Patent: 5,866,538

Summary for Patent: 5,866,538

Title:	Insulin preparations containing NaCl
Abstract:	Insulin preparations of superior chemical stability, comprising human insulin or an analogue or derivative thereof, glycerol and/or mannitol, and 5 to 100 mM of a halogenide are disclosed.
Inventor(s):	Norup; Elsebeth (Jyllinge, DK), Langkj.ae butted.r; Liselotte (Klampenborg, DK), Havelund; Svend (Bagsvaerd, DK)
Assignee:	Novo Nordisk A/S (Bagsvaerd, DK)
Application Number:	08/879,991
Patent Claims:	see list of patent claims

Claims & US Patent 5,866,538 Landscape: Insulin Formulations with Glycerol/Mannitol and Halogenides (5–100 mM) in the U.S.

Executive summary: US 5,866,538 claims insulin formulations defined by (i) an insulin polypeptide selected from human insulin and specified analogs/derivatives, (ii) glycerol and/or mannitol as bulking/tonicity agents, and (iii) a halogenide at 5 to 100 mM, with dependent claim carve-outs on halogenide identity and concentration ranges, specific insulin substitution patterns (including B28/B29 variants and des/sequence truncations), and optional excipient packages (Zn, phenols such as m-cresol/phenol). The estate is likely concentrated around formulation and excipient parameter space rather than insulin sequence per se. It is the halogenide concentration window plus the specific co-excipient matrix that is most likely to drive infringement analysis and to narrow design-around options for generics/biosimilar follow-ons using different tonicity/stability systems.

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US Patent 5,866,538: What do the claims actually cover, in infringement-relevant terms?

Core claim scope (Claim 1). A “pharmaceutical formulation” comprising:

• Polypeptide: human insulin, analogs, derivatives, or combinations.
• Tonicity/bulking: glycerol, mannitol, or glycerol and mannitol.
• Halogenide window: 5 to 100 mM halogenide.

Infringement hook: For Claim 1, an accused product must meet all three structural elements simultaneously: (a) the insulin species is within the defined genus (human insulin or the “analogue/derivative” set as interpreted in the specification), (b) the formulation includes glycerol and/or mannitol, and (c) the halogenide concentration is within 5–100 mM.

How dependent claims narrow the halogenide parameter

• Claim 2: halogenide is an alkali or alkaline earth halogenide.
• Claim 7: halogenide concentration 5–60 mM.
• Claim 11: halogenide concentration 10–100 mM.
• Claim 17: halogenide is sodium chloride.

Practical read-through: Claim 17 pins the halogenide to NaCl, reducing ambiguity on identity. Claims 7 and 11 create sub-ranges within Claim 1’s broader 5–100 mM and can matter for claim charting if a competitor chooses a mid-range NaCl concentration that falls outside one sub-range but inside another.

How dependent claims narrow the insulin species

• Claims 4–6: specify insulin analog patterns:

  • Analogue group where B28 is Asp, Lys, Leu, Val or Ala and B29 is Lys or Pro, plus truncation options like des(B28-B30), des(B27), des(B30).
  • Further narrowing:
    • Claim 5: B28 is Asp or Lys; B29 is Lys or Pro.
    • Claim 6: des(B30) human insulin.

• Claims 8–10: specify derivatives with lipophilic substituents, enumerating multiple acylated/lipophilized des(B30) and related insulin structures including:

  • B29-Nε–myristoyl-des(B30) human insulin (Claim 10).
  • palmitoyl, B28 acylated + Lys/Pro at B29, B30-acylated variants, and glutamyl- or lithocholyl-linked derivatives.

• Claim 12: allows formulations that include an insulin analogue as well as an insulin derivative, expanding inclusion logic where a mixture is used.

How dependent claims broaden product archetypes via excipient packages

• Claim 13: insulin concentration 60–3000 nmol/mL.
• Claim 14: additional Zn: 10–40 μg Zn per 100 U insulin.
• Claims 15–16: optional phenolic preservative system:
  • Claim 15: 0–5 mg/mL of a phenolic compound.
  • Claim 16: specific m-cresol and/or phenol levels (0.5–4.0 mg/mL phenol or 0.5–4.0 mg/mL m-cresol; mixture permitted).

Design-around implication: Optional features are not required unless claimed in a specific dependent claim. For validity/infringement defense, accused products can attempt to avoid at least one limitation of the asserted dependent claim while still falling within Claim 1’s matrix if the halogenide window and glycerol/mannitol are maintained.

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What patents protect insulin formulations with glycerol/mannitol and halogenides? (How 5,866,538 fits an excipient-based landscape)

What 5,866,538 is most likely “about” in the patent ecology: The claim set is structured as a formulation parameter claim:

• a defined insulin composition set (human insulin and particular analog/derivatives),
• a defined tonicity system (glycerol/mannitol),
• and a defined electrolyte window (halogenide 5–100 mM, with NaCl-specific claim language).

In this landscape, the most common competitive patent types are:

1. Protein sequence claims (insulin analog structures).
2. Manufacturing/process claims (making the insulin species).
3. Formulation parameter claims (stability, solubility, precipitation control).
4. Preservative/excipient-system claims (phenols, Zn, buffers, chelators).
5. Device/administration claims (not implicated by the provided claim text).

Given the provided claim text, US 5,866,538 belongs primarily to (3) and (4). That means the main competitive pressure is other patents claiming different electrolyte windows, different tonicity agents (e.g., trehalose/sucrose instead of glycerol/mannitol), different preservative systems, or different insulin spec sets.

Where the claim language creates a defensible “narrowness wedge”

• Halogenide concentration window combined with glycerol/mannitol presence is more specific than generic “saline-like” formulation claims.
• The insulin derivative set is explicit and includes specific lipophilization patterns.
• The phenolic and Zn ranges are typical insulin stability/preservation levers but are locked to numeric endpoints.

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Which insulin analogs and derivatives are explicitly within US 5,866,538 claim coverage?

Explicit analog/truncation carve-outs (Claims 4–6):

• B28 substitutions: Asp, Lys, Leu, Val, Ala.
• B29 residues: Lys or Pro.
• truncations: des(B28-B30), des(B27), des(B30).

Explicit derivative carve-outs (Claims 8–10):

• Myristoyl/palmitoyl and mixed substitution patterns at specific positions and linkers.
• Specific enumerated derivatives in Claim 9 and a key subset in Claim 10.

Mixture logic (Claim 12):

• Allows both an insulin analogue and an insulin derivative to be present.

Infringement lens: A competitor product using insulin species outside the claim-defined analogue/derivative sets avoids these dependent claims, but Claim 1 still recites “an analogue thereof, a derivative thereof.” That means claim construction will depend heavily on how “analogue” and “derivative” are defined in the patent’s intrinsic record (specification definitions, examples, and synonym use). The numeric electrolyte matrix then becomes the remaining dominant limitation for Claim 1.

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When does insulin formulation protection expire for US 5,866,538 in the U.S.?

No answer provided. The document does not include the patent’s filing date, issue date, expiration adjustments, terminal disclaimers, or any regulatory exclusivity tethering (for formulations this is typically patent-term only). Without those data, a complete and accurate exclusivity timeline cannot be produced.

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What generic or follow-on entry risks exist if a product uses glycerol/mannitol and NaCl?

Claim 1 risk profile (broad)

• Any insulin formulation that uses glycerol and/or mannitol and has 5–100 mM halogenide potentially overlaps.
• If the product uses NaCl and sits within Claim 1’s window, Claim 17 becomes a direct infringement vector.

Claim 7/11 split risk (range-based)

• If halogenide is NaCl:
  • falling in 5–60 mM implicates Claim 7.
  • falling in 10–100 mM implicates Claim 11.
• Competitors may attempt to place NaCl outside one or more dependent ranges. But they must avoid the broader Claim 1 range (5–100 mM) to clear the independent claim.

Excipient-system risk

• Phenolic system: if a product includes m-cresol/phenol in the numeric ranges, it can increase vulnerability to dependent claims 15–16.
• Zn presence: if Zn is present in 10–40 μg/100 U insulin, it can increase vulnerability to Claim 14.

Design-around playbook suggested by the claim structure

• Replace or omit glycerol/mannitol (if not required for the product’s stability) to break Claim 1’s tonicity element.
• Adjust halogenide identity away from alkali/alkaline earth halogenides to avoid Claim 2 (but Claim 1 still requires “halogenide,” so identity shifts may not fully clear).
• Adjust NaCl concentration outside 5–100 mM to avoid Claim 1 entirely (not merely dependent sub-ranges).
• Use insulin species outside the explicitly covered analogue/derivative sets to defeat dependent claims, while Claim 1 still may cover “human insulin” per wording.

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How strong is the patent estate for US 5,866,538 given claim specificity?

Strength indicators from the claim text

• Numeric windows (halogenide 5–100 mM; Zn; phenols; insulin concentration) make validity arguments more concrete and enable claim charting.
• Inclusion of explicit structural insulin derivative enumeration reduces interpretive sprawl for key dependent claims (8–10).
• Dependent claims create multiple independent “attack surfaces” for infringement analysis: halogenide identity and concentration; insulin variant identity; excipient presence.

Litigation-relevant vulnerability areas (structural, not event-based)

• Formulation patents are often litigated on obviousness and enablement: broad genus (Claim 1) with known tonicity/electrolyte/preservative roles can increase obviousness exposure unless the patent’s specification shows an unexpected stabilization effect tied to the specific ranges.
• “Analogue” and “derivative” interpretation can become a claim construction battleground if the specification uses non-exhaustive definitions.

No litigation status supplied. The prompt provides no case docket, asserted parties, or PTAB actions.

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What patent claim would a competitor most likely avoid: halogenide concentration, glycerol/mannitol, or the insulin species?

Most directly avoidable is the halogenide window and tonicity matrix.

• Claim 1 requires both glycerol/mannitol and halogenide 5–100 mM.
• If a product is designed with a different tonicity system (e.g., no glycerol and no mannitol), it breaks the independent claim.
• If a product uses halogenide outside 5–100 mM, it breaks the independent claim even if glycerol/mannitol remain.

Secondary avoidance is excipient package and Zn/phenols.

• Even if the product remains within the Claim 1 core, it can attempt to avoid dependent claims by omitting or shifting Zn and phenol/m-cresol ranges.

Species avoidance helps only for dependent claims on specific analog/derivatives.

• Because Claim 1 already covers human insulin and unspecified “analog/derivative” categories, redesigning insulin species can be insufficient unless the species falls entirely outside the claim-defined scope as interpreted in the patent record.

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Does US 5,866,538 read on modern insulin products (pen/cap formulation) using glycerol and saline?

No direct product-to-claim mapping is provided. The prompt does not include the composition or excipient analytics of any specific branded insulin, nor the identity and concentration of halogenide, glycerol/mannitol, Zn, and phenolic preservative in those products. Without such composition tables, an accurate infringement or non-infringement mapping cannot be produced.

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Key Takeaways

• US 5,866,538 is a formulation parameter patent focused on insulin species plus a glycerol/mannitol tonicity system and a halogenide concentration window of 5–100 mM (with NaCl-specific and sub-range dependent claims).
• Dependent claims add specificity through insulin analog/derivative identity, halogenide identity/range, insulin concentration, and optional stability excipients (Zn; m-cresol/phenol).
• Design-around leverage is highest on Claim 1 elements: remove glycerol/mannitol and/or move halogenide outside 5–100 mM. Tuning Zn or phenols can clear dependent claims but may not clear the independent claim.
• Claim strength is driven by numeric boundaries that are amenable to direct formulation testing and claim charting, but the formulation nature of the claims can create obviousness risk unless the patent’s record ties the ranges to an unexpected technical effect.

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FAQs

1. If an insulin product uses glycerol but has no halogenide, does it avoid US 5,866,538 Claim 1?
2. How would a change from NaCl to a different halogenide salt affect exposure to Claims 2 and 17?
3. What lab assays are typically used to quantify halogenide concentration for testing against the 5–100 mM window?
4. If Zn is present outside 10–40 μg per 100 U insulin, does that eliminate risk under Claim 14 specifically?
5. Which claim elements most strongly determine whether a formulation that includes phenol/m-cresol is exposed under Claims 15–16?

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References

None. The prompt provides only claim text and does not include bibliographic details (issue date, filing date, family members) or any external source material to cite.

Details for Patent 5,866,538

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Novo Nordisk Inc.	NOVOLOG	insulin aspart	Injection	020986	June 07, 2000		2017-06-20
Novo Nordisk Inc.	NOVOLOG	insulin aspart	Injection	020986	January 19, 2001		2017-06-20
Novo Nordisk Inc.	NOVOLOG	insulin aspart	Injection	020986	April 23, 2004		2017-06-20
Novo Nordisk Inc.	NOVOLOG	insulin aspart	Injection	020986	October 31, 2013		2017-06-20
Novo Nordisk Inc.	NOVOLOG MIX 70/30	insulin aspart protamine and insulin aspart	Injectable Suspension	021172	November 01, 2001		2017-06-20

International Patent Family for US Patent 5,866,538

Country	Patent Number	Estimated Expiration
Austria	E208208
Australia	3253697
Australia	720484
Brazil	9709845
Canada	2258097