The IP ABCs of ADCs Deborah Smith, PhD., J.D. and

slide1. The IP ABCs of ADCs Deborah Smith, PhD., J.D. and Julia Minitti PhD., J.D.Wilson SonsiniPatents and Innovations Group<br>
slide2. Disclaimer The information in this presentation is for general informational purposes only and may not reflect the current law in your jurisdiction. Nothing in this presentation should be interpreted as legal advice for any individual case or situation. This information does not aim to create, and receipt or viewing does not establish, an attorney-client relationship. No participant in this presentation should take action, or avoid taking action, based on any information included in or accessible through this presentation without seeking legal or other professional advice from an appropriately licensed professional in their state, country, or other appropriate jurisdiction. The views expressed in this presentation reflect those of the presenter herself and do not necessarily reflect the views of Wilson Sonsini and its clients.<br>
slide3. Overview Intro to Antibody-Drug Conjugates (ADCs)
ADC Components
ADC Areas of Innovation
ADC Patenting Approach
Types of Patent Filings
Payload-Focused Patent Filings
Linker and Linker/Payload-Focused Patent Filings
Antibody-Focused Patent Filings
Enhertu® Case Study
Timing of ADC Patent Filings
Ownership of ADC Filings
FTO for ADC Products
Conclusions<br>
slide4. Intro to Antibody-Drug Conjugates (ADCs) ADCs, often referred to as 'guided missiles' in cancer therapy, combine the precision of monoclonal antibodies with the killing power of cytotoxic drugs
Antibody drug conjugates (ADCs) have the advantages of good tolerance, accurate target recognition, and small effects on non-cancerous cells as compared to traditional antitumor therapies such as chemotherapy and radiation therapy
ADCs are a growing sector of approved oncology drugs with at least 13 approved to date and 100s currently in clinical development
ENHERTU® revenue exceeding $2.5B annually (as of March 2024)
KADCYLA® sales exceeding $2B (for 2025)

Mol Cancer, 2024 Mar 23; 23:62
https://www.daiichisankyo.com/files/investors/library/materials/2023/March%202024%20ENHERTU%20Business%20Briefing_E_Final.pdf<br>
slide5. Intro to Antibody-Drug Conjugates (ADCs) Copyright 2022 Springer Nature<br>
slide6. Antibody-Drug Conjugate (ADC) Components Overexpression in cancer cells
Low expression in healthy cells
Expressed on cancer cell surface
Antigen secretion into bloodstream Binding affinity
Cell permeability
Low immunogenicity
Extended Half-life
Scaffold
Blocking/non-blocking
Bioconjugation sites Antigen Antibody<br>
slide7. Antibody-Drug Conjugate (ADC) Components Linker Payload Avoid inducing ADC aggregation
Prevent premature payload release in bloodstream
Balance hydrophobicity of the payload
Bioconjugation handle for consistent Drug-to-Antibody Ratio (DAR)
Payload attachment and release
Cleavable or non-cleavable<br>
slide8. Antibody-Drug Conjugate (ADC) Innovations Exemplary areas of innovation:
Novel payloads/targets
Novel antigen targets
Modifying internalization properties
Modifying drug release properties
Modifying hydrophobicity
Modifying or controlling homogeneity of DAR
Modifying bystander activity
Bioconjugation improvements
Heterogenous (multiple) payloads<br>
slide9. Antibody-Drug Conjugates (ADC) Patenting Approach Filing Patents on ADC innovations:
Where is your focus of innovation?
Antibody? Payload? Linker?
Are you innovating a platform (e.g., linker) that you plan to license to third parties?
Are you using one or two known components (from a third party) in your ADC?
How similar is your innovated component to what is known?
What is your drug discovery timeline, and how close are you to identifying a lead?
If you have innovated in one of the three components, have you shown examples with variability at the other two?
e.g., If you invented a new linker, have you attached it to a variety of payloads and antibodies (or plan to)?
How many molecules can you make and test in the coming year?<br>
slide10. Refresher on the Patentability Requirements:
Novelty: Is my invention new and clearly distinguished from the prior art?
Non-obviousness/Inventive: Is my invention sufficiently innovative? What specific problem does it address, and what unexpected advantages does it offer?
Written Description: Have I included a representative number of examples to show possession of the full scope of the claimed invention at the time of filing the application? This ensures that broader aspects are not prematurely claimed.
Enablement: Is there enough guidance and examples for a skilled chemist to make and use the full scope of the claimed invention without undue experimentation? Antibody-Drug Conjugates (ADC) Patenting Approach<br>
slide11. Antibody-Drug Conjugates (ADC) Patenting Approach Types of Patents Filed on ADCs, for example:
Full ADC: specifying the antibody, linker, and payload.
Conjugated Linker: linker specified, payload/antibody can be any suitable option
Conjugated Payload: payload specified, linker/antibody can be any suitable option
Conjugated Antibody: antibody specified, linker/payload can be any suitable option
Dual Combination: e.g., payload-linker specified, antibody can be any suitable option
Unconjugated Linker: linker intermediate
Unconjugated Antibody: antibody intermediate
Unconjugated Payload: payload intermediate
DAR Innovations: improvements to Drug-to-Antibody Ratio (DAR)<br>
slide12. Consider how best to Enable and Describe your innovation as these are common challenges for ADC patents
Consider how broadly your innovation may be applicable to other molecules
New linker:
How would you attach it to a variety of small molecule payloads? Could you attach multiple payloads to a single linker? How do you plan to bioconjugate the linker?
New linker-payload:
What structural diversity have you tested for your linker-payloads? Have you tested the attachment of the linker at different positions on the payload? How versatile is the linker-payload to variable antibody bioconjugation?
How many ADCs do you plan to generate in the coming year? Will you attach to a variety of antigen-targeting antibodies? How will you make them? Antibody-Drug Conjugates (ADC) Patenting Approach<br>
slide13. Payload-Focused Patent Filings<br>
slide14. Conjugated Payload Example: Immunogen US Patent No. 5,208,020 Antibody and linker (with disulfide bridge) can be any suitable option<br>
slide15. Unconjugated Payload Example: Daiichi US Patent No. 5,658,920 Protection of potential synthetic intermediate<br>
slide16. Unconjugated Payload/Active Metabolite Example: Daiichi US Patent No. 10,973,924 Protection of DXd active metabolite extends patent term<br>
slide17. Unconjugated Payload Example: Seagen US Patent No. 6,884,869<br>
slide18. Linker or Linker/Payload-Focused Patent Filings<br>
slide19. Conjugated Linker Example: Daiichi US Patent No. 9,808,537 Antibody and drug can be any suitable option<br>
slide20. Conjugated Linker Example: Seagen US Patent No. 7,659,241 Antibody can be any suitable option<br>
slide21. Conjugated Payload-Linker Example: Daiichi US Patent No. 9,808,537 (cont.) Antibody can be any suitable option<br>
slide22. Unconjugated Linker Example: Daiichi US Patent No. 12,186,310 Protection of synthetic intermediate<br>
slide23. Antibody-Focused Patent Filings<br>
slide24. Conjugated Antibody-Drug Example: Immunogen US Patent No. 8,337,856<br>
slide25. Unconjugated Antibody Example: Genentech US Patent No. 9,518,118 Protection of synthetic intermediate<br>
slide26. Enhertu® Case Study<br>
slide27. Enhertu® From Enhertu® Product Label HER2 directed antibody and topoisomerase inhibitor conjugate indicated for HER2-positive or mutant cancers including Metastatic Breast, Metastatic Non-Small Cell Lung, Metastatic Gastric and Metastatic Solid Tumors

First approved by the FDA on December 20, 2019 Trastuzumab<br>
slide28. Enhertu® Antibody Unconjugated Antibody (Herceptin, aka trastuzumab) developed by Roche and FDA approved September 25, 1998
Antibody composition of matter patent expired between 2012 and 2015 with first biosimilar approved in December of 2017 (Ogivri)
To date, six Herceptin biosimilars have been approved and multiple ADC companies have incorporated Herceptin into their ADC products and product candidates https://purplebooksearch.fda.gov/patent-list<br>
slide29. Enhertu® Deruxtecan Payload (DXd) https://pubchem.ncbi.nlm.nih.gov/compound/Exatecan
https://pubchem.ncbi.nlm.nih.gov/compound/Camptothecine Exatecan Camptothecin Isolated from the bark of the “Happy Tree” native to China and used in traditional Chinese medicine DXd<br>
slide30. Enhertu® Linker-Payload Deruxtecan Exatecan is not approved in the US as a stand-alone drug and is not covered under an active patent
Daiichi Sankyo holds active patents on ADCs including deruxtecan and the released drug DXd extending patent term to 20332 2https://patents.google.com/patent/US9808537B2/en<br>
slide31. Enhertu® Linker-Payload Deruxtecan Patent Protection<br>
slide32. Linker Patent Dispute: Daiichi Sankyo v. Seagen (Federal Circuit, December 2025) In 2008, Daiichi Sankyo and Seagen partnered to develop ADCs targeting cancer cells
Following the collaboration, Daiichi Sankyo developed Enhertu®, an anti-HER2 antibody covalently conjugated to drug-linker deruxtecan, approved for treating breast cancer, non-small cell lung cancer, and gastric/gastroesophageal cancer
Seagen sued Daiichi for infringing US Patent No. 10,808,039
(October 2022) The District Court upheld a jury verdict finding that Seagen’s patent was valid and infringed and ordered Daiichi to pay $41.8 M in damages and ongoing royalty of 8% on sales of ENHERTU®
(Dec 2025) U.S. Federal Circuit Court reversed the District Court’s decision, ruling that Seagen’s patent was invalid. Consequently, the infringement judgement and damages award against Daiichi Sankyo were vacated.<br>
slide33. An antibody-drug conjugate having the formula:

or a pharmaceutically acceptable salt thereof,

wherein: Ab is an antibody,
S is sulfur,
each —Ww— unit is a tetrapeptide;
wherein each —W— unit is independently an Amino Acid unit having the formula denoted below in the square bracket:
wherein R19 is hydrogen or benzyl,
Y is a Spacer unit,
y is 0, 1 or 2,
D is a drug moiety, and
p ranges from 1 to about 20,
wherein the S is a sulfur atom on a cysteine residue of the antibody, and
wherein the drug moiety is intracellularly cleaved in a patient from the antibody of the antibody-drug conjugate or an intracellular metabolite of the antibody-drug conjugate. Daiichi Sankyo v. Seagen (Federal Circuit, December 2025): Exemplary Seagen Claim<br>
slide34. Outcome of Daiichi Sankyo v. Seagen (Federal Circuit, December 2025) Patent Invalidated: The Federal Circuit invalidated Seagen’s US Patent No. 10,808,039,which was directed to ADCs with subgenus of tetrapeptide linkers (including Enhertu® GGFG linker)
Lack of Written Description: insufficient detail on the claimed subgenus of tetrapeptide linkers in the 2004 priority application
Seagen’s issued patent (filed July 2019) covered 81 tetrapeptide linkers, including G/F-only linkers, while the original 2004 application covered >47M tetrapeptide linkers
Only 3 exemplified tetrapeptide sequences (GFLG, ALAL, GSVQ); none included G/F-only linker
Lack of Enablement: identifying ADCs containing a drug moiety that cleaves in a patient would require undue experimentation and “trial-and-error discovery”
Lack of Priority: Seagen’s patent could not claim the 2004 priority date because the necessary support for the claimed invention was not in the original filing
Intervening Art: Daiichi’s disclosure of Enhertu® structure at 2015 conference was deemed to be anticipatory prior art to Seagen’s patent (filed July 2019), invalidating Seagen’s patent G: glycine
F: phenylalanine<br>
slide35. Lessons Gleaned from Fed Circuit’s Decision Examples within the scope of the claims are important for both written description and enablement support of claims
Consider adding known elements into your specification for components of your ADC to show that you had envisioned the full scope of your claimed invention, even if you have a limited number of examples, e.g., list a variety of drugs and drug classes that you could attach to your novel linkers
Support your application at the time of filing by generating a variety of molecules with variable components where you seek breadth to your claims, e.g., test your linker payload with multiple antibodies of different antigen targets, epitope, sequences, etc.
Consider enablement hurdles to your claim scope while drafting and include representative procedures and examples, e.g., synthetic approaches to attaching payloads to linkers, bioconjugating linkers to antibodies, achieving a consistent DAR
File a robust provisional application that includes examples that fall within your claims to secure the priority date for the full claim scope<br>
slide36. Timing of ADC Patent Filings<br>
slide37. Timing of ADC Filings Multifaceted nature of ADCs typically result in multiple innovations
Consider how to strategically file patents on these innovations to cover your Development Candidate (DC) while also protecting other innovations leading up to the DC
Consider filing on improvements to early patent applications prior to their publication to prevent your own innovations from being considered prior art
Patent filings trigger publication and costs
Patent application will publish 6 months after PCT filing (18 months from earliest priority)
National phase filings are due 18 months after PCT filing and can be very costly for a patent application covering a DC (~$200K+) Provisional
Application PCT Application
1 year National Phase
2.5 year Publication
1.5 years<br>
slide38. Ownership of ADC Patent Filings<br>
slide39. Ownership of ADC Innovations Companies developing ADCs often source one or more ADC components from third parties
It is essential to understand what patent rights exist for the third-party component and who they belong to
e.g., even if the original composition of matter patent has expired, are there other patents covering specific aspects of the component (linker handle, etc.)
If a license is needed for a third-party component, ensure you understand and negotiate contractual obligations with the third party
e.g., does the license require co-ownership of any inventions filed that include the third-party component?
If collaborating with a third party on ADC development, maintain a clear contractual agreement outlining who has rights to the innovations resulting from the collaboration<br>
slide40. FTO for ADC Products<br>
slide41. Freedom to Operate Analysis for ADCs Given the multiple components and approaches to patenting ADCs, conduct multiple searches to clear an ADC Development Candidate
Searches should consider antigen targets, antibody sequences, linker sequences, payload targets, payload structures, etc.
Understand your development timeline and strategy and how it will interact with third-party patent terms
Consider design-around possibilities if needed to avoid infringing on third-party patents
Work with licensing counsel to secure rights to third-party components on favorable terms<br>
slide42. Freedom to Operate Analysis for ADCs: Search Strategy Patentability in Reverse:
Full ADC with specified antibody, linker and payload
Conjugated linker (open to payload/antibody)
Conjugated payload (open to linker/antibody)
Conjugated antibody (open to linker/payload)
Combinations of i) conjugated linker, ii) conjugated payload, and iii) conjugated antibody
Unconjugated linker intermediate
Unconjugated antibody intermediate
Unconjugated payload intermediate
DAR-related innovations<br>
slide43. Conclusions The multifaceted nature of ADCs necessitates a comprehensive approach to IP
Focus on your areas of innovation and communicate the problems you are solving with your IP counsel
Enablement and Written Description are important considerations when filing a provisional application and throughout the priority year. Examples and procedures will be important for enabling and describing your claimed invention
Freedom to operate (FTO) searching for an ADC product should be performed from multiple angles. Searches should be routinely updated on a periodic basis to identify new third-party publications and patents as they publish
If you need to collaborate with a third party to gain rights to an ADC component, consider the impact on IP ownership and how this could impact your business plan
When one of your filings is approaching publication, consider if new filings should be made prior to the publication date<br>
slide44. Thank you dmsmith<br>