US Patent 9,439,985: Claim Scope, Lymphatic Imaging Formulation, and Patent Landscape
US Patent No. 9,439,985 protects a stabilized radiopharmaceutical composition based on DTPA-dextran, including the DTPA-mannosyl-dextran platform used in technetium-99m tilmanocept products. The patent focuses on formulation chemistry rather than the underlying biological targeting concept. Its independent claims cover both an unlabelled formulation and a formulation containing technetium-99m.
The commercially relevant embodiment is a kit containing DTPA-mannosyl-dextran, trehalose dihydrate, sodium ascorbate, stannous chloride dihydrate, and glycine. That composition corresponds closely to the formulation used to prepare technetium Tc 99m tilmanocept injection, marketed as Lymphoseek by Navidea Biopharmaceuticals (FDA, 2024a).
What does US Patent 9,439,985 cover?
The patent covers pharmaceutical compositions containing five required formulation elements:
| Required element |
Claimed limitation |
| DTPA-dextran |
Up to 0.5 mg/mL |
| Non-reducing disaccharide |
Up to 2% w/v |
| Non-sulfhydryl antioxidant |
Includes ascorbic acid or a salt |
| Stannous salt dihydrate |
Up to 75 micrograms/mL |
| Transchelator |
Up to approximately 0.5 mg/mL |
Claim 1 is the principal composition claim. It does not require technetium-99m, a diluent, nitrogen, mannose substitution, or a specific molecular weight for the dextran. Those limitations appear in dependent claims.
The claim is formulation-centered. It requires the listed excipients and concentration ceilings in combination with DTPA-dextran. A competing product containing DTPA-dextran but omitting one required component may avoid literal infringement of claim 1, although other claims, patents, or equivalents could remain relevant.
How should the independent claims be interpreted?
Claim 1
Claim 1 requires a composition comprising:
- DTPA-dextran;
- a non-reducing disaccharide;
- a non-sulfhydryl antioxidant;
- a stannous salt dihydrate; and
- a transchelator.
The use of "comprising" makes the claim open-ended. Additional excipients, buffers, preservatives, gases, diluents, and radiolabels may be present without avoiding the claim, provided the five required components are included.
The concentration language creates upper limits:
- DTPA-dextran: no more than 0.5 mg/mL;
- sugar: no more than 2% w/v;
- stannous salt dihydrate: no more than 75 micrograms/mL;
- transchelator: approximately no more than 0.5 mg/mL.
The claim does not state a minimum concentration for most components. In practical claim construction, a composition containing a nominally present but functionally insignificant amount could create issues concerning written description, enablement, or claim construction. Commercial formulations are the more relevant infringement benchmark.
Claim 21
Claim 21 is narrower and more commercially specific. It requires:
- DTPA-dextran;
- trehalose dihydrate;
- sodium ascorbate;
- stannous dichloride dihydrate; and
- glycine.
This claim removes the broader Markush alternatives in claim 1. It is more closely aligned with the Lymphoseek kit formulation and may be easier to compare against an abbreviated new drug application or competing kit composition.
What dependent claim limitations materially narrow the patent?
DTPA-dextran structure
Claims 2 and 3 narrow the carrier:
- Claim 2 requires multiple DTPA groups conjugated to dextran in a molar range of approximately 2:1 to 12:1.
- Claim 3 limits the dextran average molecular weight to approximately 5,000 to 20,000 Daltons.
Claim 4 adds mannose substitution and requires a molar ratio of approximately 2:1 to 12:1 for conjugated mannose groups to DTPA-dextran. This limitation is particularly relevant to tilmanocept, which is a mannose-receptor-targeted radiopharmaceutical based on a dextran scaffold.
Excipients
The principal dependent excipient limitations are:
- Claim 5: trehalose dihydrate;
- Claim 6: ascorbic acid or a salt;
- Claim 7: glycine as the transchelator;
- Claim 19: glycine and sodium ascorbate together;
- Claim 20: antioxidant concentration of approximately 0.5 mg/mL;
- Claim 22: sodium ascorbate concentration of approximately 0.5 mg/mL.
Claims 19, 21, and 22 define the formulation most closely associated with the marketed kit.
pH and reconstitution
Claims 8 and 9 require buffering within approximately pH 3 to 4, with claim 9 specifying pH 3.2 +/- 0.2.
Claims 10 through 15 cover a two-part kit or reconstitution system involving a diluent. Claim 11 specifies sterile water. Claims 12 and 13 require the diluent to raise the formulation from an acidic range to above pH 5. Claims 14 and 15 identify phosphate salts, sodium chloride, and phenol as diluent components.
These claims create a separate infringement pathway for the kit architecture. A competitor could avoid some claims by using a different diluent composition or by supplying a ready-to-use formulation rather than a two-vial reconstitution system.
Radiolabel and manufacturing environment
Claim 16 adds technetium-99m. Claim 17 requires activity greater than approximately 100 curies of technetium-99m per millimole of DTPA-dextran. Claim 18 adds nitrogen gas.
The inclusion of nitrogen suggests protection for oxygen-sensitive manufacturing, storage, or reconstitution conditions. It may be particularly relevant to vial headspace and kit manufacturing processes.
What formulation is most exposed to US Patent 9,439,985?
The highest-risk formulation is one containing all of the following:
| Component |
Commercially relevant limitation |
| DTPA-mannosyl-dextran |
Within the claimed DTPA and dextran ranges |
| Trehalose dihydrate |
Up to 2% w/v |
| Sodium ascorbate |
Approximately 0.5 mg/mL |
| Stannous chloride dihydrate |
Up to 75 micrograms/mL |
| Glycine |
Up to approximately 0.5 mg/mL |
| Acidic formulation |
Approximately pH 3.2 |
| Sterile-water diluent |
Raises pH above 5 |
| Technetium-99m |
Added before administration |
A generic or follow-on product with this same excipient architecture could implicate claim 21 even if it uses a different vial, label, manufacturing site, or commercial name.
The patent does not require every optional feature at once. A product can fall within claim 1 without mannose, technetium-99m, nitrogen, or the specified diluent. Conversely, a product may fall within several dependent claims if it uses the complete kit formulation.
When does US Patent 9,439,985 expire?
Public patent records identify US 9,439,985 as a Navidea-related patent directed to radiopharmaceutical compositions and associated with a priority date in 2012. The ordinary 20-year term measured from the earliest nonprovisional priority filing is expected to extend into 2033, subject to patent-term adjustment, terminal disclaimers, patent-term extension, and any post-grant changes recorded by the USPTO.
| Event |
Approximate timing |
| Earliest priority |
April 2012 |
| US patent grant |
September 6, 2016 |
| Expected ordinary expiration |
April 2033 |
| Relevant term modifiers |
PTA, terminal disclaimer, PTE, maintenance status |
The grant date does not determine expiration. A definitive expiration analysis must distinguish the patent term from FDA regulatory exclusivity and any patent-term extension under 35 U.S.C. § 156.
What is the FDA and Orange Book significance?
The FDA approved Lymphoseek, a kit for the preparation of technetium Tc 99m tilmanocept injection, for lymphatic mapping in patients with breast cancer, melanoma, or squamous cell carcinoma of the head and neck. The product uses a radiolabeled dextran-based targeting agent that binds mannose receptors on macrophages and dendritic cells (FDA, 2024a).
The Orange Book relevance is narrower than the patent’s technical scope:
- FDA listing concerns patents submitted for an approved drug product.
- A patent can be technically relevant without being listed in the Orange Book.
- A formulation patent may be listed if it claims the approved drug, formulation, or method of use.
- An Orange Book listing does not establish validity or infringement.
- The patent’s composition claims may be relevant to an ANDA even where the applicant does not copy the branded label verbatim.
For Lymphoseek, regulatory exclusivity and patent exclusivity should be analyzed separately. The product received FDA approval in 2013. Any five-year new chemical entity exclusivity would have expired before the expected patent term, leaving later generic entry primarily dependent on Orange Book patents, Paragraph IV certifications, litigation, and regulatory requirements for the radiopharmaceutical.
Are there Paragraph IV challenges or generic litigation?
The claim text does not establish whether an ANDA applicant has filed a Paragraph IV certification, whether Navidea has sued an applicant, or whether a settlement has been executed. Those events are separate from the patent’s prosecution history.
For this patent, the principal Paragraph IV theories would likely involve:
- non-infringement based on omission or substitution of one required excipient;
- non-infringement based on concentration outside the claimed ranges;
- invalidity based on anticipation or obviousness over earlier DTPA-dextran and radiopharmaceutical formulations;
- indefiniteness challenges to terms such as "up to," "about," and "sufficient to buffer";
- written-description or enablement challenges to the broad genus in claim 1;
- design-around arguments using a different antioxidant, chelator, sugar, tin source, or pH system.
The narrow claim 21 formulation is likely more important in a commercial challenge than claim 1’s broader Markush language because it maps directly onto the marketed excipient combination.
How strong is the patent estate?
The patent estate has moderate formulation strength but does not independently control every tilmanocept product.
Strengths
- Claim 1 covers a multi-component formulation with a defined stabilizer and reduction system.
- Claim 21 targets the specific trehalose, sodium ascorbate, stannous chloride, and glycine combination.
- Claims 8 through 15 cover pH and diluent features that can capture a complete reconstitution kit.
- Claims 16 and 17 address the radiolabeled product and high-specific-activity use.
- The claims can apply to both prelabelled and unlabelled compositions.
Limitations
- Claim 1 does not broadly claim all DTPA-dextran compositions.
- The claim requires a stannous salt dihydrate, which may permit alternative technetium-labeling chemistry.
- A competitor could explore a different sugar, antioxidant, transchelator, pH system, or carrier molecular weight.
- The patent does not, based on the supplied claims, claim the full therapeutic or diagnostic use of mannose-receptor targeting.
- Validity may depend on the technical distinction between this excipient combination and earlier radiopharmaceutical kit formulations.
The patent is strongest against a copycat kit that replicates the Lymphoseek formulation. It is weaker against a redesigned product that changes several excipients and the reconstitution system while preserving the same targeting biology.
How does this patent compare with the broader tilmanocept estate?
US 9,439,985 should be evaluated alongside three other patent categories:
| Patent category |
Protected subject matter |
Commercial impact |
| Carrier and conjugate patents |
Dextran, DTPA, mannose substitution, receptor targeting |
Can cover the active targeting agent |
| Formulation patents |
Trehalose, antioxidant, tin salt, glycine, pH, diluent |
Can block copycat kits |
| Method-of-use patents |
Lymphatic mapping and cancer-related imaging |
May affect labeled clinical use |
| Manufacturing patents |
Conjugation, purification, radiolabeling, vial filling |
Can create process and supply barriers |
A competitor must clear the entire family and related patent groups, not only US 9,439,985. The practical freedom-to-operate question is whether the proposed product uses the same active conjugate, formulation, labeling process, and approved indications.
What manufacturing and IP barriers exist?
The patent creates several manufacturing constraints for a follow-on product:
- controlled conjugation of DTPA to dextran;
- reproducible mannose substitution;
- control of molecular weight distribution;
- low-level stannous chemistry;
- oxygen control and nitrogen headspace;
- sterile filling of a low-dose radiopharmaceutical kit;
- stability of the unlabelled kit before reconstitution;
- validated radiolabeling with technetium-99m;
- high specific activity and quality-control testing.
These barriers may have greater commercial importance than the formulation patent alone. Radiopharmaceutical manufacturers also require access to technetium supply, validated sterile facilities, specialized distribution, and short shelf-life logistics.
What licensing and ownership issues matter?
Navidea has been associated with the commercial development and commercialization of tilmanocept and Lymphoseek. The underlying tilmanocept technology also has university-originated research and licensing history. Patent ownership, exclusive-license scope, sublicenses, and field restrictions should be reviewed through the current USPTO assignment record and applicable SEC disclosures.
A license covering the active DTPA-mannosyl-dextran technology does not automatically prove that the same license covers US 9,439,985. Formulation patents, continuation patents, and university rights may have separate ownership or royalty provisions.
What generic launch scenarios exist?
Scenario 1: Direct formulation copy
A product copying the five-component formulation in claim 21 faces the highest risk. A Paragraph IV challenge would likely need to contest validity or dispute one or more quantitative limitations.
Scenario 2: Excipients redesign
Replacing glycine, trehalose, sodium ascorbate, or the stannous salt could reduce literal infringement risk. The redesigned product would still require equivalent stability and radiolabeling performance.
Scenario 3: Different kit architecture
A ready-to-use product, alternative diluent, or different pH strategy could avoid claims 10 through 15 while leaving claims 1 or 21 in issue.
Scenario 4: Different targeting agent
A non-dextran targeting scaffold may avoid this patent but would create a separate development program and potentially trigger other active-agent patents.
Scenario 5: Post-expiration launch
A launch after the effective patent expiration avoids patent infringement risk from this patent, subject to other unexpired patents, regulatory exclusivity, and patent-term adjustments.
Key Takeaways
- US 9,439,985 is a formulation patent centered on DTPA-dextran radiopharmaceutical compositions.
- Claim 21 is the most commercially important claim because it recites the Lymphoseek-like combination of trehalose, sodium ascorbate, stannous chloride dihydrate, and glycine.
- The patent also covers acidic pH, sterile-water reconstitution, nitrogen, technetium-99m, and high-specific-activity embodiments.
- The expected ordinary patent term extends into approximately April 2033, subject to statutory term adjustments.
- The principal generic risk is a copycat kit using the same active conjugate and excipient system.
- A redesigned formulation may reduce literal infringement risk but must be assessed against the complete tilmanocept patent family.
- FDA approval, Orange Book listing, patent validity, Paragraph IV litigation, and settlement status are separate questions and must not be treated as interchangeable.
FAQs
Does US 9,439,985 claim Lymphoseek by name?
No. The patent claims chemical and formulation features. A product may infringe without using the Lymphoseek brand, and Lymphoseek-related products may require analysis under additional patents.
Does the patent cover every DTPA-dextran radiopharmaceutical?
No. The composition must contain the required sugar, antioxidant, stannous salt dihydrate, and transchelator within the claimed formulation framework.
Can a generic use a different antioxidant?
Potentially. A different antioxidant may avoid the narrower sodium ascorbate claims, but claim 1 covers a broader category of non-sulfhydryl antioxidants.
Does adding technetium-99m create the infringement?
No. Technetium-99m is optional under claim 1. Claims 16 and 17 add radiolabeled limitations, but the unlabelled formulation may already fall within claim 1 or claim 21.
Is patent expiration the same as FDA exclusivity expiration?
No. FDA exclusivity is a regulatory period. Patent expiration is governed by the patent term and applicable adjustments. Generic entry also depends on Orange Book patents, certifications, litigation, and approval requirements.
References
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Food and Drug Administration. (2024a). Lymphoseek (technetium Tc 99m tilmanocept) injection: Prescribing information. U.S. Department of Health and Human Services.
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Food and Drug Administration. (2024b). Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services.
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United States Patent and Trademark Office. (2016). U.S. Patent No. 9,439,985: Radiopharmaceutical compositions and methods of making and using same. U.S. Department of Commerce.
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United States Patent and Trademark Office. (2024). Patent term adjustment and patent term calculation guidance. U.S. Department of Commerce.
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U.S. Congress. (2012). Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284.
