Patent: 7,101,882

Summary for Patent: 7,101,882

Title:	Morpholin-acetamide derivatives for the treatment of inflammatory diseases
Abstract:	The present invention relates to novel morpholin-acetamide compounds of formula (I) useful for the treatment of inflammatory diseases. Compounds of formula (I) ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, a, b and Z are as defined in the specification, processes for preparing them, formulations containing them and their use in therapy for the treatment of inflammatory diseases.
Inventor(s):	Ancliff; Rachael Anne (Stevenage, GB), Cook; Caroline Mary (Stevenage, GB), Eldred; Colin David (Stevenage, GB), Gore; Paul Martin (Stevenage, GB), Harrison; Lee Andrew (Stevenage, GB), Hodgson; Simon Teanby (Stevenage, GB), Judd; Duncan Bruce (Stevenage, GB), Keeling; Suzanne Elaine (Stevenage, GB), Lewell; Xiao Qing (Stevenage, GB), Robertson; Graeme Michael (Stevenage, GB), Swanson; Stephen (Stevenage, GB)
Assignee:	Glaxo Group Limited (Greenford, GB)
Application Number:	10/381,767
Patent Claims:	see list of patent claims

United States Patent 7,101,882 claim-by-claim analysis and US patent landscape

US Patent 7,101,882 is an early-generation small-molecule chemical patent with a broad Markush-style independent claim (claim 1) covering an inflammatory-condition pharmacophore family, plus a dense set of dependent fallback claims that narrow to particular substituents, linker definitions, and named compounds. The estate is structured to preserve core chemical coverage while adding specific claims to individual examples (claims 9, 15, 19) and to downstream use and product-formulation concepts (claims 11–13, 16–18, 24–25). From a competitive-risk standpoint, the claim set is designed to attack both “generic exact hit” products and broader design-around attempts that keep the same morpholine-amine-acyl motif, the same aryl–acetamide/benzamide linker chemistry, and the same halogenated benzyl/aromatic substitution patterns.

What claim 1 actually covers (functional map)

Claim 1 is a compound-of-Formula (I) claim with:

• A variable N-benzyl morpholine element (through R¹, Y¹, and “(trans/cis)” morpholine states captured in the named species set).
• Variable aryl acyl cap (R⁵, including halogenated phenyl and thiophenyl).
• A variable “tail/linker” region Z (bond, amide-adjacent substituents such as CHR⁶(CH₂)n, CHR⁶(CH₂)nCO, and CHR⁶(CH₂)nO forms).
• A variable acid side/amide region (R⁶ as H, alkyl, CONR⁷R⁸, or COOR⁶ alkyl).
• Enumerated ring constraints for M (C3-8 cycloalkyl or cycloalkenyl fused to monocyclic aryl).
• Optional t (0 or 1) to govern aryl-(O)t-aryl patterning in R¹ definitions.
• Salt/solvate coverage (explicitly included).

Claim 2–8 then tighten subsets: R¹ class selections, X fixed to methylene, Z fixed to particular linker motifs (CHR⁶(CH₂)n, or CHR⁶(CH₂)nCO, or CH₂), and R⁵ fixed to phenyl/halophenyl including 3,4-dichlorophenyl.

Litigation posture implied by this claim architecture

The combination of (i) a broad formula claim with (ii) an unusually large named-species dependent claim bundle and (iii) use and combination claims (asthma/rhinitis; anti-histamine co-formulation) is a typical strategy for chemical families where the inventors expect both:

• close design modifications by competitors that remain within the Markush boundaries; and
• easier infringement proof through example-listed compounds and salts.

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How strong are the core chemical claims in US 7,101,882 (what does claim 1 really protect)?

Featured snippet answer: Claim 1 protects a wide morpholine-linked benzyl-acyl family with specific constraints on X (ethylene vs substituted carbon), Z (bond or amide/ether sidechain variants), R⁵ (halogenated phenyl or halogenated thiophenyl), and a cycloalkyl/cycloalkenyl fused aromatic moiety M, plus salts/solvates.

Key infringement-relevant structural anchors in claim 1

1. Morpholine-2-yl-methyl “benzyl” segment is effectively fixed

   • The dependent claim list (claim 9) is dominated by N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-… scaffolds.
   • That means even if claim 1’s formula appears abstract, the patent’s practical coverage centers on this motif.

2. Halogen pattern on benzyl phenyl (frequently 3,4-dichloro) is a repeated fallback

   • Claim 8 expressly limits R⁵ to 3,4-dichlorophenyl (though note R⁵ in claim 1 refers to the “acyl/aryl cap”; the named species shows 3,4-dichlorobenzyl on the morpholine side as well, which is consistent with the dataset embedded in claim 9).

3. Linker Z provides multiple “routes” to cover homologation

   • Dependent claims 5–6 specify Z variants (CHR⁶(CH₂)n, Z = CH₂).
   • This is designed to block easy design-arounds that change methylene count or convert amide-adjacent groups into acid/amide variants.

4. R⁶ and R⁶-derivatives expand the “functional group” infringement surface

   • R⁶ includes CONR⁷R⁸ and COOC1-6 alkyl; salt/solvate coverage adds another infringement channel.

How broad is the Markush risk?

Claim 1 uses numerous Markush variables (R¹, X, Z, R⁵, R⁶, M, t, Y¹). In an infringement analysis, the practical scope is usually constrained by:

• the published chemical examples (claim 9’s list),
• the likely intended pharmacophore,
• and prosecution history (not provided here).

Still, the claim set includes enough specific dependent narrowing that a competitive product that lands on the same core atoms and substituent classes will often fall into either:

• claim 1 directly, or
• a dependent claim that is narrower but still broad (e.g., R⁵ limited to halogenated phenyl; Z limited to a class).

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Which dependent claims create the strongest “design-around barriers” (claims 2–25)?

Featured snippet answer: Claims 4–6 and 8 function as high-value narrowing anchors, while claims 9, 15, 19 create species-specific pockets that support infringement through near-exact mapping and through salts/solvates.

Claim-by-claim practical meaning (selected)

Claims 2–3: R¹ class scope

• Claim 2 includes broad selections for R¹ (C1-6 alkyl, C2-6 alkenyl/alkynyl, multiple aryl-Y¹ and aryl-O-Y¹ constructions, sulfonyl and fused ring equivalents).
• Claim 3 repeats the same concept with fewer explicit sub-classifications in the text you provided, but functionally it maintains R¹ coverage.

Design-around implication: Competitors must avoid not only the final compound but also the substituent classes that map to R¹’s enumerated options.

Claim 4: X is methylene

• X controls a direct carbon connectivity element in Formula (I).

Barrier effect: If an accused product uses a different carbon connectivity than the X = CH₂ mapping, it may escape claim 4 but can still target claim 1 unless prosecution history narrows claim 1’s X in practice.

Claims 5–6: Z limited to specified linker

• Claim 5: Z is CHR⁶(CH₂)n or CHR⁶(CH₂)nCO
• Claim 6: Z is --CH₂--

Barrier effect: Linker position is one of the most common design-around levers. These dependents attack that.

Claims 7–8: R⁵ limits

• Claim 7: R⁵ is phenyl optionally substituted with halogens.
• Claim 8: R⁵ is 3,4-dichlorophenyl.

Barrier effect: Halogenation pattern is often “minor,” but claim 9’s list shows that the inventors treated it as a key efficacy driver and built species claims around it.

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Which named compounds in claim 9 are most important for infringement proof?

Featured snippet answer: Claim 9 is a species claim list dominated by morpholine-2-ylmethyl benzyl derivatives featuring 3,4-dichlorobenzyl and a substituted phenylacyl/phenoxyacyl motif, plus numerous salts (including formate and trifluoroacetate).

Claim 9 coverage profile

Claim 9 includes dozens of N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-arylacetamides and related benzamides/benzyl variants. Examples explicitly in the text include:

• N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-phenylacetamide
• N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methylsulfonyl)phenyl acetamide (and multiple positional isomers)
• N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,3-dichlorophenyl)acetamide
• Multiple fluorinated and difluorinated analogs
• Zwitter/acid-salt variants:
  • formic acid (1:1) salts for select amides
  • trifluoroacetate for multiple acid-sensitive forms

Infringement value: If an accused product is one of these listed structures or an incorporated salt/solvate, the patentee can anchor infringement with straightforward structural comparison, not just Markush interpretation.

Where claim 9 raises “willful” risk for generic applicants

Generic product development commonly targets the salt form marketed. Because claim 9 lists multiple salts (formate; trifluoroacetate), a competitor cannot always “escape” by switching to a different counterion. If the counterion salt remains within the claimed “physiologically acceptable salt/solvate” language or is separately named in the species list, infringement exposure persists.

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What does claim 15 add beyond claim 9 (and why does it matter)?

Featured snippet answer: Claim 15 singles out N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}2-{3-[(methylsulfonyl)amino]phenyl}acetamide and covers salts/solvates.

Claim 15 is narrower than claim 9 but important for two reasons:

1. It creates a clean, single-compound infringement target, useful for both litigation and licensing.
2. It broadens the chemical family’s relevance to competitors making “halogen-swap” analogs (dichloro to difluoro) that would still be close to the core scaffold.

Claims 16–18 then follow product concepts:

• Claim 16: pharmaceutical composition
• Claim 17: method of manufacturing formulation
• Claim 18: method of treatment of inflammatory condition

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Which species are protected by claims 19–23 (what exact pockets exist)?

Featured snippet answer: Claims 19–23 protect a smaller set of specific acyl variants with an acetylphenyl or isobutyrylphenyl benzamide/acetathio analog pattern and include trifluoroacetate salts for several.

Claim 19 lists four key compounds:

• 2-(4-acetylphenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide trifluoroacetate
• 2-(4-acetylphenyl)-N-{[(4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide
• N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-isobutyrylphenyl)acetamide trifluoroacetate
• 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]-N-(2-hydroxyethyl)benzamide

Claims 20–23 then narrow each to each listed species.

Design-around implication: Competitors cannot rely solely on “aryl substituent changes.” The patent has preselected multiple acyl substituent types and includes at least one salt form for each.

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What method-of-use rights exist (claims 13, 18, 24)?

Featured snippet answer: The patent claims treatment of inflammatory conditions broadly (claims 13 and 18) and asthma or rhinitis specifically (claim 24) using compounds of claim 15.

Claim 13 and 18: inflammatory condition

• Claim 13: administering an effective amount of a compound of claim 1 for inflammatory condition treatment.
• Claim 18: administering an effective amount of a compound of claim 15 for inflammatory condition treatment.

Regulatory/litigation implication: Method-of-use patents matter because even if a generic product formulation is outside the chemical claim, the use claim can still be asserted if the generic’s label includes the patented indication and the compound infringes the chemical prerequisite.

Claim 24: asthma or rhinitis

• “A method for treating asthma or rhinitis” with a compound of claim 15.

High-value pocket: Asthma/rhinitis are common label indications. If a competitor’s product is marketed for either indication using the claimed compound family, the method-of-use claim becomes a direct leverage point for injunctive relief and settlement bargaining.

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What formulation and combination claims extend protection (claims 11, 12, 16–17, 25)?

Featured snippet answer: The patent includes general pharmaceutical composition and manufacturing formulation steps, plus a specific combination with an anti-histamine (claim 25) using methapyrilene or loratadine.

Composition claims

• Claim 11: pharmaceutical composition (claim 1 compound + diluent/carrier)
• Claim 12: manufacturing formulation including compound of claim 1
• Claim 16 and 17 mirror those for the claim 15 compound.

Practical note for enforcement: These are broad and typically do not add much if the chemical claims already cover the active ingredient in the marketed dosage form. They do, however, give additional infringement theories for combination product packaging, label, and manufacturing instructions.

Combination claim 25: anti-histamine co-formulation

• Claim 25: composition comprising a claim 15 compound and an anti-histamine, where the anti-histamine is methapyrilene or loratadine.

Strategic value: Combination claims target product-level business models and increase the settlement surface area because they can be infringed by co-packaging or co-formulation even when dosing regimens differ.

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Manufacturing process claim (claim 14): what does it protect?

Featured snippet answer: Claim 14 protects acylation-based synthesis routes, including acylation of formula (II) with R¹COOH derivatives, alternative coupling using L¹-Z-R⁵ fragments, and deprotection of protected intermediates.

This matters for two reasons:

1. It can capture method infringement tied to specific manufacturing processes, relevant in discovery.
2. If a generic or licensee uses a different synthetic route, the process claim may be avoided even if the final API infringes the chemical claims.

In typical US practice, process claims can become a litigation wedge for trade secret discovery, but they rarely eliminate chemical infringement exposure if the final compound is within the scope.

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US patent landscape for U.S. Patent 7,101,882: what are the likely adjacency risks?

Important constraint: A comprehensive, litigation-ready “landscape” requires identifying:

• the patent’s assignee and priority family,
• continuations and divisionals,
• related patents citing or cited by it,
• FDA Orange Book listings and associated exclusivities,
• and any court cases involving the patent.

That information is not present in the record provided. Without it, any landscape map would risk factual errors, which must be avoided.

What can be stated from the claim text alone is the nature of the surrounding IP boundary:

• Claim 1 is a foundational chemical scope claim.
• Claims 9, 15, and 19 are species and “salty” variants that usually correspond to concrete examples likely used for pharmacology and formulation readiness.
• Claims 13, 18, and 24 indicate the intended therapeutic use space (inflammatory conditions; asthma; rhinitis).
• Claim 25 indicates a combination product strategy with anti-histamines (loratadine and methapyrilene).

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Key takeaways

• US 7,101,882 is built to cover a morpholine-linked halogenated benzyl-acyl family through claim 1, then lock in infringement proof via extensive species-specific claim sets (claim 9), targeted analog coverage (claim 15), and additional specific acyl variants (claims 19–23).
• The design-around surfaces the patent is most actively defending are linker identity (Z and X), aryl cap halogenation patterns (R⁵ including 3,4-dichloro), and salt/solvate forms (formate and trifluoroacetate repeatedly appear in the listed species).
• Method-of-use protection targets both broad inflammatory indications (claims 13 and 18) and the specific asthma/rhinitis indication in claim 24.
• Combination/composition rights include a high-leverage co-formulation claim with loratadine or methapyrilene (claim 25), expanding enforcement into product strategy, not just API structure.
• A full US “landscape” that includes related patents, Orange Book status, expiration/exclusivity timelines, and litigation would require assignee, application family metadata, and FDA/Orange Book ties, none of which are contained in the supplied text.

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FAQs

1. Does US 7,101,882 claim salts and solvates of the core compounds, and how does that affect infringement?
   Yes. Claim 1 and claim 15 expressly include “physiologically acceptable salt or solvate,” and claim 9 and claim 19 list specific salt forms such as formic acid salts and trifluoroacetates.

2. Which structural levers are most constrained by the dependent claims (X, Z, R⁵, R⁶)?
   X is constrained to methylene in claim 4; Z is constrained to specific sidechain patterns in claims 5–6; R⁵ is constrained to halophenyl and to 3,4-dichlorophenyl in claims 7–8; R⁶ includes additional functional group states through the Markush definition in claim 1.

3. Can a competitor avoid infringement by changing the anti-histamine partner in the combination claim?
   Claim 25 is limited to methapyrilene or loratadine. Changing to another anti-histamine could avoid claim 25, but other composition or method-of-use claims may still be relevant.

4. If a generic product does not use the patented compound but targets the same indication, does the method-of-use claim matter?
   Method claims (13, 18, 24) still require infringement of the chemical prerequisite in each claim (claim 1 for claim 13; claim 15 for claims 18 and 24). Without chemical infringement, method-of-use exposure is reduced.

5. How do the process claim constraints (claim 14) interact with chemical compound infringement?
   Process claim avoidance can occur via alternative synthesis routes, but if the final API falls within the chemical claims (1, 9, 15, 19), process differences may not eliminate infringement.

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References

No external sources were provided in the prompt.

Details for Patent 7,101,882

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	7,101,882	2021-09-28