Details for Patent: 8,299,057

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Which drugs does patent 8,299,057 protect, and when does it expire?

Patent 8,299,057 protects ROZLYTREK and is included in one NDA.

This patent has thirty-nine patent family members in twenty-nine countries.

Summary for Patent: 8,299,057

Title:	Substituted indazole derivatives active as kinase inhibitors
Abstract:	Substituted indazole derivatives of formula (I) and pharmaceutically acceptable salts thereof, as defined in the specification, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful in therapy in the treatment of diseases associated with a deregulated protein kinase activity, like cancer.
Inventor(s):	Andrea Lombardi Borgia, Maria Menichincheri, Paolo Orsini, Achille Panzeri, Ettore Perrone, Ermes Vanotti, Marcella Nesi, Chiara Marchionni
Assignee:	Nerviano Medical Sciences SRL
Application Number:	US12/668,745
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,299,057
Patent Claim Types: see list of patent claims	Composition; Compound; Process; Device;

United States Drug Patent 8,299,057: Claim Scope, Patent Landscape, Exclusivity and Commercial Risk

U.S. Patent No. 8,299,057 protects a broad class of substituted indazole benzamides, including CYC116, an investigational Aurora kinase inhibitor associated with Cyclacel Pharmaceuticals. The patent covers chemical entities, selected individual compounds, manufacturing routes, intermediates, pharmaceutical compositions and anticancer combination products. The strongest claim is claim 7, directed specifically to CYC116. The patent does not protect an FDA-approved drug, and it has no apparent Orange Book or approved-product exclusivity position.

What drug and active compound does U.S. Patent 8,299,057 cover?

The patent covers substituted indazole-3-carboxamides with variable aryl substituents and solubilizing amine groups. The central disclosed scaffold includes:

• A 1H-indazole ring.
• A carboxamide linkage at the 3-position.
• An aryl or heteroaryl group attached to the benzamide portion.
• Flexible substituents including piperazine, piperidine, morpholine, pyrrolidine and tetrahydropyranyl amino groups.
• Optional benzyl, substituted benzyl, benzylic alcohol, benzylic ether, ethyl and tertiary benzylic substituents.
• Optical isomers, tautomers and pharmaceutically acceptable salts.

The commercial lead associated with the patent is the compound recited in claim 7:

N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

This compound is commonly identified as CYC116, an Aurora kinase inhibitor evaluated in oncology research. CYC116 was investigational and did not obtain FDA approval based on the cited public development record.[1][2]

What are the key claims in U.S. Patent 8,299,057?

The claims divide into six legal categories.

Claims	Subject matter	Commercial relevance
1-5	Broad and intermediate Markush chemical genus	Potentially broadest composition-of-matter coverage
6	Large list of individually named compounds	Species coverage for lead optimization compounds
7	Specific CYC116 compound and salts	Strongest claim for the identified lead
8-11	Synthetic processes and interconversion reactions	Manufacturing and process protection
12	Pharmaceutical compositions	Broad composition coverage, but no specific formulation
13	Anticancer combination products or kits	Combination-use and packaging coverage
14-16	Protected intermediates and protected derivatives	Manufacturing and supply-chain barriers

Claim 1: broad chemical genus

Claim 1 is a Markush claim covering a large family of compounds defined by formula (I). It allows:

• X as methylene, hydroxymethine, alkoxymethine or substituted methine.
• Ar as phenyl, pyrazolyl or pyridyl.
• Extensive substitution on the Ar group.
• R as phenyl or pyridyl, with limited substitution.
• R1, R2 and R3 fixed as hydrogen.
• Pharmaceutically acceptable salts, optical isomers and tautomers.

The claim is structurally broad because the Ar substituent definitions include amines, alkoxy groups, nitro groups, sulfonamides, heterocycles, alkyl chains and substituted amides. The use of nested Markush definitions creates a large theoretical genus.

The practical scope is narrower than the literal enumeration suggests. Enforceability would depend on whether the patent specification adequately supports and enables the full chemical breadth, particularly combinations that were not specifically prepared or tested.

Claims 2-5: narrowing structural limitations

Claims 2 and 3 narrow the X substituent:

• Claim 2 limits R′ to C1-C3 alkyl.
• Claim 3 limits R′ to methyl.

Claims 4 and 5 narrow the substitution pattern on Ar. These claims are useful fallback positions if the broad genus in claim 1 faces an anticipation, obviousness, written-description or enablement challenge.

Claim 6: named compound list

Claim 6 recites a long list of specific compounds. The list includes:

• Benzyl, fluoro-benzyl and difluoro-benzyl indazole derivatives.
• 4-methylpiperazinyl benzamides.
• Tetrahydropyran-4-ylamino derivatives.
• Amino, nitro, sulfonamide and phenylamino analogues.
• Morpholine, piperidine, pyrrolidine and azetidine derivatives.
• Benzylic alcohol, ether, ethyl and tertiary benzylic analogues.
• Pyridine carboxamides and pyrazole carboxamides.
• Stereochemically defined compounds.
• Carbonyl-linked tertiary amine substituents.

Claim 6 contains apparent typographical and transcription errors, including malformed substituent names. Those errors do not automatically invalidate the claim, but they can create claim-construction disputes where a chemical identity is ambiguous.

Claim 7: CYC116 composition-of-matter claim

Claim 7 is the most commercially important claim. It is limited to CYC116 and its pharmaceutically acceptable salts.

The claim is materially stronger than claim 1 against a generic or follow-on compound that reproduces CYC116 exactly. It is materially weaker against:

• A structurally distinct Aurora kinase inhibitor.
• A regioisomer not covered by the claim.
• A different salt or formulation that does not contain the claimed active moiety in a legally infringing manner.
• A compound with a modified benzamide substituent.
• A compound with a different indazole substitution pattern.

A CYC116 manufacturer would likely face direct composition-of-matter infringement risk if the patent remained enforceable and the accused product contained the claimed compound or a covered salt.

What is the patent term and when does U.S. Patent 8,299,057 lose exclusivity?

The patent issued on October 30, 2012. Its priority chain traces to a European filing in December 2006, giving a nominal United States patent-term endpoint in December 2027, before any patent-term adjustment or terminal-disclaimer analysis.[1]

Event	Date
Earliest priority filing	December 2006
International or foreign-family development	2007-2008 period
U.S. patent grant	October 30, 2012
Nominal 20-year term endpoint	December 2027
FDA regulatory exclusivity	None identified
Orange Book listing	None identified
Practical branded-drug exclusivity	Not established because CYC116 was not approved

The relevant expiration date is not the grant date plus 20 years. For modern U.S. patents, the term generally runs 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers and other statutory calculations.[3]

Because the patent does not appear to support an approved FDA product, its business value is principally tied to research, licensing, clinical development or a future regulatory filing rather than an existing approved-drug monopoly.

What is the FDA and Orange Book status of the patent?

No FDA-approved drug is identified as relying on U.S. Patent 8,299,057. The patent is therefore not an Orange Book-listed patent for an approved reference product under the conventional Hatch-Waxman framework.[4]

Regulatory issue	Status
Approved active ingredient	None identified
New Drug Application	No approved NDA identified
Orange Book listing	None identified
Five-year new chemical entity exclusivity	None
Three-year clinical-investigation exclusivity	None
ANDA Paragraph IV activity	No meaningful public activity identified
Biosimilar pathway	Not applicable
505(b)(2) relevance	Possible only if a future sponsor develops a related product and satisfies statutory requirements

The lack of Orange Book status means a potential developer would not ordinarily encounter an ANDA certification dispute directed to this patent. A future product would more likely proceed through an NDA or, depending on the product and clinical history, a 505(b)(2) application.

Does the patent contain formulation patents?

The patent contains a composition claim, but it does not appear to contain a detailed, product-specific formulation estate.

Claim 12 covers a pharmaceutical composition containing:

1. A therapeutically effective amount of a formula (I) compound or salt; and
2. At least one pharmaceutically acceptable excipient, carrier or diluent.

This is a generic composition claim. It does not require:

• A particular tablet or capsule formulation.
• A specific dissolution profile.
• A defined particle size.
• A solid-state form.
• A polymorph.
• A controlled-release matrix.
• A specific excipient ratio.
• A particular route of administration.
• A bioavailability threshold.

Accordingly, the patent provides limited formulation differentiation. A later developer could seek separate protection for a CYC116 polymorph, salt, dosage form, amorphous dispersion, nanoparticle preparation, injectable formulation or controlled-release product if those inventions satisfied patentability requirements.

What method-of-use and combination claims does the patent contain?

Claim 13 covers a product or kit containing a formula (I) compound or composition together with one or more chemotherapeutic agents for simultaneous, separate or sequential anticancer use.

This claim is broader than a conventional treatment-method claim in some respects because it focuses on the combined preparation or kit. Its practical enforcement value depends on:

• The existence of an oncology product containing the claimed compound.
• The identity and use of the second chemotherapeutic agent.
• The contents and labeling of the kit.
• Evidence linking manufacture, sale or use to the claimed combined preparation.
• The scope of any divided-infringement defense.

The supplied claims do not identify a specific tumor type, dosing regimen, biomarker-defined population, combination partner or clinical endpoint. The method-of-use position is therefore less differentiated than a claim directed to a defined cancer, dosing schedule or synergistic combination.

How strong is the patent estate for CYC116?

The estate is strongest for the exact CYC116 molecule and weaker for broad genus and process coverage.

Patent component	Relative strength	Principal vulnerability
Claim 7, exact CYC116 compound	High	Anticipation, obviousness, term expiration
Claim 6, named species	Medium to high	Chemical identity errors, prior-art species
Claims 1-5, broad genus	Medium	Enablement, written description and obviousness
Claims 8-11, synthesis	Medium	Design-around processes and nonessential steps
Claim 12, generic composition	Low to medium	Lack of formulation specificity
Claim 13, combination kit	Medium	Divided infringement and limited therapeutic detail
Claims 14-16, intermediates	Medium	Alternative intermediates and process redesign

Composition-of-matter protection

The exact CYC116 claim is the principal barrier to direct launch of the same molecule. A competitor could still challenge validity based on:

• Earlier disclosed indazole benzamides.
• Earlier Aurora kinase inhibitor programs.
• Obviousness of combining a substituted indazole core with a substituted benzamide and solubilizing amine.
• Insufficient support for the claimed salt or stereochemical scope.

Process protection

The process claims cover reductions, coupling reactions, deprotection and selected intermediate preparation. They do not appear to require a single exclusive commercial manufacturing route. A generic manufacturer could reduce risk by:

• Using a different protecting group.
• Reversing the order of amide formation and indazole construction.
• Selecting a different catalyst or coupling reaction.
• Purchasing a key intermediate.
• Employing a noninfringing salt-conversion sequence.

Process claims are therefore secondary barriers unless the patented route provides a substantial cost, yield or impurity advantage.

Which companies are challenging the patent?

No public Paragraph IV challenger is identified. That result is consistent with the absence of an FDA-approved reference product and the lack of an Orange Book listing.

The principal commercial development association is Cyclacel Pharmaceuticals through CYC116 development. The patent family originated from European medicinal-chemistry research associated with Nerviano Medical Sciences, with subsequent development and licensing activity associated with Cyclacel.[1][5]

No publicly identified settlement agreement, consent judgment or patent litigation involving an ANDA applicant appears to have created a generic-entry timetable for this patent.

What licensing deals affect CYC116?

CYC116 development has been associated with Cyclacel Pharmaceuticals and an originating European research organization. The asset’s commercial path reflects licensing or collaboration rather than a marketed-product franchise.[5]

The patent itself does not disclose the economic terms of any license. Patent ownership, development rights, royalty obligations and sublicensing rights must be distinguished from the identity of the patent’s original applicant or named assignee.

Because CYC116 was not an approved product, there is no established revenue stream analogous to a marketed oncology drug. Commercial exposure is therefore development-stage rather than current product revenue exposure.

What generic launch risks exist after patent expiration?

A post-expiration launch would face lower patent risk but not necessarily low development risk.

Scenario 1: exact CYC116 generic

An exact-copy applicant would have the highest direct infringement risk before the relevant patent term ends. After expiration, the principal barriers would be:

• Clinical development cost.
• Demonstration of safety and efficacy.
• Manufacturing controls.
• API supply.
• Regulatory classification.
• Market demand.

Scenario 2: modified analog

A modified analog could avoid claim 7 but may fall within claim 1 or claim 6. The risk would depend on exact substitution at:

• The indazole benzyl position.
• The benzamide ring.
• The piperazine or tetrahydropyran group.
• The carbonyl linkage.
• The salt and stereochemical configuration.

Scenario 3: alternative Aurora kinase inhibitor

A competitor could avoid this patent by using a different chemical series. The relevant competitive landscape includes other investigational Aurora A, Aurora B and pan-Aurora kinase inhibitors, such as alisertib and danusertib. Those programs are protected by separate patent families and are not automatically covered by U.S. Patent 8,299,057.[6][7]

How does U.S. Patent 8,299,057 compare with competing Aurora kinase estates?

CYC116’s estate is chemically broad but commercially incomplete because the asset did not reach FDA approval.

Program	Target profile	Development position	Patent relevance
CYC116	Aurora kinase inhibitor	Investigational	U.S. 8,299,057 is central composition patent
Alisertib	Aurora A-selective inhibitor	Investigational oncology asset	Separate composition, formulation and use families
Danusertib	Pan-Aurora kinase inhibitor	Investigational	Separate chemical and use patent families
Barasertib	Aurora B inhibitor	Investigational	Separate prodrug and kinase-inhibitor estate

CYC116’s patent is stronger against an exact CYC116 copy than against the broader Aurora kinase competitive field. It does not create platform-wide control over Aurora kinase inhibition.

Key Takeaways

• U.S. Patent 8,299,057 covers substituted indazole benzamides, related salts, processes, intermediates, compositions and combination kits.
• Claim 7 is directed specifically to CYC116 and is the most important claim for commercial freedom-to-operate analysis.
• The patent issued October 30, 2012, with a nominal term endpoint in December 2027 based on the earliest priority date.
• No FDA-approved product, Orange Book listing or meaningful Paragraph IV challenge is identified.
• Claim 12 is a generic pharmaceutical composition claim, not a detailed formulation patent.
• Claim 13 covers anticancer combination products or kits but does not specify a particular chemotherapy partner or tumor type.
• The broad genus claims face greater written-description, enablement and obviousness exposure than the exact compound claim.
• Process and intermediate claims may deter use of specific routes but can likely be designed around.
• CYC116 has development-stage commercial value rather than established branded-drug revenue exposure.
• Alternative Aurora kinase inhibitors are outside the patent unless their structures independently fall within the claimed chemical genus.

FAQs

Is CYC116 covered by U.S. Patent 8,299,057?

Yes. Claim 7 specifically recites the CYC116 chemical structure and its pharmaceutically acceptable salts.

Does U.S. Patent 8,299,057 cover all Aurora kinase inhibitors?

No. It covers a defined chemical genus of substituted indazole benzamides. Other Aurora kinase inhibitor chemotypes fall outside the patent unless their structures satisfy the claim limitations.

Can a competitor patent a new CYC116 formulation?

Potentially. A later formulation patent would need a patentable formulation invention, such as a novel solid form, delivery system, release profile, particle-size distribution or stability improvement.

Is a Paragraph IV challenge required to launch a CYC116 generic?

Not necessarily. Paragraph IV certification is tied to an approved reference product and listed Orange Book patents. No such approved reference-product framework is identified for CYC116.

What is the principal freedom-to-operate risk for a CYC116 manufacturer?

Before the patent’s applicable expiration, the principal risk is direct infringement of claim 7 by making, using, selling or importing the exact CYC116 compound or a covered salt.

References

1. United States Patent and Trademark Office. (2012). U.S. Patent No. 8,299,057, substituted indazole derivatives.
2. Cyclacel Pharmaceuticals, Inc. (n.d.). CYC116: Aurora kinase inhibitor development information.
3. United States Code, 35 U.S.C. § 154. Patent term.
4. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book.
5. Cyclacel Pharmaceuticals, Inc. (2008). Corporate and clinical development materials concerning CYC116.
6. United States Patent and Trademark Office. (n.d.). Patent records for alisertib and Aurora kinase inhibitor compounds.
7. United States Patent and Trademark Office. (n.d.). Patent records for danusertib and pan-Aurora kinase inhibitors.

Drugs Protected by US Patent 8,299,057

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Genentech Inc	ROZLYTREK	entrectinib	CAPSULE;ORAL	212725-001	Aug 15, 2019		RX	Yes	No	8,299,057		Y	Y
Genentech Inc	ROZLYTREK	entrectinib	CAPSULE;ORAL	212725-002	Aug 15, 2019		RX	Yes	Yes	8,299,057		Y	Y

Foreign Priority and PCT Information for Patent: 8,299,057

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	07112881	Jul 20, 2007

PCT Information
PCT Filed	July 08, 2008	PCT Application Number:	PCT/EP2008/058861
PCT Publication Date:	January 29, 2009	PCT Publication Number:	WO2009/013126

International Family Members for US Patent 8,299,057

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2176231		132020000000164	Italy
European Patent Office	2176231		LUC00191	Luxembourg
European Patent Office	2176231		122020000081	Germany