Details for Patent: 8,163,902

Which drugs does patent 8,163,902 protect, and when does it expire?

Patent 8,163,902 protects TAVALISSE and is included in one NDA.

This patent has ten patent family members in eight countries.

Summary for Patent: 8,163,902

Title:	Prodrugs of 2,4-pyrimidinediamine compounds and their uses
Abstract:	The present disclosure provides prodrugs of biologically active 2,4-pyrimidinediamine compounds, salts and hydrates of the prodrugs, compositions comprising the prodrugs, intermediates and methods for synthesizing the prodrugs and methods of using the prodrugs in a variety of applications.
Inventor(s):	Somasekhar Bhamidipati, Rajinder Singh, Thomas Sun, Esteban Masuda
Assignee:	Rigel Pharmaceuticals Inc
Application Number:	US11/943,506
Patent Claim Types: see list of patent claims	Use; Composition; Formulation;

Patent 8,163,902 Scope and Claims Analysis: crystalline prodrug salt hydrate, formulation, and use claims for Syk/FC receptor signaling inhibition

US Drug Patent 8,163,902 is a US utility patent centered on a specific crystalline form of a prodrug salt hydrate, defined by (i) powder X-ray diffraction (PXRD) peak positions, (ii) crystallographic parameters (space group P21/c and unit cell dimensions), and (iii) downstream compositions and biological/therapeutic use claims tied to inhibition of Syk kinase activity and Fc receptor signal transduction, including rheumatoid arthritis (RA) and broader autoimmune disease indications. The patent’s strongest scope is the identity of the crystalline solid form (claims 1 and 2) and any composition and administration that use that same solid form; secondary scope extends to generic-purpose “pharmaceutical compositions” and broad mechanistic method claims that can be implemented with the same crystalline salt hydrate.

The claim set also includes specific process claims for making the salt hydrate (pH adjustment with sodium-based base, precipitation, solvent addition, and controlled moisture exposure to generate the crystalline form). These process claims can be used to capture certain manufacturing routes even where the final dosage form differs, provided the infringement theory is tied to making the patented crystalline hydrate.

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What patents protect the crystalline prodrug salt hydrate in US 8,163,902, and how are the claims limited?

What is actually claimed: the crystalline identity is the anchor

Claim 1 and claim 2 define the claimed product as “a crystal comprising the prodrug salt hydrate” with precise physical characterization.

Claim 1 (PXRD-based identity)

• Requires “characteristic powder X-ray diffraction peaks” at specific 2θ values, each with a tight tolerance:
  • 3.4° ± 0.1°
  • 6.6° ± 0.1°
  • 9.9° ± 0.1°
  • 13.2° ± 0.1°
  • 17.2° ± 0.1°
  • 19.7° ± 0.1°
  • 21.2° ± 0.1°
  • 21.8° ± 0.1°
• This is a “metrology-defined” product claim. In practice, infringement turns on whether the accused solid exhibits the claimed PXRD peak set within tolerance at the defined measurement conditions.

Claim 2 (single-crystal-like crystallography identity)

• Adds a structural definition:
  • Space group symmetry: P21/c
  • Unit cell parameters:
    • a = 27.73 Å
    • b = 7.98 Å
    • c = 15.17 Å
    • α = 90°
    • β = 103.2°
    • γ = 90°

Scope implication

• Claims 1 and 2 are mutually reinforcing: claim 2 supplies an orthogonal crystallographic hook. A product that meets claim 1 but not claim 2 (or vice versa) can be litigated depending on which characterization is available and how the court construes the “comprising” language for the crystal.

Key constraint: “comprising” does not mean “anything goes”

Each product claim uses “comprising the prodrug salt hydrate,” which typically permits the crystal to include other features (e.g., minor impurities or defects) without losing coverage, but it does not dilute the requirement that the crystal exhibits the specified PXRD peaks and/or crystallographic parameters that identify the claimed crystalline form.

How claim construction usually gets tested

For a PXRD-defined crystal claim, disputes tend to focus on:

• Sample preparation and measurement settings.
• Peak indexing accuracy and background subtraction.
• Whether the accused material is the same crystalline hydrate or a closely related polymorph/solvate that shifts peaks outside tolerance.

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How broad are the composition and administration claims in US 8,163,902?

Composition claim 3: broad but tethered to the crystalline hydrate

Claim 3

• “A pharmaceutical composition comprising the prodrug salt hydrate according to claim 1 or 2 and a pharmaceutically-acceptable carrier…”

This is a classic formulation placeholder. Its breadth is limited by the requirement that the composition contains the patented crystalline prodrug salt hydrate (the solid form meeting claim 1 and/or claim 2).

Design-around pressure point

• A competitor can avoid claim 3 by using a different solid form (e.g., a different hydrate, polymorph, or amorphous form) or by using a salt form that does not generate the specified PXRD signature.

Method of administering claim 4: still tethered to the crystal

Claim 4

• Administration of “the prodrug salt hydrate according to claim 1 or 2 or the pharmaceutical composition according to claim 3.”

This claim is broad in route and dosing context (it does not restrict to oral/injectable), but infringement still requires administering the patented solid form or composition.

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What biological mechanism and therapeutic claims are in US 8,163,902? (Syk and Fc receptor signaling)

Claim 6: Syk inhibition method claim

Claim 6

• Administer the prodrug salt hydrate (claims 1/2) effective to inhibit Syk kinase activity.

Claim 11 adds a pharmacodynamic threshold

• “effective to achieve a serum concentration … at or above the IC50 of Syk inhibition of the drug, as measured in an in vitro assay.”

Scope implications

• Claim 6 is mechanistic and can cover both RA and other autoimmune diseases where Syk drives pathophysiology.
• Claim 11 increases enforceability by providing a concrete exposure benchmark. It is still tied to administration of the claimed crystalline prodrug salt hydrate.

Claims 7 and 8: Fc receptor signal transduction cascade

Claim 7

• Administer the prodrug salt hydrate effective to inhibit an Fc receptor signal transduction cascade.

Claim 8

• Specifies Fc receptors:
  • FcαRI
  • FcγRI
  • FcγRIII
  • FcεRI

Scope implications

• This is broader than a single receptor subtype and maps onto immunological signaling pathways relevant to multiple autoimmune conditions.

Claim 5: cell degranulation linked to rheumatoid arthritis

Claim 5

• Inhibiting cell degranulation in a subject, where degranulation is associated with RA.

Scope implications

• This adds another functional endpoint. It can capture dosing regimes that achieve degranulation inhibition even if the competitor disputes the mechanistic route.

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What autoimmune disease claims are covered, and how does rheumatoid arthritis scope expand?

Claim 9: autoimmune disease “selected from” a long list

Claim 9 covers treating an autoimmune disease or symptoms associated with it, with the autoimmune disease selected from:

• Hashimoto's thyroiditis
• autoimmune hemolytic anemia
• autoimmune atrophic gastritis of pernicious anemia
• autoimmune encephalomyelitis
• autoimmune orchitis
• Goodpasture's disease
• autoimmune thrombocytopenia
• sympathetic ophthalmia
• myasthenia gravis
• Graves' disease
• primary biliary cirrhosis
• chronic aggressive hepatitis
• ulcerative colitis
• membranous glomerulopathy
• systemic lupus erythematosis
• rheumatoid arthritis
• Sjogren's syndrome
• Reiter's syndrome
• polymyositis-dermatomyositis
• systemic sclerosis
• polyarthritis nodosa
• multiple sclerosis
• bullous pemphigoid

Scope implications

• The “selected from” structure generally means any one listed disease qualifies. The scope is therefore wide across autoimmune indications, with RA expressly included.

Claim 10: specific rheumatoid arthritis treatment claim

Claim 10

• Treat RA by administering an amount effective to provide therapeutic benefit.

Scope implications

• Claim 10 narrows the therapeutic target but benefits from the clinical relevance of RA and ties naturally to later claims 11 (serum concentration vs IC50).

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How strong are the manufacturing/process claims in US 8,163,902 for infringement risk?

Process claims add a different infringement vector: even if a competitor markets a different dosage form, they may still infringe if their manufacturing makes the claimed crystal via the claimed steps.

Claim 12: preparation via sodium-based pH adjustment and precipitation

Claim 12

• Adjust pH of aqueous solution of the prodrug to about 8 to 11 with a [Na+]-containing base
• Precipitate the prodrug salt hydrate from the solution

Claim 13–15: narrower pH and base specificity

• Claim 13: pH 9 to 11
• Claim 14: pH 9.3 to 10.5
• Claim 15: NaOH, NaOMe, Na2CO3

Scope implications

• These claims can be read to cover any manufacturing route that operationally falls inside the pH window and uses sodium-containing base among the enumerated reagents.

Claim 16–18: water-miscible solvent precipitation and thermal control

• Claim 16: precipitating comprises adding a water-miscible solvent to the aqueous solution
• Claim 17: solvent is acetonitrile, acetone, isopropanol, methanol, ethanol, or mixtures
• Claim 18: aqueous solution heated before, after, or both, then cool to precipitate

Claim 19: isolating the hydrate

• Further includes isolating from solution.

Claim 20–21: making the crystalline form via moisture exposure

Claim 20

• Steps:
  • (a) adjust pH to about 9 to 11 with [Na+]-containing base
  • (b) precipitate salt hydrate
  • (c) expose prodrug salt to moisture to yield “the crystalline form of the prodrug salt hydrate”

Claim 21 adds operational refinements

• Prior to (b): optional water-miscible solvent addition and heating
• (b): cooling to precipitate
• Prior to (c): washing with a wash solvent and removing substantially all wash solvent

Scope implications

• These claims target a specific “crystalline form generation” pathway where moisture exposure converts the precipitated material into the targeted crystal form.

Design-around pressure point

• A competitor could attempt to avoid the process claims by:
  • avoiding precipitation windows,
  • not using the enumerated sodium bases,
  • avoiding the enumerated solvent set,
  • avoiding cooling patterns,
  • eliminating moisture exposure conditions that “yield the crystalline form.” But any change that still results in the same marketed crystal can trigger product claims regardless of process differences.

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What is claim 22 and how does it further constrain PXRD measurement?

Claim 22

• “X-ray diffraction peaks are generated in response to radiation of wavelength 1.54059 Å.”

This ties the PXRD measurement condition to Cu Kα radiation (common Cu Kα wavelength is 1.5406 Å). That tightens infringement analysis because PXRD peak positions can shift with instrumentation/target source and optical geometry.

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Claim chart style mapping: what would an infringement allegation need to prove?

For product claims (1–2)

1. The accused crystal contains the prodrug salt hydrate.
2. The accused crystal exhibits PXRD peaks at the specified 2θ values within ±0.1°.
3. Alternatively, the accused crystal corresponds to P21/c with the stated unit cell parameters.

For use claims (4–11)

1. The accused acts administer the claimed solid form (or composition containing it).
2. The administered dose is effective for the claimed functional endpoints:
   • inhibiting Syk activity (claim 6),
   • inhibiting Fc receptor signal transduction (claims 7–8),
   • inhibiting cell degranulation associated with RA (claim 5),
   • treating RA (claim 10),
   • achieving serum concentration at or above the in vitro IC50 (claim 11).

For composition claims (3)

1. The marketed composition includes the claimed crystalline prodrug salt hydrate and a carrier.

For manufacturing claims (12–21)

1. The accused process uses the claimed pH adjustment window with sodium base and precipitation mechanics.
2. If targeting claim 20–21: the accused process includes moisture exposure yielding the crystalline form.

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Patent landscape analysis: what other patents typically surround this type of claim set, and where the risk concentrates

Because only the claim text for US 8,163,902 is provided, a complete, jurisdiction-accurate landscape (other family members, related US patents, Orange Book listings, and cited art) cannot be enumerated here without external record access. The practical landscape analysis for this specific patent therefore focuses on what the claim structure implies about surrounding patent layers commonly present in prodrug salt hydrate programs:

1. Crystalline form “solid-state” layer

   • US 8,163,902 is itself a solid-state patent. Expect related patents in the same family to cover:
     • other polymorphs/hydrates/solvates,
     • amorphous forms,
     • methods of producing alternative forms,
     • stability and moisture sorption behavior.

2. Prodrug chemistry and salt identity layer

   • US 8,163,902 presumes the “prodrug” exists and the salt hydrate identity is established. Programs typically also have:
     • prodrug compound patents,
     • salt selection patents (different counterions),
     • prodrug composition patents (before crystallinity is specified).

3. Formulation and dosage-form layer

   • Claim 3 is only a carrier composition placeholder. Separate patents often exist for:
     • tablet/capsule/injectable formulations,
     • specific excipient systems,
     • particle size control,
     • dissolution enhancement,
     • stability and shelf-life specifications.

4. Method-of-use and mechanistic layer

   • Claims 5–11 are broad on RA and autoimmune diseases and mechanistic pathways (Syk and Fc receptor signaling).
   • Other patents in the family or prosecution history often cover:
     • additional therapeutic indications,
     • dosing regimens,
     • combination therapies,
     • biomarkers and response criteria.

5. Manufacturing process and control strategy layer

   • Claims 12–21 define a manufacturing route. Additional process/control patents often cover:
     • scale-up constraints,
     • specific mixing order,
     • drying steps and moisture thresholds,
     • impurity control via solvent selection and wash solvent removal.

Risk concentration

• For a competitor, the highest risk zone is use and sales of products that contain this specific crystalline hydrate, regardless of dosage form.
• The next risk zone is manufacturing: if a competitor uses a sodium-based precipitation pathway and moisture exposure that yields the targeted crystalline form, process claims can attach even if the competitor tries to switch formulation components.

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Business implications: how infringement and design-around strategies map to the claim set

If a generic or biosimilar-like competitor wants to launch

• Avoiding infringement is easiest when the competitor can sell a different solid form that does not meet the PXRD peak set and/or crystallographic parameters.
• If the competitor uses the same crystalline hydrate, then:
  • composition claims (3),
  • administration claims (4),
  • Syk/Fc use claims (6–11),
  • RA and autoimmune treatment claims (9–10) become direct exposure vectors.

If a formulation supplier changes excipients

• Excipients alone generally do not avoid claim 3 because the claim requires the patented crystal.
• Excipients can matter for whether the product still includes the patented crystalline hydrate (e.g., whether the hydrate converts during storage or manufacturing). If conversion occurs, that can affect infringement.

If a manufacturer changes synthesis route

• Manufacturing changes can avoid process claims (12–21).
• But if the end product crystal still matches claims 1–2, product and use claims remain.

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Key Takeaways

• US 8,163,902 is a crystalline solid-state patent with product identity defined by PXRD peak positions (claim 1) and crystallography (space group P21/c and unit cell) (claim 2).
• Composition and administration claims (3–4) are broad but tethered to the patented crystalline hydrate.
• Therapeutic and mechanistic claims (5–11) are wide across autoimmune diseases, with explicit rheumatoid arthritis coverage and mechanistic endpoints tied to Syk inhibition and Fc receptor signal transduction.
• Process claims (12–21) are structured around sodium-based pH adjustment, precipitation with defined solvent classes, and moisture exposure to generate the crystalline form, creating manufacturing-route infringement risk even where dosage form differs.
• Practical design-around requires avoiding the specific solid form (PXRD/crystallography mismatch); changes to excipients or dosing language do not eliminate risk if the patented crystal is still used.

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FAQs

1. What does “characteristic PXRD peaks” in claim 1 require for infringement?
It requires the accused crystalline material to show PXRD peaks at the specified 2θ values within ±0.1°, measured under the claimed conditions.

2. Does claim 2 provide a stronger identity test than claim 1?
Claim 2 adds crystallographic parameters (P21/c and unit cell constants), which can be decisive if crystallographic characterization of the accused material is available.

3. Can process changes avoid US 8,163,902 even if the marketed crystal matches claims 1–2?
Process changes can avoid process claims (12–21) but do not avoid product claims (1–2) and downstream composition/use claims (3–11) if the accused crystal matches.

4. How does claim 11 affect method-of-use enforcement?
It ties infringement to achieving a serum concentration at or above the in vitro IC50 for Syk inhibition of the drug, which can be used to argue dosing adequacy and exposure.

5. Are Fc receptor claims limited to specific receptor subclasses?
Claim 7 is broad to Fc receptor signal transduction cascades; claim 8 narrows to FcαRI, FcγRI, FcγRIII, and FcεRI.

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References

1. United States Patent 8,163,902 (claims provided in prompt).

Drugs Protected by US Patent 8,163,902

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				Y		TREATMENT OF THROMBOCYTOPENIA IN ADULT PATIENTS WITH CHRONIC IMMUNE THROMBOCYTOPENIA (ITP) WHO HAVE HAD AN INSUFFICIENT RESPONSE TO A PREVIOUS TREATMENT
Rigel Pharms	TAVALISSE	fostamatinib disodium	TABLET;ORAL	209299-002	Apr 17, 2018	AB	RX	Yes	Yes				Y		TREATMENT OF THROMBOCYTOPENIA IN ADULT PATIENTS WITH CHRONIC IMMUNE THROMBOCYTOPENIA (ITP) WHO HAVE HAD AN INSUFFICIENT RESPONSE TO A PREVIOUS TREATMENT

International Family Members for US Patent 8,163,902

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	E540041
Canada	2673137
Denmark	2078026