Details for Patent: 8,859,504

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Which drugs does patent 8,859,504 protect, and when does it expire?

Patent 8,859,504 protects NINLARO and is included in one NDA.

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

Summary for Patent: 8,859,504

Title:	Boronate ester compounds and pharmaceutical compositions thereof
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):	Eric L. Elliott, Abu J. Ferdous, Michael J. Kaufman, Sonja A. Komar Lay, Debra L. Mazaik, Quentin J. McCubbin, Phuong M. Nguyen, Vaithianathan Palaniappan, Raymond D. Skwierczynski, Nobel T. Truong, Csanad M. Varga, Peter N. Zawaneh
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US13/667,164
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,859,504
Patent Claim Types: see list of patent claims	Composition; Compound;

US Patent 8,859,504: Ixazomib Compound, Crystalline Forms, Scope, Expiration and Patent Landscape

US Patent 8,859,504 covers ixazomib-related boronic acid compounds, stereochemical variants, crystalline forms, and pharmaceutical compositions. The strongest commercial claims are claims 2, 6-14, which identify the active compound and specific solid forms by molecular structure, powder X-ray diffraction peaks, and thermal-transition ranges. Claim 15 covers compositions containing the claimed compounds but does not independently define a dosage regimen, indication, or manufacturing process.

The patent is assigned to the Takeda/Millennium pharmaceutical group and is relevant to NINLARO (ixazomib citrate), an oral proteasome inhibitor approved by the FDA for multiple myeloma in combination with lenalidomide and dexamethasone.[1]

What drug is protected by US Patent 8,859,504?

The principal compound identified by the claims is ixazomib, administered commercially as ixazomib citrate under the brand name NINLARO.

The claimed molecular framework contains:

• A boron-containing cyclic ester or boronic acid-derived structure.
• An L-leucine-derived side chain, reflected by the isobutyl substituent.
• A 2,5-dichlorobenzoyl-aminoacetyl group.
• One or more carboxymethyl substituents.
• Defined stereochemistry at the amino-acid-derived carbon center.
• Pharmaceutically acceptable salts.

Ixazomib citrate is a prodrug formulation that converts in solution to the active boronic acid species ixazomib. The commercial product is supplied as oral capsules in 2.3 mg, 3 mg and 4 mg strengths, expressed as ixazomib equivalent.[1]

Commercial product and regulatory status

Item	Status
Active ingredient	Ixazomib
Commercial salt	Ixazomib citrate
Brand	NINLARO
Sponsor	Takeda Pharmaceuticals USA
FDA application	NDA 208462
FDA approval	November 20, 2015
Dosage form	Oral capsule
Primary indication	Multiple myeloma with lenalidomide and dexamethasone
Regulatory pathway	New drug application
Biologic status	Not a biologic; biosimilar pathway does not apply

The FDA-approved product is a small-molecule drug. Future competition would therefore arise through an abbreviated new drug application, subject to applicable patent certifications and regulatory exclusivity, rather than through a biosimilar application.[1,2]

What compounds do claims 1 through 5 cover?

Claims 1 through 5 are structure-based compound claims. They cover a narrow chemical genus and expressly recite the substituent selections that define the ixazomib-related molecules.

Claim 1: defined compound genus

Claim 1 covers compounds of formula II where:

• The boron-containing core has the specified cyclic structure.
• The acyl group is derived from 2,5-dichlorobenzoic acid.
• The side chain is isobutyl.
• The principal stereocenter is in the R configuration.
• The remaining substituents are hydrogen or carboxymethyl groups.
• The compounds may be present as pharmaceutically acceptable salts.

The claim is narrower than a broad proteasome-inhibitor Markush claim because the aromatic acyl substituent and aliphatic side chain are fixed. Its principal value is directed to the ixazomib chemical entity and closely related regioisomeric or ring-form variants.

Claims 2 and 4: formula III and IIIa compounds

Claims 2 and 4 focus on the compound identified as:

2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid

These claims are the closest structural claims to the principal ixazomib-related active moiety. Claim 2 identifies the compound by name and formula. Claim 4 recites a corresponding formula IIIa embodiment.

The claims extend to pharmaceutically acceptable salts. This is important because a generic or competing product using a different salt of the same claimed acid could remain within the literal scope of the claims.

Claims 3 and 5: formula IV and IVa compounds

Claims 3 and 5 cover a related dioxaborinane compound:

4-(R,S)-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid

These claims cover a distinct ring or tautomeric form from the formula III/IIIa compounds. The inclusion of both formula III and formula IV structures reduces the opportunity for a competitor to avoid infringement by using a closely related boron-containing ring system.

What crystalline forms are protected by US 8,859,504?

Claims 6 through 14 cover three identified crystalline-form groups. These are solid-state claims. They do not merely cover the active molecule; they require a material having the claimed diffraction and thermal characteristics.

Crystalline form in claims 6 through 8

Claims 6 and 7 identify a crystalline form of the formula III compound by characteristic X-ray powder diffraction peaks.

The primary diagnostic peaks are approximately:

2θ	Relative intensity
6.441°	100
8.304°	29.5
15.077°	28.2
16.352°	28.7
19.086°	21.4

Claim 8 adds an endothermic transition with an onset melting temperature of approximately 191.8°C to 225°C.

The claim construction issue is material. A competing solid must be evaluated against the claimed diffraction pattern and thermal behavior, not merely against the chemical identity of ixazomib. Differences in hydration, solvation, polymorphism, or crystallization conditions could affect infringement analysis.

Crystalline form in claims 9 through 11

Claims 9 and 10 cover another crystalline form of the formula III compound. The principal powder diffraction peaks include:

2θ	Relative intensity
5.817°	100
7.614°	93.4
11.575°	71.1
11.896°	67.1
16.689°	65.8
18.232°	53.9
19.596°	77.6
19.959°	63.8
22.407°	77.6

Claim 11 requires an onset melting range of approximately 206.5°C to 225°C.

This second solid-form family is commercially significant because it creates a separate infringement theory from the compound claims. A generic product could avoid one polymorph claim while still being exposed under another if the finished dosage form contains the claimed crystalline material.

Crystalline form in claims 12 through 14

Claims 12 and 13 cover a crystalline form of the formula IV compound. The principal peaks include:

2θ	Relative intensity
5.69°	100
7.64°	66
11.42°	51
11.79°	37
16.53°	32
18.07°	31
19.39°	55
19.79°	41
22.23°	63

Claim 14 requires an onset melting-temperature range of approximately 231.3°C to 239.9°C.

This group is narrower than the core compound claims because it requires a particular solid-state form. Its enforcement value depends on whether the commercial product, active pharmaceutical ingredient, or manufacturing intermediate contains that form.

What does claim 15 protect?

Claim 15 covers a pharmaceutical composition containing a compound of claims 1 through 5 and a pharmaceutically acceptable carrier.

The claim is broad in formulation language but narrow in its dependency. It requires the composition to contain one of the specifically claimed compounds. It does not expressly require:

• A particular dose.
• A particular capsule shell.
• A particular excipient.
• A particular release profile.
• Lenalidomide or dexamethasone.
• A multiple-myeloma treatment method.
• A specific manufacturing process.

Claim 15 is therefore useful against a dosage form containing the claimed active compound, but it is not a standalone method-of-use claim.

How strong is the patent estate for ixazomib?

The patent estate is stronger when viewed as a layered system rather than through US 8,859,504 alone.

Protection layer	Present in US 8,859,504?	Commercial significance
Core chemical compound	Yes	Direct composition-of-matter protection
Pharmaceutically acceptable salts	Yes	Limits salt-switch strategies
Stereochemical definition	Yes	Protects the active stereochemical configuration
Polymorphs	Yes	Covers specified crystalline forms
Pharmaceutical compositions	Yes	Applies to formulations containing claimed compounds
Method of treatment	No express independent claim in the supplied claims	Must be assessed in related patents
Manufacturing process	No express process claim	Process exposure may exist in related family members
Dosing regimen	No	Usually addressed in separate method patents
Combination with lenalidomide/dexamethasone	No express claim	Relevant claims may appear elsewhere in the estate

The strongest claims are the compound claims if the commercial active ingredient falls literally within the claimed structure. The crystalline-form claims provide additional protection but are more dependent on analytical testing and the physical form used by a competitor.

When does US Patent 8,859,504 lose exclusivity?

The issue date was October 14, 2014. US patent exclusivity does not normally run for 20 years from issue. For a patent arising from a pre-1995 or post-1995 application chain, the ordinary term is generally measured from the earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers and any patent-term extension.[3]

The expiration date cannot be calculated reliably from the claims alone. The relevant determinants are:

1. The earliest effective nonprovisional filing date.
2. Continuation and divisional relationships.
3. Patent-term adjustment.
4. Any terminal disclaimer.
5. Patent-term extension under 35 U.S.C. §156.
6. Whether the patent is listed for NINLARO and whether the listed expiration reflects an extended term.

The FDA Orange Book, USPTO Patent Center and the patent’s front page control the operative expiration analysis.[2,3] An issued patent date of October 14, 2014 should not be treated as the expiration date or as evidence of a 2034 term.

What is the Orange Book status of US 8,859,504?

US 8,859,504 is associated with the ixazomib/NINLARO patent estate and should be evaluated with the other patents listed for NDA 208462. Orange Book listing, however, is product-specific. A patent may cover the active ingredient, a formulation, or an approved use, and the regulatory consequences depend on the listing category and the ANDA applicant’s certification.[2]

For a generic ixazomib applicant, the relevant pathway would normally involve:

• Paragraph I certification if the patent is not listed or relevant information is absent.
• Paragraph II certification if the patent has expired.
• Paragraph III certification accepting a later expiry date.
• Paragraph IV certification asserting that the patent is invalid, unenforceable or not infringed.

A Paragraph IV notice can trigger patent litigation under the Hatch-Waxman framework. A first substantially complete ANDA with a valid Paragraph IV challenge may also create a 180-day generic exclusivity opportunity, subject to statutory conditions.[4]

Which companies are challenging ixazomib patents?

Publicly reported challenge activity must be evaluated against current FDA and court records. The supplied claims do not identify an ANDA challenger, litigation case, settlement, or licensing agreement. No conclusion about a live Paragraph IV dispute, litigation dismissal, or settlement can be drawn from the patent text itself.

The principal commercial parties are:

Party	Role
Takeda Pharmaceuticals	Current NINLARO sponsor and commercial rights holder
Millennium Pharmaceuticals	Original development organization within Takeda
Generic applicants	Potential ANDA filers for ixazomib capsules
FDA	NDA and Orange Book regulator
USPTO	Patent grant and term authority

What generic entry risks exist?

A generic ixazomib entrant would face several technical and legal issues:

Chemical identity

The applicant would need to establish that its active ingredient is not within the literal scope of claims 1 through 5 or challenge those claims under Sections 102, 103, 112 or enforceability doctrines.

Salt and prodrug selection

Changing the counterion may not avoid infringement because claims 1 through 5 expressly extend to pharmaceutically acceptable salts. A different salt may also create pharmaceutical-equivalence and bioequivalence questions.

Solid-state form

The applicant would need to characterize the active pharmaceutical ingredient and finished dosage form using powder X-ray diffraction, thermal analysis and related solid-state methods. If the material matches the claimed peaks and melting behavior, claims 6 through 14 could present additional exposure.

Formulation

Claim 15 could apply to a capsule or other dosage form containing a claimed compound, even if the excipient system differs from NINLARO, provided the composition falls within the claim.

Manufacturing and supply

The patent claims supplied do not include a manufacturing method. Separate process patents, confidential know-how, crystallization procedures and specifications may still create practical barriers even where a generic avoids this patent.

How does ixazomib compare with bortezomib and other proteasome inhibitors?

Product	Active class	Administration	Patent risk type
NINLARO	Ixazomib boronic-acid prodrug	Oral	Compound, salt, polymorph, formulation and use patents
Velcade	Bortezomib	Injectable/subcutaneous	Compound, formulation and use patents
Kyprolis	Carfilzomib	Intravenous	Peptide epoxyketone, formulation and use patents
Empliciti	Elotuzumab	Intravenous biologic antibody	Biologic exclusivity and biosimilar-related issues

Ixazomib has a different generic risk profile from bortezomib and carfilzomib because oral delivery makes solid-state and capsule composition claims commercially important. It does not have biosimilar risk because it is a small molecule.

What litigation or settlement agreements affect US 8,859,504?

The patent text identifies no litigation or settlement. A complete litigation assessment requires current PACER, district-court, Federal Circuit, FDA Orange Book and ANDA records. The patent number alone does not establish whether a Paragraph IV notice has been served, whether a 30-month stay has been triggered, or whether a settlement restricts generic entry.

What is the revenue exposure for NINLARO?

NINLARO remains a commercial multiple-myeloma product with revenue exposure tied to the duration of compound, formulation and use protection. Takeda reports NINLARO sales in its annual and quarterly financial disclosures.[5] The relevant risk is not limited to the expiry of US 8,859,504. Generic entry may depend on the last-expiring enforceable patent, pediatric exclusivity, regulatory exclusivity, litigation stays and the scope of any settlement.

Key Takeaways

• US 8,859,504 covers ixazomib-related compounds, salts, crystalline forms and pharmaceutical compositions.
• Claims 2 and 4 are the principal named-compound claims.
• Claims 6 through 14 protect three defined crystalline-form groups through X-ray diffraction and thermal-transition limitations.
• Claim 15 covers compositions containing the claimed compounds but does not independently claim a dosing regimen or multiple-myeloma indication.
• Ixazomib is a small molecule, so biosimilar rules do not apply. Generic competition would proceed through the ANDA pathway.
• The patent’s October 14, 2014 issue date does not establish its expiration date.
• Expiration must be calculated from the effective filing chain, patent-term adjustment, terminal disclaimers and any patent-term extension.
• Generic risk will depend on the full NINLARO Orange Book estate, not US 8,859,504 alone.
• A solid-state challenge requires analytical comparison of the generic API and dosage form against the claimed diffraction peaks and melting ranges.

FAQs About US Patent 8,859,504 and Ixazomib

Does US 8,859,504 claim NINLARO by brand name?

No. The patent claims chemical compounds, salts, crystalline forms and compositions. Brand-name protection is not the legal basis of the claims.

Can a generic avoid this patent by using a different ixazomib salt?

Not necessarily. Claims 1 through 5 expressly include pharmaceutically acceptable salts. A different salt may remain within the claims.

Are claims 6 through 14 method-of-use claims?

No. They are solid-state claims defined by crystalline structure, powder X-ray diffraction and thermal-transition characteristics.

Does this patent protect the combination of ixazomib, lenalidomide and dexamethasone?

The supplied claims do not expressly recite that combination or a multiple-myeloma treatment method. Related patents must be reviewed for combination or regimen claims.

Is an ixazomib generic eligible for biosimilar approval?

No. Ixazomib is a chemically synthesized small molecule. A competitor would generally use the ANDA pathway rather than the biologics license application or biosimilar pathway.

References

1. U.S. Food and Drug Administration. (2015). NINLARO (ixazomib citrate) prescribing information.
2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term extension resources.
4. U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application submissions and patent certifications.
5. Takeda Pharmaceutical Company Limited. (2024). Annual report and financial results materials.
6. United States Patent No. 8,859,504. (2014). Boronic acid compounds and crystalline forms thereof. United States Patent and Trademark Office.

Drugs Protected by US Patent 8,859,504

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			Y	Y
Takeda Pharms Usa	NINLARO	ixazomib citrate	CAPSULE;ORAL	208462-002	Nov 20, 2015		RX	Yes	No			Y	Y
Takeda Pharms Usa	NINLARO	ixazomib citrate	CAPSULE;ORAL	208462-003	Nov 20, 2015		RX	Yes	Yes			Y	Y

International Family Members for US Patent 8,859,504

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	072162
Argentina	095554
Argentina	095566
Argentina	100011
Australia	2009260778
Brazil	122014008750