Obviousness

US Patent 12297278 describes soluble, bivalent, bispecific Wnt surrogate molecules designed to agonize Wnt signaling pathways. These molecules comprise one or more regions that specifically bind to one or more Frizzled (Fzd) receptors and one or more regions that specifically bind to Low-density lipoprotein (LDL) receptor-related protein 5 (LRP5) and/or LRP6. The patent claims the molecules, pharmaceutical compositions containing them, and methods of using them to treat diseases associated with reduced Wnt signaling, such as bone disorders and liver regeneration.

Under 35 U.S.C. § 103, an invention is obvious if "the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains."

A person having ordinary skill in the art (PHOSITA) would have been motivated to combine several known prior art elements to arrive at the claimed invention for the following reasons:

Motivation to Combine:

1. Known Problem and Desired Improvement: The patent itself establishes the motivation by stating that "Wnt ligands and their signals play key roles in the control of development, homeostasis and regeneration of many essential organs and tissues" and that "Modulation of Wnt signaling pathways has potential for treatment of degenerative diseases and tissue injuries". A PHOSITA would recognize the therapeutic benefit of agonistic Wnt pathway modulation for diseases and disorders associated with reduced Wnt signaling.
2. Known Mechanism of Action: It was well-understood that Wnt proteins naturally activate signaling by interacting with both Frizzled receptors and LRP5/6 co-receptors. Therefore, a clear objective for a PHOSITA would be to develop a synthetic molecule that mimics this natural dual engagement to initiate or enhance Wnt signaling.

Combinations of Prior Art References and Rationale for Obviousness:

The core of the claimed invention is a bispecific, bivalent molecule that brings together Fzd and LRP5/6 binding capabilities to activate the Wnt pathway. The individual components and methods for assembling such molecules were known in the art prior to the priority date of December 19, 2017.

Combination 1: Known Fzd-binding fragments + Known LRP5/6-binding fragments + Established Bispecific/Multivalent Antibody Engineering Formats.

• Prior Art Elements:

  • Fzd Binding Regions: The patent explicitly states that "Anti-Fzd antibodies and antigen-binding fragments there that may be used or present in the Wnt surrogate molecules disclosed herein include, but are not limited to, those described in the U.S. provisional application No. 62/607,877, titled Anti-Frizzled Antibodies and Methods of Use, filed on Dec. 19, 2017". Furthermore, it references "OMP-18R5 (vantictumab)" and its CDR sequences, citing "U.S. Pat. No. 8,507,442". These references establish the availability of Fzd-specific binding agents.
  • LRP5/6 Binding Regions: Similarly, the patent notes that "Anti-LRP5/6 antibodies and antigen-binding fragments there that may be used or present in the Wnt surrogate molecules disclosed herein include, but are not limited to, those described in the U.S. provisional application No. 62/607,879, titled Anti-LRP5/6 Antibodies and Methods of Use, filed on Dec. 19, 2017". It also mentions naturally occurring LRP5/6 binding domains like DKK1, DKK2, DKK3, DKK4, sclerostin, and Wise, and cites "Gong et al. (2010) PLoS One. 5(9):e12682; Ettenberg et al. (2010) Proc Natl Acad Sci USA" for known LRP5/6 antibodies. These demonstrate the existence of LRP5/6-specific binding agents.
  • Bispecific/Multivalent Formats: The patent itself details various known formats for constructing multivalent and bispecific antibodies and fusion proteins, including IgG, scFv, Fab, VHH or sdAb, and diabodies (citing "WO94/13804"). It also describes "knobs-into-holes engineering" (citing "J. B. B. Ridgeway et al., Protein Eng., 9, 616-621, 1996") and "Fabs-in-tandem IgG (FIT-IG) format" (citing "PCT Application Publication No. WO2017/136820" and "Shiyong Gong, Fang Ren, Danqing Wu, Xuan Wu & Chengbin Wu (2017) mAbs, 9:7, 1118-1128"). These technologies were well-established for creating molecules with multiple specificities or valencies.

• Rationale for Combination: A PHOSITA, motivated to create a Wnt agonist by mimicking the natural Wnt ligand's dual binding to Fzd and LRP5/6 receptors, would find it obvious to combine known anti-Fzd binding fragments with known anti-LRP5/6 binding fragments into a single bispecific, multivalent molecule. The selection of specific formats (e.g., Fab-IgG fusions, VHH-Fc fusions, scFv combinations, diabodies) for linking these binding regions would be a routine design choice, involving conventional molecular biology and protein engineering techniques, aimed at optimizing expression, stability, and desired functional properties. The expectation of achieving Wnt agonist activity through such a combination would be predictable, given the established biological understanding of Wnt signaling.

Lack of Evidence for Unexpected Results:

While the patent provides experimental data demonstrating the Wnt agonist activity of the surrogate molecules and their therapeutic effects (e.g., increased bone mineral density in FIGS. 20A-20B, 21A-21E, and liver regeneration in FIGS. 37A-37C, 38A-38B, 39A-39D, 40A-40H, 41A-41N, 42A-42D), the specification does not articulate any unexpected properties or results. The observed agonistic activity and therapeutic benefits are consistent with the predictable outcome of designing a molecule that co-engages Fzd and LRP5/6 receptors to activate the Wnt pathway, which was the known biological mechanism and the explicit goal of the invention. The exploration of various formats is a matter of routine optimization, not an indication of non-obviousness.

Therefore, the claimed Wnt surrogate molecules, which combine known binding specificities (anti-Fzd and anti-LRP5/6) using established bispecific and multivalent antibody engineering techniques, would have been obvious to a PHOSITA given the clear motivation to create a Wnt agonist by mimicking the natural ligand's mechanism of action.