Patent: 7,838,524

Summary for Patent: 7,838,524

Title:	Substituted pyrazolyl urea derivatives useful in the treatment of cancer
Abstract:	The present invention relates to compounds of formula (I), pharmaceutical compositions which contain them and methods for treating cancer using compounds of formula (I). ##STR00001##
Inventor(s):	Lee; Wendy (South San Francisco, CA), Ladouceur; Gaetan (Guilford, CT), Dumas; Jacques (Waltham, MA), Smith; Roger (Madison, CT), Ying; Shihong (Orange, CT), Wang; Gan (Wallingord, CT), Chen; Zhi (Lyndhurst, NJ), Liu; Qingjie (Orange, CT), Mokdad; Holia Hatoum (Guilford, CT)
Assignee:	Bayer Healthcare LLC (Tarrytown, NY)
Application Number:	11/579,093
Patent Claims:	see list of patent claims

Executive summary US 7,838,524 is a broad US patent covering a structural class of substituted pyrazole-containing small-molecule compounds (Formula I), closely related homologs/formula subsets (Formula II and related compound sets), and downstream subject matter including salts, stereoisomers, alkyl ester prodrugs, and at least one explicit pharmaceutical composition claim set (claims 33-37). The independent claim 1 is a “genus” claim with extremely wide substituent ranges across three aromatic linkers (A, B, M), multiple heteroatom bridging options (L, X), and a two-Z substituted alkyl/heterocycle side-chain (Y), with multiple conditional exclusions. This structure breadth makes design-around possible but narrow in the places the claim explicitly constrains (notably the Z set exclusions tied to n and X, and the adjacency constraints for A-(CH2)n-X-Y and pyrazole ring versus A/B). Enforcement risk is driven less by novelty of a single moiety and more by whether an accused compound falls within the claimed substitution grammar. The explicit compound listing in claim 32 functions as strong exemplars inside the genus, supporting a broad construction and limiting “it is outside the invented concept” arguments.

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What claims are covered by US 7,838,524 and how broad is Formula I?

Bottom line: Claim 1 broadly covers compounds having a pyrazole core (implied by the exemplified “pyrazol-1-yl” structures in claim 32 and by sub-structures referenced in claims 5 and 6) linked to (i) an A ring via a spacer and bridging group (A-(CH2)n-X-Y), (ii) a B ring that incorporates a urea/amide-type linkage including a bridging group L between aromatic elements, and (iii) an M ring attached through another substitutable pattern. It also covers salts, stereoisomers, and alkyl ester prodrugs/phenyl(C1-C5) alkyl ester prodrugs.

Claim 1 structure “grammar” and inclusion mechanics

Claim 1 is written as: “A compound of Formula I, or a salt, stereoisomer, alkyl ester prodrug or phenyl(C1-C5) alkyl ester prodrug thereof” with a large substituent grammar defining R1, R2, A, B, L, M, n, X, and side-chain Y (with substituent groups Z).

Core substituent variables

• R1 and R2: independent choices of hydrogen, C1-C5 alkyl (optionally hydroxy or fluoro substituted), or halogen.
• A: phenyl, pyridine, or pyrimidine, optionally substituted with 1-2 substituents selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C1-C5 haloalkoxy, or halogen.
• B: phenylene or naphthylene, optionally substituted with 1-4 substituents from the same “alkyl/alkoxy/haloalkyl/haloalkoxy/halogen” set.
• L: bridging group = O, S, or CH2.
• M: phenyl, pyridine, or pyrimidine, optionally substituted with up to 1-3 groups from an expanded set including alkyl, haloalkyl, O-alkyl ethers (--O--R3), tertiary amine-type (--NR3R4), halogen, urea/amide-like groups (--C(O)NR3R4), cyano, carbonyl substituents (--C(O)R3), ethynyl-like (--C≡C--R3), and nitro.

Linker topology variables

• n: zero or one.
• X: bridging/linkage selected from:
  • oxygen (--O--)
  • sulfone (--SO2--)
  • nitrogen (--NR5--)
  • sulfone-adjacent nitrogen (--NR5--SO2--)
  • sulfonamide nitrogen branch (--N(SO2NR7R8)--)
  • reverse sulfone nitrogen (--SO2--NR5--)
  • urea-like (--NR5--C(O)--)
  • amide-like (--C(O)--NR5--)
  • carbonyl (--C(O)--)
  • or single bond.
• Y: linear or branched C1-C6 alkyl fragment substituted with one or two Z groups.
• Z: one of eight families including:
  • hydroxyl ether (--OR6)
  • ester ether (--O-C(O)-R6)
  • amino (--NR7R8)
  • sulfone alkyl (--SO2-(C1-C5)alkyl)
  • carbonyloxy (--C(O)-O-R6)
  • amino carbonyl (--NH-C(O)-R6)
  • carboxamides (--C(O)-NR7R8)
  • or a 5-7 member heterocycle with N/O/S and optional 1-3 substituents.

Exclusions that materially narrow the genus

Two conditional provisos operate as “carve-outs”:

1. When n is zero and X is --O--, --NR3--, or a single bond, then Z is not morpholine, piperidine, imidazole, or tetrazole.
2. When n is zero and X is a single bond, then Z is not --NR7R8 (i.e., an unsubstituted/allowed amino substituent family is barred under that specific topology).

These exclusions are not cosmetic; they target particular Z heterocycles and amino forms under specific linker constraints, which is likely to affect design-around strategies and claim construction.

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Which dependent claims narrow Formula I into specific embodiments?

Bottom line: Dependent claims 2-31 carve out narrower substituent choices (R1/R2 values, A/B options, specific X or Y selections, specific Z ring selections) and also impose positional constraints about where the spacer/bridging is attached relative to the pyrazole and aromatic rings.

Key narrowing claim clusters

• R1/R2 narrowers (claims 2, 3, 16, 17):
  • Claim 2: R1 is C1-C5 alkyl; R2 hydrogen.
  • Claim 3: R1 is tert-butyl, isopropyl, or cyclopentyl; R2 hydrogen.
  • Claim 16/17 mirror the same narrowers for Formula II.
• A and ring substitution narrowers (claims 4, 18):
  • A is phenyl or pyridine with 1-2 substituents in the limited set (C1-C5 alkyl/alkoxy/halogen).
• Positional adjacency constraints (claims 5, 6):
  • Claim 5: “-A-(CH2)n-X-Y is ... formulae 1x or 1xx” and the pyrazole ring plus “-(CH2)n-X-Y are not bound to contiguous ring carbons of A”; instead there are “1 or 2 ring carbons separating them.”
  • Claim 6: similar separation rule for the urea group and the bridging group relative to contiguous ring carbons of B.
• X and Y specific bridge choices (claims 9, 10, 11, 19, 20, 21, 31):
  • Claim 9: X limited to oxygen, NR5, NR5-C(O)-, C(O)-NR5-, or single bond.
  • Claim 10: Y substituted with one Z group limited to OR6, NR7R8, NH-C(O)R6, or C(O)NR7R8.
  • Claim 11: Y specifically methylene/ethylene/n-propylene/n-butylene.
  • Claim 31: Formula V/VI sets with Hal = Br/Cl/F and Y limited to those Z options with a single Z group.
• R3-R6 and R7/R8 substitution limitations (claims 12, 14, 22, 24, 30):
  • Claim 12/22: R3-R6 each independently H or C1-C5 alkyl optionally substituted with hydroxy.
  • Claim 14/24/30: R7/R8 H or C1-C5 alkyl optionally substituted with hydroxy.
• Z heterocycle selections (claims 13, 23, 29):
  • Claim 13: Z = --NR7R8 in monocyclic saturated heterocycle set including pyrrolidine, piperidine, azepane, morpholine, thiomorpholine, piperazine, homopiperazine, each optionally carbon-substituted with hydroxy.
  • Claim 23/29 replicate with slightly different specificity.

“Formula II” family (claims 15-24)

Claims 15-24 define a second family (Formula II) that tracks Formula I but is constrained at the outset (e.g., Rb defined as F or Cl in claim 15, plus Z and X constraints are substantially similar). The presence of a separate formula claim family strengthens the portfolio argument that multiple genus variants were contemplated.

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Do claim 32’s explicit compounds expand infringement exposure beyond the genus?

Bottom line: Claim 32 lists dozens of specific chemical names and prodrugs/esters/amides and includes stereochemical and ring-specific examples (e.g., morpholine, piperazine, tetrahydro-2H-pyran-4-ylmethoxy, pyrrolidine/piperidine linkers, fluorinated aromatic ethers). Under most US claim frameworks, explicit examples within a dependent/format claim set reinforce the breadth and provide clear in-claim targets for claim charting.

What claim 32 suggests about intended scope

The explicit structures cluster around:

• tert-butyl substitution at the pyrazole-associated position (repeated in the examples as “3-tert-butyl-5-...”)
• aromatic ether motifs “pyridin-4-yloxy” and “pyridin-3-yloxy”
• fluorinated aryl ether patterns “2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl”
• varied amino side chains attached via ethyl/propyl/butyl spacers, including aminoalkyl and cyclic amines

These exemplars likely reflect the company’s “working set” and are critical for litigation claim construction because they show how the inventor understood the generic terms.

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What is protected in the pharmaceutical composition claims (claims 33-37)?

Bottom line: Claims 33-37 add composition protection: a pharmaceutical composition including at least one compound of claim 1 plus a physiologically acceptable carrier. Claims 34-37 extend to combination therapy with an additional agent, and in claim 35-37 the “additional anti-hyper-proliferative agent” is specifically exemplified with a long list, including irinotecan, topotecan, and many oncology agents.

Composition claim structure

• Claim 33: composition comprising claim 1 compound + pharmaceutically acceptable carrier.
• Claim 34: adds “further including an additional pharmaceutical agent.”
• Claim 35: further including an additional anti-hyper-proliferative agent.
• Claim 36: examples include epothilines/derivatives, irinotecan, raloxifene, topotecan.
• Claim 37: broad list of possible additional pharmaceutical agents (oncology, endocrine, immunotherapy and more).

Practical impact: Even if a generic can avoid the small-molecule claim by changing a structural element, composition claims can still be asserted if the commercial product contains the patented compound and is formulated as claimed or combined with an agent listed in the dependent claims. The presence of “carrier” language means routine formulation activities could still trigger exposure if the product uses the patented compound.

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How many separate invention “layers” exist inside US 7,838,524?

Bottom line: The patent has at least three distinct layers of subject matter that can independently support enforcement leverage:

1. Genus compounds (Formula I, including prodrugs/salts/stereoisomers).
2. Secondary genus/formula subsets (Formula II, plus compound set embodiments in claims 25-31).
3. Downstream formulations/combination compositions (claims 33-37).

Infringement mapping implication

• Layer 1 drives straightforward small-molecule infringement analysis (substituent grammar).
• Layer 2 expands the possibility that close variants still land inside the protected chemical space.
• Layer 3 supports infringement theories based on product form and combination regimens, which matters for labeling, commercialization plans, and potential settlement structures.

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What design-arounds are suggested by the claim exclusions and topology limits?

Bottom line: The claim is wide, but it has targeted exclusions based on the relationship between n and X, and the suitability of specific Z heterocycles and amino substituent families.

High-leverage variables for a design-around

1. Use n=0 vs n=1: Exclusions are explicitly conditioned on n=0.
2. Use X=single bond: The claim excludes Z=--NR7R8 under n=0 and X=single bond.
3. Avoid excluded Z heterocycles under n=0 with X=--O--, --NR3--, or single bond: The “morpholine, piperidine, imidazole, tetrazole” exclusion is conditional.

Positional constraints for A and B

Claims 5 and 6 impose “not bound to contiguous ring carbons” rules relative to A and B. If an accused compound places those groups on contiguous positions, it can attempt to escape those dependent embodiments. That said, claim 1 itself does not appear to encode the contiguous-ring restriction; those constraints are in dependent claims, so escape would depend on whether the asserted claim is independent or a dependent narrower claim is selected in litigation.

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What is the practical strength of the patent estate around a competitor’s lead candidate?

Bottom line: The independent claim 1’s breadth means the “strength” is less about a single prior-art reference and more about whether the competitor’s molecule matches the substituent grammar. The conditional exclusions and adjacency constraints reduce some overlap but do not eliminate it. If an accused compound uses common motifs from claim 32 (aryl pyridine oxy groups, tert-butyl pyrazole substitution, fluorinated ether patterns, aminoalkyl/cyclic amines), the patent creates a high litigation risk profile.

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Key takeaways

• US 7,838,524 claim 1 is a broad genus covering substituted pyrazole-related small molecules defined by a large combinatorial grammar over A, B, L, M, n, X, Y, and Z, including salts, stereoisomers, and alkyl ester prodrugs.
• Conditional exclusions tied to n=0 and specific X choices materially narrow portions of the genus, especially against certain Z heterocycles (morpholine, piperidine, imidazole, tetrazole) and against Z=--NR7R8 when n=0 and X=single bond.
• Dependent claims narrow substituent identity and impose positional separation rules relative to contiguous ring carbons of A and B, which matters for design-around and for choosing which claims to assert.
• Claim 32’s extensive explicit compound list provides strong internal exemplars, supporting broad claim interpretation and easing claim charting.
• Claims 33-37 extend protection to pharmaceutical compositions and combination regimens with an additional anti-hyper-proliferative agent, increasing product-level enforcement paths.

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FAQs

1) Does US 7,838,524 cover salts and stereoisomers even if the competitor markets only a free base or racemate?
Yes. Claim 1 explicitly includes salts and stereoisomers; downstream dependent claims and formula claims also preserve salt/stereoisomer coverage.

2) Which claim elements are most determinative for infringement: A, B, M, or the linker X/Y/Z system?
For claim 1, the linker and side-chain system (n, X, Y, Z) typically controls inclusion because of the conditional exclusions and the Z chemical-family restrictions; A/B/M define aromatic substitution and are also important but generally less “carved out.”

3) If a competitor changes the identity of the Z heterocycle (e.g., swaps morpholine), does that avoid the patent?
Not automatically. The exclusion is conditional on n=0 and specific X selections. If the competitor uses different n/X topology or chooses a Z option outside the excluded heterocycles, it may avoid, but topology is decisive.

4) Do composition claims (33-37) require the additional agent to be in the product label?
The claims are written as pharmaceutical compositions including an additional pharmaceutical agent and, in dependent claims, an anti-hyper-proliferative agent. Whether a particular commercial product falls inside depends on formulation facts, not only labeling language.

5) Can a competitor avoid infringement by shifting the positional relationship on A or B?
Shifting contiguous ring positioning may avoid the specific dependent “not bound to contiguous ring carbons” embodiments in claims 5 and 6, but claim 1 itself does not necessarily carry the same constraint. Escape depends on which claim(s) are asserted.

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References

No external sources were cited because the request was limited to the claim text provided for US 7,838,524.

Details for Patent 7,838,524

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Teknika Llc	TICE BCG	bcg live	For Injection	102821	June 21, 1989	7,838,524	2025-05-02
Merck Sharp & Dohme Llc	INTRON A	interferon alfa-2b	For Injection	103132	June 04, 1986	7,838,524	2025-05-02
Merck Sharp & Dohme Llc	INTRON A	interferon alfa-2b	For Injection	103132		7,838,524	2025-05-02