Details for Patent: 8,754,091

Which drugs does patent 8,754,091 protect, and when does it expire?

Patent 8,754,091 protects IMBRUVICA and is included in three NDAs.

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

This patent has one hundred and sixty-eight patent family members in twenty-eight countries.

Summary for Patent: 8,754,091

Title:	Inhibitors of bruton's tyrosine kinase
Abstract:	Disclosed herein are compounds, including compounds having the structure of Formula (A), (B), (C), and (D), as described in further detail herein, that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
Inventor(s):	Lee Honigberg, Erik Verner, Zhengying Pan
Assignee:	Pharmacyclics LLC
Application Number:	US13/542,440
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,754,091
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Dosage form;

US Patent 8,754,091: Scope, Claim Strategy, and Patent Landscape for Irreversible Btk Formulations

US Patent 8,754,091 claims a pharmaceutical formulation defined by (i) an irreversible Bruton's tyrosine kinase (Btk) inhibitor in a broad structural family (Formula (A) and related embodiments) and (ii) pharmaceutically acceptable excipients, with dependent claims narrowing to specific routes of administration and solid oral capsule excipient systems. The claims function as a formulation patent around a chemistry-defined irreversible Btk inhibitor scaffold, combining a broad chemical genus with relatively specific dosage-form and excipient compositions.

What does claim 1 cover? (Core scope of US 8,754,091)

1. Claimed subject matter

Claim 1 covers:

• A pharmaceutical formulation comprising:

  • an irreversible Btk inhibitor having a structure of Formula (A), and
  • a pharmaceutically acceptable excipient.

• The inhibitor scaffold is defined by nested substituent variables:

  • A is N.
  • R1 is an L2-linked aryl/heteroaryl unit:
  • L2 is a bond or heteroatom or linkage type selected from O, S, —S(═O), —S(═O)2, C(═O), -(C1-C6 alkylene), -(C2-C6 alkenylene) (all optionally substituted/unsubstituted by the claim language).
  • R2 and R3 are independently H or lower alkyl.
  • R4 is the key connecting segment: R4 is L3 - X - L4 - G
  • L3 is optional and, when present, is an optional alkylene/cycloalkylene/alkenylene/alkynylene.
  • X is optional and, when present, is selected from a long list of heteroatom-containing bridging units and heteroarylene/arylene/condensed nitrogen-containing patterns (the claim lists many specific linker types).
  • L4 is optional and, when present, is an optional substituted/unsubstituted alkylene/cycloalkylene/alkenylene/alkynylene/arylene/heteroarylene/heterocyclene.
  • Alternatively, L3, X and L4 taken together form a nitrogen-containing heterocyclic ring.
  • G is a substituent substituent-defined group:
  • G is defined through R6, R7, R8 selection:
    • each of R6/R7/R8 is independently selected from H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted/unsubstituted lower cycloalkyl, substituted/unsubstituted lower heterocycloalkyl.
  • R9 is:
  • H, or substituted/unsubstituted lower alkyl, or substituted/unsubstituted lower cycloalkyl.
  • R10 is:
  • independently H, lower alkyl, or lower cycloalkyl (and two R10 groups can close a 5-, 6-, 7-, or 8-membered heterocycle).
  • R11 is selected from H, —S(═O)2R8, —S(═O)2NH2, —C(O)R8, —CN, —NO2, heteroaryl, or heteroalkyl.
  • The claim also allows the inhibitor to be a pharmaceutically acceptable solvate, hydrate, or salt.

Net effect: claim 1 is a genus formulation claim: any pharmaceutical composition containing an irreversible Btk inhibitor within a large structural envelope is within scope, provided a pharmaceutically acceptable excipient is present.

2. Claim 1 is not limited to a specific dose form or route

The only “product-form” limitation in claim 1 is that it is a pharmaceutical formulation with an excipient. Everything else (route, solid dosage form, capsule packaging, excipient microstructure) appears in dependent claims.

How is the “irreversible Btk inhibitor” narrowed in dependent claims?

Claim 2: specific embodiment of the inhibitor scaffold (Formula D)

Claim 2 limits the irreversible Btk inhibitor to a compound of Formula (D) with constrained sub-variables:

• La is O or S
• Ar is phenyl
• Y is either:
  • a 4-, 5-, 6-, or 7-membered cycloalkylene ring, or
  • azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl
• Z is selected from:
  • C(═O), OC(═O), NHC(═O), S(═O)x, or NHS(═O)x, with x = 2
• R8 and R7 are H, or R7 and R8 taken together form a bond
• R6 is H
• includes solvate/hydrate/salt forms.

Scope impact: claim 2 narrows from the full Formula (A) genus to a more specific sub-family while still covering multiple ring sizes and linker oxosulfur substituents.

Claims 15–19: additional structural tightening around Y/R12 and substituent patterns

• Claim 15 imposes:
  • Y and R12 form a 4-, 5-, or 6-membered heterocyclic ring, and
  • G is “where R6, R7, R8…” is defined.
• Claim 16 further selects:
  • Y and R12 form a 6-membered heterocyclic ring
• Claim 18 sets:
  • R6, R7, and R8 are independently H
• Claim 19 sets specific subset:
  • La is O, Z is C(O), and R6, R7, R8 are H.

Scope impact: these claims function as fallback positions against validity/avoidance challenges, with increasingly specific substituent patterns.

Claim 20 and Claim 21: additional inhibitor embodiment claims

• Claim 20 narrows claim 1 further to another inhibitor structure (Formula depicted in claim text).
• Claim 21 is a second independent-style formulation claim:
  • A pharmaceutical formulation comprising an irreversible Btk inhibitor (structure shown) and excipient.

Landscape inference: claim 21 reinforces product coverage around at least one additional defined structural embodiment, likely used to preserve coverage if claim 1 is weakened.

What does the formulation scope cover for dosage form and excipients?

Claim 3 through claim 14 define routes and solid oral capsule formulation components. This is the most practically relevant segment for manufacturing and design-around.

Which routes of administration are claimed?

Claim 3 covers administration routes:

• oral
• parenteral
• buccal
• nasal
• topical
• rectal

Claim 4 selects oral administration.

Scope impact: oral is explicitly claimed, but the dependent chain still leaves other routes potentially covered depending on the construction of dependent claims and claim dependency.

What solid dosage forms are claimed?

Claim 5: oral, solid dosage form
Claim 6: solid dosage form is contained in one or more capsules

Scope impact: the claim targets capsule-based oral solids. A tablet-focused product could fall outside claims 5–6, unless doctrine of equivalents or literal infringement arguments succeed under the “capsules” limitation.

What excipient systems are claimed?

Claims 7–14 specify an excipient “package” with binder/disintegrant/surfactant, and then quantify binder content.

Claim 7: excipient comprises one or more carrier materials from:

• binders
• disintegration agents
• surfactants
• lubricants
• combinations

Claim 8: excipient comprises:

• a binder
• a disintegration agent
• a surfactant

Claim 9: binder amount: 20 to 70 w/w %

Claim 10: binder is microcrystalline cellulose

Claim 11: disintegration agent is croscarmellose sodium

Claim 12: surfactant is sodium lauryl sulfate

Claim 13: excipient further comprises a lubricant

Claim 14: lubricant is magnesium stearate

Table: excipient coverage in the dependent claim chain

Component	Claim	Specification
Binder	10	microcrystalline cellulose
Binder amount	9	20 to 70 w/w %
Disintegrant	11	croscarmellose sodium
Surfactant	12	sodium lauryl sulfate
Lubricant	13–14	magnesium stearate
Dosage format	5–6	oral solid, in capsules

Landscape inference: these excipient selections are typical of immediate-release capsule blends; the claim is not a formulation “generic pack” only. It is constrained to identifiable excipient names and one quantified component range, making it a litigation-ready infringement hook for products using this blend or a near-identical blend.

What is the overall claim architecture? (Strategy and attack surfaces)

1) Chemistry breadth with formulation anchoring

• Claim 1 gives a broad structural genus for an irreversible Btk inhibitor.
• Dependent claims 3–14 anchor the formulation to oral capsule solid dosage and a named excipient system.

2) Fallback redundancy through multiple inhibitor embodiments

• Claim 2 provides a Formula (D) embodiment.
• Claims 15–20 provide further constrained patterns.
• Claim 21 offers another structural embodiment route.

3) A two-stage infringement pathway

For enforcement against a competitor:

• Stage A: show that competitor’s active is an irreversible Btk inhibitor within the claimed structural envelope (claim 1 or embodiment claims).
• Stage B: show the product is a pharmaceutical formulation with excipients that match claim 3–14 limitations (for oral capsule cases) or at least satisfy the dependent chain up to the relevant claim.

4) Design-around levers are clear in claim language

• Avoid capsule dosage form: switching from capsules to tablets or other forms may avoid claim 6.
• Change excipient system: substituting away from microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, or magnesium stearate could avoid claims 10–14.
• Change binder content: moving binder outside 20 to 70 w/w % could avoid claim 9, if claim 9 becomes a direct infringement requirement in asserted claim sets.
• Change inhibitor structure: altering R-group pattern or the core “irreversible” substituent framework may avoid claims 1/2/15–20.

Related patent landscape: what can this US patent most plausibly overlap with?

Without prosecution history, assignee identifiers, or the complete claim set beyond what you provided, the only defensible landscape statements are structural and claim-type driven:

A. Landscape bucket 1: formulation patents around irreversible Btk chemotypes

US 8,754,091 is a formulation patent whose enforceability depends on:

• presence of a defined irreversible Btk inhibitor structural family, plus
• presence of a pharmaceutically acceptable excipient,
• and, for narrower claims, alignment with oral capsule solid and specific excipient choices.

This type of patent commonly overlaps with:

• process patents for the inhibitor synthesis
• drug substance patents claiming the active molecule(s)
• other formulation patents covering alternative excipient blends, coatings, or release profiles

B. Landscape bucket 2: excipient system IP adjacency

The excipient chain (microcrystalline cellulose + croscarmellose sodium + sodium lauryl sulfate + magnesium stearate) likely appears across multiple product dossiers for Btk inhibitors and other oral solids. The scope here is specifically tied to an irreversible Btk inhibitor scaffold.

Practical implication: even if competitors use the same excipient package, infringement still requires the active inhibitor to fall within claimed Formula (A) or the dependent formula embodiments.

C. Landscape bucket 3: “capsule vs tablet” differentiation

Claim 6 is capsule-focused. Landscape in this area often sees:

• capsule formulations claimed in one patent set,
• tablet or sachet formulations claimed in separate patents,
• plus separate patents for immediate-release vs modified-release.

Risk map: where competitors are most likely to hit US 8,754,091

Direct hit conditions (most likely)

A competitor’s marketed product would be at high risk under this patent if it satisfies all of the following:

1. Active ingredient is an irreversible Btk inhibitor with structural variables falling within Formula (A) (or a specific embodiment like Formula (D)).
2. Product is an oral solid dosage in capsules.
3. The capsule excipient system matches the dependent claims:
   • microcrystalline cellulose binder present at 20–70 w/w %
   • croscarmellose sodium as disintegration agent
   • sodium lauryl sulfate as surfactant
   • magnesium stearate as lubricant (if claim 13–14 are asserted)

Partial hit conditions (fallback litigation)

If the inhibitor matches but excipient packaging differs, enforcement is likely to focus on:

• claim 1 (active + excipient definition) rather than the narrow capsule excipient claims,
• or claim 2 / claims 15–20 depending on which structural embodiment matches the competitor’s active.

What are the enforceable claim boundaries for manufacturing?

Manufacturing change levers (high leverage)

• Replace binder type away from microcrystalline cellulose (claim 10).
• Replace disintegrant away from croscarmellose sodium (claim 11).
• Replace surfactant away from sodium lauryl sulfate (claim 12).
• Replace lubricant away from magnesium stearate (claim 14).
• Move binder content outside 20 to 70 w/w % (claim 9).
• Switch dosage form away from capsules (claim 6).

Chemistry change lever (largest but harder)

• Modify the inhibitor substituent variables such that the compound no longer satisfies Formula (A) or dependent formula limitations.
• Ensure the inhibitor is not “irreversible” in the sense required by the claimed class (the claim text ties the inhibitor to irreversible Btk inhibitor, without detailing the covalent mechanism; enforcement would likely rely on the inhibitor’s known Btk irreversibility in the asserted context).

Key Takeaways

• US 8,754,091 is a formulation patent that combines a broad structural genus for an irreversible Btk inhibitor (Formula (A)) with narrow product form and excipient claims for oral solid capsules.
• The practical enforcement core is a two-step proof: active inhibitor structural inclusion plus, for narrower claims, matching excipient package (microcrystalline cellulose + croscarmellose sodium + sodium lauryl sulfate + magnesium stearate) with binder at 20–70 w/w %.
• Design-around is most feasible by changing capsule vs tablet, and by modifying excipient selections or binder loading; the deepest avoidance lever is to move the active inhibitor outside the claimed Formula (A) or dependent embodiments (Formula (D), Y/R12 patterns, and R6/R7/R8 subsets).

FAQs

1) Is US 8,754,091 limited to one specific Btk inhibitor compound?
No. Claim 1 defines an inhibitor genus under Formula (A), with dependent claims narrowing to specific embodiments (including Formula (D) in claim 2 and additional constrained patterns in claims 15–20).

2) Does the patent require capsules?
Capsules are required only for the narrower dependent chain: claim 6 requires that the oral solid dosage form is contained in one or more capsules (claims 5–6).

3) Which excipients are explicitly claimed by name?
Microcrystalline cellulose (binder), croscarmellose sodium (disintegrant), sodium lauryl sulfate (surfactant), and magnesium stearate (lubricant) appear in claims 10–14.

4) Is binder quantity constrained?
Yes. Claim 9 specifies binder present at 20 to 70 w/w %.

5) What routes of administration are covered?
Claim 3 lists oral, parenteral, buccal, nasal, topical, and rectal; claim 4 narrows to oral, and claims 5–6 narrow further to oral solid dosage in capsules.

References (APA)

1. United States Patent No. 8,754,091.

Drugs Protected by US Patent 8,754,091

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Pharmacyclics Llc	IMBRUVICA	ibrutinib	CAPSULE;ORAL	205552-002	Dec 20, 2017		RX	Yes	No	8,754,091*PED				Y
Pharmacyclics Llc	IMBRUVICA	ibrutinib	CAPSULE;ORAL	205552-001	Nov 13, 2013		RX	Yes	Yes	8,754,091*PED				Y
Pharmacyclics Llc	IMBRUVICA	ibrutinib	SUSPENSION;ORAL	217003-001	Aug 24, 2022		RX	Yes	Yes	8,754,091*PED				Y
Pharmacyclics Llc	IMBRUVICA	ibrutinib	TABLET;ORAL	210563-001	Feb 16, 2018		RX	Yes	No	8,754,091*PED				Y
Pharmacyclics Llc	IMBRUVICA	ibrutinib	TABLET;ORAL	210563-002	Feb 16, 2018		RX	Yes	No	8,754,091*PED				Y

International Family Members for US Patent 8,754,091

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2201840		C300728	Netherlands
European Patent Office	2201840		CA 2015 00021	Denmark
European Patent Office	2201840		PA2015017	Lithuania
European Patent Office	2201840		C20150014 00145	Estonia
European Patent Office	2201840		15C0029	France