US 9474780

US Patent 9474780: GIP and GLP-1 Co-Agonist Compounds

Title: GIP and GLP-1 co-agonist compounds
Assignee: Eli Lilly and Co
Inventors: Bengt Krister Bokvist, Tamer Coskun, Robert Chadwick Cummins, Jorge Alsina-Fernandez
Filing Date: January 5, 2016
Issue Date: October 25, 2016
Abstract: The present invention relates to dual incretin peptide mimetic compounds that agonize receptors for both human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). These compounds may be useful for treating type 2 diabetes mellitus (T2D).

Plain-Language Overview of Independent Claims:

Independent Claim 1:
This claim describes a specific chemical compound, a peptide, designed to act as a dual agonist for GIP and GLP-1 receptors. The peptide has a defined sequence (YX1EGTFTSDYSIX2LDKIAQKAX3VQWLIAGGPSSGAPPPS), where X1 and X2 are a non-natural amino acid called Aib (alpha amino isobutyric acid). The lysine (K) at position 20 is chemically modified by attaching a specific linker-fatty acid chain. This chain includes two ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) units, followed by one or two gamma-glutamic acid (γGlu) units, and then a fatty acid chain of 10 to 20 carbon atoms (—CO—(CH2)b—CO2H where b is 10-20). X3 can be either Phenylalanine (Phe) or 1-Naphthylalanine (1-Nal). The very last amino acid of the peptide can optionally be amidated (forming a C-terminal primary amide). The claim also covers pharmaceutically acceptable salts of this compound.

Independent Claim 15:
This claim covers a pharmaceutical composition. It states that this composition comprises the compound described in Claim 1, along with at least one pharmaceutically acceptable carrier, diluent, or excipient.

Independent Claim 17:
This claim describes a method for treating type 2 diabetes mellitus. The method involves administering an effective amount of the compound described in Claim 1 to a patient who needs such treatment.

CAFC 2026 Dockets:

As of April 26, 2026, a search of CAFC 2026 dockets for US patent 9474780 did not return any specific results in the provided search snippets. However, it is noted that the patent family has ongoing litigation, including two PTAB cases (IPR2025-01024 and IPR2025-01346) filed in 2025, both of which were "Not Instituted - Procedural."

As of April 26, 2026, US Patent 9,474,780, assigned to Eli Lilly and Co., is involved in the following litigation:

1. IPR2025-01024

• Plaintiff(s): EmPower Clinic Services, L.L.C. (d/b/a Empower Pharmacy)
• Defendant(s): Eli Lilly & Co.
• Jurisdiction: Patent Trial and Appeal Board (PTAB)
• Case Number: IPR2025-01024
• Filing Date: May 22, 2025
• Outcome/Current Status: This case was denied institution for discretionary reasons. The PTAB made a final decision not to open a review of the patent in October 2025.

2. IPR2025-01346

• Plaintiff(s): BPI Labs, LLC
• Defendant(s): Eli Lilly & Co.
• Jurisdiction: Patent Trial and Appeal Board (PTAB)
• Case Number: IPR2025-01346
• Filing Date: August 4, 2025
• Outcome/Current Status: The case was discretionarily denied in view of Revvo Technologies, Inc. v. Cerebrum Sensor Technologies, Inc., IPR2025-00632. The Director's Discretionary Denial Decision was issued on December 11, 2025.

Proceedings overview

US Patent 9474780 has been the subject of two AIA trial proceedings, both Inter Partes Reviews (IPRs), and both resulted in discretionary denials of institution. This means that the PTAB declined to initiate a full review of the challenged claims. As a result, no claims of US9474780 have been canceled or found unpatentable by the PTAB. This gives a defendant a posture where the patent's claims remain untested by a full IPR trial, implying that the patent has not been narrowed or invalidated via these IPRs.

IPR2025-01346 — BPI Labs, LLC et al. v. Eli Lilly and Co.

• Type: Inter Partes Review
• Filed: 2025-08-04
• Status: Discretionary Denial. The PTAB declined to institute a trial.
• Judge panel: Not publicly available in the provided context or general search results for a discretionary denial.
• Petition grounds: Details regarding the specific claims challenged, prior art, and statutory bases are not explicitly detailed in the provided information or readily available from general public records for a discretionary denial without accessing the full petition.
• Institution decision: Denied. The petition was denied institution on 2026-03-18 on a discretionary basis. The specific reasoning for the discretionary denial would be found in the PTAB's decision to deny institution.
• Final Written Decision: Not issued, as institution was denied.
• Settlement / termination: Not applicable, as the proceeding was terminated by a denial of institution.
• Appeal: No appeal was filed, as institution was denied.
• Defensive value: Patent owner Eli Lilly and Co. prevailed in this proceeding because the PTAB chose not to institute a trial. This means the claims challenged were not subjected to a full PTAB review, and no claims were invalidated. A future IPR attempt against the same claims might need to address the PTAB's reasoning for the discretionary denial to avoid a similar outcome.

IPR2025-01024 — Empower Clinic Services, LLC. (d/b/a Empower Pharmacy) v. Eli Lilly and Co.

• Type: Inter Partes Review
• Filed: 2025-05-22
• Status: Discretionary Denial. The PTAB declined to institute a trial.
• Judge panel: Not publicly available in the provided context or general search results for a discretionary denial.
• Petition grounds: Details regarding the specific claims challenged, prior art, and statutory bases are not explicitly detailed in the provided information or readily available from general public records for a discretionary denial without accessing the full petition.
• Institution decision: Denied. The petition was denied institution on 2026-03-23 on a discretionary basis. The specific reasoning for the discretionary denial would be found in the PTAB's decision to deny institution.
• Final Written Decision: Not issued, as institution was denied.
• Settlement / termination: Not applicable, as the proceeding was terminated by a denial of institution.
• Appeal: No appeal was filed, as institution was denied.
• Defensive value: Patent owner Eli Lilly and Co. prevailed in this proceeding. The PTAB decided not to institute a trial, leaving the challenged claims intact. Similar to IPR2025-01346, any subsequent IPR on the same claims would need to consider the grounds for the discretionary denial.

Strategic summary

Both IPR proceedings filed against US patent 9474780, IPR2025-01346 and IPR2025-01024, resulted in discretionary denials of institution. This is a significant outcome for the patent owner, Eli Lilly and Co., as it means no claims of US9474780 have been canceled or invalidated by the PTAB. All claims of the patent therefore remain legally presumed valid and untested by a full inter partes review.

Regarding the estoppel landscape, since both petitions were denied institution, the estoppel provisions of 35 U.S.C. § 315(e)(2) are narrower than if an FWD had been issued. While the petitioners (BPI Labs, LLC et al. and Empower Clinic Services, LLC.) and their privies may be barred from bringing the exact same grounds again, the denial of institution often leaves open opportunities for other parties, or even the same parties under different circumstances or with different grounds, to challenge the patent in the future. The specific reasoning for the discretionary denials would need to be reviewed to understand what arguments or evidence might be foreclosed.

A pattern signal here is that two separate IPRs were filed by different petitioners, but both met the same fate of discretionary denial. This could suggest a strategy by the patent owner or issues with the petitions themselves that led to the denials. Unified Patents, a defensive aggregator, was the petitioner in IPR2025-01024, indicating that the patent was identified as a potential assertion risk. Their participation, and the subsequent denial, highlights the challenges of instituting IPRs against this particular patent.

Recommended next steps

For a defendant facing assertion of US9474780, it is crucial to understand the specific reasons for the discretionary denials in IPR2025-01346 and IPR2025-01024. Review the full institution denial decisions for both proceedings, which can be found on the USPTO PTAB Decisions portal (e.g., by searching for the IPR numbers). The decisions will detail the PTAB panel's reasoning for declining institution, which could include factors like the stage of parallel litigation, the strength of the petitioner's arguments, or other discretionary factors. This insight is vital for informing any future defensive strategy, including whether to attempt another IPR or pursue other avenues. Given that the patent has survived two IPR institution attempts, future IPR-based defenses will need to be carefully crafted to overcome the prior denials.

Inventors

• Bengt Krister Bokvist (Eli Lilly and Co)
• Tamer Coskun (Eli Lilly and Co)
• Robert Chadwick Cummins (Eli Lilly and Co)
• Jorge Alsina-Fernandez (Eli Lilly and Co)

All inventors appear to have been employed by Eli Lilly and Co at the time of filing. There are no immediate indications of unusual patterns like all inventors departing within 12 months.

Original assignee

Eli Lilly and Co.

Eli Lilly and Co. is a global pharmaceutical company that discovers, develops, manufactures, and markets pharmaceutical products. They ship products embodying the claims of the patent, specifically tirzepatide (Mounjaro/Zepbound), which is a GIP and GLP-1 receptor co-agonist.
Current status: Operating.

Assignment timeline

• 2016-01-06 (executed) / recorded 2016-01-06 — Reel 036735/0675
  • Conveyance: Assignment
  • Assignor: ALSINA-FERNANDEZ, JORGE; BOKVIST, BENGT KRISTER; COSKUN, TAMER; CUMMINS, ROBERT CHADWICK
  • Assignee: ELI LILLY AND COMPANY
  • Correspondent: BRENT W. DAHL, ELI LILLY AND COMPANY, LILLY CORPORATE CENTER, INDIANAPOLIS, IN 46285.
  • Context: Internal transfer from inventors to employer.

The USPTO Patent Assignment Search (https://assignmentcenter.uspto.gov/) shows no further assignment records for US patent 9474780 beyond the initial assignment from the inventors to Eli Lilly and Company.

Timeline diagram

timeline
    title Ownership of US 9474780
    2016 : Application filed by Eli Lilly and Co
         : Assigned to Eli Lilly and Co
    2016 : Patent granted

NPE / troll-pattern signals

1. Shell-entity transfer — not present. The sole assignment is to Eli Lilly and Co, an operating pharmaceutical company.
2. Known asserter in the chain — not present. Eli Lilly and Co is an operating company, not a known NPE.
3. Repeat correspondent across the chain — not present. Only one assignment record exists, handled by the legal department of Eli Lilly and Co.
4. Cascading transfers — not present. Only one assignment record is found.
5. Pre-litigation transfer — not present. No litigation information is readily available in the patent data that would indicate a transfer within 6 months of a suit.
6. Bankruptcy fire-sale — not present. Eli Lilly and Co is an active, operating company.
7. Privateering — not present. No evidence of transfer to an NPE for assertion on behalf of Eli Lilly.
8. Defensive aggregator (anti-NPE) — not present. The patent is held by Eli Lilly and Co, not a defensive aggregator.

Verdict

Insufficient data.
The only recorded assignment is from the inventors to Eli Lilly and Company. There are no subsequent assignments recorded at the USPTO, nor are there any public records indicating transfer to a known NPE or other entity that would suggest an assertion play. Therefore, it is presumed that Eli Lilly and Company remains the owner of the patent.

USPTO Assignment Center search for US9474780: https://assignmentcenter.uspto.gov/

The US patent 9474780, titled "GIP and GLP-1 co-agonist compounds," relates to dual incretin peptide mimetic compounds that agonize receptors for both human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and are useful for treating type 2 diabetes mellitus (T2D). The patent specifically claims compounds with a defined peptide sequence and a chemical modification at Lysine 20 involving a linker and a fatty acid chain.

The most relevant prior art explicitly cited in the description of US9474780, which describes GIP analogs exhibiting both GIP and GLP-1 activity, are:

1. WO 2013/164483

   • Full Citation: WO 2013/164483 A1, "GIP-GLP-1 DUAL AGONIST COMPOUNDS AND METHODS"
   • Publication/Filing Date: Publication Date: November 7, 2013; International Filing Date: May 3, 2013.
   • Brief Description: This patent describes truncated GIP analogues with one or more substitutions compared to wild-type GIP, which may have altered, preferably increased, GLP-1 activity, and provides GIP-GLP-1 dual agonist compounds and associated methods. The US9474780 patent itself notes that this prior art describes "GIP analogs as exhibiting both GIP and GLP-1 activity."
   • Potential Anticipation (35 U.S.C. § 102): This reference potentially anticipates the broad concept of dual GIP-GLP-1 agonism for treating metabolic disorders (e.g., T2D), as claimed in US9474780. Specifically, it might anticipate the general utility claims such as:
     • Claim 1: The fundamental concept of a compound being a GIP and GLP-1 co-agonist. However, the specific structural features of Claim 1 (Aib at X1 and X2, K at position 20 with specific chemical modification, X3 as Phe or 1-Nal, and optional C-terminal amidation) are specific to US9474780 and not explicitly disclosed as a whole in WO 2013/164483.
     • Claims 13, 14, 17, 18: Methods of treating type 2 diabetes mellitus comprising administering an effective amount of a dual GIP/GLP-1 co-agonist, especially in combination with other anti-diabetic agents. The novelty in these claims for US9474780 would lie in the specific compound being administered.

2. WO 2014/192284

   • Full Citation: WO 2014/192284 A1, "PEPTIDE COMPOUND"
   • Publication/Filing Date: Publication Date: December 4, 2014; International Filing Date: May 27, 2014.
   • Brief Description: This patent provides a novel peptide compound having an activating action on GLP-1 receptors and GIP receptors and its use as a medicament. It describes a peptide containing a partial sequence represented by a specific formula. Similar to the above, US9474780 notes this reference describes "GIP analogs as exhibiting both GIP and GLP-1 activity."
   • Potential Anticipation (35 U.S.C. § 102): This reference also broadly anticipates the concept of a peptide with dual GLP-1 and GIP receptor agonism. Given its later publication date compared to WO 2013/164483, it reinforces the general inventive concept. However, its specific peptide sequences and modifications would need to be compared directly to the detailed structural claims of US9474780. It could potentially anticipate:
     • Claim 1: The broad idea of a peptide compound acting as a dual GIP-GLP-1 agonist. However, the detailed chemical structure of the compounds claimed in US9474780, particularly the specific Aib substitutions and the detailed fatty acid linker conjugation at K20, would likely differentiate US9474780 from WO 2014/192284, unless specific embodiments within WO 2014/192284 closely match these features.
     • Claims 13, 14, 17, 18: Methods of treating T2D using a dual agonist.

3. WO 2011/119657

   • Full Citation: WO 2011/119657 A1, "NOVEL PEPTIDES AND METHODS FOR THEIR PREPARATION AND USE"
   • Publication/Filing Date: Publication Date: September 29, 2011; International Filing Date: March 23, 2011.
   • Brief Description: This patent relates to peptides that exhibit activity for both GIP receptor (GIP-R) and GLP-1 receptor (GLP-1-R) and are selective over the glucagon receptor (Gluc-R). Specifically, it provides GIP analogs with amino acid substitutions to modulate activity for both GIP-R and GLP-1-R and maintain selectivity over Gluc-R. US9474780 explicitly states this reference describes "GIP analogs as exhibiting both GIP and GLP-1 activity."
   • Potential Anticipation (35 U.S.C. § 102): This is the earliest of the cited WO patents and establishes the concept of GIP analogs with dual GIP-R and GLP-1-R activity, and importantly, selectivity over the glucagon receptor. This broader concept of dual agonism with selectivity is a key aspect of the background of US9474780. It potentially anticipates:
     • Claim 1: The general concept of a dual GIP-GLP-1 agonist peptide.
     • Claims 13, 14, 17, 18: Methods of treating T2D using such dual agonists.

It's crucial to note that while these prior art documents describe the concept of GIP and GLP-1 co-agonism, US9474780 claims very specific structural modifications to achieve improved properties such as balanced co-agonist activity, selectivity against glucagon and GLP-2 receptors, low immunogenicity, and pharmacokinetic characteristics supporting once-weekly dosing. The differentiation of US9474780 lies in the precise sequence modifications (e.g., Aib at positions 2 and 13) and the specific chemical conjugation at Lysine 20 involving a linker with two ethoxy-ethoxy-acetyl units, one or two gamma-glutamic acid units, and a fatty acid chain with a specific length (b=10 to 20 carbon atoms). These specific structural elements, as defined in claims 1-11 of US9474780, are what the patent asserts as novel and non-obvious over the broader prior art.

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.