Patent: 7,745,446

Summary for Patent: 7,745,446

Title:	Pyrazolo[1,5-c]pyrimidines
Abstract:	Compounds of a certain formula I ##STR00001## in which R1, R2, R3 and R4 have the meanings indicated in the description are novel compounds expected to be useful in the therapy of (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis.
Inventor(s):	Maier; Thomas (Stockach, DE), Zuelch; Armin (Constance, DE), Ciossek; Thomas (Ravensburg, DE), Baer; Thomas (Reichenau, DE), Beckers; Thomas (Constance, DE)
Assignee:	Bayer Schering Pharma Aktiengesellschaft (Berlin, DE)
Application Number:	11/661,111
Patent Claims:	see list of patent claims

Executive summary United States Patent 7,745,446 is a high-coverage, formula-driven US patent claim set that spans a broad genus of substituted pyrazolopyrimidine compounds (and their salts), with dependent claims extending into specific substituent classes and into pharmaceutical compositions and combination regimens for cancer therapy. The claim language is structured to maximize literal coverage through (i) multiple substituent “choice blocks” for R1, R3 and heterocycle definitions, (ii) extensive allowance of optional substitution and ring heteroatom counts, and (iii) broad permissive definitions for linkages and saturated/partially unsaturated ring members. From an enforcement and freedom-to-operate perspective, the claim breadth cuts both ways: it increases the probability that many close analogs fall within literal scope, but it also increases invalidity leverage against non-predictable structure-activity boundaries, and it concentrates litigation risk around whether particular accused compounds match the scaffold and the defined substituent attachment rules.

What compounds does US 7,745,446 claim and how broad is the genus coverage?

Short answer: The independent claim covers Formula I pyrazolopyrimidine scaffold derivatives where core substituents are selected from wide sets of aryl, heteroaryl, fused heterocycles, and saturated/partially unsaturated heterocycles, plus salts. Claim 1 also captures three structural “families” for R1 (aryl/heteroaryl/heterocycle-like radicals) and four broad structural options for R3 (linker-terminated groups, aryl-terminated, heteroaryl-terminated, or a second cyclic group).

Core scaffold and binding-point linkage constraints

Claim 1 includes a hard scaffold requirement: each of Har1, Har2, Har3, Hh1, and Ah1 is bonded via a ring carbon atom to the pyrazolopyrimidine scaffold. That “attachment via ring carbon” constraint is an enforcement hinge. It narrows accidental inclusion of tautomers or attachment through heteroatoms, but it still leaves wide latitude for which ring system can supply that ring carbon.

Parameter space: the claim is a “combinatorial” genus

Claim 1 defines:

• R1: Ar1 or one of multiple aryl/heteroaryl/heterocycle radicals:
  • Ar1 options: phenyl, naphthyl, fluorenyl, or bisaryl radical Aa1 (two phenyl/naphthyl units linked by single bond)
  • Har1/Harlike options: unsaturated monocyclic 5- or 6-membered heteroaryl (1 to 4 heteroatoms chosen from N/O/S), with optional alkyl substitution R12
  • Har2 options: unsaturated fused bicyclic 9- or 10-membered heteroaryl (1 to 4 heteroatoms from N/O/S), with optional alkyl R13
  • Har3 options: unsaturated fused tricyclic 13- or 14-membered heteroaryl (1 to 4 heteroatoms from N/O/S), with optional alkyl R14
  • Cyc1: saturated or partially unsaturated heterocycle (5- or 6-membered; one or two O/S; attached via substitutable carbon atom)
  • Hh1: bisheteroaryl radical (two monocyclic 5/6-membered heteroaryls linked via single bond) with R15 = 1-4C-alkyl
  • Ah1: aryl-heteroaryl radical (phenyl/naphthyl linked to monocyclic 5/6-membered heteroaryl) with R16 = 1-4C-alkyl
  • Ha1: heteroaryl-aryl radical with R17 = 1-4C-alkyl
  • R11 (Ar1 substitution) is limited to small substituent set (alkoxy, halogen, nitro, hydroxyl, phenoxy, carboxy-alkoxy, carboxy-alkylcarbonylamino, etc.)
• R2: hydrogen, halogen, or 1-4C-alkyl
• R3: one of four major families:
  1. -T-R30 where T is 1-4C-alkylene and R30 is a defined amine/guanidino/ureido/carbamoyl/cyano-type or Het2
  2. --U--Ar2 with Ar2 = phenyl or substituted phenyl, with Ar2 substituents R31/R32 including amidino/guanidino-like precursors via W-R311
  3. --V--Har4 where Har4 is a monocyclic or fused bicyclic heteroaryl (5 to 10 members; 1 to 4 heteroatoms from N/O/S) with optional R33
  4. Cyc2 where Cyc2 is defined by another “formula A” group attached via substitutable carbon atom
• R4: hydrogen or halogen, in the claims provided

Practical implication: Literal coverage is driven more by (i) scaffold presence (pyrazolopyrimidine) and (ii) exact nature of the R3 terminus and its linkage than by R1 alone, because R1 definitions are wide. R3 options include both acyclic linker-to-amine/guanidine-like termini and cyclic amine-like termini and aromatic termini bearing amidino/guanidino-like groups.

Dependent claims narrow into enumerated “hit-like” exemplars

The dependent claims (2 through 10 shown in your excerpt) repeatedly re-cut the genus into specific R1 “named” classes, and specify particular R3 architectures such as:

• Formula Ib/ Ic specific embodiments (claim 3+4+5+6+7+8+9+10 depending on the R1 family and the value of R4, and in some cases R3 sub-selection).
• R4 explicitly set to bromine in several of the later claims.
• Specific R1 members: biphenyl variants, dibenzofuran, phenyl-pyridyl, pyrazolyl-phenyl, naphthyl derivatives with dialkoxy/dialkoxyethoxy patterns, and others.
• Specific Har4 sets: pyridyl and furanyl/pyridyl analogs with R33-substitution defined as -Z-R331 where Z is 1-4C-alkylene and R331 is R30-like (amine/guanidine-like option set).

Which claim elements create enforceable “fences” against design-arounds?

Short answer: The enforceable fences are (i) scaffold identity and attachment mode, (ii) R3 terminus selection and linkage definitions, and (iii) ring-size and heteroatom count constraints for heteroaryl radicals.

Fence 1: “pyrazolopyrimidine scaffold” + ring-carbon attachment

The claim’s explicit statement that each of Har1/Har2/Har3/Hh1/Ah1 is bonded via a ring carbon atom to the scaffold is a distinct narrowing language. A design-around that attaches the substituent through heteroatoms (or through a different constitutional attachment point) risks falling outside literal coverage.

Fence 2: R3 is not any substituent; it is one of four defined families

R3 must be either:

• alkylene linker to R30 (R30 contains specific nitrogen-rich functional group set), or
• linker to Ar2 (phenyl with restricted substitution set), or
• linker to Har4 (5 to 10 member heteroaryl, restricted heteroatom types and optional substitution), or
• Cyc2 defined by another “formula A” structure.

This matters because many competitors can mimic R1 and still avoid literal infringement by using a different amine class or a different functional group topology for the R3 terminus.

Fence 3: heteroaryl ring composition restrictions

Har1/Har2/Har3/Har4 are restricted by:

• ring size (monocyclic 5/6 for Har1; fused bicyclic 9/10 for Har2; fused tricyclic 13/14 for Har3; Har4 monocyclic or fused bicyclic 5 to 10),
• heteroatom counts (one to four), and
• heteroatom types (N/O/S only).

A design-around using ring members outside N/O/S (e.g., inclusion of halogens inside the heteroring as core heteroatom analogs, or different heteroatom types) can break literal matching. This fence is less helpful if the accused compound uses N/O/S but differs only in substitution patterns; those tend to remain within optional substitution allowances.

How do dependent claims 2 to 10 change scope and what are their key practical targets?

Short answer: Dependent claims tighten R1 and R3 sub-classes and fix certain variables (like R4 = bromine and R1 exemplars), improving infringement certainty for those specific chemical neighborhoods.

Claim 2

• Narrows to specific R1 classes and modifies R3 so that R3 is limited to variants where:
  • R30 includes ureido/Het2 with specific Het1/R304 configurations,
  • and R4 is hydrogen (in the excerpt for claim 2).

This is a narrower “version” of claim 1 but still broad due to heterocycle breadth in Het1/Het2 and Har4 options.

Claims 3 and 4

• They lock into structures “either from formula Ib or from formula Ic,” which is typically a key scaffold sub-configuration.
• Claim 3 sets R2 = hydrogen and provides named R1 families:
  • Ar1/biphenyl/biphenyl-like where Aa1 is biphenyl,
  • R1 includes dibenzofuranyl, phenyl-pyridyl, pyrazolyl-phenyl, and pyrazolyl analogs with R17 = 1-4C-alkyl.
• Claim 4 restricts:
  • R4 = hydrogen or bromine (depending on the specific claim snippet) and
  • Ar1 substituent patterns to defined methoxy/halo/nitro/carbonylamino and multi-biphenyl configurations,
  • Cyc2 includes specific radical sets shown in the excerpt (tetrahydroisoquinolinyl variants).

Claims 5 through 8

• They continue “Ib/Ic” narrowing and provide:
  • explicit examples of Cyc2 groups (tetrahydroisoquinolinyl variants in claim 5),
  • explicit R3 Ar2 patterns including dichloro phenyl patterns and amidino/guanidino substitution positions,
  • Har4 fixed to R33-substituted pyridyl or furanyl with amino-like R331.

These claims are practically useful in enforcement because they map to identifiable medicinal chemistry series rather than abstract variables.

Claims 9 and 10

• Claim 9 collapses R1 into Ar1/Har3/Ah1 subsets and fixes R2 and restricts R3 to specific Ar2/Har4/Cyc2 options.
• Claim 10 lists specific R1 members (multiple biphenyl and naphthyl derivatives and dibenzofuran) and restricts R3 to a curated set of aminomethyl/aminopropyl/tetrahydroisoquinolinyl-like termini.

Enforcement takeaway: Claims 9 and 10 look like “final-form” examples that are likely closer to marketed or clinical candidates. In litigation, these are often the claims defendants can’t easily avoid unless they remove or substantially change the R3 terminal functionality (aminomethyl/guanidino/aminomethyl pyridyl/furan-like patterns).

What pharmaceutical compositions and combination claims are included, and what do they mean for generic entry risk?

Short answer: The patent includes:

• a composition claim (Claim 11) for a therapeutically effective amount of the claimed compounds in a pharmaceutical composition, and
• combination therapy claims (Claims 12-14) combining the compound with a second active ingredient, including broadly enumerated chemotherapeutic classes and a wide list of target-specific agents and biologics.

Claim 11: pharmaceutical compositions

This claim is standard. If a competitor makes and sells a compound within claim 1’s scope, a composition claim increases leverage because marketing can be framed as infringement even if the active ingredient is known to be the same, regardless of formulation excipients.

Claims 12 to 14: combination with chemotherapeutics and target-specific agents

Claim 12 requires:

• first active ingredient: at least one compound of claim 1 (or salt),
• second active ingredient: at least one anti-cancer agent selected from a broad list,
• use modalities: separate, sequential, simultaneous, concurrent, or chronologically staggered.

Claim 13 and 14 expand the enumerated categories:

• Chemotherapeutics include alkylating/carbamylating agents, platinum derivatives, antimitotic/tubulin inhibitors, topoisomerase inhibitors, pyrimidine and purine antagonists, folic acid antagonists.
• Target-specific agents include kinase inhibitors, proteasome inhibitors, HDAC inhibitors, HSP90 inhibitors, vascular targeting agents, and a large list of monoclonal antibodies (trastuzumab, rituximab, alemtuzumab, tositumomab, cetuximab, bevacizumab, plus conjugates), oligonucleotide therapeutics (oblimersen), TLR9 agonists, hormonal therapeutics (anti-estrogens/anti-androgens, LHRH agents, aromatase inhibitors), plus bleomycin, retinoids, DNA methyltransferase inhibitors, alanosine, cytokines, interferons, and death receptor agonists.

Generic entry risk consequence: If a generic compound is found to fall within claim 1 scope, combination therapy claims can create additional infringement theories around prescribed regimens. That said, in many jurisdictions, combination method-of-use enforceability can turn on actual clinical use and evidence of induced infringement. Still, Claim 12’s broad modality language (“separate, sequential, simultaneous… chronologically staggered”) reduces room for “we don’t do concurrent administration” defenses.

How to read the patent landscape impact without the family/expiry metadata

Your excerpt contains the full claim text of the independent claim and several dependent claims, but does not include:

• application number(s),
• priority dates,
• filing/publication identifiers,
• assignee,
• prosecution history,
• cited references,
• number of continuations/related family members, or
• the FDA/orange book status that would normally anchor launch and expiry calculations.

Under those constraints, only the claim-coverage mechanics and design-around fences can be analyzed from the text you provided.

Key takeaways

• US 7,745,446 is a broad genus claim over substituted pyrazolopyrimidine compounds with wide R1 diversity and structured R3 diversity defined by four major families.
• The strongest literal fences are scaffold identity and the requirement that Har1/Har2/Har3/Hh1/Ah1 attach via a ring carbon atom to the scaffold, plus the tightly defined R3 family options and heteroatom/ring-size constraints.
• Dependent claims (3-10 in your excerpt) narrow into identifiable medicinal chemistry neighborhoods by fixing “Ib/Ic” variants, named R1 exemplars, R4 = hydrogen/bromine variants, and specific R3 terminal patterns (aminomethyl/guanidino/amidino-like motifs and tetrahydroisoquinolinyl-like cyclic groups).
• The patent adds composition and very broad combination therapy claims that increase infringement pathways if an accused compound falls within claim 1 scope.

FAQs

1. Can competitors avoid US 7,745,446 by changing only R1 while keeping R3 constant?
   Likely harder because R1 options are expansive; the more reliable design changes often occur in R3 termini and attachment/linkage architecture.

2. Does the “bonded via a ring carbon atom” language affect hydrogen-bond tautomers and regioisomers?
   It mainly targets constitutional attachment point differences; regioisomers that change attachment through different atoms can raise literal non-infringement arguments.

3. Which part of the claim is most likely to be litigated in infringement disputes: R1, R2, R3, or R4?
   R3 is typically most litigated because it carries the most functional-group identity constraints and defines the permissive set of amine/guanidino/Het2/Ar2/Har4 endpoints.

4. How do the combination claims expand risk beyond making the compound itself?
   They create additional method-of-use style theories tied to therapeutic regimens that include the claimed compound as the first active ingredient with a broad range of second anti-cancer agents.

5. Do the dependent claims materially narrow the scope enough to matter in a launch or ANDA strategy?
   Yes for specific product-like analogs: dependent claims that enumerate Cyc2 and R3 terminal patterns can capture concrete candidate structures, reducing the practical utility of generic “near miss” arguments.

Details for Patent 7,745,446

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	November 26, 1997		2025-09-05
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	February 19, 2002		2025-09-05
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	September 25, 1998		2025-09-05
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	February 10, 2017		2025-09-05