Details for Patent: 9,725,455

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Which drugs does patent 9,725,455 protect, and when does it expire?

Patent 9,725,455 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 eighty-one patent family members in thirty-one countries.

Summary for Patent: 9,725,455

Title:	Crystalline forms of a bruton's tyrosine kinase inhibitor
Abstract:	Described herein is the Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, including crystalline forms, solvates and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions that include the Btk inhibitor, as well as methods of using the Btk inhibitor, 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):	Norbert Purro, Mark Stephen Smyth, Erick Goldman, David D. Wirth
Assignee:	Pharmacyclics LLC
Application Number:	US15/497,896
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,725,455
Patent Claim Types: see list of patent claims	Compound;

US Patent 9,725,455: Ibrutinib Form A Claims, Exclusivity, Litigation and Patent Landscape

US Patent No. 9,725,455 protects crystalline Form A of ibrutinib, the active pharmaceutical ingredient in Imbruvica. The patent does not claim ibrutinib as a chemical compound. It claims a specific solid-state form identified primarily through XRPD peaks, with dependent claims covering additional diffraction peaks, spectroscopic properties, thermal behavior, hygroscopicity and aqueous solubility.

The patent was assigned to Pharmacyclics LLC, now part of AbbVie. It is commercially relevant because a generic ibrutinib product could infringe even if it uses a different manufacturing process, provided the finished drug contains the claimed Form A.

What drug and solid form does US Patent 9,725,455 cover?

The claimed compound is ibrutinib, also known by the chemical name:

1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.

Ibrutinib is an irreversible Bruton’s tyrosine kinase inhibitor marketed as Imbruvica for certain B-cell malignancies, including chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma and Waldenström macroglobulinemia. The FDA approved Imbruvica in 2013 under NDA 205552 and later expanded its indications and dosage forms.[2]

The patent covers crystalline Form A rather than amorphous ibrutinib, another polymorph, a salt, a solvate or the free compound in every physical state.

Patent identification

Item	Data
U.S. patent	9,725,455
Patent type	Crystalline-form product patent
Title	Crystalline forms of ibrutinib
Patent owner at issuance	Pharmacyclics LLC
Current commercial group	AbbVie, through Pharmacyclics
Priority date	March 15, 2013
U.S. filing date	March 14, 2014
Issue date	August 8, 2017
Drug	Ibrutinib
Product	Imbruvica
Core technology	Crystalline Form A
Principal analytical method	XRPD
Estimated ordinary patent expiration	March 14, 2034, subject to patent-term adjustment, patent-term extension and terminal-disclaimer analysis

The patent term estimate is based on the U.S. filing date and the statutory 20-year term. The enforceable expiration date must be determined from the issued patent’s term-adjustment calculation and any applicable regulatory extension.[1]

What does independent claim 1 of US 9,725,455 require?

Claim 1 requires a crystalline Form A of ibrutinib having an XRPD pattern that includes all three of the following peaks:

• 5.7° ± 0.1° 2-theta
• 18.9° ± 0.1° 2-theta
• 21.3° ± 0.1° 2-theta

The word “comprising” is important. Claim 1 does not require the product to have only those peaks. It requires at least those specified peaks. Other peaks may be present without avoiding the claim.

A competing product may therefore fall within claim 1 if its ibrutinib XRPD pattern includes the three required peaks, even if the manufacturer reports additional peaks, uses different terminology, or produces the material through a different crystallization process.

Scope of the XRPD limitation

XRPD peak positions are analytical limitations. In practice, infringement analysis would examine:

1. The identity of the active ingredient.
2. The crystalline state of the ibrutinib.
3. The XRPD measurement protocol.
4. Instrument calibration and radiation source.
5. Whether the observed peaks fall within the claimed tolerances.
6. Whether the product contains a mixture of Form A and another solid form.

A 0.1° tolerance is relatively narrow. Peak shifts can result from instrument calibration, sample preparation, particle size, preferred orientation, impurities, hydration, temperature and data-processing methods. The patent specification and prosecution history would be relevant to determine how the claims should be applied to borderline diffraction results.[1]

How do claims 2 through 8 narrow the Form A protection?

Claims 2 through 8 depend on claim 1 and require additional XRPD peaks. They create narrower positions within the broader three-peak claim.

Claim	Additional required XRPD peak or peaks
1	5.7°, 18.9° and 21.3°
2	16.1°
3	13.6°
4	21.6°
5	13.6°, 16.1° and 21.6°
6	13.6° and 16.1°
7	13.6° and 21.6°
8	16.1° and 21.6°

Claims 5 through 8 are particularly useful as fallback positions because they require combinations of secondary peaks. If a court or patent office limits the practical scope of claim 1 based on analytical ambiguity, these dependent claims may provide narrower infringement theories.

The claims do not expressly require a complete XRPD pattern, a particular relative intensity, a particular peak order or a specific crystallization solvent. They also do not expressly claim the process used to make Form A.

What do claims 9 through 13 add?

Claims 9 through 13 add non-XRPD characteristics. Each remains dependent on claim 1, so the product must still meet the three primary XRPD requirements.

IR spectrum

Claim 9 requires weak IR peaks at approximately:

• 1584 cm−1
• 1240 cm−1
• 1147 cm−1
• 1134 cm−1
• 1099 cm−1
• 1067 cm−1

This claim creates an orthogonal analytical limitation. IR data could support identification of the form, but the claim does not replace the XRPD requirement. A product with the IR peaks but without the claim 1 XRPD peaks would not satisfy claim 9 as written.

Melting temperature

Claim 10 requires a melting temperature of about 155°C to 156°C.

The term “about” introduces a degree of tolerance that would likely depend on the specification, testing method and prosecution record. Melting behavior can vary with heating rate, sample purity, particle size, instrument calibration and thermal history.

DSC profile

Claim 11 requires:

• DSC endotherm onset at about 154°C;
• peak at about 157°C; and
• exotherm at about 159°C.

This claim is more technically specific than claim 10 because it requires a defined thermal profile rather than only a melting-temperature range.

Non-hygroscopic behavior

Claim 12 requires that Form A be non-hygroscopic. Hygroscopicity is ordinarily determined by a moisture-uptake test under specified relative-humidity conditions. The claim does not state the test conditions in the text supplied. The patent specification, examples and prosecution history would therefore be central to defining the operative threshold.

Aqueous solubility

Claim 13 requires an observed aqueous solubility of approximately 0.013 mg/mL at approximately pH 8.

The claim does not state a temperature, equilibration time, buffer composition, solid-to-liquid ratio or assay method in the supplied claim text. Those variables can materially affect the result. The claim is therefore strongest when used with the XRPD identity limitation and the patent’s experimental procedures, rather than as a standalone commercial specification.

What is the strongest infringement theory under US 9,725,455?

Claim 1 is the principal commercial claim. It directly covers a finished pharmaceutical composition containing ibrutinib Form A if the material meets the claimed XRPD profile.

A patent owner would likely rely on:

• XRPD testing of the active pharmaceutical ingredient;
• XRPD testing of drug product extracted from tablets or capsules;
• comparison against the patent’s Form A reference pattern;
• batch records and solid-form specifications;
• manufacturing and release documentation; and
• admissions in regulatory filings or technical reports.

The patent does not require proof that the accused manufacturer knew it was making Form A. Patent infringement is generally assessed against the claim limitations, not the accused party’s intent.

Can a generic avoid the patent by using another polymorph?

Yes, in principle. A generic manufacturer could attempt to use:

• an amorphous form;
• a different crystalline polymorph;
• a solvate;
• a co-crystal;
• a salt, if pharmaceutically suitable; or
• a physical mixture that does not contain Form A in the claimed form.

That strategy carries technical and regulatory risk. A different polymorph may have different dissolution, stability, bioavailability, manufacturability or impurity characteristics. The FDA may require comparative pharmaceutical development data if the solid form affects product performance.[3]

What is the Orange Book status of US 9,725,455?

US 9,725,455 is associated with the Imbruvica ibrutinib product and is relevant to Orange Book-based generic litigation. Orange Book listing is determined by the NDA holder and FDA listing rules, not by the patent alone.[2]

For an approved small-molecule generic applicant, a Paragraph IV certification against a listed patent can trigger patent litigation under the Hatch-Waxman framework. If the NDA holder sues within the statutory period, FDA approval can be subject to a 30-month stay, subject to statutory exceptions and court rulings.[4]

The Form A patent is materially different from a method-of-use patent. A Paragraph IV applicant seeking approval for all or part of the ibrutinib label would need to address listed patents applicable to the proposed product and indications. A section viii statement may be available for a patent that claims only a method of use omitted from the proposed label, but it generally would not remove a product or crystalline-form patent from the approval analysis.

When does ibrutinib lose exclusivity?

Ibrutinib has several separate exclusivity layers.

Exclusivity layer	Relevance
New chemical entity exclusivity	The original FDA approval received five years of NCE exclusivity beginning in 2013.
Orphan-drug exclusivity	Certain indications received seven-year exclusivity periods from their respective approvals.
Core compound patents	Protect ibrutinib or related therapeutic use claims.
Crystalline-form patent	US 9,725,455 protects Form A, with an ordinary term estimate extending into 2034.
Formulation and method patents	May create additional barriers depending on the product and proposed label.
Regulatory exclusivity	Does not automatically expire on the same date as any particular patent.

The five-year NCE exclusivity period has expired. The commercial barrier now depends primarily on patent claims, remaining orphan exclusivity for particular indications, FDA listing status and the timing of generic litigation.

A generic could obtain approval before every patent expires if it successfully defeats the relevant patents, obtains a favorable settlement, uses a non-infringing form, or limits its label to avoid protected uses.

What other patents protect ibrutinib?

The ibrutinib estate includes several patent categories.

Core composition patents

The earliest patent family claims substituted pyrazolopyrimidine compounds that include ibrutinib. These patents provide the broadest chemical protection but generally have earlier expiration dates than later solid-form patents.[5]

Crystalline-form patents

US 9,725,455 is directed to Form A. Other jurisdictions and related U.S. filings may protect different crystalline forms, processes or analytical definitions. A generic must analyze the full family rather than relying on one U.S. patent.

Method-of-use patents

Separate claims may cover treatment of specific diseases, patient populations, treatment regimens or combination therapies. These patents can remain relevant after the composition patent expires, particularly where the generic label includes protected indications.

Formulation patents

Ibrutinib is marketed in capsules and tablets. Formulation patents may address dosage forms, excipients, dissolution, particle engineering, solid dispersions or manufacturing processes. A Form A patent remains relevant even when the final product claim is directed to a tablet or capsule, because the dosage form may contain the patented crystalline active ingredient.

Manufacturing and process patents

Process claims may cover crystallization, purification, solvent systems, intermediates or selective production of Form A. Process patents are less directly relevant to a finished-product infringement case unless the accused product was made by the claimed process or the claims reach the resulting product.

How strong is the patent estate for Form A?

The Form A estate is technically meaningful but narrower than a compound patent.

Factor	Assessment
Claim type	Product-by-solid-state-form
Primary proof	XRPD and supporting characterization
Breadth	Narrower than a composition-of-matter claim
Design-around potential	Possible through another polymorph or amorphous material
Detection risk	High if the product contains Form A as the released API
Process dependence	Low for claim 1; the process of manufacture is not required
Regulatory relevance	High because the API form affects pharmaceutical quality
Litigation vulnerability	Depends on polymorph identity, claim construction and prior-art validity
Commercial value	High if Imbruvica and authorized generic products use Form A

The patent’s strength comes from product coverage. A manufacturer cannot avoid infringement merely by changing the crystallization process if the resulting API is still Form A.

Its principal weakness is claim narrowness. A true non-infringing polymorph may avoid the patent, although that approach can create substantial development and regulatory cost.

Which companies could challenge ibrutinib patents?

Potential challengers include generic-drug manufacturers that seek abbreviated new drug application approval for ibrutinib capsules or tablets. A Paragraph IV challenge may target:

• the core ibrutinib compound patents;
• Form A patents;
• formulation patents;
• method-of-use patents; or
• later-listed patents covering specific dosage forms or indications.

Public identification of a challenger requires a filed ANDA litigation complaint, a declaratory-judgment action, a district-court docket, or a recognized patent settlement disclosure. The patent itself does not identify future challengers.

The commercial parties with direct interests are AbbVie and Pharmacyclics on the innovator side, Janssen for the former U.S. collaboration and co-commercialization relationship, and generic manufacturers pursuing ibrutinib approval.[6]

What litigation and settlement issues affect US 9,725,455?

A Paragraph IV case involving this patent would normally raise four technical issues:

1. Whether the accused ibrutinib is Form A.
2. Whether the XRPD peaks fall within the claimed tolerances.
3. Whether Form A was anticipated or rendered obvious by prior solid-state disclosures.
4. Whether the claims are definite and adequately supported under the Patent Act.

A generic may also argue that the patent claims a predictable or routine polymorph, lacks sufficient characterization, or fails to provide a reproducible boundary for terms such as “about” and “non-hygroscopic.” The patent owner would respond that the particular peak combination and associated properties identify a distinct, reproducible crystalline form with useful pharmaceutical characteristics.

Settlement agreements can defer generic entry, permit an authorized generic, grant a license, or provide a date certain before patent expiration. FTC reporting requirements and court filings can disclose certain settlement terms, but commercial license terms may remain confidential.[7]

What generic launch scenarios exist?

Scenario 1: Form A remains the generic API

This is the highest litigation-risk scenario. A generic using Form A would likely need to challenge the patent through Paragraph IV litigation or obtain a license.

Scenario 2: The generic uses a different polymorph

This can avoid literal infringement of claims 1 through 13 if the alternative form does not contain the claimed Form A characteristics. The generic would still face equivalence arguments, regulatory comparability issues and possible separate patents.

Scenario 3: The generic uses an amorphous or mixed form

A mixed solid may avoid a pure-form claim only if Form A is absent or below any legally relevant threshold. If Form A is present as a detectable or intentional component, infringement analysis becomes fact-specific.

Scenario 4: Settlement or licensed entry

The parties may agree to an entry date before the estimated patent expiration. The economic value would depend on the number of approved generic competitors, launch exclusivity, authorized-generic strategy and remaining indication-specific patents.

How does US 9,725,455 compare with the core ibrutinib patent?

Issue	Core compound patent	US 9,725,455
Subject matter	Ibrutinib chemical structure or genus	Crystalline Form A
Scope	Broad chemical protection	Narrow solid-state protection
Technical proof	Chemical identity	XRPD and physical characterization
Design-around	Difficult without changing active ingredient	Possible through another form
Likely expiration	Earlier than later-developed solid-form patents	Estimated March 2034, subject to term adjustments
Product relevance	Direct	Direct if Form A is used
Manufacturing relevance	Usually low	Form-specific crystallization may be relevant
Litigation focus	Validity, claim construction, chemical identity	Polymorph identity, XRPD reproducibility and obviousness

Key Takeaways

• US 9,725,455 claims crystalline Form A of ibrutinib, not ibrutinib in every physical state.
• Claim 1 requires XRPD peaks at 5.7°, 18.9° and 21.3° 2-theta, each within ±0.1°.
• The dependent claims add diffraction peaks, IR peaks, thermal properties, non-hygroscopicity and pH 8 solubility.
• The word “comprising” makes claim 1 open-ended. Additional XRPD peaks do not necessarily avoid infringement.
• A different manufacturing process does not avoid the patent if it produces the claimed Form A.
• The patent has an estimated ordinary expiration date in March 2034, subject to patent-term calculations.
• Generic risk is highest when the proposed product uses the same Form A API as Imbruvica.
• A different polymorph may provide a design-around, but it creates pharmaceutical-development and regulatory risk.
• Ibrutinib has no biosimilar pathway because it is a small-molecule drug. The relevant challenge pathway is ANDA approval and Paragraph IV litigation.
• The complete commercial analysis requires review of the Orange Book patent list, later ibrutinib patents, FDA exclusivity entries and active district-court litigation.

Frequently Asked Questions

Does US 9,725,455 cover all ibrutinib tablets?

No. It covers tablets or capsules containing ibrutinib only if the ibrutinib is crystalline Form A meeting the claimed analytical limitations.

Can a generic avoid US 9,725,455 by changing excipients?

Usually not. Changing excipients does not avoid a claim directed to the crystalline API if the product still contains Form A.

Is Form A the same as the active ingredient ibrutinib?

No. Ibrutinib identifies the chemical compound. Form A identifies a particular crystalline arrangement of that compound.

Does the patent cover the method of crystallizing ibrutinib?

The claims supplied do not claim a crystallization process. They claim the resulting crystalline Form A and its properties.

Are biosimilars relevant to ibrutinib patent risk?

No. Ibrutinib is a small-molecule drug regulated through the ANDA pathway, not a biologic regulated through the biosimilar pathway.

References

1. U.S. Patent No. 9,725,455, Crystalline forms of ibrutinib (2017).
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (2007). ANDAs for certain highly purified synthetic peptides: Guidance for industry.
4. Drug Price Competition and Patent Term Restoration Act, 21 U.S.C. § 355(j); 35 U.S.C. § 271(e).
5. U.S. Patent No. 8,735,405, 2-amino-4-phenylpyrimidine compounds as inhibitors of Bruton's tyrosine kinase (2014).
6. AbbVie Inc. (2024). Annual report.
7. Federal Trade Commission. (2023). Agreements filed with the Federal Trade Commission under the Medicare Prescription Drug, Improvement, and Modernization Act of 2003.

Drugs Protected by US Patent 9,725,455

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					Y
Pharmacyclics Llc	IMBRUVICA	ibrutinib	CAPSULE;ORAL	205552-001	Nov 13, 2013	AB	RX	Yes	Yes					Y
Pharmacyclics Llc	IMBRUVICA	ibrutinib	SUSPENSION;ORAL	217003-001	Aug 24, 2022		RX	Yes	Yes					Y
Pharmacyclics Llc	IMBRUVICA	ibrutinib	TABLET;ORAL	210563-001	Feb 16, 2018		RX	Yes	No					Y
Pharmacyclics Llc	IMBRUVICA	ibrutinib	TABLET;ORAL	210563-002	Feb 16, 2018		RX	Yes	No					Y

International Family Members for US Patent 9,725,455

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	092844
Argentina	118108
Australia	2013271918
Australia	2016250445
Australia	2018211201