Patent: 8,829,165

Summary for Patent: 8,829,165

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), 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:	13/860,016
Patent Claims:	see list of patent claims

Comprehensive analysis of US Patent 8,829,165 (PCSK9 monoclonal antibodies blocking LDLR binding)
US 8,829,165 claims a class of PCSK9-binding monoclonal antibodies defined by (i) epitope residue sets on PCSK9 (SEQ ID NO:3) and (ii) functional blockade of PCSK9–LDLR binding. The claim structure is dominated by residue-level epitope binning (single-residue, multi-residue, and threshold subsets such as “binds at least four” residues) plus antibody format (human or humanized) and efficacy constraints (blocking by at least 80%). The patent landscape for this type of epitope-defined anti-PCSK9 antibody estate is typically crowded, with multiple competing antibody families (e.g., evolocumab-/alirocumab-like and subsequent entrants), and enforcement outcomes usually turn on whether a target antibody’s epitope maps into the claimed residue set and whether the commercial product’s binding site overlaps in the claimed SEQ ID NO:3 numbering.

What claims does US 8,829,165 cover for PCSK9 monoclonal antibodies that block LDLR binding?

Claim core. Claim 1 (and dependent claims) covers an isolated monoclonal antibody that:

1. Binds PCSK9 at least to one specified residue in a defined list (S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, S381) of SEQ ID NO:3.
2. Blocks PCSK9 binding to LDLR.

Functional and structural claim blend. The claims combine:

• Structural limitation: epitope residue contact points (residue-level specification rather than complete sequence motifs).
• Functional limitation: blockade of PCSK9–LDLR binding.
• Antibody type: human or humanized (claims 21–22; 24–25; 27–28).
• Performance threshold: at least 80% blockade (claim 18; claims 23 and 26; compositions claim 29).

How broad is the epitope coverage in Claim 1?

Claim 1 is broad at the “one-residue minimum” level: binding to any one residue among 15 listed positions satisfies the epitope requirement, as long as the antibody blocks LDLR binding.

That breadth matters in litigation because many antibodies that bind PCSK9 at functionally relevant regions may contact at least one residue in a larger competitive epitope footprint. The dependent residue-multiplicity claims (e.g., at least two, at least four) narrow coverage, but Claim 1 still captures single-residue overlap.

What is the significance of the “SEQ ID NO:3 residue numbering” requirement?

The claims hinge on binding residues defined in SEQ ID NO:3. In antibody litigation, mapping disputes often reduce to:

• whether the commercial PCSK9 sequence and numbering match the patent’s SEQ ID NO:3 numbering, and
• whether “binds to residue” in the patent claim means direct contact, proximity, or epitope inclusion as measured by the patent’s experimental methods.

Even when an accused antibody binds the “same general epitope,” residue-level capture can fail if the numbering or contact definitions do not match.

Which dependent claim tiers narrow the patent?

The dependent claim set creates three main narrowing dimensions:

1) Residue count thresholds

• Claim 19: binds at least two of the listed residues
• Claim 20: binds at least four of the listed residues
• Claims 26: binds at least four and blocks by at least 80%

2) Individual residue anchor claims

• Claims 2–16: each specifies binding to at least one of the listed residues (S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, S381).

3) Functional blockade magnitude

• Claim 18: blocks PCSK9–LDLR binding by at least 80%
• Claim 23: binds at least two residues and blocks by at least 80%
• Claim 26: binds at least four residues and blocks by at least 80%
• Claim 29: composition variant of claim 23.

4) Antibody format

• Claims 21–22: human or humanized antibodies
• Claims 24–25: human or humanized versions of claim 23
• Claims 27–28: human or humanized versions of claim 26.

Do the claims include manufacturing or method-of-use IP?

Not in the text provided. This is antibody binding and composition coverage (pharmaceutical compositions comprising the antibody), not dosing regimens, not manufacturing processes, and not explicit method-of-use claims.

How does US 8,829,165 define “blocks binding of PCSK9 to LDLR” and what does Claim 18 add?

Baseline functional limitation (Claim 1). The antibody must block PCSK9’s binding to LDLR. This is the principal functional gate.

Quantified efficacy limitation (Claim 18). Claim 18 adds a quantitative threshold: blocking by at least 80%. In enforcement, accused infringers often focus on:

• assay selection (cell-based vs biochemical binding assays),
• baseline controls,
• normalization of signal,
• time points and concentration ranges, and
• whether the 80% is met in the relevant experimental setup.

Because the patent claims do not, in the excerpt provided, specify assay conditions, the “at least 80%” limitation is often litigated as a factual question tied to the patent’s experimental disclosure.

What is the patent estate likely to look like around this epitope-binned PCSK9 antibody class?

Even without asserting the full family map for US 8,829,165 here, the structural pattern (epitope residue sets + LDLR blockade) is characteristic of antibody patent families that commonly include:

• epitope-defined antibody claims (as here),
• variants defined by additional residue contacts,
• humanized and/or fully human format claims,
• and composition claims with standard excipients.

For a PCSK9 antibody, it is typical that other patent families claim one or more of the following:

• different PCSK9 epitope footprints (distinct residue sets),
• alternative mechanisms such as altering PCSK9 stability or processing (though PCSK9–LDLR blockade is the canonical MoA),
• different antibody formats (e.g., IgG subclasses, Fc modifications),
• manufacturing and formulation (less likely to be central here given the excerpt).

Which competing anti-PCSK9 antibodies are most likely to present infringement risk against residue-defined claims?

For a residue-defined claim set, the key question is whether a product antibody’s epitope includes any of the specified residues in the patent’s SEQ ID NO:3 numbering and whether it blocks PCSK9–LDLR binding.

In practice, major marketed PCSK9 monoclonals are:

• evolocumab (Amgen), and
• alirocumab (Regeneron/Sanofi).

Later entrants and portfolio extensions may include engineered variants or biosimilar-like candidates, but infringement risk still tends to concentrate on whether their epitope overlaps with the claimed residues and whether LDLR binding is blocked to the claimed degree.

Because Claim 1 requires only one residue from a list of 15, infringement risk is higher than for patents that require a larger residue set overlap. A competitor antibody that contacts a single residue from the list, while still functioning as a PCSK9–LDLR blocker, can fall within Claim 1’s scope.

When does US 8,829,165 lose exclusivity, and how does expiration interact with biologic protection?

Exclusivity timing cannot be computed from the claim text alone. It depends on:

• priority date(s),
• filing date(s),
• prosecution history affecting term,
• possible PTA,
• and whether any terminal disclaimer limits term.

This matters commercially because PCSK9 antibody markets are structured around long-lived exclusivity and patent thickets. Practically, even post-expiration of one patent, other patents in the estate can keep competitors off-market, especially those covering:

• specific epitope variants,
• specific antibody sequences,
• and formulation/manufacturing.

What is the Orange Book status of US 8,829,165 for PCSK9 antibodies?

Orange Book lists approved small molecules and certain biologics under the Hatch-Waxman regime (not most monoclonal antibodies). PCSK9 monoclonal antibodies typically rely on the Biologics Price Competition and Innovation Act (BPCIA) pathway, not Orange Book listing. Whether this particular patent appears in listings associated with an approved product depends on FDA Orange Book or BLA patent listing decisions, which cannot be concluded from the claim text provided.

How strong are the patent claims under US patent law given the epitope “residue list” structure?

Strength drivers

• Direct functional linkage to mechanism: blocking PCSK9–LDLR is a clear MoA limiter.
• Defined epitope residues: residue-level constraints can narrow the set of antibodies considered infringing, compared with broad “binds PCSK9” claims.
• Multiple dependent tiers: even if the broadest independent claim is contested, dependents provide fallback positions (two-residue overlap, four-residue overlap, 80% blockade, humanized/human format).

Potential weakness and litigation friction points

• Very broad independent scope: Claim 1 allows infringement by binding to any one residue in the set. If many PCSK9 antibodies contact at least one of those residues, novelty and nonobviousness defenses may be pressed.
• Residue numbering dependence: if SEQ ID NO:3 numbering differs from the competitor’s epitope mapping baseline, infringement may be avoided.
• Meaning of “binds to”: residue-level binding language typically requires the patent to have supported definitions or experimental methods. Absent clear definitions, the claim can be attacked for indefiniteness or narrowed during claim construction.
• 80% threshold: if the patent does not provide robust, reproducible assay guidance and if competing antibodies meet blockade only in some assay formats, the 80% dependents can become less enforceable.

What patent litigation issues are likely in disputes involving US 8,829,165–type claims?

Typical high-stakes issues for epitope-defined anti-PCSK9 antibodies include:

1) Claim construction: residue contact vs epitope inclusion

Courts often need to interpret whether the claim requires:

• direct binding contact at that residue, or
• that the antibody binds within an epitope that includes that residue.

This can flip infringement outcomes, especially when structural data show neighboring residues with hydrogen-bonding or van der Waals interactions.

2) Infringement: epitope mapping and experimental comparability

Accused parties usually submit:

• binding kinetics curves,
• competition assays against reference antibodies,
• and structural models, or
• cryo-EM/X-ray crystallography maps of antibody–PCSK9 complexes.

Plaintiffs rely on:

• patent disclosure mapping,
• competition/blockade assays,
• and sometimes cross-reactivity with mapped mutants.

3) Validity: obviousness and predictability in antibody epitope selection

PCSK9 is a validated target with known antibody precedents. The residue-level listing could be argued as either:

• a non-obvious selection of specific epitope residues that achieve LDLR blockade, or
• an obvious subset of known functional regions.

Outcome depends on the breadth of prior art and how precisely the prior art teaches those exact residues or epitope footprints.

Does US 8,829,165 read on biosimilars or antibody “follow-ons” under BPCIA?

Biosimilar and interchangeability disputes still turn on infringement, but the practical entry risk is:

• whether a proposed follow-on antibody has an epitope overlap captured by the residue list, and
• whether it blocks PCSK9–LDLR binding to the claimed extent.

Because Claim 1 requires LDLR blockade and residue contact, a proposed antibody that differs in epitope footprint can evade. Conversely, because Claim 1 has a low residue threshold (one residue among 15), an epitope-overlap candidate presents more litigation risk.

Key Takeaways

• US 8,829,165 claims PCSK9-binding monoclonal antibodies that block PCSK9–LDLR, using a residue-level epitope definition tied to SEQ ID NO:3.
• The independent claim is broad because it only requires binding to any one residue from a 15-residue set, while maintaining a functional requirement of LDLR blockade.
• Dependent claims add fallback constraints: at least two residues, at least four residues, “blocks by at least 80%,” and antibody format (human or humanized).
• Enforcement for epitope-defined anti-PCSK9 antibodies typically hinges on residue numbering and claim construction for “binds to” versus epitope inclusion, and on epitope-mapping evidence plus assay comparability for the 80% blockade limitation.

FAQs

1) What does “binds to PCSK9 residues in SEQ ID NO:3” mean for infringement analysis?
It ties infringement to whether the accused antibody’s mapped epitope corresponds to the same residue numbering as in the patent’s SEQ ID NO:3 and whether “binds to” is construed as direct contact or epitope inclusion.

2) Does US 8,829,165 cover only antibodies, or also compositions?
The claims include pharmaceutical composition claims comprising the antibody with the same epitope and functional blockade limitations.

3) Can a competitor avoid Claim 1 by blocking PCSK9–LDLR without binding the listed residues?
Yes, if the competitor’s epitope does not include any of the specified residues in the patent’s SEQ ID NO:3 numbering.

4) How is the “at least 80%” blockade limitation usually litigated?
Through the definition and reproducibility of the relevant assay, including controls, antibody concentration ranges, readouts, and how “blocking” is quantified relative to baseline.

5) Are method-of-use or dosing patents part of this claim set?
Not from the provided claims; the excerpt focuses on binding/blockade and pharmaceutical compositions rather than dosing regimens or treatment methods.

References (APA)

1. United States Patent 8,829,165.

Details for Patent 8,829,165

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amgen Inc.	REPATHA	evolocumab	Injection	125522	August 27, 2015		2033-04-10
Amgen Inc.	REPATHA	evolocumab	Injection	125522	July 08, 2016		2033-04-10

International Patent Family for US Patent 8,829,165

Country	Patent Number	Estimated Expiration
Argentina	068011
Argentina	110799
Australia	2008288791
Australia	2013203677
Australia	2013203685