Patent: 8,436,008

Summary for Patent: 8,436,008

Title:	Substituted heterocyclic compounds
Abstract:	The present invention relates to substituted heterocyclic compounds of Formula I: ##STR00001## or pharmaceutically acceptable salts or N-oxides or quaternary ammonium salts thereof wherein constituent members are provided hereinwith, as well as their compositions and methods of use, which are histamine H4 receptor inhibitors/antagonists useful in the treatment of histamine H4 receptor-associated conditions or diseases or disorders including, for example, inflammatory diseases or disorders, pruritus, and pain.
Inventor(s):	Zhang; Colin (Ambler, PA), Qian; Ding-quan (Newark, DE), Zhuo; Jincong (Garnet Valley, PA), Yao; Wenqing (Kennett Square, PA)
Assignee:	Incyte Corporation (Wilmington, DE)
Application Number:	12/643,739
Patent Claims:	see list of patent claims

US Patent 8,436,008 Landscape Analysis: claim scope, enforceability risks, and US/Orange Book exposure

US Patent 8,436,008 (USPTO) is a broad genus claim directed to substituted 4-(methylpiperazinyl)pyrimidin-2-amine linked to (tetrahydro)isoquinoline scaffolds bearing a wide range of heteroaryl and heterocycle substituents, plus downstream salt and N-oxide coverage. The claim set also covers compositions (with carriers, optional combination therapy, and optional co-administration with selected histamine receptor inhibitors, including specific H4 antagonists).

Given the breadth and the “selected from” style structure of claim 1, the enforceability and infringement analysis turns on (i) whether an accused product falls within one of the listed genus-member structures, (ii) whether it uses a claimed salt/N-oxide/quaternary ammonium form, and (iii) whether the accused formulation includes the claimed combination with additional histamine receptor inhibitors (claim 4/5). The practical value for a generic or challenger depends on whether the target drug substance is a listed compound (or an equivalent that is proven to be identical to a listed member or its salts), and whether later patents cover formulation, polymorphs, methods of use, or specific crystalline forms.

What patents protect United States Patent 8,436,008 claim 1 compounds (genus vs listed compounds)?

How claim 1 is structured and what it actually covers

Claim 1 is drafted as a selected-from list of specific chemical entities plus a fallback to pharmaceutically acceptable salt / N-oxide / quaternary ammonium salt. In practice, this behaves like a large “enumerated genus” where infringement requires the accused compound to match one of the named structures (or its salt/N-oxide/quaternary ammonium salt).

Key structural anchors repeated across the list:

• Pyrimidin-2-amine core substituted with 4-(4-methylpiperazin-1-yl) (or close variants in the list).
• Linkage to a tetrahydroisoquinoline / dihydroisoquinoline system at the 2(1H)-yl or adjacent position.
• A broad set of substituents at positions on the isoquinoline portion, including:
  • halo- and fluoro-substituted heteroaryl groups (e.g., chloro/fluoro pyridyl, bromo-dihydroisoquinolinyl)
  • pyrazolyl/imidazo-containing motifs
  • carbonitriles and carboxamides at varied termini
  • additional ring systems on the “side chain” portion (piperidine, morpholine, diazepane, diazabicyclo, pyrrolidine, azetidine, etc.)
• Stereochemical embodiments appear (e.g., (3S) and (3R)) for certain listed members, which matters for infringement if the accused product is a single-enantiomer.

Salt, N-oxide, and quaternary ammonium coverage: where infringement is easiest

Claim 1 expressly extends to:

• pharmaceutically acceptable salts
• N-oxides
• quaternary ammonium salts

For enforcement, this typically strengthens infringement because products sometimes market a particular salt form (hydrochloride, fumarate, maleate, etc.) or an N-oxide derivative even if the free base is not manufactured for sale. For a challenger, it increases freedom only if the accused product is:

• a non-salt form not falling into “pharmaceutically acceptable salt” as claimed
• an N-oxide not actually marketed/manufactured
• a different chemical entity not listed in claim 1

How broad is claim 1 in functional terms

The list is large enough that it is unlikely a single small deviation will avoid infringement if the accused structure matches one of the enumerated members. Avoidance typically requires demonstrating the accused compound is not one of the enumerated structures, not a salt/N-oxide/quaternary ammonium derivative, or is an enantiomer not encompassed (for stereochemically specific listed members).

Enforceability pressure point

Because claim 1 is “selected from” a long list, the patent’s leverage is strongest when:

• the accused API is known to be one of the enumerated entities (or its exact salt form)
• the drug’s INN/INCI, dossier, or API specification ties the marketed active to one of these members

If the accused product is a different compound in the same pharmacologic class, the claim 1 list format can be an infringement barrier for the patentee.

What do claims 2-5 add: composition coverage, combination therapy, and histamine co-therapy?

Claim 2: composition with carrier

Claim 2 covers:

• a composition comprising a compound of claim 1 (or its salt/N-oxide/quaternium ammonium salt) plus a pharmaceutically acceptable carrier.

This is standard formulation coverage. It tends to be broad enough to read on most oral solid and liquid formulations so long as the same API (or covered derivative) is used.

Claim 3: composition plus “one or more therapeutic agents”

Claim 3 adds optional combination therapy with any additional therapeutic agents. This can capture combination products where the active is still the claim 1 compound.

Claim 4: composition plus additional histamine receptor inhibitors/antagonists

Claim 4 specifies:

• one or more other histamine H1, H2, H3, and/or H4 receptor inhibitors/antagonists.

This is narrower than claim 3 because it requires the co-therapeutics to be histamine receptor inhibitors/antagonists.

Claim 5: composition plus specific histamine H4 receptor inhibitors/antagonists

Claim 5 narrows further by identifying an H4 inhibitor/antagonist set:

• N-Cyclohexyl-4-(1H-imidazol-4-yl)piperidine-1-carbothioamide
• 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indole
• 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-benzimidazole

If an accused product is a fixed-dose combination including any one of these specific H4 antagonists, claim 5 provides a more targeted infringement hook. If the co-therapy uses different H4 antagonists, claim 5 likely does not apply, though claim 4 might if the co-therapeutic qualifies as an H1/H2/H3/H4 inhibitor.

Critical strategic implication

For commercial and litigation posture:

• If the accused product is single-agent, claim 5 is less relevant; claim 1 and claim 2 matter.
• If it is a combination, the combination identity and dosing form matter for claim 4/5.

How strong is the patent estate for US Patent 8,436,008 compounds? (claim scope vs typical weaknesses)

Strength drivers

1. Enumerated chemical coverage anchored on an identifiable scaffold core and specific listed members.
2. Salt/N-oxide/quaternary ammonium coverage expands the practical infringement surface across marketed forms.
3. Composition claims (2-4) provide a formulation pathway even when the API is the same.

Primary risk vectors for challengers

1. Stereochemistry and exact structure matching: challengers can argue the accused stereoisomer does not map to a stereochemically specific listed member, or the substitution pattern does not match.
2. Derivative forms: if the accused API is a different salt type than any salt encompassed by “pharmaceutically acceptable,” or not actually a marketed quaternary ammonium/N-oxide.
3. Combination identity: claim 5 is only triggered by the listed H4 antagonists; claim 4 needs any H1/H2/H3/H4 antagonist, so the co-therapy label and regimen matter.

Primary weaknesses (as a matter of claim construction and infringement proof)

Because claim 1 is a list of many specific compounds, infringement proof becomes a technical exercise:

• The patentee must show the accused API corresponds to one of the listed structures or its expressly covered derivative.
• A challenger can limit exposure by sourcing a non-listed analog even if it is in the same pharmacologic space.

What this means for litigation outcomes

• If the accused drug’s active ingredient is one of these enumerated compounds, the patent is “structurally” strong because claim 1’s breadth reduces the need for doctrine-of-equivalents.
• If the accused drug is only “related” chemically, the list-format can narrow the infringement map and make invalidity harder to avoid but easier to contest on non-infringement.

When does US Patent 8,436,008 lose exclusivity? (expiration and term model)

No filing, priority, prosecution history, maintenance fee status, or expiration/adjustment data is provided in the prompt. Without those inputs, the exclusivity timeline cannot be computed accurately.

What is the Orange Book status of US Patent 8,436,008?

No Orange Book listing data or tied NDA/ANDA reference product is provided. Without the FDA application number and listed active(s), Orange Book status and paragraph IV relevance cannot be determined.

Which companies are challenging or will challenge this patent estate via Paragraph IV?

No ANDA filing history, paragraph IV notices, litigation captions, or challengers are provided. Without those inputs, the list of challengers cannot be produced.

What generic entry risks exist for compounds covered by this patent? (entry pathways by claim type)

Single-agent generic risk

• High if the generic API matches a claim 1 listed compound (or its exact salt/N-oxide/quaternary ammonium).
• Lower if the generic uses a non-listed analog in the same class.

Combination-product generic risk

• Claim 4 can create risk where the combination includes a histamine H1/H2/H3/H4 antagonist.
• Claim 5 creates risk only for the specified H4 antagonist set; generic combination dossiers using other H4 antagonists may avoid claim 5.

How do claim 1 members compare with common marketed histamine H4 antagonist combinations?

The prompt does not identify a target drug, nor does it map any of the enumerated structures to a named marketed active. Without that mapping, a defensible crosswalk to actual marketed compounds and combination regimens cannot be generated.

Patent landscaping for US Patent 8,436,008: what related US patents typically surround these chemical-genus claims?

Although specific family members are not provided, patents in this class usually cluster into four buckets that drive freedom-to-operate:

1. Immediate analog/genus descendants (later priority continuing applications) that refine substitutions around the same scaffold.
2. Polymorph/crystal form and solid-state patents (often issued separately from chemical-genus).
3. Salt form, co-crystal, and formulation patents tied to specific excipients and dose forms.
4. Method-of-use and combination therapy patents tied to histamine receptor pathways.

Key Takeaways

• US Patent 8,436,008 is dominated by an enumerated chemical claim (claim 1) covering many specific substituted pyrimidinyl tetrahydroisoquinoline members plus salt/N-oxide/quaternary ammonium derivatives.
• Claims 2-4 expand to formulations and broad combination therapy, while claim 5 narrows combination coverage to three specific H4 antagonist structures.
• Infringement risk is highest when the marketed API (and its marketed salt/N-oxide/quaternary ammonium form) matches a claim 1-listed member. Combination risk additionally depends on whether the co-therapeutic matches claim 4 categories and, for claim 5, the exact H4 antagonist set.

FAQs

1. Does a generic avoid US Patent 8,436,008 by using a different salt form than the patentee’s examples?
2. If the accused drug contains an enantiomer not named in claim 1, does that defeat infringement?
3. How does claim 5 differ from claim 4 for histamine H4 antagonists in fixed-dose combinations?
4. Can an N-oxide derivative of a listed compound fall outside “pharmaceutically acceptable” coverage?
5. If a challenger markets a non-listed analog with similar receptor activity, does the “selected from” list create a non-infringement path?

References

1. USPTO. United States Patent 8,436,008. (Claims text provided in prompt).

Details for Patent 8,436,008

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	March 13, 1924	8,436,008	2029-12-21