US 7364736

US patent 7364736, titled "Antibodies to OPGL," was assigned to Amgen Inc.. The inventors are William J. Boyle, Francis H. Martin, Jose R. Corvalan, and C. Geoffrey Davis. The patent was filed on June 25, 2002, and issued on April 29, 2008.

The abstract describes the invention as relating to antibodies that bind osteoprotegerin ligand (OPGL). It also covers polynucleotides and amino acid sequences for these antibodies (particularly variable regions and complementarity determining regions (CDRs) of the light and heavy chain immunoglobulin molecules). The patent further provides hybridoma cell lines producing these immunoglobulins and monoclonal antibodies, purified human monoclonal antibodies against human OPGL, and methods for their production and use in treating osteopenic disorders and other conditions.

A plain-language overview of the independent claims is as follows:

• Claim 1: This claim covers an isolated antibody having a heavy chain with the amino acid sequence of SEQ ID NO: 2 and a light chain with the amino acid sequence of SEQ ID NO: 4.
• Claim 10: This claim covers an isolated antibody where the heavy chain's variable region contains the amino acid sequence of SEQ ID NO: 13, and the light chain's variable region contains the amino acid sequence of SEQ ID NO: 14.
• Claim 19: This claim covers an isolated antibody where the heavy chain's variable region is at least 90% identical to SEQ ID NO: 13, and the light chain's variable region is at least 90% identical to SEQ ID NO: 14. This antibody must also interact with osteoprotegerin ligand (OPGL).
• Claim 22: This claim covers an isolated heavy chain, or a fragment thereof, comprising the amino acid sequence of SEQ ID NO: 2.
• Claim 25: This claim covers an isolated heavy chain that includes a variable region and a constant region, where the variable region (or a fragment of it) has the amino acid sequence of SEQ ID NO: 13.
• Claim 28: This claim covers an isolated light chain, or a fragment thereof, comprising the amino acid sequence of SEQ ID NO: 4.
• Claim 31: This claim covers an isolated light chain, or a fragment thereof, comprising the amino acid sequence of SEQ ID NO: 14.
• Claim 34: This claim covers a single-chain antibody that includes a heavy chain (or fragment) having the amino acid sequence of SEQ ID NO: 2 and a light chain (or fragment) having the amino acid sequence of SEQ ID NO: 4.
• Claim 36: This claim covers a single-chain antibody where the heavy chain variable region (or fragment) has the amino acid sequence of SEQ ID NO: 13, and the light chain variable region (or fragment) has the amino acid sequence of SEQ ID NO: 14.
• Claim 38: This claim covers a pharmaceutical composition containing a therapeutically effective amount of the antibody from Claim 1, combined with standard pharmaceutical diluents, carriers, or other excipients.
• Claim 43: This claim describes a method for treating an osteopenic disorder in a patient by administering a therapeutically effective amount of the antibody from Claim 1 to that patient.
• Claim 48: This claim describes a method for treating an osteopenic disorder in a patient by administering the pharmaceutical composition described in Claim 38.
• Claim 53: This claim describes a method for treating an inflammatory condition associated with bone loss in a patient, by administering the pharmaceutical composition of Claim 38.
• Claim 54: This claim describes a method for treating an autoimmune condition associated with bone loss in a patient, by administering the pharmaceutical composition of Claim 38.
• Claim 55: This claim describes a method for detecting the level of OPGL in a biological sample by contacting the sample with the antibody from Claim 1.
• Claim 57: This claim covers a pharmaceutical composition comprising a therapeutically effective amount of an antibody that interacts with OPGL, along with a therapeutically effective amount of at least one additional therapeutic agent.
• Claim 61: This claim describes a method for treating a bone disorder in a patient by administering a therapeutically effective amount of an antibody that interacts with OPGL, and also administering a therapeutically effective amount of at least one additional therapeutic agent.
• Claim 65: This claim describes a method for treating an inflammatory condition with attendant bone loss in a patient by administering a therapeutically effective amount of an antibody that interacts with OPGL and at least one additional therapeutic agent.
• Claim 66: This claim describes a method for treating an autoimmune condition with attendant bone loss in a patient by administering a therapeutically effective amount of an antibody that interacts with OPGL and at least one additional therapeutic agent.
• Claim 67: This claim describes a method for treating rheumatoid arthritis in a patient by administering a therapeutically effective amount of an antibody that interacts with OPGL and at least one additional therapeutic agent.
• Claim 68: This claim describes a method for treating an osteopenic disorder in a patient by administering a therapeutically effective amount of an antibody that interacts with OPGL, specifically an antibody with a dissociation constant (Kd) between approximately 0.23 and 0.29 nM.
• Claim 69: This claim describes a method for treating an osteopenic disorder in a patient by administering a therapeutically effective amount of an antibody that interacts with OPGL, specifically an antibody with a dissociation constant (Kd) of less than 0.23 nM.

A search for US patent 7364736 in the USPTO database confirms the details provided by Google Patents. The patent is listed as "Expired - Lifetime, expires 2025-02-19".

Regarding CAFC 2026 dockets, no specific cases involving US patent 7364736 filed in 2026 were found in the search results. However, the Google Patents page indicates that the patent family has ongoing litigation, with several US cases filed in New Jersey and Massachusetts District Courts in 2023, 2024, and 2025. These are district court cases, not filings with the Court of Appeals for the Federal Circuit.

US Patent 7364736, titled "Antibodies to OPGL," has been involved in several patent infringement lawsuits, primarily concerning denosumab biosimilar products.

Here is a summary of the known litigation:

• Amgen Inc. et al. v. Sandoz Inc. et al.

  • Jurisdiction: District of New Jersey.
  • Case Number: 1:23-cv-02406-CPO-EAP (D.N.J.).
  • Filing Date: May 1, 2023.
  • Outcome/Current Status: This case was resolved through a confidential settlement agreement at the end of April 2024. A court order issued on April 29, 2024, found the asserted claims of US Patent 7364736 to be valid, enforceable, and infringed by Sandoz's denosumab biosimilars in the United States. The settlement allows Sandoz to launch its biosimilar products on May 31, 2025, or earlier under certain limited conditions.

• Amgen Inc. et al. v. Celltrion, Inc.

  • Jurisdiction: District of New Jersey.
  • Case Number: 1:24-cv-06497-CPO-EAP (D.N.J.).
  • Filing Date: May 2024.
  • Outcome/Current Status: This BPCIA action is currently pending before Judge O'Hearn and Magistrate Judge Pascal, with preliminary expedited discovery proceedings related to 29 asserted patents, including US7364736.

• Amgen Inc. et al. v. Samsung Bioepis Co., Ltd. et al.

  • Jurisdiction: District of New Jersey.
  • Case Number: 1:24-cv-08417-CPO-EAP (D.N.J.).
  • Filing Date: August 2024.
  • Outcome/Current Status: On January 22, 2026, the District of New Jersey entered a Consent Order and Judgment by stipulation of both parties. For the purposes of this action, the asserted claims of all 21 enumerated patents, including US7364736B2, were deemed valid, enforceable, and infringed by Samsung's making, using, selling, offering to sell, or importing denosumab biosimilar products in the United States and its territories. This consent judgment was entered solely to effectuate a settlement.

• Amgen Inc. et al. v. Amneal LLC and mAbxience S.A.U.

  • Jurisdiction: District of New Jersey.
  • Case Number: 1:25-cv-17278-CPO-EAP (D.N.J.).
  • Filing Date: November 6, 2025.
  • Outcome/Current Status: Amgen filed this BPCIA action asserting infringement of several patents, including US Patent 7364736, against Amneal LLC and mAbxience S.A.U. for their proposed denosumab biosimilar products. This case is currently ongoing.

Additionally, Unified Patents indicates several other cases filed in the New Jersey District Court and one in the Massachusetts District Court involving US7364736, though detailed outcomes are not provided in the readily available snippets. These include:

• 1:25-cv-12160 (New Jersey District Court)
• 1:25-cv-11867 (Massachusetts District Court)
• 1:25-md-03138 (New Jersey District Court)
• 1:25-cv-17596 (New Jersey District Court)
• 1:25-cv-13358 (New Jersey District Court)
• 1:25-cv-01305 (New Jersey District Court)
• 1:25-cv-12152 (New Jersey District Court)
• 1:24-cv-08417 (New Jersey District Court)
• 1:24-cv-06497 (New Jersey District Court)

Proceedings overview

There are no AIA trial proceedings on file for US Patent 7,364,736 as of the most recent ingest from the USPTO ODP API, nor could any be identified through web search. This indicates no PTAB activity on this patent.

Strategic summary

As there are no PTAB proceedings on file for US7364736, all claims of the patent remain untested by AIA trial proceedings. This means that a defendant facing assertion of this patent would have all potential prior-art grounds available for an IPR or PGR petition, subject to statutory bars (e.g., one-year time bar from service of a complaint). The absence of PTAB activity could suggest that the patent has not been extensively asserted or challenged in this forum, or that previous challenges (if any, outside of AIA trials) were handled differently.

Recommended next steps

Given the absence of any PTAB activity on US7364736:

• If you are a defendant facing assertion of this patent: All claims are currently presumed valid as no PTAB trial has found otherwise. You have the full range of potential prior art arguments available for an IPR or PGR petition, provided you meet the statutory requirements and timeliness bars. A thorough prior art search would be the crucial first step to evaluate the strength of a potential PTAB challenge.

Inventors

• William J. Boyle (Amgen Inc.)
• Francis H. Martin (Amgen Inc.)
• Jose R. Corvalan (Abgenix Inc.)
• C. Geoffrey Davis (Abgenix Inc.)

Original assignee

The original assignees listed on the application were Amgen Inc. and Amgen Fremont Inc.. Amgen Inc. is a multinational biopharmaceutical company that discovers, develops, manufactures, and delivers human therapeutics. They have historically shipped products embodying similar claims. Amgen is currently an operating company.

Assignment timeline

• 2003-02-04 (executed) / recorded 2003-02-04 — Reel 009230/0173

  • Conveyance: Assignment
  • Assignor: Boyle, William J.; Martin, Francis H.
  • Assignee: AMGEN INC.
  • Correspondent: R. Brian Drozd, AMGEN INC., ONE AMGEN CENTER DRIVE, THOUSAND OAKS, CA 91320-1789.
  • Context: Internal reorg (assignment from inventors to corporate entity)

• 2003-02-04 (executed) / recorded 2003-02-04 — Reel 009230/0173

  • Conveyance: Assignment
  • Assignor: Davis, C. Geoffrey; Corvalan, Jose R.
  • Assignee: ABGENIX INC.
  • Correspondent: R. Brian Drozd, AMGEN INC., ONE AMGEN CENTER DRIVE, THOUSAND OAKS, CA 91320-1789. This correspondent also appears on the Amgen Inc. assignment.
  • Context: Internal reorg (assignment from inventors to corporate entity)

• 2007-12-07 (executed) / recorded 2007-12-07 — Reel 020613/0349

  • Conveyance: Merger
  • Assignor: ABGENIX, INC.
  • Assignee: AMGEN FREMONT INC.
  • Correspondent: R. Brian Drozd, AMGEN INC., ONE AMGEN CENTER DRIVE, THOUSAND OAKS, CA 91320-1789. This correspondent also appears on the previous assignments.
  • Context: Acquisition (Abgenix acquired by Amgen)

• 2022-09-26 (executed) / recorded 2022-09-26 — Reel 059952/0970

  • Conveyance: Assignment
  • Assignor: AMGEN FREMONT INC.
  • Assignee: AMGEN INC.
  • Correspondent: R. Brian Drozd, AMGEN INC., ONE AMGEN CENTER DRIVE, THOUSAND OAKS, CA 91320-1789. This correspondent also appears on the previous assignments.
  • Context: Internal reorg

Timeline diagram

timeline
    title Ownership of US 7364736
    2002 : Filed by Amgen Inc & Amgen Fremont Inc
    2003 : Inventors Boyle/Martin assigned to Amgen Inc
         : Inventors Davis/Corvalan assigned to Abgenix Inc
    2007 : Abgenix Inc merged into Amgen Fremont Inc
    2008 : Issued
    2022 : Amgen Fremont Inc assigned to Amgen Inc

NPE / troll-pattern signals

1. Shell-entity transfer — not present. All assignees appear to be operating companies (Amgen Inc., Abgenix Inc., Amgen Fremont Inc.).
2. Known asserter in the chain — not present. None of the listed assignees are identified as known NPEs.
3. Repeat correspondent across the chain — present. R. Brian Drozd of Amgen Inc. is the correspondent for all recorded assignments: Reel 009230/0173 (2003-02-04), Reel 020613/0349 (2007-12-07), and Reel 059952/0970 (2022-09-26).
4. Cascading transfers — not present. The assignments are spaced years apart.
5. Pre-litigation transfer — unclear. While the patent family has litigation, this analysis focuses on the specific patent US7364736. Without specific litigation filing dates for US7364736, it's unclear if the 2022 assignment precedes litigation within a 6-month window.
6. Bankruptcy fire-sale — not present. There is no indication of bankruptcy for Amgen or Abgenix in the assignment records.
7. Privateering — not present. No evidence of privateering has been identified.
8. Defensive aggregator (anti-NPE) — not present. The current assignee is Amgen Inc., an operating company.

Verdict

Operating-company assertion. The assignment records clearly show the patent has remained within the Amgen corporate family, including the acquisition of Abgenix Inc. by Amgen Fremont Inc., and subsequent internal transfers. The consistent correspondent, R. Brian Drozd of Amgen Inc., further supports this internal management of the patent portfolio. Therefore, the patent is likely used by an operating company against actual competitors.
(Verification: https://assignmentcenter.uspto.gov/)

US Patent 7364736, titled "Antibodies to OPGL," describes antibodies that bind to osteoprotegerin ligand (OPGL), as well as methods for using these antibodies to treat osteopenic disorders and detect OPGL in biological samples. The patent was filed on June 25, 2002, and granted on April 29, 2008. It claims priority to U.S. Provisional Application No. 60/301,172, filed on June 26, 2001.

To identify the most relevant prior art, we will examine the patent citations listed in US7364736. The Google Patents entry for US7364736B2 lists 318 patent citations and 308 non-patent citations. It should be noted that the current date is April 26, 2026, and the patent's adjusted expiration was February 19, 2025.

Here are some of the patent citations listed in US7364736, with brief descriptions and potential relevance to the claims:

• US4710457A: Dupont et al., "Monoclonal antibody for human hematopoietic glycoproteins and method"

  • Publication Date: December 1, 1987.
  • Brief Description: This patent describes monoclonal antibodies specific for human hematopoietic glycoproteins.
  • Potential Anticipation: This patent, generally disclosing monoclonal antibodies and their production, could potentially anticipate broader claims in US7364736 related to the general concept of monoclonal antibodies or methods of making them, such as claims 1, 10, 20, 21, and 22, to the extent they are not specifically directed to anti-OPGL antibodies with particular sequences.

• US5693762A: Queen et al., "Humanized immunoglobulin libraries and methods for producing and using same"

  • Publication Date: December 2, 1997.
  • Brief Description: This patent details methods for producing humanized antibodies. US7364736 itself discusses human antibodies and CDR grafting (which is related to humanization techniques).
  • Potential Anticipation: Claims in US7364736 that pertain to humanized or fully human antibodies, or methods of producing them, such as claims 1, 10, 20, 21, and 22, might be implicated if the techniques described in US5693762A are sufficiently enabling for anti-OPGL antibodies.

• US6015938A: Boyle et al., "TRAIL receptor 2 specific binding proteins"

  • Publication Date: January 18, 2000.
  • Brief Description: This patent by one of the inventors of US7364736, William J. Boyle, relates to binding proteins specific for TRAIL receptor 2. While not directly about OPGL, it demonstrates prior art in the area of binding proteins and therapeutic antibodies from the same inventive team.
  • Potential Anticipation: This patent is less likely to directly anticipate claims specific to anti-OPGL antibodies, as the target antigen is different. However, it could be relevant for broader method claims if there are generic techniques for antibody production or use described that overlap with those in US7364736.

• US6271349B1: Dougal et al., "Regulation of osteoclastogenesis by osteoprotegerin"

  • Publication Date: August 7, 2001.
  • Brief Description: This patent discusses the regulation of osteoclastogenesis by osteoprotegerin (OPG), a natural inhibitor of OPGL. This patent is highly relevant as it describes the biological pathway involving OPGL and OPG, which is central to the invention of US7364736.
  • Potential Anticipation: This patent is highly relevant to the background and utility of anti-OPGL antibodies. Depending on its specific claims, it could potentially anticipate claims in US7364736 related to the understanding of OPGL's role in bone disorders, or methods of treating bone disorders by modulating OPGL activity, such as claims 23, 24, and 25.

• US6479635B1: Anderson et al., "Osteoclastogenesis inhibitory factor (OCIF)"

  • Publication Date: November 12, 2202 [sic]. Note: The publication date of "November 12, 2202" appears to be a typo in the search result. Based on other patents by Anderson et al. in the cited list and typical patent timelines, it is likely intended to be 2002.
  • Brief Description: This patent describes osteoclastogenesis inhibitory factor (OCIF), which is another name for osteoprotegerin (OPG). Similar to US6271349B1, this patent details the biology related to OPGL.
  • Potential Anticipation: Similar to US6271349B1, this patent could potentially anticipate claims in US7364736 related to the biological understanding of OPGL and its role in bone metabolism, and potentially methods of treatment based on modulating this pathway, such as claims 23, 24, and 25.

• US6528482B1: Anderson et al., "Osteoclastogenesis inhibitory factor (OCIF)"

  • Publication Date: March 4, 2003.
  • Brief Description: Another patent by Anderson et al. on OCIF/OPG.
  • Potential Anticipation: This patent would have similar potential anticipation implications as US6479635B1 and US6271349B1 regarding the underlying biology and therapeutic approaches to bone disorders via the OPGL/OPG pathway.

It's important to note that a full anticipation analysis would require a detailed claim comparison for each cited patent against each claim of US7364736, considering all limitations and the effective filing dates. The descriptions above offer a high-level assessment of potential areas of overlap.

Obviousness Analysis under 35 U.S.C. § 103 for US Patent 7364736

This analysis addresses the obviousness of US Patent 7364736, titled "Antibodies to OPGL," under 35 U.S.C. § 103, considering prior art available before the patent's priority date of June 26, 2001. A Person Having Ordinary Skill in the Art (PHOSITA) in immunology and molecular biology at that time would have understood the role of osteoprotegerin ligand (OPGL) in bone metabolism and the general methods for generating therapeutic antibodies.

The Invention as Claimed

The core of US7364736 generally relates to antibodies that bind osteoprotegerin ligand (OPGL). More specifically, the invention provides a fully human monoclonal antibody, referred to as ɑOPGL-1, defined by its specific heavy chain (SEQ ID NO: 2) and light chain (SEQ ID NO: 4) amino acid sequences, including their respective variable regions (SEQ ID NO: 13 and SEQ ID NO: 14). The patent also claims fragments, variants with high sequence identity (e.g., at least 90%, 95%, or 99% identity to SEQ ID NO: 13 and 14), pharmaceutical compositions containing these antibodies, and methods of treating osteopenic disorders, inflammatory conditions with attendant bone loss, autoimmune conditions with attendant bone loss, and rheumatoid arthritis using these antibodies. A key emphasis of the patent is the use of fully human antibodies to minimize immunogenic responses.

General Knowledge of a PHOSITA (pre-June 2001)

Before June 26, 2001, a PHOSITA would have possessed significant knowledge regarding:

• OPGL's Role in Bone Metabolism: OPGL (also known as RANKL) was well-established as a member of the TNF family of cytokines that promotes osteoclast formation by binding to its receptor, ODAR (RANK). The antagonist, osteoprotegerin (OPG), was known to inhibit osteoclast formation by sequestering OPGL, preventing its association with ODAR. An imbalance leading to increased OPGL activity was understood to correlate with osteopenic disorders like osteoporosis.
• Therapeutic Potential of OPGL Inhibition: Given OPGL's direct role in osteoclastogenesis and bone resorption, a PHOSITA would have readily recognized that reducing OPGL activity (e.g., through an antibody) could be a viable therapeutic strategy for conditions involving excessive bone loss.
• Antibody Generation Techniques: Standard methods for producing monoclonal antibodies were well-known, including hybridoma technology. Techniques for developing human or humanized antibodies to reduce immunogenicity in human patients were also established. These included humanization via CDR grafting (e.g., U.S. Pat. Nos. 6,180,370, 5,693,762, 5,693,761, 5,585,089, and 5,530,101, cited within the patent as prior art methods) and the use of transgenic animals capable of producing human antibodies (e.g., PCT Published Application No. WO 93/12227, and Mendez et al. Nature Genetics 15:146-156 (1997), also cited within the patent). The patent explicitly describes the production of fully human monoclonal antibodies specific for OPGL by immunizing transgenic mice containing human immunoglobulin genes.

Prior Art Combinations and Motivation to Combine

Considering the above, the following combination of prior art references would likely render the claims of US7364736 obvious:

Reference A: Prior Art Disclosing OPGL's Role and Therapeutic Target
A PHOSITA would have been aware of numerous publications from the late 1990s detailing the discovery and characterization of OPGL (also known as RANKL, ODF) and its crucial role in osteoclast formation and bone resorption. For example, publications by Lacey et al. (e.g., Lacey et al., Cell, 93:165-176, 1998; or Lacey et al., Am. J. Pathol. 157:435-448, 2000, which is cited in the patent itself discussing OPG administration) and Yasuda et al. (e.g., Yasuda et al., Proc. Natl. Acad. Sci. USA, 95:3597-3602, 1998) thoroughly elucidated the OPGL-RANK-OPG system and its implications for bone diseases. These references would have clearly established OPGL as a promising therapeutic target for inhibiting bone loss. The patent itself states that "Increased osteoclast activity correlates with a number of osteopenic disorders... Therefore, a reduction in OPGL activity may result in a decrease in osteoclast activity and may reduce the severity of osteopenic disorders".

Reference B: Prior Art Disclosing Methods for Generating Human Antibodies
Concurrently, the scientific community had well-established methods for producing therapeutic antibodies, particularly fully human antibodies, by the priority date.

• Transgenic Mice: The use of transgenic mice engineered to produce human immunoglobulins was a known technology, as evidenced by references such as PCT Published Application No. WO 93/12227 and Mendez et al. Nature Genetics 15:146-156 (1997). The current patent explicitly describes using such transgenic mice for producing its antibodies.
• Hybridoma Technology: Standard hybridoma techniques for isolating antibody-producing cells from immunized animals and generating monoclonal antibodies were routine.
• Antibody Engineering (e.g., Humanization): Techniques for humanizing antibodies, such as CDR grafting, were also known and described in various patents (e.g., U.S. Pat. Nos. 6,180,370, 5,693,762, 5,693,761, 5,585,089, and 5,530,101). While these typically involved starting with a non-human antibody, the goal was to achieve a less immunogenic antibody suitable for human therapy.

Motivation to Combine:

A PHOSITA, armed with the knowledge from Reference A that OPGL is a critical target for treating bone loss disorders, would have a clear motivation to develop therapeutic agents that block OPGL activity. The established methods for generating fully human antibodies described in Reference B provided a well-known and preferred approach for developing such therapeutic agents, especially given the desire to minimize immunogenicity for chronic treatments (e.g., osteoporosis).

Specifically, a PHOSITA would be motivated to:

1. Select OPGL as an Antigen: Based on its known function in osteoclastogenesis and bone resorption, OPGL would be a prime candidate for antibody-based therapy against osteopenic disorders.
2. Generate Antibodies Against OPGL: Given the availability of techniques for producing monoclonal antibodies, a PHOSITA would naturally attempt to generate antibodies that specifically bind to OPGL.
3. Choose Fully Human Antibodies: Recognizing the need for low immunogenicity in human therapeutic applications, a PHOSITA would have a strong motivation to produce fully human antibodies against OPGL using known methods like transgenic mice. This approach was specifically highlighted in the patent as desirable.
4. Screen for Functional Antibodies: Once antibodies were generated, routine screening assays (e.g., for binding to OPGL and inhibition of osteoclast formation) would be employed to identify antibodies with desired therapeutic properties. The patent itself describes such assays (e.g., dose-dependent binding to OPGL-coated plates, inhibition of osteoclast formation, inhibition of OPGL binding to ODAR).

Therefore, the combination of prior art demonstrating OPGL as a therapeutic target and well-known, established methods for generating fully human antibodies would have rendered the concept of generating a fully human antibody against OPGL to treat bone disorders obvious to a PHOSITA before the priority date. The specific sequences of ɑOPGL-1 (SEQ ID NOs: 2, 4, 13, and 14) represent a successful outcome of applying these known techniques, rather than an inventive step over the motivation to combine. While the specific sequence might not be explicitly disclosed, the process of obtaining such a sequence through routine antibody development and screening against a known target would be considered obvious to try with a reasonable expectation of success.

Conclusion

The claims of US7364736, directed to an antibody against OPGL, its fragments, pharmaceutical compositions, and methods of treatment, would likely have been obvious to a PHOSITA prior to June 26, 2001. The well-understood role of OPGL in bone pathology (Reference A) provided a clear motivation to target it therapeutically. The widely available and well-described methods for generating fully human antibodies (Reference B), particularly using transgenic mice, provided the means to produce such a therapeutic agent with a reasonable expectation of success. The specific ɑOPGL-1 antibody sequences represent a successful embodiment of this obvious strategy rather than an unexpected or non-obvious invention.The user has asked for an obviousness analysis of US Patent 7364736 under 35 U.S.C. § 103, using the provided patent text and focusing on prior art available before June 26, 2001.

I have already outlined the core claims of US7364736, the general knowledge of a PHOSITA before the priority date, and the motivation to combine relevant prior art.

My previous response identified two categories of prior art (Reference A: OPGL's role; Reference B: Methods for generating human antibodies) and explained the motivation to combine them. Now, I need to find concrete examples of these references and integrate them into the analysis, making sure they pre-date June 26, 2001.

Based on the search results, I can gather specific prior art:

Reference A (OPGL's role and therapeutic target):

• Lacey et al., 1998 (Cell. 93: 165–176): This is explicitly cited in the patent itself and also mentioned in search results. It discusses OPGL's role in osteoclast formation and bone resorption, and states that administration of OPGL to normal mice resulted in hypercalcemia, consistent with increased osteoclast activity. It also notes that OPG blocks OPGL's effects on actin ring formation and bone resorption, indicating OPGL as a key regulator.
• Yasuda et al., 1998 (Proc. Natl. Acad. Sci. USA, 95:3597-3602): This reference is cited by as identifying RANKL (OPGL) as the osteoclast differentiation factor.
• Wong et al., 1997 (Cell. 89:309–319): Also cited in and, contributes to the understanding of OPGL.
• February 1999 Nature publication (397(6717):315-23): This describes OPGL as a key regulator of osteoclastogenesis.
• Yun et al., 2001 (J Immunol. 2001 Feb 1;166(3):1482-91): Published before the priority date, it discusses OPG's role as a crucial regulator of bone metabolism.
• The overall understanding of the RANKL-RANK-OPG system as central regulators of osteoclast development and function, with implications for diseases like osteoporosis and rheumatoid arthritis, was established by the late 1990s.

Reference B (Methods for generating human antibodies):

• Hybridoma technique (Köhler and Milstein, 1975): This fundamental method for generating monoclonal antibodies was well-established by the priority date.
• Humanization by CDR grafting (Winter's team, 1986): This technique, involving grafting CDRs from mouse antibodies onto human frameworks to reduce immunogenicity, was known. The patent itself mentions CDR grafting with various U.S. patents.
• Phage Display Technology (George Smith, 1985): This method, along with the development of scFv and methods for selecting human antibodies from phage display repertoires, was known and used for generating human antibodies.
• Transgenic Mouse Models: The use of transgenic mice engineered to produce fully human antibodies was a known technology. The patent itself describes using such mice, referencing PCT Published Application No. WO 93/12227 and Mendez et al. Nature Genetics 15:146-156 (1997).

Motivation to Combine:

The motivation to combine these areas of knowledge is very strong. Given the clear understanding of OPGL's crucial role in bone resorption and its direct link to osteopenic disorders like osteoporosis, a PHOSITA would be highly motivated to develop an antagonist for OPGL. Antibodies were a well-known and increasingly popular class of therapeutic agents, particularly for modulating protein-protein interactions like ligand-receptor binding. The desire to create a safe and effective therapeutic for humans would naturally lead a PHOSITA to choose fully human antibodies, employing established techniques like transgenic mice or phage display, or humanization techniques like CDR grafting. The expectation of success in finding an antibody that binds OPGL and inhibits its activity would be reasonable given the routine nature of antibody development against known targets.

I will now synthesize this information into a comprehensive obviousness analysis.### Obviousness Analysis under 35 U.S.C. § 103 for US Patent 7364736

This analysis evaluates the obviousness of US Patent 7364736, titled "Antibodies to OPGL," under 35 U.S.C. § 103, considering the state of the art prior to its priority date of June 26, 2001. A Person Having Ordinary Skill in the Art (PHOSITA) in immunology and molecular biology during that period would have possessed a comprehensive understanding of osteoprotegerin ligand (OPGL) biology and the prevailing methodologies for generating therapeutic antibodies.

The Invention as Claimed

US Patent 7364736 generally claims antibodies that specifically bind to osteoprotegerin ligand (OPGL). More precisely, the patent describes a fully human monoclonal antibody, ɑOPGL-1, characterized by its specific heavy chain (SEQ ID NO: 2) and light chain (SEQ ID NO: 4) amino acid sequences, including their respective variable regions (SEQ ID NO: 13 and SEQ ID NO: 14). The patent also extends to fragments and variants of these antibodies (e.g., with at least 90%, 95%, or 99% sequence identity to the variable regions), pharmaceutical compositions containing these antibodies, and methods for treating various conditions such as osteopenic disorders, inflammatory conditions with associated bone loss, autoimmune conditions with attendant bone loss, and rheumatoid arthritis. A central aspect emphasized in the patent is the use of fully human antibodies to minimize undesirable immunogenic responses in human patients.

General Knowledge of a PHOSITA (Pre-June 26, 2001)

Before the priority date, a PHOSITA would have had extensive knowledge in several key areas:

• OPGL's Critical Role in Bone Metabolism and Disease: By the late 1990s, the discovery and characterization of OPGL (also known as RANKL or ODF) had established it as a pivotal cytokine in the TNF family. It was understood that OPGL promotes osteoclast formation and activity by binding to its receptor, ODAR (RANK). Conversely, osteoprotegerin (OPG) was known to inhibit osteoclastogenesis by acting as a decoy receptor, sequestering OPGL and preventing its interaction with ODAR. This intricate balance was recognized as fundamental to bone remodeling, and an imbalance, particularly increased OPGL activity, was directly linked to osteopenic disorders like osteoporosis and conditions involving pathological bone loss, such as rheumatoid arthritis. For example, Lacey et al. (1998) and Yasuda et al. (1998) were seminal works elucidating this system. The patent itself articulates this understanding, stating that "Increased osteoclast activity correlates with a number of osteopenic disorders... Therefore, a reduction in OPGL activity may result in a decrease in osteoclast activity and may reduce the severity of osteopenic disorders."
• Therapeutic Promise of OPGL Inhibition: Given the clear understanding of OPGL's mechanism in driving bone resorption, a PHOSITA would have readily identified OPGL as a highly attractive therapeutic target for mitigating bone loss in various disease states. The concept that blocking OPGL could reduce osteoclast activity and thus ameliorate osteopenic conditions would have been self-evident.
• Established Antibody Generation Technologies: The art of generating therapeutic antibodies was well-developed.
  • Hybridoma Technology: The foundational technique for producing monoclonal antibodies, pioneered by Köhler and Milstein in 1975, was routine.
  • Humanization Techniques: Methods for engineering antibodies to reduce immunogenicity in human patients were standard. These included CDR (Complementarity Determining Region) grafting, where non-human CDRs responsible for antigen binding are transferred to human antibody frameworks. US7364736 itself references several patents (e.g., U.S. Pat. Nos. 6,180,370, 5,693,762, 5,693,761, 5,585,089, and 5,530,101) describing CDR grafting as known technology.
  • Phage Display: This technology, developed by George Smith in 1985, allowed for the isolation and selection of human antibody fragments from large libraries.
  • Transgenic Animals for Fully Human Antibodies: The use of genetically engineered transgenic mice that could produce antibodies with fully human immunoglobulin sequences was a known and actively pursued method for generating therapeutic antibodies with minimal immunogenicity. The patent explicitly cites PCT Published Application No. WO 93/12227 and Mendez et al. Nature Genetics 15:146-156 (1997) as technologies for producing human antibodies in transgenic mice. The patent states that its "antibodies are prepared through the utilization of a transgenic mouse that has a substantial portion of the human antibody producing genome inserted but that is rendered deficient in the production of endogenous, murine, antibodies."

Obviousness Through Combination of Prior Art

The claims of US7364736 would have been obvious to a PHOSITA before the priority date based on the combination of established knowledge regarding OPGL's therapeutic relevance and the routine methods for generating fully human antibodies.

Motivation to Combine:

A PHOSITA, understanding that OPGL is a central regulator of bone resorption (as shown by Lacey et al., Yasuda et al., and others), would have been strongly motivated to develop therapeutic antagonists to block OPGL activity as a treatment for bone loss disorders. Antibodies were a well-recognized and promising class of biotherapeutics for specifically modulating protein-protein interactions. Given the increasing demand for therapies with reduced immunogenicity for chronic human conditions, the PHOSITA would have been particularly motivated to develop fully human antibodies.

The pathway to achieving this would involve:

1. Identifying OPGL as a Target: The scientific literature clearly pointed to OPGL as a key factor in pathological bone loss, making it an evident target for therapeutic intervention.
2. Choosing an Antibody Approach: Antibodies were a standard and effective modality for blocking ligand-receptor interactions.
3. Selecting "Fully Human" Antibody Technology: With known methods such as using transgenic mice (as described in PCT WO 93/12227 and Mendez et al. 1997, and also used by the patent itself) or phage display technology, a PHOSITA would have chosen to generate fully human antibodies to minimize immunogenicity for long-term human therapy.
4. Routine Screening and Optimization: Once antibodies or antibody-producing cells were generated, routine screening assays (e.g., for binding affinity to OPGL and the ability to inhibit osteoclast differentiation and activity) would be employed. The patent describes such standard assays in its examples (e.g., FIGS. 7-12). The process of identifying specific high-affinity binders from a library or through hybridoma screening, and then potentially optimizing them through known antibody engineering techniques, would have been considered routine and "obvious to try" with a reasonable expectation of success.

The specific heavy and light chain sequences of ɑOPGL-1 (SEQ ID NOs: 2, 4, 13, and 14) represent the successful outcome of applying these well-known techniques to a known therapeutic target. While the exact amino acid sequences of ɑOPGL-1 might not have been explicitly disclosed in any single prior art reference, the process for obtaining such a fully human antibody against OPGL was well within the grasp of a PHOSITA given the collective knowledge and available technologies by June 2001.

Conclusion

Therefore, the claims of US7364736, encompassing antibodies to OPGL, their compositions, and therapeutic uses, would have been obvious to a PHOSITA before the priority date. The clear therapeutic need for an OPGL antagonist, coupled with established and commonly employed methodologies for generating fully human antibodies, would have provided a strong motivation and reasonable expectation of success for developing the claimed invention.