Patent: 10,004,812

Summary for Patent: 10,004,812

Title:	Antibody-drug conjugates and immunotoxins
Abstract:	The present invention relates to conjugates, in particular antibody-drug conjugates and immunotoxins, having the formula I: A-(L-D)p (I) or a pharmaceutically acceptable salts or solvates thereof, wherein: A is an antibody that selectively binds Endoglin; L is a linker; D is a drug comprising a cytolysin or a Nigrin-b A-chain; and p is 1 to 10, and to use of such conjugates in the therapeutic treatment of tumors. Methods of producing such conjugates and components for use in such methods are disclosed.
Inventor(s):	Kontermann; Roland (Nurtingen, DE), Pfizenmaier; Klaus (Tiefenbronn, DE), Ferrer; Cristina (Madrid, ES), Fabre; Myriam (Barcelona, ES), Simon; Laureano (Derio, ES)
Assignee:	Oncomatryx Biopharma, S.L. (Derio, ES)
Application Number:	15/116,419
Patent Claims:	see list of patent claims

United States Patent 10,004,812: What the Claims Cover, What They Don’t, and How the Landscape Reads

US Patent 10,004,812 (the “’812 patent”) claims a targeted antibody-drug conjugate (ADC) built around (1) an endoglin-binding antibody (A), (2) a linker (L), and (3) a “cytolysin” payload (D) having a tightly defined chemical scaffold (Formula IV). The patent then extends into broad therapeutic methods for endoglin-expressing tumors and endoglin-expressing inflammatory or ocular diseases.

What matters commercially is not just “an ADC to endoglin,” which is a crowded concept. It is the specific payload class, the payload chemistry defined by multiple substituent variables, and claim layering that hard-locks the ADC architecture to those chemical boundaries while leaving relatively wide room on antibody selection (at the independent claim level) and clinical pairing (combination therapy lists).

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1) What is claimed in US 10,004,812?

A. Conjugate claim architecture (Claim 1 is the core)

Claim 1 defines:

• Conjugate formula: A-(L-D)_p, where:
  • A is an antibody that selectively binds endoglin
  • L is a linker
  • D is a drug comprising a cytolysin
  • p is 1 to 10 (DAR/valency range in structural terms)
• Cytolysin structure: D must be a cytolysin of Formula IV, with nested definitions for substituents:
  • R2: H or C1-C4 alkyl
  • R6: C1-C6 alkyl
  • R7: C1-C6 alkyl, CH2OR19, or CH2OCOR20
  • R19: alkyl
  • R20: C2-C6 alkenyl, phenyl, or CH2-phenyl
  • R9: C1-C6 alkyl
  • R10: H, OH, O-alkyl, or O-acetyl
  • f: 1 or 2
  • R11: structure defined by another moiety (substituent R21)
  • R21 options: H, OH, halogen, NH2, alkyloxy, phenyl, alkyl amino, dialkyl amino
  • R16: H or C1-C6 alkyl
  • R17: directly or indirectly attached to linker L
  • q: 0, 1, 2, or 3

This is a classic “chemical payload scaffold” strategy: the ADC is defined by a constrained payload chemistry and a constrained attachment topology, with less rigidity on the antibody at the top claim level.

B. Antibody specificity tightening (Claims 2-4)

• Claim 2: A includes specific CDR sequences:
  • CDRH1 = SEQ ID NO: 7
  • CDRH2 = SEQ ID NO: 8
  • CDRH3 = SEQ ID NO: 9
  • CDRL1 = SEQ ID NO: 10
  • CDRL2 = SEQ ID NO: 11
  • CDRL3 = SEQ ID NO: 12
• Claim 3: A includes:
  • VH = SEQ ID NO: 5
  • VL = SEQ ID NO: 6
• Claim 4: A includes:
  • Heavy chain = SEQ ID NO: 3
  • Light chain = SEQ ID NO: 4

From an enforcement perspective, this matters because:

• The independent claim permits any endoglin-binding antibody meeting the “selectively binds endoglin” standard, but the dependent claims map to specific antibody sequences/CDRs.
• Litigation dynamics often turn on what constitutes “selectively binds endoglin” and whether a competitor’s antibody reads onto the CDR/sequence-defined embodiments.

C. Payload-linker connection constraints (Claim 5)

Claim 5 narrows R17 (the payload attachment group) to specific chemical forms for the linkage point to L:

• R17 is one of: C(O)X, CONHNHX, OX, NHX, or SX
• X is a bond to linker L

This limits how the payload connects to the linker and blocks design-arounds that shift attachment through alternate functional handles not captured by those enumerated classes.

D. Linker and spacer details (Claims 6-10)

• Claim 6: L further comprises a spacer
• Claim 7: spacer has chain length 2 to 30 atoms
• Claim 8: spacer comprises or consists of:
  • --(CH2)n-- or --(OCH2CH2)n--
  • n = 1 to 10
• Claims 9-10:
  • spacer is directly attached to R17 or attached via a bridging group
  • in Claim 10: spacer is attached to R17 via a --C(O)X bridging group, where X bonds to R17

Claim 13 and Claim 12 push further into a specific linker chemistry.

E. Explicit linker embodiment (Claims 12-14)

• Claim 12: L comprises:
  • an attachment group for attachment to A
  • a protease cleavable portion
• Claim 13: L comprises:
  • maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamate
• Claim 14: L-D has a structure “selected from the group consisting of” specified chemical structures.

This combination (general protease-cleavable linker + a specific named sequence + payload conjugate structures) gives the patent multiple footholds: broad method coverage plus specific chemical embodiments.

F. Payload identity via structural depiction (Claim 11)

Claim 11 recites that D comprises a cytolysin having the structure(s) shown (two depicted alternatives). Even without the drawn images reproduced in the claim text, claim language indicates specific payload exemplars consistent with Formula IV coverage.

G. Method claims for therapy (Claims 15-22)

• Claim 15: treating a tumor in a mammal where tumor and/or surrounding stroma expresses endoglin, by administering therapeutically effective amount of the conjugate of Claim 1.
• Claim 16: conjugate can be administered simultaneously, sequentially, or separately with other antitumor drugs.
• Claim 17-19: other antitumor drugs include cytotoxic chemotherapeutics, anti-angiogenics, immunotherapeutics, with a non-exhaustive list:
  • Gemcitabine
  • Abraxane
  • bevacizumab
  • itraconazole
  • carboxyamidotriazole
  • anti-PD-1 / anti-PD-L1 molecules
  • nivolumab
  • pembrolizumab
• Claim 20: tumor types include:
  • endoglin-expressing blood neoplasms, pancreatic cancer, Ewing sarcoma, breast cancer, melanoma, lung cancer, head and neck cancer, ovarian cancer, bladder cancer, colon cancer
• Claim 21-22: method to treat an endoglin-expressing inflammatory condition or endoglin-expressing eye disease:
  • inflammatory condition: endoglin-expressing rheumatoid arthritis
  • eye disease: endoglin-expressing diabetic retinopathy or endoglin-expressing macular degeneration

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2) How strong are these claims as enforceable coverage?

A. Claim 1’s strongest lever: the cytolysin scaffold (Formula IV)

The independent claim is chemically tethered to a cytolysin class via Formula IV with multiple defined substituents. That is a strong novelty-and-nonobviousness posture compared to a “generic cytotoxic payload” ADC.

However, enforceability depends on:

• whether competitors’ payloads fall literally within Formula IV scope (substituent bounds)
• whether “cytolysin of Formula IV” is interpreted strictly or whether functional equivalence doctrines apply in the relevant jurisdiction
• whether the payload is substantially equivalent but outside exact substituent sets

The breadth is moderate-to-high on substituent selection because many parameters allow multiple options (e.g., R7 includes multiple structural forms; R21 allows a set of amino/halo/hydroxy options; q ranges 0-3). But it is not “anything that kills cells.” It is a constrained payload universe.

B. The second lever: payload-to-linker attachment (R17 and X)

Claim 5 limits the attachment-group categories. This can block common ADC redesigns such as switching the conjugation handle to alternate reactive groups not mapped to the enumerated R17 classes.

Still, Claim 1 already includes “R17 directly or indirectly attached to linker L,” while Claim 5 narrows that attachment types in a dependent claim. That structure can create staggered claim strategies in litigation:

• literal infringement could require the dependent-claim features only if the accused product is asserted under those dependent claims
• broader asserted coverage could rely on Claim 1’s more permissive “directly or indirectly attached” language, unless an examiner or court reads Claim 5 limitations into Claim 1

C. The third lever: linker architecture with a named protease-cleavable linker

Claim 13 names a specific maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamate linker motif. This is a high-value claim for enforcement if accused products use that exact linker sequence.

But Claim 1 and Claims 12-14 also leave room:

• Claim 12 requires protease cleavable portion
• Claim 6-10 cover a spacer of specific structural classes and chain length
• Claim 14 covers selected L-D conjugate structures

That gives the patent a layered approach: broad chemical class plus specific exemplified linker embodiment.

D. Antibody scope: broad at Claim 1, narrow at Claims 2-4

Claim 1 does not limit A to a specific sequence. It only requires selective binding to endoglin. Dependent claims 2-4 narrow A to specific CDRs or full variable regions.

For patent strength:

• The independent claim could be attacked for obviousness if multiple endoglin-binding antibodies were known, unless the ADC payload/linker combination drives the inventive step.
• The dependent claims provide tighter hooks that can survive prior art antibody disclosures if the specific sequences were not known.

Practically, enforcement will hinge on whether the competitor’s antibody binds endoglin “selectively” in the way construed by the patent, and whether the antibody meets the CDR/SEQ ID embodiments.

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3) Claim-by-claim risk and likely design-around paths

A. Likely design-around lever: payload substitution to exit Formula IV

If competitors can identify cytolysins that remain cytotoxic but change substituents so that one or more variables fall outside Formula IV definitions (e.g., R7 substituent categories, R21 substitution set, R10 oxygenation pattern, f, q), they can avoid literal infringement of Claim 1.

This is the most common ADC strategy: keep the binding and general linker logic, swap the payload to a closely related structure outside the patent’s scaffold.

B. Likely design-around lever: attachment chemistry for linker connection

If the accused ADC uses a different payload attachment group than the “R17 is C(O)X / CONHNHX / OX / NHX / SX” categories in Claim 5, a narrow argument can be raised against dependent-claim coverage.

C. Likely design-around lever: spacer type and spacer length

Claims 6-10 restrict the spacer:

• chain length 2 to 30 atoms
• spacer group is specifically --(CH2)n-- or --(OCH2CH2)n--, with n = 1 to 10 This is a direct map for competitors. If they use a different spacer chemistry (e.g., PEG units outside the enumerated form, aromatic spacers, branched linkers), they can avoid those dependent claims.

D. Likely design-around lever: linker cleavability and specific named linker

Claim 12 is broad: L includes attachment group to A and a protease cleavable portion. Competitors can still use protease-cleavable linkers, but if they use non-protease cleavability or different cleavage chemistries not meeting “protease cleavable portion,” they can reduce risk.

Claim 13 is narrower: maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamate. Avoiding that specific linker sequence reduces the strongest embodiment coverage.

E. Likely design-around lever: antibody identity

If the competitor uses an endoglin-binding antibody that differs in CDRs/variable regions from SEQ ID NO sets (Claims 2-4), dependent-claim coverage narrows. The independent claim remains harder to avoid because it only asks “selectively binds endoglin.”

So antibody design-around matters most if the patent’s enforceability strategy relies on dependent claims.

F. Method claims: evidence gating in practice

Method claims (Claims 15-22) are broad but depend on:

• endoglin expression in tumor or stroma or inflammatory/ocular tissue
• administration of the conjugate of Claim 1
• in some claims, co-administration with specified drug classes (but the list is not exclusive)

Method enforcement is evidence-heavy and can be constrained by:

• how “endoglin-expressing” is determined and documented in clinical practice
• whether the accused therapy uses a conjugate that truly meets Claim 1 chemical definition

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4) What the patent landscape likely looks like (and how this patent positions)

Without prosecution-history and without an external citation set to other patents or non-patent literature, the only defensible landscape conclusions are structural: where the patent is likely to face crowded prior art and where it is likely to carve out distinctiveness.

A. Crowded area: endoglin targeting ADC concept

Endoglin (CD105) is a known tumor angiogenesis target. The general concept of anti-endoglin antibodies and ADC formats typically exists in earlier filings. Those concepts alone would be insufficient to differentiate the ’812 patent.

B. Differentiation anchor: payload chemistry defined by Formula IV

The key differentiator is the cytolysin definition with specific substituent sets and attachment constraints. If earlier endoglin ADC work used different cytotoxins or different conjugation handles, ’812 can still be novel.

C. Differentiation anchor: protease-cleavable linker and spacer composition

The inclusion of:

• protease cleavable portion
• a defined spacer composition (alkylene or ethylene glycol-like repeating units) and chain length
• a named linker embodiment creates additional separation from designs using non-protease cleavage, non-matching spacer chemistry, or different drug-linker junctions.

D. Differentiation anchor: explicit therapeutic pairing (PD-1/PD-L1 and standard agents)

Claims 16-19 enumerate combination therapy including:

• checkpoint inhibitors (nivolumab, pembrolizumab)
• cytotoxics and anti-angiogenics This could meet combination-utility expectations but also invites prior art scrutiny for obvious combination routines, depending on what existed for anti-endoglin modalities plus PD-1/PD-L1.

Claims 21-22 expand outside oncology into endoglin-expressing inflammation and eye disease. That expansion can be vulnerable if endoglin-based therapies were already applied to those indications, but it also can remain enforceable if the claimed ADC composition is still novel.

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5) Practical implications for investors and R&D teams

A. Commercial risk profile

The business risk pivots on three technical gates:

1. Payload match to Formula IV (most decisive)
2. Linker spacer and attachment topology (decisive for dependent-claim coverage)
3. Antibody mapping (decisive for dependent-claim coverage; independent claim still broad on “selectively binds endoglin”)

B. Litigation posture and likely infringement theories

A patent asserting under:

• Claim 1 relies on a close structural payload match and the endoglin binding requirement
• Claims 2-4 relies on antibody sequence/CDR mapping
• Claims 6-10 relies on spacer chemistry and chain length
• Claim 12-14 relies on linker cleavability and specific linker/L-D embodiments
• Claims 15-22 relies on clinical indication, dosing, and whether the administered conjugate matches Claim 1

C. Design-around roadmap for competitors

Most effective design-arounds, in order of typical cost-to-benefit:

• Select a cytolysin scaffold that intentionally falls outside Formula IV substituent constraints.
• Use a different linker-drug junction that avoids Claim 5’s R17 enumerated categories.
• Replace the spacer with non-alkylene or non-ethylene glycol-like repeating patterns not captured by Claims 7-10.
• Use a different cleavage-linker system not meeting the “protease cleavable portion” requirement if feasible.
• Use an endoglin antibody not matching the SEQ ID/CDR-defined embodiments, then litigate toward Claim 1’s antibody interpretive burden.

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Key Takeaways

• Claim 1 is an ADC scaffold anchored to a specific cytolysin class (Formula IV) with multiple constrained substituent variables, plus endoglin-selective antibody binding and defined linker-drug attachment generality.
• Dependent claims materially narrow antibody identity (CDRs/SEQ IDs), spacer chemistry (alkylene/ethylene-oxide-like patterns), linker cleavability, and specific named linker embodiment.
• Method claims are broad across oncology and selected inflammation/ocular indications and include combination therapy lists with checkpoint inhibitors (nivolumab, pembrolizumab) and other agents.
• The patent’s enforceability most likely turns on literal structural payload match and linker-drug junction mapping, with antibody identity most important for the dependent-claim hooks.

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FAQs

1) What is the most important element of US 10,004,812 for infringement analysis?

The cytolysin payload defined by Formula IV in Claim 1 and the linker-drug attachment constraints tied to R17 and R17 attachment to linker L.

2) Do the claims require a specific antibody sequence?

Not in Claim 1. Claim 1 only requires an antibody selectively binds endoglin. Claims 2-4 require specific CDRs and SEQ ID-defined variable regions.

3) How do spacer claims limit potential design-arounds?

Claims 6-10 restrict spacer composition to --(CH2)n-- or --(OCH2CH2)n-- with n = 1 to 10, and spacer length to 2 to 30 atoms.

4) Does the patent claim a specific linker?

Yes. Claim 13 specifies maleimidocaproyl-valine-citrulline-p-aminobenzylcarbamate, while Claim 12 also requires a linker with an attachment group plus a protease cleavable portion.

5) What indications are covered beyond tumors?

Claims 21-22 cover endoglin-expressing inflammatory conditions (including rheumatoid arthritis) and endoglin-expressing eye diseases (diabetic retinopathy and macular degeneration).

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References

[1] US Patent 10,004,812 (claims text as provided).

Details for Patent 10,004,812

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	February 26, 2004		2035-02-04
Merck Sharp & Dohme Llc	KEYTRUDA	pembrolizumab	For Injection	125514	September 04, 2014		2035-02-04
Merck Sharp & Dohme Llc	KEYTRUDA	pembrolizumab	Injection	125514	January 15, 2015		2035-02-04
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	December 22, 2014		2035-02-04
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	October 04, 2017		2035-02-04
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	August 27, 2021		2035-02-04

International Patent Family for US Patent 10,004,812

Country	Patent Number	Estimated Expiration
World Intellectual Property Organization (WIPO)	2015118031
United States of America	2017007714
Poland	3102606
South Korea	20160113623
South Korea	102342934
Japan	6616776