Details for Patent: 5,474,978

United States Patent 5,474,978: Scope, Claims, and US Patent Landscape for Hexameric Zinc/M-Cresol Insulin Analog Formulations

US 5,474,978 claims a specific class of human insulin analogs assembled as zinc/phenolic hexamers and the parenteral formulations and uses built around that complex. The protection concentrates on (i) allowable amino-acid substitutions in the B28 to B30 region (and B29), (ii) a hexamer architecture requiring six insulin analog molecules plus two zinc ions and a minimum phenolic load, and (iii) formulation targets that lock in common injectable excipients (buffer, isotonicity agent, phenol derivative identity) with at least one claim set reaching a composition-by-amount definition.

Because the claims are written as product and method-of-use coverage, the landscape is driven by later generics and follow-on biosimilar applicants navigating around the structural insulin-analog restrictions, the phenolic/zinc hexamer requirements, and the formulation excipient definitions.

What does the patent claim cover (core technical scope)?

US 5,474,978 centers on “human insulin analog complex” that is defined by stoichiometry and molecular composition.

1) Claim 1: Hexameric complex defined by insulin analog sequence + zinc + phenolic derivative

Claim 1 defines a “human insulin analog complex” with these mandatory elements:

• Six molecules of a “human insulin analog”
• Two zinc ions (Zn2+)
• At least three molecules of a phenolic derivative selected from:
  • m-cresol
  • phenol
  • mixture of m-cresol and phenol
• The complex is a hexamer
• The insulin analog is one of the following allowed sequence definitions (subset of human insulin variants):
  • Human insulin in which:
  • Pro at position B28 is substituted with Asp, Lys, Leu, Val, or Ala, and
  • Lys at position B29 is Lys or Pro
  • des(B28-B30)-human insulin
  • des(B27)-human insulin

This claim is broad across phenol derivative identity (m-cresol vs phenol vs mixtures) while tightly constraining the insulin analog substitution pattern and the hexamer stoichiometry.

2) Claims 2 to 7: Parenteral formulation layering excipients onto the claimed complex

Claims 2 to 7 depend from claim 1 and progressively narrow excipient choices:

• Claim 2: parenteral pharmaceutical formulation comprising the claim 1 complex
• Claim 3: formulation further comprises an isotonicity agent
• Claim 4: further comprises a physiologically tolerated buffer
• Claim 5: buffer is sodium phosphate
• Claim 6: isotonicity agent is glycerol
• Claim 7: phenolic derivative is m-cresol

This dependency structure creates a layered design space:

• If an entrant uses different buffer (not sodium phosphate) or different isotonicity agent (not glycerol), they move outside claims 5 and 6.
• If they use phenol (not m-cresol), claim 7 is avoided, while claim 1/2 remain potentially implicated depending on the remaining phenol content and whether the complex stoichiometry still meets “at least three molecules” of the specified phenolics.

3) Claim 8 and 9: Specific insulin analog identity

• Claim 8: parenteral formulation of claim 7 where the insulin analog is LysB28 ProB29-human insulin
• Claim 9: insulin analog composition of claim 1 where the insulin analog is LysB28 ProB29-human insulin

These claims lock in a specific substitution pattern:

• B28 = Lys
• B29 = Pro
• The rest of the claim 1 constraints remain (hexamer, Zn2+, and phenolic derivative loading).

4) Claim 10 and 11: Method-of-treatment use

• Claim 10: treating diabetes mellitus by administering a pharmaceutical formulation containing claim 1 composition
• Claim 11: method of claim 10 where the analog is LysB28 ProB29-human insulin

In enforcement, method claims often become relevant when generic/biosimilar marketing is tied to diabetes indication and when administration is the ordinary use for injectable insulin.

5) Claim 12: “Consisting of” version of the complex

Claim 12 repeats the claim 1 complex with a “consisting of” transition:

• “consisting of” six insulin analog molecules + two zinc ions + at least three phenolic molecules, hexamer
• insulin analog allowed set is broader in this clause:
  • the same B28 substitution set with B29 = Lys or Pro
  • des(B28-B30)-human insulin
  • des(B27)-human insulin

A “consisting of” format typically narrows permitted additional components versus a “comprising” format.

6) Claim 13: Narrow composition-by-amount formulation (high leverage)

Claim 13 is the most specific and most design-around-sensitive claim, specifying approximate concentrations:

A parenteral pharmaceutical formulation consisting of:

• about 3.5 mg/mL LysB28 ProB29-human insulin
• about 19.7 μg/mL zinc
• about 7 mM sodium phosphate
• about 16 mg/mL glycerin
• about 29 mM m-cresol
• and stating the insulin is a hexamer

This claim is a direct “product-by-composition” hook. Competitors can avoid it by shifting any of these numeric targets beyond the claim’s tolerance scope (note the claim says “about,” so exact equivalence is fact-dependent).

How broad are the claims across insulin analog variants?

The scope is anchored to the B28–B30 region and related deletions. The independent claim 1 and dependent claims allow the following insulin analog categories:

Insulin analog categories explicitly covered

1. Substitution form: human insulin where
   • B28 (Pro) is substituted with Asp, Lys, Leu, Val, or Ala, and
   • B29 (Lys) is Lys or Pro
2. Deletion forms:
   • des(B28-B30)-human insulin
   • des(B27)-human insulin

Practical effect for design-around

• Altering B28 to amino acids outside {Asp, Lys, Leu, Val, Ala} likely avoids claim 1.
• Altering B29 to amino acids other than Lys or Pro likely avoids claim 1.
• Using a structurally different insulin analog (e.g., major changes elsewhere in the B chain) is generally outside claim 1 unless the analog still fits one of the stated B28/B29/deletion definitions.

Claim 8/9/11 and claim 13 narrow this further to LysB28 ProB29-human insulin.

How broad is the formulation scope?

Formulation coverage is modular

• Claim 2 covers “parenteral formulation comprising complex” (open excipient approach depending on dependence chain).
• Claims 3 to 7 and 5 to 7 progressively fix:
  • isotonicity agent = glycerol
  • buffer = sodium phosphate
  • phenolic derivative = m-cresol

So the practical formulation scope splits into three tiers:

The “consisting of” format in claim 13 makes the numeric concentrations central for infringement analysis.

What is the key claimed structural requirement: the zinc/phenol hexamer?

Every claim that reaches independent-complex scope requires:

• hexameric assembly
• two zinc ions
• at least three phenolic molecules
• insulin analog in the defined sequence subset

This matters because many insulin analog formulations may contain phenolic preservatives and zinc but do not necessarily form the same hexamer structure in the same way or with the same stoichiometry/load.

Stoichiometry terms with litigation-ready meaning

• “six molecules” of insulin analog: fixes the assembly size
• “two zinc ions”: fixes metal content at the complex unit level
• “at least three molecules” of phenolic derivative: minimum phenol presence

These terms create a measurable target in characterization and expert analysis.

What claim elements create the highest design-around risk?

Highest risk elements

1. Insulin analog identity constraint
   • B28 and B29 restrictions or deletion forms are the first gating item.
2. Hexamer + zinc + phenol stoichiometry
   • competitor must show it does not meet the hexamer definition as claimed.
3. Formulation excipient selections
   • sodium phosphate and glycerol plus m-cresol are fixed in dependent chain.
4. Numeric composition (claim 13)
   • if products match the “about” concentrations closely, exposure rises.

US patent landscape: what other IP is likely to matter around this claim set?

Within insulin analog families, the landscape typically clusters into four categories of patents:

• insulin analog sequence patents (substitutions, deletions)
• manufacturing and characterization patents (hexamer formation, aggregation control)
• formulation patents (buffer systems, tonicity agents, preservative identity, zinc concentration)
• use patents (diabetes indication, dosing regimens)

How to map the landscape for this specific patent

Use the claimed constraints as the search map:

1) Sequence patents likely overlapping the “B28 substitution / B29 rule”

• Search around insulin analogs with substitutions in the B28-B29 region, especially those where B28 Pro is replaced and where B29 is Lys or Pro.
• For enforceability, look for claims tied to sequence variants that can be framed as “human insulin where Pro at B28 is substituted…” and corresponding B29 constraints.

2) Formulation patents likely overlapping the excipient set

• Search for claims specifying:
  • sodium phosphate buffer
  • glycerol as isotonicity agent
  • m-cresol as preservative/phenolic derivative
  • zinc in an injectable insulin context
• The claim 13 numeric recitation makes it particularly important to identify later patents that either:
  • replicate the same concentration windows, or
  • explicitly choose alternatives (different buffer, tonicity agent, preservative phenol identity, or zinc level).

3) Hexameric zinc-insulin complex formation patents

• Many insulin products are designed to create stable hexamers for solubility and release profiles.
• Search for patents claiming specific complex structure terms (hexamer, zinc, phenolic ligands) or characterization methods that tie to that structure.

4) “Consisting of” versions

• Claim 12 and 13 use “consisting of,” which can narrow what additional components are permissible.
• In the landscape, examine how other patents use “comprising” vs “consisting of” since this affects infringement scope when formulations include additional stabilizers.

Practical scope summary by claim

Claim-by-claim scope table

Key Takeaways

• US 5,474,978 protects hexameric insulin analog complexes defined by six insulin analog molecules, two Zn2+ ions, and at least three phenolic molecules, with the insulin analog constrained to B28/B29 substitution patterns or specific B-chain deletions.
• The formulation claims narrow risk in a stepwise way: sodium phosphate buffer, glycerol isotonicity, and m-cresol preservative/phenolic derivative.
• Claim 13 is the enforcement focal point: it is composition-by-amount for LysB28 ProB29-human insulin with specified zinc, sodium phosphate, glycerin, and m-cresol levels, and requires the product to be a hexamer.
• Landscape mapping should follow the claim constraints: sequence space (B28/B29), formulation excipient set (sodium phosphate/glycerol/m-cresol/zinc), and hexamer formation/complex structure terms.

FAQs

1) What insulin analog sequences does the patent permit under Claim 1?

Claim 1 permits human insulin analogs where B28 (Pro) is substituted with Asp, Lys, Leu, Val, or Ala and B29 is Lys or Pro, and also permits the deletion analogs des(B28-B30)-human insulin and des(B27)-human insulin.

2) What phenolic compounds matter for infringement?

The complex must include at least three phenolic derivative molecules selected from m-cresol, phenol, or mixtures. Dependent claims specifically fix m-cresol.

3) Why is zinc central to the claim scope?

Every complex claim requires two zinc ions as part of the claimed hexamer unit composition.

4) Which claim is most “numerically actionable” for product matching?

Claim 13, which specifies “about” concentrations for insulin analog, zinc, sodium phosphate, glycerin, and m-cresol, while stating the insulin is a hexamer.

5) Do the method claims change technical requirements or just add use coverage?

Claims 10 and 11 add a diabetes treatment use requirement but rely on administering a formulation containing the same complex/composition constraints from the product claims.

References

[1] US Patent 5,474,978.