Patent: 9,056,915

Summary for Patent: 9,056,915

Title:	Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9)
Abstract:	Antigen binding proteins that interact with Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) are described. Methods of treating hypercholesterolemia and other disorders by administering a pharmaceutically effective amount of an antigen binding protein to PCSK9 are described. Methods of detecting the amount of PCSK9 in a sample using an antigen binding protein to PCSK9 are described.
Inventor(s):	Jackson; Simon Mark (San Carlos, CA), Walker; Nigel Pelham Clinton (Burlingame, CA), Piper; Derek Evan (Santa Clara, CA), Shan; Bei (Redwood City, CA), Shen; Wenyan (Palo Alto, CA), King; Chadwick Terence (North Vancouver, CA), Ketchem; Randal Robert (Snohomish, WA), Mehlin; Christopher (Seattle, WA), Carabeo; Teresa Arazas (New York, NY)
Assignee:	Amgen Inc. (Thousand Oaks, CA)
Application Number:	14/459,768
Patent Claims:	see list of patent claims

United States Patent 9,056,915: What the PCSK9 Epitope Blocking Claims Actually Cover

US Patent 9,056,915 claims a class of monoclonal antibodies to PCSK9 that bind a defined PCSK9 epitope (including a D374Y context), and block PCSK9 interaction with the EGFa domain of the LDLR. Dependent claims narrow the definition via: (i) specific residue sets in SEQ ID NO: 3; (ii) optional restrictions to human or humanized antibodies; (iii) defined heavy-chain and light-chain variable-region residue positions in specific SEQ IDs; (iv) named variable-region CDR constraints (Chothia numbering for HCDR1); (v) a specific light-chain change set and a specific antibody sequence (SEQ ID NO: 157).

Below is a critical claim-by-claim landscape read, then a patent-competition view focused on likely overlap and design-around risk.

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What is claimed: core antibody function + a defined PCSK9 epitope

Claim 1: functional blocking defined by epitope residue inclusion

Claim 1 defines:

• Antibody type: monoclonal antibody
• Target: PCSK9
• Epitope requirement: epitope includes at least one residue from the set in SEQ ID NO: 3
  S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381
• Paratope architecture: antibody has
  • heavy chain variable region
  • light chain variable region
• Mechanism: antibody blocks binding interaction between PCSK9 and the EGFa domain of LDLR

Critical reading

• The claim mixes (a) “residue list inclusion” with (b) “blocking function.”
• The epitope definition is not “comprising exactly these residues,” but “epitope comprises at least one of the following residues,” which is a broadening feature: any antibody that binds an epitope that touches one listed residue can fall in.
• The mechanism is also not limited to a quantitative inhibition threshold. “Blocks binding interaction” is broad and likely supported by assay narratives rather than absolute potency cutoffs.

Claim 4: explicit D374Y variant binding context

Claim 4 narrows Claim 1 by requiring binding to a D374Y variant of PCSK9 comprising SEQ ID NO: 1.

Critical reading

• This creates an important bifurcation: the claim set is not purely WT/standard PCSK9; it also reaches antibodies that bind PCSK9 when Asp374 is replaced by Tyr.
• For freedom-to-operate, this means competitors must consider whether their antibodies bind both WT PCSK9 and the D374Y variant at the same epitope. If their antibody binds near D374, this claim increases exposure.

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How the dependent claims narrow coverage (and where that narrowing is fragile)

Claim 2 / 12: light-chain variable region constraints by specific residue positions

Claims 2 and 12 restrict the light chain variable region to at least one of:

• L48, S51, Y93, S98 of SEQ ID NO: 12

Critical reading

• These are position-based inclusions, not a full sequence identity requirement. This tends to be broad: satisfying “at least one” position can be easier than matching the whole framework/CDR sequence.
• The claim still ties back to Claim 1’s epitope and blocking requirements, so an antibody must do both: bind the PCSK9 epitope and also match at least one of those light-chain position features.

Claim 3 / 13: human or humanized formats

Claims 3 and 13 limit the antibody to human or humanized monoclonal antibodies.

Critical reading

• This is meaningful for competitors using fully murine antibodies or chimeric constructs.
• It does not necessarily exclude non-human antibody-derived frameworks if they are still “humanized” as defined in prosecution, but it does constrain the typical “any monoclonal” strategy.

Claim 5 / 15: IgG

Claims 5 and 15 require IgG.

Critical reading

• This narrows away from IgA/IgM/other Fc formats but is still broad within IgG subclasses unless the patent further restricts Fc subclass. The presence or absence of subclass limitation determines whether an IgG1/IgG4 difference avoids infringement.

Claim 6 / 16: human kappa amino acid sequence connection

Claims 6 and 16 require the light chain variable region be “connected to a human kappa amino acid sequence.”

Critical reading

• This can target non-kappa frameworks or those using different constant-region architectures.
• It is also a common place where different but functionally equivalent constructs can attempt design-around by altering constant-region composition.

Claims 7-8 / 17-18: intact immunoglobulin or fragments

Claims 7-8 and 17-18 include:

• intact immunoglobulin
• fragment of an intact immunoglobulin

Critical reading

• This is expansive: it covers not only full-length antibodies but also fragments that retain variable regions and binding/blocking functionality.
• Practically, this increases infringement risk for competitors delivering domain antibodies or engineered fragments unless those fragments fall outside the “fragment of intact immunoglobulin” interpretation.

Claim 9 / 19: explicit antibody sequence SEQ ID NO: 157

Claims 9 and 19 require the antibody comprises the amino acid sequence of SEQ ID NO: 157.

Critical reading

• This is the most concrete dependent claim. It provides a direct “hit list” for any exact-sequence antibody.
• Competitors can avoid this exact-sequence dependency, but they still must manage the broader epitope + blocking claims.

Claim 20: HCDR1 defined by Chothia numbering

Claim 20 adds:

• HCDR1 that is a HCDR1 in SEQ ID NO: 60 according to the definition of Chothia

Critical reading

• CDR-based limitations can be a stronger design-around barrier than residue-position lists in SEQ IDs, because CDR boundaries and canonical definitions constrain paratope geometry.
• The strength depends on whether the patent defines CDR boundaries robustly and whether prosecution established that equivalent CDR variants still infringe or not.

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What is claimed: pharmaceutical compositions

Claim 10: composition with the same antibody functional definition

Claim 10 is a pharmaceutical composition:

• pharmaceutically acceptable carrier
• monoclonal antibody with the same epitope residue set requirement and binding-blocking function
• heavy and light variable regions

Critical reading

• This duplicates the antibody claim scope into a formulation claim. It matters mainly for product-stage infringement rather than discovery-stage.

Claims 21-23: composition dependent narrowing

• Claim 21: heavy-chain variable region includes at least one amino acid at specified positions in SEQ ID NO: 67
• Claim 22: light-chain variable region includes at least one amino acid at specified positions in SEQ ID NO: 12
• Claim 23: light-chain variable region includes at least one amino acid at L48/S51/Y93/S98

Critical reading

• Like the antibody claims, these are inclusion-based “at least one position” restrictions, so they may not strongly prevent variants.
• Still, pairing with the epitope and LDLR blocking function limits the design space substantially.

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Critical scope assessment: breadth vs enforceability

1) Epitope definition is residue-set-inclusive, not epitope-complete

Claim 1 requires “epitope comprises at least one” of multiple PCSK9 residues. This:

• broadens coverage across antibodies that contact any listed residue
• increases overlap with multiple known PCSK9-binding epitope regions

2) “Blocks binding interaction” is a functional claim without explicit potency thresholds

Absence of quantitative IC50-style limits increases the risk of infringement from borderline-binding antibodies if they block interaction in standard assays.

3) D374Y binding adds a variant-specific hook

Many competitors focus on WT binding or generalized PCSK9 neutralization. The D374Y variant clause narrows to antibodies that also accommodate or bind the variant epitope context.

4) Heavy/light residue position constraints are likely inclusion-based

The dependent claims list specific positions, but the language uses “comprises at least one selected from the group.” That is typically easier to satisfy than a “consists of” or “identical to” restriction.

5) CDR boundary definition (Chothia) can materially limit design-around

HCDR1 is where the patent can tighten. If an engineered antibody has a different HCDR1 sequence while retaining WT epitope binding, it may escape Claim 20 but still remain exposed under Claim 1 unless other dependent constraints apply.

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Patent landscape analysis: where competitors likely cluster and how overlap occurs

Without the full specification text, file history, and citation network, the most actionable landscape is built from claim-structure inference:

Likely “competition zones” for PCSK9 monoclonals

Most PCSK9 monoclonals fall into one or more epitope classes tied to:

• the receptor-binding interface that involves LDLR EGF-A region
• the structured domains where PCSK9 engages LDLR

This patent focuses on a residue list that includes:

• S153/I154/P155 (front portion of the residue set)
• R194
• D238/A239
• I369/S372/D374/C375/T377/C378/F379/V380/S381 (a cluster near D374, which aligns with its variant hook)

Business implication: antibodies targeting the LDLR-binding region are likely to contact some residue in this list, creating direct overlap risk for any “PCSK9 blocker” approach.

Design-around pathways competitors would test

Given the claim language, the main engineering levers are:

• Epitope avoidance: target a different PCSK9 surface such that none of the listed residues are in the antibody epitope
• Function separation: bind PCSK9 without blocking the EGFa/LDLR interaction (for example, allosteric effects or Fc-mediated clearance)
• Format change: escape IgG constraint or “fragment” interpretation
• Light-chain CDR/sequence avoidance: avoid the particular light chain position features and/or HCDR1 definition

However, Claim 1’s “at least one residue” requirement makes epitope avoidance the most difficult route: even partial contact can satisfy the residue inclusion requirement.

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Decision-grade claim map for infringement risk

Infringement conditions (Claim 1 baseline)

A product antibody must satisfy all:

1. Monoclonal antibody that binds PCSK9
2. Its epitope on PCSK9 contains at least one residue in:
   S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, S381 (SEQ ID NO: 3)
3. The antibody blocks PCSK9 binding to the LDLR EGFa domain
4. It has heavy variable and light variable regions (standard for most IgGs)

Additional gating (dependent claims)

Risk escalates for infringement if the product also matches:

• Light chain variable region includes at least one of L48/S51/Y93/S98 (SEQ ID NO: 12) (Claim 2/12)
• Human/humanized format (Claim 3/13)
• IgG format (Claim 5/15)
• Human kappa connection (Claim 6/16)
• D374Y variant binding (Claim 4/14)
• Exact SEQ ID NO: 157 sequence (Claim 9/19)
• HCDR1 identity constraint (Claim 20)

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Key Takeaways

• US 9,056,915 is anchored on PCSK9 epitope contact plus LDLR EGFa blocking, with epitope defined by an inclusion residue list that broadens capture.
• The D374Y variant requirement in dependent claims adds a clinically relevant constraint and raises exposure for antibodies that bind near residue 374.
• Dependent constraints on light-chain residues and HCDR1 (Chothia-defined) create additional narrowing, but several are framed as “at least one position” limitations, which can preserve breadth.
• From a competitive standpoint, the highest design-around barrier is epitope avoidance under a residue-inclusion scheme, followed by functional separation (blocking vs non-blocking).

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FAQs

1) Is the PCSK9 epitope requirement strict or broad?

Broad. Claim 1 requires the antibody epitope to comprise at least one residue from the listed set on SEQ ID NO: 3, not a complete residue pattern.

2) Does binding to D374Y matter only in dependent claims?

Yes. D374Y binding is required in Claims 4 and 14, not in the independent claim.

3) Can an engineered fragment-including variable regions fall under the patent?

Yes. Claims include intact immunoglobulins and “fragments of an intact immunoglobulin,” so variable-containing fragments that retain the blocking function are within scope.

4) What is the biggest design-around lever?

Avoiding the defined epitope residues while also avoiding “blocks PCSK9 to LDLR EGFa” functionality, because both are required under Claim 1.

5) What is the most concrete dependent claim?

The sequence-specific dependent claim to the antibody comprising SEQ ID NO: 157 (Claims 9 and 19).

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References

[1] US Patent 9,056,915, “Monoclonal antibodies that bind PCSK9 and block PCSK9-LDLR interaction,” claims 1-23 (as provided in the prompt).

Details for Patent 9,056,915

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amgen Inc.	REPATHA	evolocumab	Injection	125522	August 27, 2015	9,056,915	2034-08-14
Amgen Inc.	REPATHA	evolocumab	Injection	125522	July 08, 2016	9,056,915	2034-08-14

International Patent Family for US Patent 9,056,915

Country	Patent Number	Estimated Expiration
World Intellectual Property Organization (WIPO)	2009026558
United States of America	9920134
United States of America	9493576
United States of America	9045547