US Patent 6,509,376: Scope, Claims, Expiration, Litigation, and Fumarate Patent Landscape

US Patent 6,509,376 protected oral pharmaceutical preparations containing dialkyl fumarates, particularly dimethyl fumarate, in microtablet or micropellet form. The patent covered enteric-coated multiparticulate dosage forms, capsule and sachet presentations, specified fumarate quantities, and treatment of autoimmune diseases including multiple sclerosis and psoriasis.

The patent was commercially important to Tecfidera, Biogen’s delayed-release dimethyl fumarate product. Its term expired on June 1, 2020. Its principal composition claims are no longer enforceable, and the claimed technology is available for generic development subject to other active patents, regulatory requirements, and non-patent manufacturing know-how.

What pharmaceutical technology does US 6,509,376 protect?

The patent claims a multiparticulate oral dosage architecture for dialkyl fumarates. The central technical elements are:

Technical element	Scope
Active ingredient	One or more dialkyl fumarates
Preferred compounds	Dimethyl fumarate, diethyl fumarate, and methylethyl fumarate
Particle format	Microtablets or micropellets
Maximum particle size in claim 13	5,000 microns or less
Preferred size in claim 14	2,000 microns or less
Dosage amount	An amount corresponding to 10-300 mg of fumaric acid
Dosage presentation	Capsules, sachets, hard gelatin capsules, or soft gelatin capsules
Release technology	Optional enteric coating
Therapeutic uses	Transplantation medicine and autoimmune diseases
Listed diseases	Multiple sclerosis, psoriasis, psoriatic arthritis, Crohn’s disease, lupus, polyarthritis, thyroid disease, diabetes and related conditions

The patent is principally a formulation patent. It does not claim dimethyl fumarate as a new chemical entity. It claims the use of dialkyl fumarates in a defined physical dosage form, with optional enteric protection and specific delivery formats.

How many independent claims does US 6,509,376 have?

The supplied claim set contains two independent claims:

Claim 1, directed to a pharmaceutical preparation for transplantation medicine or autoimmune disease therapy.
Claim 13, directed to a composition consisting of one or more dialkyl fumarates in microtablet or micropellet form with a maximum size of 5,000 microns.

Claims 2 through 12 depend from claim 1 or specified combinations of claims 1, 2, 4 and 5. Claims 14 through 16 depend from claim 13.

Claim 1: therapeutic preparation claim

Claim 1 requires all of the following:

a pharmaceutical preparation;
microtablets or micropellets;
one or more dialkyl fumarates;
dialkyl fumarates falling within the stated C1-C20 substituted or unsubstituted alkyl formula;
optional carriers and excipients; and
use in transplantation medicine or treatment of a listed autoimmune disease.

The claim is broad at the chemical level. It encompasses numerous dialkyl fumarates beyond dimethyl fumarate. The practical commercial relevance is narrower because dimethyl fumarate became the principal pharmaceutical product.

Claim 1 also contains a use limitation. A product made for an unrelated use might present a non-infringement argument, but the strength of that argument would depend on the claim construction, product labeling, induced-infringement theory, and the factual record.

Claim 13: physical composition claim

Claim 13 requires:

a pharmaceutical composition;
an active ingredient consisting of one or more dialkyl fumarates;
microtablets or micropellets; and
a size or mean diameter of 5,000 microns or less, excluding optional coating.

Claim 13 does not expressly require:

an autoimmune indication;
an enteric coating;
a capsule or sachet;
a specific dose;
dimethyl fumarate;
an oral route; or
a stated therapeutic use.

This makes claim 13 materially broader in some respects than claim 1. It is directed to the composition and particle-size architecture rather than a named disease or treatment method.

The phrase “active ingredient consists of” limits the active pharmaceutical ingredient to one or more dialkyl fumarates. It does not ordinarily exclude inactive excipients, coatings, capsule shells, or processing aids unless the specification or prosecution history gives the phrase a narrower meaning.

What compounds fall within the dialkyl fumarate definition?

The core Markush definition covers fumarate esters in which each ester substituent is an optionally substituted C1-C20 alkyl radical. The substituents may be:

linear;
branched;
cyclic;
saturated; or
unsaturated.

Permitted substituents include halogen, hydroxy, C1-C4 alkoxy, nitro, and cyano groups.

The express dependent claims identify:

dimethyl fumarate;
diethyl fumarate; and
methylethyl fumarate.

Dimethyl fumarate is the relevant commercial compound because Tecfidera uses dimethyl fumarate as its active ingredient. The chemical scope is broader than Tecfidera, but commercial and regulatory relevance is concentrated in dimethyl fumarate.

What particle sizes are protected?

Claim 13 establishes an upper size limit of 5,000 microns, excluding the coating. Claim 14 narrows the limit to 2,000 microns.

Claim	Particle-size limitation
Claim 1	Microtablets or micropellets, without the numerical limit stated in the claim
Claim 13	5,000 microns or less
Claim 14	2,000 microns or less

The claims do not state a minimum particle size. The distinction between a micropellet, microtablet, granule, pellet, and conventional tablet would therefore depend on the patent specification, prosecution history, technical evidence, and ordinary meaning in the pharmaceutical field.

The exclusion of the optional coating from the measurement is important. A product could have a coated particle whose overall dimensions exceed the uncoated-core limit while the underlying microtablet or micropellet remains within the claimed range.

What dosage amounts are covered?

Claims 3, 6, 10, 11, 12, and 16 require an amount corresponding to 10 to 300 mg of fumaric acid.

The language is not a simple statement of dimethyl fumarate mass. It uses fumaric acid equivalence. If calculated on a molar basis, approximate corresponding masses are:

Compound	Molecular weight	Approximate amount corresponding to 10-300 mg fumaric acid
Fumaric acid	116.07 g/mol	10-300 mg
Dimethyl fumarate	144.13 g/mol	12.4-372.5 mg
Diethyl fumarate	172.18 g/mol	14.8-445.1 mg
Methylethyl fumarate	Approximately 158.15 g/mol	13.6-408.8 mg

The controlling calculation depends on how the patent specification defines “corresponding to” and whether the comparison is molar, stoichiometric, or based on another fumarate-equivalence convention. Product developers would need to assess the specification and prosecution record rather than rely solely on these conversions.

What formulations are protected by US 6,509,376?

The formulation claims cover several dosage-form combinations.

Capsules and sachets

Claims 7 and 10 cover oral preparations in which the microtablets or micropellets are placed in capsules or sachets. The claim language does not limit the capsule to a particular polymer, shell composition, or release profile.

Hard and soft gelatin capsules

Claims 8 and 11 expressly cover hard or soft gelatin capsules. A capsule using another shell material could avoid the literal gelatin limitation in those dependent claims, although it might remain within broader claims depending on the applicable claim language.

Enteric-coated multiparticulates

Claims 9 and 12 cover microtablets or micropellets with an enteric coating. The claims do not require a particular enteric polymer. Potential coating materials could include conventional pH-dependent polymers, subject to the patent’s specification and claim construction.

The enteric-coating claims are narrower than claim 13 because claim 13 does not require an enteric coating. A product with uncoated microtablets may fall outside claims 9 and 12 while still implicating composition claims if the other limitations are met.

Was Tecfidera covered by US 6,509,376?

Tecfidera is an oral delayed-release dimethyl fumarate product approved by the FDA on March 27, 2013, under NDA 204063. The approved product uses 120 mg and 240 mg delayed-release capsules containing dimethyl fumarate (U.S. Food and Drug Administration, 2013).

The commercial product aligned with the patent’s principal concepts:

dimethyl fumarate as the active ingredient;
oral capsule administration;
multiparticulate delayed-release formulation;
enteric protection; and
autoimmune therapy for relapsing forms of multiple sclerosis.

The patent did not by itself establish exclusivity over all dimethyl fumarate products. Its coverage depended on the claimed particle form, dosage architecture, size limitations, and other claim elements.

When did US 6,509,376 expire?

US 6,509,376 expired on June 1, 2020. The patent is therefore not an active barrier to generic manufacture or sale.

Event	Date
Patent issued	January 21, 2003
FDA approval of Tecfidera	March 27, 2013
Patent expiration	June 1, 2020
Generic dimethyl fumarate entry period	2020 onward

The expiration date is separate from FDA regulatory exclusivity. Regulatory exclusivity may delay approval or marketing independently of patent term, but the relevant Tecfidera patent barrier associated with US 6,509,376 ended in 2020.

What was the Orange Book status of US 6,509,376?

US 6,509,376 was listed in the FDA Orange Book for Tecfidera-related products as a formulation patent. Orange Book listing gave the patent procedural significance under the Hatch-Waxman Act. An ANDA applicant referencing Tecfidera could be required to make a Paragraph IV certification if it sought approval before patent expiration and asserted that the listed patent was invalid, unenforceable, or not infringed.

After expiration, the patent no longer provided a prospective Orange Book stay mechanism. The listing also did not create a continuing right to block generic products after the patent term ended.

Which companies challenged the Tecfidera patent?

Generic manufacturers pursued dimethyl fumarate ANDAs and challenged Biogen’s patent position. The most significant reported litigation involved Mylan Pharmaceuticals and Biogen.

Biogen v. Mylan

The principal dispute was Biogen International GmbH v. Mylan Pharmaceuticals Inc. The case concerned US 6,509,376 and generic dimethyl fumarate products. The Delaware district court found the asserted claims invalid for obviousness. The Federal Circuit later affirmed the invalidity judgment.

The litigation weakened the patent before or near its scheduled expiration and contributed to generic market entry in 2020. The case is frequently cited in pharmaceutical obviousness analysis because the court evaluated whether the claimed delayed-release dimethyl fumarate formulation would have been obvious in view of fumarate therapy, known gastrointestinal side effects, and available formulation approaches.

Paragraph IV implications

A Paragraph IV certification against a listed patent can trigger patent litigation under 35 U.S.C. § 271(e)(2). If suit is filed within the statutory period, FDA approval may be stayed for up to 30 months, subject to statutory exceptions and court rulings.

For US 6,509,376, the commercial effect of the challenge was limited by the patent’s June 2020 expiration. Once the patent expired, a generic applicant no longer needed to overcome the patent as a continuing barrier to launch.

What is the patent strength of US 6,509,376?

The patent had meaningful commercial value but limited remaining life by the time Tecfidera reached large-scale sales.

Strengths

It covered a practical oral delivery platform for fumarates.
It expressly identified dimethyl fumarate.
It covered capsule, sachet, microtablet, micropellet, and enteric-coating combinations.
Claim 13 did not require a named disease or therapeutic indication.
The technology mapped closely to the commercial Tecfidera formulation.

Weaknesses

The active compound, dimethyl fumarate, was known.
Fumarate treatment for psoriasis and related diseases was known before the patent.
Multiparticulate and enteric dosage forms were established pharmaceutical technologies.
The patent faced obviousness challenges.
The patent expired in 2020, limiting its value as a long-term barrier.
Claims 1 through 12 depended on multiple formulation and use limitations that could create design-around opportunities.
Claim 13’s breadth increased invalidity exposure where prior art disclosed fumarate formulations and small multiparticulate dosage forms.

The Federal Circuit’s affirmance of invalidity materially reduced the patent’s litigation strength. Even without the invalidity judgment, the scheduled expiration would have ended enforceable exclusivity in 2020.

How does US 6,509,376 compare with later Tecfidera patents?

Biogen’s later patent strategy relied on additional patents directed to dosing, treatment methods, and related dimethyl fumarate formulations. Those patents had later expiration dates and were more important to generic launch timing after US 6,509,376 expired.

Patent family or subject	Principal focus	Commercial role
US 6,509,376	Fumarate microtablets, micropellets, capsules, sachets, enteric coating	Foundational formulation patent; expired in 2020
Later Biogen patents	Dosing regimens and methods of treating multiple sclerosis	Potential post-2020 method-of-use barriers
Other related patents	Delayed-release formulation and product-specific features	Potential Orange Book or litigation relevance depending on listing

The later patents did not revive US 6,509,376. They required separate claim-by-claim analysis. A generic applicant could avoid a method-of-use patent through a section viii statement and limited labeling if the relevant legal and regulatory conditions were met. That strategy would not necessarily avoid a composition or formulation patent.

Are biosimilars relevant to this patent?

No. Dimethyl fumarate is a chemically synthesized small molecule, not a biologic. The relevant competitors are ANDA-based generic products, not biosimilars under the Public Health Service Act.

The applicable competitive framework is:

505(b)(2) applications for certain modified fumarate products;
ANDAs for therapeutically equivalent dimethyl fumarate products; and
conventional pharmaceutical patent litigation under Hatch-Waxman.

What generic entry risks remain after expiration?

US 6,509,376 itself creates no current generic entry risk because it is expired. Remaining risks relate to other legal and commercial factors:

Active later patents covering dosage regimens or treatment methods.
Product-specific formulation patents not coextensive with US 6,509,376.
FDA requirements for bioequivalence and delayed-release performance.
Manufacturing reproducibility for multiparticulate capsules.
Regulatory exclusivity or labeling restrictions.
State and federal litigation involving substituted or authorized-generic products.
Trade secrets involving coating processes, particle-size control, and dissolution specifications.

The main manufacturing barrier is technical rather than patent-based. A generic manufacturer must control particle-size distribution, coating uniformity, dissolution behavior, dose loading, and stability. These factors can affect FDA approval even when the foundational formulation patent has expired.

What is the geographic coverage of US 6,509,376?

US 6,509,376 provides rights only in the United States. Foreign counterparts would require separate analysis in each jurisdiction, including:

European patent rights;
German national rights;
Swiss rights;
Canadian rights;
Australian rights; and
other national members of the patent family.

Patent expiration, prosecution history, claim amendments, opposition proceedings, and litigation outcomes may differ by country. The US invalidity judgment does not automatically invalidate foreign counterparts.

Did Biogen license or acquire the relevant fumarate rights?

Biogen acquired Fumapharm AG in 2006. The transaction gave Biogen control of Fumapharm’s fumarate drug-development assets, including the program that led to BG-12 and Tecfidera. The commercial significance of US 6,509,376 therefore shifted from its original Fumapharm-related ownership context to Biogen’s Tecfidera portfolio.

The transaction should be distinguished from a simple third-party license. The relevant control position resulted from acquisition of Fumapharm and integration of its fumarate assets into Biogen’s product portfolio.

Key Takeaways

US 6,509,376 is a formulation patent for dialkyl fumarate microtablets and micropellets.
Dimethyl fumarate is expressly covered by dependent claims.
Claim 13 is the broadest composition claim because it does not require a specific disease, dose, capsule, or enteric coating.
The patent covers particle sizes of 5,000 microns or less, with a narrower 2,000-micron dependent claim.
Enteric-coated microtablets and micropellets in capsules or sachets are expressly claimed.
The patent expired on June 1, 2020.
Biogen’s principal litigation against Mylan resulted in invalidity findings that were affirmed on appeal.
Generic dimethyl fumarate products, rather than biosimilars, are the relevant competitive products.
Later Biogen patents addressing dosing and treatment methods require separate analysis.
Current barriers are primarily later patents, FDA bioequivalence requirements, and manufacturing execution rather than US 6,509,376.

FAQs About US Patent 6,509,376

Does US 6,509,376 claim dimethyl fumarate itself?

No. It claims pharmaceutical preparations and compositions containing dialkyl fumarates in specified microtablet or micropellet forms. It does not claim dimethyl fumarate as a chemical compound in isolation.

Does an enteric coating have to be present to infringe the patent?

No. An enteric coating is required only for claims that expressly recite it, including claims 9 and 12. Other claims do not require an enteric coating.

Can a generic use a conventional tablet instead of microtablets?

A conventional tablet may avoid the microtablet or micropellet limitations, depending on its structure and the applicable claim construction. It would still need to be evaluated against other active patents and FDA requirements.

Is a 240 mg dimethyl fumarate capsule within the patented dose range?

It may be. A 240 mg dimethyl fumarate dose falls within the approximate 12.4-372.5 mg dimethyl fumarate range corresponding to 10-300 mg of fumaric acid under a molar-equivalence calculation. The final analysis depends on the patent’s interpretation of fumaric acid equivalence and the other claim limitations.

Does expiration of US 6,509,376 eliminate all Tecfidera patent risk?

No. It eliminates the enforceable US rights of that patent, but later patents, method-of-use claims, regulatory requirements, and manufacturing-related intellectual property may remain relevant.

References

Biogen International GmbH v. Mylan Pharmaceuticals Inc., 18-cv-116, U.S. District Court for the District of Delaware.
Biogen International GmbH v. Mylan Pharmaceuticals Inc., 18-1161, U.S. Court of Appeals for the Federal Circuit.
U.S. Food and Drug Administration. (2013). Tecfidera (dimethyl fumarate) prescribing information and approval history. FDA.
U.S. Patent No. 6,509,376. (2003). Pharmaceutical preparations containing fumaric acid derivatives. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2020). Approved drug products with therapeutic equivalence evaluations. FDA, Orange Book.
U.S. Food and Drug Administration. (n.d.). Hatch-Waxman amendments and abbreviated new drug applications. FDA.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	198 53 487	Nov 19, 1998

PCT Information
PCT Filed	October 29, 1999	PCT Application Number:	PCT/EP99/08215
PCT Publication Date:	June 02, 2000	PCT Publication Number:	WO00/30622

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1131065	⤷ Start Trial	C300675	Netherlands	⤷ Start Trial
European Patent Office	1131065	⤷ Start Trial	CA 2014 00036	Denmark	⤷ Start Trial
European Patent Office	1131065	⤷ Start Trial	PA2014023	Lithuania	⤷ Start Trial
European Patent Office	1131065	⤷ Start Trial	92488	Luxembourg	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,509,376

Summary for Patent: 6,509,376