Details for Patent: 8,377,921

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Which drugs does patent 8,377,921 protect, and when does it expire?

Patent 8,377,921 protects ZYKADIA and is included in two NDAs.

This patent has one hundred and four patent family members in forty-eight countries.

Summary for Patent: 8,377,921

Title:	Compounds and compositions as protein kinase inhibitors
Abstract:	The invention provides novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine and pyridine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of anaplastic lymphoma kinase (ALK) activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70), insulin-like growth factor (IGF-1R), or a combination thereof.
Inventor(s):	Pierre-Yves Michellys, Wei Pei, Thomas H. Marsilje, Bei Chen, Tetsuo Uno
Assignee:	Novartis AG
Application Number:	US13/172,572
Patent Claim Types: see list of patent claims	Use;

US Patent 8,377,921: Ceritinib Patent Scope, Claims, Expiration and Patent Landscape

US Patent 8,377,921 is a method-of-treatment patent covering anaplastic lymphoma kinase (ALK) inhibition with compounds in two related chemical genera. Its most commercially important species is ceritinib, marketed by Novartis as Zykadia. The patent covers treatment of ALK-mediated diseases, including ALK-positive non-small cell lung cancer (NSCLC), neuroblastoma, anaplastic large cell lymphoma, ALK-positive non-Hodgkin's lymphoma and inflammatory myofibroblastic tumor.

The patent issued on February 19, 2013. Its principal term is understood to expire on September 23, 2028, subject to any applicable patent-term adjustment or extension. The patent is listed in the FDA Orange Book for Zykadia. FDA approval of ceritinib occurred on April 29, 2014, initially under the accelerated-approval pathway for ALK-positive metastatic NSCLC.[1-3]

What does US Patent 8,377,921 protect?

US 8,377,921 protects administering specified ALK-inhibitory compounds to treat ALK-mediated conditions. The patent does not broadly claim every ALK inhibitor or every use of ceritinib. Its protection depends on the structural limitations in Formula (1) or Formula (2), the disease limitation, and the administration of a therapeutically effective amount.

The claims divide into four groups:

Claim group	Claims	Principal subject matter
Formula (2), ALK-mediated disease	1-4	Genus of substituted pyrimidine diamines; disease and combination-treatment limitations
Formula (1), ALK-mediated disease	5-9	Second chemical genus with a heterocyclic substituent; includes specific compounds
Formula (2), ALK-response condition	10-15	Recast method claims using "condition which responds to inhibition"
Formula (1), ALK-response condition	16-20	Recast method claims with specific species, including a methylpiperidine analog

Claims 1 and 10 are substantially overlapping in chemical and therapeutic scope. Claims 5 and 16 perform the same function for Formula (1). The later claim groups use different wording for the disease requirement but do not materially change the commercial significance of the principal ceritinib claims.

What compound is specifically protected by US 8,377,921?

Claim 7 specifically covers ceritinib, also known as LDK378:

5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine

Ceritinib has the following key structural elements:

• A 5-chloropyrimidine core.
• Two aniline-type nitrogen substituents at the 2- and 4-positions.
• A 2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl group.
• A 2-(propan-2-sulfonyl)phenyl group.
• Pharmaceutically acceptable salts, including the marketed drug substance form.

Claim 15 repeats this species under the Formula (2) method category. Claims 7 and 15 are therefore the clearest direct coverage of ceritinib treatment, while claims 1 and 10 provide broader genus protection around the same chemical architecture.

Claim 9 and claim 20 cover a related compound containing a 1-methylpiperidin-4-yl group and a 5-methylpyrimidine core. That species is structurally distinct from ceritinib but remains within the patent's ALK-inhibitor program.

How broad are the Formula (2) claims?

Formula (2) claims cover substituted pyrimidine-diamine compounds with a defined substitution pattern. The most commercially relevant constraints are:

Limitation	Scope
R1	Halogen or C1-6 alkyl
R2	Hydrogen
R3	Sulfonyl-containing substituent, including alkylsulfonyl-linked groups
R4	Hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, halo, nitro, sulfonyl or related substituents
R6	Isopropoxy or methoxy
R8/R9	One substituent is a cyclic amine-containing group; the other is alkyl, cyano, ester, amide or related functionality
Y	Pyrrolidinyl, piperidinyl or azetidinyl
q	Zero
Therapeutic use	ALK-mediated disease or a condition responsive to ALK inhibition

The Formula (2) claims are broad enough to reach multiple analogs sharing the ceritinib pharmacophore. The claims are narrower than a pure composition-of-matter claim because they require a therapeutic method and a disease-related limitation.

The most important chemical limitations are the pyrimidine-diamine scaffold, the sulfonyl-substituted aryl ring and the cyclic amine substituent attached directly through a carbon atom. A compound that changes the core heterocycle, removes the sulfonyl group, replaces the cyclic amine with a materially different group or falls outside the specified substitution ranges may avoid literal infringement, subject to equivalents analysis.

How broad are the Formula (1) claims?

Formula (1) claims cover a related class of pyrimidine compounds in which one of the specified ring positions carries a heterocycle through a carbon atom. The claim requires:

• A defined pyrimidine ring system.
• Carbon atoms at A1 through A4 as specified.
• Hydrogen at R5, R5', R7 and R10.
• A heterocyclic group at one of R8 or R9.
• A 5- to 12-membered heterocycle containing nitrogen, oxygen or sulfur.
• Optional alkyl, hydroxyalkyl, alkoxyalkyl or heterocyclic substitution on that ring.
• Use against an ALK-mediated or ALK-responsive condition.

Formula (1) is structurally broader in the permitted heterocycle definition than Formula (2), which is directed to pyrrolidinyl, piperidinyl and azetidinyl groups. The Formula (1) claims can reach compounds with larger or differently substituted heterocycles, provided the attachment and ring-composition limitations are satisfied.

Claims 9 and 20 identify a specific methylpiperidine-containing compound. Those claims narrow the genus substantially and are easier to evaluate against a particular accused molecule than claims 5 and 16.

What diseases are covered by the patent?

The patent expressly identifies the following conditions:

Disease or condition	Claim coverage
Anaplastic large cell lymphoma	Claims 1, 5, 10 and 16
ALK-positive non-Hodgkin's lymphoma	Claims 1, 5, 10 and 16
Inflammatory myofibroblastic tumor	Claims 1, 5, 10 and 16
Neuroblastoma	Claims 1-3, 5, 10-12 and 16-18
Non-small cell lung cancer	Claims 1, 2, 5, 10, 11, 16 and 17
Combination with chemotherapy	Claims 4 and 13

The claims do not require a specific ALK mutation, fusion partner or biomarker threshold. In practice, the strongest commercial application is ALK-positive NSCLC, particularly tumors driven by an ALK rearrangement or fusion.

The claims also cover treatment with a second therapeutic agent. Claims 4 and 13 expressly identify a chemotherapeutic agent, while the independent claims use broader optional-combination language.

Does the patent cover ceritinib as a product?

No. The claims provided are method claims, not ordinary composition-of-matter claims. Claim 7 identifies ceritinib, but it does so in the context of treating an ALK-mediated condition.

That distinction affects enforcement:

• A manufacturer making or selling ceritinib may implicate other composition, formulation or product-by-process patents.
• US 8,377,921 is most directly asserted against treatment instructions, prescribing, use, labeling or induced infringement theories.
• A generic applicant seeking approval for ceritinib could challenge the patent through a Paragraph IV certification if the patent is listed against the relevant reference product and drug product.
• A generic label that removes the patented ALK-related indication may reduce, but not necessarily eliminate, infringement risk if the remaining label encourages a patented use.

The claim language "administering to a subject" creates a treatment-use requirement. Mere possession or manufacture is less directly within the literal scope of these claims.

What is the Orange Book status of US 8,377,921?

US 8,377,921 is listed in the FDA Orange Book for Zykadia, the reference product for ceritinib.[2] The relevant regulatory milestones are:

Event	Date
FDA approval of Zykadia	April 29, 2014
Initial indication	ALK-positive metastatic NSCLC
Initial regulatory pathway	Accelerated approval
Confirmatory indication development	First-line ALK-positive metastatic NSCLC
Principal patent expiration	September 23, 2028
Five-year NCE exclusivity	Ended in 2019
Seven-year orphan exclusivity, where applicable	No longer blocks ordinary generic filing

The regulatory exclusivity period ended well before the patent term. The remaining commercial barrier is therefore patent protection, not new chemical entity exclusivity.

FDA later expanded ceritinib use to first-line treatment of patients with metastatic NSCLC whose tumors are ALK-positive.[3] The label's expansion increases the commercial importance of the method claims directed to NSCLC.

When does ceritinib lose patent exclusivity?

The key US patent term for US 8,377,921 is September 23, 2028. The date should be distinguished from regulatory exclusivity:

Protection	Approximate endpoint	Commercial effect
NCE exclusivity	April 2019	Prevented ANDA filing during the five-year period
Orphan exclusivity for the original indication	April 2021, if applied to the relevant indication	Blocked approval of the same orphan indication
US 8,377,921 patent term	September 23, 2028	Can block infringing treatment use
Other Orange Book patents	Generally later or coextensive dates in the ceritinib estate	May independently delay approval or launch

A generic applicant can file an ANDA before patent expiration through a Paragraph IV certification. Filing does not itself authorize commercial launch. The patent holder may sue within the statutory period, triggering a regulatory stay of approval, generally for up to 30 months under the Hatch-Waxman framework.[4]

What other patents protect Zykadia and ceritinib?

US 8,377,921 is one part of the Zykadia patent estate. The broader estate includes patents directed to chemical matter, salts, formulations, dosing regimens, crystalline forms and therapeutic uses. The exact Orange Book listing can change as FDA records are updated, and patent families may contain continuations with overlapping but distinct claims.

The relevant protection categories are:

Protection category	Typical risk to a generic applicant
Compound or chemical-genus patents	Direct protection for ceritinib or close analogs
Method-of-treatment patents	Risk from an ANDA label that encourages ALK-positive NSCLC treatment
Formulation patents	Risk from the particular tablet composition or dosage form
Salt or solid-form patents	Risk from the selected API form
Dosing patents	Risk from specific administration schedules
Manufacturing patents	Risk to API production routes, intermediates or purification steps
Pediatric or regulatory extensions	Potential delay beyond the ordinary patent date

US 8,377,921 is particularly important because it identifies ceritinib by name and ties that species to the clinically relevant ALK and NSCLC indications.

What formulation patents protect ceritinib?

The supplied claims do not contain formulation limitations. They do not require:

• A tablet.
• A particular excipient.
• A dissolution profile.
• A particle size.
• A crystalline polymorph.
• A specific ceritinib salt.
• A controlled-release system.
• A defined bioavailability range.

Formulation and solid-form risk must therefore be assessed separately from US 8,377,921. A generic tablet could avoid a formulation patent while still facing the method claims in this patent. Conversely, a generic formulation may be outside the scope of US 8,377,921 if its proposed labeling does not practice a claimed treatment method.

Which companies are challenging ceritinib patents?

A definitive public determination of all Paragraph IV filers cannot be made from the claims supplied. FDA Orange Book records identify listed patents but do not provide a complete public database of every Paragraph IV notice letter or settlement term.

As of the publicly documented regulatory record through the available FDA approval materials, no FDA-approved generic ceritinib product has displaced Zykadia. Generic applicants could pursue an ANDA with Paragraph IV certifications against the listed patents or a Section viii statement carving out patented uses.

The principal commercial parties are:

• Novartis Pharmaceuticals Corporation, the Zykadia sponsor and patent holder or affiliated rights holder.
• ANDA applicants seeking approval for ceritinib tablets.
• FDA, which determines approval timing and labeling.
• Patent litigation courts, which determine infringement, validity and enforceability.

A Paragraph IV challenge would most likely focus on claim construction, written description, enablement, obviousness, anticipation and the relationship between the claimed treatment methods and the proposed generic label.

How strong is the patent estate for generic entry?

US 8,377,921 has meaningful but limited protection.

Strengths

1. Claim 7 expressly identifies ceritinib.
2. The patent covers the primary commercial disease, ALK-positive NSCLC.
3. The claims cover both monotherapy and optional combination treatment.
4. Multiple independent claim groups create overlapping method theories.
5. Claims 7 and 15 provide narrower species claims that may survive even if broader genus claims are challenged.

Vulnerabilities

1. The patent is a method patent rather than a simple composition-of-matter patent.
2. The claims require practice of a treatment method.
3. The Formula (1) and Formula (2) definitions contain numerous Markush limitations.
4. A generic label may attempt to omit or carve out patented indications.
5. The patent expires in 2028, leaving a significant period for validity and noninfringement challenges.
6. The "condition which responds to inhibition of anaplastic lymphoma kinase" language may create claim-construction disputes regarding patient selection and disease characterization.

The strongest claims against an ordinary ceritinib label are claims 7 and 15, provided the product is promoted or labeled for the claimed ALK-mediated conditions. The broader genus claims are more exposed to validity challenges because they cover a large number of possible analogs and therapeutic uses.

What patent litigation issues are most likely?

A ceritinib Paragraph IV case involving US 8,377,921 would likely address four issues.

Infringement

The patentee would compare the proposed label and product to the claimed ceritinib treatment method. A label identifying ALK-positive metastatic NSCLC and recommending ceritinib administration would create a strong induced-infringement theory.

Validity

The generic applicant could challenge whether the patent adequately supports the full scope of the Markush genera. Potential arguments include lack of written description, lack of enablement and obviousness based on earlier ALK inhibitors or kinase-inhibitor scaffolds.

Indication carve-out

A Section viii statement may attempt to omit a patented indication. That strategy is difficult if the remaining label still encourages treatment of ALK-positive NSCLC or otherwise instructs use that falls within the claims.

Claim construction

The parties could dispute:

• The meaning of "condition mediated by anaplastic lymphoma kinase."
• Whether "responds to inhibition" requires clinical response data.
• The scope of "attached ... via a carbon atom."
• The meaning of "therapeutically effective amount."
• Whether a specific salt is covered by the pharmaceutically acceptable salt language.
• Whether the disease limitation is satisfied by all ALK-positive NSCLC or only a defined molecular subtype.

How does US 8,377,921 compare with competing ALK inhibitor patents?

Drug	Sponsor	ALK role	Key competitive distinction
Ceritinib	Novartis	ALK inhibitor	Second-generation inhibitor; Zykadia patent estate
Crizotinib	Pfizer	ALK, ROS1, MET	Earlier-generation ALK inhibitor; Xalkori estate
Alectinib	Roche/Genentech	ALK inhibitor	CNS-active second-generation therapy
Brigatinib	Takeda/Ariad	ALK inhibitor	Activity against resistant ALK mutations
Lorlatinib	Pfizer	ALK/ROS1 inhibitor	Designed for CNS penetration and resistance coverage
Ensartinib	Xcovery/Innovent	ALK inhibitor	Later-generation competitor
Repotrectinib	Bristol Myers Squibb	ROS1/TRK/ALK activity	Broader kinase profile and CNS positioning

These competing products have separate patent estates. A competitor's ALK patent does not ordinarily invalidate or eliminate US 8,377,921 because the patents claim different compounds, uses or formulations.

What generic launch scenarios exist for ceritinib?

The principal launch scenarios are:

1. No challenge before September 2028. Generic entry occurs after the principal patent and any relevant co-owned or related patents expire.
2. Paragraph IV challenge with litigation. Approval may be delayed by litigation and the statutory regulatory stay.
3. Settlement with an authorized launch date. Novartis and an ANDA applicant could agree to a licensed entry date before September 2028, subject to antitrust and regulatory considerations.
4. Section viii carve-out. A generic applicant may remove a patented indication, but the strategy depends on whether the remaining label still induces infringement.
5. At-risk launch. A generic could launch before final resolution, exposing the applicant to damages and injunctive relief.

The most commercially credible early-entry pathway would involve a Paragraph IV challenge combined with a noninfringing label strategy and a validity attack against the method claims.

What is the geographic scope of US 8,377,921?

The patent has United States territorial scope. It can be asserted against conduct occurring in the United States, including:

• Sale of ceritinib in the United States.
• Distribution to US patients.
• Labeling or promotional activity encouraging the claimed treatment.
• Importation of an infringing product.
• Certain acts associated with an ANDA filing under 35 U.S.C. § 271(e)(2).

Foreign counterparts must be analyzed separately. European, Japanese, Canadian, Chinese and other national-phase patents may have different claim scope, expiration dates, prosecution histories and litigation outcomes. A US noninfringement or invalidity result does not automatically affect foreign rights.

Key Takeaways

• US 8,377,921 is a method-of-treatment patent for ALK inhibition.
• Claim 7 specifically identifies ceritinib, the active ingredient in Zykadia.
• The patent covers ALK-positive NSCLC, neuroblastoma, ALCL, ALK-positive non-Hodgkin's lymphoma and inflammatory myofibroblastic tumor.
• Claims 1-4 and 10-15 cover Formula (2); claims 5-9 and 16-20 cover Formula (1).
• The patent does not directly claim a tablet formulation, polymorph, excipient system or manufacturing process.
• Its principal US patent term is September 23, 2028.
• FDA regulatory exclusivity ended before the patent term.
• Generic risk centers on method-of-use infringement, Paragraph IV litigation, label carve-outs and validity challenges to broad Markush claims.
• Zykadia's overall protection depends on US 8,377,921 together with separate compound, formulation, salt, dosing and manufacturing patents.

FAQs

Does US 8,377,921 cover ceritinib hydrochloride?

The claims cover ceritinib and pharmaceutically acceptable salts. Whether a particular ceritinib salt is covered depends on its chemical identity and the claim construction applied to the salt limitation.

Can a generic manufacturer launch ceritinib before September 2028?

Potentially, but only through a successful patent challenge, settlement, licensed entry, noninfringing label strategy or at-risk launch. The patent expiration date alone does not determine the earliest commercial entry date because other listed patents may apply.

Is US 8,377,921 a composition-of-matter patent?

No. The supplied claims are method claims requiring administration of a claimed compound to treat an ALK-mediated or ALK-responsive condition.

Does a ceritinib formulation automatically infringe US 8,377,921?

No. The formulation itself is not the claimed act. Infringement depends principally on whether the product is used, labeled or promoted in a manner that practices the claimed ALK-treatment method.

Does the patent cover treatment of ALK-negative lung cancer?

The claims require a condition mediated by or responsive to ALK inhibition and expressly identify ALK-positive disease contexts. Treatment of ALK-negative NSCLC would present a materially different infringement analysis and would not automatically fall within the claims.

References

1. U.S. Patent and Trademark Office. (2013). U.S. Patent No. 8,377,921: Inhibitors of anaplastic lymphoma kinase.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (2017). FDA approves ceritinib for metastatic non-small cell lung cancer.
4. U.S. Food and Drug Administration. (n.d.). Hatch-Waxman amendments and abbreviated new drug applications.

Drugs Protected by US Patent 8,377,921

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Novartis	ZYKADIA	ceritinib	CAPSULE;ORAL	205755-001	Apr 29, 2014		DISCN	Yes	No						TREATMENT OF A CANCER MEDIATED BY AN ANAPLASTIC LYMPHOMA KINASE (ALK)
Novartis	ZYKADIA	ceritinib	TABLET;ORAL	211225-001	Mar 18, 2019		RX	Yes	Yes						TREATMENT OF A CANCER MEDIATED BY AN ANAPLASTIC LYMPHOMA KINASE (ALK)

International Family Members for US Patent 8,377,921

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2091918		CA 2015 00047	Denmark
European Patent Office	2091918		C20150037 00157	Estonia
European Patent Office	2091918		92785	Luxembourg
European Patent Office	2091918		PA2015034	Lithuania