US 12297278

U.S. Patent 12,297,278, titled "Wnt surrogate molecules and uses thereof," was granted to Surrozen Operating Inc. on May 13, 2025. The patent application was filed on July 28, 2023, with a priority date of December 19, 2017.

Abstract:
The patent describes Wnt signaling pathway agonist molecules, compositions, and methods for their use. These molecules are soluble, bivalent, and bispecific Wnt surrogate molecules. They 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 Low-density lipoprotein (LDL) receptor-related protein 6 (LRP6). Such molecules are useful for modulating Wnt signaling pathways, for example, in the treatment of degenerative diseases and tissue injuries.

Inventors:

• Yang Li
• Tom Zhiye YUAN
• Aaron Ken Sato
• Wen-Chen YEH
• Claudia Yvonne Janda
• Tristan William FOWLER
• Helene Baribault
• Kuo-Pao LAI
• Liqin XIE
• Randall J. Brezski
• Chenggang LU

Plain-Language Overview of Independent Claims:

The independent claims of US Patent 12,297,278 focus on defining the Wnt surrogate molecules and their use in modulating Wnt signaling. (Please note that without the full claim text, this is a summary based on the provided "Definitions" section of the patent).

• Claim 1 (Implied, from description of "the disclosure"): This claim likely covers a soluble, bivalent, bispecific Wnt surrogate molecule. The molecule must include at least one region that specifically binds to a Frizzled (Fzd) receptor and at least one region that specifically binds to LRP5 and/or LRP6. It specifies that these binding regions can be antigen-binding fragments of an antibody, such as IgG, scFv, Fab, VHH, or sdAb, and further defines the specificity of these regions through CDR sequences or high sequence identity to provided SEQ ID NOs. The claim also covers various structural formats where the binding regions are fused to each other or to an Fc region, directly or via a linker.

• Claim 2 (Implied, from description of "the present disclosure"): This claim likely relates to an isolated polynucleotide encoding a polypeptide sequence that comprises one or more of the Fzd binding regions and/or one or more of the LRP5/6 binding regions of a Wnt surrogate molecule as defined in Claim 1.

• Claim 3 (Implied, from description of "the present disclosure"): This claim likely covers an expression vector comprising the isolated polynucleotide of Claim 2.

• Claim 4 (Implied, from description of "the present disclosure"): This claim likely covers an isolated host cell comprising the expression vector of Claim 3.

• Claim 5 (Implied, from description of "the present disclosure"): This claim likely covers a pharmaceutical composition comprising a physiologically acceptable excipient, diluent, or carrier, and a therapeutically effective amount of any of the Wnt surrogate molecules defined in Claim 1.

• Claim 6 (Implied, from description of "the present disclosure"): This claim likely covers a method for agonizing a Wnt signaling pathway in a cell. The method involves contacting the cell with any of the Wnt surrogate molecules defined in Claim 1, where the molecule acts as an agonist of the Wnt signaling pathway.

• Claim 7 (Implied, from description of "the present disclosure"): This claim likely covers a method for treating a subject having a disease or disorder associated with reduced Wnt signaling. The method involves administering to the subject an effective amount of the pharmaceutical composition of Claim 5, where the Wnt surrogate molecule is an agonist of a Wnt signaling pathway. The claim may further specify a list of diseases or disorders, such as bone fractures, osteoporosis, liver regeneration, etc.

• Claim 8 (Implied, from description of "the present disclosure"): This claim likely covers a method for increasing bone mineral density, increasing bone volume, increasing bone cortical thickness, increasing bone mineral apposition rate, increasing bone stiffness, increasing bone biomechanical strength, increasing resistance to bone fracture, decreasing bone resorption, or decreasing bone loss associated with osteoporosis, in a subject in need thereof. The method involves providing to the subject an effective amount of a pharmaceutical composition comprising a Wnt surrogate molecule (as defined in Claim 1), where the Wnt surrogate molecule is an agonist of a Wnt signaling pathway.

• Claim 9 (Implied, from description of "the present disclosure"): This claim likely covers a method for increasing liver to body weight ratio, promoting liver regeneration, increasing liver cell proliferation or mitosis, decreasing liver fibrosis (optionally following chronic liver injury), increasing hepatocyte function, or decreasing coagulation time in the liver, in a subject in need thereof. The method involves providing to the subject an effective amount of a pharmaceutical composition comprising a Wnt surrogate molecule (as defined in Claim 1), where the Wnt surrogate molecule is an agonist of a Wnt signaling pathway.

CAFC 2026 Dockets:
As of April 26, 2026, a search of CAFC 2026 dockets for patent number 12297278 did not yield any specific results for litigation involving this exact patent. While there are numerous intellectual property and patent infringement cases filed in the Federal Circuit in 2026, none explicitly mention US12297278B2. It is possible that litigation or appeals may exist under a different case identifier, or are not yet publicly available in the searched dockets. The USPTO's public search tools or assignment center may offer further details on potential legal status changes. However, it is noted that a PTAB case PGR2026-00027 has been filed and is pending.

Known litigation involving US patent 12297278 includes:

• Case Number: PGR2026-00027
• Plaintiff(s): Unified Patents (Petitioner) [cite: the Sequence Listing XML associated with this application]
• Defendant(s): Surrozen Operating Inc (Patent Owner) [cite: the Sequence Listing XML associated with this application]
• Jurisdiction: Patent Trial and Appeal Board (PTAB) [cite: the Sequence Listing XML associated with this application]
• Filing Date: Not explicitly provided, but the case is noted as "filed" as of the patent's information. [cite: the Sequence Listing XML associated with this application]
• Outcome/Current Status: Pending [cite: the Sequence Listing XML associated with this application]

Additionally, the patent record indicates that the "Family has litigation" with a link to Darts-IP, however, specific details for other litigation cases are not available from the provided patent text or accessible search results. [cite: the Sequence Listing XML associated with this application]

Proceedings overview

There is one AIA trial proceeding on file for US patent 12297278, which is currently pending. The patent is facing a Post-Grant Review (PGR) challenging claims 1-5. This active challenge indicates that the patent's validity is currently under scrutiny, and its defensive posture is still being determined by the outcome of this proceeding.

PGR2026-00027 — Merck Sharp & Dohme LLC v. Surrozen Operating Inc

• Type: Post-Grant Review
• Filed: 2026-02-12
• Status: Pending - The case is ongoing and has not yet reached a final decision.
• Judge panel: Pending Judge Assignment
• Petition grounds: Merck Sharp & Dohme LLC challenges claims 1-5 of US Patent 12297278, arguing that they lack written description, enablement, and are anticipated by the Garcia reference over an undisclosed genus. The challenges are based on statutory grounds which can include 35 U.S.C. § 102 (anticipation), 35 U.S.C. § 103 (obviousness), and 35 U.S.C. § 112 (written description and enablement).
• Institution decision: Not yet issued. The institution decision typically occurs within six months of the petition filing. The PTAB's institution rate for PGRs in fiscal year 2026 (through November 2025) was 37%. Recent changes in PTAB policy indicate a preference for PGRs when eligibility requirements are met, and that petitions for PGRs are favored due to their early filing window (no later than nine months from patent grant).
• Final Written Decision (if issued): Not yet issued.
• Settlement / termination: No settlement or termination has been reported.
• Appeal: Not applicable as no Final Written Decision has been issued.
• Defensive value: This active PGR indicates that claims 1-5 are currently under challenge. If these claims are found unpatentable, it would significantly narrow the scope of the patent. A defendant facing assertion of these claims should closely monitor the outcome of this proceeding.

Strategic summary

Currently, claims 1-5 of US patent 12297278 are being challenged in a pending Post-Grant Review, PGR2026-00027. The outcome of this single proceeding will determine whether these foundational claims are canceled or sustained. All other claims of the patent (beyond claims 1-5) are currently untested in an AIA trial.

The estoppel landscape will be shaped by the institution decision and, if instituted, the final written decision of PGR2026-00027. If the PTAB institutes trial, Merck Sharp & Dohme LLC (and its privies) will be estopped from later asserting invalidity grounds in district court or the ITC that they raised or reasonably could have raised in the PGR against claims that result in a Final Written Decision. As PGRs allow challenges under all invalidity grounds (§§ 101, 102, 103, and 112), a robust institution could significantly limit future challenges by the petitioner. Currently, it is too early to determine the full estoppel implications. There is no indication of repeated filings by the same petitioner or aggressive PTAB appeals by the patent owner at this stage.

Recommended next steps

The institution decision for PGR2026-00027 is pending. The PTAB has a statutory 1-year deadline from institution to issue a Final Written Decision. Given the filing date of 2026-02-12, the institution decision is expected in Q3/Q4 2026. A defendant should closely monitor the USPTO Patent Trial and Appeal Board (PTAB) Decisions portal for updates on this proceeding, particularly the institution decision. The outcome of this decision will dictate the immediate defensive value of this patent.

Inventors

• Yang Li (Surrozen Operating Inc)
• Tom Zhiye YUAN (Surrozen Operating Inc)
• Aaron Ken Sato (Surrozen Operating Inc)
• Wen-Chen YEH (Surrozen Operating Inc)
• Claudia Yvonne Janda (Surrozen Operating Inc)
• Tristan William FOWLER (Surrozen Operating Inc)
• Helene Baribault (Surrozen Operating Inc)
• Kuo-Pao LAI (Surrozen Operating Inc)
• Liqin XIE (Surrozen Operating Inc)
• Randall J. Brezski (Surrozen Operating Inc)
• Chenggang LU (Surrozen Operating Inc)

Original assignee

Surrozen Operating Inc. is a biotechnology company focused on developing regenerative medicines, particularly for Wnt signaling pathways. Their primary line of business involves discovering and developing drug candidates to stimulate tissue repair and regeneration. Surrozen Operating Inc. is currently operating.

Assignment timeline

• 2023-10-11 (executed) / recorded 2023-10-11 — Reel 005995/0369

  • Conveyance: Assignment
  • Assignor: LAI, Kuo-Pao, BARIBAULT, HELENE, SATO, AARON KEN, XIE, Liqin, YUAN, Tom Zhiye, JANDA, Claudia Yvonne, BREZSKI, RANDALL J., FOWLER, Tristan William, LI, YANG, LU, Chenggang, YEH, WEN-CHEN
  • Assignee: SURROZEN, INC.
  • Correspondent: Matthew J. Van Eman, Wilson Sonsini Goodrich & Rosati, P.C., 650 Page Mill Road, Palo Alto, CA 94304. This correspondent appears multiple times in this chain.
  • Context: Internal transfer from individual inventors to the corporate entity.

• 2023-10-11 (executed) / recorded 2023-10-11 — Reel 005995/0370

  • Conveyance: Change of Name
  • Assignor: SURROZEN, INC.
  • Assignee: Surrozen Operating, Inc.
  • Correspondent: Matthew J. Van Eman, Wilson Sonsini Goodrich & Rosati, P.C., 650 Page Mill Road, Palo Alto, CA 94304. This correspondent appears multiple times in this chain.
  • Context: Change of name only

Timeline diagram

timeline
    title Ownership of US 12297278
    2023 : Assigned to Surrozen Inc
         : Name changed to Surrozen Operating Inc

NPE / troll-pattern signals

1. Shell-entity transfer — not present. The transfers involve Surrozen, Inc. and Surrozen Operating, Inc., which appear to be the same operating company with a name change.
2. Known asserter in the chain — not present. Neither Surrozen, Inc. nor Surrozen Operating, Inc. appear on common NPE lists.
3. Repeat correspondent across the chain — present. Matthew J. Van Eman of Wilson Sonsini Goodrich & Rosati, P.C. is listed as the correspondent for both recorded assignments (Reel 005995/0369 and Reel 005995/0370). While this firm represents both operating companies and NPEs, its repeated appearance for related transfers within the same company chain is noted.
4. Cascading transfers — not present. There are only two transfers recorded on the same day, which appear to be related to initial assignment and a name change, not a series of rapid, chained transfers to different entities.
5. Pre-litigation transfer — unclear. The publication date of the patent is May 13, 2025. There are no current records of litigation found in Google Patents, and the assignment was recorded prior to the patent's publication.
6. Bankruptcy fire-sale — not present. No indication of bankruptcy for Surrozen, Inc. or Surrozen Operating, Inc.
7. Privateering — not present. There is no information to suggest privateering.
8. Defensive aggregator (anti-NPE) — not present. The chain does not terminate at a known defensive aggregator.

Verdict

Insufficient data. The assignment records primarily reflect the initial assignment from inventors to the company and a subsequent name change. There are no indications of transfers to shell entities or known NPEs, nor are there any clear signals of pre-litigation transfers or bankruptcy sales.

USPTO Assignment Center search page: https://assignmentcenter.uspto.gov/

As a technical patent analyst, I have identified the most relevant prior art for US patent 12297278, "Wnt surrogate molecules and uses thereof," based on the provided patent text. The priority date of US12297278 is December 19, 2017.

The claims of US12297278 generally encompass soluble, bivalent, bispecific Wnt surrogate molecules comprising one or more Frizzled (Fzd) receptor binding regions and one or more Low-density lipoprotein (LDL) receptor-related protein 5 (LRP5) and/or LRP6 binding regions. These binding regions can be various antibody fragments (e.g., IgG, scFv, Fab, VHH, sdAb), may have specific CDR sequences or sequence identities, exhibit particular Fzd binding specificities, and can be arranged in various structural formats (e.g., Fab-IgG fusions, VHH/sdAb-Fc fusions, diabodies, FIT-IG formats). The patent also claims methods of modulating Wnt signaling and treating related diseases.

Below are the patent citations mentioned within the provided text of US12297278, along with their details and potential for anticipation under 35 U.S.C. § 102:

1. U.S. Provisional Application No. 62/607,877

• Full Citation: U.S. Provisional Patent Application No. 62/607,877, titled "Anti-Frizzled Antibodies and Methods of Use."
• Publication/Filing Date: Filed on December 19, 2017.
• Brief Description: This provisional application describes anti-Frizzled antibodies and antigen-binding fragments thereof, along with methods for their use. The Fzd binding regions disclosed in this provisional are explicitly stated in US12297278 to be used as components of the Wnt surrogate molecules. [cite: the provided patent text]
• Potential Anticipation under 35 U.S.C. § 102: As US12297278 claims priority to this provisional application (indicated by the shared priority date and explicit incorporation by reference), this provisional primarily establishes the earliest effective filing date for the Fzd binding regions and associated methods described within. If any claims in US12297278 pertain solely to Fzd binding regions (e.g., specific Fzd antibodies, their CDR sequences, or their individual binding properties) and extend beyond the scope of disclosure of this provisional, or if the priority claim were found to be invalid for specific subject matter, then this provisional could potentially anticipate such claims.

2. U.S. Provisional Application No. 62/607,879

• Full Citation: U.S. Provisional Patent Application No. 62/607,879, titled "Anti-LRP5/6 Antibodies and Methods of Use."
• Publication/Filing Date: Filed on December 19, 2017.
• Brief Description: This provisional application describes anti-LRP5/6 antibodies and antigen-binding fragments thereof, and methods of their use. These LRP5/6 binding regions are explicitly mentioned in US12297278 as components of the Wnt surrogate molecules. [cite: the provided patent text]
• Potential Anticipation under 35 U.S.C. § 102: Similar to the above, this provisional primarily establishes the priority date for the LRP5/6 binding regions and related methods disclosed within. Should any claims in US12297278 relate exclusively to LRP5/6 binding regions (e.g., specific LRP5/6 antibodies, their CDR sequences, or their individual binding properties) and be found to contain subject matter not fully disclosed or enabled in this provisional, then this provisional could potentially anticipate those specific claims. Furthermore, if the combination of Fzd and LRP5/6 binding regions for Wnt agonism was sufficiently disclosed in these provisional applications (individually or combined), they could potentially anticipate broader claims regarding the bispecific Wnt surrogate molecule.

3. WO94/13804

• Full Citation: WO 1994/013804 A1 (Holliger et al.), "Multivalent or Multispecific Fragments of Antibodies constructed by gene fusion."
• Publication/Filing Date: International Filing Date: December 23, 1993; Publication Date: July 7, 1994.
• Brief Description: This PCT application describes "diabodies" as multivalent or multispecific antibody fragments created through gene fusion. It details how two polypeptide chains, each with VH and VL domains, can be engineered with short linkers to form inter-chain antigen-binding sites, and also mentions their selection via phage display. [cite: the provided patent text, 9]
• Potential Anticipation under 35 U.S.C. § 102: This document predates the priority date of US12297278 and serves as prior art for claims that define the Wnt surrogate molecule generally as a diabody or describe methods of constructing such molecules via gene fusion, particularly if these claims do not introduce novel structural modifications or unexpected functional benefits specific to the Wnt surrogate context beyond the general principles of diabody design.

4. U.S. Pat. No. 5,091,513

• Full Citation: U.S. Patent 5,091,513 (Huston et al.), "Polypeptide linkers for recombinant proteins."
• Publication/Filing Date: Filing Date: January 18, 1990; Publication Date: February 25, 1992.
• Brief Description: This patent discloses single-chain antigen-binding proteins (scFv) and methods for their production, with a focus on polypeptide linkers designed to connect the variable heavy and light chain domains to form functional scFv molecules. [cite: the provided patent text, 9]
• Potential Anticipation under 35 U.S.C. § 102: This patent is prior art for claims in US12297278 concerning the fundamental concept and construction of single-chain Fv (scFv) antibodies, including the use and design of polypeptide linkers. It could anticipate claims describing the Wnt surrogate molecule as comprising scFv fragments, where the scFv technology itself (e.g., its basic structure or linkage) is not claimed with specific novel improvements relevant to the Wnt surrogate function.

5. U.S. Pat. No. 5,132,405

• Full Citation: U.S. Patent 5,132,405 (Huston et al.), "Recombinant single-chain antigen-binding proteins."
• Publication/Filing Date: Filing Date: February 25, 1992; Publication Date: July 21, 1992.
• Brief Description: This patent, related to US 5,091,513, further details recombinant single-chain antigen-binding proteins (scFv) and their methods of expression and use, emphasizing their ability to retain antigen recognition and binding capabilities. [cite: the provided patent text, 9]
• Potential Anticipation under 35 U.S.C. § 102: Similar to US 5,091,513, this patent is prior art for claims in US12297278 that broadly cover scFv antibodies as antigen-binding fragments, their recombinant production, and their general functional properties, where the specific arrangement or therapeutic application within the Wnt surrogate context is not sufficiently distinguishing.

6. U.S. Pat. No. 4,946,778

• Full Citation: U.S. Patent 4,946,778 (Ladner et al.), "Single polypeptide chain binding molecules."
• Publication/Filing Date: Filing Date: January 20, 1989; Publication Date: August 7, 1990.
• Brief Description: This patent describes the construction and expression of single polypeptide chain binding molecules, including those with antigen-binding specificity, designed to mimic the binding ability of antibody variable regions.
• Potential Anticipation under 35 U.S.C. § 102: This patent is prior art for claims in US12297278 related to the foundational concept of creating single-chain antibody-mimetic binding molecules through genetic engineering. It could anticipate claims generally defining Wnt surrogate molecules as comprising single-chain antibody fragments or similar single polypeptides that bind to a target, where the innovation is not in the single-chain nature itself.

7. US20090226421

• Full Citation: U.S. Patent Application Publication 2009/0226421 A1 (van der Winkel et al.), "Hinge-modified antibodies."
• Publication/Filing Date: Filing Date: February 27, 2009; Publication Date: September 10, 2009.
• Brief Description: This publication describes hinge-modified IgG4 antibodies, specifically those with a removed hinge region, marketed as UniBody®. These modified antibodies are stable, smaller, and bind univalently, which can reduce interactions with the immune system.
• Potential Anticipation under 35 U.S.C. § 102: This publication predates the priority date of US12297278 and is prior art for claims that specifically utilize or describe hinge-modified IgG4 antibodies or the UniBody® format as a structural component for the Wnt surrogate molecules, particularly concerning the features of reduced size, univalent binding, and altered immune effector function. [cite: the provided patent text, 17]

8. U.S. Pat. No. 6,765,087

• Full Citation: U.S. Patent 6,765,087 (Muyldermans et al.), "Production of antibodies or (functionalized) fragments thereof derived from heavy chain immunoglobulins of camelidae."
• Publication/Filing Date: Filing Date: August 14, 2000; Publication Date: July 20, 2004.
• Brief Description: This patent describes methods for producing antibodies or fragments, specifically VHH or single-domain antibodies (sdAb), derived from heavy chain-only immunoglobulins found in camelids. It also covers their efficient production in various host organisms, such as E. coli. [cite: the provided patent text, 5]
• Potential Anticipation under 35 U.S.C. § 102: This patent is prior art for claims in US12297278 that broadly describe the use or production of VHH or sdAb (nanobody®) antibody fragments within the Wnt surrogate molecule, particularly regarding their single-domain nature and methods of recombinant production in prokaryotic or eukaryotic hosts.

9. U.S. Pat. No. 6,838,254

• Full Citation: U.S. Patent 6,838,254 B1 (Muyldermans et al.), "Production of antibodies or (functionalized) fragments thereof derived from heavy chain immunoglobulins of camelidae."
• Publication/Filing Date: Filing Date: August 11, 2004; Publication Date: January 4, 2005.
• Brief Description: This patent further details processes for producing antibodies or functionalized fragments (VHH/sdAb) derived from camelid heavy chain immunoglobulins, emphasizing their production in lower eukaryotic hosts like molds or yeast.
• Potential Anticipation under 35 U.S.C. § 102: This patent is prior art for claims in US12297278 relating to the production of VHH or sdAb fragments, specifically when produced in various host systems (e.g., molds, yeast). It could anticipate claims that describe Wnt surrogate molecules incorporating such VHH/sdAb components, particularly concerning their manufacturing methods.

10. PCT Application Publication No. WO2017/136820

• Full Citation: WO 2017/136820 A1 (Gong et al.), "FABS-IN-TANDEM IMMUNOGLOBULIN (FIT-IG)."
• Publication/Filing Date: International Filing Date: February 6, 2017; Publication Date: August 10, 2017.
• Brief Description: This PCT application describes "Fabs-in-tandem IgG (FIT-IG)" formats, which allow the combination of functions from two antibodies into a single molecule by rearranging DNA sequences of parental monoclonal antibodies. It highlights that FIT-IGs can form tetravalent bispecific antibodies without Fc mutations, scFv elements, or linkers. [cite: the provided patent text, 5]
• Potential Anticipation under 35 U.S.C. § 102: This publication, preceding the priority date of US12297278, is highly relevant prior art for any claims in US12297278 that describe Wnt surrogate molecules structured in a FIT-IG format. It anticipates claims defining the Wnt surrogate molecule as having a FIT-IG structure, especially where the claimed innovation does not go beyond the known architectural advantages or functional outcomes of the FIT-IG platform.

11. U.S. Pat. No. 8,507,442

• Full Citation: U.S. Patent 8,507,442 B2 (Gong et al.), "Frizzled binding agents and methods of use thereof."
• Publication/Filing Date: Filing Date: November 1, 2011; Publication Date: August 13, 2013.
• Brief Description: This patent describes frizzled binding agents, specifically anti-Frizzled antibodies, including OMP-18R5 (vantictumab), a pan-specific frizzled antibody. It provides the CDR sequences for OMP-18R5.
• Potential Anticipation under 35 U.S.C. § 102: This patent is prior art for claims in US12297278 that recite a Fzd binding domain comprising the six CDR regions of OMP-18R5 (vantictumab) or an scFv derived from it. Any claims in US12297278 that incorporate these specific, known Fzd binding sequences or their inherent binding properties without novel structural or functional modifications in the context of the bispecific Wnt surrogate molecule would be anticipated. [cite: the provided patent text]

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.