United States Patent 6,140,329: Scope, Claims, Expiration, and Tadalafil Patent Landscape

U.S. Patent 6,140,329 covered the use of tadalafil-related tetracyclic compounds for treating erectile dysfunction, including tadalafil itself, pharmaceutical compositions, oral administration, combination therapy, and specified chemical analogs. The patent was assigned to ICOS Corporation and commercialized through the Eli Lilly and ICOS Cialis alliance. Its U.S. patent term expired in 2017, eliminating current U.S. blocking rights under the patent. The patent remains relevant for historical freedom-to-operate analysis, Paragraph IV litigation, patent-family tracing, and interpretation of the earlier Cialis intellectual-property strategy.

What does U.S. Patent 6,140,329 cover?

The patent covers four principal subject-matter groups:

Broad methods of treating erectile dysfunction with a Markush class of pyrazino-pyrido-indole diones.
Specific tadalafil compounds and related stereoisomers.
Pharmaceutical compositions containing those compounds.
Combination products containing one of the claimed compounds and another therapeutic agent.

The claims are directed to erectile dysfunction in a "male animal." In practice, the commercial relevance was human erectile dysfunction, particularly treatment with tadalafil, the active ingredient in Cialis.

The patent is a second-generation species and use patent around a chemical series that includes tadalafil. It is broader than a single claim to tadalafil but narrower than a pure composition-of-matter patent covering every possible formulation or manufacturing process.

Core chemical structure

The claims identify a tetracyclic scaffold generally described as a pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione. The principal substituent pattern associated with tadalafil is:

A methylenedioxyphenyl group at the 6-position;
A methyl substituent at the 2-position;
The stereochemistry designated as (6R,12aR);
The dione-containing tetracyclic core.

The principal commercial compound is tadalafil, commonly identified as:

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione.

How broad is claim 1 of U.S. Patent 6,140,329?

Claim 1 is the broadest method claim. It covers treatment of erectile dysfunction by administering a compound of formula (I), including physiologically acceptable salts and solvates.

Its breadth comes from the permitted substituent definitions:

Claim element	Scope
R0	Hydrogen, halogen, or C1-C6 alkyl
R1	Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, or heteroarylalkyl
R2	Substituted or unsubstituted benzene, thiophene, furan, pyridine, or specified fused bicyclic rings
R3	Hydrogen or C1-C3 alkyl
Ring relationship	R1 and R3 may form a 3- or 4-membered alkyl or alkenyl chain
Therapeutic use	Treatment of erectile dysfunction
Patient	Male animal
Dosage route	Not limited in claim 1; oral administration is added by claim 8

Claim 1 is therefore a genus method claim. It does not require tadalafil specifically. A compound can fall within the claim if it satisfies the structural limitations, is administered for erectile dysfunction, and is covered by the defined salts or solvates.

Practical limitation of the genus claim

The claim does not cover every PDE5 inhibitor. Sildenafil, vardenafil, avanafil, and other chemically unrelated PDE5 inhibitors do not fall within claim 1 merely because they treat erectile dysfunction. The claim requires the specified tetracyclic chemical framework and substituent architecture.

The claim also requires treatment of erectile dysfunction. A compound structurally within the genus would not necessarily infringe claim 1 through a non-ED use, although other claims or patent families could apply to different indications.

Which claims specifically cover tadalafil?

Claims 2, 3, 5, 9, 11, 12, 13, 14, 19, and 21 contain or depend on species that include tadalafil or closely related tadalafil analogs.

Claim group	Relevance to tadalafil
Claim 2	Expressly lists tadalafil and a 3-methyl analog
Claim 3	Covers pharmaceutical compositions containing the listed compounds
Claim 5	Covers treatment using a composition under claim 3
Claim 9	Lists tadalafil among a larger group of chemical species
Claims 11-12	Composition and treatment claims corresponding to claim 9
Claims 13-14	Combination composition and formulation claims
Claim 19	Lists tadalafil and four closely related compounds
Claim 21	Treatment with compositions containing the claim 19 compounds

Claim 2 is particularly important because it expressly identifies the commercial tadalafil structure. Claim 3 adds a composition claim, which is commercially significant because it reaches a pharmaceutical product containing tadalafil with a pharmaceutically acceptable diluent or carrier.

What do claims 2 through 5 protect?

Claims 2 through 5 create a compound-specific treatment and composition package.

Claim 2: specific compounds

Claim 2 covers administration of two named compounds:

Tadalafil;
A 3S,6R,12aR dimethyl analog.

The claim also covers physiologically acceptable salts and solvates.

Claim 3: pharmaceutical composition

Claim 3 covers a pharmaceutical composition containing one of the two specified compounds with a pharmaceutically acceptable diluent or carrier.

The claim does not specify a particular dose, tablet strength, excipient, release profile, or manufacturing process. A conventional immediate-release tablet could fall within the claim if it contains a listed compound and a qualifying carrier.

Claim 4: preparation process

Claim 4 covers formulating the claim 3 compounds with a pharmaceutically acceptable diluent or carrier. This is a process claim directed to preparation of the pharmaceutical composition.

Claim 5: treatment using the composition

Claim 5 covers treating a male animal with an effective amount of the claim 3 composition. It links the composition to the therapeutic method.

What is the scope of claims 6 and 7 covering combination therapy?

Claims 6 and 7 cover combinations of a listed tadalafil-related compound with "another therapeutically active agent."

The other active agent is not limited to a named compound in the text supplied. The combination may be used simultaneously, separately, or sequentially for erectile dysfunction.

This language creates a broad combination-therapy category, but infringement would depend on several elements:

The combination must contain a claimed tetracyclic compound;
It must contain another therapeutically active agent;
The intended use must relate to erectile dysfunction;
The product or treatment must satisfy the composition or formulation limitations.

Claim 6 is a composition claim. Claim 7 requires a pharmaceutical formulation containing the combination and a pharmaceutically acceptable diluent or carrier.

The combination claims do not automatically cover Cialis co-administered with every prescription medicine. The product, label, marketing, or treatment protocol must support the claimed therapeutic combination and other claim elements.

What do claims 8 through 21 add?

Claims 8 through 21 increase species and formulation coverage.

Oral administration

Claims 8, 10, 17, and 20 add oral administration. These claims are narrower than the corresponding parent methods because they require the compound to be administered orally.

They could historically have been relevant to Cialis tablets, but they would not independently cover every oral erectile-dysfunction product. The active compound must still fall within the applicable chemical claim.

Expanded species list

Claims 9 through 14 cover a list of specific analogs, including compounds with:

Pyridylmethyl substitution;
Dihydrobenzofuranyl substitution;
Bromothienyl substitution;
Butyl or cycloalkyl substitution;
Methoxyphenyl and chloromethoxyphenyl groups;
Methylenedioxyphenyl groups;
Alternative stereochemical configurations;
A fused pyrrolo-pyrazino structure.

These claims extend beyond tadalafil but remain limited to the enumerated chemical species or compositions containing them.

Narrower formula claims

Claims 16 and 18 recite a narrower formula in which the R2 aromatic substituent is not expressly included in the text provided. These claims appear directed to a more limited portion of the chemical series, with restrictions on R0, R1, and R3.

Claims 15 and 18 also contain formulation limitations requiring a pharmaceutically acceptable diluent or carrier.

Drafting and transcription issues

The supplied claim text contains apparent transcription errors, including:

"siluent" instead of "diluent";
"pyrido...indole-14-dione" instead of "1,4-dione";
inconsistent bracket and stereochemical formatting;
a reference in claim 20 to claim 18 despite the preceding species claim structure;
inconsistent use of "sulfur" and "sulphur."

For legal analysis, the issued patent, certified file history, and any reexamination or court construction control over the reproduced text.

When did U.S. Patent 6,140,329 lose exclusivity?

The U.S. patent expired in 2017. The relevant commercial conclusion is that U.S. Patent 6,140,329 no longer provides an enforceable patent barrier against a qualifying tadalafil product.

Event	Date or period
Priority and development period	Mid-1990s
U.S. patent grant	October 31, 2000
Patent number	U.S. 6,140,329
Commercial product associated with patent	Cialis, tadalafil
U.S. patent expiration	2017
Generic tadalafil entry	2018 onward, subject to other patent settlements and remaining patents

The patent's expiration did not necessarily eliminate every Cialis-related patent. Eli Lilly held additional patents involving dosing regimens, formulations, polymorphs, and other product attributes. Generic entry therefore depended on the specific product, indication, dosage regimen, and certification strategy.

What was the Orange Book status of U.S. Patent 6,140,329?

U.S. Patent 6,140,329 was associated with Cialis and was relevant to the Orange Book patent landscape for tadalafil. Orange Book listing does not itself establish validity or enforceability. It identifies patents submitted by the NDA holder as potentially claiming the approved drug or an approved method of use.

For an ANDA applicant, a listed patent could trigger:

Paragraph I certification if the patent was not listed as relevant;
Paragraph II certification if the patent had expired;
Paragraph III certification if the applicant accepted approval after expiration;
Paragraph IV certification if the applicant alleged that the patent was invalid, unenforceable, or not infringed.

After expiration, the patent ceased to provide a future patent-based delay against approval, although the historical listing remained important to earlier ANDA litigation and settlement analysis.

Which companies challenged the Cialis patent estate?

The Cialis patent estate was challenged by multiple generic-drug manufacturers through ANDA Paragraph IV procedures. Publicly reported generic participants included Teva, Watson/Actavis, Mylan, and other ANDA sponsors pursuing tadalafil products.

The challenges generally addressed the broader Cialis patent portfolio rather than U.S. Patent 6,140,329 in isolation. Generic companies had commercial incentives to challenge:

The core tadalafil method and composition patents;
Formulation patents;
Once-daily dosing patents;
Other Orange Book-listed patents associated with Cialis.

Eli Lilly entered settlement arrangements that permitted generic tadalafil entry before the expiration of all asserted Cialis-related patents. The precise entry date depended on the generic company, dosage form, indication, and patent claims included in the settlement.

What patent litigation affected tadalafil and Cialis?

The main litigation issue was whether generic tadalafil products could launch before the full expiration of the Cialis patent portfolio.

Typical ANDA litigation questions included:

Whether the generic product practiced a claimed tadalafil composition or method.
Whether the listed patent was invalid for anticipation or obviousness.
Whether the patent claims were enabled and adequately described.
Whether the generic label induced infringement of method-of-use claims.
Whether a settlement unlawfully delayed generic competition.
Whether the generic formulation avoided later formulation or dosing patents.

For U.S. Patent 6,140,329, the most commercially important defenses would have involved claim construction, written description, enablement, anticipation, obviousness, and non-infringement. Because the patent covered a large genus and numerous analogs, the strength of a challenge could differ substantially between the broad genus claims and the expressly recited tadalafil species.

How strong was the patent estate for tadalafil?

The patent estate was strongest when considered as a portfolio rather than as U.S. Patent 6,140,329 alone.

Estate component	Strategic value
Core chemical and treatment claims	Covered tadalafil and related compounds
Species claims	Reduced design-around options for tadalafil itself
Composition claims	Applied to drug products containing specified compounds
Oral-use claims	Relevant to commercial tablet products
Combination claims	Added secondary-use coverage
Formulation patents	Potentially delayed specific product designs
Dosing patents	Protected once-daily or other regimen claims
Manufacturing patents	Could restrict production routes or intermediates

The broad genus claims were exposed to validity challenges because they covered many compounds and substituent combinations. The express tadalafil claims were easier to analyze but could be more commercially important. A generic manufacturer could avoid some claims by changing the active ingredient, but a product intended to be tadalafil could not avoid an unexpired valid claim directed specifically to tadalafil or its approved use merely by changing excipients.

What manufacturing and formulation barriers did the patent create?

U.S. Patent 6,140,329 was not primarily a manufacturing-process patent. Its principal barriers were therapeutic-use and composition claims.

The patent could nevertheless affect manufacturing through:

Production of tadalafil-containing pharmaceutical compositions;
Preparation of salts or solvates;
Formulation of tablets or other dosage forms;
Combination products with another active agent.

Separate patents in the Cialis family were more likely to address:

Specific crystalline or polymorphic forms;
Tablet formulation;
Dissolution or stability characteristics;
Manufacturing intermediates;
Alternative synthetic routes.

A manufacturer could avoid a process patent while still infringing a composition or method claim. Conversely, a manufacturer could use a different manufacturing route without avoiding a product claim directed to tadalafil itself.

How did tadalafil compare with competing erectile-dysfunction drugs?

Drug	Active ingredient	Principal innovator	Chemical relationship to claim 1
Cialis	Tadalafil	ICOS/Eli Lilly	Directly within the claimed tadalafil-related series
Viagra	Sildenafil	Pfizer	Chemically distinct; not covered merely by treating ED
Levitra/Staxyn	Vardenafil	Bayer/GlaxoSmithKline	Chemically distinct
Stendra/Spedra	Avanafil	Vivus/Menarini	Chemically distinct
Zydena	Udenafil	Dong-A	Chemically distinct

U.S. Patent 6,140,329 did not function as a general erectile-dysfunction patent. Its commercial significance came from its relationship to tadalafil and the Cialis product, not from its coverage of the entire PDE5 inhibitor market.

What was the licensing and commercial structure behind Cialis?

ICOS Corporation discovered and developed tadalafil. In 1998, ICOS entered a development and commercialization alliance with Eli Lilly and Company. Lilly later acquired ICOS in 2007, consolidating ownership and commercialization rights for Cialis and related assets.

The alliance was commercially important because the patent estate and product rights were developed through a combined biotechnology-pharmaceutical structure. U.S. Patent 6,140,329 is associated with that ICOS-originated tadalafil program and the subsequent Lilly commercial franchise.

No separate public license is required to understand the patent's current U.S. status: the patent has expired, and the historical ICOS-Lilly relationship explains its ownership and commercialization history.

What generic launch risks remain after expiration?

After expiration of U.S. Patent 6,140,329, the primary remaining risks for a tadalafil generic are regulatory and portfolio-specific rather than infringement risks under this patent.

A generic launch analysis should distinguish:

Tadalafil active ingredient;
As-needed erectile-dysfunction labeling;
Once-daily erectile-dysfunction labeling;
Benign prostatic hyperplasia indication;
Dosage strength;
Formulation and excipients;
Polymorphic or crystalline form;
Manufacturing route;
Combination use;
Remaining Orange Book patents.

The expiration of one patent does not automatically clear every Cialis-related claim. A product may be clear of the '329 patent yet face a separate patent directed to a dosing regimen, formulation, polymorph, or additional indication.

What is the current business significance of U.S. Patent 6,140,329?

The patent has no remaining U.S. exclusionary value because its term expired. Its business significance is historical and analytical:

It identifies the chemical series underlying tadalafil;
It shows how ICOS and Lilly layered genus, species, formulation, and method claims;
It explains part of the timing of generic Cialis entry;
It remains relevant in patent-family and prosecution-history reviews;
It can help determine whether older litigation or settlement documents involved tadalafil species claims.

Cialis generated multibillion-dollar global sales during its commercial peak. Lilly reported Cialis revenue of approximately $2.3 billion in 2013, before generic competition and loss of exclusivity reduced sales.[5]

Key Takeaways

U.S. Patent 6,140,329 covered tadalafil-related tetracyclic compounds for erectile dysfunction.
Claim 1 is a broad Markush method claim; claims 2 and 3 are more commercially focused because they expressly cover tadalafil and tadalafil-containing compositions.
Claims 8, 10, 17, and 20 add oral-use limitations.
Claims 6, 7, 13, and 14 address combination therapy and combination formulations.
The patent expired in 2017 and no longer blocks U.S. tadalafil commercialization.
Generic challengers pursued the broader Cialis portfolio through Paragraph IV ANDA procedures.
The patent was important, but the full tadalafil exclusivity position depended on additional formulation, dosing, polymorph, and method-of-use patents.
The patent does not cover sildenafil, vardenafil, avanafil, or other chemically unrelated erectile-dysfunction drugs.
The ICOS-Lilly alliance explains the patent's commercial ownership and Cialis development history.

FAQs About U.S. Patent 6,140,329

Does U.S. Patent 6,140,329 cover Cialis?

Yes. The patent's claims include tadalafil, the active ingredient in Cialis, along with tadalafil-related compounds, compositions, oral-use methods, and combination products.

Can a generic tadalafil manufacturer still infringe U.S. Patent 6,140,329?

The patent's term expired in 2017, so it cannot presently support a new U.S. infringement action based solely on post-expiration conduct.

Is tadalafil a compound of formula (I) in claim 1?

Yes. Tadalafil is an expressly identified species within the chemical genus recited in claim 1 and is separately listed in several later claims.

Did the patent protect the Cialis tablet formulation?

Claims 3, 4, 5, 11, 12, 15, 18, and 21 cover compositions or formulations containing listed compounds with pharmaceutically acceptable carriers. Separate Cialis formulation patents may have provided more specific protection for particular tablet designs or excipient systems.

Does expiration of the '329 patent clear all tadalafil patent risk?

No. Other patents may have covered dosing regimens, formulations, polymorphs, manufacturing methods, or additional indications. Clearance must be performed against the full tadalafil patent portfolio and the specific proposed product label.

References

U.S. Patent No. 6,140,329. (2000). Treatment of erectile dysfunction. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
U.S. Food and Drug Administration. (2018). FDA approves first generic versions of Cialis to treat erectile dysfunction, benign prostatic hyperplasia. https://www.fda.gov/
Eli Lilly and Company. (2007). Lilly completes acquisition of ICOS Corporation. Lilly investor and corporate reports.
Eli Lilly and Company. (2013). 2013 annual report. Indianapolis, IN: Eli Lilly and Company.
U.S. Patent and Trademark Office. (n.d.). Patent Center. https://patentcenter.uspto.gov/

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9514464	Jul 14, 1995

PCT Information
PCT Filed	July 11, 1996	PCT Application Number:	PCT/EP96/03024
PCT Publication Date:	February 06, 1997	PCT Publication Number:	WO97/03675

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0740668	⤷ Start Trial	SPC004/2003	Ireland	⤷ Start Trial
European Patent Office	0740668	⤷ Start Trial	91017	Luxembourg	⤷ Start Trial
European Patent Office	0740668	⤷ Start Trial	PA2003001	Lithuania	⤷ Start Trial
European Patent Office	0740668	⤷ Start Trial	300124	Netherlands	⤷ Start Trial
European Patent Office	0740668	⤷ Start Trial	SPC/GB03/007	United Kingdom	⤷ Start Trial
European Patent Office	0740668	⤷ Start Trial	PA2003001,C0740668	Lithuania	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 6,140,329