Patent: 9,365,632

Summary for Patent: 9,365,632

Title:	Exendin-4 derivatives as dual GLP1/glucagon agonists
Abstract:	The present invention relates to exendin-4 derivatives and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as reduction of excess food intake.
Inventor(s):	Haack; Torsten (Frankfurt am Main, DE), Wagner; Michael (Frankfurt am Main, DE), Henkel; Bernd (Frankfurt am Main, DE), Stengelin; Siegfried (Frankfurt am Main, DE), Evers; Andreas (Frankfurt am Main, DE), Bossart; Martin (Frankfurt am Main, DE)
Assignee:	SANOFI (Paris, FR)
Application Number:	14/049,597
Patent Claims:	see list of patent claims

Executive summary

• US Patent 9,365,632 claims a large, combinatorial peptidic compound family built around a defined peptide “core” (formula II) with variable N- and C-terminal caps (R¹/R²), constrained substitutions at selected core positions (notably X2, X3, X14, X15, X16, X17, X18, X20, X21, X28, X29, X35, X39, X40), and a broad set of side-chain N-acyl / C(O)-substituted lipophilic R⁵ moieties (up to 100 carbons; optionally heteroatoms; with optional linkers).
• The patent’s commercial blocking power is driven less by any single sequence and more by breadth at the “handle points”: the Lys/ornithine/dab/“Dap” acylation (X14/X40) and the sequence-tolerant substitutions across the core.
• The enforceable claim set includes (i) generic Markush-style genus claims to “formula (I)/(II)” peptidic compounds and (ii) narrower anchor claims to specific SEQ ID NO(s) plus (iii) formulation/composition claims (including a “high solubility” limitation) and (iv) composition claims combining with a long list of metabolic/diabetes agents.
• The patent landscape risk for a would-be competitor is concentrated in whether their candidate peptide differs from the claimed genus only by changes that fall outside the enumerated position sets or the R⁵ / linker constraints, or whether their design can carve out the solubility limitation.

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US Patent 9,365,632: What peptidic compounds do the claims cover and how broad are the genus and Markush positions?

Short answer: Claim 1 covers a genus of peptidic compounds where the peptide contains the defined sequence framework in formula (II) (with enumerated residue options at multiple positions), with N-terminus (R¹) and C-terminus (R²) chosen from constrained lists, and with optional side-chain functionalization at X14 and/or X40 using R⁵ groups defined broadly (up to 100 carbons) and optionally attached through defined linkers.

Key structural elements in Claim 1

A. Genus architecture

• Compound is a peptidic compound: R¹–Z–R²
• Z is peptide moiety with formula (II), whose “spine” is fixed and includes a long run of residues from His–X2–X3–Gly–Thr–Phe–Thr–Ser–Asp–Leu–Ser–Lys–Gln ... through the later segment ending ... X39–X40.
• The core is a single-peptide family with variation at multiple enumerated positions.

B. Position-by-position degrees of freedom Claim 1 enumerates permitted options for:

• X2: Ser, D-Ser, Aib
• X3: Gln, His, or α-amino-functionalized Gln
• X14: amino acid with a functionalized –NH₂ side chain; functionalized via one of:
  • –C(O)R⁵, –C(O)O R⁵, –C(O)NH R⁵, –S(O)₂ R⁵, or –R⁵
• X15: Glu or Asp
• X16: Ser, Glu, Lys
• X17: Arg, Glu, Gln, Leu, Aib, Lys
• X18: Arg, Ala, Lys
• X20: Gln, Arg, Lys, His, Glu, Aib
• X21: Asp, Leu, Glu
• X28: Asn, Arg, Lys, Aib, Ser, Glu, Ala, Asp
• X29: Gly, Ala, D-Ala, Thr
• X35: Ala, Glu, Arg, Lys
• X39: Ser or absent
• X40: absent or an amino acid residue having –NH₂ side chain, optionally functionalized similarly to X14.

C. N-terminus and C-terminus caps (R¹ and R²)

• R¹ (N-terminal group): selected from a set of N-terminal amino substituents including:
  • –NH₂ or mono/bis-functionalized NH₂ forms
  • includes amines substituted by alkyl or alkylene-cycloalkyl; amide-type substitutions (–NH–C(O)H, –NH–C(O)(C1–C5 alkyl), etc.)
• R² (C-terminal group): either
  1. –OH or functionalized hydroxyl (O-alkyl or O-alkylene-cycloalkyl), or
  2. –NH₂ or mono/bis-functionalized amino forms with constrained alkyl/heterocyclyl/aryl/alkylene-aryl/heterocycle parameters.

D. R⁵ lipophilic/covalent moiety breadth

• R⁵ is a moiety up to 100 carbon atoms, with optional heteroatoms from halogen, N, O, S, P.
• This R⁵ can be attached directly or via defined functional linkages at the side-chain (claim 1: includes –C(O)-, –C(O)O-, –C(O)NH-, –S(O)₂-, or –R⁵ options).
• Dependent claims narrow the list of acceptable R⁵ classes and give explicit examples.

Claim scope profile (what matters for freedom-to-operate)

• The claim’s “center of gravity” is the core sequence in formula II, but the real capture risk is in:
  1. X14 and X40 functionalization by a wide R⁵ set
  2. substitution tolerated at multiple internal positions (serine/alanine/lysine/arg/acidic residues and α-aminois substitution at X3)
  3. N- and C-cap options that include amine/amide and protected terminal motifs.

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Which dependent claims narrow the landscape most: X14/X40 acylation, specific R⁵ examples, and SEQ ID anchors?

Short answer: Dependent claims 2–16 are the highest-value narrowing for infringement analysis because they constrain X14/X40 to specific side-chain types (Lys/Orn/Dab/Dap) and constrain R⁵ to lipophilic hydrocarbon classes or explicit named hydrophobic acyl structures. Claims 17–18 introduce sequence anchors that reduce ambiguity.

X14/X40 narrowing: Lys/Orn/Dab/Dap and R⁵ class controls (Claims 2–8)

• Claim 2:

  • X14 and X40 are Lys/Orn/Dab/Dap, and each has a –C(O)R⁵ functionalization.
  • R⁵ is explicitly constrained to lipophilic moieties that are:
    • acyclic (C4–C30) hydrocarbon (linear/branched, saturated/unsaturated) or
    • cyclic hydrocarbon (saturated/unsaturated/aromatic),
  • attachment may use linkers: (β-Ala)1–4, (γ-Glu)1–4, (ε-Ahx)1–4, or (GABA)1–4.

• Claim 3:

  • X14 and X40 similarly constrained, but R⁵ is narrowed to a large enumerated set of exact named acyl structures (includes many long-chain fatty acyls: C16/C18, unsaturated variants; also bulky chroman-based and polyol-containing linkers/phosphoryl derivatives; and multi-unit ethoxy-linked variants).
  • This is the most “infringement-friendly” dependent set because it lists specific R⁵ constructs that a competitor might approximate.

• Claim 4: R¹ and R² each can be –NH₂ or both –NH₂.

• Claims 5–7:

  • X14 is Lys with –C(O)R⁵
  • R⁵ is narrowed to “up to 100 carbons” in claim 5, then narrowed to acyclic C12–C22 hydrocarbon in claim 6 with a direct or linker attachment using β-Ala/γ-Glu/β-Ala-β-Ala/γ-Glu-γ-Glu.

• Claim 8:

  • specific residue set with X14 Lys or Orn; multiple other internal substitutions are constrained (e.g., X2 in D-Ser or Aib; X3 fixed to Gln; X35 fixed to Ala; X39 fixed to Ser or absent; X40 either absent or Lys).

Strongest “handle” for infringement: explicit R⁵ “lipophilic moiety with defined linker classes”

• Claims 2, 6, 7, 8 tie together:
  • the exact identity of the nucleophilic side-chain (Lys/Orn/Dab/Dap or Lys only)
  • the attachment type (–C(O)R⁵)
  • and linker classes (β-Ala, γ-Glu, ε-Ahx, GABA or related di-/tetrameric linkers).
• Competitors who choose different attachment chemistries (e.g., non-amide linkages) or different linker chemistries may fall outside the dependent claims but still hit the broad genus in claim 1 if the “formula (I)/(II)” requirements remain satisfied.

Sequence anchors: Claims 17–18

• Claim 17: compound is any one of SEQ ID NO. 4–181 (single claim directed to any one sequence in that range).
• Claim 18: compound is any one of SEQ ID NO. 4–181, 196–223, 226–229.

These dependent claims convert the genus into a definitional net around sequences actually disclosed in the specification. In litigation, SEQ ID anchors usually drive claim construction because they map to concrete structures.

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How does Claim 1 define the “core” peptide: what substitutions at X2/X3 and acidic/basic positions keep you inside?

Short answer: The claim allows conservative but strategically placed substitutions across polar and charged positions and includes α-amino-functionalized Gln at X3, which increases the design space for analogs without leaving the claim.

X2 and X3: small but legally meaningful gates

• X2 restricts to Ser, D-Ser, Aib.
  • Changing X2 to threonine, alanine, glycine, or other residues is a direct out.
• X3 restricts to Gln, His, or α-amino-functionalized Gln where the α-amino H is substituted by (C1–C4)-alkyl.
  • This means competitors can add small alkyls at the α-amino group but cannot replace X3 with other side-chain functional residues.

Acidic/basic positions: X15, X16, X17, X18, X20, X21, X28, X35

The claim permits limited swaps among Glu/Asp (X15, X21), a mixed set including Lys (X16, X17, X18, X35), and a wider neutral/acidic/basic set at X20 and X28, with Aib permitted at X17 and X20 and X28.

From an FTO perspective:

• If a candidate peptide swaps a residue outside each enumerated set, it exits that position’s constraint and avoids claim 1 if the change is irreconcilable with all other positions.
• If only the lipophilic R⁵ moiety changes, the broad R⁵ definition in claim 1 remains a capture risk unless the change breaks X14/X40 functionalization requirements.

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What formulations are protected: pharmaceutical compositions, high solubility, and combination therapy claim coverage?

Short answer: The patent includes:

• a generic composition claim for the compound plus pharmaceutically acceptable carriers (Claim 20),
• composition claims adding “additional therapeutically active agents” across a wide diabetes/metabolic toolbox (Claims 21–23),
• and a “high solubility” limitation tied to pH 4.5 and pH 7.4 at 25°C (Claims 19 and 24–25).

Carrier and combination claims (Claims 20–23)

• Claim 20: pharmaceutical composition comprising compound + at least one pharmaceutically acceptable carrier.
• Claim 21: further comprising at least one additional therapeutically active agent chosen from a long list that includes:
  • insulin products and analogs
  • GLP-1/GLP-1 analogues (extensive list: liraglutide, semaglutide, exenatide variants, dulaglutide, etc.)
  • dual GLP1/GIP agonists
  • SGLT2 inhibitors and dual SGLT2/SGLT1 inhibitors
  • DPP-IV inhibitors
  • and many other metabolic/obesity/drug classes
• Claims 22–23 narrow this combinatorial set to specific additional agents:
  • Claim 22 includes a GLP-1 compound, insulinic compound, or gastrointestinal peptide
  • Claim 23 includes insulin or insulinic compound.

“High solubility” limitation (Claims 19, 24–25)

• Claim 19: high solubility at at least one pH value (acidic or physiological), with solubility at that pH of at least 0.5 mg/mL.
• Claim 24: makes it specific to pH 4.5 at 25°C and/or pH 7.4 at 25°C.
• Claim 25: increases the bar to at least 1.0 mg/mL at those pH values.

In enforcement, if the accused product’s solubility profile at the specified pH/temperature differs, claim 19/24/25 may become harder to assert, but the base “carrier” claim 20 can still apply if the compound itself matches.

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What specific solubility and terminal group claims create additional barriers to generic or analog design?

Short answer: Claim 4 (R¹/R² both –NH₂) and Claims 19/24/25 impose additional limitations that competitors can target by changing terminal caps and/or solubility engineering.

Terminal group constraints (Claim 4)

• Claim 4 limits R¹ and/or R² to –NH₂ forms.

If a candidate product uses different terminal protection/capping chemistry than the defined set, it can avoid dependent claim 4 but still remain in claim 1 if its R¹/R² options fall within the claim 1 list.

Solubility engineering

• If solubility at pH 4.5 or pH 7.4 at 25°C is not met at the specified thresholds, claims 19/24/25 can be avoided without changing the core peptide.
• The risk is that solubility could be achieved through formulation, not sequence changes. Claim scope depends on whether the solubility limitation is tied to the compound itself or the composition. The wording “compound, salt or solvate” suggests it is directed to the substance form.

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What is the likely patent strength profile from a litigation and challenge standpoint, given this claim drafting?

Short answer: The patent combines (i) broad genus coverage in claim 1 with (ii) tight dependent constraints and (iii) many enumerated concrete R⁵ exemplars and SEQ ID anchor claims. That structure generally improves litigation leverage for at least some candidate embodiments, while still leaving room for design-around through residue changes or chemistry shifts.

Strength drivers

1. Defined core peptide with many tolerated substitutions
   • Broad capture of analog series that retain the spine but vary select polar/basic residues.
2. Broad R⁵ moiety definition coupled to functional attachment options at X14/X40
   • Competitors modifying lipophilicity can still fall within claim 1 unless they break the allowed attachment modes or residue identity constraints.
3. SEQ ID anchor claims
   • If the accused compound maps to a disclosed sequence, the claim set becomes easier to apply.

Weakness/attack surface

• The claim is extremely broad and combinatorial. That can be vulnerable to validity attacks, especially where claim coverage depends on functional or generic selection rules rather than discrete exemplification.
• Solubility dependent claims (19/24/25) can be attacked on factual grounds if solubility measurements for the accused form do not meet thresholds, or if the accused product’s form differs (salt/solvate/formulation).

(Actual enforceability, prior art mapping, and prosecution history determinations require file history and cited references; those are not provided in the prompt.)

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Which SEQ ID ranges are covered, and why they matter for “generic entry” risk?

Short answer: The patent expressly covers compounds that match disclosed sequences across extensive SEQ ID ranges, so any product using an in-spec disclosed peptide sequence has higher infringement risk than an analog that is only “conceptually similar.”

• Claim 17: “any one of SEQ ID NO. 4–181”
• Claim 18: “any one of SEQ ID NO. 4–181, 196–223, 226–229”

For launch planning:

• If your candidate is one of the anchored sequences, you do not need to evaluate full Markush alignment; you can directly compare structures to SEQ ID entries.
• If your candidate is a novel analog not in those SEQ IDs, you revert to full position-by-position and R¹/R²/R⁵ mapping.

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Key comparison: how dependent claim narrowing changes the “infringement math”

Short answer: The genus (claim 1) is permissive; dependent claims convert permissive options into constrained ones. That means a competitor can sometimes avoid assertion of specific dependent claims, while still being within claim 1.

Practical mapping

• Changing X14/X40 from Lys/Orn/Dab/Dap to a different side-chain identity could avoid dependent claims 2–3, 6–8, 10–16, 14–16, 26–28.
• But claim 1 still allows X14 to be “an amino acid residue having a side chain with a functionalized –NH₂ group” and X40 to be absent or similarly functionalized. If the competitor uses a different amino acid with a –NH₂ side-chain and functionalization that still fits the X14/X40 rules, claim 1 can remain implicated.
• Changing R⁵ chemistry away from the allowed attachment types in claim 1 may provide a cleaner carve-out than changing only the R⁵ carbon count within the 100-carbon cap.

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Key Takeaways

• US 9,365,632 claim 1 covers a broad genus of peptidic compounds defined by a fixed formula II core framework with enumerated substitutions plus constrained N- and C-terminal caps (R¹/R²).
• The patent’s most actionable infringement vectors are X14/X40 side-chain functionalization (–C(O)R⁵ / –C(O)O R⁵ / –C(O)NH R⁵ / –S(O)₂R⁵ / –R⁵) and the ability to tolerate many charged/polar residue swaps at internal positions.
• Dependent claims 2–16 meaningfully narrow key parameters for high-confidence infringement assessments, especially where R⁵ is constrained to specific lipophilic categories or explicitly enumerated structures.
• Claims 17–18 add litigation-friendly specificity by capturing compounds matching extensive SEQ ID NO ranges.
• Composition coverage extends beyond carriers into broad metabolic co-therapy lists and includes solubility thresholds at pH 4.5 and pH 7.4 that can be targeted for design-around depending on whether the limitation is met by the accused form.

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FAQs

1. Can a peptide analogue avoid US 9,365,632 by changing only internal residues not in the enumerated sets (X2/X15/X21/X28/etc.)?
   If the substitution falls outside every enumerated option at the changed position while maintaining the rest of formula (II), it can exit the position-specific constraints of claim 1.

2. Do modifications to lipophilicity (R⁵ chain length) automatically avoid infringement?
   Not if the modification stays within the claim 1 definition (up to 100 carbons; optional heteroatoms; allowed attachment types at X14/X40). Escape requires breaking enumerated constraints, not merely tuning hydrophobicity.

3. How do SEQ ID anchor claims change risk versus Markush-only analysis?
   Mapping to a listed SEQ ID makes infringement comparison structural and direct, reducing reliance on full position-by-position argumentation.

4. Does the “high solubility” limitation require reformulation or a different compound form?
   The claim text is tied to the “compound, salt or solvate,” but if the accused product relies on different salts/solvates or doesn’t meet the pH/temperature thresholds, solubility dependent claims can be harder to assert.

5. Can combination therapy claims expand infringement to products used with insulin or GLP-1 agents?
   Yes, the composition claims (Claims 20–23) can capture products where the accused compound is formulated with specified additional therapeutics.

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References

1. US Patent 9,365,632. Claims as provided in prompt (Claims 1–38).

Details for Patent 9,365,632

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	October 28, 1982		2033-10-09
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	December 29, 2015		2033-10-09
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	August 06, 1998		2033-10-09
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	March 31, 1994		2033-10-09