was the patent estate for arsenic trioxide?

The patent estate was narrow in subject matter but commercially meaningful while unexpired.

Strengths

It claimed the exact 0.15 mg/kg daily dose reflected in the approved regimen.
It included both induction and consolidation schedules.
It covered patient-specific dose calculation.
It applied to treatment of humans.
The FDA-approved label closely tracked several limitations.

Weaknesses

It did not cover arsenic trioxide as a compound.
It did not cover all APL treatment regimens.
It did not claim a formulation or manufacturing process.
Many claims were repetitive and dependent on overlapping limitations.
The patent term was relatively short compared with the commercial life of the product.
The regimen was clinically specific, making design-around through a different dose, schedule, or indication possible.
The patent expired in 2019.

The patent was therefore a regimen patent, not a broad platform patent.

What generic launch risks existed before patent expiration?

Before expiration, generic launch risk depended on the label and the actual promoted use.

Launch scenario	Historical risk
Generic label included the patented APL regimen	Higher method-of-use risk
Label carved out the patented APL indication	Lower induced-infringement risk, subject to actual conduct
Generic product supplied for off-label APL treatment	Potential induced-infringement questions depended on labeling, marketing, and evidence
Product used at a nonclaimed dose or schedule	Reduced literal-infringement risk
Product launched after August 2019	No prospective infringement risk from this patent

A skinny-label strategy would not necessarily eliminate all risk if the manufacturer actively promoted the patented use or supplied materials encouraging physicians to follow the claimed regimen. Conversely, the mere sale of a drug with substantial noninfringing uses would not automatically establish induced infringement.

What licensing deals affected the patent?

The patent itself does not establish the complete commercial licensing history for Trisenox. FDA product records identify the sponsor and approved product, while USPTO assignment records identify recorded ownership transfers. Those records should be distinguished from private license agreements, which may not be publicly recorded in full.

For commercial analysis, the relevant separation is:

Patent ownership: determined from USPTO assignments and recorded documents.
Product sponsorship: determined from FDA approval records.
Commercial marketing rights: determined from SEC filings, transaction documents, and license agreements.
Patent enforcement rights: determined from ownership, exclusive-license terms, and standing.

No current license can restore exclusivity after expiration of Patent 6,723,351.

Does the patent create current geographic protection?

No current U.S. protection exists under Patent 6,723,351. U.S. patent rights are territorial and expired rights cannot be extended through foreign family members.

Foreign counterparts, if any, required separate review for:

Filing dates;
National-phase status;
Patent term;
Patent-term extensions;
Supplementary protection certificates;
Local Orange Book equivalents; and
National litigation.

A U.S. expiration date does not establish the status of corresponding patents in Europe, Canada, Japan, China, or other jurisdictions.

What manufacturing and intellectual-property barriers remain?

Patent 6,723,351 creates no current manufacturing barrier. A manufacturer must still address:

Arsenic trioxide active-ingredient specifications;
Impurity controls;
Sterility assurance;
Container closure;
Stability;
Injectable-product quality systems;
FDA chemistry, manufacturing, and controls requirements;
Pharmacovigilance;
Differentiation syndrome and QT-prolongation warnings; and
Supply-chain controls for a toxic active ingredient.

These are regulatory and operational barriers, not surviving rights under the expired patent.

Key Takeaways

U.S. Patent 6,723,351 covers arsenic trioxide treatment methods for APL and related AML wording.
Its central limitation is 0.15 mg/kg once daily in a human.
Dependent claims cover induction to remission or up to 60 days, followed by 25-dose consolidation courses.
The consolidation schedule begins 3 to 6 weeks after induction and can repeat for two to ten cycles.
The patent does not claim arsenic trioxide as a chemical compound, a formulation, or a manufacturing process.
The claims closely track the Trisenox FDA regimen.
The patent expired in August 2019.
It presents no current Paragraph IV, biosimilar, or generic launch barrier.
Any remaining competition concerns involve product quality, regulatory compliance, formulation rights, or separate foreign patents.

FAQs

Does a generic arsenic trioxide product infringe Patent 6,723,351?

No current infringement claim can be based on this patent because it expired in August 2019. Before expiration, infringement depended on the approved label, marketing conduct, and whether the product was used according to the claimed APL regimen.

Does the patent cover arsenic trioxide for all leukemia indications?

No. The claims focus on acute promyelogenous or acute promyelocytic leukemia, with certain claims using broader acute myelogenous leukemia language. The patent does not cover every leukemia use of arsenic trioxide.

Does administering 10 mg instead of 0.15 mg/kg avoid the claims?

Potentially, but the answer depends on patient weight. A fixed 10-mg dose could equal 0.15 mg/kg for a patient weighing approximately 66.7 kg. Literal infringement would require analysis of the actual dose, patient weight, administration frequency, and other claim limitations.

Is Trisenox protected by a biosimilar patent strategy?

No. Trisenox contains a small-molecule active ingredient. Generic-drug rules, including the ANDA pathway, apply rather than the biosimilar pathway.

Can a patent license extend the term of U.S. Patent 6,723,351?

No. A license can allocate enforcement or commercial rights during the patent term, but it cannot extend the statutory expiration date or create an exclusionary right after expiration.

References

United States Patent and Trademark Office. (2004). U.S. Patent No. 6,723,351: Method of treating acute promyelogenous leukemia with arsenic trioxide. https://patents.google.com/patent/US6723351B2/en
U.S. Food and Drug Administration. (2024). Trisenox (arsenic trioxide) injection prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	1397399	⤷ Start Trial
Australia	2002300339	⤷ Start Trial
Australia	747474	⤷ Start Trial
Brazil	9814857	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,723,351

Summary for Patent: 6,723,351