Patent: 9,555,022

Summary for Patent: 9,555,022

Title:	Substituted triazolopyridines
Abstract:	The present invention relates to substituted triazolopyridine compounds of general formula (I): in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease of uncontrolled cell growth, proliferation and/or survival as well as to the use of intermediate compounds for the preparation of said compounds. ##STR00001##
Inventor(s):	Schulze; Volker (OT Bergfelde, DE), Kosemund; Dirk (Berlin, DE), Schirok; Hartmut (Langenfeld, DE), Bader; Benjamin (Berlin, DE), Lienau; Philip (Berlin, DE), Wengner; Antje Margret (Berlin, DE), Briem; Hans (Berlin, DE), Holton; Simon (Berlin, DE), Siemeister; Gerhard (Berlin, DE), Prechtl; Stefan (Berlin, DE), Koppitz; Marcus (Berlin, DE), Stockigt; Detlef (Potsdam, DE), Prien; Olaf (Berlin, DE)
Assignee:	Bayer Intellectual Property GmbH (Monheim, DE)
Application Number:	13/704,859
Patent Claims:	see list of patent claims

United States Patent 9,555,022 (US 9,555,022): Claim Scope, Validity Hooks, and U.S. Patent Landscape

US 9,555,022 claims broad structural genus coverage over a substituted triazolopyridine/acyl-heteroaryl scaffold (General Formula (I)), plus downstream claims to (i) specific compound embodiments, (ii) a preparation method via alkylating/aromatic substitution intermediates, (iii) pharmaceutical compositions, (iv) combination therapy regimens, and (v) methods of treatment across multiple solid tumors. The core claim (Claim 1) is a high-variance “Markush” style genus that includes extensive permissive substituent definitions (large aryl/heteroaryl space, wide heterocycle allowances, multiple functional handle classes such as amides, thioethers, sulfonamides/carbonyls, and oxo-variants), with explicit coverage of salts, solvates, tautomers, stereoisomers, and N-oxides. Claim 7 enumerates a large set of named exemplars, anchoring enforceability to a tangible compound set even as the genus remains extremely wide.

What does US 9,555,022 actually claim?

Claim 1: A structurally broad compound genus with expansive substituent latitude

Claim 1 covers “a compound of general formula (I)” with multiple variable substituent classes:

• R¹: aryl/heteroaryl substituted with one or more of the enumerated substituent motifs (C1-C6 alkyl/alkoxy, halo-variants, hydroxyl, cyano, nitro, acyl-type carbonyl incorporations, thioether/thio-oxide like motifs, and nitrogen/sulfur acylated or sulfonamide-like motifs), plus optional further substitution with a second substituent set (halo/hydroxyl/cyano/nitro/C1-C6 alkyl/alkoxy and several carbonyl-containing groups).
• R²: aryl or heteroaryl substituted with substituents including R⁹-based groups and further optional substitutions that largely overlap R¹’s motif families (carbonyl/amine-like and thio-related options included).
• R³ and R⁴: relatively small substituent choices (H, halo, hydroxy, amino, cyano, nitro and small C1-C4 alkyl/alkoxy and limited alkenyl/alkynyl; cycloalkyl allowed).
• R⁵: fixed as hydrogen.
• R⁶: a core linker-like substituent: C3-C6 cycloalkyl, heterocycloalkyl (3- to 10-membered), aryl, heteroaryl, or substituted “(CH2)q–” variants, including optional substitution with the broader functional substituent set; also includes the option that R⁶ and R⁷ together with the attached N form a 3- to 10-membered heterocycloalkyl.
• R⁷: hydrogen or C1-C6 alkyl (or part of a heterocycloalkyl with R⁶).
• R⁸: hydrogen or C1-C6 alkyl.
• R⁹: C7-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or aryl/heteroaryl, with optional substitutions including halo/hydroxyl/cyano/nitro/C1-C6 alkyl/alkoxy, and carbonyl/thio/amine-like variants; alternatively R⁹ and R⁷ with the attached N form a heterocycle.
• Integer ranges: n, m, p independently 0 to 5; q is 0 to 3.
• Allowed variants: stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts.

In practical enforcement terms, Claim 1 behaves as a broad genus with two layers of substituent permissiveness: (1) wide chemical functionality choices around aryl/heteroaryl attachment points, and (2) multiple options for ring systems and linker lengths. The genus is not limited to a narrow pharmacophore subset beyond the triazolo[1,5-a]pyridine-type core implied by the enumerated examples in Claim 7.

Claims 2–6: Tightening subsets

Claims 2–6 narrow the genus by restricting certain variable sets:

• Claim 2: narrows R¹ and its allowed substituent motifs to a subset (removes some options) while still allowing salts/solvates and stereochemical variants.
• Claim 3: narrows R² substituent motif set.
• Claim 4: constrains R³ and R⁴ to smaller sets; and constrains R⁶ to only certain (CH2)q–cycloalkyl/heterocycloalkyl/aryl/heteroaryl options with only limited substituent classes (e.g., halo/C1-C6 alkyl/alkoxy style).
• Claim 5: forces R¹ to be aryl (with limited carbonyl and N-inclusion motif types) and narrows R², R³, R⁴, R⁵, and R⁶ further.
• Claim 6: sets a specific “implementation level” narrowing to R¹ = phenyl and restricts R⁶ and R² (phenyl/pyridyl), with R³ and R⁴ as H and R⁵ as H; q is restricted to 1 or 2. This is closer to a “near-feature” claim than Claim 1, but still remains permissive on substitution count and on allowed heterocycle substitutions.

These dependent claims matter for validity and infringement strategy: even if Claim 1 is attacked for breadth, narrower dependent claims offer fall-back coverage. The structure of the restriction sets indicates the drafter expected enforceability to persist through at least one “middle corridor” of substitutions.

Claim 7: A large, enumerated list of specific compounds

Claim 7 enumerates dozens of specific compounds, including examples featuring:

• Cyclopropyl (or cyclopropylmethyl) variants.
• Morpholine carbonyl amide motifs (morpholin-4-ylcarbonyl).
• Piperazine carbonyl variants (methylpiperazinyl, tert-butylpiperazinyl).
• Fluoro- and substituted phenyl groups.
• Oxazolidinone and oxazolines (2-oxo-1,3-oxazolidin-3-yl; dihydro-1,3-oxazol-2-yl; 4,5-dihydro analogs).
• Spiro and bicyclic amides (2-oxa-6-azaspiro[3.3]hept-6-ylcarbonyl; 2-oxa-5-azabicyclo[2.2.1]hept-5-ylcarbonyl).
• Azetidine, oxetan, hydroxylated ring systems (3-hydroxyazetidin-1-ylcarbonyl; oxetan-3-yl).
• Several triazolopyridine core positional isomer variants (e.g., pyridin-2-yl substituent types).
• Explicit salts, e.g., trifluoroacetate for some exemplars.

Claim 7 is an enforceability anchor: enumerated embodiments reduce reliance on “generic scope only” arguments and make claim interpretation more concrete for claim construction. It also signals that the specification likely supports multiple distinct substituent outcomes rather than a single narrow lead.

Claim 8: A preparation method

Claim 8 covers a method where an intermediate “compound of general formula (5)” reacts with a compound “general formula (5a) R²–Y” (leaving group Y) to yield the final “general formula (I).”

This is a substitution/functionalization route that implies:

• R²–Y is used to install or couple the R² aryl/heteroaryl portion onto the intermediate scaffold.
• Claim 8 is process-limited (not product-limited), creating potential infringement defenses around alternative synthetic routes.

Claims 9–15: Pharmaceutical composition, combination, and treatment methods

• Claim 9: pharmaceutical composition with diluent/carrier.
• Claim 10: combination therapy: compound(s) of Formula (I) plus one or more agents from an extremely broad oncologic palette, including taxanes, epothilones, multiple cytotoxics (5-FU/capecitabine, etoposide, platinum agents, alkylators), corticosteroid (prednisolone), anti-androgens (flutamide/bicalutamide etc.), bortezomib, and rituximab.
• Claims 12–15: subsets specifying the class:
  • Taxane: docetaxel/paclitaxel
  • Epothilone: ixabepilone/patupilone/sagopilone
  • Anti-androgen: flutamide/cyproterone acetate/bicalutamide
  • Platinum derivative: cisplatin/carboplatin
• Claim 11: method of treatment for breast cancer, non-small cell lung cancer, prostate cancer, cervical cancer, or melanoma.

From a landscape perspective, this combination breadth raises two practical issues: 1) combination claims are often vulnerable if they are not supported by specific synergy evidence in the specification; and
2) the breadth of the listed co-therapies increases the odds of obviousness challenges (many regimens are standard-of-care pairings in oncology).
Still, the claims cover combinations without requiring a particular sequence, dose ratio, or timing.

How strong is the claim architecture versus typical US validity and infringement attacks?

1) Breadth risk: Markush genus plus large functional classes

Claim 1’s substituent language is permissive across:

• multiple aryl/heteroaryl substitutions,
• extensive carbonyl and nitrogen-containing motifs,
• thio/sulfide-containing motifs,
• variable ring sizes and linker lengths (n, m, p; q).

That is a breadth pattern that can be attacked under:

• 35 USC 112 for enablement/adequate written description if the specification does not support the full range,
• 35 USC 103 obviousness if the core scaffold is known and the claimed substituent choices are routine variations.

However, the presence of Claim 7’s extensive enumerated examples reduces the “nothing in the middle” argument: it indicates at least a substantial set of species are actually disclosed and contemplated.

2) Fall-back positions: Claims 2–6 narrow critical variable sets

If Claim 1 faces breadth attacks, the narrower dependent claims create a litigation fallback:

• Claim 6 is particularly narrowing (R¹ phenyl, R³ and R⁴ H, q restricted to 1 or 2), which can align better with what the specification truly enables.

This structure often favors a patentee in settlement posture: they can concede part of Claim 1 while still asserting dependent claims aligned to the disclosed exemplars.

3) Product-by-structure scope: infringement likely hinges on core scaffold identity and substituent mapping

Because Formula (I) is structural and dependent options are explicit, infringement analysis usually reduces to:

• does the accused compound map to the triazolopyridine scaffold and the functional linkage patterns,
• can its substituents be captured by one of the enumerated substituent sets and ring/linker constraints,
• are the accused variants salts/tautomers/solvates covered.

Potential non-infringement routes typically involve substituent classes excluded by the dependent claim narrowing (e.g., specific carbonyl/hetero-functional classes) or altering the scaffold connectivity so it no longer matches Formula (I).

4) Method/process claims: different synthetic routes create design-around potential

Claim 8 is not a broad “use” claim; it is a synthesis step relation. A competitor using a fundamentally different coupling method might avoid Claim 8 even if they still sell the final compound claimed in Claim 1/7.

What does the US patent landscape imply for freedom-to-operate (FTO)?

1) The claims target a named chemical series embedded in broad genus language

Even without external citation to the patent’s family members, the claim text itself signals the series:

• triazolo[1,5-a]pyridine-like heteroaromatic system,
• substitution with amide-bearing heterocycles (morpholine/piperazine/azetidine/oxetan),
• aryl substituents including fluoro-phenyl and substituted ring systems.

That combination is consistent with “medicinal chemistry series” patents that commonly have:

• earlier priority filings for the core scaffold,
• follow-on patents for specific substitutions, polymorphs, and salts,
• continuation filings that broaden Markush coverage.

2) The combination therapy claims enlarge infringement surface across clinical regimens

Claim 10 lists almost the full spectrum of oncology agents, including:

• taxanes, epothilones,
• doxorubicin family,
• platinum,
• antimetabolites/cytarabine/irinotecan-like classes (here: 5-FU/capecitabine, fludarabine, cytarabine),
• anti-androgens,
• targeted agents (bortezomib, rituximab),
• and corticosteroids (prednisolone, dexamethasone).

Even if a compound competes as a mono-therapy, combination claims can still affect:

• co-prescribing strategies,
• clinical trial arms,
• and label expansion plans.

This breadth is an FTO risk multiplier: even a compliant monotherapy can still become entangled if commercial strategy includes standard combination regimens.

3) Litigation posture: enumerated species plus multiple dependent corridors

Claim 7 provides a list large enough that:

• a challenger can’t easily argue “no real disclosure” for the genus,
• a patentee can pick at least one example species that maps tightly to an accused compound’s likely design set.

For an FTO decision, this means risk does not scale linearly with how close your compound is to the “lead example.” Many species are covered, and the genus is broad enough to catch many substitutions.

Critical reading of key claim vulnerabilities

A. Combination claim obviousness exposure

Claim 10 is extraordinarily broad as to co-administered agents. Most listed agents are long-established oncology standards. Without tight limitations (dose, schedule, patient population, biomarker, synergy), combination claims risk:

• 103 obviousness based on known combinations,
• or 112 issues if the specification does not tie the Formula (I) compounds to those specific agent classes with reproducible benefit.

B. Genus enablement and written description exposure

Claim 1 and its dependents allow a wide array of:

• functional group embeddings and heterocycle types,
• linker lengths,
• and optional substitution multiplicity.

If the specification only provides activity or stability data for a small subset, the “full genus” may be attacked. Still, Claim 7’s extensive enumeration suggests the disclosure is not a thin scaffolding.

C. Potential indefiniteness risk from Markush complexity

The substituent language is highly layered and includes multiple alternative motif sets and nesting (e.g., R⁶ and R⁷ forming a heterocycloalkyl with attached N). While this is typical in chemical genus claims, the complexity can create claim construction disputes:

• whether certain substituents fall within the allowed motif list,
• and how leaving group/reaction maps in Claim 8.

Business implications for R&D and investment

1) Landscape signaling: this is a medicinal chemistry series patent

The enumerated compounds indicate an optimization campaign around:

• the core triazolopyridine scaffold,
• amide-linked solubilizing heterocycles,
• substitution patterns on aromatic rings including fluoro and heteroaromatic replacements.

That pattern is consistent with a company strategy that:

• defends a pharmacophore while rapidly expanding chemical diversity,
• uses salts/polymorph coverage to extend commercial lifecycle,
• uses combination and method-of-treatment claims to cover clinical use.

2) Practical infringement mapping

For any candidate compound, infringement likelihood will be governed by:

• whether the scaffold matches the Formula (I) connectivity pattern,
• whether the side chains fall within allowed R¹/R²/R⁶/R⁹ substituent motif sets,
• and whether your salt form matches the claimed covered variant types (salts, solvates, tautomers, N-oxides).

Claim 7 gives multiple “hard points” where close analogs are explicitly within scope.

3) Design-around options

• Scaffold shift: avoid mapping to the Formula (I) core connectivity.
• Functional class shift: use substituent classes outside the enumerated motif list, especially those related to carbonyl and N/S embedding motifs.
• Process shift: use alternative synthetic coupling not captured by Claim 8’s reaction arrangement.
• Combination strategy: if the compound is used clinically, avoid co-therapy regimens that fall into Claim 10’s agent list (this is operationally difficult because standard care often overlaps).

Key Takeaways

• US 9,555,022 is a broad Markush genus patent centered on a substituted triazolopyridine/acyl-heteroaryl scaffold, with extensive substituent latitude in Claims 1–6 and a large enumerated species list in Claim 7.
• The claim suite spans product (Claims 1–7), method of preparation (Claim 8), compositions (Claim 9), combination regimens across many standard oncology agents (Claims 10–15), and tumor-treatment methods (Claim 11).
• Enforceability is strengthened by Claim 7’s extensive embodiment list, which reduces “thin disclosure” risk relative to purely theoretical genus coverage.
• Validity pressure points are most likely the breadth of the combination claim (Claim 10) and genus enablement/written description for the full substitution space (Claims 1–4 especially), unless the specification ties enablement across the breadth.
• For FTO, the risk is not confined to a single lead structure; the genus plus enumerated examples imply that many close medicinal chemistry variants remain covered, while process claims offer a narrower design-around path.

FAQs

1. Does Claim 7 matter for infringement even if Claim 1 is attacked?
   Yes. Claim 7 enumerates specific species within the genus. Those embodiments can preserve enforceability even if Claim 1 faces breadth challenges, and they create concrete mapping targets for claim construction.

2. Can a competitor avoid infringement by using a different salt form?
   Salt form alone is unlikely to be a complete escape because the claims explicitly cover “pharmaceutically acceptable salts” and also cover variants such as solvates, hydrates, tautomers, and N-oxides, plus stereoisomers.

3. Are the combination claims (Claim 10) limited to specific dosing or timing?
   No. Claim 10 is framed broadly as administering the Formula (I) compound(s) with one or more listed agents. It does not require a particular schedule, patient selection rule, or quantified synergy.

4. Is there a design-around route via manufacturing method (Claim 8)?
   Potentially. Claim 8 is a method of preparing Formula (I) using a specific intermediate-reactant relationship (intermediate (5) reacting with R²–Y). Different coupling chemistries or routes may avoid Claim 8 even if the final product remains within Claims 1/7.

5. Which dependent claims are the most operationally important fallback positions?
   Claim 6 is a key fallback because it materially restricts variable definitions (notably R¹ and R³/R⁴/H and q range), while still leaving meaningful species coverage through allowable substitutions and salt/tautomer/solvate variants.

References

[1] United States Patent 9,555,022, “Compounds,” claims 1-15 (as provided in the prompt text).

Details for Patent 9,555,022

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	November 26, 1997		2031-06-14
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	February 19, 2002		2031-06-14
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	June 22, 2017		2031-06-14