Executive summary
United States Patent 12,564,592 claims a ready-to-use aqueous injectable leucovorin calcium formulation stabilized by a water-soluble cyclodextrin inclusion complex (notably SBE-β-CD and/or HP-β-CD). The claim core is a narrow formulation parameter set: leucovorin calcium 5–25 mg/mL, cyclodextrin 20–100 mg/mL, Leucovorin:cyclodextrin weight ratio 1:4 to 1:10, pH 6.5–8.5, osmolality 200–600 mOsm, and crystallization-free stability at 2–8°C for 6 months and up to 3 months at 25°C ±2°C, with no reconstitution or dilution for IV/IM use. Dependent claims broaden scope to specific excipient systems (co-solubilizer, buffering agent, pH adjusters), specify impurity limits by HPLC, require preservative/antioxidant-free embodiments, and extend protection to container fill volumes and treatment methods tied to high-dose methotrexate and related oncology/hematology use.
What is the scope of U.S. Patent 12,564,592 (leucovorin calcium cyclodextrin injectable), and what do the claims actually cover?
Answer: The patent covers formulation chemistry and product functionality. It is not a broad “leucovorin + cyclodextrin” claim; it is a parameter-constrained, stability- and administration-ready aqueous injectable composition, plus downstream product and method-of-use claims.
Claim 1 scope (independent composition claim)
Claim 1 is an aqueous injectable comprising:
- Active ingredient: leucovorin calcium “consisting essentially of” leucovorin calcium
- Stabilizer/complexing agent: a water-soluble cyclodextrin derivative that forms a complex with leucovorin calcium
- Cyclodextrins covered:
- SBE-β-CD
- HP-β-CD
- and combinations
Quantitative ranges and functional requirements
- Cyclodextrin concentration: 20–100 mg/mL
- Leucovorin calcium concentration: 5–25 mg/mL
- Weight ratio leucovorin calcium : cyclodextrin derivative: 1:4 to 1:10
- pH: 6.5–8.5
- Osmolality: 200–600 mOsm
- Stability / crystallization: “substantially free from crystallization for at least 6 months” at
- 2–8°C, and
- “up to 3 months” at 25°C ±2°C
- Administration condition: suitable for IV or IM “without reconstitution or dilution”
Interpretation for claim scope
- The formulation must be a true aqueous injectable meeting physicochemical parameters and shelf stability thresholds.
- The “complex” language ties protection to inclusion-complex behavior between leucovorin calcium and cyclodextrin derivative, constrained by the disclosed concentration/ratio windows.
- The “consisting essentially of” on the active ingredient limits the active-side novelty to leucovorin calcium, but does not eliminate excipients in the formulation (excipient content is expressly addressed in dependent claims).
Claim 2 scope (excipient-flexible dependent claim)
Adds formulation embodiments that further include co-solubilizer, buffering agent, pH adjusting agent, and/or pharmaceutically acceptable vehicle.
Claims 3–7 scope (specific co-solubilizer and buffer systems)
- Claim 3: co-solubilizer is sodium chloride at ~4–12 mg/mL
- Claim 4: buffering agent selected from tromethamine, phosphate, acetate, citrate, or combinations
- Claim 5: if tromethamine, at ~5–10 mg/mL
- Claim 6: pH adjuster is HCl and/or NaOH
- Claim 7: vehicle is water for injection
These dependent claims create litigation leverage against designs that deviate from the required excipient identity or concentration, even if they remain within Claim 1’s broad parameter ranges.
Which specific formulation features and stability criteria define infringement risk for U.S. Patent 12,564,592?
Answer: The highest infringement risk is tied to meeting all of: (i) specific leucovorin and cyclodextrin concentration windows and ratio, (ii) specific pH/osmolality ranges, and (iii) the crystallization-free stability conditions, while staying a ready-to-administer IV/IM injectable.
Stability and “substantially free from crystallization”
The claim uses a functional shelf test:
- ≥6 months crystallization-free at 2–8°C
- and up to 3 months at 25°C ±2°C
For an accused product, technical teams would typically evaluate:
- time-temperature profile,
- analytical crystallization detection approach (not specified in the claim),
- and whether the product is “substantially free” rather than fully zero crystals.
pH and osmolality narrowness
The claim requires:
- pH 6.5–8.5
- osmolality 200–600 mOsm
This is a classic infringement separator: many candidate leucovorin injectable solutions use different buffering systems and ionic strengths that can swing osmolality and promote precipitation.
How does Claim 8 broaden the product coverage (specific exemplar with fixed concentrations)?
Answer: Claim 8 is a more specific embodiment with fixed levels and a defined osmolality target, which can make it easier to prove infringement for products matching the exemplar.
Claim 8 requires:
- leucovorin calcium ~10 mg/mL
- cyclodextrin derivative ~50 mg/mL (SBE-β-CD, HP-β-CD, or combination)
- co-solubilizer ~5 mg/mL (identity not repeated in Claim 8 text you provided; it is constrained via Claim 2/3 linkage in the claim set logic)
- buffering agent ~7 mg/mL
- pH adjusting agent is HCl and/or NaOH
- vehicle water for injection
- pH 8.0–8.5
- osmolality ~350 mOsm
- leucovorin is the only active ingredient
- crystallization-free stability and ready IV/IM use same as Claim 1
Infringement impact
- A product matching Claim 8’s fixed concentrations, osmolality target, and pH range is a direct hit.
- Even if a competitor stays within Claim 1 ranges, Claim 8 can provide an additional, narrower claim anchor.
What impurity limits are claimed in U.S. Patent 12,564,592, and how do they affect design-around?
Answer: The patent claims controlled impurity profiles by HPLC for the formulation.
Claims 9–10 impurity constraints
- Not more than:
- 2.0% of 4-amino benzoyl glutamic acid
- 1.0% of 10-formyl dihydrofolic acid
- 0.5% of “unspecified impurity”
- 2.5% of total impurities
- basis: by weight of leucovorin calcium
- determined by HPLC
Claim 9 applies to Claim 1 variants; Claim 10 applies to Claim 8 variants.
Design-around reality
- Competitors can attempt to source different leucovorin calcium material with a different impurity profile or change purification and formulation conditions.
- However, these impurity limits act as quality-matching constraints. If the competitor’s API or formulation yields impurities above these thresholds, infringement analysis may fail even if excipient and stability parameters match.
Does the patent cover preservative-free and antioxidant-free versions, and why does it matter?
Answer: Yes. Claims 11–12 require the formulation to be free of preservative and antioxidant.
- Claim 11: Claim 1 formulation “does not contain a preservative or an antioxidant.”
- Claim 12: Claim 8 formulation same.
Commercial and infringement relevance
- If an accused product uses common preservatives (depending on the market and regulatory history), it may avoid these dependent claims even if Claim 1 is still potentially asserted.
- For litigation strategy, the preservative/antioxidant element is often an easy separation: a competitor can attempt to move outside preservative-free subspace while keeping composition within Claim 1’s core parameters.
What additional physical stress tests are claimed (free-thaw cycles)?
Answer: Claim 13 adds a freeze-thaw robustness requirement.
Claim 13 requires:
- remains clear and free from crystallization after:
- at least 10 cycles of freezing at about −20°C for 48 hours
- then thawing at about 25°C for 48 hours
Impact
- This is a high-value constraint for hospitals and distributors who may experience temperature excursions.
- It raises the bar for proof of noninfringement if the accused product faces similar shipping and storage profiles.
What product packaging limitations are included (amber single-dose container)?
Answer: Claim 14 ties the formulation to a packaging configuration.
- Amber single-dose container
- fill volume configured to receive 5 mL, 35 mL, or 50 mL
Infringement posture
- If a competitor sells the same formulation in a different container type or different fill volume, this dependent claim may not read on it.
- Packaging claims also matter for Orange Book-style listings if the formulation is tied to a specific labeled container.
Which therapeutic method claims are covered, and what are the scope limits?
Answer: The patent includes method-of-treatment claims for:
- high-dose methotrexate therapy conditions (including osteosarcoma, impaired methotrexate elimination toxicity, folic acid antagonist overdose)
- megaloblastic anemia due to folic acid deficiency when oral folinic acid is not possible
- advanced colorectal cancer in combination with 5-fluorouracil
Claims 15–17 (method claims using Claim 1 formulation)
- Claim 15: administering Claim 1 formulation for:
- (a) osteosarcoma
- (b) toxicity/adverse effects of impaired methotrexate elimination
- (c) inadvertent overdose of folic acid antagonists
- Claim 16: megaloblastic anemia due to folic acid deficiency where subject cannot undergo oral folinic acid therapy
- Claim 17: advanced colorectal cancer in combination with 5-FU
Claims 18–20 (method claims using Claim 8 formulation)
Same indications as claims 15–17 but tied to administering the Claim 8 formulation.
Scope note
- The claims are broad on the treated population (“a subject in need thereof”) and tied to standard clinical indications.
- The dependent nature matters: the accused activity must use the patented formulations (Claim 1 or Claim 8) and meet their composition constraints.
How strong is the patent estate likely to be versus generic or competitor formulations?
Answer: Strength is driven by tight formulation parameter ranges, functional stability criteria, and impurity plus preservative-free dependent limitations. Those features can reduce the number of plausible “design-around” products that still deliver equivalent solubility and shelf stability.
Key “lock-in” elements
- Concentration and ratio windows (leucovorin 5–25 mg/mL; cyclodextrin 20–100 mg/mL; ratio 1:4 to 1:10)
- pH and osmolality windows (pH 6.5–8.5; 200–600 mOsm)
- Crystallization-free stability at 2–8°C and 25°C
- No reconstitution/dilution requirement for IV/IM
- Dependent traps: impurity limits (HPLC), no preservative/antioxidant, freeze-thaw clarity
Potential infringement-evasion vectors
- Move pH outside 6.5–8.5
- Move osmolality outside 200–600 mOsm
- Use different cyclodextrin derivative outside SBE-β-CD/HP-β-CD (or modify inclusion chemistry such that the claimed complex is not achieved)
- Shift leucovorin/cyclodextrin ratio outside 1:4–1:10
- Use preservative or antioxidant (to avoid Claims 11–12)
- Alter formulation to induce crystallization at the claimed stability timepoints (to avoid the functional stability limitation)
- Alter API impurity profile beyond the claimed HPLC thresholds
What does the claim set suggest about the underlying technology and commercial relevance?
Answer: The patent targets a practical product need: stable, injectable leucovorin calcium that avoids precipitation without reconstitution. Cyclodextrin derivatives (SBE-β-CD, HP-β-CD) are used to enhance solubility and prevent crystallization, while the formulation parameters and stability claims protect the specific product behavior and handling profile.
Key Takeaways
- U.S. Patent 12,564,592 is a formulation-stability patent: it claims a ready-to-use aqueous injectable leucovorin calcium stabilized by SBE-β-CD and/or HP-β-CD inclusion complex, with tight concentration, ratio, pH, osmolality, and crystallization-free shelf performance.
- Dependent claims add meaningful separation: specific excipient identities and concentrations (sodium chloride co-solubilizer; tromethamine/buffer types), HPLC impurity limits, preservative/antioxidant-free embodiments, freeze-thaw robustness, and amber container fill-volume configuration.
- Method claims extend the patent into clinical use for high-dose methotrexate-related indications, folic-acid-deficiency megaloblastic anemia when oral folinic acid is not possible, and advanced colorectal cancer with 5-FU, tied to using either the Claim 1 or Claim 8 formulation.
FAQs
1) Does the patent require a specific cyclodextrin inclusion-complex formation, or is “presence of cyclodextrin” enough?
The claim requires a complex of leucovorin calcium and the water-soluble cyclodextrin derivative.
2) Can a competitor infringe by using HP-β-CD only or SBE-β-CD only?
Yes. Claim 1 covers either derivative individually or in combination.
3) If a generic matches leucovorin and cyclodextrin concentrations but uses a different pH, does Claim 1 still apply?
Claim 1 requires pH 6.5–8.5, so moving outside that range is a direct hedge against Claim 1.
4) Are the method-of-use claims enforceable without proving the exact excipient package?
Method claims require administering “the formulation according to claim 1/8,” tying infringement to meeting the formulation identity and limitations of those claims.
5) What is the strongest dependent claim lever for product testing?
The freeze-thaw “clear and free from crystallization after at least 10 cycles” in Claim 13 and the impurity limits in Claims 9–10 provide concrete laboratory readouts.
References
- U.S. Patent 12,564,592 (claims provided in prompt).
