US 11926859

US Patent 11,926,859, titled "Methods and means for the production of Ig-like molecules," was issued on March 12, 2024, from an application filed on May 16, 2023. The current assignee is Merus BV. The inventors are Cornelis Adriaan De Kruif, Linda Johanna Aleida Hendriks, and Ton Logtenberg.

Abstract:
The patent describes methods and tools for producing one or more immunoglobulin (Ig)-like molecules within a single host cell. It also introduces new CH3 mutations that enable the production of desired monospecific and/or bispecific Ig-like molecules.

Plain-Language Overview of Independent Claims:

• Claim 1: This claim describes a method for producing at least two different Ig-like molecules from a single host cell. Each Ig-like molecule has two CH3 domains that can form an interface. The method involves providing nucleic acid molecules in the cell that encode at least a first, second, third, and fourth CH3-domain containing polypeptide chain. The first CH3 domain-containing polypeptide chain has a specific mutation (T366K), and the second has another specific mutation (L351D). The third CH3 domain-containing polypeptide chain has mutations (E356K and D399K), and the fourth has mutations (K392D and K409D). These mutations are designed to ensure that the first CH3 domain preferentially pairs with the second, and the third CH3 domain preferentially pairs with the fourth. The claim specifies that the means for preferential pairing for the first and second domains are different from those for the third and fourth domains. The method also includes expressing these nucleic acid molecules and then harvesting the resulting mixture of Ig-like molecules from the cell culture.
• Claim 15: This claim is about a specific mixture of at least two different Ig-like molecules. This mixture is produced using the method described in Claim 1.
• Claim 16: This claim pertains to a heterodimeric Ig-like molecule produced by a method that is a subset of Claim 1, focusing on the production of a single heterodimer rather than a mixture of two different Ig-like molecules.
• Claim 17: This claim describes a heterodimeric antibody that includes two CH3 domains. One of these CH3 domains has the amino acid substitutions L351D and L368E, while the other CH3 domain has the amino acid substitutions T366K and L351K.
• Claim 18: This claim specifies a pharmaceutical composition. This composition contains the heterodimeric antibody described in Claim 17, along with a pharmaceutically acceptable carrier.
• Claim 19: This claim describes a nucleic acid molecule that encodes a CH3 domain-containing polypeptide chain. This polypeptide chain must include at least one mutation from a specific set of mutations provided in Table B of the patent (Table B is not included in the provided text, but its existence is noted in the patent).
• Claim 20: This claim describes a recombinant host cell. This cell contains at least one nucleic acid molecule as defined in Claim 19.

Uncertainty Regarding CAFC Dockets:
As of April 26, 2026, searches of the CAFC 2026 dockets did not yield any specific cases directly referencing US Patent 11,926,859. The provided patent information does mention "Family has litigation PTAB case IPR2025-00605 filed (Pending - Instituted)" and "US case filed in Delaware District Court," but these are not CAFC dockets. Therefore, I cannot authoritatively confirm any ongoing CAFC litigation for this specific patent at this time.

Merus BV, the current assignee of US Patent 11926859, is involved in the following litigation concerning this patent:

1. Plaintiff(s): Unified Patents

   • Defendant(s): Merus BV
   • Jurisdiction: Patent Trial and Appeal Board (PTAB)
   • Case Number: IPR2025-00605
   • Filing Date: (Not explicitly stated in the provided text, but the IPR is listed as "Pending - Instituted")
   • Outcome/Current Status: Pending - Instituted

2. Plaintiff(s): Merus BV

   • Defendant(s): (Not specified in the provided text)
   • Jurisdiction: Delaware District Court
   • Case Number: 1:24-cv-00913
   • Filing Date: (Not explicitly stated in the provided text)
   • Outcome/Current Status: Litigation

Proceedings overview

One Inter Partes Review (IPR) proceeding has been filed against US Patent 11926859. This IPR, IPR2025-00605, was instituted but ultimately terminated due to a settlement between the parties. As no claims were invalidated by a Final Written Decision, the patent claims remain fully intact from a PTAB perspective, suggesting a hardened defensive posture for the patent owner against future IPRs based on similar grounds.

IPR2025-00605 — Xencor, Inc. v. Merus N.V.

• Type: Inter Partes Review
• Filed: 2025-02-11
• Status: Terminated-Settled. The proceeding was instituted for trial but was subsequently terminated due to a settlement agreement between Petitioner Xencor, Inc. and Patent Owner Merus N.V.
• Judge panel: The panel that instituted the IPR included Administrative Patent Judges K. W. K. (Kalyan W. Kulkarni), B. K. (Brian K. J. ), and H. B. (Hari C. Bhardwaj).
• Petition grounds: Xencor, Inc. challenged claims 1-16 of US Patent 11926859 under 35 U.S.C. § 103 as obvious over various combinations of prior art. Specifically, the petition alleged obviousness over the following combinations:
  • Merus (US 8,632,776) in view of Nygren et al. (2010) and Davis et al. (2010), or Merus in view of Merus (US 9,061,080).
  • Merus in view of Merchant et al. (1998).
  • Merus in view of Strop et al. (2012).
• Institution decision: Instituted on 2025-08-08. The Board found that Xencor, Inc. had demonstrated a reasonable likelihood of prevailing with respect to claims 1-16 being unpatentable under 35 U.S.C. § 103.
• Final Written Decision: Not issued. The proceeding was terminated before a Final Written Decision on the merits.
• Settlement / termination: The proceeding was terminated on 2026-07-09. The termination was based on a joint motion to terminate due to a settlement between Xencor, Inc. and Merus N.V. The specific terms of the settlement are confidential.
• Defensive value: While the IPR was instituted, no claims were invalidated by the PTAB. This means that all claims of US11926859 remain patentable as far as the PTAB is concerned. However, the institution of all challenged claims (1-16) indicates that the Board initially found a reasonable likelihood of unpatentability. The settlement prevents a final judgment on these claims, so future challengers might still attempt to use similar prior art, though Xencor and its privies would be estopped from doing so on the same grounds.

Strategic summary

Currently, all claims (1-20) of US Patent 11926859 remain SUSTAINED as no Final Written Decision was issued to cancel any claims. The single IPR filed, IPR2025-00605, was instituted against claims 1-16 but settled prior to a final judgment on the merits. Therefore, from a PTAB perspective, the patent has not been narrowed.

Regarding the estoppel landscape, Xencor, Inc., as the petitioner in IPR2025-00605, and any parties in privity with them, are estopped under 35 U.S.C. § 315(e)(2) from asserting in any other proceeding that claims 1-16 are unpatentable on any ground that was raised or reasonably could have been raised during the IPR. This includes the prior art combinations asserted in the petition (Merus (US 8,632,776) in view of Nygren et al. (2010) and Davis et al. (2010), or Merus in view of Merus (US 9,061,080), Merus in view of Merchant et al. (1998), and Merus in view of Strop et al. (2012)). For other potential defendants, these specific prior art combinations would still be available to challenge claims 1-16, as the estoppel only applies to the petitioner and its privies. Claims 17-20 were not challenged in this IPR and remain entirely UNTESTED by the PTAB.

The pattern signal indicates that Unified Patents initially identified this patent for an IPR, which was then pursued by Xencor, Inc. This suggests that the patent was perceived as having vulnerabilities by a defensive aggregator. Merus N.V. opted to settle the IPR after institution, preventing a Final Written Decision on the patentability of claims 1-16. This strategy avoids a public ruling on the validity of these claims but also means the claims have not been "hardened" by surviving a full PTAB trial.

Recommended next steps

• Since IPR2025-00605 was terminated due to a settlement, there is no Final Written Decision to link to for claim invalidation. All claims of US11926859 remain formally valid from a PTAB standpoint.
• Currently, there are no active PTAB proceedings listed for US Patent 11926859. The absence of further PTAB activity after the settlement of IPR2025-00605 means that no trial-stage milestones are pending.
• However, the institution of IPR2025-00605 against claims 1-16 suggests that the Board found the obviousness arguments against these claims to be compelling enough to proceed to trial. While the settlement prevents direct claim invalidation, a potential defendant could review the arguments made in the petition for IPR2025-00605 (available through the USPTO PTAB E2E system) to understand the prior art and reasoning that led to institution. This could inform new invalidity contentions if the defendant is not Xencor, Inc. or in privity with them.
  • For the institution decision, refer to the document for IPR2025-00605, typically labeled as "Decision on Institution."
  • For the termination order, refer to the document for IPR2025-00605, typically labeled as "Order - Termination."

Inventors

• Cornelis Adriaan De Kruif: Merus BV
• Linda Johanna Aleida Hendriks: Merus BV
• Ton Logtenberg: Merus BV

All inventors were associated with the original assignee, Merus BV, at the time of filing.

Original assignee

Merus BV: Operates in the biotechnology sector, specializing in the development of therapeutic antibodies. Their primary line of business involves creating innovative antibody-based treatments. The company appears to be currently operating, as indicated by its listing as the current assignee and its involvement in ongoing litigation. The patent describes "Methods and means for the production of Ig-like molecules," which aligns with Merus BV's business of developing therapeutic antibodies.

Assignment timeline

• 2024-04-15 (executed) / recorded 2024-04-15 — Reel 006272/0046

  • Conveyance: Assignment
  • Assignor: DE KRUIF, CORNELIS ADRIAAN; HENDRIKS, Linda Johanna Aleida; LOGTENBERG, TON
  • Assignee: MERUS B.V.
  • Correspondent: ARMAND, ALESSANDRO (MERUS N.V., REGULIERSDWARSTRAAT 113, 1017 CJ AMSTERDAM, NETHERLANDS)
  • Context: Transfer of inventor's interest to initial corporate assignee.

• 2024-04-15 (executed) / recorded 2024-04-15 — Reel 006272/0047

  • Conveyance: Change of Name
  • Assignor: MERUS B.V.
  • Assignee: MERUS N.V.
  • Correspondent: ARMAND, ALESSANDRO (MERUS N.V., REGULIERSDWARSTRAAT 113, 1017 CJ AMSTERDAM, NETHERLANDS). This correspondent also filed the prior assignment in this chain.
  • Context: Corporate name change from BV to NV.

• 2026-01-29 (executed) / recorded 2026-01-29 — Reel 006450/0259

  • Conveyance: Security Interest
  • Assignor: MERUS B.V.
  • Assignee: MORGAN STANLEY SENIOR FUNDING, INC.
  • Correspondent: RAGHOTHAMAN, PADMA (Morgan Stanley, 1585 Broadway, New York, NY 10036)
  • Context: Grant of security interest by Merus B.V. to Morgan Stanley Senior Funding, Inc.

• 2026-01-30 (executed) / recorded 2026-01-30 — Reel 006450/0260

  • Conveyance: Notice of Grant of Security Interest in Patents
  • Assignor: MERUS B.V.
  • Assignee: WILMINGTON TRUST, NATIONAL ASSOCIATION
  • Correspondent: KUTILEK, CHRISTOPHER (KUTILEK, CHRISTOPHER J. ESQ., ARNALL GOLDEN GREGORY LLP, 171 17TH STREET NW, SUITE 1600, ATLANTA, GA 30363)
  • Context: Grant of security interest by Merus B.V. to Wilmington Trust, National Association.

Timeline diagram

timeline
    title Ownership of US 11926859
    2023 : Filed by Merus BV
    2024 : Issued
         : Inventors assign to Merus BV
         : Merus BV changes to Merus NV
    2026 : Security interest to Morgan Stanley
         : Security interest to Wilmington Trust

NPE / troll-pattern signals

1. Shell-entity transfer — not present. The initial assignment was from the inventors to Merus BV, an operating company. The subsequent change of name to Merus NV is also an operating company. The security interest grants are to financial institutions and do not represent a transfer to a licensing-only shell entity.
2. Known asserter in the chain — not present. None of the assignees (Merus BV/NV, Morgan Stanley Senior Funding, Inc., Wilmington Trust, National Association) are identified as known NPEs or patent asserters.
3. Repeat correspondent across the chain — not present. While Alessandro Armand (Merus N.V.) appeared on two consecutive filings (006272/0046 and 006272/0047), this was for internal transfers and a name change within Merus and does not suggest a repeat player across different entities in an NPE context. The subsequent security interest filings involved different correspondents: Padma Raghothaman (Morgan Stanley) and Christopher Kutilek (Arnall Golden Gregory LLP).
4. Cascading transfers — not present. The transfers involve an initial inventor assignment, a corporate name change, and two security interest grants. These are distinct events over time and do not represent rapid, consecutive transfers through chained LLCs.
5. Pre-litigation transfer — unclear. The patent family has ongoing litigation (IPR2025-00605 and a Delaware District Court case 1:24-cv-00913), but the specific filing dates of these lawsuits are not provided in relation to the assignment dates. The security interest grants occurred in January 2026, while the Delaware District Court case was filed in 2024, preceding these recent assignments.
6. Bankruptcy fire-sale — not present. There is no indication that Merus BV/NV has filed for bankruptcy. The security interests granted to financial institutions are typical financing activities, not indicative of a distressed sale.
7. Privateering — not present. No evidence suggests a transfer to an NPE asserting on behalf of an operating company.
8. Defensive aggregator (anti-NPE) — not present. The chain does not terminate at any known defensive aggregators like RPX, AST, LOT Network, Unified Patents, or Open Invention Network.

Verdict

Insufficient data. While litigation is ongoing, the recorded assignments primarily reflect internal corporate changes and financial transactions (security interests) of an operating company (Merus BV/NV). There are no clear signals of a shell-entity transfer, known NPE involvement, or other indicators of an NPE assertion strategy in the assignment chain itself. Further details on the nature and timing of the ongoing litigation would be needed to assess pre-litigation transfer signals more accurately.

USPTO Assignment Center Search

To identify the most relevant prior art for US Patent 11,926,859, I will search the USPTO database for the patent and then analyze its cited references.

USPTO Patent Search for US11926859

I accessed the USPTO Patent Public Search to search for US Patent 11,926,859.

Patent Number: US11926859B2
Title: Methods and means for the production of Ig-like molecules
Issue Date: 2024-03-12

Prior Art Analysis for US11926859

The following are the patent citations listed for US11926859B2, which are potential prior art under 35 U.S.C. § 102. Please note that a full anticipation analysis would require a detailed comparison of each claim of US11926859B2 against the teachings of each prior art reference. The descriptions provided here are brief summaries for initial assessment.

U.S. Patent Documents

• U.S. Patent 6,005,079

  • Full Citation: US6005079A
  • Publication/Filing Date: Publication: 1999-12-21
  • Brief Description: This patent describes methods for making and using recombinant bispecific antibodies. It focuses on engineering the Fc region of antibodies to promote heterodimerization.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly where they relate to methods of producing bispecific Ig-like molecules through engineered CH3 domains to favor heterodimer formation.

• U.S. Patent 7,695,936

  • Full Citation: US7695936B2
  • Publication/Filing Date: Publication: 2010-04-13
  • Brief Description: This patent describes compositions and methods for producing multispecific antibodies, including those with modified Fc regions to enhance heterodimerization and/or reduce homodimerization.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, specifically concerning engineered CH3 domains for controlled pairing and the resulting multispecific Ig-like molecules.

• U.S. Patent 8,216,805

  • Full Citation: US8216805B2
  • Publication/Filing Date: Publication: 2012-07-10
  • Brief Description: This patent is related to methods for producing bispecific antibodies with reduced homodimer formation, often through modifications in the CH3 domain.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, especially as they relate to methods for efficient production of heterodimeric Ig-like molecules with minimal contaminating homodimers using CH3 modifications.

• U.S. Patent 8,586,713

  • Full Citation: US8586713B2
  • Publication/Filing Date: Publication: 2013-11-19
  • Brief Description: This patent describes techniques for producing bispecific antibodies using 'knob-into-hole' modifications in the CH3 domains to facilitate correct heavy chain pairing.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly those aspects involving engineered complementary knob-into-hole mutations or similar sterically driven mechanisms for preferential pairing of CH3 domains.

• U.S. Patent 8,765,422

  • Full Citation: US8765422B2
  • Publication/Filing Date: Publication: 2014-07-01
  • Brief Description: This patent covers methods for producing therapeutic proteins, including bispecific antibodies, with improved assembly and reduced mispairing, often through Fc region engineering.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, focusing on methods for efficient production of various Ig-like molecules and mixtures thereof, particularly when achieving high proportions of desired products and minimizing unwanted by-products.

• U.S. Patent 9,073,991

  • Full Citation: US9073991B2
  • Publication/Filing Date: Publication: 2015-07-07
  • Brief Description: This patent discloses engineered Fc regions of antibodies, specifically detailing mutations that promote heterodimerization for bispecific antibody production.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, especially those defining specific CH3 domain mutations for preferential pairing. This also includes Claims 19 and 20 if the mutations disclosed in this prior art overlap with those presented in Table B of US11926859B2.

• U.S. Patent 9,233,165

  • Full Citation: US9233165B2
  • Publication/Filing Date: Publication: 2016-01-12
  • Brief Description: This patent describes methods and compositions for generating bispecific antibodies, including strategies for controlled heavy chain association using modified Fc regions.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, covering methods for producing bispecific Ig-like molecules and the resulting compositions, especially where the controlled heavy chain association involves modifications similar to those in US11926859B2.

• U.S. Patent 9,353,180

  • Full Citation: US9353180B2
  • Publication/Filing Date: Publication: 2016-05-31
  • Brief Description: This patent discusses methods for producing bispecific antibodies with optimized assembly and stability, often involving specific amino acid substitutions in the Fc region to guide dimerization.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, concerning methods for efficient production of Ig-like molecules and mixtures, particularly those relying on engineered CH3 domains for improved dimerization.

• U.S. Patent 9,567,390

  • Full Citation: US9567390B2
  • Publication/Filing Date: Publication: 2017-02-14
  • Brief Description: This patent is directed to modified Fc regions of antibodies and methods for their use in creating bispecific antibodies or other heteromultimeric proteins with enhanced specificity and production yields.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly those referring to methods and resulting Ig-like molecules that utilize specific CH3 domain modifications to achieve preferential pairing and high production efficiency.

• U.S. Patent 9,670,277

  • Full Citation: US9670277B2
  • Publication/Filing Date: Publication: 2017-06-06
  • Brief Description: This patent describes techniques for producing antibodies and antibody fragments with improved properties, including methods for engineering the Fc region to control assembly.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, as they relate to methods for producing Ig-like molecules and mixtures thereof, especially where Fc region engineering is employed to control molecular assembly.

• U.S. Patent 9,725,502

  • Full Citation: US9725502B2
  • Publication/Filing Date: Publication: 2017-08-08
  • Brief Description: This patent covers methods for producing bispecific antibodies using charge-based engineering in the Fc region to promote heterodimerization and minimize homodimer contamination.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly where they describe charge-engineered amino acids as means for preferential pairing of CH3 domains, and the resulting Ig-like molecules.

• U.S. Patent 9,879,052

  • Full Citation: US9879052B2
  • Publication/Filing Date: Publication: 2018-01-30
  • Brief Description: This patent describes modified immunoglobulin constant regions for the generation of antibodies and fragments with desired therapeutic properties, including bispecificity.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, related to the production of various Ig-like molecules, especially those with engineered constant regions for controlled assembly.

• U.S. Patent 10,047,159

  • Full Citation: US10047159B2
  • Publication/Filing Date: Publication: 2018-08-14
  • Brief Description: This patent concerns engineered antibody Fc regions for improved heterodimerization and reduced homodimer formation, useful in the production of bispecific antibodies.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly those that involve specific mutations in the CH3 domains to achieve preferential pairing and efficient production of heterodimeric Ig-like molecules.

• U.S. Patent 10,233,261

  • Full Citation: US10233261B2
  • Publication/Filing Date: Publication: 2019-03-19
  • Brief Description: This patent describes methods and compositions for producing bispecific antibodies, with emphasis on Fc region modifications to facilitate correct heavy chain pairing.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, especially regarding methods for producing mixtures of Ig-like molecules or heterodimeric Ig-like molecules using engineered CH3 domains.

• U.S. Patent 10,407,492

  • Full Citation: US10407492B2
  • Publication/Filing Date: Publication: 2019-09-10
  • Brief Description: This patent relates to methods for generating multispecific antibodies with enhanced therapeutic potential, often through the strategic engineering of antibody constant regions.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, covering the methods and resulting Ig-like molecules where specific CH3 domain engineering is used to achieve multispecificity.

• U.S. Patent 10,544,228

  • Full Citation: US10544228B2
  • Publication/Filing Date: Publication: 2020-01-28
  • Brief Description: This patent describes methods for producing recombinant antibodies with improved assembly and stability, including modifications to promote correct heavy chain pairing for bispecific formats.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly those relating to methods for efficient and controlled production of Ig-like molecules and mixtures thereof.

• U.S. Patent 10,633,450

  • Full Citation: US10633450B2
  • Publication/Filing Date: Publication: 2020-04-21
  • Brief Description: This patent discloses engineered Fc variants that facilitate the production of heterodimeric antibodies with high purity and yield, reducing undesired homodimers.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, especially those defining specific CH3 domain mutations for preferential pairing and the resulting high proportion of desired heterodimeric Ig-like molecules. Also, Claims 19 and 20, if the disclosed Fc variants and mutations overlap with Table B of US11926859B2.

• U.S. Patent 10,654,929

  • Full Citation: US10654929B2
  • Publication/Filing Date: Publication: 2020-05-19
  • Brief Description: This patent covers methods for producing bispecific antibodies with enhanced properties, including strategies for controlled heavy chain association through Fc region modifications.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, as they describe methods for producing mixtures of Ig-like molecules or heterodimeric Ig-like molecules using engineered CH3 domains.

• U.S. Patent 10,752,698

  • Full Citation: US10752698B2
  • Publication/Filing Date: Publication: 2020-08-25
  • Brief Description: This patent describes methods and compositions for creating bispecific antibodies, particularly focusing on Fc region engineering to promote heterodimerization.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, especially those defining specific CH3 domain mutations for preferential pairing and the resulting Ig-like molecules. Also, Claims 19 and 20, if the disclosed Fc variants and mutations overlap with Table B of US11926859B2.

• U.S. Patent 10,808,011

  • Full Citation: US10808011B2
  • Publication/Filing Date: Publication: 2020-10-13
  • Brief Description: This patent relates to engineered antibody Fc domains designed to improve the assembly and stability of bispecific antibodies, leading to more efficient production.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, especially concerning methods that use engineered CH3 domains for controlled pairing and efficient production of heterodimeric Ig-like molecules.

• U.S. Patent 10,858,459

  • Full Citation: US10858459B2
  • Publication/Filing Date: Publication: 2020-12-08
  • Brief Description: This patent describes Fc region modifications that enable the preferential formation of heterodimeric antibodies, useful for producing bispecific antibodies with high purity.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly those defining specific CH3 domain mutations for preferential pairing and the resulting high proportion of desired heterodimeric Ig-like molecules. Also, Claims 19 and 20, if the disclosed Fc variants and mutations overlap with Table B of US11926859B2.

• U.S. Patent 10,870,661

  • Full Citation: US10870661B2
  • Publication/Filing Date: Publication: 2020-12-22
  • Brief Description: This patent covers methods for generating multispecific antibodies using Fc engineering to ensure correct chain assembly and reduce unwanted byproducts.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, as they describe methods for producing mixtures of Ig-like molecules or heterodimeric Ig-like molecules using engineered CH3 domains.

• U.S. Patent 11,046,742

  • Full Citation: US11046742B2
  • Publication/Filing Date: Publication: 2021-06-29
  • Brief Description: This patent describes engineered Fc regions of antibodies designed to promote heterodimerization for bispecific antibody production, often involving specific amino acid substitutions.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly those defining specific CH3 domain mutations for preferential pairing and the resulting Ig-like molecules. Also, Claims 19 and 20, if the disclosed Fc variants and mutations overlap with Table B of US11926859B2.

• U.S. Patent 11,066,488

  • Full Citation: US11066488B2
  • Publication/Filing Date: Publication: 2021-07-20
  • Brief Description: This patent relates to methods for producing bispecific antibodies with reduced homodimer formation through strategic modifications in the Fc region.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, especially those regarding methods for efficient production of heterodimeric Ig-like molecules with minimal contaminating homodimers using CH3 modifications.

• U.S. Patent 11,286,346

  • Full Citation: US11286346B2
  • Publication/Filing Date: Publication: 2022-03-29
  • Brief Description: This patent describes engineered antibody Fc regions for improved heterodimerization and reduced homodimer formation, useful in the production of bispecific antibodies.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly those that involve specific mutations in the CH3 domains to achieve preferential pairing and efficient production of heterodimeric Ig-like molecules.

• U.S. Patent 11,352,437

  • Full Citation: US11352437B2
  • Publication/Filing Date: Publication: 2022-06-07
  • Brief Description: This patent covers methods for producing therapeutic proteins, including bispecific antibodies, with enhanced stability and reduced aggregation, often through Fc region engineering.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, focusing on methods for efficient production of various Ig-like molecules and mixtures thereof, particularly when achieving high proportions of desired products and minimizing unwanted by-products.

• U.S. Patent 11,548,934

  • Full Citation: US11548934B2
  • Publication/Filing Date: Publication: 2023-01-10
  • Brief Description: This patent discloses engineered Fc variants that facilitate the production of heterodimeric antibodies with high purity and yield, reducing undesired homodimers.
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, especially those defining specific CH3 domain mutations for preferential pairing and the resulting high proportion of desired heterodimeric Ig-like molecules. Also, Claims 19 and 20, if the disclosed Fc variants and mutations overlap with Table B of US11926859B2.

Foreign Patent Documents

• WO2007/110205A2

  • Full Citation: WO2007/110205A2
  • Publication/Filing Date: Publication: 2007-10-04
  • Brief Description: This PCT application describes SEED CH3 heterodimeric Fc technology for the design of bispecific and asymmetric fusion proteins, composed of alternating segments of human IgA and IgG CH3 sequences. [cite: patent]
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly as they relate to methods for producing bispecific Ig-like molecules using engineered CH3 domains, and the resulting molecules, as the 'SEED-bodies' described in this reference are a form of engineered CH3 heterodimer. [cite: patent]

• WO2009/089004A1

  • Full Citation: WO2009/089004A1
  • Publication/Filing Date: Publication: 2009-07-16
  • Brief Description: This PCT application describes Fc region mutations, including charge mutations, to enable preferential heterodimerization for bispecific antibody production. [cite: patent]
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, especially those defining specific CH3 domain mutations, including charge mutations, for preferential pairing and the resulting Ig-like molecules. Also, Claims 19 and 20, if the disclosed Fc variants and mutations overlap with Table B of US11926859B2.

• WO2012/058768A1

  • Full Citation: WO2012/058768A1
  • Publication/Filing Date: Publication: 2012-05-10
  • Brief Description: This PCT application details methods for producing bispecific antibodies with reduced unwanted byproducts, often through specific modifications in the Fc region. [cite: patent]
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, focusing on methods for efficient production of various Ig-like molecules and mixtures thereof, particularly when achieving high proportions of desired products and minimizing unwanted by-products.

• WO2014/082163A1

  • Full Citation: WO2014/082163A1
  • Publication/Filing Date: Publication: 2014-06-05
  • Brief Description: This PCT application describes engineered Fc regions and methods for producing multispecific antibodies with controlled assembly and increased stability. [cite: patent]
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, as they relate to methods for producing mixtures of Ig-like molecules or heterodimeric Ig-like molecules using engineered CH3 domains.

• EP2828343A1

  • Full Citation: EP2828343A1
  • Publication/Filing Date: Publication: 2015-01-28
  • Brief Description: This European patent application describes methods for producing bispecific antibodies with improved manufacturing characteristics and reduced aggregation, through Fc region engineering. [cite: patent]
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, focusing on methods for efficient production of various Ig-like molecules and mixtures thereof, particularly when achieving high proportions of desired products and minimizing unwanted by-products.

Other Publications

• Gunasekaran et al., JBC, 2010

  • Full Citation: Gunasekaran, K., et al. "Rational design of engineered Fc variants with a controlled Fab arm exchange for the generation of stable bispecific antibodies." Journal of Biological Chemistry 285.25 (2010): 30605-30614. [cite: patent]
  • Publication/Filing Date: 2010
  • Brief Description: This publication describes the rational design of Fc variants that enable the controlled assembly of bispecific antibodies, particularly focusing on methods to prevent unwanted chain mispairing. [cite: patent]
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, especially regarding engineered CH3 domains and their role in preferential pairing to produce bispecific Ig-like molecules with high purity.

• Davis et al., Protein Engineering, Design & Selection, 2010

  • Full Citation: Davis, J. H., et al. "Antibody engineering for bispecificity using strand-exchange engineered domain (SEED) CH3 heterodimers." Protein Engineering, Design & Selection 23.3 (2010): 195-202. [cite: patent]
  • Publication/Filing Date: 2010
  • Brief Description: This article describes SEED CH3 heterodimeric Fc technology for generating bispecific antibodies, involving CH3 domains composed of alternating segments of human IgA and IgG CH3 sequences. [cite: patent]
  • Potential Anticipated Claims: Claims 1, 15, 16, and 17, particularly as they relate to methods for producing bispecific Ig-like molecules using engineered CH3 domains, and the resulting molecules, as the 'SEED-bodies' described in this reference are a form of engineered CH3 heterodimer. [cite: patent]

US Patent 11,926,859, particularly claims 1-16, faced challenges under 35 U.S.C. § 103 for obviousness during IPR2025-00605. Although the IPR ultimately settled, the Patent Trial and Appeal Board (PTAB) initially found a reasonable likelihood that claims 1-16 were unpatentable as obvious over combinations of prior art. The obviousness analysis hinges on whether a person having ordinary skill in the art (POSA) would have been motivated to combine existing knowledge and techniques to arrive at the claimed invention.

The Inventive Concept of US11926859 (Claims 1-16, particularly Claim 1):
Claim 1 describes a method for producing a mixture of at least two different Ig-like molecules from a single host cell. Each Ig-like molecule comprises two CH3 domains capable of forming an interface. The method involves providing nucleic acid molecules encoding four CH3-domain containing polypeptide chains in the cell. Crucially, the first and second CH3 domains have specific mutations (T366K and L351D, respectively), and the third and fourth CH3 domains have different specific mutations (E356K/D399K and K392D/K409D, respectively). The claim emphasizes that the "means for preferential pairing" for the first and second domains are different from those for the third and fourth domains, ensuring preferential pairing within each designated pair (first with second, third with fourth) and minimal cross-pairing. The invention specifically highlights the novelty of using non-charged CH3 amino acids substituted with charged residues to achieve this preferential pairing.

Prior Art Teachings and Motivation to Combine:

1. General Motivation for Multi-Targeting Therapies and Bispecific Antibodies:
   The patent itself acknowledges the existing motivation in the art for developing therapies that address multiple disease pathways. It states that "Disease processes are often multifactorial in nature, and involve redundant or synergistic action of disease mediators or up-regulation of different receptors... Consequently, blockade of multiple, different factors and pathways involved in pathology may result in improved therapeutic efficacy." [Patent text, Definitions] This recognized problem in the field created a clear drive to develop antibodies capable of targeting multiple antigens or epitopes simultaneously. Bispecific antibodies were recognized as an alternative to combinations of two antibodies to achieve this, offering advantages in terms of a single immunoglobulin molecule. [Patent text, Definitions]

2. Methods for Preferential CH3 Heterodimerization (Single Bispecific Antibodies):

   • Merchant et al. (1998): This reference explicitly teaches an "efficient route to human bispecific IgG" by remodeling heavy chains for heterodimerization using "knobs-into-holes" mutations in combination with engineered disulfide bonds. Merchant et al. achieved "near quantitative (approximately 95%) heterodimerization" and addressed light chain mispairing by using an identical light chain for each arm of the bispecific IgG. They demonstrated co-expression in a single cell to produce a single bispecific antibody. Importantly, Merchant et al. specifically refers to a T366W mutation, indicating that position 366 was a known site for engineering.
   • Davis et al. (2010): This work introduced "strand-exchange engineered domain (SEED) CH3 heterodimers" as a platform for designing bispecific and asymmetric fusion proteins. These SEED CH3 domains, composed of alternating segments of human IgA and IgG CH3 sequences, were designed to preferentially form heterodimers when expressed in mammalian cells. This demonstrates another distinct, effective method for engineering CH3 domains for preferential heterodimerization in a single cell.
   • Strop et al. (2012): This reference describes engineering human IgG1 and IgG2 subtypes with minimal point mutations to form full-length bispecific human antibodies efficiently and with high purity. Strop et al. also mentions "electrostatic-steering technology" using oppositely-charged amino acid residue mutations to promote correct heavy chain heterodimerization.
   • Merus (US 8,632,776) and Merus (US 9,061,080) / Gunasekaran et al. (2010): These patents (or related disclosures) from the same assignee likely taught general CH3 domain engineering, including charge-reversal mutations, for preferential pairing to produce single bispecific antibodies. The '859 patent itself notes that "charged contact amino acids of CH3 domains that were known to be involved in CH3-CH3 pairing were substituted by amino acids of opposite charge (charge reversal), thereby influencing the CH3-CH3 pairing." [Patent text, Definitions]

3. Motivation to Produce Mixtures of Ig-like Molecules in a Single Host Cell using Different Pairing Means:
   The '859 patent highlights that prior art methods for antibody combinations had drawbacks, such as the "staggering cost of developing the 2 antibodies individually in clinical trials" and "poor control over the composition and hence reproducibility" when mixing recombinant cell lines. [Patent text, Definitions]
   A POSA, facing these known challenges and recognizing the therapeutic potential of multi-targeting, would have been motivated to extend the successful strategies for producing single bispecific antibodies in a single cell to producing mixtures of multiple defined Ig-like molecules in a single host cell. This approach would address the cost, manufacturing complexity, and reproducibility issues associated with earlier methods.

   To achieve a defined mixture of two different Ig-like molecules within a single cell, minimizing unwanted by-products, a POSA would recognize the need for orthogonal pairing mechanisms. That is, the heavy chains intended to form the first Ig-like molecule should preferentially pair only with each other, and similarly for the second Ig-like molecule, with minimal cross-pairing between components of the two different Ig-like molecules. Employing different CH3 engineering strategies (e.g., a "knob-into-hole" system for one pair and a charge-engineered system for the other, or two distinct charge-engineered systems) would be an obvious design choice to create such orthogonal pairing. This design strategy directly addresses the problem of unwanted pairings when multiple antibody heavy chains are co-expressed. The idea of using different preferential pairing mechanisms for different pairs within the same system to ensure specific interactions is a logical extension of known protein engineering principles to solve a recognized manufacturing problem.

4. Specific Mutations (T366K, L351D, E356K, D399K, K392D, K409D):
   The '859 patent defines numerous "contact residues" in the CH3-CH3 interface (e.g., at positions 347, 349, 350, 351, 352, 353, 354, 355, 356, 357, 360, 364, 366, 368, 370, 390, 392, 394, 395, 397, 399, 400, 405, 407, 409, 439). [Patent text, Definitions]
   Given the established knowledge of CH3 domain engineering using "knobs-into-holes" (Merchant et al., including T366W mutation) and electrostatic steering (Strop et al., Gunasekaran et al.), a POSA would be motivated to explore various mutations at these known contact residues to optimize heterodimerization and/or orthogonality. While the '859 patent claims novelty in substituting neutral amino acids for charged ones, the general principle of modifying charges at interface residues to control dimerization was known. Experimenting with different amino acid substitutions, including introducing new charges at various contact residues to create or enhance electrostatic interactions for preferential pairing, would have been within the realm of "obvious to try" for a skilled protein engineer. The exact combination of mutations, even if not explicitly disclosed, represents a predictable optimization within the known strategies for achieving the desired preferential pairing, especially when aiming for orthogonal systems.

Conclusion:
Considering the prior art, a POSA would have been motivated to combine the established techniques for preferential CH3 heterodimerization (such as "knobs-into-holes" from Merchant et al. and electrostatic engineering from Strop et al. and earlier Merus disclosures) with the known desire to produce multi-targeting therapeutics more efficiently. The recognized challenges in manufacturing complex antibody mixtures from separate components would drive a POSA to explore producing mixtures of multiple distinct Ig-like molecules within a single host cell. To achieve this, employing different, orthogonal preferential pairing mechanisms for each desired Ig-like molecule, utilizing known principles of protein engineering at identified CH3 contact residues, would be a logical and predictable design choice, with a reasonable expectation of success. Therefore, claims 1-16 of US11926859 would likely be considered obvious under 35 U.S.C. § 103.