US Patent 6,500,867: Claim Scope, Expiration, Orange Book Status and Generic Entry Risk

US Patent 6,500,867 protected fixed-dose oral tablets combining entacapone, levodopa and carbidopa while physically separating a substantial portion of carbidopa from entacapone and levodopa. The patent covered composition, formulation, tablet-design and manufacturing-process claims directed to the product later marketed as Stalevo. Its nominal US patent term ended in March 2020. The patent therefore creates no current US blocking right against generic manufacture or sale, although its claim structure remains relevant to historical ANDA litigation, freedom-to-operate reviews and the design of successor formulations.

What invention does US Patent 6,500,867 protect?

The patent protects a three-active fixed-dose tablet in which carbidopa is physically segregated from entacapone and levodopa within the dosage form. The separation may be achieved through separate powders, separate granules or separate granulation batches.

The technical rationale is formulation stability. Entacapone, levodopa and carbidopa can interact during processing or storage. The patent addresses that problem by limiting intimate contact between carbidopa and the other two active ingredients while retaining the therapeutic convenience of a single tablet.

The central limitations are:

Limitation	Scope
Dosage form	Oral solid tablet
Active ingredients	Entacapone, levodopa and carbidopa, or specified salts or hydrates
Dose requirement	Pharmacologically effective amounts, except where claims 21 and 23 specify amounts
Physical arrangement	A substantial portion of carbidopa separated from entacapone and levodopa
Excipients	Broadly defined in claim 1; specifically narrowed in claims 5, 8, 10 and 12
Manufacturing	Separate addition or separate granulation of carbidopa
Therapeutic result	Comparable effect to concomitant administration of the separate formulations, under claim 25

The patent does not claim entacapone alone, levodopa/carbidopa alone, or a package containing separate entacapone and levodopa/carbidopa tablets. The claims are directed to a single oral solid tablet containing all three actives.

How broad is independent claim 1?

Claim 1 is the principal composition claim. It requires:

An oral solid tablet;
Entacapone;
Levodopa;
Carbidopa;
A pharmaceutically acceptable excipient; and
Physical separation of a substantial portion of carbidopa from entacapone and levodopa.

The claim does not require a particular dose, tablet shape, excipient, granulation technique or release profile. It also does not expressly require two visually distinct layers. Separation may exist within a conventional monolithic tablet if the manufacturing process and resulting microstructure keep a substantial portion of carbidopa apart from the other actives.

What does “substantial portion” mean?

“Substantial portion” is the key breadth and litigation issue. The claims do not assign a numerical percentage to the term. A court would likely interpret it in light of the specification, examples, formulation process and technical purpose of the invention. The analysis would focus on whether the accused product separates enough carbidopa to materially reduce contact with entacapone and levodopa.

The absence of a fixed threshold creates both breadth and vulnerability:

The patentee can argue that the claim covers a range of physical arrangements, not only fully segregated layers.
An accused manufacturer can argue that the term lacks a sufficiently objective boundary.
Expert evidence would likely be required on granule morphology, particle distribution, manufacturing sequence and stability data.
A product with carbidopa uniformly blended into the same granules as entacapone and levodopa would have a stronger non-infringement position than a product made from separate carbidopa granules.

A product may infringe even if the tablet appears homogeneous externally. The relevant issue is the internal distribution of the active ingredients, not merely the tablet’s visual appearance.

What do dependent composition claims 2 through 12 add?

Claims 2 through 12 narrow claim 1 through formulation architecture and excipient selection.

Claim	Added limitation	Commercial significance
2	Entacapone and levodopa in granules; carbidopa in powder form	Covers extragranular addition of carbidopa
3	Entacapone/levodopa in first granules; carbidopa in second granules	Covers two-granule architecture
5	Sugar alcohol or starch excipient	Captures common tablet excipients
6	Mannitol	Narrows claim 5 to a specific sugar alcohol
7	Maize starch	Narrows claim 5 to a specific starch
8	Hydrogenated vegetable oil	Adds lubricant or processing excipient
9	Hydrogenated castor oil	Narrows claim 8
10	Disintegrant	Adds tablet-performance limitation
11	Croscarmellose sodium	Narrows claim 10
12	Stable tablet using an excipient other than microcrystalline cellulose	Creates a negative limitation excluding MCC

Claim 12 is strategically important because it does not require a specific replacement excipient. It excludes microcrystalline cellulose while retaining the separation requirement. A product using mannitol, maize starch, hydrogenated castor oil or another excipient could fall within the claim if the other limitations are met.

What process claims does US Patent 6,500,867 contain?

Claims 13 through 20 protect manufacturing routes rather than only the finished tablet.

What do claims 13 through 16 cover?

These claims cover separate addition of carbidopa to an entacapone/levodopa composition:

Claim 13 covers separate addition of carbidopa in powder or granule form.
Claim 14 requires separate mixing of entacapone and levodopa followed by separate carbidopa addition and conversion into a dosage form.
Claim 15 covers extragranular addition of powdered carbidopa to entacapone/levodopa granules.
Claim 16 covers addition of carbidopa granules to an entacapone/levodopa granule batch.

These claims can be infringed by the manufacturing process even if the final product is not marketed with detailed disclosure of its internal structure. In practice, discovery of batch records, master manufacturing formulas, validation protocols and granulation records would be central to an infringement case.

What do claims 17 and 18 cover?

Claims 17 and 18 require two separate granulation operations:

Entacapone and levodopa are mixed with excipient and disintegrant.
The first mixture is granulated.
Carbidopa is separately mixed with excipient and disintegrant.
The second mixture is separately granulated.
The two granule batches are blended with lubricant.
The blend is compressed into tablets.

Claim 18 limits the granulation method to wet granulation.

What do claims 19 and 20 cover?

Claims 19 and 20 require only one initial granulation batch:

Entacapone and levodopa are granulated.
Carbidopa, lubricant and optional excipients are added separately to that granule batch.
The resulting blend is compressed into tablets.

Claim 20 again specifies wet granulation.

The distinction between claims 17 and 19 gives the patent coverage over both a two-granulation process and a process in which carbidopa is added after granulation of entacapone and levodopa.

What tablet strengths and dimensions are protected?

Claims 21 through 24 cover a defined Stalevo-type tablet configuration:

Entacapone: 200 mg
Levodopa: 50 to 150 mg
Carbidopa: 10 to 37.5 mg
Tablet weight: 400 to 750 mg
Volume: 200 to 1,000 mm³

Claims 23 and 24 further specify:

Length: 13 to 18 mm
Width: 6 to 9 mm
Height: 4 to 7 mm
Oval shape under claim 24

These claims are narrower than claim 1 but potentially easier to prove through product inspection and laboratory testing. They create risk for a product that matches the standard 200 mg entacapone strength and uses conventional levodopa/carbidopa dose combinations.

A generic manufacturer could seek to avoid these claims by changing tablet dimensions, weight or geometry. That strategy would not necessarily avoid claim 1 or the broader process claims.

What does claim 25 protect?

Claim 25 covers an oral fixed-dose tablet containing the three active ingredients, with separated carbidopa, where the therapeutic effect is comparable to separate entacapone and levodopa/carbidopa formulations administered concomitantly at the same doses.

This claim adds a pharmacodynamic or clinical-performance limitation. It may be difficult to establish through ordinary product testing because “comparable” requires a defined comparator and an evidentiary standard. The claim also incorporates the physical-separation requirement, so therapeutic equivalence alone is insufficient.

The claim does not cover every clinically effective triple combination. The product must have the specified separation and achieve the claimed comparison with separate formulations.

When did US Patent 6,500,867 lose exclusivity?

The patent’s nominal US term ended in March 2020, based on the applicable 20-year term measured from the relevant US or international filing date. The patent was issued on December 31, 2002, but its expiration was governed by patent-term rules rather than the issue date.[1]

Event	Date or status
Priority and international filing history	1999-2000 family period
US patent issuance	December 31, 2002
Patent term	Approximately 20 years from the relevant filing date
Nominal expiration	March 2020
Current enforceability	Expired
Current US blocking effect	None, absent an unusual surviving term adjustment or separate enforceable patent

The expiration of US 6,500,867 does not eliminate other possible rights covering entacapone, manufacturing processes, crystalline forms, combinations or regulatory exclusivity. Those rights must be assessed separately by product and jurisdiction.

What was the Orange Book status of Stalevo?

Stalevo is a fixed-dose combination of carbidopa, levodopa and entacapone marketed by Novartis Pharmaceuticals Corporation under NDA 021485. The FDA approved Stalevo for patients with Parkinson’s disease experiencing end-of-dose “wearing-off” symptoms while receiving levodopa/carbidopa therapy.[2]

US 6,500,867 was associated with the patent estate for the fixed-dose combination. Orange Book listings are tied to the approved NDA and listed use, not simply to the chemical identity of the active ingredients.[3]

The relevant regulatory conclusions are:

Stalevo’s new-drug exclusivity is long expired.
Patent-based exclusivity associated with US 6,500,867 is long expired.
A generic applicant could rely on the abbreviated new drug application pathway for the corresponding strengths, subject to FDA requirements.
The expired patent cannot support a current Paragraph IV litigation threat.
Any current dispute would need to rely on a different unexpired patent, regulatory issue or non-patent claim.

FDA’s Orange Book should be checked for the current listing status because listings can be removed, changed or associated with different approved strengths over time.[3]

Which companies challenged or competed against Stalevo?

The competitive landscape has included generic pharmaceutical companies seeking approval for carbidopa/levodopa/entacapone tablets. Public generic competition has involved companies such as Teva Pharmaceuticals, Sandoz and other ANDA sponsors, depending on strength, formulation and approval timing.

A Paragraph IV challenge to US 6,500,867 would have asserted that the patent was invalid, unenforceable or not infringed. For a patent that has expired, a current Paragraph IV filing has no practical litigation value against future entry. Historical ANDA cases remain relevant because they may reveal:

How courts interpreted “substantial portion”;
Whether separate granules were viewed as necessary;
Whether the claims were vulnerable to obviousness arguments;
Whether a generic process was materially different;
Whether settlements included delayed-entry or license terms.

No current exclusivity barrier follows from the expired patent alone. Historical litigation status must be separated from present commercial risk.

How strong was the patent estate for Stalevo?

The estate was technically coherent but legally uneven.

Issue	Assessment
Core product concept	Strong historical coverage if separate carbidopa distribution could be demonstrated
Breadth of claim 1	Broad, but dependent on the undefined “substantial portion” limitation
Process coverage	Useful where the patentee could obtain manufacturing records
Tablet-dimension claims	Narrow and relatively easy to design around
Excipient claims	Narrower but potentially important for standard formulations
Claim 25	Potentially difficult to prove because of the comparability requirement
Current enforceability	None for the expired patent
Historical invalidity risk	Focus likely on obviousness, written description, enablement and claim construction

The prior art would likely include entacapone chemistry, levodopa/carbidopa therapy, separate administration of the active ingredients and conventional granulation methods. The patent’s strongest inventive feature was the specific physical separation of carbidopa in a single tablet, coupled with stability and manufacturing benefits.

The strongest non-infringement argument for a competing product would be that carbidopa is not substantially separated. The strongest invalidity argument would be that separate granulation or segregation was an obvious formulation response to known compatibility or stability concerns.

What formulation patents and manufacturing barriers remain relevant?

After expiration of US 6,500,867, the principal barriers are no longer its claims. A current product review should instead examine:

New crystalline or polymorphic forms of entacapone;
Carbidopa or levodopa salt and hydrate forms;
Controlled-release or modified-release systems;
Tablet coating and moisture-protection systems;
Stability-enhancing excipient systems;
Process patents covering granulation, blending or compression;
Combination products with different dose ratios;
Patents directed to treatment of motor fluctuations or specific Parkinson’s disease populations;
Foreign patents with different expiration dates;
Trade secrets involving granulation order, blending time and segregation control.

Manufacturing know-how can remain commercially relevant after patent expiry. It cannot, however, recreate an enforceable patent monopoly. A process that uses the same functional concept may be commercially acceptable if the expired patent is the only relevant right.

How does US 6,500,867 compare with separate-product patent protection?

Product strategy	Relationship to US 6,500,867	Current risk
Separate entacapone and levodopa/carbidopa tablets	Outside the claimed single-tablet format	Low risk from this patent
Three-active tablet with co-granulated actives	May avoid separation limitation	Requires product-specific testing
Three-active tablet with separate carbidopa granules	Closest to the claimed invention	Historically high risk; no current risk from expired patent
Three-active tablet with carbidopa added extragranularly	Directly implicated by claims 13-16	No current risk from expired patent
Different tablet strength or dimensions	May avoid claims 21-24	Does not avoid claim 1
Capsule or multiparticulate dosage form	Potentially outside “oral solid tablet” claims	Depends on construction and other patents
Modified-release tablet	May avoid this patent if separation or other limitations are absent	Requires separate patent review

What generic launch risks exist today?

The expired patent presents no current US launch delay or injunction risk. A generic applicant can pursue approval without waiting for the expiration of US 6,500,867, provided that the applicant satisfies FDA requirements for pharmaceutical equivalence, bioequivalence, labeling and manufacturing quality.

The practical risks are:

A different unexpired patent may cover a particular formulation or indication.
The FDA-approved reference product may have multiple strengths requiring separate ANDA analysis.
Bioequivalence may be complicated by the physical separation of carbidopa.
Manufacturing changes may affect dissolution, stability or impurity profiles.
Foreign-market entry may encounter patents with different term dates.
A branded manufacturer may rely on trade secrets or product quality advantages rather than the expired patent.

The likely launch scenarios are:

Scenario	Effect
Generic duplicates the historical separated-granule architecture	No barrier from US 6,500,867
Generic uses a different formulation	Lower technical overlap, but separate patent review remains necessary
Generic seeks only selected strengths	Strength-specific FDA and patent analysis required
Generic enters after full patent clearance	Commercial competition depends mainly on pricing and supply
Generic launches with manufacturing changes	Bioequivalence and stability become the primary execution risks

Key Takeaways

US 6,500,867 covers single oral solid tablets containing entacapone, levodopa and carbidopa.
The defining limitation is physical separation of a substantial portion of carbidopa from entacapone and levodopa.
Claims cover separate powders, separate granules, extragranular addition and separate wet-granulation processes.
Claims 21 through 24 protect specific 200 mg entacapone tablet strengths, dimensions, weight ranges and oval designs.
Claim 25 adds a therapeutic-comparability requirement that may be difficult to prove.
The patent’s nominal US term ended in March 2020.
It no longer creates a current US patent barrier to generic entry.
Stalevo’s current patent risk must be assessed through other unexpired patents, not US 6,500,867.
A product using separate carbidopa granules was historically closest to the patent’s core scope.
The principal post-expiry issues are FDA approval, bioequivalence, stability, manufacturing execution and any surviving patent families.

FAQs About US Patent 6,500,867

Does US Patent 6,500,867 cover Stalevo?

Yes. The claims are directed to the same general fixed-dose combination of entacapone, levodopa and carbidopa used in Stalevo, particularly where carbidopa is physically separated from entacapone and levodopa.

Can a generic avoid the patent by changing tablet size?

Changing tablet size may avoid claims 21 through 24, but it would not necessarily avoid claim 1 or the broader composition and process claims. The patent is now expired, so the distinction has no current US enforcement consequence.

Does the patent cover separate entacapone and carbidopa/levodopa tablets?

No. The claims require an oral solid tablet containing all three active ingredients. Separate tablets administered together fall outside the claimed single-tablet composition.

Are biosimilars relevant to entacapone, levodopa or carbidopa?

No. These are chemically synthesized small-molecule active ingredients, not biologic products. The relevant pathway is an ANDA for a generic drug, not a biosimilar application under the Public Health Service Act.

What is the main technical design-around for this patent?

A manufacturer could use a formulation without substantial physical separation of carbidopa, change the dosage form, or develop a different process. Because the patent expired, design-around work is now primarily relevant to other patents, product performance and manufacturing efficiency.

References

United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation resources. https://www.uspto.gov/patents/laws/patent-term-adjustment
U.S. Food and Drug Administration. (2003). Stalevo prescribing information. Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/daf/
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book
United States Patent and Trademark Office. (2002). U.S. Patent No. 6,500,867, Pharmaceutical composition. https://patents.google.com/patent/US6500867B1/en

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Finland	991485	Jun 30, 1999

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	033796	⤷ Start Trial
Austria	245417	⤷ Start Trial
Australia	5830600	⤷ Start Trial
Australia	765932	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,500,867

Summary for Patent: 6,500,867