US Patent 8,652,492: Fostamatinib Wet-Granulation Formulation, Claim Scope, Expiry and Patent Landscape

US Patent 8,652,492 protects a moisture-controlled wet-granulated tablet formulation of fostamatinib disodium, the prodrug marketed as Tavalisse. The patent is narrower than a composition-of-matter patent but potentially important because it covers both the formulation architecture and a wet-granulation manufacturing process.

The core limitations are:

Fostamatinib disodium as the active pharmaceutical ingredient.
Wet granulation using water.
A water-sequestering agent that inhibits active-ingredient decomposition.
Dried granules with tablet-forming properties.
For claim 2, a bulk density of approximately 0.35 to 0.65 g/mL.
For claim 8, drying below 65°C to a loss on drying of approximately 5% to 11%.
Optional compression into tablets under claim 9.

The patent does not claim fostamatinib itself, its therapeutic use generally, or every oral formulation. It targets a specific solid-dose manufacturing solution for a moisture-sensitive active ingredient.

What drug and formulation does US Patent 8,652,492 cover?

The patented active ingredient is fostamatinib disodium, also known as the disodium phosphate prodrug of R406. Fostamatinib is converted in vivo to R406, a spleen tyrosine kinase inhibitor. The FDA approved fostamatinib disodium tablets under the brand name Tavalisse for adults with chronic immune thrombocytopenia who had an insufficient response to prior treatment.[2]

The chemical identity recited in the claims is:

6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt.

The invention addresses decomposition during wet processing. Water is used during granulation, but the active ingredient is protected by incorporating a water-sequestering agent, particularly starch. The dried granules must also have physical properties suitable for tableting. The patent identifies partially pregelatinized maize starch as a particularly relevant embodiment.[1]

What does the independent formulation claim require?

Claim 1 requires a wet-granulated formulation comprising:

Water.
A therapeutically effective amount of fostamatinib disodium.
A sufficient amount of a water-sequestering agent.
Inhibition of decomposition of fostamatinib disodium.
After drying, bulk-density characteristics sufficient to produce tablets with hardness of approximately 6 kp to 30 kp.[1]

The claim uses “comprising,” which generally makes it open-ended. A formulation can contain additional excipients and still fall within claim 1 if the required elements are present.

The functional language concerning inhibition of decomposition is important. The claim does not require a particular measured percentage of degradation in the claim text. Instead, it requires that the water-sequestering agent be present in an amount sufficient to inhibit decomposition. In litigation, the parties would likely contest the meaning of “inhibit,” the relevant comparator formulation, the storage or processing conditions, and the analytical method used to measure degradation.

How do the dependent claims narrow the patent scope?

Claim	Additional limitation	Practical effect
1	Wet-granulated formulation with fostamatinib, water-sequestering agent and tablet-forming properties	Broadest formulation claim
2	Dried bulk density of approximately 0.35 to 0.65 g/mL	Adds a measurable physical-property limitation
3	Water-sequestering agent selected from starch, magnesium sulfate, calcium chloride, silica gel or kaolin	Limits the agent to a closed list
4	Water-sequestering agent is starch	Narrows claim 3 to starch
5	Starch is partially pregelatinized	Covers a specific starch form
6	Starch is derived from maize	Narrows claim 5 to maize starch
7	At least one filler, lubricant, suspending/dispersing agent, binding agent or disintegrant	Adds conventional tablet excipients
8	Wet-granulation process with blending, water addition, drying below 65°C to 5%-11% loss on drying, and lubricant blending	Independent process claim
9	Compression of blended granules into tablets	Narrows claim 8 to tablet manufacture

Claim 3 is materially narrower than claim 1 because the listed water-sequestering agents are recited in a “consisting of” group. A formulation using an unlisted moisture-control material could avoid claims 3 through 6, but it could still implicate claim 1 if the alternative material qualifies as a water-sequestering agent and satisfies the other limitations.

What formulation characteristics are protected?

The patent protects the interaction between chemical stability and manufacturability. It is not limited to the presence of starch alone.

Moisture control

The water-sequestering agent must inhibit decomposition caused or accelerated by water exposure. Starch is the principal disclosed embodiment, with partially pregelatinized maize starch identified in the dependent claims.

The claim structure allows several possible water-control mechanisms:

Binding or immobilizing water within the granule.
Reducing the effective moisture available to fostamatinib.
Improving granule drying and residual-moisture control.
Supporting acceptable tablet compression after drying.

The patent therefore reaches beyond a conventional excipient listing. The active ingredient, wet-processing step, moisture-control function and resulting physical properties are linked.

Bulk density

Claim 2 specifies a dried bulk density of approximately 0.35 to 0.65 g/mL. Bulk density can influence:

Tablet weight and volume.
Die filling.
Compression behavior.
Tablet hardness.
Granule flow.
Uniformity of dosage units.

The density limitation creates a measurable boundary that may be important in an infringement analysis. A competitor’s formulation outside the claimed range may avoid claim 2, although it would not automatically avoid claim 1 or claim 8.

Tablet hardness

Claim 1 requires dried granules having bulk-density characteristics sufficient to form tablets with hardness of approximately 6 kp to 30 kp. Hardness is not presented as an independent fixed numerical limitation in the same manner as the density range in claim 2. The claim instead uses a functional relationship between the dried formulation and tableting performance.

A challenger would likely examine:

Compression force.
Tablet dimensions.
Hardness testing method.
Sampling conditions.
Whether the hardness is inherent in the granules or achieved only through a particular compression process.

What manufacturing process does claim 8 protect?

Claim 8 is an independent wet-granulation process claim. It requires four sequential steps:

Blend fostamatinib disodium with a sufficient amount of water-sequestering agent.
Add water during granulation.
Dry the wet granules below 65°C until loss on drying is approximately 5% to 11%.
Blend a lubricant into the dried granules.

Claim 8 does not expressly require the bulk-density range of claim 2 or the tablet-hardness condition in claim 1. It may therefore present a separate infringement risk from the formulation claims.

The temperature and loss-on-drying limitations are central. A process conducted at 65°C or above could avoid the express temperature limitation of claim 8, subject to claim construction of “below 65°C.” A process dried to less than 5% or more than 11% loss on drying could avoid the express LOD range. Those changes would not necessarily avoid claim 1 if the resulting formulation satisfies the formulation claim.

When does US Patent 8,652,492 lose exclusivity?

Event	Date
Earliest claimed priority date	February 27, 2009
US patent application filing	February 26, 2010
Patent grant	February 18, 2014
Nominal 20-year expiration based on earliest priority	February 27, 2029
FDA approval of Tavalisse	May 17, 2018

The nominal patent-term endpoint is February 27, 2029, calculated from the earliest claimed priority date and the 20-year term applicable to the relevant US application. The operative expiration date for commercial planning should be taken from the current USPTO patent record and any applicable patent-term adjustment. The patent was issued before the 2018 approval of Tavalisse, so patent-term extension analysis is relevant, although a formulation patent does not automatically receive the same regulatory protection as the approved active ingredient.

FDA approval did not create exclusivity for the entire patent term. Regulatory exclusivity and patent exclusivity are separate rights. The FDA approved Tavalisse in 2018 for chronic immune thrombocytopenia, while patent protection continues according to the patent statute and any applicable term adjustment.[2][3]

What is the Orange Book status of US Patent 8,652,492?

US Patent 8,652,492 has been associated with the Tavalisse regulatory patent estate and should be evaluated against the current FDA Orange Book listing for NDA 210873. The patent covers an approved tablet formulation and therefore has a plausible regulatory-listing basis under the Orange Book framework.

The relevant regulatory questions are:

Whether the patent remains listed for the current Tavalisse strengths.
Whether the FDA listing identifies the patent as a formulation, drug-substance, or method-of-use patent.
Whether the listed claims read on the approved 100 mg and 150 mg tablets.
Whether an ANDA applicant must make a Paragraph IV certification.

The Orange Book is the controlling public source for current listed-patent status. Patent ownership, expiration and Orange Book listing are separate fields and should not be treated as interchangeable.[3]

Are there Paragraph IV challenges or generic companies challenging this patent?

A Paragraph IV certification is the principal ANDA mechanism for challenging a listed patent before expiration. Based on the cited public sources, no specific Paragraph IV challenger or final court judgment concerning US Patent 8,652,492 is identified here.

A generic applicant could pursue several certification positions:

Paragraph III certification, agreeing not to market until patent expiration.
Paragraph IV certification, asserting invalidity, unenforceability or non-infringement.
A section viii statement carving out a patented method of use, although that route is less relevant to a formulation patent covering the approved tablet.
A hybrid approach in which a proposed product uses a different manufacturing route or formulation architecture.

For this patent, a Paragraph IV case would likely focus on claim construction, written description, enablement, obviousness, inherent anticipation and whether the accused formulation or process satisfies the moisture-inhibition requirement.

How strong is the patent estate for fostamatinib?

The estate is stronger when considered as a layered portfolio rather than through US 8,652,492 alone.

Patent layer	Commercial objective	Relevance to US 8,652,492
Composition-of-matter patents	Protect R406 or fostamatinib-related chemical entities	Broader than the formulation patent
Prodrug and salt patents	Protect the phosphate prodrug and disodium form	Define the active form used in Tavalisse
Formulation patents	Protect stability, granulation and tablet performance	US 8,652,492 is in this category
Method-of-use patents	Protect treatment of immune thrombocytopenia and other conditions	Can create additional regulatory barriers
Manufacturing patents	Protect processing conditions and scale-up methods	Claim 8 is the main process protection here
Regulatory exclusivity	Delay certain abbreviated approvals	Separate from patent term

The focal patent is narrower than a composition-of-matter patent because it requires a particular formulation and, for claim 8, a particular manufacturing sequence. Its commercial value is higher if the approved Tavalisse tablets depend on the claimed wet-granulation process or starch-based moisture-control system.

Its vulnerability is also concentrated. A generic manufacturer may be able to design around the patent by using:

Direct compression.
Dry granulation or roller compaction.
A nonaqueous granulation process.
A different moisture-control excipient.
A different drying temperature or endpoint.
A formulation outside the claim 2 bulk-density range.
A different solid form or dosage architecture, if permitted by the regulatory product requirements.

A design-around must avoid all asserted claims, not merely claim 2.

What patent litigation affects Tavalisse and fostamatinib?

The principal litigation risk is likely to arise when an ANDA applicant seeks approval before the patent-term endpoint. A patent dispute could address both the product claims and the process claims, depending on what manufacturing information is available to the brand company.

For an ANDA, the applicant’s commercial exposure may include:

A 30-month stay triggered by a timely Paragraph IV notice and patent-owner litigation.
Injunctive relief or a judgment delaying approval.
A settlement providing a licensed launch date.
At-risk launch before final resolution.
Discovery into formulation composition, granulation conditions and manufacturing records.

No settlement agreement or final merits judgment involving US Patent 8,652,492 is identified in the cited sources. The absence of an identified public case does not establish that no confidential commercial agreement exists. Public settlement reporting, court dockets and FDA Orange Book updates remain the relevant evidence for a live challenge.

Does fostamatinib have biosimilar risk?

Fostamatinib does not present conventional biosimilar risk because it is a chemically synthesized small-molecule drug, not a biologic licensed under the Public Health Service Act. The relevant competitive pathway is an ANDA for a generic equivalent, not a biosimilar application.

The practical risk is therefore driven by:

Orange Book-listed patents.
Paragraph IV certifications.
Generic formulation development.
Bioequivalence requirements.
Manufacturing-process design around the wet-granulation claims.
Patent settlements or licenses.

What licensing deals affect the commercial landscape?

Rigel has commercialized fostamatinib through regional and strategic arrangements, including licensing and commercialization relationships outside the United States. These agreements can affect geographic launch timing, but they do not themselves expand the territorial scope of US Patent 8,652,492.

Patent rights are territorial. A US patent can block or delay US manufacture, importation, sale or use within the patent term, but it does not directly prevent a separate product launch in Europe, Japan or other jurisdictions. Regional partners must evaluate corresponding national patent families, supplementary protection certificates, regulatory exclusivity and local generic pathways.

How does the patent compare with a generic launch scenario?

Launch scenario	Risk under US 8,652,492	Main issue
Copy of Tavalisse wet-granulated tablet	High	Likely overlap with claims 1, 2, 7 and 9
Same excipients but dry granulation	Reduced	Avoids the wet-granulation limitation if no wet step is used
Wet granulation with starch and drying below 65°C	High	Direct concern under claims 1, 4-6 and 8
Wet granulation with calcium chloride	Potentially high	Listed in claim 3; process limitations still apply
Wet granulation with an unlisted moisture-control agent	Intermediate	May avoid claims 3-6 but not necessarily claim 1
Direct compression with no water	Lower	Strongest design-around against claims requiring wet granulation
Process drying outside 5%-11% LOD	Reduced for claim 8	Does not necessarily avoid formulation claims
Product with density outside 0.35-0.65 g/mL	Reduced for claim 2	Does not necessarily avoid claim 1

The most credible generic strategy is a nonaqueous or dry-processing route that produces bioequivalent tablets without the claimed wet-granulation parameters. The commercial feasibility of that strategy depends on stability, dissolution, tablet strength, content uniformity and FDA bioequivalence requirements.

Key Takeaways

US Patent 8,652,492 covers a wet-granulated fostamatinib disodium formulation, not fostamatinib as a chemical entity.
Claim 1 combines moisture protection with tablet-forming performance.
Claim 2 adds a dried bulk-density range of approximately 0.35 to 0.65 g/mL.
Claims 3 through 6 focus on specified water-sequestering agents, especially partially pregelatinized maize starch.
Claim 8 independently covers wet granulation, drying below 65°C and a 5%-11% loss-on-drying endpoint.
Claim 9 extends the process claim to tablet compression.
The nominal patent-term endpoint is February 27, 2029, subject to the official USPTO term calculation.
Fostamatinib is a small molecule, so generic ANDA risk is more relevant than biosimilar risk.
The strongest design-around is likely a dry or direct-compression process, provided the resulting product meets FDA performance requirements.
Current Orange Book status and any Paragraph IV activity should be checked against the live NDA 210873 record.

FAQs About US Patent 8,652,492 and Fostamatinib

Does US Patent 8,652,492 cover Tavalisse generally?

No. It covers a defined wet-granulated formulation and a related manufacturing process. It does not claim every formulation or use of fostamatinib.

Can a generic avoid the patent by replacing starch with another excipient?

Possibly, but not automatically. An alternative excipient could avoid the narrower claims directed to starch or the listed Markush group while still falling within claim 1 if it functions as a water-sequestering agent and the remaining limitations are met.

Does claim 8 require making tablets?

No. Claim 8 is directed to the wet-granulation process through lubricant blending. Claim 9 adds the tablet-compression step.

Is a bulk density of 0.35 to 0.65 g/mL required for every claim?

No. That range is expressly recited in claim 2. Claim 1 contains a functional tablet-forming limitation, while claim 8 does not expressly recite the claim 2 density range.

What is the primary invalidity risk for this formulation patent?

Obviousness is likely to be the principal risk, particularly if prior art combines fostamatinib or a related compound with wet granulation, moisture-control excipients and conventional tablet-processing parameters. Anticipation, enablement and written-description issues may also arise depending on the asserted claim and evidentiary record.

References

United States Patent No. 8,652,492. (2014). Pharmaceutical compositions comprising fostamatinib disodium. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2018). FDA approves fostamatinib for adults with chronic immune thrombocytopenia. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
Rigel Pharmaceuticals, Inc. (2024). Annual report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934. U.S. Securities and Exchange Commission.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Rigel Pharms	TAVALISSE	fostamatinib disodium	TABLET;ORAL	209299-001	Apr 17, 2018	AB	RX	Yes	No	8,652,492	⤷ Start Trial	Y				⤷ Start Trial
Rigel Pharms	TAVALISSE	fostamatinib disodium	TABLET;ORAL	209299-002	Apr 17, 2018	AB	RX	Yes	Yes	8,652,492	⤷ Start Trial	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

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2008323938	⤷ Start Trial
Brazil	PI0820389	⤷ Start Trial
Canada	2704474	⤷ Start Trial
China	101998857	⤷ Start Trial
Colombia	6280491	⤷ Start Trial
Costa Rica	11476	⤷ Start Trial
Cuba	20100089	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,652,492

Which drugs does patent 8,652,492 protect, and when does it expire?

Summary for Patent: 8,652,492