US Drug Patent RE39221: Scope, Claims, Expiration, Orange Book Status, and Tramadol-Acetaminophen Patent Landscape

US Reissue Patent RE39,221 covered pharmaceutical compositions combining tramadol and acetaminophen, including the 37.5 mg tramadol hydrochloride/325 mg acetaminophen formulation commercialized as Ultracet. Its principal protection was a weight-ratio limitation, with claim coverage extending from approximately 1:1 to 1:1600 and narrower protection for ratios from approximately 1:5 to 1:19 and 1:19 to 1:50.

RE39,221 is no longer an enforceable US patent. The underlying patent family traces to US Patent No. 5,336,691, and the patent term expired in 2011. The patent therefore presents historical freedom-to-operate relevance and claim-construction value, but it does not create a current US barrier to generic tramadol-acetaminophen products.

What drug and formulation did US RE39221 protect?

RE39,221 protected combinations of tramadol and acetaminophen for pain treatment. The claims covered:

Tramadol generally, described in several claims as a “tramadol material.”
Tramadol hydrochloride.
Racemic tramadol hydrochloride.
Acetaminophen.
Weight ratios between tramadol and acetaminophen.
Pharmaceutical carriers.
Powders, capsules, tablets, suspensions, and solutions.
Oral treatment of pain in mammals.
Certain additional active ingredients, including decongestants, bronchodilators, antitussives, antihistamines, muscle relaxants, and sleep aids.

The commercially important formulation was the combination of 37.5 mg tramadol hydrochloride and 325 mg acetaminophen per tablet. The ratio is approximately 1:8.67 by weight, which falls within every relevant narrower ratio band in the patent:

Product strength	Tramadol HCl:acetaminophen ratio	Relevant claim ranges
37.5 mg/325 mg	1:8.67	1:1 to 1:1600; 1:5 to 1:1600; 1:5 to 1:50; 1:5 to 1:19
75 mg/650 mg	1:8.67	Same ranges
50 mg/300 mg	1:6	Same ranges
100 mg/650 mg	1:6.5	Same ranges

The ratio is calculated from the claimed materials. This creates a technical issue for products labeled by tramadol free-base equivalent rather than tramadol hydrochloride mass. A product developer must determine which mass the claim construction requires and whether the product’s actual composition falls within the claimed ratio.

What are the independent claims in US RE39221?

The independent claim groups are claims 1, 16, 31, 43, 55, and 67.

Claim	Core subject matter	Principal limitation
1	Pharmaceutical composition	Tramadol material and acetaminophen at about 1:1 to 1:1600
16	Composition with limited active ingredients	Active ingredient consists essentially of tramadol and acetaminophen; ratio about 1:1 to 1:1600
31	Narrower composition	Active ingredient consists essentially of tramadol and acetaminophen; ratio about 1:5 to 1:50
43	Narrower composition	Ratio about 1:5 to 1:19
55	Alternative ratio band	Ratio about 1:19 to 1:50
67	Most specific composition	Racemic tramadol hydrochloride and acetaminophen; ratio about 1:5 to 1:19; pharmaceutically acceptable carrier

Claims 1 and 16 are the broadest composition claims. Claim 1 permits a broader set of additional ingredients because it recites a composition “comprising” tramadol material and acetaminophen. Claim 16 uses “consists essentially of” for the active ingredient, limiting the active pharmaceutical portion while still permitting conventional excipients and carriers.

Claim 67 is materially narrower. It requires:

Racemic tramadol hydrochloride.
Acetaminophen.
A ratio of approximately 1:5 to 1:19.
A pharmaceutically acceptable carrier.
A composition “consisting essentially of” those specified components.

Claims 68 through 71 narrow claim 67 by dosage form. Claims 72 through 76 narrow the method claims by oral administration and, in some cases, by the specified dosage form.

How do the “comprising” and “consisting essentially of” limitations affect scope?

The transition terms create different infringement risks.

Claims using “comprising”

“Comprising” is open-ended. A composition may infringe even if it contains ingredients beyond tramadol and acetaminophen. Claims 1 through 15 therefore potentially reach combination products containing a third active ingredient, subject to the relevant dependent claim.

For example, a product containing tramadol, acetaminophen, and an antihistamine could fall within claim 12 if it also satisfies the inherited ratio and composition limitations.

Claims using “consists essentially of”

“Consists essentially of” is narrower than “comprising” but broader than “consisting of.” The claim generally permits ingredients that do not materially alter the basic and novel characteristics of the claimed composition.

The basic claimed combination is tramadol plus acetaminophen in a specified weight ratio. A third analgesic, opioid, sedative, or pharmacologically active ingredient could create a materiality dispute. Conventional excipients, binders, coatings, carriers, lubricants, and stabilizers are more likely to remain within the claim because the claims expressly contemplate pharmaceutically acceptable carriers.

The phrase does not automatically exclude every additional ingredient. The analysis depends on whether the additional component materially changes the claimed combination’s relevant characteristics.

What ratio ranges are protected by US RE39221?

The claims establish nested and adjacent ratio bands.

Ratio band	Claims	Practical significance
About 1:1 to 1:1600	1, 16 and dependents	Broadest numerical scope
About 1:5 to 1:1600	5, 22 and related claims	Excludes ratios closer to 1:1
About 1:19 to 1:800	7	Intermediate broad range
About 1:19 to 1:50	8, 55 and dependents	Commercially relevant narrow range
About 1:5 to 1:50	31 and dependents	Covers the commercial 37.5/325 ratio
About 1:5 to 1:19	43, 67 and dependents	Most commercially important narrow range

The repeated claim structure creates multiple infringement paths. A product that falls within the 1:5 to 1:19 range may also fall within the broader 1:5 to 1:50 and 1:1 to 1:1600 ranges.

The term “about” introduces tolerance around each endpoint. The patent does not provide a universal numerical percentage that automatically defines “about.” A court would evaluate the intrinsic evidence, technical context, prosecution history, and whether the accused ratio is meaningfully outside the claimed range.

Does Ultracet fall within the claims of RE39221?

Yes. Ultracet’s core immediate-release formulation contains 37.5 mg tramadol hydrochloride and 325 mg acetaminophen per tablet. The resulting ratio of approximately 1:8.67 falls between 1:5 and 1:19.

The product also fits the specific features of claim 67:

Racemic tramadol hydrochloride: yes.
Acetaminophen: yes.
Ratio between approximately 1:5 and 1:19: yes.
Pharmaceutical carrier or excipients: yes.
Tablet form: yes.

The formulation also falls within claim 69, which depends on claim 67 and specifies a tablet. An oral administration of that tablet would implicate claim 74, assuming the other limitations are met.

What is the patent history and expiration date of US RE39221?

RE39,221 is a reissue patent based on US Patent No. 5,336,691. The underlying patent concerns pharmaceutical compositions containing tramadol and acetaminophen. The reissue did not create a new patent term extending beyond the term available for the original patent.

Event	Date or status
Underlying US patent	US 5,336,691
Reissue patent	US RE39,221
Reissue grant	February 13, 2007
Original patent-term framework	Pre-URAA 17-year term from grant
Underlying patent expiration	August 9, 2011
Current enforceability	Expired
Current generic blocking effect	None

The key commercial date is August 9, 2011. The reissue grant date should not be treated as the start of a fresh 20-year term. Reissue practice corrects or changes patent claims within the statutory framework; it does not ordinarily reset the term.

Patent term adjustment, patent term extension, pediatric exclusivity, or regulatory exclusivity must be checked separately from the patent grant record. Those mechanisms do not change the current conclusion that RE39,221 is expired.

Sources for the patent record include the USPTO Patent Center and the official patent document for RE39,221. [1][2]

What was the Orange Book status of RE39221?

The relevant FDA product was Ultracet, an immediate-release tramadol hydrochloride and acetaminophen product marketed under NDA 021123. The patent was historically associated with the product’s regulatory exclusivity and generic-entry disputes.

An Orange Book listing does not itself determine validity, enforceability, infringement, or current commercial exclusivity. It identifies patents submitted by the NDA holder and accepted for listing under FDA rules.

RE39,221 no longer provides active Orange Book-based protection because its patent term expired. Current Orange Book review should distinguish:

Historical patent listings for Ultracet.
Active patents listed for any currently marketed NDA product.
Regulatory exclusivity, which is separate from patent rights.
The status of the NDA, including whether the reference product is active, discontinued, or subject to an approved generic market.

FDA’s Orange Book is the controlling public source for listed patent and exclusivity information. [3]

Were there Paragraph IV challenges to the Ultracet patent?

Yes. Generic applicants challenged the Ultracet patent estate through the ANDA Paragraph IV process, and litigation followed. The central patent disputes concerned whether generic tramadol-acetaminophen products infringed the combination claims and whether those claims were valid and enforceable.

The litigation risk was concentrated in three technical issues:

Whether the generic product used the claimed tramadol form and ratio.
Whether the product’s active ingredients “consisted essentially of” tramadol and acetaminophen.
Whether the asserted claims were valid over prior art concerning analgesic combinations.

Paragraph IV litigation can trigger a 30-month FDA approval stay under the Hatch-Waxman Act if statutory requirements are met. That mechanism had commercial significance before patent expiration. It has no current ability to delay approval based on an expired RE39,221 claim.

Public case records should be used to confirm the specific defendant, asserted claims, filing date, and disposition for each historical case. The patent record alone does not establish that every ANDA applicant challenged every claim.

Which companies competed with or challenged Ultracet?

The competitive field included generic manufacturers seeking approval for tramadol hydrochloride/acetaminophen tablets. Publicly reported generic applicants and manufacturers included companies such as Mylan, Teva, and Apotex, among others, depending on the specific strength, dosage form, and period reviewed.

The relevant commercial distinction is between:

A Paragraph IV filer challenging an Orange Book patent.
A Paragraph III filer accepting delayed entry.
An applicant whose product was approved after patent expiry.
A later generic manufacturer that entered without active patent litigation.

Those categories should not be treated as interchangeable. ANDA approval data, FDA litigation records, and federal court dockets provide the controlling evidence for a company-specific chronology. [3][4]

What formulation patents protect tramadol-acetaminophen products?

RE39,221 is primarily a composition and method-of-use patent. It is not narrowly limited to a particular tablet manufacturing process, dissolution profile, coating system, particle-size distribution, or excipient matrix.

The patent’s formulation-related coverage arises from:

The presence of tramadol and acetaminophen.
The ratio between those components.
The use of a pharmaceutical carrier.
The dosage form in dependent claims.
Oral administration for pain.

Claims 25 through 29 and 37 through 41 identify powder, capsule, tablet, suspension, and solution forms. Claims 68 through 71 are narrower because they apply those dosage-form limitations to the racemic tramadol hydrochloride formulation in claim 67.

A product may avoid these claims by changing the active ingredients, using a materially different ratio, or adopting a formulation outside the claimed composition. Changing only the excipient system may not avoid the broad composition claims if the active combination and ratio remain within scope.

Separate patents may have covered manufacturing, taste masking, modified release, abuse deterrence, or specific solid-state forms. Those patents must be analyzed independently. RE39,221 does not establish freedom to operate for every technical feature of a modern tramadol-acetaminophen product.

Does RE39221 create biosimilar risk?

No. Biosimilar risk is not relevant to RE39,221.

Tramadol and acetaminophen are chemically synthesized small molecules, not biological products regulated through the biosimilar pathway under the Public Health Service Act. Competitive entry occurs through abbreviated new drug applications, not biosimilar applications.

The relevant regulatory risks are:

ANDA patent certification.
Paragraph IV litigation.
Controlled-substance compliance for tramadol.
Labeling and bioequivalence requirements.
Acetaminophen safety and dosage controls.
Manufacturing and quality-system compliance.

How strong was the patent estate for RE39221?

The patent had meaningful historical commercial strength because it covered the active combination itself rather than only a narrow delivery technology. Its strongest claims were those directed to racemic tramadol hydrochloride and acetaminophen at approximately 1:5 to 1:19, particularly in tablet form.

Its weaknesses included:

Broad numerical ranges that invited prior-art and claim-construction challenges.
Dependence on the interpretation of “about.”
Potential disputes over whether ratios were calculated using tramadol free base or tramadol hydrochloride.
Limited protection against products with substantially different ratios.
A composition claim structure that did not necessarily protect noninfringing delivery technologies.
Expiration of the underlying patent term in 2011.

Strength factor	Assessment
Coverage of commercial 37.5/325 formulation	Strong
Coverage of alternative ratios	Broad
Protection of dosage forms	Moderate, through dependent claims
Manufacturing-process protection	Limited or absent from supplied claims
Method-of-use protection	Present but tied to the claimed composition
Biosimilar relevance	None
Current enforceability	None because expired

What generic launch scenarios existed and what risks remain?

Before expiration, generic launch scenarios included:

At-risk launch

A generic applicant could launch before final resolution of patent litigation after filing a Paragraph IV certification. This created potential damages and injunctive risk if the patent survived and the product was found to infringe.

Delayed launch

An applicant could accept a launch date tied to patent expiry, litigation settlement, or another agreed event. This reduced litigation exposure but delayed market entry.

Noninfringing design

A manufacturer could attempt to use a ratio outside the asserted claim range or a formulation that did not satisfy the “consists essentially of” limitation. Such a design would require technical and legal validation.

Post-expiry launch

After August 9, 2011, RE39,221 no longer supported an injunction or damages claim based on future manufacture, sale, or use.

Current risks are therefore commercial and regulatory rather than based on RE39,221. They include generic price erosion, controlled-substance supply requirements, acetaminophen labeling obligations, and potential rights under unrelated patents.

How does RE39221 compare with competing drug patent estates?

Product or estate	Active ingredient type	Primary patent risk	Biosimilar risk	Current RE39,221 relevance
Ultracet	Tramadol HCl plus acetaminophen	Historical composition and ratio claims	None	Expired
Tramadol monotherapy	Tramadol	Separate product, formulation, or method patents	None	Generally outside the combination claims
Acetaminophen monotherapy	Acetaminophen	Separate formulation and method patents	None	Outside the combination requirement
Other opioid-acetaminophen combinations	Different opioid plus acetaminophen	Separate composition estates	None	Outside tramadol limitation
Modified-release tramadol combinations	Tramadol plus another analgesic or delivery technology	Potential formulation and manufacturing patents	None	Requires separate analysis

RE39,221 was stronger against direct copies of the claimed tramadol-acetaminophen ratio than against products using a different active combination or a materially different ratio.

What is the current commercial and revenue exposure?

The direct revenue exposure attributable to RE39,221 is zero because the patent has expired. The patent no longer supports exclusivity pricing, an Orange Book stay, or a patent-based barrier to generic entry.

Historical exposure was concentrated in Ultracet and equivalent tramadol-acetaminophen products. Once generic products entered, the relevant economic effect shifted from patent exclusivity to generic substitution and reimbursement dynamics.

The patent remains relevant for:

Historical litigation review.
Due diligence on legacy Ultracet assets.
Analysis of settlement timing.
Interpretation of ANDA product design decisions.
Prior-art and claim-scope benchmarking for combination analgesics.

Key Takeaways

RE39,221 covered tramadol-acetaminophen compositions and pain-treatment methods.
The core commercial ratio, 37.5 mg tramadol hydrochloride to 325 mg acetaminophen, is approximately 1:8.67.
That formulation falls within the broad and narrow ratio claims, including claim 67 and tablet claim 69.
The patent’s strongest claim set required racemic tramadol hydrochloride, acetaminophen, a 1:5 to 1:19 ratio, and a pharmaceutical carrier.
The underlying patent term expired on August 9, 2011.
RE39,221 does not create current US generic-entry or Orange Book exclusivity risk.
The patent has no biosimilar relevance because the products are small-molecule drugs.
Current freedom-to-operate analysis must examine unrelated formulation, manufacturing, labeling, and controlled-substance patents separately.

FAQs About US RE39221 and Tramadol-Acetaminophen Patents

What was the main invention claimed by US RE39221?

The main invention was a pharmaceutical combination of tramadol and acetaminophen within specified weight ratios for treating pain.

Does a 37.5 mg tramadol and 325 mg acetaminophen tablet infringe RE39221 today?

No. Although that formulation historically fell within the claims, RE39,221 expired in 2011 and cannot support a current infringement action.

Did RE39221 cover tramadol alone?

No. The asserted composition claims require both tramadol material and acetaminophen.

Could a product with tramadol free base instead of tramadol hydrochloride avoid the patent?

Not necessarily. Some claims use the broader term “tramadol material,” while others specifically require tramadol hydrochloride. The answer depends on the particular claim, the product’s actual composition, and claim construction.

Are extended-release tramadol-acetaminophen products automatically covered by RE39221?

No. The supplied claims do not impose an extended-release limitation. Coverage would depend primarily on the active ingredients, ratio, dosage form, and other claim limitations, as well as any separate formulation patents.

References

United States Patent and Trademark Office. (2007). Reissue patent RE39,221: Pharmaceutical compositions containing tramadol and acetaminophen. USPTO Patent Center.
United States Patent and Trademark Office. (1994). United States Patent No. 5,336,691: Pharmaceutical compositions containing tramadol and acetaminophen. USPTO Patent Center.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. FDA.
U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application patent certifications and 30-month stays. FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0566709	⤷ Start Trial	91079	Luxembourg	⤷ Start Trial
European Patent Office	0566709	⤷ Start Trial	SPC/GB04/012	United Kingdom	⤷ Start Trial
European Patent Office	0566709	⤷ Start Trial	300152	Netherlands	⤷ Start Trial
European Patent Office	0566709	⤷ Start Trial	SPC023/2008	Ireland	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: RE39221

Summary for Patent: RE39221