Details for Patent: 7,459,561

Summary for Patent: 7,459,561

Title:	N-substituted carbamoyloxyalkyl-azolium derivatives
Abstract:	N-substituted carbamoyloxyalkyl-azolium derivatives which have antifungal activity and are useful for the treatment of fungal diseases.
Inventor(s):	Hiroshi Fukuda, Tadakatsu Hayase, Eisaku Mizuguchi, Nobuo Shimma, Jun Ohwada, Nobuhiro Oikawa, Masahiro Sakaitani, Masao Tsukazaki, Isao Umeda
Assignee:	Basilea Pharmaceutica International AG
Application Number:	US11/504,299
Patent Claim Types: see list of patent claims	Compound;

US Patent 7,459,561: Isavuconazonium Patent Scope, Claims, Expiration, and Generic Entry Risk

US Patent 7,459,561 protects triazole prodrugs structurally related to isavuconazole, including the cationic moiety used in Cresemba, isavuconazonium sulfate. The strongest commercial claims are claims 9, 10, 19, 20, and 21, which narrow the patent to defined pyridyl carbamate prodrug structures and pharmaceutically acceptable salts. The patent is listed in the FDA Orange Book for Cresemba and has an Orange Book expiration date of March 29, 2026.[1]

What drug does US Patent 7,459,561 protect?

US 7,459,561 is directed to water-soluble triazolium compounds that function as prodrugs of antifungal triazole compounds. The commercial product most closely associated with the patent is isavuconazonium sulfate, marketed as Cresemba by Pfizer in the United States.

Isavuconazonium is converted in vivo to isavuconazole. Isavuconazole is the active antifungal agent and inhibits fungal lanosterol 14-alpha-demethylase, an enzyme required for ergosterol biosynthesis.

Item	Description
Brand	Cresemba
Active ingredient	Isavuconazonium sulfate
Active antifungal moiety	Isavuconazole
Drug class	Triazole antifungal
Dosage forms	Oral capsules and intravenous injection
FDA approval	March 6, 2015
Initial sponsor	Basilea Pharmaceutica
U.S. commercial partner	Pfizer
Core patent	US 7,459,561
Orange Book expiration	March 29, 2026
FDA regulatory pathway	New drug application
Biosimilar pathway	Not applicable

The patent does not claim isavuconazole as a simple neutral compound. It claims cationic prodrug structures in which an isavuconazole-related triazole nitrogen is quaternized and connected to a pyridyl carbamate substituent.

What is the claimed chemical architecture?

The independent claims contain two related structural classes.

Claim 1 covers a triazolium cation combined with a pharmaceutically acceptable anion. The cation contains:

1. A triazole derivative, Q, based on a substituted butanol antifungal core.
2. A nitrogen linkage from the triazole ring to the remainder of the cation.
3. A pyridin-2-yl-containing carbamate framework.
4. Variable substituents R1 through R6.
5. A pharmaceutically acceptable counterion.

The Q group in claim 1 includes three aryl variants:

• 2,4-difluorophenyl;
• 2,4,5-trifluorophenyl; and
• 3-fluorophenyl.

Claim 15 creates a second independent genus directed specifically to the 2,5-difluorophenyl Q group. It separately defines a pyridyl carbamate structure and limits R6 to alkylaminoalkylcarbonyloxy or aminoalkylcarbonyloxy.

The commercial isavuconazonium structure is captured by the claim set through the combination of:

• the 2,4-difluorophenyl isavuconazole-derived Q group;
• the N-methyl pyridyl carbamate;
• the methylaminoacetoxy substituent;
• the triazolium linkage; and
• a pharmaceutically acceptable anion, including sulfate.

How broad is claim 1 of US 7,459,561?

Claim 1 is a broad genus claim. It does not require one single salt, one single aryl group, or one single R6 substituent. It covers numerous combinations of the listed structural variables.

Its principal breadth comes from five features:

Claim element	Scope
Q	Three specified substituted triazole antifungal cores
R1	Hydrogen or alkyl
R2	Hydrogen, alkyl, acyl, carbonate, and aminoalkyl-containing groups
R4 and R5	Broad aromatic substitution set, including halogen, alkoxy, cyano, nitro, sulfo, and related groups
R6	Hydroxy, amino, alkylamino, carbamate, ester, acylamino, and related substituents

The claim is limited to the disclosed chemical framework. It does not cover every triazole antifungal prodrug. A potentially competing compound would need to satisfy the structural limitations, including the defined Q group, the N-linked triazolium arrangement, the pyridin-2-yl carbamate system, and one of the enumerated substituent classes.

The phrase "pharmaceutically acceptable anion" broadens the salt coverage. A product containing the claimed cation with sulfate, chloride, bromide, or another pharmaceutically acceptable counterion may fall within the claim if all other structural limitations are satisfied.

What do claims 2 through 8 add?

Claims 2 through 8 progressively narrow claim 1.

Claim	Main limitation
2	R4 and R5 are hydrogen, halogen, or alkoxy
3	R4 and R5 are hydrogen
4	R6 is alkylaminoalkylcarbonyloxy
5	R1 is hydrogen or alkyl
6	R2 is alkyl
7	Q is the 2,4-difluorophenyl derivative
8	Combines the principal limitations and specifies a pharmaceutically acceptable acid anion

Claims 7 and 8 are commercially significant because they concentrate the claim scope around the 2,4-difluorophenyl derivative associated with isavuconazole.

Claim 8 is narrower than claim 1 but is potentially stronger as an infringement claim against a product using the exact commercial Q group, the defined pyridyl carbamate substitution pattern, and an acid-derived counterion.

What do claims 9 and 10 cover?

Claim 9 recites the specific isavuconazonium-type cation. The cation includes:

• an N-methyl-N-substituted pyridin-2-yl carbamate;
• a 3-[(methylamino)acetoxymethyl] pyridyl substituent;
• an ethyl carbamate linkage;
• the 2,4-difluorophenyl isavuconazole-derived Q group; and
• a triazolium nitrogen connection.

Claim 10 narrows this structure to the chloride salt, while also extending to pharmaceutically acceptable salts.

The claim language in claim 10 is important for Orange Book analysis. Although isavuconazonium sulfate is not chloride, the phrase "or a pharmaceutically acceptable salt thereof" can capture the sulfate form if the sulfate salt contains the same claimed cation and otherwise meets the claim limitations.

Claims 9 and 10 are therefore the most direct composition claims for the commercial isavuconazonium structure.

What do claims 11 through 14 cover?

Claims 11 through 14 cover alternative aryl Q groups:

• claims 11 and 12: the 2,4,5-trifluorophenyl derivative;
• claims 13 and 14: the 3-fluorophenyl derivative.

The cationic prodrug framework remains substantially the same as in claims 9 and 10. The change is the aryl substitution on the antifungal core.

These claims expand the patent beyond the commercial 2,4-difluorophenyl compound. They may have greater relevance to follow-on development programs using related isavuconazole analogues rather than to a conventional generic Cresemba product.

What do claims 15 through 21 cover?

Claims 15 through 21 constitute a second claim family directed to the 2,5-difluorophenyl Q group.

Claim 15 is independently structured and differs from claim 1 in several ways:

• Q is limited to the 2,5-difluorophenyl derivative.
• R6 is limited to alkylaminoalkylcarbonyloxy or aminoalkylcarbonyloxy.
• The R4 and R5 list includes additional substituent categories.
• The claim separately defines the pyridyl carbamate framework.

Claims 19 through 21 narrow the genus to the specific 2,5-difluorophenyl cation and its inorganic acid salts. Claim 21 expressly identifies chloride, bromide, and sulfate.

These claims are structurally important but less central to a generic isavuconazonium sulfate challenge if the generic product uses the commercial 2,4-difluorophenyl Q group.

What patent claims are most relevant to Cresemba?

The highest-risk claims for a generic isavuconazonium sulfate product are claims 8, 9, and 10.

Claim	Commercial relevance	Generic litigation relevance
1	High	High, broad genus
7	High	High, 2,4-difluorophenyl species
8	Very high	Very high, combined commercial configuration
9	Very high	Very high, specific cation
10	Very high	Very high, chloride and pharmaceutically acceptable salts
11-14	Moderate	Lower for standard Cresemba
15	Moderate	Low to moderate
19-21	Moderate	Lower for standard Cresemba

The commercial sulfate product is most likely evaluated against the cation limitations rather than the identity of the counterion alone. A generic manufacturer cannot avoid the patent merely by using sulfate instead of chloride if the relevant claim covers the pharmaceutically acceptable salt of the same cation.

When does US Patent 7,459,561 lose exclusivity?

The FDA Orange Book lists March 29, 2026, as the expiration date for US 7,459,561 in connection with Cresemba.[1] That date controls the principal patent-based barrier reflected in the Orange Book.

Exclusivity type	Relevant date
FDA approval	March 6, 2015
Five-year new chemical entity exclusivity	Approximately March 6, 2020
Seven-year orphan-drug exclusivity for original orphan indications	Approximately March 6, 2022
Core patent expiration	March 29, 2026

NCE and orphan exclusivity are regulatory protections, not patent rights. Their expiration does not invalidate the patent or authorize a product that infringes an unexpired Orange Book patent.

The March 29, 2026, date also should be distinguished from any other Cresemba-related patents covering formulations, dosing regimens, manufacturing processes, or other product attributes.

What is the Orange Book status of US 7,459,561?

US 7,459,561 is listed in the FDA Orange Book for Cresemba. The listing gives the patent commercial significance because an ANDA applicant must address the patent through one of the statutory certification routes.[1]

A generic applicant generally has four options:

• Paragraph I: no patent information is listed;
• Paragraph II: the patent has expired;
• Paragraph III: approval is requested after patent expiration; or
• Paragraph IV: the patent is invalid, unenforceable, or will not be infringed.

For a product filed before March 29, 2026, a Paragraph III certification would defer approval until the patent expires. A Paragraph IV certification can support earlier approval but creates litigation exposure.

Have generic manufacturers challenged Cresemba patents under Paragraph IV?

Public patent litigation involving generic isavuconazonium products has focused on Orange Book-listed Cresemba patents, including composition and related product protection. A Paragraph IV notice typically triggers a 45-day period in which the NDA holder or patent owner may sue for infringement under 35 U.S.C. §271(e)(2).[2]

A timely infringement suit can create a 30-month approval stay under the Hatch-Waxman framework, subject to court action and statutory exceptions.[3]

The relevant business question is not only whether a generic applicant has filed a Paragraph IV certification. It is whether:

1. the notice identifies US 7,459,561;
2. the patent owner files within 45 days;
3. the litigation is dismissed, settled, or decided;
4. the court issues a final judgment before March 29, 2026; and
5. other Orange Book patents independently delay approval.

The supplied claim set supports a strong infringement theory against a generic that reproduces the commercial isavuconazonium cation. A generic applicant could instead pursue a noninfringement position based on a different prodrug structure, a different linkage, a different Q group, or a non-equivalent substituent. Those approaches would require a separate pharmaceutical development program rather than a standard ANDA copy.

What patent litigation affects Cresemba generic entry?

Patent litigation risk is concentrated in Delaware and other federal venues commonly used for Hatch-Waxman disputes. The central issues for US 7,459,561 would likely include:

• construction of "pharmaceutically acceptable salt thereof";
• whether sulfate is covered by claims drafted around chloride;
• whether the accused product contains the claimed triazolium cation;
• the scope of the "linked ... by a nitrogen in the triazole" limitation;
• written description and enablement for the Markush genus;
• anticipation or obviousness based on earlier triazole prodrug disclosures; and
• terminal-disclaimer or patent-term issues, if applicable.

The most vulnerable portions of the patent are the broad genus claims, particularly claim 1 and claim 15. The most defensible commercial claims are the narrower species claims, particularly claims 9, 10, 19, and 20, assuming the patent specification adequately supports the exact structures and the claims survive validity challenges.

A litigation settlement could allow an authorized or licensed generic launch before the patent expiration date. The commercial terms of any settlement, including launch date, royalty, supply rights, and authorized-generic restrictions, would determine the actual entry date. No settlement term should be inferred from the patent expiration date alone.

How strong is the patent estate for isavuconazonium?

US 7,459,561 is a strong composition-of-matter patent for the commercial prodrug structure because it claims the molecular architecture itself rather than only a use or formulation.

Strength factor	Assessment
Direct coverage of commercial cation	Strong
Salt coverage	Strong if "pharmaceutically acceptable salt" is enforced broadly
Coverage of alternative analogues	Broad
Dependence on formulation	Low
Dependence on method of treatment	Low
Vulnerability of genus claims	Moderate
Vulnerability of exact species claims	Lower
Generic design-around difficulty	High for an ANDA copy
Post-expiration substitution risk	Limited for the exact compound

The patent does not depend on a particular capsule excipient, intravenous vehicle, dosing schedule, or treatment indication. That reduces the ability of a generic applicant to avoid infringement through ordinary formulation changes.

What formulation and method-of-use patents may affect entry?

A complete Cresemba freedom-to-operate review must separate the 7,459,561 composition claims from other patent categories.

Formulation patents

Formulation patents may cover:

• oral capsules containing isavuconazonium sulfate;
• injectable compositions;
• lyophilized formulations;
• reconstitution media;
• stabilizers and excipient ratios;
• improved solubility or bioavailability systems; and
• manufacturing and packaging configurations.

A generic could avoid a formulation claim while still infringing the composition patent. Conversely, expiration or invalidity of US 7,459,561 would not automatically eliminate separate formulation-patent risk.

Method-of-use patents

Method-of-use claims may address:

• treatment of invasive aspergillosis;
• treatment of invasive mucormycosis;
• dosing regimens;
• patient populations;
• renal impairment;
• hepatic impairment; and
• intravenous-to-oral conversion.

A section viii statement may be available for a generic that omits patented indications from its labeling, but that route depends on the precise Orange Book-listed use code and the final proposed label.[1]

Manufacturing patents

Manufacturing and process patents may cover:

• preparation of the triazolium prodrug;
• selective formation of the stereochemical Q group;
• salt formation;
• purification;
• crystallization;
• impurity control; and
• conversion between salt forms.

Process patents are usually less visible in the Orange Book than drug-product patents. They can still create commercial and supply-chain risk, particularly if the generic relies on the same synthetic route.

Is biosimilar risk relevant to Cresemba?

No. Cresemba is a small-molecule drug, not a biologic. The relevant competitive pathway is an ANDA for a generic isavuconazonium product, not a biosimilar application under the Public Health Service Act.

The generic must demonstrate pharmaceutical equivalence and bioequivalence to the listed drug. It does not need to establish biosimilarity or interchangeability.

Which companies could compete with Cresemba?

Competition can arise from four sources:

1. generic isavuconazonium sulfate products after patent and regulatory barriers fall;
2. an authorized generic launched under a settlement or licensing arrangement;
3. alternative triazole antifungals, including voriconazole, posaconazole, and itraconazole;
4. new antifungal classes or agents used in invasive mold infections.

Drug	Active ingredient	Main competitive position
Cresemba	Isavuconazonium sulfate	Invasive aspergillosis and mucormycosis
Vfend	Voriconazole	Established mold-active triazole
Noxafil	Posaconazole	Broad mold activity and prophylaxis
Sporanox	Itraconazole	Older triazole with broader tolerability and interaction limitations

Isavuconazonium has commercial differentiation from its prodrug design, which improves aqueous solubility and permits intravenous administration without the cyclodextrin vehicle associated with some competing azole products.

What is the generic launch scenario after March 2026?

The base case is potential generic entry shortly after March 29, 2026, subject to:

• ANDA approval;
• completion of any 30-month stay;
• resolution of other listed patents;
• approval of the generic’s manufacturing sites;
• satisfactory bioequivalence;
• any pediatric exclusivity adjustment; and
• settlement terms that may authorize an earlier launch.

A first-filer may obtain 180-day generic exclusivity if the statutory conditions are satisfied. That period can delay broad generic competition even after the core patent expires.

The highest-value commercial asset is therefore the exact isavuconazonium sulfate product. A successful Paragraph IV challenge could bring entry before March 2026. A failed challenge or Paragraph III certification would preserve the reference product’s effective composition protection until the listed expiration date.

What licensing deals affect the patent position?

Basilea developed isavuconazonium and entered into commercial arrangements with Pfizer for Cresemba in the United States and other territories. The commercial agreement affects marketing rights and revenue allocation but does not by itself change the patent’s term or claim scope.

Any generic settlement involving Pfizer, Basilea, or a patent-owning affiliate would be analyzed separately from the original license. The key terms would be the permitted launch date, royalty obligations, supply arrangements, and whether an authorized generic is allowed.

Key Takeaways

• US 7,459,561 is a composition patent covering cationic triazole prodrugs related to isavuconazole.
• The patent is directly relevant to isavuconazonium sulfate, the active ingredient in Cresemba.
• Claims 9 and 10 are the closest claims to the commercial isavuconazonium structure.
• Claims 1 and 15 provide broader genus coverage across multiple Q groups and substituent classes.
• The FDA Orange Book expiration date is March 29, 2026.
• Cresemba is subject to generic, not biosimilar, competition.
• A sulfate generic may remain exposed even though claims 10 and related claims identify chloride, because the claims extend to pharmaceutically acceptable salts.
• Formulation, method-of-use, manufacturing, and other Orange Book patents must be assessed separately.
• The principal generic strategy is a Paragraph IV challenge, a Paragraph III certification, or a design-around that avoids the claimed cation.
• The commercial generic-entry date may be earlier or later than March 29, 2026, depending on litigation, settlement, exclusivity, and other listed patents.

FAQs

Does US 7,459,561 claim isavuconazole itself?

No. The patent primarily claims cationic prodrug compounds containing an isavuconazole-related triazole core. Isavuconazole is released from the prodrug after administration.

Does the patent cover isavuconazonium sulfate?

The claims recite pharmaceutically acceptable anions and pharmaceutically acceptable salts. That language is capable of covering the sulfate salt of the claimed isavuconazonium cation, subject to claim construction and validity.

Can a generic avoid the patent by using a chloride-to-sulfate salt switch?

Not necessarily. A salt switch does not avoid a claim that covers the same cation with a pharmaceutically acceptable anion or salt. The full claim language must be compared with the proposed generic structure.

Is US 7,459,561 a formulation patent?

No. It is principally a composition-of-matter patent directed to defined triazolium prodrug structures and salts. Separate formulation or process patents may create additional risk.

What is the most important claim for Cresemba litigation?

Claims 9 and 10 are the most commercially focused because they recite the specific isavuconazonium-type cation and its salt forms. Claims 1, 7, and 8 provide broader or intermediate coverage.

References

1. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Cresemba, isavuconazonium sulfate. Orange Book.
2. United States Code. (2024). 35 U.S.C. § 271(e)(2): Infringement of patents relating to drug applications.
3. United States Code. (2024). 21 U.S.C. § 355(j): Abbreviated applications for new drugs.
4. U.S. Patent and Trademark Office. (2008). U.S. Patent No. 7,459,561, Triazole compounds.
5. Basilea Pharmaceutica Ltd. (n.d.). Cresemba product and corporate licensing information.

Drugs Protected by US Patent 7,459,561

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: 7,459,561

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	99121694	Nov 2, 1999

International Family Members for US Patent 7,459,561

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1280795		CA 2016 00002	Denmark
European Patent Office	1280795		92939	Luxembourg
European Patent Office	1280795		15C0096	France