Details for Patent: 11,236,328

Which drugs does patent 11,236,328 protect, and when does it expire?

Patent 11,236,328 protects DEFITELIO and is included in one NDA.

This patent has twenty-five patent family members in sixteen countries.

Summary for Patent: 11,236,328

Title:	Euglobulin-based method for determining the biological activity of defibrotide
Abstract:	It is disclosed a method for determining the biological activity of defibrotide, which comprises the steps of: a) bringing into contact defibrotide, mammalian euglobulin and a substrate specific for the plasmin which, by reaction with the plasmin, provides a measurable product; and b) measuring the amount of product formed at successive times, to thereby determine the biological activity of the defibrotide. Liquid defibrotide formulations are also disclosed, preferably water solutions, having a defined biological activity and, in particular, having an activity of 25 to 35 IU/mg of defibrotide, preferably from 27 to 32 IU/mg and, more preferably, from 28 to 32 IU/mg.
Inventor(s):	Terenzio Ignoni, Vijay Kumar, Khalid Islam
Assignee:	Gentium SRL
Application Number:	US17/459,169
Patent Claim Types: see list of patent claims	Use; Formulation;

US Patent 11,236,328: Defibrotide Formulation, VOD Treatment, and Patent Landscape

US Patent 11,236,328 covers a narrow combination of VOD treatment, a high-concentration defibrotide formulation, defined potency, and a specific plasmin-generation assay used to measure potency. The broadest claim requires every element: defibrotide, sodium citrate, water for injection, potency of 25 to 35 IU/mg, concentration of at least 80 mg/mL, and potency determination through mammalian euglobulin and a plasmin-specific substrate. The patent is therefore more limited than a conventional composition patent covering defibrotide generally.

The commercial product most closely aligned with the claims is Defitelio, the FDA-approved defibrotide sodium injection supplied at 80 mg/mL in a sodium citrate and water-based formulation.[1] The principal enforcement questions concern the meaning of "consisting of," the required potency assay, and whether a competing product has at least 80 mg/mL defibrotide.

What does US Patent 11,236,328 protect?

The patent protects a method of treating hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome, by administering a specified defibrotide formulation. Claim 1 is the controlling independent claim.

Claim element	Requirement in claim 1	Commercial significance
Disease	Veno-occlusive disease	Limits the method to VOD treatment
Active ingredient	Defibrotide	Does not cover unrelated anticoagulants or fibrinolytics
Excipients	Sodium citrate and water for injection	Narrows the formulation to a defined aqueous vehicle
Potency	25 to 35 IU/mg	Requires assay-defined biological potency
Concentration	At least 80 mg/mL	Captures the high-concentration injectable format
Assay	Mammalian euglobulin, plasmin substrate, time-based product measurement	Creates a potentially significant infringement and validity issue
Administration	Administration to a patient in need	Requires a treatment method, not merely manufacture or sale

Claims 2 through 19 narrow the scope further. They do not create independent protection for every listed feature. A product or treatment must first satisfy claim 1 before the dependent limitations become relevant.

How do claims 1 through 19 divide the patent scope?

Claims 1 through 6: formulation, potency, concentration, and pH

Claim 1 requires a formulation consisting of defibrotide, sodium citrate, and water for injection. Claim 2 narrows potency to 27.5 to 32.5 IU/mg. Claim 3 narrows it again to 28 to 32 IU/mg.

Claim 4 requires a water solution. Claims 5 and 6 impose pH ranges of 6.5 to 8.5 and 7 to 8, respectively.

These limitations map closely to the known Defitelio formulation. The FDA prescribing information identifies Defitelio as a 200 mg/2.5 mL concentrate, equivalent to 80 mg/mL, containing defibrotide sodium and sodium citrate in water for injection.[1]

The concentration limitation is important. A competing formulation below 80 mg/mL would not literally satisfy claim 1, even if it used the same active ingredient and excipients. A concentrated formulation above 80 mg/mL could fall within the claim, provided the remaining limitations are met.

Claims 7 through 13: assay reagents and detection chemistry

Claims 7 through 13 define the potency test:

• Human, rabbit, or bovine euglobulin may be used.
• Plasmin is released from plasminogen contained in the euglobulin.
• The substrate must be plasmin-specific.
• The substrate may be chromogenic or fluorogenic.
• The substrate may have the structure A1-A2-A3-X.
• A3 is lysine or arginine.
• X may be para-nitroaniline or 2-naphthylamine.
• The product may be measured by spectrophotometry or spectrofluorimetry.
• H-D-Valyl-L-Leucyl-L-Lysine-p-nitroaniline is expressly covered.

These claims are not directed only to the final formulation. They also define how potency must be established. That construction creates a potential distinction between:

1. A formulation that has the required actual biological potency; and
2. A formulation whose potency is established using the claimed assay.

The claim language ties the potency range to a method comprising the assay steps. A patent dispute could therefore turn on whether the assay is a required limitation of the administered product or only the method used to characterize that product.

Claims 14 through 19: operating parameters for the assay

The remaining claims specify assay conditions:

Claim	Limitation
14	Euglobulin reconstituted to original plasma volume or diluted up to 1:10; substrate concentration of 2.5 to 3.5 mM
15	Aqueous reaction medium buffered to pH 7 to 8
16	Reaction temperature of 35 to 39°C
17	Substrate concentration of 0.3 to 4 mM
18	Comparison of standard and test samples and correlation of product-release rate with defibrotide concentration
19	Substrate concentration of 3 mM

Claim 19 depends on claim 17, while claim 18 independently depends on claim 1. Claims 14 through 19 would be harder to assert than claim 1 because they require evidence about laboratory testing conditions, not merely product labeling or composition.

What is the strongest construction of claim 1?

The strongest patent-holder position is that claim 1 requires a treatment using the specified Defitelio-type formulation and that the potency must be determined by the recited plasmin/euglobulin assay. Under that interpretation, a generic entrant would need to avoid at least one of the following:

• Use of sodium citrate;
• Use of water for injection as the claimed formulation;
• Concentration of at least 80 mg/mL;
• Potency between 25 and 35 IU/mg;
• The claimed mammalian-euglobulin plasmin assay;
• Treatment of VOD rather than another indication.

The strongest challenger position is that claim 1 is internally narrow and potentially vulnerable to construction disputes. The phrase "consisting of" generally excludes additional unrecited components from the claimed formulation, although incidental impurities and manufacturing residues may not necessarily avoid the claim. The claim also combines product characteristics with a particular analytical method. A challenger may argue that a formulation cannot infringe unless the claimed assay was actually used, or that the potency limitation is indefinite if the assay lacks sufficient reproducibility.

What formulations are protected by US 11,236,328?

The patent protects a liquid, high-concentration formulation with the following core profile:

Attribute	Claimed range or requirement
Active	Defibrotide
Concentration	At least 80 mg/mL
Excipients	Sodium citrate and water for injection
Potency	25 to 35 IU/mg
Preferred potency	27.5 to 32.5 IU/mg
Narrower preferred potency	28 to 32 IU/mg
pH	6.5 to 8.5, or 7 to 8 under narrower claims
Dosage form	Water solution

The claims do not expressly cover lyophilized defibrotide, oral tablets, capsules, liposomal formulations, polymeric depots, or formulations using a different buffer instead of sodium citrate. They also do not directly claim the manufacturing process for producing defibrotide sodium.

The use of "consisting of" gives the formulation limitations particular importance. A formulation with an additional preservative, stabilizer, surfactant, chelating agent, or other excipient could become a design-around candidate. The legal result would depend on claim construction and the doctrine of equivalents.

How strong is the patent estate for Defitelio?

US 11,236,328 is strongest as a product-use combination patent. It is weaker as a stand-alone barrier against every defibrotide product because it does not claim defibrotide broadly, and because several limitations are tied to a particular potency assay.

Protection category	Scope under US 11,236,328	Barrier assessment
Defibrotide molecule	Not broadly claimed	Low under this patent
VOD treatment	Covered when using the claimed formulation	Moderate to strong
80 mg/mL injectable formulation	Covered if composition and potency match	Strong for close copies
Sodium citrate formulation	Covered in combination with other limitations	Strong for formulation matches
Potency assay	Detailed assay coverage	Potentially strong, but fact-intensive
Manufacturing process	Not directly claimed	Low under this patent
Oral or alternative dosage forms	Not covered expressly	Low
Generic defibrotide treatment	Not automatically covered	Moderate, depending on product and label

The patent is commercially important because Defitelio's labeled concentration is 80 mg/mL, exactly at the lower boundary of claim 1.[1] A generic product that copies the concentration, sodium citrate vehicle, VOD indication, and potency profile would face a materially higher risk than a product using a different concentration or formulation.

When does defibrotide lose regulatory exclusivity?

The FDA approved Defitelio for treatment of adult and pediatric patients with hepatic VOD, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation.[1] The approval was granted to Jazz Pharmaceuticals subsidiary Gentium in March 2016.[2]

Defitelio received orphan-drug designation. Orphan exclusivity generally runs for seven years from approval under the Orphan Drug Act, subject to statutory exceptions.[3] On that basis, the core U.S. orphan exclusivity period would have ended in 2023. Orphan exclusivity is separate from patent protection and does not establish the patent expiration date.

Regulatory right	Approximate status
FDA approval	March 2016
Orphan designation	Yes
Seven-year orphan exclusivity	Generally ran to March 2023
Patent protection	Depends on the specific patent family and term adjustment
Generic pathway	ANDA, subject to applicable patents and exclusivities
Biosimilar pathway	Not applicable to defibrotide as a conventional small-molecule drug

Defibrotide is not a biologic for purposes of the biosimilar pathway. A competitor would ordinarily pursue an abbreviated new drug application rather than a biosimilar application.

What is the Orange Book status of Defitelio?

Defitelio is approved under NDA 208114. The FDA Orange Book is the relevant source for listed patents and regulatory exclusivity associated with approved small-molecule drug products.[4]

A patent claim is not automatically enforceable against an ANDA applicant merely because it concerns an approved drug. For a patent to create a standard Orange Book Paragraph IV pathway, it generally must be properly submitted and listed for the relevant drug product and use. Method-of-use patents may be listed with a corresponding use code, while formulation patents may be listed if they satisfy FDA listing requirements.

US 11,236,328 should therefore be evaluated against the current Orange Book entry for NDA 208114, including:

• Whether the patent is listed;
• Whether the listing covers the 80 mg/mL formulation;
• Whether a use code covers VOD treatment;
• The listed expiration date;
• Any delisting, correction, or certification history.

The claims supplied do not establish Orange Book listing status or a statutory patent expiration date. Those facts cannot be derived from claim language alone.

What patent expiration date applies to US 11,236,328?

The patent number and claims do not establish the expiration date. U.S. patent term generally runs 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension, terminal disclaimers, and continuation-practice rules.[5]

For commercial diligence, the relevant record is the USPTO patent center file history and patent-term data, not the issue date. The 2022 issue date does not mean that protection runs 20 years from 2022. Any investment or launch model should use the official term calculation for US 11,236,328 and separately test whether the patent is subject to a terminal disclaimer or patent-term adjustment.

Which companies could challenge the patent?

The likely challengers would be generic pharmaceutical companies seeking to market an 80 mg/mL defibrotide injection for the approved VOD indication. A Paragraph IV challenger could argue that:

1. The claims are anticipated or obvious over earlier defibrotide formulations and VOD-treatment disclosures.
2. The claimed concentration and excipient combination lack nonobviousness.
3. The assay limitations were known analytical techniques.
4. The term "potency" lacks adequate objective boundaries.
5. The claim improperly combines a product limitation with a testing method.
6. A proposed generic uses a different assay and therefore does not practice the claimed method.

No Paragraph IV notice, ANDA litigation, or settlement agreement is established by the claims supplied. A confirmed litigation assessment requires the relevant FDA, PACER, Delaware, New Jersey, or other district-court records.

What generic launch scenarios exist?

Scenario 1: Same formulation and same VOD label

This is the highest-risk scenario. A generic matching 80 mg/mL, sodium citrate, water for injection, and the claimed potency range could implicate claim 1 directly. The applicant would likely need to address the patent through a Paragraph IV certification, a section VIII carve-out if legally available, or a negotiated launch strategy.

Scenario 2: Same formulation but different potency assay

This scenario creates a factual dispute. If the potency limitation is interpreted as requiring the claimed assay, use of a materially different validated assay could support a noninfringement position. The patent holder could respond that the product still has the claimed potency and that the assay language defines the measurement standard rather than the manufacturer's internal quality-control procedure.

Scenario 3: Concentration below 80 mg/mL

A product below 80 mg/mL would fall outside the literal concentration limitation in claim 1. It could still face other patents, regulatory obstacles, or equivalence arguments, but US 11,236,328 would be materially less effective against it.

Scenario 4: Alternative excipient system

Replacing sodium citrate or adding formulation components may avoid the "consisting of" limitation. The commercial tradeoff is that the alternative product would need to demonstrate comparable stability, compatibility, sterility, and FDA approval.

What manufacturing and IP barriers remain?

The claims do not directly cover defibrotide manufacture, purification, viral clearance, sterilization, filling, or container-closure systems. Those areas may still create practical barriers even where claim 1 can be designed around.

The principal non-patent barriers include:

• Defibrotide quality and batch-to-batch potency control;
• Validation of the biological assay;
• Sterile manufacturing at high concentration;
• Stability of the aqueous sodium citrate solution;
• FDA requirements for pharmaceutical equivalence and bioequivalence;
• Supply of qualified defibrotide sodium;
• Clinical and labeling requirements for VOD treatment.

For an ANDA applicant, the claimed assay may matter even if the applicant argues noninfringement. The FDA may accept a different potency assay if adequately validated, but a regulatory alternative does not automatically eliminate patent risk.

Key Takeaways

• US 11,236,328 is a narrow combination patent, not a broad defibrotide molecule patent.
• Claim 1 targets a Defitelio-type formulation: defibrotide, sodium citrate, water for injection, at least 80 mg/mL, and 25 to 35 IU/mg potency.
• Claims 2 through 19 narrow potency, pH, assay reagents, substrate chemistry, concentration, temperature, and analytical procedure.
• The patent is strongest against a generic that copies the 80 mg/mL formulation and uses the claimed VOD indication.
• The assay limitations create both enforcement value and claim-construction vulnerability.
• Defibrotide has no biosimilar pathway because it is regulated as a conventional drug rather than a biologic.
• Orphan exclusivity associated with the 2016 approval generally ended in 2023, but that does not resolve patent protection.
• The statutory expiration date, Orange Book listing status, Paragraph IV history, and litigation status require the official patent and FDA records; they are not established by the claim text.

FAQs

Does US 11,236,328 cover all Defitelio products?

No. It covers products and treatment methods meeting all claim 1 limitations, including the concentration, excipient, potency, VOD-use, and assay requirements.

Can a generic avoid the patent by using a different potency assay?

Possibly. The answer depends on whether the assay is construed as a required limitation of the claimed method and whether the alternative assay produces a potency value within the claimed range.

Does the patent cover defibrotide manufacturing?

Not based on the supplied claims. The claims focus on treatment, formulation characteristics, and potency determination rather than synthesis or purification.

Is an 80 mg/mL formulation automatically infringing?

No. It must also satisfy the other limitations, including the sodium citrate and water-for-injection formulation, potency range, VOD treatment, and assay-related requirements.

Does expiration of orphan exclusivity eliminate the patent risk?

No. Orphan exclusivity and patent rights are separate. A product may become eligible for generic competition after regulatory exclusivity ends while remaining subject to unexpired patents.

References

1. U.S. Food and Drug Administration. (2023). Defitelio (defibrotide sodium) injection prescribing information.
2. U.S. Food and Drug Administration. (2016). FDA approves Defitelio for treatment of hepatic veno-occlusive disease.
3. Orphan Drug Act, 21 U.S.C. § 360cc.
4. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
5. 35 U.S.C. §§ 154, 156.
6. U.S. Patent No. 11,236,328. (2022). Defibrotide formulation and method of treatment. United States Patent and Trademark Office.

Drugs Protected by US Patent 11,236,328

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Jazz Pharms Inc	DEFITELIO	defibrotide sodium	SOLUTION;INTRAVENOUS	208114-001	Mar 30, 2016		RX	Yes	Yes						TREATMENT OF ADULT AND PEDIATRIC PATIENTS WITH HEPATIC VENO-OCCLUSIVE DISEASE (VOD), ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME (SOS), WITH RENAL OR PULMONARY DYSFUNCTION FOLLOWING HEMATOPOIETIC STEM-CELL TRANSPLANTATION (HSCT)

International Family Members for US Patent 11,236,328

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2012383169
Brazil	112014031934
Canada	2874960
China	104619857