The GLP-1 story did not stop at one receptor, and US10981967B2 - "Long-acting conjugate of triple glucagon/GLP-1/GIP receptor agonist," issued April 20, 2021 to Hanmi Pharm. Co., Ltd. - shows where the science was heading two years before tirzepatide's dominance made multi-receptor agonism a household idea.

There are two inventive limitations braided together, and claim 1 sets them out in a single chemical formula, X-La-F. X is a peptide having activities to a glucagon receptor, a GLP-1 receptor, and a GIP receptor - one molecule hitting all three targets, a step beyond the dual GIP/GLP-1 mechanism. F is an immunoglobulin Fc region. L is a polyethylene glycol linker, with the subscript fixed at a=1, that covalently joins X and F. The peptide X is itself defined by a long position-by-position formula (Xaa1 is His, 4-imidazoacetyl, or Tyr; Xaa2 is Aib or alpha-methyl-glutamic acid; and so on across the chain), and claim 1 adds a functional floor: the peptide must show at least 1% of native activity at the relevant receptors. So the claim couples receptor breadth (the triple-agonist peptide) to half-life extension (the PEG-linked Fc) in one defined construct.

"A long-acting conjugate of a triple agonist which has activities to all of glucagon, GLP-1, and GIP receptors and uses thereof."- U.S. Patent No. 10,981,967 source

The half-life-extension half of the invention is the disclosed mechanism worth dwelling on. By tethering the agonist peptide to an immunoglobulin Fc through a PEG linker, the construct borrows the Fc's neonatal-Fc-receptor (FcRn) recycling to slow clearance - the same long-acting strategy behind Hanmi's LAPSCOVERY platform. Claim 9 specifies that F is a dimeric Fc with one peptide X linked per dimer; the broader independent claims 13 and 17 generalize F to "a material capable of increasing the half-life of the peptide" and enumerate alternatives (albumin, fatty acid, transferrin, other polymers in claims 23-26), while claim 1 itself stays narrow on the Fc-plus-PEG form. The R1 element in the peptide formula (which can be the sequence GKKNDWKHNIT, SEQ ID NO: 106) is the kind of specific sequence disclosure that anchors the claim to a defined molecule.

Why does the conjugation carry weight equal to the pharmacology? Because in the metabolic-peptide market, dosing frequency is a commercial battleground. A triple-agonist that must be injected daily is a different product from one dosed weekly, and the long-acting conjugate is what converts the former into the latter. The CPC tags make the dual nature explicit: C07K 14/605 (glucagon-family peptides) for the agonist, A61K 47/60 (polymer-conjugated actives) for the half-life extension.

The genus-versus-species framing is instructive. The genus is incretin-receptor agonism; the species this claim stakes is the specific triple-agonist-peptide-plus-PEGylated-Fc construct, with the peptide constrained by the position-by-position formula and the 1%-activity floor. A challenger would probe whether the triple-receptor combination was obvious over known dual agonists, and whether the PEG-Fc conjugation was conventional - which is why the specification's disclosure of the specific construct and its activity data matters to validity, and why the claim's defensive strength lies in the defined peptide formula rather than in the "triple agonist" concept alone.

The position-by-position peptide formula in claim 1 is the structural core, and it is worth appreciating how it both defines and constrains the invention. Rather than claiming "a triple agonist," the patentee specifies the peptide as a defined sequence with variable residues enumerated at each position (Xaa1 is His, 4-imidazoacetyl, or Tyr; Xaa2 is Aib or alpha-methyl-glutamic acid; Xaa15 is Cys, Asp, Glu, or Leu; and so on). The Aib or alpha-methyl-glutamic acid at position 2 is a familiar design choice - a non-natural residue that resists DPP-4 cleavage - and its presence in the formula shows the claim is anchored to engineered, protease-stabilized peptides rather than native hormone sequences. The R1 tail, which may be the sequence GKKNDWKHNIT (SEQ ID NO: 106) per claim 2, further pins the molecule down.

The activity floor is a second constraint that does real work. Claim 1 requires that the isolated peptide X show at least 1% of native activity at the relevant receptors, and claims 38-41 break that requirement into combinations - at least 1% versus native glucagon and native GLP-1, or versus glucagon and GIP, or at all three. That functional limitation means infringement is not purely a sequence question: an accused peptide must both fall within the formula and meet the cross-receptor activity threshold. It is the patentee's way of ensuring the claim reaches genuine triple agonists, not inert sequences that merely match the formula on paper.

The conjugation claims show the half-life strategy as a graded structure. Claim 1 fixes the long-acting moiety narrowly as a PEG-linked immunoglobulin Fc with one peptide per dimer (claim 9), while the parallel independent claims 13 and 17 broaden F to "a material capable of increasing the half-life of the peptide" and enumerate alternatives - albumin, fatty acid, transferrin, fibronectin, elastin, and a roster of polymers (claims 23-26, 30-33). So the patent family is layered: a tight Fc-plus-PEG species at its center and broader half-life-extension genera around it. For a teardown, that layering is the strategic signature - the central claim is defensible because it is specific, and the surrounding claims try to capture the wider design space of long-acting incretin conjugates.

For the landscape, this grant is a marker that the metabolic-peptide estate was already racing past single- and dual-agonism by 2021. The claim-construction question for any later triple-agonist program is whether its peptide-plus-conjugate construct reads on prior species like this one - a reminder that the GLP-1 IP map was never only about the two best-known incumbents, and that the half-life-extension chemistry is as much a part of the claimed invention as the receptor pharmacology.