Details for Patent: 8,871,745

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Which drugs does patent 8,871,745 protect, and when does it expire?

Patent 8,871,745 protects NINLARO and is included in one NDA.

This patent has sixty-one patent family members in thirty-six countries.

Summary for Patent: 8,871,745

Title:	Proteasome inhibitors
Abstract:	The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.
Inventor(s):	Edward J. Olhava, Mihaela Diana Danca
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US13/964,708
Patent Claim Types: see list of patent claims	Use; Composition; Delivery; Dosage form;

United States Patent 8,871,745: Scope, Claims, Expiration, and Ixazomib Patent Landscape

U.S. Patent No. 8,871,745 is a method-of-treatment patent assigned to Millennium Pharmaceuticals, Inc., now part of Takeda Pharmaceutical Company. Its claims cover administering specified boronic acid proteasome inhibitors, including the ixazomib chemical series, in combination with another anticancer agent to treat multiple myeloma, lymphoma, or recurrence of those cancers.

The patent is strategically important because it protects combination use rather than merely the active compound. The broadest independent claim reaches treatment with the claimed boronic acid compound plus any second therapeutic agent. Separate claim sets expressly identify lenalidomide and melphalan.

What drug and technology does U.S. Patent 8,871,745 cover?

The patent covers substituted amino-acyl boronic acid compounds. The principal commercial compound in the disclosed series is ixazomib, administered clinically as ixazomib citrate under the brand name Ninlaro.

Ixazomib is a reversible proteasome inhibitor. Its active boronic acid form contains the following core structure:

• An L-leucine-derived boronic acid warhead.
• An aminoacetyl linker.
• A substituted benzoyl group.
• In the commercial compound, a 2,5-dichlorobenzoyl substituent.

Claim 4 expressly lists:

[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid

That compound is ixazomib free boronic acid, also known as MLN2238-related ixazomib chemistry. The approved pharmaceutical product is ixazomib citrate, a prodrug-related salt form that converts to the active boronic acid species under physiological conditions.

The claims also cover pharmaceutically acceptable salts and boronic acid anhydrides. This language is significant because boronic acids can exist in chemically distinct forms, including cyclic anhydrides and other protected or complexed forms.

What are the independent claims in Patent 8,871,745?

The patent has three principal independent method claims.

Claim	Core subject matter	Combination requirement	Cancer scope
1	Treatment with a formula (I) boronic acid compound or composition	Any second therapeutic agent	Multiple myeloma, lymphoma, or recurrence
14	Treatment with a formula (I) boronic acid compound	Lenalidomide	Multiple myeloma, lymphoma, or recurrence
20	Treatment with a formula (I) boronic acid compound	Melphalan	The claim text supplied does not restate the cancer limitation, but dependent claims specify multiple myeloma and lymphoma

Claim 1 is the commercially broadest claim because it does not limit the second therapeutic agent to lenalidomide or melphalan. It requires, however, that the treatment involve the claimed compound and another therapeutic agent.

Claims 14 and 20 narrow the combination to two established multiple-myeloma agents:

• Lenalidomide, an immunomodulatory agent.
• Melphalan, an alkylating agent.

The patent does not claim ixazomib as a standalone chemical composition in the claims provided. Its protection is directed to therapeutic use and combination treatment.

How broad is the scope of Claim 1?

Claim 1 has five material limitations:

1. A patient must need cancer treatment.
2. The method must administer a therapeutically effective amount.
3. The administered active must be a formula (I) compound, acceptable salt, or boronic acid anhydride.
4. The treatment must occur with a second therapeutic agent.
5. The disease must be multiple myeloma, lymphoma, or recurrence of either disease.

The phrase "with a second therapeutic agent" is materially broader than the express lenalidomide and melphalan claims. It can encompass combination treatment with other anticancer therapies if the remaining limitations are met.

The claim does not require:

• A specific dose.
• A specific dosing schedule.
• A specific route in the independent claim.
• A specific order of administration.
• A specific patient line of therapy.
• A specific formulation.
• A specific second-agent mechanism.

Those omissions increase the theoretical breadth of Claim 1. The claim remains limited by the molecular definition of formula (I), the cancer indication, and the requirement for combination administration.

What compounds are expressly protected?

Claim 4 lists 20 substituted benzoyl analogues of the boronic acid scaffold. The listed substituents include fluoro, chloro, bromo, difluoro, dichloro, and mixed chloro-fluoro substitution patterns.

The listed species include:

• 2,3-Difluoro
• 5-Chloro-2-fluoro
• 3,5-Difluoro
• 2,5-Difluoro
• 2-Bromo
• 2-Fluoro
• 2-Chloro-5-fluoro
• 4-Fluoro
• 3,4-Difluoro
• 3-Chloro
• 2,5-Dichloro
• 3,4-Dichloro
• 3-Fluoro
• 2-Chloro-4-fluoro
• 2,3-Dichloro
• 2-Chloro
• 2,4-Difluoro
• 4-Chloro-2-fluoro
• 4-Chloro
• 2,4-Dichloro
• 3,5-Dichloro

The 2,5-dichloro analogue is the most commercially relevant because it corresponds to ixazomib chemistry. Claim 4 depends on Claim 1, so the expressly listed compounds remain subject to the combination-treatment and cancer limitations of Claim 1.

What do the dependent claims add?

Formula and boronic acid form

Claims 2 and 3 narrow the ring and substituent definitions. They cover compounds in which:

• Z1 and Z2 are hydroxyl groups; or
• Z1 and Z2 together form a moiety derived from a boronic acid complexing agent.

Claim 3 further limits the compound to the free boronic acid arrangement in which both substituents are hydroxyl groups.

Disease limitations

Claims 5 through 7 narrow the indication to:

• Multiple myeloma.
• Lymphoma.
• Patients with, at risk of, or experiencing recurrence of multiple myeloma or lymphoma.

The recurrence language is commercially relevant because it reaches maintenance, relapse, and re-treatment scenarios, provided the factual patient and treatment requirements are satisfied.

Administration routes

Claims 10 through 13 cover administration:

• Orally.
• Intravenously.
• Subcutaneously.
• Parenterally.
• By inhalation.
• Topically.
• Rectally.
• Nasally.
• Buccally.
• Vaginally.
• Through an implanted reservoir.
• Systemically or locally.

For Ninlaro, the oral route is the most important commercial embodiment. The broad route language also makes the claims potentially relevant to alternative formulations and clinical-development programs involving injectable or localized delivery.

What formulations are protected by Patent 8,871,745?

The patent does not appear, based on the claims supplied, to contain a detailed composition claim directed to a particular tablet, capsule, excipient system, particle-size distribution, or release profile.

Its formulation reach is indirect. Claim 1 covers a pharmaceutical composition containing:

• The formula (I) compound, salt, or boronic acid anhydride.
• A pharmaceutically acceptable carrier.
• Use with a second therapeutic agent.

That language can reach a composition used in a claimed combination treatment, but it does not necessarily protect every formulation of ixazomib. A product-specific formulation may instead be covered by separate formulation patents directed to:

• Ixazomib citrate stability.
• Solid-state forms.
• Oral dosage forms.
• Manufacturing processes.
• Capsule or tablet composition.
• Combination packaging.
• Dosing schedules.

An abbreviated new drug application that uses the same active ingredient but avoids the patented combination method may present a different infringement analysis from an ANDA seeking approval for the patented use.

How do Claims 14 and 20 protect lenalidomide and melphalan combinations?

Claim 14 specifically covers administering formula (I) with lenalidomide to treat multiple myeloma, lymphoma, or recurrence of either condition.

Claim 20 covers administering formula (I) with melphalan. Dependent claims 23 through 25 identify multiple myeloma, lymphoma, and recurrence-risk patients.

These claims are narrower than Claim 1 because they identify the second agent. They may nevertheless have stronger infringement clarity in a product label or clinical protocol that expressly combines ixazomib with lenalidomide or melphalan.

The claims are method claims. Infringement generally turns on whether a party performs, induces, or contributes to performance of the claimed treatment method. A generic product label that includes a patented combination indication may create greater risk than a label limited to unclaimed uses.

What is the patent expiration date?

Patent 8,871,745 issued on October 28, 2014. Its expected nominal U.S. patent-term expiration is in November 2029, based on the relevant nonprovisional filing date and subject to any patent-term adjustment, terminal disclaimer, or other term modification recorded by the USPTO.

Event	Date
U.S. Patent No. 8,871,745 issued	October 28, 2014
Expected nominal patent expiration	November 2029
FDA approval of Ninlaro	November 20, 2015
Five-year new chemical entity exclusivity	Ended November 2020
Potential pediatric extension	Requires confirmation from FDA records

The exact terminal date should be taken from the USPTO patent-term calculation and current Orange Book listing. Patent expiration is separate from FDA regulatory exclusivity. A patent can remain enforceable after NCE exclusivity ends, and FDA approval does not itself establish patent validity.

What is the Orange Book status of ixazomib and Ninlaro?

Ninlaro is an FDA-approved small-molecule drug, not a biologic. Its generic pathway is an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act, not a biosimilar application under section 351(k) of the Public Health Service Act.

The relevant Orange Book issues include:

• Whether Patent 8,871,745 is listed against the approved product.
• The listed use code.
• The listed expiration date.
• Whether the patent is marked as a method-of-use patent.
• Whether later patents cover the active ingredient, formulation, or manufacturing process.
• Whether pediatric exclusivity modifies the effective date for approval of a competing ANDA.

Patent 8,871,745 is principally a method-of-use asset. Its commercial significance depends heavily on the approved label and the scope of any listed use code. A generic applicant can seek a Paragraph IV certification against an Orange Book patent or use a section viii statement to carve out a patented indication, where FDA labeling rules permit the carve-out.

Are there Paragraph IV challenges to Patent 8,871,745?

A Paragraph IV certification would allege that the patent is invalid, unenforceable, or not infringed. The most likely attack points would be:

• Written-description support for the full formula (I) genus.
• Enablement across the broad class of second therapeutic agents.
• Obviousness based on prior boronic acid proteasome inhibitors and known myeloma combinations.
• Claim construction for "with a second therapeutic agent."
• Adequacy of support for recurrence and lymphoma indications.
• Infringement avoidance through label carve-outs.
• The relationship between ixazomib citrate and the claimed free boronic acid, salts, and anhydrides.

The supplied record does not establish a particular ANDA filer, Paragraph IV notice date, district-court complaint, or settlement agreement directed specifically to Patent 8,871,745. No such event should be assumed solely from the patent text.

What patent landscape surrounds ixazomib?

Ixazomib protection is likely distributed across several patent categories rather than concentrated in Patent 8,871,745.

Patent category	Typical protected subject matter	Relevance
Composition of matter	Boronic acid proteasome inhibitor structures	Core molecule protection
Salt and solid state	Ixazomib citrate and related forms	Product and stability protection
Combination therapy	Ixazomib with lenalidomide, melphalan, or other agents	Patent 8,871,745
Method of treatment	Multiple myeloma, lymphoma, relapsed disease	Label and clinical-use protection
Formulation	Oral dosage forms and excipient systems	ANDA design-around risk
Manufacturing	Synthesis, purification, and isolation	Process patent risk
Dosing regimen	Cycles, schedules, and combination sequencing	Later-use protection

The main competitive comparison is with other proteasome inhibitors:

Drug	Class	Administration	Key distinction
Ixazomib	Boronic acid proteasome inhibitor	Oral	Combination and oral-maintenance positioning
Bortezomib	Boronic acid proteasome inhibitor	Subcutaneous or intravenous	Earlier-generation injectable therapy
Carfilzomib	Epoxyketone proteasome inhibitor	Intravenous	Irreversible proteasome inhibition
Oprozomib	Oral epoxyketone proteasome inhibitor under development	Oral	Different chemical and clinical-development profile

Biosimilar risk is not applicable to ixazomib itself because ixazomib is a small molecule. The principal post-exclusivity risk is generic substitution through ANDA filings. Patent risk can remain significant if an applicant must address composition, formulation, manufacturing, and method-of-use patents in parallel.

How strong is the patent estate?

Patent 8,871,745 has moderate-to-strong practical value for labeled combination use, but its strength depends on the broader patent family and the approved label.

Strengths

• Expressly identifies ixazomib-relevant chemistry.
• Covers combination treatment rather than a narrow dosing schedule.
• Includes lenalidomide and melphalan claims.
• Reaches multiple myeloma, lymphoma, and recurrence.
• Includes salts and boronic acid anhydrides.
• Contains broad administration-route language.

Weaknesses

• The claims supplied are method claims, not standalone composition claims.
• Claim 1 requires combination treatment.
• The "second therapeutic agent" language may raise scope and enablement questions.
• Generic applicants may attempt indication carve-outs.
• The claim transcription omits structural drawings for Ring A and formula (I).
• Claims 15 and 16 appear internally inconsistent: Claim 15 requires both Z1 and Z2 to be hydroxyl, while Claim 16 states that Z1 and Z2 together form a complexing-agent moiety. The issued patent should control over this transcription.

What litigation and settlement issues matter?

For commercial diligence, the critical questions are:

1. Whether an ANDA applicant has filed a Paragraph IV certification.
2. Whether the patent owner filed suit within the 45-day statutory period.
3. Whether a 30-month stay was triggered.
4. Whether the parties entered a license or launch-date settlement.
5. Whether a settlement permits an authorized generic or licensed generic.
6. Whether the settlement includes covenants covering later patents or only Patent 8,871,745.
7. Whether the generic label excludes multiple myeloma combination use.
8. Whether a later patent creates a separate launch barrier after this patent expires.

The patent text alone does not establish any settlement or litigation outcome. Those facts must be tied to FDA, Orange Book, USPTO, PACER, and SEC records.

Key Takeaways

• Patent 8,871,745 protects combination treatment methods using formula (I) boronic acid proteasome inhibitors.
• Ixazomib is the commercially relevant compound in the claimed chemical series.
• Claim 1 covers combination treatment with a second therapeutic agent for multiple myeloma, lymphoma, or recurrence.
• Claims 14 and 20 specifically cover combinations with lenalidomide and melphalan.
• The patent does not, in the claims supplied, provide a standalone composition-of-matter claim to ixazomib.
• The expected nominal expiration is in November 2029, subject to USPTO term calculations and any terminal disclaimer.
• Ixazomib is subject to generic, not biosimilar, competition.
• The principal generic strategies are Paragraph IV invalidity or noninfringement challenges and section viii label carve-outs.
• Claims 15 and 16 contain an apparent inconsistency in the supplied text and should be checked against the issued patent PDF.
• Commercial risk cannot be assessed from this patent alone; the full ixazomib family, Orange Book listings, approved labeling, formulation patents, and any ANDA litigation must be reviewed together.

FAQs

Does Patent 8,871,745 cover ixazomib citrate?

It can cover treatment using an ixazomib-related boronic acid, acceptable salt, or boronic acid anhydride in the claimed combination methods. Whether a specific ixazomib citrate product falls within an asserted claim depends on the formula, conversion to the active species, and the patent's claim construction.

Can a generic ixazomib product avoid Patent 8,871,745?

Potentially. A generic applicant could challenge validity, contest infringement, or seek approval with a label that omits patented combination uses. Avoiding this patent would not necessarily avoid separate composition, formulation, manufacturing, or dosing patents.

Does the patent cover ixazomib monotherapy?

The claims supplied do not. Claim 1 requires treatment "with a second therapeutic agent," and Claims 14 and 20 identify lenalidomide and melphalan combinations.

Is melphalan required for every claim?

No. Melphalan is required only by independent Claim 20 and its dependents. Claim 1 covers a broader class of second therapeutic agents, while Claim 14 specifically requires lenalidomide.

Is there biosimilar exposure for Ninlaro?

No. Ixazomib is a small-molecule drug. Competition would proceed through the ANDA pathway for generics rather than the biosimilar pathway.

References

1. U.S. Patent No. 8,871,745. (2014). Methods of treating cancer using boronic acid compounds. United States Patent and Trademark Office.

2. U.S. Food and Drug Administration. (2015). Ninlaro (ixazomib citrate) prescribing information. FDA.

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

4. United States Patent and Trademark Office. (2024). Patent term adjustment and patent examination records for U.S. Patent No. 8,871,745. USPTO.

5. Takeda Pharmaceutical Company Limited. (2024). Ninlaro product information and corporate disclosures. Takeda.

Drugs Protected by US Patent 8,871,745

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Takeda Pharms Usa	NINLARO	ixazomib citrate	CAPSULE;ORAL	208462-001	Nov 20, 2015		RX	Yes	No						USE IN COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE FOR THE TREATMENT OF PATIENTS WITH MULTIPLE MYELOMA WHO HAVE RECEIVED AT LEAST ONE PRIOR THERAPY
Takeda Pharms Usa	NINLARO	ixazomib citrate	CAPSULE;ORAL	208462-002	Nov 20, 2015		RX	Yes	No						USE IN COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE FOR THE TREATMENT OF PATIENTS WITH MULTIPLE MYELOMA WHO HAVE RECEIVED AT LEAST ONE PRIOR THERAPY
Takeda Pharms Usa	NINLARO	ixazomib citrate	CAPSULE;ORAL	208462-003	Nov 20, 2015		RX	Yes	Yes						USE IN COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE FOR THE TREATMENT OF PATIENTS WITH MULTIPLE MYELOMA WHO HAVE RECEIVED AT LEAST ONE PRIOR THERAPY

International Family Members for US Patent 8,871,745

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2178888		PA2017010	Lithuania
European Patent Office	2178888		300871	Netherlands
European Patent Office	2178888		122017000025	Germany