Patent: 8,637,531

Summary for Patent: 8,637,531

Title:	Pyrido(3,2-d)pyridmidines useful for treating viral infections
Abstract:	This invention provides pyrido(3,2-d)pyrimidine derivatives represented by the structural formula (I), wherein: R.sub.1 is amino, R.sub.4 is hydrogen, and R.sub.2 and R.sub.3 together provide a specific substitution pattern, pharmaceutical acceptable addition salts, stereochemical isomeric forms, N-oxides, solvates and pro-drugs thereof, are useful in the treatment of hepatitis C.
Inventor(s):	Bondy; Steven S. (Danville, CA), Watkins; William J. (Saratoga, CA), Chong; Lee S. (Newark, CA), Herdewijn; Piet Andre Maurits Maria (Rotselaar/Wexemaal, BE), De Jonghe; Steven Cesar Alfons (Brugge, BE)
Assignee:	Gilead Sciences, Inc. (Foster City, CA)
Application Number:	12/519,500
Patent Claims:	see list of patent claims

United States Patent 8,637,531 Claims and US Patent Landscape Analysis (Pyrido(3,2-d)pyrimidine Derivatives)

Executive summary: US Patent 8,637,531 claims a broad chemical genus of pyrido(3,2-d)pyrimidine derivatives defined by a core scaffold with variable substituents at R1 (amino), R2 (a highly enumerated ether/sulfonyl-ether/cycloalkyl/alkenyl/alkynyl/functional ether set), R3 (halogen/aryl/heteroaryl with extensive optional substituent sets), and R4 (H or pharmaceutically acceptable forms/salts/N-oxides/isomers). Dependent claims narrow by phenyl substitution patterns (ortho/meta/para; mono/di/tri-substituted; identical substituents) and by specific named compounds. Independent claim 1 is a structural formula claim with expansive Markush groups, while claims 11–19 add composition, combination therapy, and HCV treatment method-of-use coverage, including large lists of contemplated co-administered antivirals. The claim set is designed to capture both (i) multiple chemical embodiments across a wide chemical space and (ii) downstream commercial use through composition and HCV treatment method claims.

Because the prompt contains only the claims text and does not provide (a) the patent’s specification, (b) priority and filing dates, (c) inventor/assignee, (d) the exact publication/application number, (e) the full list of claims and dependent-claim numbering, or (f) the US prosecution history and litigation status, a complete, citation-backed “patent landscape” across related US patents and families cannot be produced accurately. The analysis below therefore focuses on claim construction risk points (scope, enforceability, and common invalidity angles) and the practical competitive implications for chemical and use-based freedom-to-operate.

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What does US Patent 8,637,531 claim under 35 USC 112 and claim construction?

Short answer: Claim 1 is a genus defined by a pyrido(3,2-d)pyrimidine core with variable substituents at R2 and R3 using broad Markush language and long lists of permissible substituents. Enforceability and validity hinge on whether the application’s specification supports the full breadth and whether the Markush limits are sufficiently definite.

How broad is claim 1’s chemical genus?

Claim 1 requires:

• A pyrido(3,2-d)pyrimidine derivative represented by a structural formula (core scaffold shown as ##STR00037## in the prompt).
• R1 is amino.
• R2 is selected from an extensive set dominated by C1–6 alkylthio-C1–6 alkoxy, C2–6 alkenyloxy, C2–6 alkynyloxy, multiple cycloalkenyloxy and cycloalkenyl–alkoxy formats, alkylsulfonyl C1–6 alkoxy and aryl/similar sulfonyl C1–6 alkoxy formats, and a set of functionalized ether substituents including multiple “propoxyethoxy”/“ethoxypropoxy”/difluoroethoxy variants, plus cyclobutoxy, cyclopentylmethoxy, morpholinyl-propoxy/butoxy, tetrahydropyranoxy/methoxy, tetrahydrofuranyl/oxy/methoxy, “3-methyl-3-methoxybutoxy,” and oxetan-3-yloxy, among others.
• R3 is selected from halogen, heterocyclic and aryl groups, where those heterocyclic/aryl groups can optionally bear substituents from another very large enumerated set (including amino/aminoalkyl, acyl/amide-type patterns, alkoxy/alkylthio/alkyl, carboxylic acid, hydroxy, halo/haloalkyl, haloalkoxy, alkenyl, alkylene dioxy, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl-amino/alkylamino combinations, aryl/aryloxy/formyl/heterocyclic/heterocyclic-oxy, tri-alkylammonium-alkyl, and multiple “aryl/heterocyclic-substituted alkyl” definitions).
• R4 is hydrogen or acceptable forms: pharmaceutically acceptable addition salt and stereochemical isomeric form or N-oxide.

Practical implication: This structure supports “around-the-core” design changes primarily in R2 (ether/sulfonyl-ether motifs) and R3 (aryl substitution and additional substituents). For competitors, meaningful design-around generally requires either:

1. moving outside the R2 set (different linker class not captured by the enumerated ether/sulfonyl-ether templates),
2. moving outside the R3 definition (e.g., replacing with a substituent class not “aryl/heterocyclic” or restricting substitutions in a way that avoids the allowed optional substituent list), or
3. altering the core scaffold such that it is not a “pyrido(3,2-d)pyrimidine derivative” of the claimed structure.

Definiteness risk: are the lists effectively closed or open?

The claim uses “selected from the group consisting of …” for R2 and for the optional substituent set on R3. Those formulations tend to be treated as closed Markush sets. That can reduce definiteness risk for “what is inside,” but it also raises a different enforceability challenge: infringement analysis must map an accused compound’s substituent features to the specific enumerated categories. For litigation, that can become a claim construction exercise about whether a given group (especially sulfonyl-ether and substituted heteroaryl patterns) falls within an enumerated category.

Enablement and written description risk: does the spec need to cover the entire breadth?

With an extremely broad and highly varied R2 and R3 substitution space, the strongest invalidity posture is that the spec may not support the full genus. In practice, the patent’s defensibility depends on whether it provides:

• guidance for synthesizing across the full R2 and R3 sets,
• examples that span the breadth sufficiently,
• and credible, commensurate biological rationale for the entire scope.

Without the specification, this cannot be assessed factually here. What can be stated from the claim design is that the breadth creates a higher probability of genus-level enablement pressure.

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How do dependent claims 2–8 narrow the aryl substitution pattern (ortho/meta/para; mono/di/tri)?

Short answer: Claims 2–8 impose positional constraints on the phenyl substituent at R3, switching from a general “aryl group” to phenyl with specific ortho/meta/para placement and with mono-, di-, and tri-substitution patterns.

Claim mapping for R3 phenyl positioning

• Claim 2: R3 is a mono-substituted phenyl with the substituent in para position relative to the core.
• Claim 3: R3 is di-substituted phenyl with one substituent para.
• Claim 4: R3 is tri-substituted phenyl (no positional constraint beyond tri-substitution).
• Claim 5: tri-substituted phenyl where at least two substituents are identical.
• Claim 6: mono-substituted phenyl with meta substitution.
• Claim 7: mono-substituted phenyl with ortho substitution.
• Claim 8: di-substituted phenyl with one substituent ortho.

Practical implication: These are narrower than claim 1 but still allow substantial freedom:

• “one substituent at para/ortho” in di-substituted phenyl means the second substituent is not tightly constrained.
• tri-substituted phenyl remains broad.
• These dependent claims may cover many “typical medicinal chemistry” analogs even if competitors avoid the exact enumerated specific compounds in claim 9 or 10.

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Which specific embodiments are explicitly listed in claims 9 and 10?

Short answer: Claims 9 and 10 list a large number of named pyrido(3,2-d)pyrimidine derivatives, including:

• 2-amino-4-(pentyn-1/2-oxy/butyn-1-oxy/propyn-1-oxy/buten-1-oxy/cyclobutoxy/cyclopentylmethoxy/cyclopentoxy/tetrahydrofuranyl motifs)/6-(4-fluorophenyl) variants,
• 2-amino-4-(methylsulfonyl)ethoxy and phenylsulfonyl ethoxy variants,
• additional aryl variants such as 3,4-dimethoxyphenyl, 2-formylphenyl, 4-carboxyphenyl, and
• chiral ether substituents such as (S)/(R)-tetrahydrofuranyloxy and (S)/(R)-1-methoxy-2-propoxy analogs.

Claims 9 vs 10: what coverage strategy do they show?

• Claim 9 focuses on a narrower “representative set” dominated by:

  • 2-amino at the core,
  • R3 = 6-(4-fluorophenyl),
  • varied R2 as alkyne/alkenyl ether positional isomers (pentyn-, butyn-, propyn-, buten-, octen- frameworks),
  • cycloalkenyl oxy/methoxy,
  • and sulfonyl-ether substituents (methylsulfonyl ethoxy, phenylsulfonyl ethoxy),
  • plus multiple named alkoxy-ether variants (tetrahydrofuranyl-oxy, tetrahydrofuranmethoxy, etc.).

• Claim 10 expands coverage substantially by listing additional R3 aryl types beyond 4-fluorophenyl, including:

  • 6-chloro analogs with multiple tetrahydropyran/tetrahydrofuran methoxy/oxy patterns,
  • 2-formylphenyl analogs with the same “tetrahydrofuran-based” ether motif series,
  • 3,4-dimethoxyphenyl analogs with alkyne ether motif series,
  • 4-carboxyphenyl analogs,
  • and additional named hetero/functional aryl substituents (triazolyl and “pyrid(3,2-d)pyrimidinyl core” variants such as 4(3H)-thione; sulfur-containing core “thione” forms; cyclohexyloxy; etc.).

Practical implication: Claim 1 can capture these anyway if the R2 and R3 elements fall in the enumerated sets. Claims 9 and 10 provide:

• easier infringement proof for those exact named embodiments,
• fallback narrower coverage if claim 1 is narrowed by construction or invalidation pressure,
• and additional anchors for commercial mapping (formulation and method-of-use claims likely track specific lead compounds).

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What do claims 11–12 cover: pharmaceutical composition and combinations?

Short answer: Claim 11 is a straightforward composition claim: a composition including carriers plus at least one compound of claim 1. Claim 12 adds optional one or more antiviral agents.

Is claim 12 a combination of actives or a broad “any antiviral” basket?

Claim 12 states “further comprising one or more antiviral agents,” without limiting which antivirals until claim 17. That makes claim 12 broad in principle, but downstream novelty and enforceability generally depend on the scope of claim 17 and any specification support.

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What is covered by claims 13–16: HCV treatment method-of-use with combination therapy?

Short answer: Claims 13 and 15 claim methods of treatment for a patient with a viral infection, specifically HCV in dependent claim 15, using an effective amount of the claim 1 compound. Claim 14 and 16 add co-administration of other antivirals.

How broad is the contemplated co-therapy list?

Claim 18 provides a very large list of antiviral agents that can be used with the pyrido(3,2-d)pyrimidine derivatives. Claim 19 adds additional nucleoside/nonnucleoside antivirals including ribavirin, interferons, HIV antivirals, and many additional agents.

Practical implication: These method and combination claims are designed for HCV regimens that were historically multi-drug, but enforcement depends on:

• whether an accused product’s label or promotion supports the claimed “HCV treatment method” usage, and
• whether induced infringement arguments are available (for method-of-use claims, proving direct acts and intent matters).

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How strong is the claim set for enforcing chemical infringement vs method-of-use infringement?

Short answer: The claim set is strongest on chemical infringement of embodiments that fall squarely within claim 1’s R2 and R3 Markush categories, and on composition claims. Method-of-use claims are typically harder to enforce absent clear clinical practice, labeling, or direct instruction.

Enforceability split by claim type

1. Independent genus (claim 1):

   • Broad coverage of structural analogs.
   • Higher validity risk (genus enablement/written description).
   • More complex infringement mapping due to long enumerations.

2. Dependent positional phenyl claims (2–8):

   • Narrower; easier to map if accused R3 is a phenyl with specific substitution patterns.
   • Still broad enough for multiple analogs.

3. Specific exemplars (9–10):

   • Highest practical infringement leverage against “known” commercial compounds within the list.
   • Provide case targets for counsel and technical teams.

4. Composition and method-of-use (11–19):

   • Composition: enforcement tied to manufacturing and sale of formulations containing claim 1 compounds.
   • Method: enforcement tied to patient treatment acts, typically via labeling, promotional materials, and actual regimen design.

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What patent landscape risk exists from neighboring prior art, design-arounds, and claim breadth?

Short answer: The main competitive risks are that (i) the genus might be anticipated or rendered obvious by earlier pyridopyrimidine derivatives with similar ether and substituted aryl patterns, and (ii) design-arounds must avoid the enumerated R2/R3 category sets.

Design-around logic competitors typically apply

• R2 avoidance: Replace the ether class with a different linkage type not captured in claim 1’s R2 list (e.g., non-ether substituents or ether types outside the “C1–6 alkyl thio-C1–6 alkoxy / C2–6 alkenyloxy / C2–6 alkynyloxy / cycloalkenyloxy / sulfonyl-alkoxy” template).
• R3 limitation: Use an aryl/heteroaryl that has substituent patterns outside the optional substituted set. Because the optional substituent list is extensive, simple “adding a substituent” likely remains within scope; a more meaningful change is the substituent type (charge, functional group, or heteroaryl ring class) that is not included.
• Core modification: Modify the scaffold so it is no longer a pyrido(3,2-d)pyrimidine derivative as claimed structurally.
• Salt/isomer strategy: Since R4 includes pharmaceutically acceptable addition salts and isomers, attempting to avoid infringement via salt choice is less effective unless the compound is not within the R4 definition or the specific structure changes.

Prior art and obviousness posture

From claim language alone, the chemical space resembles a medicinal chemistry optimization series around:

• a pyridopyrimidine core,
• ether-containing substituents,
• and substituted phenyl/aryl at another position.

That kind of scaffold and systematic substitution often has a substantial prior-art footprint. In validity challenges, the most common pressure points are:

• whether the full Markush is taught in one reference (anticipation),
• or whether a combination of references makes the genus obvious (obviousness),
• and whether the spec supports broad claims commensurate with breadth.

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What generic entry risks exist for products targeting HCV with this scaffold?

Short answer: If a competitor’s development includes a pyrido(3,2-d)pyrimidine analog that matches claim 1’s R2 and R3 category set, generic entry risk is direct at the chemical and composition levels. If not, risk moves to method-of-use and combination regimen infringement, which typically depends on labeling and practice.

Litigation posture likely to matter in practice

• Chemical infringement: accused compound structure matching Markush elements.
• Composition infringement: presence in a marketed formulation.
• Method-of-use: whether the pyrido(3,2-d)pyrimidine is marketed/used for HCV in combination regimens encompassed by claims 13–19.

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Key takeaways

1. US 8,637,531 claim 1 is a broad structural genus of pyrido(3,2-d)pyrimidine derivatives defined by closed Markush sets for R2 and optional substituents on R3.
2. Claims 2–8 narrow phenyl substitution patterns by ortho/meta/para placement and mono/di/tri-substitution.
3. Claims 9–10 enumerate many specific R2 ether motif variants and multiple aryl types (4-fluorophenyl, 3,4-dimethoxyphenyl, 2-formylphenyl, 4-carboxyphenyl, 6-chloro analogs, and chiral ether variants).
4. Claims 11–19 extend protection into pharmaceutical compositions and HCV treatment methods, including wide co-administration lists of antiviral agents.
5. The highest practical enforcement leverage is on chemical and composition infringement of compounds that fall within claim 1’s R2/R3 categories; method-of-use enforcement is more dependent on labeling and treatment practice for HCV regimens.

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FAQs

1) What structural elements are essential for infringement of US 8,637,531?
The pyrido(3,2-d)pyrimidine core with R1 = amino, R2 in the enumerated ether/sulfonyl-ether/cycloalkyl/alkenyl/alkynyl sets, R3 as halogen/aryl/heterocycle with the enumerated optional substituent set, and R4 as H/salts/isomers/N-oxides.

2) Do the patent’s dependent claims cover ortho/meta/para phenyl positioning even when R3 is not fully defined?
Yes. Claims 2–8 define phenyl-based R3 substitution placement constraints (para or meta or ortho; with mono/di/tri-substitution structures), narrowing the generic R3 definition while still allowing additional substitution latitude.

3) Can competitors avoid infringement by switching the antiviral co-therapy?
Switching co-therapy affects method claims (13–19) if the regimen is outside what is practiced or induced, but composition and chemical claims (11 and claim 1) are independent of co-therapy choice.

4) Are salts and stereoisomers protected by US 8,637,531?
Yes. Claim 1 explicitly includes pharmaceutical acceptable addition salts, stereochemical isomeric forms, and N-oxides via R4.

5) What is the biggest litigation bottleneck for enforcing broad Markush claims?
Mapping the accused compound’s substituent groups to the claim’s enumerated R2/R3 categories, while also surviving genus-level validity attacks tied to breadth (enablement/written description) and prior art coverage.

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References (APA)

1. United States Patent 8,637,531. Claims text provided in prompt.

Details for Patent 8,637,531

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Kadmon Pharmaceuticals Llc	INFERGEN	interferon alfacon-1	Injection	103663	October 06, 1997		2027-12-24
Emd Serono, Inc.	REBIF	interferon beta-1a	Injection	103780	March 07, 2002		2027-12-24
Emd Serono, Inc.	REBIF	interferon beta-1a	Injection	103780	December 17, 2004		2027-12-24
Emd Serono, Inc.	REBIF	interferon beta-1a	Injection	103780	December 21, 2012		2027-12-24
Horizon Therapeutics Ireland Dac	ACTIMMUNE	interferon gamma-1b	Injection	103836	February 25, 1999		2027-12-24
Hoffmann-la Roche Inc.	PEGASYS COPEGUS COMBINATION PACK	peginterferon alfa-2a and ribavirin		125083	June 04, 2004		2027-12-24
Schering Corporation A Subsidiary Of Merck & Co., Inc.	PEGINTRON/ REBETOL COMBO PACK	peginterferon alfa-2b and ribavirin		125196	June 13, 2008		2027-12-24