United States Patent 9,144,568: Bendamustine Formulation, Method-of-Use Claims and Patent Landscape

US Patent No. 9,144,568 protects a rapid intravenous administration method for a liquid bendamustine formulation used to treat chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin's lymphoma (NHL). The patent is directed primarily to the combination of formulation composition, administration volume, infusion time, dosing schedule, and disease indication.

The commercial product most closely associated with the claimed technology is Bendeka, Eagle Pharmaceuticals' low-volume, short-infusion bendamustine hydrochloride injection. The patent does not broadly claim bendamustine itself. Its enforceable scope depends on whether a competing product and treatment protocol satisfy the claimed composition and administration limitations.

What does US Patent 9,144,568 protect?

US 9,144,568 protects a method of treating CLL or indolent B-cell NHL by parenterally administering a small-volume bendamustine liquid composition over approximately 15 minutes or less.

The independent claim requires all of the following:

Limitation	Claim requirement
Disease	CLL or indolent B-cell NHL
Route	Parenteral administration
Volume	About 100 mL or less
Bendamustine concentration	About 0.5 to about 5.6 mg/mL
Solubilizer	PEG and propylene glycol
Solubilizer amount	About 0.5% to about 26.5% by volume
Diluent	Parenterally acceptable diluent
Antioxidant	Optional
Administration time	About 15 minutes or less

The claims therefore combine a formulation patent concept with a method-of-treatment claim. A product that contains bendamustine and the claimed excipients is not, by that fact alone, necessarily within the claims. The claimed conduct is administration of the composition to a patient for one of the specified diseases under the claimed volume and timing conditions.

What are the key claim limitations in US 9,144,568?

The patent has 23 claims. Claim 1 is the controlling independent claim. Claims 2 through 23 add patient, formulation, dose, cycle, route, and disease-specific limitations.

Independent claim 1

Claim 1 covers administration of a bendamustine composition with:

Bendamustine or a pharmaceutically acceptable salt;
0.5 to 5.6 mg/mL bendamustine;
PEG and propylene glycol as the solubilizer;
0.5% to 26.5% v/v solubilizer;
A parenterally acceptable diluent;
Optional antioxidant;
A total administration volume of 100 mL or less; and
Administration over 15 minutes or less.

The claim is not limited to bendamustine hydrochloride, although claim 23 expressly narrows the invention to that salt.

Dependent claim structure

Claims	Subject matter
2	Human subject
3	Solubilizer amount of 2.0% to 22.4% v/v
4	PEG 400
5	PEG-to-propylene glycol weight ratio of about 90:10
6	Approximately 50 mL administration volume
7	Monothioglycerol antioxidant
8	Approximately 50 mL administration volume
9	CLL treatment
10-12	Intravenous dosing on days 1 and 2 of a 28-day cycle, up to six cycles
13-14	CLL dose range of 25 to 100 mg/m², including 100 mg/m²
15	CLL formulation concentration of 1.85 to 4.84 mg/mL
16	Indolent B-cell NHL treatment
17-19	Intravenous dosing on days 1 and 2 of a 21-day cycle, up to eight cycles
20-21	NHL dose range of 60 to 120 mg/m², including 120 mg/m²
22	NHL formulation concentration of 2.19 to 5.59 mg/mL
23	Bendamustine hydrochloride

How does the patent map onto Bendeka?

Bendeka is a low-volume bendamustine hydrochloride injection supplied as a concentrated solution. The FDA-approved labeling describes administration after dilution in a 50 mL infusion bag, with infusion over 10 minutes. The labeled CLL regimen is 100 mg/m² on days 1 and 2 of a 28-day cycle. The labeled indolent B-cell NHL regimen is 120 mg/m² on days 1 and 2 of a 21-day cycle. These parameters correspond closely to claims 10 through 22. [1]

Bendeka characteristic	Corresponding patent limitation
Bendamustine hydrochloride	Claim 23
Intravenous administration	Claims 10 and 17
Approximately 50 mL final volume	Claims 6 and 8
Approximately 10-minute infusion	Claims 10, 11, 17 and 18
CLL, 100 mg/m²	Claims 9, 13 and 14
CLL days 1 and 2 of a 28-day cycle	Claim 10
Up to six CLL cycles	Claim 12
Indolent B-cell NHL, 120 mg/m²	Claims 16, 20 and 21
NHL days 1 and 2 of a 21-day cycle	Claim 17
Up to eight NHL cycles	Claim 19

The strongest product-to-claim correspondence exists for a 50 mL intravenous administration over 10 minutes using a bendamustine hydrochloride formulation containing PEG 400 and propylene glycol. Claims 4, 5 and 7 add formulation-specific limitations that may depend on the product's actual qualitative and quantitative composition.

What formulations are protected by US 9,144,568?

The patent protects formulations containing both polyethylene glycol and propylene glycol. Claim 1 does not require PEG 400 specifically, but claim 4 narrows the PEG component to PEG 400.

The claim ranges are broad enough to cover multiple formulations:

Formulation element	Broad claim range	Narrower dependent claim
Bendamustine concentration	0.5-5.6 mg/mL	CLL: 1.85-4.84 mg/mL; NHL: 2.19-5.59 mg/mL
Total solubilizer	0.5-26.5% v/v	2.0-22.4% v/v
PEG type	Any polyethylene glycol	PEG 400
PEG/propylene glycol ratio	Not specified in claim 1	About 90:10 by weight
Antioxidant	Optional	Monothioglycerol
Administration volume	100 mL or less	About 50 mL
Administration time	15 minutes or less	About 10 minutes

The presence of an antioxidant is not required by the independent claim. A formulation without an antioxidant can still fall within claim 1 if the other limitations are met. Monothioglycerol is required only for claim 7.

The claims also require a solubilizer comprising PEG and propylene glycol. A formulation using a different solvent system, such as ethanol, a different glycol combination, or a non-PEG solubilizer, presents a stronger literal non-infringement position. The outcome would depend on whether the substituted excipient system is equivalent under the doctrine of equivalents and whether prosecution history limits that argument.

What treatment regimens are protected?

The patent divides the treatment methods into CLL and indolent B-cell NHL regimens.

CLL regimen

Claims 9 through 15 cover the CLL-specific embodiments:

Intravenous administration;
Approximately 50 mL;
Administration in 10 minutes or less;
Days 1 and 2 of a 28-day cycle;
Up to six cycles;
Bendamustine dose of 25 to 100 mg/m²;
Preferred dose of 100 mg/m²;
Bendamustine concentration of 1.85 to 4.84 mg/mL.

The combination of a 100 mg/m² dose, 50 mL volume, 10-minute administration and two consecutive treatment days creates a narrow but commercially important dependent-claim configuration.

Indolent B-cell NHL regimen

Claims 16 through 22 cover:

Intravenous administration;
Approximately 50 mL;
Administration in approximately 10 minutes or less;
Days 1 and 2 of a 21-day cycle;
Up to eight cycles;
Bendamustine dose of 60 to 120 mg/m²;
Preferred dose of 120 mg/m²;
Bendamustine concentration of 2.19 to 5.59 mg/mL.

A competing regimen that uses a different cycle length, administration duration, dose, volume, or concentration could avoid one or more dependent claims. It could still infringe claim 1 if it remains within the broader ranges and treats one of the claimed diseases.

How strong is the patent estate for this technology?

US 9,144,568 is strongest against a product and label that reproduce the complete Bendeka-style administration protocol. Its commercial strength comes from the convergence of several elements:

A ready-to-administer or readily diluted liquid formulation.
PEG and propylene glycol as solubilizers.
Low administration volume.
A 10-minute infusion.
The CLL and indolent B-cell NHL dosing regimens.

The patent is less effective against:

Oral bendamustine products;
Non-parenteral formulations;
Formulations without both PEG and propylene glycol;
Infusions exceeding 15 minutes;
Volumes above 100 mL;
Use in diseases outside CLL and indolent B-cell NHL;
Products with concentrations outside the claimed ranges.

The claims are method claims rather than pure composition claims. This distinction affects enforcement against generic manufacturers. A manufacturer may be exposed through a product label that instructs the claimed administration method, even if the formulation is not sold as a separately patented composition.

When does US Patent 9,144,568 expire?

The patent has a 20-year term measured from the applicable non-provisional priority framework, subject to patent-term adjustment, patent-term extension, terminal disclaimers and other statutory adjustments. Public patent records associate the patent with a September 2011 priority date and a nominal 2031 expiration timeframe. The precise enforceable expiration date should be taken from the current USPTO patent record and any applicable Orange Book entry. [2]

Event	Date or status
Patent	US 9,144,568
Patent type	Utility patent
Priority framework	2011 filing family
Grant	2015
Nominal term horizon	2031
Product association	Bendamustine hydrochloride injection, including Bendeka
Regulatory relevance	Formulation and method-of-use protection

Patent expiration is separate from FDA regulatory exclusivity. FDA marketing exclusivity may expire before the patent term, and a patent may remain enforceable after FDA exclusivity ends.

What is the Orange Book status of Bendeka?

FDA Orange Book listings identify patents submitted by the New Drug Application holder and may include formulation, method-of-use and other patent categories. The Orange Book is the primary source for determining which patents are formally listed against a specific NDA and the expiration dates reported for those patents. [3]

US 9,144,568 has been associated with the Bendeka patent estate. A complete Orange Book analysis must distinguish:

Patents listed against the Bendeka NDA;
Patents listed against other bendamustine products;
Patent-use codes;
Current listed expiration dates;
Delisted or expired patents;
Any pediatric exclusivity or patent-term adjustment.

The presence of US 9,144,568 in the Orange Book can support a Paragraph IV certification challenge when a generic applicant seeks approval before the listed patent expires.

What Paragraph IV challenges and generic entry risks exist?

A generic applicant seeking approval for a bendamustine injection before expiration of a listed patent may file a Paragraph IV certification stating that the patent is invalid, unenforceable or will not be infringed. Under the Hatch-Waxman framework, the NDA holder may bring patent litigation within 45 days of receiving notice. A timely action can trigger a statutory stay of approval of up to 30 months, subject to statutory exceptions and court developments. [4]

The principal Paragraph IV theories against US 9,144,568 would likely involve:

Non-infringement

A challenger could argue that its product or proposed label does not meet one or more limitations, including:

No PEG;
No propylene glycol;
A different PEG-to-glycol ratio;
Concentration outside the claimed range;
Volume greater than 100 mL;
Infusion longer than 15 minutes;
A different indication;
A different dosing schedule.

Invalidity

Potential validity attacks could address:

Anticipation by earlier bendamustine formulations or treatment protocols;
Obviousness based on known bendamustine formulations, solvents and infusion regimens;
Lack of written description or enablement for the breadth of the claimed ranges;
Indefiniteness involving approximation terms such as "about";
Patentable distinction between the claimed rapid administration method and prior clinical practice.

The formulation limitations may provide the patent holder with a stronger position than the broad treatment limitations. Conversely, prior art showing bendamustine, PEG, propylene glycol and short infusion times in combination could materially weaken the claims.

What litigation affects US 9,144,568?

Publicly available patent information should be reviewed for district court actions, Paragraph IV notices, inter partes review petitions and Federal Circuit decisions involving the patent. The key procedural question is whether any challenge reached a final judgment on validity or infringement. A patent's grant and Orange Book listing do not establish that all claims have been judicially tested.

For business planning, litigation risk should be separated into four categories:

Risk category	Principal issue
ANDA litigation	Whether a generic label induces the patented administration method
Formulation dispute	Whether the generic contains the claimed PEG/propylene glycol system
Claim-construction dispute	Meaning of "about," "comprising," "volume," and "solubilizer"
Regulatory dispute	Whether the proposed indication and dosing instructions trigger the listed method claims

No final invalidity or non-infringement determination should be inferred solely from the patent's prosecution history or Orange Book status.

How does US 9,144,568 compare with earlier bendamustine patents?

Earlier bendamustine patents generally protected the active compound, broad therapeutic use, or earlier formulations. US 9,144,568 occupies a later-generation position focused on commercial delivery and administration.

Patent category	Typical protected subject matter	Relevance to US 9,144,568
Compound patents	Bendamustine molecule or salt	Earlier and generally broader chemical protection
Broad treatment patents	Use of bendamustine against hematologic malignancies	Potential prior art and overlapping use
Formulation patents	Solubility, stability, excipient systems	Directly relevant
US 9,144,568	Low-volume, rapid parenteral administration for CLL and indolent B-cell NHL	Product-specific method protection
Later patents	Additional formulations, containers, dosing or manufacturing methods	Potential blocking or follow-on rights

The patent's commercial value is therefore linked to the delivery advantage of the formulation, not to exclusive control over bendamustine as an active ingredient.

What manufacturing and intellectual-property barriers remain after patent expiry?

Patent expiry would remove the principal statutory patent barrier from the covered claims, but commercial entry may still face:

FDA approval requirements for a generic injectable;
Sterility and aseptic manufacturing controls;
Container-closure compatibility;
Stability and impurity specifications;
Extractables and leachables testing;
Demonstration of pharmaceutical equivalence;
Labeling restrictions;
Manufacturing capacity for sterile oncology products;
Additional unexpired formulation or process patents;
Trade-secret know-how relating to preparation and packaging.

An ANDA applicant would need to evaluate the full patent family and all other patents listed against the relevant bendamustine NDA. A non-infringing alternative formulation may require additional development work and could lose the low-volume or short-infusion commercial advantages protected by the patent.

What licensing deals and competitive factors matter?

Eagle Pharmaceuticals commercialized Bendeka after developing the low-volume, short-infusion formulation. Bendamustine products have also been commercialized by companies associated with the Treanda brand and by generic manufacturers after relevant regulatory and patent barriers permitted entry.

The main competitive factors are:

Ten-minute administration compared with longer infusion protocols;
Reduced infusion-bag volume;
Use in CLL and indolent B-cell NHL;
Hospital pharmacy handling;
Drug acquisition cost;
Reimbursement;
Competing chemoimmunotherapy and targeted agents;
Generic bendamustine availability.

No separate license should be inferred from the patent's assignment history alone. Patent assignments, development agreements, product commercialization agreements and settlement agreements are legally distinct documents and require separate verification in USPTO and court records.

What revenue exposure is tied to this patent?

Revenue exposure is concentrated in bendamustine injection sales using the Bendeka-style formulation and label. The patent does not protect all bendamustine revenue because it excludes or may not reach:

Other dosage forms;
Alternative formulations;
Other hematologic indications;
Administration outside the claimed time and volume ranges;
Products using different solubilizers;
Products marketed after patent expiry.

The commercial exposure is highest before generic entry, during any litigation stay, and while the product label continues to direct the patented 50 mL, 10-minute regimen. Revenue impact after expiry depends on the number of approved competitors, price erosion, supply reliability and the availability of alternative oncology treatments.

What generic launch scenarios exist?

Scenario 1: Launch after patent expiry

This is the lowest litigation-risk pathway if no other listed or unexpired patent blocks approval. The generic may use a formulation and label substantially similar to Bendeka.

Scenario 2: Paragraph IV challenge

The applicant seeks approval before expiration and alleges invalidity, unenforceability or non-infringement. Litigation may delay approval and creates potential damages exposure if the generic launches at risk.

Scenario 3: Carve-out or label modification

A generic may seek to remove a patented indication or administration instruction, provided the resulting label remains adequate and does not otherwise induce infringement. This route is difficult where the claimed method covers the principal FDA-approved indications and dosing regimens.

Scenario 4: Formulation design-around

The applicant uses a different solubilizer system, concentration, volume or infusion duration. This may reduce patent risk but can create pharmaceutical equivalence, stability or commercial-use disadvantages.

Key Takeaways

US 9,144,568 is a method-of-treatment patent, not a broad bendamustine compound patent.
Claim 1 requires a parenteral bendamustine composition containing PEG and propylene glycol, administered in 100 mL or less over 15 minutes or less.
The narrowest commercial embodiments track Bendeka: approximately 50 mL, a 10-minute intravenous infusion, bendamustine hydrochloride, and dosing on days 1 and 2.
CLL claims center on 100 mg/m² every 28 days for up to six cycles.
Indolent B-cell NHL claims center on 120 mg/m² every 21 days for up to eight cycles.
The patent's commercial strength comes from its formulation and administration combination.
A generic challenge would likely focus on non-infringement, obviousness, anticipation, claim construction and the scope of any label carve-out.
The patent is associated with a 2031 expiration horizon, subject to the official USPTO and Orange Book term data.
Patent expiry would not eliminate FDA, sterile-manufacturing, formulation and supply-chain barriers.
A complete freedom-to-operate opinion requires review of the entire bendamustine patent family, Orange Book listings, prosecution history and current litigation docket.

FAQs

Is US 9,144,568 a composition patent or a method patent?

It is principally a method-of-treatment patent. The claims require administering a specified bendamustine composition to treat CLL or indolent B-cell NHL.

Does using bendamustine hydrochloride automatically infringe the patent?

No. Bendamustine hydrochloride alone does not satisfy all claim limitations. Infringement depends on the formulation, solubilizer system, volume, administration time, indication and treatment protocol.

Can a 30-minute infusion avoid US 9,144,568?

A 30-minute infusion would generally fall outside the express "15 minutes or less" administration-time limitation. It would not, however, resolve risk under other patents or under a different claim construction without a complete claim and patent-family analysis.

Are PEG 400 and propylene glycol both required?

Both PEG and propylene glycol are required by claim 1. PEG 400 is required only by dependent claim 4. A formulation using another PEG grade may still fall within claim 1.

Does patent expiry allow immediate generic sale?

No. FDA approval, applicable Orange Book certifications, sterile injectable manufacturing, pharmaceutical equivalence and any other unexpired patents or regulatory exclusivities must also be addressed.

References

U.S. Food and Drug Administration. (2024). Bendeka (bendamustine hydrochloride) injection prescribing information.
United States Patent and Trademark Office. (2015). U.S. Patent No. 9,144,568, Bendamustine formulations and methods of use thereof.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, Orange Book.
U.S. Food and Drug Administration. (2017). Guidance for industry: 180-day exclusivity and abbreviated new drug applications.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Eagle Pharms	BENDEKA	bendamustine hydrochloride	SOLUTION;INTRAVENOUS	208194-001	Dec 7, 2015		RX	Yes	Yes	⤷ Start Trial	⤷ Start Trial				FOR USE IN THE TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AND/OR NON-HODGKINS LYMPHOMA	⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2867295	⤷ Start Trial
Canada	2867343	⤷ Start Trial
China	104271135	⤷ Start Trial
China	104302291	⤷ Start Trial
China	107157988	⤷ Start Trial
Denmark	2827862	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 9,144,568

Which drugs does patent 9,144,568 protect, and when does it expire?

Summary for Patent: 9,144,568