Obviousness

US patent 9474780, titled "GIP and GLP-1 co-agonist compounds," claims dual incretin peptide mimetic compounds for treating type 2 diabetes mellitus (T2D). The patent specifically describes compounds of Formula I, which is a peptide sequence (based on SEQ ID NO: 11) with specific modifications:

• X1 is Aib (alpha amino isobutyric acid).
• X2 is Aib.
• K (Lysine) at position 20 is chemically modified through conjugation to its epsilon-amino group with a linker-fatty acid structure: ([2-(2-Amino-ethoxy)-ethoxy]-acetyl)₂-(γGlu)a-CO—(CH₂)b—CO₂H, where 'a' is 1 to 2 and 'b' is 10 to 20.
• X3 is Phe (Phenylalanine) or 1-Nal (1-Naphthylalanine).
• The C-terminal amino acid is optionally amidated as a C-terminal primary amide.

Obviousness Analysis under 35 U.S.C. § 103

To establish obviousness, it must be shown that the claimed invention, as a whole, would have been obvious to a person having ordinary skill in the art (POSITA) at the time of the invention, based on prior art references and a motivation to combine or modify them with a reasonable expectation of success.

1. Primary Prior Art - Known GIP and GLP-1 Co-agonists:
The patent itself explicitly states that "Certain GIP analogs have been described as exhibiting both GIP and GLP-1 activity in WO 2013/164483, WO 2014/192284, and WO 2011/119657." This is a crucial admission, as it establishes that the core concept of a dual GIP/GLP-1 co-agonist was known in the art prior to the present invention. For the purpose of this analysis, any of these references, for instance, WO 2011/119657, could serve as a primary reference disclosing a GIP/GLP-1 co-agonist.

2. Motivation to Modify Known Co-agonists:
A POSITA in the field of peptide therapeutics for T2D would have been highly motivated to improve upon existing GIP/GLP-1 co-agonists to overcome known limitations of native incretin hormones and enhance their therapeutic utility. The present patent itself outlines these needs:

• Rapid Inactivation: Native GIP and GLP-1 are rapidly inactivated by the ubiquitous protease, dipeptidyl peptidase IV (DPP-IV). This necessitates modifications to improve proteolytic stability.
• Short Half-Life: To achieve patient convenience and compliance, there is a need for compounds that support less frequent dosing, such as once-weekly administration. This requires extending the pharmacokinetic (PK) half-life.
• Tolerability and Immunogenicity: Dosing of GLP-1 analogues can be limited by adverse effects like nausea and vomiting, and non-natural amino acids can increase the likelihood of undesirable immune reactions. A POSITA would seek to minimize these issues.
• Balanced Activity and Selectivity: There is a need for compounds with balanced GIP and GLP-1 activity and selectivity against related glucagon and GLP-2 receptors to maximize glucose lowering and reduce potential long-term carcinogenic risks.

3. Obvious Combinations and Modifications:

Given the aforementioned motivations, a POSITA would have routinely employed established peptide modification strategies to improve a known GIP/GLP-1 co-agonist (e.g., from WO 2011/119657):

• Incorporation of Aib for Proteolytic Stability:

  • The patent acknowledges, "The introduction of non-natural amino acids in a sequence can increase the proteolytic stability of any given peptide." Aib (alpha-aminoisobutyric acid) is a well-known non-natural amino acid that, when substituted at the N-terminus (e.g., position 2, as for X1) or other susceptible positions, confers resistance to DPP-IV degradation. Therefore, a POSITA would be motivated to substitute Aib at positions X1 (position 2) and X2 (position 13) in the peptide backbone of a GIP/GLP-1 co-agonist from WO 2011/119657 to enhance its stability against proteolytic enzymes.

• Fatty Acid Conjugation for Extended Half-Life:

  • The patent explicitly states, "Fatty acids, through their albumin binding motifs, can improve the pharmacokinetics of a peptide by extending the half-life, for example." Conjugating a fatty acid to a peptide via a linker is a widely recognized and practiced method to promote albumin binding, thereby prolonging systemic exposure and enabling less frequent dosing regimens (e.g., once-weekly).
  • Lysine (K) residues are common and convenient sites for side-chain conjugation. A POSITA would be motivated to introduce or utilize a Lysine at an appropriate position (such as position 20 as claimed) in the co-agonist peptide and conjugate a fatty acid chain to it.
  • Linker Design and Fatty Acid Chain Length: The linker described (comprising two [2-(2-Amino-ethoxy)-ethoxy]-acetyl units and one or two γGlu units) represents commonly used motifs in peptide drug development. Polyethylene glycol (PEG)-like components (e.g., the ethoxy-ethoxy acetyl moieties) are known for increasing solubility, flexibility, and reducing immunogenicity, while gamma-glutamic acid is frequently incorporated as a spacer and for its potential contribution to albumin binding. Varying the length of the fatty acid alkyl chain (parameter 'b' from 10 to 20, or optimizing to 16-18 as shown in the examples) is a routine optimization step to fine-tune albumin binding affinity, half-life, and overall pharmacokinetic profile.

• Amino Acid Substitution for Optimization (X3 is Phe or 1-Nal) and C-terminal Amidation:

  • Substituting amino acids at specific positions, such as Phe or 1-Nal (a naphthylalanine derivative, which is a known aromatic amino acid mimetic) at position X3 (position 22), is a standard approach in medicinal chemistry to optimize receptor binding affinity, selectivity, or other pharmacological properties of a peptide.
  • C-terminal amidation is also a common modification in peptide synthesis, often explored to improve proteolytic stability or modulate receptor interactions.

4. Conclusion:

A person having ordinary skill in the art, motivated by the known limitations of existing GIP/GLP-1 co-agonists (as implicitly acknowledged by the patent's objectives) and armed with conventional knowledge and techniques in peptide drug development, would have had a clear rationale to combine:

1. A known GIP/GLP-1 co-agonist peptide backbone (e.g., from WO 2011/119657).
2. The substitution of Aib at positions like 2 and 13 to enhance DPP-IV stability.
3. The conjugation of a fatty acid chain (e.g., a C10-C20 fatty acid, optimized to C16 or C18) to a Lysine residue (e.g., at position 20) via a known linker system (e.g., involving PEG-like moieties and gamma-glutamic acid) to extend the pharmacokinetic half-life for once-weekly dosing.
4. Further routine optimizations, such as the choice between Phe and 1-Nal at position 22 and C-terminal amidation, to fine-tune the compound's overall profile.

While the patent claims "unexpected effects" regarding the balance of agonist activity, immunogenicity, and specific PK characteristics, the fundamental motivation to make these types of modifications to a known GIP/GLP-1 co-agonist for T2D treatment, with a reasonable expectation of achieving improved stability and half-life, renders the claimed compounds prima facie obvious under 35 U.S.C. § 103. Any alleged unexpected results or synergistic effects would be considered secondary considerations of non-obviousness, to be weighed against the strong prima facie case.