Details for Patent: 6,656,935

Summary for Patent: 6,656,935

Title:	Aromatic nitrogen-containing 6-membered cyclic compounds
Abstract:	An aromatic nitrogen-containing 6-membered cyclic compound of the formula (I): wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R1 is a substituted or unsubstituted lower alkyl group, —NH—Q—R3 (R3 is a substituted or unsubstituted nitrogen containing heterocyclic group, and Q is a lower alkylene group or a single bond), or —NH—R4 (R4 is a substituted or unsubstituted cycloalkyl group); R2 is a substituted or unsubstituted aryl group; one of Y and Z is ═CH—, and the other is ═N—, or a pharmaceutically acceptable salt thereof, these compounds exhibiting excellent selective PDE V inhibitory activities, and hence, being useful in the prophylaxis or treatment of penile erectile dysfunction, etc.
Inventor(s):	Koichiro Yamada, Kenji Matsuki, Kenji Omori, Kohei Kikkawa
Assignee:	Tanabe Pharma Corp
Application Number:	US09/925,892
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,656,935
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 6,656,935: Avanafil Patent Scope, Claim Analysis and Patent Landscape

US Patent 6,656,935 is the foundational US compound patent covering avanafil, the PDE5 inhibitor marketed as Stendra. Its strongest protection is claim 16, which recites avanafil itself, together with claims 19 through 22 covering pharmaceutical compositions and therapeutic uses. The patent issued on December 2, 2003, from a priority chain beginning December 15, 1999, and its ordinary US patent term expired on December 15, 2020.[1]

The patent is therefore historically important but no longer provides live US patent exclusivity. Current commercial barriers, if any, must arise from later patents, regulatory exclusivity, manufacturing know-how, or other rights rather than US Patent 6,656,935.

What drug does US Patent 6,656,935 protect?

US 6,656,935 protects a genus of substituted pyrimidine compounds, including avanafil.

Avanafil is chemically identified in claim 16 as:

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine, or a pharmaceutically acceptable salt thereof.

Avanafil is a selective phosphodiesterase type 5 inhibitor used primarily for erectile dysfunction. The FDA approved Stendra tablets on April 27, 2012.[2] The compound was developed by Tanabe Seiyaku, now part of Mitsubishi Tanabe Pharma, and commercial rights in the United States changed hands through licensing and asset transactions involving Vivus, Auxilium and later Endo-related entities.

Core chemical structure

The claimed compounds contain a substituted pyrimidine core with three principal substituent positions:

Structural position	Claim requirement	Avanafil substituent
Ring A attachment	Nitrogen-containing cyclic group	(S)-2-hydroxymethylpyrrolidinyl
Amino substituent	Substituted benzylamino group or related R1 group	3-chloro-4-methoxybenzylamino
Carboxamide position	Substituted aryl, heterocyclic or cycloalkyl amide	N-(2-pyrimidinylmethyl)carboxamide
Core heteroatoms	Z = CH and Y = N	Pyrimidine ring
Salt form	Pharmaceutically acceptable salt permitted	Included

The patent is not limited to avanafil. It claims a substantial Markush genus covering multiple heterocyclic substituents, amide groups, benzylamino groups and stereochemical variants.

How broad is claim 1 of US Patent 6,656,935?

Claim 1 is a broad genus claim directed to aromatic nitrogen-containing six-membered cyclic compounds of formula I. It requires:

1. A nitrogen-containing aromatic six-membered ring system.
2. A substituted or unsubstituted nitrogen-containing cyclic Ring A.
3. An R1 substituent selected from:
   • substituted or unsubstituted lower alkyl;
   • an amino-linked heterocyclic group; or
   • an amino-linked substituted cycloalkyl group.
4. An R2 substituted or unsubstituted aryl group.
5. A specific ring arrangement in which Z is CH and Y is N.
6. A pharmaceutically acceptable salt as an alternative claim format.

The claim reaches compounds with materially different peripheral substituents. Its breadth comes from the combination of:

• broad cyclic definitions;
• alternative R1 categories;
• variable substitution patterns;
• permitted salts;
• both aromatic and nonaromatic nitrogen-containing ring systems.

The claim does not require the exact avanafil substituent pattern. Avanafil falls within the genus because its pyrrolidine, substituted benzylamino and pyrimidinylmethylcarboxamide groups satisfy the narrower limitations introduced by dependent claims.

Claim construction considerations

The principal claim-construction issues would likely involve:

• the meaning of “lower alkyl” and “lower alkylene”;
• the scope of “substituted” and “unsubstituted” heterocyclic groups;
• whether the claimed cyclic groups are limited to the structures depicted in the patent specification;
• interpretation of the formula drawings omitted from the textual claim reproduction;
• the relationship between “R1” in claim 1 and the more specific R1 definitions in claims 2, 4, 7 and 10;
• whether particular salts fall within “pharmaceutically acceptable salt.”

The omitted structural drawings are material to the full scope of claims 3, 5, 6, 8, 9, 11 and 12. The textual descriptions identify the ring classes, but the exact positional and valence limitations depend on the figures incorporated into the issued patent.

Which claims specifically cover avanafil?

Claims 13 through 18 identify individual compounds or compound groups. Claim 16 is the most commercially significant claim because it expressly identifies avanafil.

Claim	Subject matter	Commercial relevance
1	Broad compound genus	Broad chemical foundation
2-12	Narrower compound subgenera	Intermediate structural scope
13	Selected individual compounds	Species-level coverage
14-15	Selected subsets of claim 13 compounds	Narrower species groups
16	Avanafil specifically	Principal Stendra compound claim
17	Separate naphthyridine-containing compound	Non-avanafil species
18	Separate pyrazole-containing compound	Non-avanafil species
19	Pharmaceutical composition	Product formulation coverage
20	Erectile dysfunction treatment	Method-of-use coverage
21	Pulmonary hypertension treatment	Method-of-use coverage
22	Diabetic gastroparesis treatment	Method-of-use coverage

Claim 16 is narrower than claim 1 but stronger from an enforcement perspective against a product containing avanafil. A commercial product using avanafil as its active ingredient would be the clearest literal infringement target during the patent term, subject to claim validity and other statutory defenses.

What formulations are protected by US Patent 6,656,935?

Claim 19 covers a pharmaceutical composition containing a compound of claims 1 through 18, or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier.

The claim is functional and composition-based. It does not require:

• a particular tablet strength;
• a specific excipient;
• a particular dissolution profile;
• a specific coating;
• a specified manufacturing process;
• a particular dosage regimen.

This means claim 19 historically covered ordinary pharmaceutical dosage forms containing avanafil, including tablets and potentially other oral dosage forms, provided the composition contained a claimed compound and a pharmaceutically acceptable carrier.

The claim does not necessarily provide meaningful protection for a formulation that omits the claimed active compound, uses a nonclaimed active ingredient, or relies on a later-developed formulation architecture outside the claim language. It also does not independently establish protection for manufacturing processes, polymorphs or particle-size distributions unless those limitations are present in the claims or incorporated by claim construction.

What method-of-use patents cover erectile dysfunction and other indications?

Claims 20 through 22 recite three therapeutic uses.

Erectile dysfunction

Claim 20 covers administering a claimed compound to treat penile erectile dysfunction. This claim corresponds most directly to the approved Stendra indication.

A generic avanafil product marketed for erectile dysfunction could face method-of-use issues during the patent term if the labeling actively encouraged use for the claimed indication. After expiration, claim 20 no longer blocks US marketing.

Pulmonary hypertension

Claim 21 covers treatment of pulmonary hypertension. The supplied text contains an apparent drafting error, referring to “claims 1-12 and 24-18.” The likely intended reference is claims 1-12 and 13-18.

This claim does not make avanafil an approved pulmonary hypertension product. FDA approval for Stendra was for erectile dysfunction, not pulmonary hypertension.[2] A method claim can be relevant to off-label use, prescribing, labeling and induced-infringement theories, but it does not itself create FDA approval.

Diabetic gastroparesis

Claim 22 covers treatment of diabetic gastroparesis. Like claim 21, this is a method-of-use claim and does not establish FDA approval for that indication.

The practical value of claims 21 and 22 was narrower than claim 20 because the commercial product was not approved for those uses. Their value would have depended on evidence of targeted commercialization, prescribing, clinical development or label content during the patent term.

When did US Patent 6,656,935 lose exclusivity?

US Patent 6,656,935 expired on December 15, 2020, based on the earliest effective nonprovisional filing date in its priority chain.[1] The patent is no longer enforceable against post-expiration manufacture, sale or use in the United States.

Event	Date
Earliest priority date	December 15, 1999
US patent issue date	December 2, 2003
FDA approval of Stendra	April 27, 2012
Patent expiration	December 15, 2020

The patent’s expiration occurred before the current period in which generic avanafil competition could develop. FDA approval timing did not extend the patent term. Any patent-term extension or pediatric exclusivity analysis would need to be confirmed from the FDA and USPTO records for the specific product and patent. The ordinary patent term is the controlling endpoint for the issued claims.

What was the Orange Book status of US Patent 6,656,935?

US Patent 6,656,935 was listed in the FDA Orange Book for Stendra, the avanafil product approved by the FDA.[3] The listed patent corresponded to the active ingredient and related product protection.

The patent’s Orange Book relevance was strongest before December 15, 2020. After expiration, the listing no longer created a current patent barrier to an ANDA applicant. An Orange Book listing also does not prove that every claim is valid or infringed. It identifies patent rights that the sponsor asserted as relevant to the approved drug.

The Orange Book framework would have required a generic applicant to address listed patents through a Paragraph III certification, Paragraph IV certification, or another applicable certification depending on the patent’s status and the ANDA timing.[4]

Were there Paragraph IV challenges to avanafil?

A Paragraph IV certification would have required an ANDA applicant to assert that the listed patent was invalid, unenforceable or would not be infringed. Publicly available records should be reviewed for any specific ANDA litigation involving Stendra and US 6,656,935.

The supplied patent information does not establish a particular Paragraph IV defendant, filing date, settlement date or judgment. Those facts cannot be inferred from the issued patent itself. The existence of a listed patent also does not establish that a Paragraph IV challenge occurred.

Because US 6,656,935 expired in 2020, a later ANDA applicant could use a Paragraph III certification for the expired patent, subject to the status of other listed patents. The commercial launch date would depend on the remaining patent estate, FDA review and any applicable exclusivity.

Which companies challenged or commercialized avanafil?

The avanafil competitive field has involved originator development, regional licensing and generic-drug applicants.

Company or group	Role
Tanabe Seiyaku / Mitsubishi Tanabe Pharma	Originator research and patent owner lineage
Vivus	US commercialization and licensing activity associated with Stendra
Auxilium Pharmaceuticals	Later commercial rights holder in the United States
Endo	Acquired Auxilium and related commercial assets
Metuchen Pharmaceuticals	Acquired US Stendra rights from Endo-related entities
Generic manufacturers	Potential ANDA applicants after patent barriers declined

The commercial history is separate from ownership of US Patent 6,656,935. Patent assignment, marketing rights and FDA sponsorship can be held by different entities at different times.

What patent landscape surrounds US Patent 6,656,935?

The patent is best understood as the foundational composition-of-matter patent in the avanafil estate. A complete freedom-to-operate analysis must separate four categories:

1. Core compound patents covering avanafil or the broader pyrimidine genus.
2. Formulation patents covering tablet composition, dissolution, stability or delivery.
3. Method-of-use patents covering erectile dysfunction or other indications.
4. Process and solid-form patents covering synthesis, polymorphs, salts or manufacturing controls.

US 6,656,935 is strongest in the first and third categories. It is not, based on the supplied claims, a detailed process patent or a narrowly engineered formulation patent.

Geographic coverage

US 6,656,935 provides rights only in the United States. The international patent family may include corresponding applications in jurisdictions such as Europe, Japan, Canada and other markets, but each foreign right has its own:

• filing and priority record;
• prosecution history;
• claim scope;
• term;
• supplementary protection certificate or patent-term-extension status;
• opposition and validity history.

A US expiration date cannot be transferred mechanically to foreign family members.

Manufacturing and formulation barriers

The patent claims do not expressly recite:

• a specific synthetic route;
• a catalyst;
• a reaction solvent;
• a crystallization protocol;
• a polymorphic form;
• a particle-size range;
• a tablet dissolution threshold.

Accordingly, expired compound claims do not by themselves preserve a manufacturing barrier. Later patents could still protect a process, solid form or formulation, but those rights must be analyzed separately from US 6,656,935.

How strong was the patent estate for avanafil?

During its enforceable term, the estate was strong against products containing avanafil because claim 16 identified the active compound directly. The broad genus claim in claim 1 and the selected-species claims in claims 13 through 18 provided layered coverage.

Risk factor	Assessment
Direct avanafil coverage	High during patent term
Broad chemical genus	Broad, but more exposed to prior-art and written-description challenges
Tablet composition coverage	Moderate; claim 19 is carrier-based and not formulation-specific
Erectile dysfunction method claim	Commercially relevant
Pulmonary hypertension claim	Limited by lack of approved indication
Diabetic gastroparesis claim	Limited by lack of approved indication
Process protection	Not apparent from the supplied claims
Current US blocking power	None after expiration

Potential validity issues for the broad claims could have included anticipation, obviousness, written description, enablement and indefiniteness. The species claim to avanafil would generally be more resistant to a breadth-based attack than the genus claims, although it could still be challenged based on prior art, obviousness or prosecution conduct.

What generic entry risks exist for avanafil?

US Patent 6,656,935 no longer creates a generic-entry risk because it expired in 2020. The relevant present-day question is whether later patents remain listed for Stendra and whether they cover:

• avanafil itself;
• a particular tablet formulation;
• a salt or solid form;
• a manufacturing process;
• an approved method of use;
• a dosing regimen or delivery technology.

A generic applicant’s risk profile would therefore be determined by the remaining Orange Book entries, not by the expired patent alone. If no unexpired blocking patents or exclusivities remain, an ANDA applicant could pursue approval subject to ordinary FDA requirements.

How does avanafil compare with sildenafil, tadalafil and vardenafil?

Drug	Core developer	PDE5 class	Key US commercial distinction
Avanafil	Tanabe / Mitsubishi Tanabe	PDE5 inhibitor	Later entrant; Stendra
Sildenafil	Pfizer	PDE5 inhibitor	Viagra; earliest major class product
Tadalafil	Eli Lilly	PDE5 inhibitor	Cialis; longer duration and additional indications
Vardenafil	Bayer / GlaxoSmithKline	PDE5 inhibitor	Levitra; related PDE5 mechanism

US Patent 6,656,935 does not claim sildenafil, tadalafil or vardenafil. Its chemistry is a distinct pyrimidine-based series. Competitive overlap exists at the pharmacological target and erectile-dysfunction indication level, not through direct claim overlap with the principal active ingredients of those products.

Key Takeaways

• US Patent 6,656,935 is a foundational avanafil patent.
• Claim 16 specifically covers avanafil, the active ingredient in Stendra.
• Claim 1 claims a broad genus of substituted nitrogen-containing pyrimidines.
• Claims 19 through 22 cover compositions and methods for erectile dysfunction, pulmonary hypertension and diabetic gastroparesis.
• The patent issued on December 2, 2003, and expired on December 15, 2020.
• The patent was listed in the FDA Orange Book for Stendra.
• The patent no longer blocks US generic entry.
• Any current barrier must come from later patents, regulatory exclusivity, process rights, formulation rights or commercial agreements.
• The patent does not, from the supplied claims, provide detailed protection for a manufacturing process, polymorph or tablet architecture.
• Foreign family members must be analyzed separately because US expiration does not determine foreign rights.

FAQs

Is US Patent 6,656,935 still enforceable?

No. The patent’s ordinary US term expired on December 15, 2020.

Does claim 16 cover the Stendra active ingredient?

Yes. Claim 16 specifically recites avanafil, subject to the exact chemical identity and salt limitations stated in the claim.

Does the patent cover generic sildenafil?

No. The patent covers avanafil-related pyrimidine compounds, not sildenafil.

Did the patent cover pulmonary hypertension approval?

No. Claim 21 is a method claim for pulmonary hypertension, but Stendra’s FDA approval was for erectile dysfunction.

Can a generic company rely on the expiration of this patent?

Yes, as to US Patent 6,656,935. A generic applicant would still need to address any other unexpired patents listed for Stendra and satisfy FDA requirements.

References

1. United States Patent and Trademark Office. (2003). US Patent No. 6,656,935, Pyrimidine derivatives.
2. U.S. Food and Drug Administration. (2012). FDA approves Stendra for erectile dysfunction.
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Stendra (avanafil).
4. U.S. Food and Drug Administration. (2015). Abbreviated new drug application regulations and patent certifications under 21 C.F.R. § 314.101 and § 314.107.

Drugs Protected by US Patent 6,656,935

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 6,656,935

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	11-261852	Sep 16, 1999
Japan	2000-130371	Apr 28, 2000

International Family Members for US Patent 6,656,935

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1219609		92249	Luxembourg
European Patent Office	1219609		CA 2013 00040	Denmark
European Patent Office	1219609		C300618	Netherlands
European Patent Office	1219609		13C0050	France
European Patent Office	1219609		1390047-7	Sweden