Patent: 6,869,952

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Summary for Patent: 6,869,952

Title:	Pyrrolo[2,1-f][1,2,4]triazine inhibitors of kinases
Abstract:	The present invention provides compounds of formula I, ##STR1## and pharmaceutically acceptable salts thereof. The formula I compounds inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1, thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases associated with signal transduction pathways operating through growth factor receptors.
Inventor(s):	Bhide; Rajeev S. (Princeton Junction, NJ), Cai; Zhen-Wei (Belle Mead, NJ), Qian; Ligang (Hopewell, NJ), Barbosa; Stephanie (Lambertville, NJ)
Assignee:	Bristol Myers Squibb Company (Princeton, NJ)
Application Number:	10/623,171
Patent Claims:	see list of patent claims

United States Patent 6,869,952 Landscape: Claims, Claim Scope, and US Patent Estate Risks for the Indolyl-Oxy Pyrrolo[2,1-f][1,2,4]Triazine Series

Executive summary. US Patent 6,869,952 is a chemical-entity US patent built around a tight structural scaffold: an indole (4-fluoro-2-methyl-1H-indol-5-yloxy) linked to a 5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl/oxy core, with enumerated substituent classes at the 6-position and multiple stereochemical variants, salts, and prodrug-like ester/amino acid derivatives. The claim set is dominated by broad genus-within-a-defined-structure coverage via long Markush-style enumerations, then expands to composition and combination-therapy claims that can create cross-product leverage in licensing and settlement even when the core chemistry is narrow in practice. The competitive risk for a generic or follow-on is that infringement can be argued not only for the parent substituted triazines but also for specific stereoisomers and several sulfonamide/ester derivatives named in the claim language, plus formulation and synergy/combination claims when a challenger aligns with the enumerated partner agents.

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What does US Patent 6,869,952 claim, and what is the effective “core” chemical scope?

Short answer. The patent claims a series of compounds (and salts) that all share one of a few closely related connectivity patterns: indole-oxy to the pyrrolo[2,1-f][1,2,4]triazin-6-oxygen or -carbon linkage, plus substitutions at defined positions, including stereochemical variants and several derivative forms (sulfonamides, sulfone-propoxy analogs, amino-acid ester derivatives, and related named substituents).

Claim 1 vs claim 2: what changes in the claimed genus

Both claims are Markush-type entity claims listing multiple members, but the two claims differ in the set of included enumerated compounds.

• Claim 1 includes, among other members:

  • 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol
  • Multiple chiral diol forms: (2S)/(2R)-1-[...]-propan-2-ol; (2S)/(2R)-3-[...]-propane-1,2-diol
  • Substitution patterns on the 6-oxygen substituent side chain: methoxy and ethanol analogs
  • Several sulfonamide or sulfone-type derivatives, including:
    • N-{3-[...]-propyl}-methanesulfonamide
    • N-{2-[...]-ethyl}-methanesulfonamide
    • 1-[...]-4-(aminosulfonyl)aminobutan-2-ol (notable: “amino sulfonyl” functionality)
  • Prodrug/derivative style amino acid ester members:
    • [(1R),2S]-2-Dimethylaminopropionic acid-[2-[...]]-1-methylethyl ester
    • [(1R),2S]-2-Amino-4-methylpentanoic acid [2-[...]]-1-methylethyl ester
    • [(1R),2S]-2-Aminopropionic acid [2-[...]]-1-methylethyl ester
  • Additional enumerated sidechain substituents with ring-containing groups:
    • piperidinyl propoxy/ethoxy analogs
    • pyridinyl propoxy analogs
  • sulfone-propoxy analog:
    • 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-(3-methanesulfonyl-propoxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine
  • Also includes a named methanesulfonyl butan-2-ol type:
    • (2R)-1-[...]-4-methanesulfonyl-butan-2-ol
    • (2S)-1-[...]-4-methanesulfonyl-butan-2-ol

• Claim 2 tracks a substantial overlap but is narrower/shifted in the list, removing some elements and adding/keeping others differently:

  • It includes:
    • the triazine-6-ol member
    • many stereochemical members (same chiral diol/propanol core variants)
    • specific piperidinyl and amino/alkyl derivatives
  • Notably, the claim text shown for claim 2 includes several members that appear in claim 1, but the exact coverage set differs (because each claim has its own enumeration list rather than a single “including” clause spanning both lists).

Practical impact. For infringement strategy, both claims can be used as alternative asserted routes depending on the exact competitor molecule. In licensing or litigation, you typically test a candidate product against each explicitly listed species because the claims read as species lists under a constrained structural family, not a free-form functional claim.

What structural “anchors” appear in essentially every listed compound

Even in the absence of a formal “Markush formula” in the excerpt, the enumerated names indicate the recurring anchor features:

1. Indole pharmacophore: 4-fluoro-2-methyl-1H-indol-5-yloxy.
2. Pyrrolo[2,1-f][1,2,4]triazine core: 5-methyl and 6-connection to the oxy-linked side chain.
3. Stereochemical control: chiral labels (2R)/(2S) recur for propanol/diol/butanol-like substitution patterns.
4. Side-chain heteroatom functionality: hydroxyl, methoxy, amino, sulfonamide, and methanesulfonyl substituents.
5. Named ring-bearing moieties: piperidine and pyridine substituted propoxy/ethoxy groups.

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How broad are the compound claims, and are they “genus” or “species” in practice?

Short answer. The claims function as a defined-structure species set. The entity scope is broad in the number of enumerated items, but narrow in the sense that it is constrained to a very particular scaffold and a named list of members.

Species enumeration creates claim-by-claim infringement leverage

Because the claim language lists specific compounds by IUPAC-like structural names, an accused compound can escape if it is not one of the enumerated species (or a “pharmaceutically acceptable salt” of an enumerated compound). For enforcement and freedom-to-operate:

• If the competitor’s API is one of the explicitly listed compounds, claim coverage is straightforward.
• If the competitor has a different side chain length, different ring substitution position, or different substitution class not named, infringement becomes an argument about whether the molecule still falls “selected from the group consisting of” the enumerated members. That phrasing generally does not extend to near neighbors.

Salts: what is covered

Both claim 1 and claim 2 state “compound or pharmaceutically acceptable salt thereof”. That extends coverage to salt forms of an otherwise covered API, but it does not expand beyond the underlying enumerated chemical entities.

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What does the patent add beyond chemical entities: composition and combination claims?

Short answer. Claims 3 to 7 broaden monetization opportunities: (i) formulation/composition with a carrier, and (ii) combination therapy with an enumerated list of anti-cancer/cytotoxic agents.

Composition claims 3 and 4

• Claim 3: pharmaceutical composition with at least one compound of claim 1 + pharmaceutically acceptable carrier.
• Claim 4: pharmaceutical composition with at least one compound of claim 2 + carrier.

Infringement logic. A competitor that uses the covered API in any compatible carrier-based pharmaceutical form can face infringement even if it does not match the exact chemical structure category beyond what claim 1/2 covers.

Combination therapy claim 5 and 6: where leverage appears

• Claim 5: composition with at least one compound of claim 1 + carrier + at least one additional anti-cancer or cytotoxic agent.
• Claim 6: same but using compounds of claim 2.

This can reach:

• co-formulations,
• kits,
• dosing regimens where the combination is manufactured and sold as a prescribed product.

Claim 7: lists specific partner agents

Claim 7 narrows combinations to an enumerated set of anti-cancer/cytotoxic agents, including:

• hormonal agents (tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate),
• aromatase inhibitors (anastrozole, letrozole, exemestane),
• androgen receptor therapies (flutamide, nilutamide),
• chemotherapy staples (methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin, cisplatin, carboplatin, cyclophosphamide, paclitaxel, docetaxel, etoposide, irinotecan, etc.),
• targeted/biologics (bevacizumab, cetuximab, Herceptin),
• immune and growth factor axis items phrased as “antibodies,” “receptor antibodies,” and “biological response modifiers,”
• proteasome inhibitors (bortezomib),
• and others.

Commercial implication. If the covered API is used clinically in combination with any of these enumerated agents, the patent can be invoked even where a generic API label might otherwise argue off-patent status. In settlement, this often becomes a bargaining lever: combination regimens are how products are actually used.

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What are the key infringement “entry points” for generic or follow-on manufacturers?

Short answer. Entry risk is highest where the follow-on product is (i) one of the enumerated APIs, (ii) a pharmaceutically acceptable salt, or (iii) a composition or regimen combining the API with one of the claim 7 partner agents.

1) Paragraph IV-style chemical challenge

If a challenger files an FDA application with an abbreviated pathway and asserts non-infringement or invalidity, the inventor’s enumerated species can be attacked by:

• showing the accused compound is not among the listed entities,
• attacking stereoisomer coverage (if the challenger uses an isomer not enumerated),
• arguing that a marketed salt is not “pharmaceutically acceptable” or is not a salt of an enumerated compound.

But where the accused API matches one of the named species, the remaining defenses become validity-focused (anticipation/obviousness) rather than scope-focused.

2) Composition and combination workarounds are narrower

Even if a generic tries to avoid direct API identity by changing formulation:

• Claims 3/4 cover composition in any carrier,
• Claims 5/6 cover combinations with an additional anti-cancer agent,
• Claim 7 covers the specific set of partner agents.

That means a generic strategist cannot always “design around” via formulation alone if the API identity and combination partner align.

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What is the likely patent strength profile based on claim structure alone?

Short answer. The patent’s strength is asymmetric:

• Strong on coverage if the accused compound is one of the enumerated species.
• Potentially weaker if invalidity arguments can show the scaffold and substitutions were disclosed or obvious in prior art.

Because the excerpt provides claims but not specification content, the strength profile assessed strictly from claim structure is this:

Strength drivers

• Specific stereoisomers and defined functional groups reduce the chance that prior art hits the claims accidentally.
• Enumerated species can make infringement easier to prove for exactly matching products.
• Combination claims can strengthen licensing leverage, because real-world regimens are often combination-based.

Potential weakness drivers

• Markush “consisting of” species lists can be easier for competitors to avoid by selecting a close analog not listed.
• If prior art contains many members of the same scaffold series, the novelty argument can thin out, pushing the fight into obviousness.

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How do you map US Patent 6,869,952 against a competitor molecule? (Operational checklist)

Short answer. A molecule either lands inside the enumerated entity list or it does not.

Checklist for technical/legal mapping

1. Determine whether the API is exactly one of the listed compounds in claim 1 or claim 2.
2. Check stereochemical labeling:
   • (2R) vs (2S) matters for the named propanol/diol/butanol patterns.
3. Check the sidechain type:
   • hydroxyl,
   • methoxy,
   • sulfonamide,
   • methanesulfonyl,
   • amino-acid ester derivatives,
   • piperidinyl or pyridinyl propoxy/ethoxy substituents.
4. Determine whether the competitor sells or uses a salt form:
   • if yes, verify that it is a salt of one of the enumerated compounds.
5. Determine dosage form and co-therapy:
   • composition claim triggers if the API is present in a carrier-based formulation,
   • combination claim triggers if the regimen includes a claim 7 partner agent.

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Which commercial scenarios are most exposed under this patent?

Short answer. Exposure concentrates in oncology combination regimens and marketed formulations that use the API, including any co-administered partner drug that appears in claim 7.

Highest exposure scenarios

• A product where the API is one of the enumerated compounds and is marketed as:
  • combination therapy with any of the enumerated chemotherapies, endocrine agents, biologics, proteasome inhibitors, or targeted therapies.
• Any kit or co-pack where the combination is explicitly delivered as a product offering.

Lower exposure scenarios

• Products using a non-enumerated analog that stays outside the listed chemical entities.
• Regimens that combine the API with an anti-cancer agent that is not in claim 7’s enumerated list (even if clinically used), assuming the claim 5/6 language is not pursued beyond claim 7 dependent narrowing.

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Patent estate questions that must be answered in litigation or licensing (but can’t be derived from the excerpt alone)

Short answer. The excerpt does not provide publication number(s), priority, expiration, or family members. Without those, the exclusivity and event timeline cannot be computed from claim text alone.

What you would normally extract from the INPADOC/Orange Book trail (not available in the prompt)

• grant/filing dates and remaining life in the US,
• continuations/divisionals impacting claim coverage,
• related process patents,
• method-of-use patents beyond these composition/combination claims,
• and FDA Orange Book listings tying this patent to a specific NDC/product.

Because the request requires a comprehensive and critical analysis of the US patent landscape, that portion cannot be produced accurately from the provided materials.

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Key Takeaways

• US Patent 6,869,952 claims a tightly defined indole-oxy pyrrolo[2,1-f][1,2,4]triazin scaffold with extensive enumerated species, covering specific stereoisomers and multiple derivative classes (sulfonamides, methanesulfonyl substituents, and amino-acid ester/prodrug-like members).
• The patent broadens monetization through composition claims (API + pharmaceutically acceptable carrier) and combination therapy claims with a long enumerated list of anti-cancer/cytotoxic agents.
• Design-around risk is primarily driven by whether the competitor API matches an explicitly named compound. Formulation changes alone typically do not avoid claims 3/4 if the API is covered.
• The most litigable commercial cases are those where the covered API is used in a regimen that includes a claim 7 enumerated partner agent, including biologics and standard chemotherapies.

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FAQs

1. Does US Patent 6,869,952 cover stereoisomer-specific versions of the same scaffold?
   The claim lists multiple compounds explicitly labeled (2R)/(2S); coverage tracks those enumerated stereochemical identities.

2. Can a competitor avoid infringement by selling a different salt form?
   The claims include “pharmaceutically acceptable salt thereof,” so alternative salt forms generally remain within scope if they are salts of an enumerated compound.

3. Are combination therapy claims triggered by any anticancer drug?
   The dependent language in claim 7 lists specific partner agents, so combination exposure is strongest when the co-administered agent appears in that enumerated list.

4. Do formulation changes eliminate risk under composition claims?
   Claims 3/4 are broad to “pharmaceutical composition” with a pharmaceutically acceptable carrier, so typical carrier/dosage-form variations do not, by themselves, remove risk if the API is within claims 1/2.

5. Is the chemical scope best treated as a broad genus or a limited set of specific molecules?
   The “selected from the group consisting of” structure reads as a limited set of enumerated species within a defined scaffold, so the infringement question is mostly a species-to-species mapping problem.

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References (APA)

1. United States Patent 6,869,952.

Details for Patent 6,869,952

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	January 16, 1978		2023-07-18
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	September 25, 1998		2023-07-18
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	February 10, 2017		2023-07-18
Imclone Llc A Wholly-owned Subsidiary Of Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	February 12, 2004		2023-07-18
Imclone Llc A Wholly-owned Subsidiary Of Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	March 28, 2007		2023-07-18