Details for Patent: 8,389,537

Which drugs does patent 8,389,537 protect, and when does it expire?

Patent 8,389,537 protects TASIGNA and is included in one NDA.

Protection for TASIGNA has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

This patent has fifty-three patent family members in thirty-four countries.

Summary for Patent: 8,389,537

Title:	Salts of 4-methyl N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide
Abstract:	Salts of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide are prepared by various processes.
Inventor(s):	Paul W Manley, Wen-Chung Shieh, Paul Allen Sutton, Piotr H Karpinski, Raeann Wu, Stéphanie Monnier, Jörg Brozio
Assignee:	Novartis AG
Application Number:	US13/419,132
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,389,537
Patent Claim Types: see list of patent claims	Use; Composition;

United States Patent 8,389,537: Nilotinib CML Treatment Claims, Scope, Expiration, and Patent Landscape

US Patent 8,389,537 protects the use of nilotinib hydrochloride monohydrate for treating chronic myelogenous leukemia (CML), including administration through a pharmaceutical composition. It does not broadly claim nilotinib as a chemical compound, all nilotinib uses, or every formulation containing nilotinib. Its principal commercial significance is as a method-of-use patent for Tasigna, Novartis’s nilotinib product.

The patent’s projected statutory expiration is October 10, 2026, based on the patent family’s 2006 priority date. The Orange Book listing, any patent-term adjustment, terminal disclaimer, pediatric extension, and litigation settlements determine the practical exclusivity position for a specific product and indication. [1,2]

What drug and therapeutic use does US Patent 8,389,537 protect?

The claimed active ingredient is nilotinib hydrochloride monohydrate, a crystalline salt form of nilotinib.

Nilotinib is a BCR-ABL tyrosine kinase inhibitor marketed by Novartis as Tasigna. The FDA approved Tasigna in 2007 for adults with Philadelphia chromosome-positive CML in chronic phase and accelerated phase who had resistance or intolerance to prior therapy, including imatinib. The label was later expanded to include newly diagnosed Philadelphia chromosome-positive CML in chronic phase. [3]

The patent claims are directed to:

Element	Claim 1	Claim 2
Disease	Chronic myelogenous leukemia	Chronic myelogenous leukemia
Active ingredient	Nilotinib hydrochloride monohydrate	Nilotinib hydrochloride monohydrate
Administration	Therapeutically effective amount	Therapeutically effective amount
Dosage form	Not expressly limited	Pharmaceutical composition
Excipients	Not required	At least one carrier, diluent, vehicle, or excipient
Claim category	Method of treatment	Method of treatment using a composition

The chemical name in the claims corresponds to nilotinib hydrochloride monohydrate:

4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzeneamide monohydrochloride monohydrate.

How broad are the claims of US 8,389,537?

The claims are narrow in chemical identity but commercially meaningful in therapeutic application.

Claim 1 scope

Claim 1 requires proof of each of the following:

1. A subject in need of treatment.
2. The subject has chronic myelogenous leukemia.
3. The administered substance is nilotinib hydrochloride monohydrate.
4. The amount administered is therapeutically effective.

The claim does not expressly limit:

• Dose strength.
• Dosing frequency.
• Treatment duration.
• Disease phase.
• Prior treatment history.
• Patient age.
• Route of administration.
• Capsule size.
• Specific crystalline particle characteristics.
• A particular excipient system.

The absence of a specified dose gives the claim potentially broad reach across clinically effective nilotinib regimens. The claim still requires actual administration and a CML treatment purpose. Mere possession, manufacture, or sale of nilotinib is not, by itself, infringement of claim 1.

Claim 2 scope

Claim 2 adds a composition limitation. The composition must contain:

• A therapeutically effective amount of nilotinib hydrochloride monohydrate; and
• At least one pharmaceutically acceptable carrier, diluent, vehicle, or excipient.

This formulation language is broad. It does not identify a particular capsule shell, dissolution profile, excipient, particle-size distribution, tablet coating, or release mechanism. A conventional oral capsule containing the claimed salt and an acceptable excipient can fall within the claim when used to treat CML.

Claim 2 is not a standalone composition claim. It is a method claim requiring administration of the composition to a CML patient.

What does US 8,389,537 not cover?

US 8,389,537 does not appear to claim the following subject matter directly:

• The nilotinib molecule without the hydrochloride monohydrate limitation.
• Nilotinib free base.
• Alternative nilotinib salts.
• Nilotinib polymorphs that do not satisfy the claimed salt and hydrate identity.
• Treatment of gastrointestinal stromal tumors or other non-CML cancers.
• A composition in the absence of a treatment step.
• A manufacturing process for nilotinib.
• A specific dosage regimen.
• A particular pharmacokinetic profile.
• A particular capsule formulation independent of use.
• Diagnostic testing for BCR-ABL mutations.

This distinction matters in generic litigation. An ANDA applicant may challenge the patent based on noninfringement, invalidity, or both. A product containing the same nilotinib hydrochloride monohydrate and labeled for CML treatment presents a substantially greater claim-exposure risk than a product with a different salt, different indication, or a label that omits the patented use, subject to inducement and regulatory-label analysis.

When does US Patent 8,389,537 expire?

The relevant date is generally October 10, 2026, based on the patent’s earliest priority date and the 20-year patent-term rule under 35 U.S.C. § 154. [1,4]

Event	Date or status
Earliest priority date	October 10, 2006
Patent issued	March 5, 2013
Patent number	US 8,389,537 B2
Expected base expiration	October 10, 2026
Patent type	CML method-of-treatment patent
Regulatory exclusivity	Separate from patent term
Pediatric extension	Must be assessed separately from the patent record
Small-molecule product	Yes

The precise enforceable expiration date depends on the USPTO patent-term calculation and any applicable extension or disclaimer. Patent expiration does not automatically terminate every restriction affecting generic entry because other Orange Book patents may cover nilotinib, its crystalline form, formulation, or dosing regimen.

What is the Orange Book status of nilotinib and Tasigna?

Tasigna is an FDA-approved small-molecule drug, so its relevant follow-on pathway is an abbreviated new drug application (ANDA), not a biosimilar application.

The Orange Book has historically identified several patent categories associated with nilotinib products:

Patent category	Typical subject matter	Relevance
Compound patent	Nilotinib chemical entity	Earlier core protection
Salt or solid-state patent	Hydrochloride monohydrate or crystalline form	Controls product identity and manufacturing
Method-of-use patent	CML treatment	US 8,389,537
Dosing patent	Specific dose or treatment population	May create separate launch barriers
Formulation patent	Capsule or excipient system	Relevant if listed against the reference product

US 8,389,537 is important because its claims align with the approved CML use of Tasigna. A generic applicant seeking approval for nilotinib capsules must address listed patents through the applicable certification framework. A Paragraph IV certification states that a listed patent is invalid, unenforceable, or will not be infringed. The certification can trigger patent litigation under the Hatch-Waxman Act. [2,5]

Which companies have challenged nilotinib patents?

Public ANDA activity has resulted in generic nilotinib development and approval. The FDA approved generic nilotinib capsules in 2023, including products from manufacturers such as Teva Pharmaceuticals USA. [6]

The existence of an approved generic does not establish that every patent covering Tasigna has been invalidated or expired. Generic approval can result from:

• A Paragraph III certification with launch after patent expiration.
• A Paragraph IV certification followed by litigation.
• A settlement agreement permitting a date-certain launch.
• A non-infringing label that excludes a protected indication.
• Approval after the relevant listed patents cease to block approval.
• A combination of these mechanisms.

The public FDA approval record should therefore be read together with the Orange Book patent listing and relevant federal court dockets. Approval of a generic product does not, standing alone, resolve the enforceability of US 8,389,537.

Are Paragraph IV challenges relevant to US 8,389,537?

Yes. The patent claims an approved therapeutic use, making it a potential Orange Book method-of-use patent.

A generic applicant may use one of several strategies:

Paragraph IV invalidity challenge

The applicant may argue that the claims are invalid for anticipation, obviousness, lack of written description, lack of enablement, indefiniteness, or another statutory defect.

Potential invalidity pressure points include:

• Prior art disclosing nilotinib for leukemia.
• Prior art disclosing the hydrochloride monohydrate salt.
• Evidence that CML treatment with nilotinib was predictable.
• Whether the claimed treatment result was adequately supported at filing.
• Whether the claim language distinguishes the invention from earlier nilotinib disclosures.

Noninfringement position

A generic applicant may argue that its product does not satisfy one or more limitations, such as:

• It contains a different salt or solid form.
• Its approved label omits the patented CML indication.
• It does not administer the product for the claimed treatment.
• The commercial product does not contain the claimed hydrate form.

A label carve-out is more difficult where CML is the central or commercially dominant use and the product’s prescribing information continues to encourage the patented method.

Paragraph III certification

An applicant may accept the patent’s validity and certify that it will not market the product until the listed patent expires. For US 8,389,537, that date is generally tied to the 2026 term projection, unless an earlier settlement date applies.

What formulation patents protect nilotinib?

US 8,389,537 is not a detailed formulation patent. Claim 2 covers a method using a composition with nilotinib hydrochloride monohydrate and at least one conventional pharmaceutical excipient. It does not require a specific excipient combination.

Separate nilotinib patents may protect:

• The hydrochloride monohydrate solid form.
• Crystal morphology.
• Moisture control.
• Dissolution characteristics.
• Capsule manufacturing.
• Stabilization systems.
• Bioavailability-enhancing formulations.
• Specific dosage regimens.

The practical patent barrier for a generic manufacturer is cumulative. Even if a challenger defeats the method-of-use claims, a surviving solid-state or formulation patent may restrict use of the same commercial form.

How strong is the patent estate for Tasigna?

The estate is strongest where the generic product uses the same active salt form, has CML labeling, and relies on the same oral product architecture as Tasigna.

Risk factor	Assessment
Chemical identity	High if the generic uses nilotinib hydrochloride monohydrate
CML indication	High for a full-label generic
Claim breadth	Moderate to broad within the specific CML use
Formulation limitation	Limited in claim 2 because excipient language is generic
Manufacturing barrier	Depends mainly on separate solid-state and process patents
Biosimilar risk	None; nilotinib is a small molecule
Generic challenge route	ANDA with Paragraph III or Paragraph IV certification
Geographic reach	US claims apply only in the United States
Post-expiration risk	Competition from multiple generic capsule suppliers

The patent is narrower than a composition-of-matter patent but more difficult to avoid when the generic seeks approval for the same indication and uses the same salt form.

What litigation and settlement issues affect generic launch?

Patent litigation involving a listed method-of-use patent can delay FDA approval for up to 30 months after receipt of a Paragraph IV notice, subject to statutory exceptions and court developments. [5]

A settlement may establish:

• An authorized-generic launch date.
• A license for one or more generic manufacturers.
• A permitted indication or label carve-out.
• Restrictions on launch quantities or distribution channels.
• A waiver or release of claims.
• Terms involving other patents in the same estate.

The commercial launch date for a generic nilotinib product therefore cannot be inferred solely from the October 2026 expiration date. Settlement agreements, court judgments, regulatory exclusivity, and the status of other listed patents can move the launch earlier or later.

How does nilotinib compare with competing CML drugs?

Drug	Active ingredient	Main patent risk	Follow-on pathway
Tasigna	Nilotinib	Salt, solid-state, method, formulation	ANDA generic
Gleevec	Imatinib	Core compound and formulation patents largely matured	ANDA generic
Sprycel	Dasatinib	Compound, formulation, dosing, method patents	ANDA generic
Bosulif	Bosutinib	Compound and formulation patents	ANDA generic
Iclusig	Ponatinib	Compound, formulation, and method patents	ANDA generic

Nilotinib has no biosimilar exposure because it is chemically synthesized and regulated as a small molecule. Its competitive exposure comes from generic nilotinib and from alternative BCR-ABL inhibitors used in CML treatment.

What generic entry risks exist for nilotinib?

Generic entry risk is high after the last enforceable blocking patent expires or becomes commercially irrelevant. The principal factors are:

1. Whether US 8,389,537 remains enforceable through October 2026.
2. Whether a generic applicant has secured an earlier licensed launch.
3. Whether separate solid-form patents remain active.
4. Whether the generic label includes CML treatment.
5. Whether multiple ANDA applicants enter concurrently.
6. Whether authorized-generic supply reduces the first generic entrant’s price advantage.

Tasigna revenue is exposed to rapid price erosion after broad generic entry because nilotinib is an oral small molecule with established manufacturing processes and no biologic interchangeability barrier. Novartis has reported multibillion-dollar historical annual Tasigna sales, making the end of US exclusivity commercially material. [7]

Key Takeaways

• US 8,389,537 is a nilotinib hydrochloride monohydrate method-of-treatment patent.
• It covers treatment of CML, including treatment using a pharmaceutical composition.
• It does not broadly claim nilotinib, every nilotinib formulation, or every cancer indication.
• Claim 1 is the broader claim because it does not require a pharmaceutical composition.
• Claim 2 adds a broad excipient or carrier limitation but remains a method claim.
• The projected base expiration is October 10, 2026.
• Generic nilotinib applicants use the ANDA pathway, not the biosimilar pathway.
• Paragraph IV, Paragraph III, label carve-out, and settlement strategies are all relevant.
• Separate salt, solid-state, formulation, dosing, and manufacturing patents may create additional barriers.
• The commercial risk is concentrated in post-exclusivity generic price erosion for Tasigna.

FAQs

Does US 8,389,537 claim nilotinib itself?

No. The patent claims a specific therapeutic use of nilotinib hydrochloride monohydrate for CML. The compound itself must be analyzed under separate composition-of-matter and solid-state patents.

Can a generic sell nilotinib for a non-CML indication?

Potentially, if the product and labeling avoid infringement of the CML method claims and do not induce use for CML. The analysis depends on the final label, promotional conduct, formulation, and other active patents.

Does claim 2 cover every nilotinib capsule?

No. Claim 2 requires the claimed nilotinib hydrochloride monohydrate, a pharmaceutical composition, and administration for treating CML. A capsule using a different salt or form may fall outside the claim but remain exposed to other patents.

Is nilotinib subject to biosimilar competition?

No. Nilotinib is a synthetic small-molecule drug. Follow-on products are approved through the ANDA generic-drug pathway.

Can a generic launch before October 2026?

Yes, if it has a license, settlement authorization, successful patent challenge, non-infringing label, or another legally effective basis for earlier marketing. The patent expiration date alone does not determine every possible launch date.

References

1. United States Patent and Trademark Office. (2013). US Patent No. 8,389,537 B2: Methods of treating chronic myelogenous leukemia.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (2023). Tasigna (nilotinib) prescribing information. Novartis Pharmaceuticals Corporation.
4. 35 U.S.C. § 154. Patent term.
5. 21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications.
6. U.S. Food and Drug Administration. (2023). FDA approves first generic nilotinib capsules.
7. Novartis AG. (2023). Annual report 2023.

Drugs Protected by US Patent 8,389,537

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	TASIGNA	nilotinib hydrochloride	CAPSULE;ORAL	022068-003	Mar 22, 2018	AB	RX	Yes	No	8,389,537*PED				Y
Novartis	TASIGNA	nilotinib hydrochloride	CAPSULE;ORAL	022068-002	Jun 17, 2010	AB	RX	Yes	No	8,389,537*PED				Y
Novartis	TASIGNA	nilotinib hydrochloride	CAPSULE;ORAL	022068-001	Oct 29, 2007	AB	RX	Yes	Yes	8,389,537*PED				Y

International Family Members for US Patent 8,389,537

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	057467
Austria	E514689
Australia	2006276205
Australia	2010241419
Australia	2012203844
Brazil	PI0613605
Canada	2615669