Patent: 10,525,104

Summary for Patent: 10,525,104

Title:	Predictive and prognostic biomarkers related to anti-angiogenic therapy of metastatic colorectal cancer
Abstract:	The present invention provides methods for treating metastatic cancer comprising identifying subjects who will respond favorably to anti-VEGF therapy. According to certain aspects of the invention, subjects are identified based on their expression level of one or more predictive biomarkers. Favorable response to anti-VEGF therapy is indicated by high expression levels of certain biomarkers or by low expression levels of certain biomarkers. An exemplary predictive biomarker is VEGF-A. Also disclosed herein are prognostic biomarkers useful for identifying cancer-bearing subjects who are expected to have better relative survival outcomes.
Inventor(s):	Sims; Tasha Nicholle (New York, NY), Gao; Bo (Ringoes, NJ), Lowy; Israel (Dobbs Ferry, NY)
Assignee:	REGENERON PHARMACEUTICALS, INC. (Tarrytown, NY)
Application Number:	15/509,461
Patent Claims:	see list of patent claims

United States Patent 10,525,104 (VEGF Trap) Claims and U.S. Patent Landscape for mCRC Biomarker-Selected Treatment

US Patent 10,525,104 centers on treating metastatic colorectal cancer (mCRC) with a VEGF Trap that includes specific VEGFR-derived Ig-like domains plus a multimerizing domain, and selecting patients based on elevated VEGF-A expression versus a lower VEGF-A reference level in mCRC subjects. Claim set scope narrows further to ziv-aflibercept and adds a FOLFIRI backbone in dependent claim 3. The practical risk for generic or biosimilar-style entry is not the underlying drug chemistry but the biomarker selection logic plus the exact VEGF Trap architecture requirement (Ig-like domain 2 of VEGFR1, Ig-like domain 3 of VEGFR2, multimerizing domain) and, for the strictest scope, the ziv-aflibercept identity and the FOLFIRI combination.

What patents protect biomarker-selected metastatic colorectal cancer treatment with ziv-aflibercept/VEGF Trap?

Short answer: US 10,525,104 protects a method-of-treatment with (1) a VEGF Trap defined by VEGFR domain composition and multimerizing domain and (2) patient selection by elevated VEGF-A expression compared to a reference lower level in mCRC. Dependent claims then lock to ziv-aflibercept and, in claim 3, to combination with FOLFIRI.

How does claim 1 define the VEGF Trap with structural domain requirements?

Claim 1 requires the VEGF antagonist be “a VEGF Trap” that comprises:

• Ig-like domain 2 of VEGFR1
• Ig-like domain 3 of VEGFR2
• a multimerizing domain

This is a claim drafting strategy aimed at excluding VEGF inhibitors that do not share the same domain architecture. Functionally similar VEGF-blocking agents without that exact domain arrangement are outside the literal claim language.

Material implication: A competitor attempting to avoid infringement would focus on whether its VEGF-binding construct is “a VEGF Trap” and whether it contains the same specific Ig-like domains and multimerizing domain. That is an “architecture match” problem, not just an “anti-VEGF potency” problem.

How does claim 1 define patient selection by VEGF-A expression?

Claim 1 requires:

• the patient has mCRC and has been selected for treatment with the VEGF antagonist
• selection is based on elevated VEGF-A expression
• elevated VEGF-A is determined via comparison to a “lower level of VEGF-A in subjects with mCRC”

This creates a second infringement axis: the biomarker testing and thresholding/relative comparison method.

Material implication: Even if a competitor uses a VEGF Trap with the required domain composition, infringement can hinge on whether their clinical trial or commercial program selects patients using the same comparative VEGF-A framework (elevated vs lower in mCRC subjects) and whether the “lower level” is implemented in a way that maps to the claim’s definitional language.

What does dependent claim 2 add?

Claim 2 narrows claim 1 by requiring the VEGF Trap be ziv-aflibercept.

This converts the structural domain requirement into an identity-based restriction. If ziv-aflibercept is used in the claimed manner, the domain-architecture argument becomes secondary because identity is satisfied.

What does dependent claim 3 add?

Claim 3 adds that, in addition to the VEGF Trap method, the regimen includes FOLFIRI:

• irinotecan
• 5-fluorouracil
• leucovorin

This is a combination-method narrowing provision. It targets protocols where the VEGF Trap is paired with FOLFIRI specifically, not with other mCRC backbones (eg, FOLFOX, capecitabine-based regimens, or single-agent approaches).

How strong is the patent estate for US 10,525,104 based on claim scope and typical litigation posture?

Short answer: Strength is driven by (1) a combination of a biologic/construct architecture constraint and (2) biomarker selection logic, both of which can be difficult for design-arounds to neutralize while staying in the same clinical positioning for mCRC.

Where the claim is likely hardest to design around

1. VEGF Trap architecture requirement (Ig-like domains + multimerizing domain):
   Many anti-VEGF modalities differ by scaffold. Even if the modality is an Fc-fusion decoy receptor type, the domain inclusion is a literal claim hook.

2. Biomarker “elevated expression” determined by comparison to a lower level in mCRC subjects:
   This invites arguments about clinical threshold definitions and how trials define “lower” versus “elevated.” If the competitor uses a different biomarker methodology, different cut points, or different comparator groups, it can change infringement risk.

Where the claim may be exposed

• If the market practice does not implement biomarker selection in the claimed comparative manner, enforcement can face proof burdens. Method claims in the U.S. often run into “how do you prove the selection criteria were used” issues in commercial contexts.
• If prior art already taught biomarker-enrichment in mCRC with VEGF pathway inhibition using this construct class, validity attacks under 35 U.S.C. §§ 102/103 may succeed, depending on exact claim specificity and how prior art tied VEGF-A expression to selection for ziv-aflibercept-type traps.

What prior art likely matters for validity analysis of US 10,525,104?

Short answer: The relevant validity landscape is shaped by prior publications around (1) aflibercept/ziv-aflibercept as VEGF traps, (2) use of VEGF pathway antagonism in mCRC, and (3) VEGF-A biomarker stratification in colorectal cancer.

Key prior art themes to stress in a critical analysis

• “VEGF Trap” construct identity and domain composition
  Publications and patents describing the aflibercept/vaflibercept/ziv-aflibercept decoy receptor architecture (VEGFR1/VEGFR2 Ig domains plus multimerizing moiety) would be the core reference family for anticipation-style challenges against the construct features.

• Biomarker stratification using VEGF-A in mCRC
  Prior attempts to correlate VEGF-A levels with outcome or treatment benefit in colorectal cancer, especially with VEGF inhibitor therapies, are the most relevant for obviousness arguments. The closer the prior art to a “select elevated VEGF-A” approach with a reference comparator in mCRC, the higher the validity risk.

• Combination regimen teachings in mCRC
  Claim 3’s FOLFIRI pairing would be compared against the background of mCRC standard-of-care combinations with VEGF pathway agents or agents targeting VEGF signaling, to assess whether adding FOLFIRI is obvious.

Critical point: Claim 1 mixes construct architecture with biomarker selection logic for a specific disease setting (mCRC). Even if each piece existed independently in prior art, the patentability question becomes whether the combined approach would have been obvious and whether the claim’s “comparison to a lower level of VEGF-A in subjects with mCRC” is defined tightly enough to distinguish prior biomarker work.

Which companies are likely impacted by this patent for mCRC?

Short answer: The company impacted most directly is the sponsor/holder of ziv-aflibercept in oncology, typically Regeneron Pharmaceuticals Inc. and Bayer HealthCare (ziv-aflibercept brand: Zaltrap). Other impacts come from companies developing or marketing:

• mCRC VEGF inhibitors/VEGF traps with similar decoy receptor architecture
• mCRC regimens combining VEGF pathway blockade with FOLFIRI
• biomarker-guided enrichment programs using VEGF-A in mCRC

Practical infringement vectors

• Using ziv-aflibercept as the VEGF Trap in mCRC under a clinical program that selects patients based on elevated VEGF-A expression relative to a “lower level” comparator in mCRC subjects.
• Pairing ziv-aflibercept with FOLFIRI in the biomarker-selected population.

What FDA/regulatory status matters for enforcing or challenging US 10,525,104?

Short answer: Enforcement is generally independent of FDA labeling, but FDA labeling and trial descriptions affect proof and settlement leverage. If the commercial indication or trial registry references VEGF-A biomarker selection, that supports enforcement. If labeling does not require biomarker selection, enforcement typically shifts to off-label clinical practice evidence.

Where “VEGF-A elevated expression selection” may show up

• clinical trial protocols and companion diagnostics language
• inclusion criteria describing VEGF-A levels or risk stratification
• scientific publications tied to the drug’s pivotal and biomarker studies

How does US 10,525,104 compare with the broader aflibercept patent families for oncology?

Short answer: Many aflibercept patent families focus on:

• the VEGF trap construct itself
• manufacturing and formulation
• specific cancers and combination regimens
• biomarkers that predict response

US 10,525,104 is positioned at the intersection of construct definition (Ig-like domains + multimerizing domain) and biomarker-based selection in mCRC, with additional narrowing to ziv-aflibercept and FOLFIRI.

Where it is likely to overlap with other patents

• construct patents: likely earlier in the estate (or parallel families) for the same decoy receptor architecture
• aflibercept-oncology use patents: could overlap on mCRC treatment
• biomarker companion strategy patents: could overlap on VEGF-A selection thresholds

Where it may be distinct

• the claim’s explicit biomarker comparator framing: “elevated expression of VEGF-A” determined by comparison to a lower level in mCRC subjects
• the tight dependence on the VEGF Trap’s domain composition and multimerizing domain

When does US 10,525,104 lose exclusivity, and can generics compete before then?

Short answer: Exclusivity for a method-of-use patent does not map cleanly to “Orange Book” drug exclusivity concepts because the core patent is a method claim. In practice, generics face timing determined by the latest expiring relevant method patents tied to the asserted indications and biomarker selection practice.

Expiration math

No filing date, priority date, or prosecution history is provided in the prompt. Without those data, exact expiration scheduling cannot be calculated here.

What are the litigation and Paragraph IV risks tied to this patent?

Short answer: For a method-of-use patent, the main litigation risk for generics is likely a patent infringement suit in response to:

• marketing of the accused regimen using ziv-aflibercept or a directly infringing VEGF trap construct (including evidence of biomarker selection practice)
• clinical adoption of biomarker-selected dosing and combination regimens

Paragraph IV certifications are typically relevant to ANDA-style generic challenges for small molecules. Ziv-aflibercept is a biologic. The most relevant “entry” threat framework is biosimilar or follow-on biologic pathways, where patent disputes often use other statutory mechanisms and where infringement theory depends on similarity of product plus method adoption by the provider.

Key claim-to-competitive design-around map

Short answer: Competitors can try to avoid infringement in three ways: change the VEGF Trap architecture, avoid the biomarker selection criterion, or avoid the specific regimen combination (FOLFIRI) in claim 3.

Claim element	What it requires	Design-around lever	Typical proof friction
VEGF antagonist is a VEGF Trap with Ig-like domain 2 of VEGFR1 + Ig-like domain 3 of VEGFR2 + multimerizing domain	Specific construct architecture	Use a different decoy architecture that lacks the required domain set or multimerizing domain	Structural characterization of the competing biologic
Patient selected based on elevated VEGF-A vs lower level in mCRC subjects	Biomarker selection logic and thresholding	Use a different biomarker, different comparator cohort, or different cutoff definition	Trial protocol adherence and documentation
VEGF Trap is ziv-aflibercept (claim 2)	Identity	Use a different VEGF Trap product	Product identity evidence
Administer FOLFIRI with the VEGF Trap (claim 3)	Combination regimen specificity	Use different chemo backbone (eg, FOLFOX)	Treatment regimen evidence in accused use

How might courts interpret “elevated expression” and the comparator “lower level” in mCRC subjects?

Short answer: Method claims with relative biomarker language depend on construction and on how the comparator is defined in the patent specification.

Likely construction issues

• Whether “lower level” is a specific numeric threshold implied by the patent’s examples/definition or a functional/comparative benchmark tied to patient cohorts.
• Whether “selected for treatment” requires testing before dosing, and whether retrospective association studies qualify.

These issues often decide whether a competitor’s real-world practice falls inside or outside the claim.

Key takeaways

1. US 10,525,104 protects a biomarker-enriched method for treating metastatic colorectal cancer using a VEGF Trap defined by VEGFR1 Ig-like domain 2 + VEGFR2 Ig-like domain 3 + a multimerizing domain, with patient selection based on elevated VEGF-A expression relative to a lower VEGF-A level in mCRC subjects.
2. Dependent claim 2 narrows to ziv-aflibercept. Dependent claim 3 narrows to combination with FOLFIRI.
3. Competitive risk concentrates on commercial and trial protocols that explicitly use VEGF-A selection in the claimed comparative way and administer ziv-aflibercept with FOLFIRI.
4. Validity risk is likely driven by prior art spanning VEGF trap architecture, VEGF-A biomarker stratification in colorectal cancer, and established mCRC chemo backbone combinations with VEGF pathway inhibition.
5. Exact exclusivity/expiration timing requires priority/filing date data not provided in the prompt.

FAQs

1. What would most directly infringe claim 1 of US 10,525,104 in the U.S.?
A clinical or commercial program that administers ziv-aflibercept (or another VEGF Trap with the same VEGFR1/VEGFR2 Ig-domain architecture and multimerizing domain) to mCRC patients selected using a VEGF-A “elevated vs lower” comparative criterion relative to mCRC subjects.

2. Can a competitor avoid claim 1 by using a different VEGF inhibitor (not a VEGF Trap)?
If the inhibitor is not a VEGF Trap with the required Ig-like domain composition plus multimerizing domain, it is outside the claim’s literal construct requirement.

3. Is claim 3 (FOLFIRI) a standalone infringement hook?
No. It is dependent on claim 2 and claim 1. It requires the VEGF Trap identity (ziv-aflibercept) and the VEGF-A biomarker selection method plus the FOLFIRI regimen.

4. Does “elevated VEGF-A” mean any VEGF-A increase relative to normal?
The claim language is comparative to “a lower level of VEGF-A in subjects with mCRC,” so normal reference ranges do not automatically map to the claim’s required comparator concept.

5. Is this patent likely relevant to biosimilar or follow-on biologic disputes?
Yes. The asserted claim is a method-of-treatment claim tied to a biologic class (VEGF Trap) and patient selection logic. The key disputes usually focus on construct similarity plus the clinical method actually used in practice.

References

1. United States Patent 10,525,104.

Details for Patent 10,525,104

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Regeneron Pharmaceuticals, Inc.	EYLEA	aflibercept	Injection	125387	November 18, 2011	10,525,104	2035-09-10
Regeneron Pharmaceuticals, Inc.	EYLEA	aflibercept	Injection	125387	August 16, 2018	10,525,104	2035-09-10
Sanofi-aventis U.s. Llc	ZALTRAP	ziv-aflibercept	Injection	125418	August 03, 2012	10,525,104	2035-09-10