United States Patent 8,821,927: Lapatinib Tablet Formulation Scope, Expiration, and Patent Landscape

U.S. Patent No. 8,821,927 protects a manufacturing-defined oral tablet formulation of lapatinib ditosylate monohydrate, the active ingredient in Tykerb. The patent does not broadly claim lapatinib, its anticancer use, or every lapatinib tablet. Its independent claim is limited to a tablet made through a specified fluid-bed granulation and compression process using defined composition ranges for lapatinib salt, microcrystalline cellulose, povidone, sodium starch glycolate, and magnesium stearate.

The patent is commercially relevant because formulation claims can delay generic entry even after core compound patents expire. Its practical strength depends on Orange Book listing, the precise manufacturing process used by a generic applicant, the ability to prove that the accused product was made through the claimed process, and the scope of any Paragraph IV litigation or settlement.

What drug does U.S. Patent 8,821,927 protect?

The claimed active ingredient is lapatinib ditosylate monohydrate.

Lapatinib is a small-molecule tyrosine kinase inhibitor marketed by GlaxoSmithKline as Tykerb in the United States. The drug inhibits epidermal growth factor receptor and HER2 signaling and is approved in combination regimens for certain HER2-positive breast cancer indications.[2]

The chemical name in claim 1 corresponds to the lapatinib free base:

N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine.

The claim requires the ditosylate monohydrate salt rather than the free base. That distinction matters. A formulation using a different lapatinib salt, an anhydrous form, or a different solid-state form may avoid literal infringement of the active-ingredient limitation, although other patents or infringement theories could remain relevant.

What does claim 1 of U.S. Patent 8,821,927 cover?

Claim 1 is a product-by-process claim directed to an oral pharmaceutical formulation prepared through five required manufacturing stages.

Claim element	Required limitation
Active ingredient	Lapatinib ditosylate monohydrate
Initial excipient	At least microcrystalline cellulose
Initial processing	Admixing and fluidizing in a fluid-bed granulator
Initial composition	Lapatinib salt at 45% to 57% by weight; microcrystalline cellulose at 43% to 55%
Granulation liquid	Aqueous solution containing at least povidone
Povidone solution	10% to 25% povidone in purified water
Post-granulation excipients	Sodium starch glycolate and magnesium stearate
Compression-blend composition	Active granules at 93% to 96%; sodium starch glycolate at 3.5% to 5.5%; magnesium stearate at 0.8% to 1.2%
Final processing	Compression into tablets followed by film coating

Every limitation is cumulative. A formulation that satisfies only the ingredient ranges, but is manufactured by direct compression rather than fluid-bed granulation, would not satisfy the claim as written. A tablet made by fluid-bed granulation but using lapatinib free base rather than lapatinib ditosylate monohydrate would also fall outside the literal claim.

How narrow is the patent claim?

The claim is relatively narrow compared with a conventional composition-of-matter or broad formulation claim.

Its principal narrowing features are:

The specific lapatinib salt and hydrate.
Fluidization in a fluid-bed granulator.
A defined starting ratio of lapatinib salt to microcrystalline cellulose.
Granulation with an aqueous povidone solution in a defined concentration range.
Defined final blend percentages for active granules, sodium starch glycolate, and magnesium stearate.
Compression and film coating.

The claim is not limited to a particular tablet strength, tablet weight, coating color, dissolution profile, or brand name. It also does not expressly require a particular fluid-bed granulator, processing temperature, spray rate, granulation endpoint, or drying condition.

The phrase “at least” broadens some ingredient requirements. For example, the claim requires at least microcrystalline cellulose and at least povidone, allowing other excipients unless another limitation excludes them. The claim does not require that microcrystalline cellulose or povidone be the only excipient in the relevant stage.

The percentage limitations create a separate issue. The initial lapatinib and microcrystalline-cellulose ranges total between 88% and 112%, depending on the selected endpoints. The claim therefore should be read as defining permitted ranges for each component rather than requiring the two components to total exactly 100%. The same issue exists in the compression blend, where the three stated ranges can total below or above 100%. The patent specification and prosecution history would control how those percentages are calculated.

Is U.S. Patent 8,821,927 a product-by-process claim?

Yes. The claim begins with an oral pharmaceutical formulation but defines that formulation by the process used to make it.

U.S. product-by-process doctrine generally requires the claimed product to be distinguished by the recited process limitations when determining infringement. The Federal Circuit has treated product-by-process limitations as meaningful claim limitations, while also recognizing that the patentability analysis may apply different rules when assessing prior art.[4]

For an infringement case, the patent owner would likely need to establish more than the presence of lapatinib, microcrystalline cellulose, povidone, sodium starch glycolate, magnesium stearate, and a film coat. The evidence would likely focus on the accused manufacturer’s batch records, master manufacturing instructions, equipment records, process validation documents, regulatory filings, and discovery responses.

A generic manufacturer could attempt to design around the claim by using:

Dry granulation or roller compaction.
Direct compression.
A different lapatinib salt or hydrate.
Microcrystalline cellulose outside the claimed initial range.
Povidone outside the 10% to 25% aqueous concentration range.
A different binder.
A different disintegrant or lubricant.
A non-film-coated tablet.
A manufacturing sequence that does not create the claimed active granules.

A design-around that changes only an immaterial processing parameter may not avoid infringement. A design-around that removes fluid-bed granulation or changes the active salt is materially stronger.

What are the patent expiration and exclusivity dates?

The patent’s nominal term is tied to the earliest effective U.S. nonprovisional filing date and generally runs for 20 years, subject to patent-term adjustment, terminal disclaimers, and any applicable regulatory patent-term extension.

For commercial planning, U.S. Patent 8,821,927 is generally associated with a 2026 expiration horizon. The controlling date is the expiration date recorded in the USPTO patent file and, if listed for the approved product, the FDA Orange Book.[1][3]

Event	Date or status
Patent issued	September 2, 2014
Patent number	U.S. 8,821,927
Subject	Lapatinib ditosylate monohydrate tablet formulation and manufacturing process
Nominal expiration horizon	2026
FDA relevance	Potential Orange Book formulation patent for Tykerb
Small-molecule regulatory exclusivity	Expired
Core compound-patent protection	Expired or near-expired, depending on patent and adjustment
Biosimilar exclusivity	Not applicable

The patent should not be confused with FDA marketing exclusivity. Patent term and FDA exclusivity are separate rights. Lapatinib’s original new-drug exclusivity periods have expired. The remaining commercial barrier is patent-based rather than a current new-drug exclusivity block.

What is the Orange Book status of lapatinib and Tykerb?

Tykerb was approved under NDA 022059. FDA Orange Book listings for approved small-molecule products can include patents covering the active ingredient, formulation, method of use, or approved drug product.[3]

Patent 8,821,927 is relevant to the Orange Book analysis because it claims a tablet formulation of the approved lapatinib salt. If listed against the NDA, an ANDA applicant that seeks approval before expiration would have to certify to the patent under Hatch-Waxman procedures.

The relevant certification paths are:

Paragraph I: no patent information is listed.
Paragraph II: the listed patent has expired.
Paragraph III: the applicant will wait until patent expiration.
Paragraph IV: the patent is invalid, unenforceable, or will not be infringed.

A Paragraph IV certification can trigger patent litigation if the NDA holder or patent owner files suit within the statutory 45-day period. The filing of a Paragraph IV certification does not itself invalidate the patent or establish noninfringement.

What Paragraph IV challenges affect lapatinib?

Lapatinib generic entry depends on the ANDA filing strategy and the listed patents in force when the ANDA is submitted. A generic applicant may challenge the formulation patent through a Paragraph IV certification or may defer commercial launch until patent expiry through a Paragraph III certification.

A complete Paragraph IV assessment requires the FDA Orange Book patent listing, ANDA filing information, notices sent to the NDA holder, complaints filed in federal district court, docket outcomes, and any settlement agreements. Patent 8,821,927 alone does not establish whether a particular generic applicant has challenged the patent.

The commercial distinction is important:

Generic strategy	Likely effect
Paragraph III certification	Approval may be delayed until the listed patent expires
Paragraph IV certification with no timely suit	FDA approval may proceed after statutory requirements are met
Paragraph IV certification followed by suit	Approval may be subject to the 30-month stay
Noninfringing formulation	May reduce litigation exposure, but other listed patents remain relevant
Authorized generic	May enter under a separate commercial arrangement and does not necessarily resolve third-party ANDA issues

What patent litigation and settlements affect the patent?

The formulation patent’s litigation risk is distinct from the validity of the patent on paper. A patent can remain enforceable while a generic applicant avoids it through a different formulation or manufacturing process.

Relevant litigation questions include:

Whether the patent was listed in the Orange Book during the ANDA filing period.
Whether a generic applicant certified Paragraph IV.
Whether GSK or an affiliated patent owner filed within 45 days.
Whether the court found infringement, invalidity, or unenforceability.
Whether the parties entered a confidential or public settlement.
Whether the settlement imposed a controlled-entry date or permitted an earlier launch.
Whether the settlement included an authorized-generic commitment.

No settlement term should be inferred from the patent’s issuance, Orange Book listing, or the existence of a generic lapatinib product. Settlement terms are often confidential, and a public docket may disclose only the filing, dismissal, or approval of the agreement.

What other patents protect lapatinib?

The lapatinib estate is layered rather than dependent on one patent.

Core compound and therapeutic patents

Earlier patent families protect the quinazoline chemical series, lapatinib compounds, salts, and their use in cancer treatment. U.S. Patent No. 6,727,256 is a principal early lapatinib-related patent and is associated with the compound and pharmaceutical uses underlying Tykerb.[5]

Those patents are materially broader than Patent 8,821,927 because they may cover the active molecule or therapeutic administration rather than one manufacturing route.

Salt and solid-state protection

Lapatinib is administered commercially as the ditosylate monohydrate. Patents directed to salt selection, hydration state, crystallinity, particle properties, or stability can create separate barriers. These rights may be relevant even if a generic avoids the fluid-bed process claimed in Patent 8,821,927.

Formulation protection

Patent 8,821,927 is the key formulation-process reference discussed here. Its value comes from the combination of:

High drug loading.
Microcrystalline-cellulose-based granulation.
Povidone aqueous granulation.
Specific disintegrant and lubricant ranges.
Tablet compression and film coating.

A competing formulation patent could cover dissolution control, tablet stability, taste masking, particle-size control, or a different solid form. The existence of Patent 8,821,927 does not establish that it is the only formulation patent associated with lapatinib.

Method-of-use patents

Lapatinib method-of-use patents may cover combinations with capecitabine, aromatase inhibitors such as letrozole, treatment of HER2-positive tumors, or specific patient populations. Method-of-use patents can remain relevant to an ANDA even when a generic applicant seeks approval with a label that omits patented indications.

How strong is the patent estate for lapatinib?

The estate is strongest against a generic that reproduces the branded tablet process and composition. It is weaker against a generic that uses a different process or changes the salt, binder system, or granulation method.

Risk factor	Assessment
Active ingredient	Strong if the generic uses lapatinib ditosylate monohydrate
Fluid-bed granulation limitation	Provides a meaningful design-around path
Composition ranges	Potentially enforceable, but vulnerable to formulation optimization outside the ranges
Povidone concentration	Specific and measurable limitation
Product-by-process format	Increases proof burden and manufacturing-record importance
Film coating	Easy to satisfy; weak as a standalone barrier
Core compound patents	Historically broader, but generally earlier-expiring
Biosimilar barrier	None; lapatinib is a small molecule
Regulatory barrier	ANDA pathway, not BLA pathway
Commercial barrier	Dependent on remaining listed patents and generic launch timing

The patent has moderate formulation strength, not composition-of-matter strength. Its value is highest when combined with Orange Book listing and a generic product that closely replicates the branded manufacturing architecture.

What generic launch scenarios exist for lapatinib?

Three principal launch scenarios exist.

Launch after patent expiry

A generic applicant can use a Paragraph III certification and enter after the listed formulation patent expires. This approach reduces litigation risk but may postpone approval or commercial launch.

Paragraph IV launch attempt

A generic applicant can assert that Patent 8,821,927 is invalid or not infringed. The most credible noninfringement position would likely involve a different manufacturing process, different salt or hydrate, or composition outside the claimed ranges.

Launch through an authorized or settled arrangement

The patent owner may license or authorize a generic launch before expiry. A settlement could establish an agreed entry date, royalty terms, supply terms, or an authorized-generic structure. The public availability of such a deal depends on the parties and the litigation record.

What is the competitive landscape for lapatinib?

Lapatinib competes with other HER2-directed therapies, including trastuzumab, pertuzumab, tucatinib, neratinib, and antibody-drug conjugates. The competitive position of lapatinib has weakened as newer HER2 therapies have gained use, but a low-cost generic can preserve demand in price-sensitive settings and in markets where oral administration is preferred.

The commercial value of Patent 8,821,927 is therefore linked to:

The remaining branded lapatinib revenue base.
The number and timing of approved ANDAs.
Generic price erosion.
The availability of alternative HER2 therapies.
Payer preference for oral targeted treatment.
The extent to which the generic market can avoid the claimed process.

Because the patent covers manufacturing rather than the active molecule broadly, its effect on revenue exposure is likely to be narrower than the effect of an unexpired compound patent.

Does lapatinib face biosimilar risk?

No. Lapatinib is a chemically synthesized small molecule, not a biologic. It is subject to the ANDA generic-drug pathway rather than the Biologics Price Competition and Innovation Act biosimilar pathway.

The relevant competition is from generic lapatinib tablets. Biosimilar concepts such as reference-product exclusivity, interchangeability, and the 351(k) approval pathway do not apply to this product.

Key Takeaways

U.S. Patent 8,821,927 covers a narrowly defined lapatinib ditosylate monohydrate tablet made by fluid-bed granulation, aqueous povidone granulation, compression, and film coating.
The claim requires all stated process steps and composition ranges.
The patent does not broadly claim lapatinib, every lapatinib formulation, or every lapatinib therapeutic use.
The patent’s nominal commercial relevance extends into 2026.
Its product-by-process structure places substantial importance on the generic manufacturer’s actual manufacturing records.
A generic can pursue design-around strategies involving dry granulation, direct compression, a different salt or hydrate, altered excipient ranges, or a different binder system.
Lapatinib has no biosimilar pathway; competitive entry occurs through ANDAs and generic tablets.
The patent is most valuable when combined with Orange Book listing and enforcement against a generic that copies the branded formulation process.

FAQs

Is Patent 8,821,927 a composition-of-matter patent for lapatinib?

No. It is a formulation and manufacturing-process claim directed to tablets containing lapatinib ditosylate monohydrate.

Can a generic lapatinib tablet avoid Patent 8,821,927?

Potentially. A generic may avoid literal infringement by using a different granulation process, salt form, povidone concentration, excipient range, or tablet manufacturing sequence.

Does the patent cover lapatinib oral suspension or capsules?

Not on the face of claim 1. The claim requires compression into tablet form followed by film coating.

Does a Paragraph IV certification automatically permit lapatinib generic launch?

No. A Paragraph IV certification can trigger litigation and a statutory 30-month stay if the patent owner files suit within the applicable period.

Are lapatinib tablets eligible for biosimilar approval?

No. Lapatinib is a small-molecule drug. Competing products are approved through the ANDA generic-drug pathway.

References

United States Patent and Trademark Office. (2014). U.S. Patent No. 8,821,927, pharmaceutical formulation.
U.S. Food and Drug Administration. (2007). Tykerb prescribing information. GlaxoSmithKline.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
Federal Circuit. (1999). Atlantic Thermoplastics Co. v. Faytex Corp., 970 F.2d 834; Abbott Laboratories v. Sandoz, Inc., 566 F.3d 1282 (Fed. Cir. 2009).
United States Patent and Trademark Office. (2004). U.S. Patent No. 6,727,256, quinazoline derivatives.

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	TYKERB	lapatinib ditosylate	TABLET;ORAL	022059-001	Mar 13, 2007	AB	RX	Yes	Yes	8,821,927	⤷ Start Trial	Y	Y			⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

PCT Information
PCT Filed	April 18, 2006	PCT Application Number:	PCT/US2006/014447
PCT Publication Date:	October 26, 2006	PCT Publication Number:	WO2006/113649

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	054252	⤷ Start Trial
Australia	2006236423	⤷ Start Trial
Brazil	PI0609962	⤷ Start Trial
Canada	2606207	⤷ Start Trial
China	101203211	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,821,927

Which drugs does patent 8,821,927 protect, and when does it expire?

Summary for Patent: 8,821,927