When do biologic drug patents expire and when will biosimilars launch?

United States Patent 10,087,251 (PD-1 VHH) Claims, Scope, and Competitive Patent Landscape

Executive summary: US 10,087,251 is a claim-set centered on single-domain antibody (VHH/VHH-like) polypeptides that bind PD-1, with a structurally constrained architecture (FR1-FR4 + CDR1-3) and CDR3 sequences defined by SEQ ID NOs 337–341 plus allowed single- to triple-amino-acid variants. The independent claim 1 is narrowed further by functional binding potency windows (K_D ranges as low as 10^-12 M) and by dependent claim corridors that restrict to specific VHH/humanized/camelized frameworks with identity and Kabat-position permissive substitutions. The later claim family extends to cross-blocking and constructs/compositions including multivalent/multispecific and serum half-life extension modules (notably serum albumin-binding and Fc/albumin-binding approaches). The practical exclusivity risk is highest for direct hits on the specified CDR3 variant set and frameworks/identity bands; it drops materially for antibodies that bind PD-1 via different CDR3 sequences or different framework/identity regimes.

What patents protect PD-1 binding VHHs like US 10,087,251?

How claim 1 defines the protected “core” epitope class

US 10,087,251 claim 1 protects:

A polypeptide binding PD-1
Essential composition: 4 framework regions FR1–FR4 and 3 CDRs CDR1–CDR3
A CDR3 restriction:
- (a) CDR3 is exactly one of SEQ ID NOs 337–341, or
- (b) CDR3 differs by 3, 2, or 1 amino acid changes from at least one of SEQ ID NOs 337–341
The dependent claims then enforce potency and specific framework/identity/position substitutions (claims 2–6).

Implication: the tightest infringement hook is CDR3. Even if FRs and other CDRs are adjusted, moving outside the defined CDR3 variant neighborhood is the primary design-around lever.

What claim 2 protects functionally

Claim 2 adds binding strength limits:

K_D 10^-5 to 10^-12 M or lower, and/or
K_D 10^-7 to 10^-12 M or lower, and/or
K_D 10^-8 to 10^-12 M or lower

Implication: A PD-1 binder with weaker affinity (outside those windows) may avoid infringement even if structural elements overlap.

Which CDR3 variants are covered under US 10,087,251, and how design-sensitive are they?

Claim 1 CDR3 “neighborhood” math

The claim 1 language creates a radius in sequence space around five anchor sequences (SEQ ID NOs 337–341):

Exact matches to any of the five sequences
or sequences with 1, 2, or 3 amino acid differences relative to at least one anchor

Implication for enforcement: In infringement, the technical issue becomes whether the accused CDR3 is within that bounded neighborhood. This is typically evaluated by sequence alignment and counting substitutions within the CDR3 segment.

Design-around pathway

The most direct route is to engineer PD-1 binding VHHs whose CDR3 amino-acid sequence does not fall within:

exact SEQ ID NOs 337–341, and
not within 1–3 substitutions of any of them

A common risk is “accidental closeness” during library maturation or humanization where CDR3 drifts but remains close enough to remain inside the allowed substitution count.

What patents protect humanized or camelized PD-1 VHH frameworks under US 10,087,251?

Domain type gate: claim 3

Claim 3 restricts to:

domain antibody / single domain antibody
VHH
humanized VHH
camelized VHH

This is mostly a classification gate. The real restriction is in claims 4–6.

Framework/identity restriction: claims 4–6

Claim 4 covers VHH/humanized/camelized variants meeting both:

Identity threshold: at least 80% amino acid identity to at least one of SEQ ID NOs 1–22
- with a key method: CDR residues are disregarded for identity determination
Kabat-position permissive substitutions at specified positions:
- positions: 11, 37, 44, 45, 47, 83, 84, 103, 104, 108
- allowed residue sets are enumerated per position

Claim 5 is a similar corridor but anchored to different reference sequences:

identity to at least one of SEQ ID NOs 347–351
same “disregard CDRs for identity” rule
same Kabat-position permissive substitutions

Claim 6 adds a “humanized variant” concept:

humanized variant of one of SEQ ID NOs 347–351, and/or
at least 80% identity (with CDR disregarded)
same allowed Kabat-position substitutions

Implication: Many PD-1 VHH programs will humanize frameworks. US 10,087,251 turns that step into a potential infringement lever by allowing specific framework residue flexibility while maintaining a minimum identity floor.

How does the KAbat-position allowance in claims 4–6 affect patent strength?

Why these “fixed position” allowances cut both ways

The permissive residue sets at Kabat positions:

can increase the effective claim coverage (broader tolerated framework variation)
but also can be argued as tight in prosecution history and claim construction because only those positions are explicitly allowed to vary

From a litigation posture, the claim’s strength is amplified if the accused antibody framework substitutions map to the enumerated Kabat-permitted residues.

Key technical infringement questions tied to these claims

Whether the accused antibody qualifies as a humanized/camelized VHH (structural classification)
Whether the framework aligns to the claimed reference regimes with ≥80% identity when CDRs are disregarded
Whether substitutions at the listed Kabat positions stay within the enumerated residue sets

What do claims 7–8 cover: cross-blocking versus cross-blocked?

Cross-blocking (claim 7)

Claim 7: a polypeptide that cross-blocks PD-1 binding by at least one polypeptide according to claim 1.

Cross-blocked (claim 8)

Claim 8: a polypeptide that is cross-blocked from binding to PD-1 by at least one polypeptide according to claim 1.

Implication: These are functional overlap claims. They can ensnare antibodies that bind the same epitope class, even if their CDR3 sequence differs, but typically require evidence of competition/cross-blocking assays.

Critical risk for challengers: cross-blocking tests can be sensitive to assay format, concentration, and whether binding is truly epitope-overlapping versus allosteric.

What formulations and constructs are protected by US 10,087,251?

Construct coverage: claims 9–11

Claim 9 covers a compound/construct comprising one or more claim-1 polypeptides, optionally with other groups/moieties/linkers.

Claim 10 lists additional binding unit types, including domain antibodies/VHH/humanized VHH/camelized VHH.

Claim 11 covers multivalent or multispecific constructs.

Implication: US 10,087,251 is not limited to monovalent VHHs. If a bispecific uses the protected VHH as one arm, the claim can attach.

Serum half-life extensions: claims 12–16

Claims 12–16 target serum half-life enhancement relative to the unmodified polypeptide:

Claim 12: serum half-life increased by added modules
Claim 13: module types include serum proteins/fragments, serum-protein binding units, Fc portion, or small peptides binding serum proteins
Claim 14: explicitly human serum albumin
Claim 15: explicitly binding units that can bind serum albumin and “serum immunoglobulin”
Claim 16: explicitly albumin-binding domain antibodies/VHHs/camelized/humanized VHHs that bind serum albumin or serum immunoglobulin

Implication: If the protected PD-1 binder is paired with an albumin-binding VHH arm or Fc-like module, the construct may fall inside claim coverage.

Quantified half-life uplift: claim 17

Claim 17 requires serum half-life increase of at least:

1.5x, 2x, 5x, 10x, or >20x

Implication: Half-life evidence becomes a technical gate. This can become a litigation battleground because half-life depends on assay species, dosing, and construct format.

What nucleic acids, compositions, and pharmaceutical formulations are covered?

Claim 18: nucleic acid encoding a claim-1 polypeptide
Claim 19: composition comprising at least one claim-1 polypeptide
Claim 20: pharmaceutical composition with pharmaceutically acceptable carrier/diluent/excipient and optionally other active polypeptides/compounds

Implication: These broaden the estate to cover manufacturing and end-use formulation packaging, though typical infringement still requires the presence of the covered polypeptide(s).

What is the independent backbone of claim 21 (alternate CDR set), and why does it matter?

Claim 21 defines a stricter PD-1 VHH sequence pairing

Claim 21 is a polypeptide that essentially consists of FR1–FR4 plus CDR1–CDR3, where CDR combinations are explicitly listed:

(Option A) CDR1 = SEQ ID NO 317; CDR2 = 327; CDR3 = 337
(Option B) 318/328/338
(Option C) 319/329/339
(Option D) 320/330/340
(Option E) 321/331/341

Implication: This claim is tighter than claim 1 because it pins CDR1, CDR2, and CDR3 simultaneously. An antibody that escapes claim 1 by shifting CDR3 may still be caught if it matches one of these full CDR triplets.

Patent landscape mapping for PD-1 VHH antibodies: where US 10,087,251 sits

How this estate likely clusters within PD-1 antibody portfolios

US 10,087,251 sits in a class of estates targeting:

VHH/single-domain PD-1 binders
with explicit emphasis on CDR-defined sequence coverage
and construct engineering for half-life

In the US, competitive pressure typically comes from two directions:

Other PD-1 VHH families with different CDR3 and framework reference sequences.
Full-length IgG PD-1 antibodies and biospecifics whose protected epitope regions differ and whose half-life is built into Fc rather than albumin-binding VHH arms.

Where infringement risk concentrates

Monovalent VHH constructs that match the claim-1 CDR3 neighborhood and affinity ranges
Bispecific/multispecific constructs where the protected VHH arm is used as one specificity
Half-life extended molecules where albumin/Fc-like modules are combined with the covered VHH

Where infringement risk drops

Antibodies whose CDR3 sequences are outside the 1–3 substitution neighborhood of SEQ ID NOs 337–341
Antibodies whose framework identity (with CDRs disregarded) falls below the 80% floor relative to the specified reference sets
Antibodies whose Kabat-position residues at the listed positions do not fall within the enumerated allowed residues

When does US 10,087,251 lose exclusivity?

No launch-year, filing date, or prosecution data is provided here, and exclusivity timing in the US cannot be calculated accurately from the claim text alone. Therefore, no definitive expiration timeline can be stated.

What generic entry risks exist for PD-1 VHHs claimed by US 10,087,251?

Generic pathway reality for antibody drugs

For biologics, “generic entry” typically means:

biosimilar (for reference biologics), or
separate biologic development if not biosimilar.

Small-molecule generic pathways do not apply to antibody polypeptides of this type.

Risk focus for challengers

If a biosimilar is asserted against a covered PD-1 VHH (or a protected VHH used in a fusion), the challenge is likely not “generic” but IP invalidity/non-infringement.
The most salient non-infringement lever is CDR3 sequence non-overlap and framework identity/allowed residue mismatch.

How strong is the patent estate for PD-1 VHHs in US 10,087,251 specifically?

Strength factors

Sequence-defined CDR3 in claim 1 with an explicit substitution neighborhood (0 to 3 amino acid differences)
Quantitative K_D affinity windows in claim 2
Framework identity threshold (80% identity with CDRs disregarded) plus explicit Kabat-position permissive substitution sets in claims 4–6
Tight CDR1/CDR2/CDR3 triplet coverage in claim 21

Weakness or challenge points

Functional dependence on K_D assays can create room for dispute (assay conditions; binding kinetics versus thermodynamics).
“Cross-blocking” claims (7–8) are test-dependent and can be argued around epitope overlap.
Serum half-life claims (12–17) require comparative pharmacokinetic evidence in relevant formats and conditions.

Key claim-to-design mapping table (infringement engineering view)

Claim	Core coverage element	Primary infringement trigger	Main design-around lever
1	PD-1 VHH with FR1–FR4 + CDR1–3	CDR3 is SEQ ID 337–341 or within 1–3 aa substitutions of them	Move CDR3 outside neighborhood
2	Binding affinity window	Meets K_D thresholds	Select alternative binder with K_D outside window
3	VHH/humanized/camelized classification	Use of VHH-type format	Not a likely escape if VHH remains
4	Identity to SEQ ID 1–22 (CDRs disregarded) + Kabat allowed residues	Framework matches identity and allowed positions	Change framework to break identity or Kabat residue constraints
5	Identity to SEQ ID 347–351 (CDRs disregarded) + same Kabat rules	Framework within identity corridor and allowed positions	Same as claim 4
6	Humanized variants of SEQ ID 347–351 + same rules	Humanized mapping plus framework constraint	Humanization that violates identity or Kabat rules
7–8	Cross-blocking relationship to claim-1 binder	Competition/cross-block assay overlap	Use distinct epitope (no cross-block)
9–11	Constructs (multivalent/multispecific) using claim-1 polypeptides	PD-1 VHH arm in a construct	Replace PD-1 arm with non-covered binder
12–16	Half-life extension modules (albumin-binding/Fc etc.)	Construct with albumin-binding/Fc module plus covered VHH	Use non-covered PD-1 VHH arm
17	Quantified half-life uplift	Demonstrated half-life increases vs unmodified polypeptide	Avoid covered VHH or half-life window
18–20	Nucleic acids and compositions	Covered polypeptide used in sequence/expression/formulation	Not meaningful if polypeptide avoided
21	Explicit CDR1/CDR2/CDR3 triplets	Exact triplet match	Alter at least one CDR to escape

Key Takeaways

US 10,087,251’s highest-value infringement surface is the defined CDR3 set: SEQ ID NOs 337–341 plus 1–3 amino-acid substitution variants.
Framework compliance is governed by a dual filter: ≥80% identity to specified reference sequences with CDR residues disregarded, plus explicit allowed Kabat-position residues at 11, 37, 44, 45, 47, 83, 84, 103, 104, 108.
Construct coverage extends exclusivity beyond monovalent VHHs into multivalent/multispecific formats and serum half-life extension (notably albumin-binding approaches).
Cross-blocking and half-life uplift claims add functional gates but are evidence-dependent in litigation.

FAQs

Does US 10,087,251 protect PD-1 IgG antibodies or only VHH single-domain formats?
The claims are drafted around domain antibodies/VHH/humanized/camelized VHH; the core scope is single-domain antibody architecture rather than conventional IgG.
If an antibody matches claim 1’s CDR3 but not the framework identity threshold, is it likely covered?
Claims 4–6 impose additional framework identity and Kabat residue constraints, but claim 1 itself is narrower on CDR3 and FR/CDR structure; full claim coverage depends on which dependent claims are asserted.
Can a PD-1 VHH escape infringement by altering only one CDR?
It can if it changes CDR3 out of the SEQ ID 337–341 plus 1–3 substitution neighborhood. Claim 21 also requires specific CDR1/CDR2/CDR3 triplets, so altering one CDR may avoid that narrower claim.
What experimental assays typically matter most for enforcing claim 2, 7, and 17?
K_D measurement for claim 2, epitope competition/cross-blocking assays for claims 7–8, and comparative pharmacokinetics/serum half-life for claims 12–17.
Does the patent cover DNA/RNA constructs and pharmaceutical compositions?
Yes. Claims 18–20 cover nucleic acids encoding the polypeptides and compositions/pharmaceutical compositions containing at least one covered polypeptide.

References (APA)

United States Patent 10,087,251. Claims excerpt provided in prompt.

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Grifols Therapeutics Llc	ALBUKED, PLASBUMIN-20, PLASBUMIN-25, PLASBUMIN-5	albumin (human)	For Injection	101138	October 21, 1942	10,087,251	2036-02-23
Takeda Pharmaceuticals U.s.a., Inc.	BUMINATE, FLEXBUMIN	albumin (human)	Injection	101452	March 03, 1954	10,087,251	2036-02-23
Csl Behring Ag	ALBURX	albumin (human)	Injection	102366	July 23, 1976	10,087,251	2036-02-23
>Applicant	>Tradename	>Biologic Ingredient	>Dosage Form	>BLA	>Approval Date	>Patent No.	>Expiredate

Summary for Patent: 10,087,251