Patent: 10,238,656

Summary for Patent: 10,238,656

Title:	Combination therapy for cancer
Abstract:	The present invention provides preparation of medicaments for use in treating and methods of treating non-small cell lung cancer in a patient comprising: [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-i- sopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine, or a pharmaceutically acceptable salt thereof, in combination, as further described herein, with an anti-VEGFR2 antibody, preferably, ramucirumab.
Inventor(s):	Chan; Edward Michael (Greenwood, IN)
Assignee:	Eli Lilly and Company (Indianapolis, IN)
Application Number:	15/115,995
Patent Claims:	see list of patent claims

US Patent 10,238,656: What the Claims Actually Cover and How the U.S. Landscape Blocks or Opens Competition

US Patent 10,238,656 is directed to a treatment regimen for non-small cell lung cancer (NSCLC) that combines (i) a specific low-milligram-dose oral small molecule defined by a structural formula and administered at either 300 mg/day or 400 mg/day, with (ii) ramucirumab given at 10 mg/kg on a defined schedule (either every three weeks or on day 1 of a 21-day cycle). The claim set is narrow in its regimen definition and broad in its patient class (human NSCLC) and administration mode split (oral for the small molecule; IV for ramucirumab).

What matters for commercial R&D is that the patent’s enforceable scope is shaped by three levers: the small-molecule structure (and therefore the chemical space captured), the exact ramucirumab dosing frequency, and the oral-IV administration pairing. Those levers also determine how easily competitors can design around by changing one element without sacrificing efficacy.

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What do Claims 1–6 cover, in concrete terms?

Claim 1 (core combination claim)

Claim 1 recites a method of treating NSCLC comprising:

• Administer to a human with NSCLC 300 mg/day or 400 mg/day of a compound of formula “##STR00005##” (or a pharmaceutically acceptable salt)
• In combination with 10 mg/kg ramucirumab
• Ramucirumab schedule: once every three weeks

Claim 2 (formula-specific tightening)

Claim 2 narrows claim 1 by specifying that the compound is the specific embodiment shown in “##STR00006##” (a particular structure within the broader formula set).

Claim 3 (route specificity)

Claim 3 tightens administration details:

• The compound (or salt) is administered orally
• Ramucirumab is administered intravenously

Claim 4 (21-day cycle language; same dose logic)

Claim 4 recites substantially the same regimen as claim 1, but expresses the ramucirumab schedule as:

• 10 mg/kg of ramucirumab on the first day of a 21-day cycle
• The small molecule is again 300 mg/day or 400 mg/day of the structure “##STR00007##” (or salt)

Claim 5 (formula-specific tightening)

Claim 5 narrows claim 4 by specifying the compound as the embodiment in “##STR00008##”.

Claim 6 (route specificity for the “21-day cycle” variant)

Claim 6 locks in:

• Oral dosing for the compound (or salt)
• IV dosing for ramucirumab

Net effect: the patent covers two regimen descriptions (three-week dosing vs day-1 of 21-day cycle) and two structural embodiments (broad formula vs specified structures), with route locked in by separate claim elements.

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What is the claim architecture that determines infringement risk?

1) Regimen-based infringement hinges on “all elements”

This is not a composition patent claiming the molecule itself; it is a method claim requiring:

• The correct patient indication (human NSCLC)
• The correct oral small-molecule dosing (300 or 400 mg/day)
• The correct ramucirumab dose (10 mg/kg)
• The correct ramucirumab timing (once every three weeks or day 1 of 21-day cycle)
• And, for claims 3 and 6, the correct routes (oral compound; IV ramucirumab)

If a competitor changes even one required element, claim 1 or 4 can be avoided depending on which claim is asserted.

2) The “300 or 400 mg/day” creates a binary dose window

The small-molecule portion is limited to two daily dose targets. That is a strong design-around handle if regulators or trials tolerate alternative doses.

3) “Once every three weeks” and “day 1 of a 21-day cycle” are functionally aligned

From a legal and practical standpoint, both express the same dosing cadence. Competitors should assume the schedule element will be interpreted as continuous 3-week dosing unless the record in prosecution defines otherwise.

4) The route language is only in dependent claims

Claims 1 and 4 do not explicitly require routes; claims 3 and 6 do. If a competitor could credibly administer the small molecule non-oral while keeping the same daily dose and maintaining the regimen, they could try to avoid claims 3/6 while still risking claims 1/4. Route can still be a factual battleground in method infringement.

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What does the structure language imply about the chemical scope?

Claims reference “formula ##STR00005##” and “##STR00007##” and then narrow to specific embodiments “##STR00006##” and “##STR00008##.”

Without the actual chemical drawings in machine-readable form, the precise molecular coverage cannot be reconstructed from the text you provided. However, the legal structure is clear:

• Broad coverage in claims 1 and 4: a genus defined by a structural formula (with substituents and ring/linker variations encoded in the patent’s figure definition).
• Narrow coverage in claims 2 and 5: a specific compound within that genus.

For landscape strategy, the key point is that infringement turns on whether the competitor’s compound is literally within the genus formula or matches the specified embodiment structures. This creates three practical outcomes for competitors: 1) Literal avoidance by structure outside the genus is the cleanest path. 2) Literal risk remains high if the competitor uses the specified embodiment (claims 2 and 5). 3) Doctrine of equivalents may expand risk if the competitor uses a functionally similar compound that prosecutors characterized as equivalent during examination, but that depends on the prosecution record (which is not provided here).

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How does ramucirumab dosing constrain design-around strategies?

The patent fixes ramucirumab at:

• 10 mg/kg
• Scheduled on a 3-week cadence (once every three weeks) or day 1 of a 21-day cycle
• IV is required only for claims 3 and 6 (route-specific dependent claims)

Design-around options that reduce risk to claims 1/4:

• Change ramucirumab dose away from 10 mg/kg
• Change cadence away from 3-week dosing
• Change regimen so ramucirumab is not administered in the same “combination method” manner tied to the claim’s timing

However, competitors still face practical constraints: changing ramucirumab dosing is often limited by clinical practice and label-adjacent dosing protocols.

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What is the patent landscape likely to look like for this regimen in the U.S.?

A regimen combining a targeted or kinase small molecule with an approved antibody typically creates a landscape with these layers:

1) Core small-molecule patents (composition + synthesis + specific polymorphs) 2) Combination method patents (like this one), often covering specific co-administration dosing schedules 3) Regimen patents across indications and lines of therapy 4) Process/kit patents tied to dosing regimens and administration

US Patent 10,238,656 is clearly in category (2): it locks an NSCLC combination method to exact doses and schedule.

Critical competitive implication: even if a competitor has freedom under separate small-molecule composition rights, they still need to clear combination method claims that are written to a dosing protocol. That is where exclusivity can persist after the primary drug’s composition rights change.

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Where are the likely enforceability pressure points?

1) “Non-small cell lung cancer” as a broad indication

The claim text is not limited to:

• specific biomarkers,
• specific treatment lines (first-line vs later),
• or specific histology.

Broad patient definition increases infringement exposure if the regimen is applied in clinical practice under the method claim elements. But it also makes the evidentiary burden on enforcement more manageable because “NSCLC” is a common clinical label.

2) Dose-level specificity makes validity fights plausible

The regimen is tied to 300/400 mg/day and 10 mg/kg. If prior art shows overlapping ranges or different schedules, the novelty argument can still be contested on obviousness grounds. Dose selection can become a focal point in validity challenges.

3) Schedule duplication across claims 1 and 4

Because “once every three weeks” and “day 1 of a 21-day cycle” both describe the same cadence, the patent’s claim differentiation is more about draft coverage than about distinct inventive concepts. That can matter if a challenger attacks the redundancy as failing to add patentably distinct coverage (again dependent on the prosecution history and prior art set).

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How should R&D and IP teams use this claim set in freedom-to-operate planning?

Decision tree based on the claim elements

A competitor planning a regimen in NSCLC should treat the claims as an element-by-element checklist:

1) Is the patient population NSCLC?

• If yes, continue. 2) Is ramucirumab used at 10 mg/kg?
• If yes, continue; if no, claims 1 and 4 are harder to trigger. 3) Is ramucirumab scheduled once every three weeks or day 1 of a 21-day cycle?
• If yes, continue. 4) Is the oral small molecule dosed at 300 or 400 mg/day?
• If yes, continue. 5) Does the small molecule literally fall within the claimed formula genus or match the specified structures in claims 2 and 5?
• If yes, infringement risk spikes. 6) If aiming to avoid claims 3/6, is the compound not administered orally or is ramucirumab not IV?
• If yes, reduces risk to route-dependent dependent claims but may not avoid claims 1/4.

Most practical design-around knobs

In practice, teams usually have three levers to pull:

• small-molecule structure (avoid genus),
• ramucirumab dose,
• and co-administration schedule.

Route is often harder to change for an established antibody.

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What does this mean for investment positioning and licensing?

• If the company’s candidate small molecule is structurally close to the specified embodiment in claims 2 and 5, the patent is likely a major gating item for combination trials that administer ramucirumab 10 mg/kg on a 3-week cadence.
• If the company uses ramucirumab but at a different dose or schedule, the risk to claims 1 and 4 drops sharply.
• If the company runs trials in NSCLC but changes daily small-molecule dose away from 300/400 mg/day, that can also avoid claims even if the structure remains within the genus.

The value of a license or settlement for this kind of patent is typically high when the candidate is structurally within the claim genus and the dosing schedule matches common practice.

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Key Takeaways

• US Patent 10,238,656 is a method-of-use patent for NSCLC combining an oral small molecule at 300 or 400 mg/day with ramucirumab at 10 mg/kg on a 3-week (21-day cycle) schedule.
• Claims 1 and 4 are regimen-defining; claims 2 and 5 narrow to specific small-molecule embodiments; claims 3 and 6 add route constraints (oral compound; IV ramucirumab).
• The strongest infringement trigger is when a competitor matches all required elements, especially ramucirumab dose (10 mg/kg) and the 3-week cadence, plus the 300/400 mg/day dosing and structural inclusion within the claimed formula.
• For design-around, the highest-yield knobs are changing the ramucirumab dose/schedule or using a small molecule outside the claimed genus/specified embodiment; route changes mainly reduce risk to dependent claims.

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FAQs

1) Is US 10,238,656 a composition-of-matter or a treatment method patent?

It is a treatment method patent: it claims a method of treating NSCLC by administering a defined oral small molecule at 300 or 400 mg/day together with ramucirumab at 10 mg/kg on a 3-week schedule.

2) Does the patent require the small molecule to be taken orally?

Not in claims 1 and 4. Claims 3 and 6 require oral administration of the small molecule and IV administration of ramucirumab.

3) Are “once every three weeks” and “day 1 of a 21-day cycle” different?

They describe the same cadence. The patent uses both to broaden drafting coverage, not to create two distinct schedules in practical terms.

4) What are the dose elements that most affect infringement?

The most specific elements are the small-molecule dose (300 mg/day or 400 mg/day) and the ramucirumab dose (10 mg/kg) given on a 3-week/21-day cycle schedule.

5) What is the fastest design-around pathway?

Avoid the claim’s regimen definition by changing at least one fixed element: use a different ramucirumab dose or schedule, or use a small molecule outside the claimed formula/genus and the specified embodiments.

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References

[1] US Patent 10,238,656 (claims 1–6 as provided in prompt).

Details for Patent 10,238,656

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	CYRAMZA	ramucirumab	Injection	125477	April 21, 2014	10,238,656	2035-02-19