Patent: 7,326,711

Summary for Patent: 7,326,711

Title:	Pyridino[1,2-a]pyrimidin-4-one compounds as anticancer agents
Abstract:	Pyridin[1,2-a]pyrimidinyl compounds, pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one or more of the pyridino[1,2-a]pyrimidinyl compounds, either alone or in combination with at least one additional therapeutic agent. Methods of using the pyridino[1,2-a]pyrimidinyl compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases.
Inventor(s):	Wang; Weibo (Moraga, CA), Constantine; Ryan N. (Oakland, CA), Lagniton; Liana Marie (Berkeley, CA), Pecchi; Sabina (Oakland, CA), Burger; Matthew T. (Albany, CA), Desai; Manoj C. (Pleasant Hill, CA)
Assignee:	Chiron Corporation (Emeryville, CA)
Application Number:	10/870,707
Patent Claims:	see list of patent claims

Executive summary US Patent 7,326,711 claims a broad chemical genus centered on substituted heteroaromatic core scaffolds (notably 4-oxo-4H-pyrido[1,2-a]pyrimidines) combined with highly variable substituent positions and solubilizing/derivatizing side chains, plus downstream claims to compositions and methods aimed at inhibiting KSP (kinesin spindle protein, Eg5). The claim set as provided is wide enough to cover many KSP inhibitor analogs that share the same “pyrido[1,2-a]pyrimidin-4-one” type core with benzyl/arylalkyl substituents and substituted propyl/aminopropyl linkers to benzamide/benzamide-like moieties. The same breadth creates two parallel litigation risks for competitors: (1) that minor structural changes still fall within the genus or the dependent claim funnels, and (2) that “carve-outs” used in competitive freedom-to-operate work may fail if the competitors’ structures match claim variables (R1, R3, R4, R5, and ring-substituent sets) and if salts/tautomers/esters are treated as covered equivalents.

However, a complete and accurate “comprehensive and critical analysis” of the actual US patent landscape for US 7,326,711 requires the patent’s bibliographic data (publication number, assignee, filing/priority dates, inventors, claim construction context from the specification), the prosecution history, and the family members and related continuation/IP thickets. That information is not included in the prompt. Without it, any attempt to enumerate specific expiration dates, claim charts vs. specific marketed or pipeline KSP inhibitors, or competing patent estates (including Orange Book status, PIV/ANDA, or biosimilar analogues) would be incomplete.

H1: US Patent 7,326,711 claims on KSP inhibitors: what the genus covers and where infringement risk concentrates

What does US 7,326,711 claim for KSP inhibitors, and how broad is the chemical “genus”?

Short answer: Claim 1 is a structural-genus claim for compounds of a defined formula with variable substituent sets at multiple positions, covering stereoisomers, tautomers, salts, and esters, and funneling into specific dependent examples that strongly suggest a KSP inhibitor lead series.

Core structure and constrained anchors

From the claim text, the binding scaffold is anchored by:

• A substituted bicyclic/heteroaromatic system that, in dependent examples, appears as “4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl” (and related “4H-pyrido[1,2-a]pyrimidin-4-one” phrasing).
• A linker-bearing substituent that in dependent examples is commonly an alkyl chain terminating in an amide-forming “N-(3-aminopropyl)-N-[…]benzamide” motif.
• Specific fixed relationships:
  • R2 is hydrogen.
  • R3 is limited to four choices: 2-propenyl, phenyl, thienyl, and pyridyl.
  • R1 is constrained to the enumerated substituent categories but includes aryl/heteroaryl and sulfonyl variants.
  • m (in S(O)m) is 0, 1, or 2.

Variable substituent breadth that drives infringement coverage

Claim 1’s infringement surface is primarily created by:

• R1 latitude (broad chemical class): hydrogen; substituted/unsubstituted alkyl, alkenyl, alkynyl; aryl/heteroaryl/heterocyclyl; alkylsulfonyl; arylsulfonyl.
• R3 restriction (moderate constraint): only four substituent identities, including phenyl, thienyl, pyridyl.
• R4 is the major “side-chain architecture” lever: it is hydrogen, any of the enumerated carbon-based substituent classes, or the special “L-R13” motif (a carbon chain L plus terminal R13).
• R5 is a major “cap” diversity selector: hydrogen; carbon-based substituent categories; and multiple functional groups including COR10, CO2R10, CONR11R12, S(O)mR10, SO2NR11R12.
• R6–R9 (independent aromatic ring decorations): hydrogen, halogen, nitro, cyano, hydroxy, alkoxy, methylenedioxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfonyl, arylsulfonyl.
• R11–R12 ring-forming options: either independently selected substituents or the pair taken together with N to form a 3–7 membered heterocycle.
• R13 terminal group options: substituted/unsubstituted amino, aryl, heteroaryl, heterocyclyl.

Stereochemistry, salt/ester/tautomer coverage

Claim 1 explicitly covers:

• “stereoisomer, tautomer, pharmaceutically acceptable salt, or ester thereof.” This is important because KSP inhibitors often exist as:
• salt forms for formulation,
• tautomeric variants for heteroaromatic systems,
• stereoisomers around chiral centers created by side-chain derivatization.

In litigation, this language tends to reduce “form-only” design-around arguments.

Which dependent claims narrow to specific KSP inhibitor embodiments (and how do the funnels work)?

Short answer: Dependent claims 2–14 are narrowings on specific substituent categories (arylalkyl, benzyl; R4 equals L-R13; R13 equals amino/cycloalkyl/aryl/heterocyclyl; benzamide-like R5=COR10). Dependent claims 15–17 are extensive specimen lists of concrete compounds, including many with:

• N-(3-aminopropyl)-N-[1-(3-benzyl-…pyrido[1,2-a]pyrimidin-2-yl)propyl]-substituted benzamides,
• multiple benzo substituent patterns (bromo, chloro, methyl, methoxy, difluoro, CF3O, etc.),
• multiple linker variants (aminopropyl vs. butyl variants; cyclopropylmethyl; piperidinylmethyl; aminoethoxy, aminopropoxy),
• analogs where the core’s substituent count changes (e.g., “7-chloro” core variant; “8-methyl” core variant).

Claim 4 and Claim 5: why benzyl and L-R13 matter

• Claim 4: R1 is benzyl.
• Claim 5: R4 is L-R13. These two dependent claims, combined with Claim 1’s broad R4/R13/R1 enumerations, create a high-probability overlap zone for competitors developing “benzylated” core variants with aminated terminal groups used to tune potency and pharmacokinetics.

Claim 8–9: aminopropyl as a targeted pattern

• Claim 8: L-R13 is substituted/unsubstituted aminoalkyl.
• Claim 9: L-R13 is aminopropyl. This is an explicit funnel for a common KSP inhibitor SAR theme: propyl-amine side chain for solubility and binding orientation.

Claim 10–13: benzamide-like functionality via R5=COR10

• Claim 10: R5 is COR10.
• Claim 12: R10 is substituted phenyl or substituted pyridyl.
• Claim 13: substituted phenyl is alkyl- or halo-substituted phenyl.

These dependent claims map onto the dependent specimen lists that show many “-benzamide” final caps.

How does the claim structure map to representative claim-15 through claim-17 compounds?

Short answer: Claims 15–17 list multiple concrete structures that all share the same mechanistic design logic: a substituted pyrido[1,2-a]pyrimidin-4-one core fused into a side-chain bearing a benzamide (or benzamide-like) moiety, with an aminopropyl-containing linker and a benzyl group on the core.

Repeated motifs across the listed compounds

Across claim 15–17, the repeated “deal-breaker” elements for design-around are:

• “3-benzyl-…-pyrido[1,2-a]pyrimidin-2-yl” core substitution pattern in the named structures.
• “N-(3-aminopropyl)-N-[…]propyl]-X-benzamide” (and derivatives).
• Benzamide aromatic substitution patterns (halo, methyl, methoxy, CF3O, difluoro, dichloro, etc.).
• Occasional core variants:
  • “8-methyl” and “7-chloro” appear in different specimen lists.
  • Some cases switch from propyl to butyl or to cyclopropylmethyl, piperidinylmethyl, and other alkyl/heterocyclic linkers.

Implication for “close substitutes”

If a competitor’s KSP inhibitor:

• retains the pyrido[1,2-a]pyrimidin-4-one type core,
• uses a benzyl substituent at the corresponding R1 position,
• keeps the aminopropyl/L-R13 motif at R4,
• uses a benzamide-like R5 cap with substituted phenyl or substituted pyridyl, then the competitor’s compound has multiple hooks to fall within dependent examples and, by extension, within Claim 1’s broader genus.

What patents protect US 7,326,711’s same KSP chemotype in the US, and how do families typically overlap?

Short answer: The claim text alone does not identify assignee, priority, or family members, so a true “landscape” (specific adjacent patents and their claim scopes) cannot be enumerated reliably here.

That said, the claim architecture strongly indicates that US 7,326,711 is one member of a typical KSP-inhibitor IP bundle that often includes:

• a core heterocycle scaffold patent,
• side-chain linker/amine-tuning patents,
• benzamide cap refinements,
• salt/formulation patents,
• method-of-treatment patents (cancer indications),
• continuation patents that broaden genus coverage after early examples.

Any landscape work that ignores family members and continuations risks missing the controlling expiry boundary and the litigation “real target” claims.

When does the patent claim coverage expire, and does generic entry depend on Orange Book status?

Short answer: The prompt does not provide the patent’s grant and expiry dates, whether it has FDA regulatory exclusivity protections, or the drug product associated with the KSP inhibitors. Without that, an exclusivity-timeline analysis tied to FDA approvals cannot be produced correctly.

Why this matters for KSP inhibitors

KSP inhibitor programs are often oncology candidates that are not always marketed as single branded products in a way that creates an Orange Book listing equivalent to small-molecule chronic drugs. Even when there is an FDA-approved cancer drug, follow-on ANDAs may not be the route for entry if the product is never approved as an oral small-molecule with generic-ready labeling.

What generic entry risks exist for KSP inhibitors if Claim 1 is broad?

Short answer: The key risk is not “ANDA generics” per se, but that any small-molecule KSP inhibitor with the same scaffold and substituent variables may be captured under genus claim 1, even with small variations in aromatic substituent patterns or side-chain terminal groups, because:

• R6–R9 enumerations are extremely permissive,
• R1 and R4 allow a wide substitution set,
• R5 includes multiple functional-group classes that can absorb many SAR variants,
• salts/esters/tautomers are covered.

For risk modeling, infringement is most likely when the competitor compound:

• uses a “L-R13” type amine-containing carbon chain motif,
• retains benzyl substitution on the core,
• retains benzamide or benzamide-like caps with substituted phenyl/pyridyl.

How strong is the patent estate for KSP inhibitors under US validity and enforceability frameworks?

Short answer: Structural-genus claims can be strong if the specification supports the breadth and if the claimed variables correspond to disclosed synthetic examples and functional data. The dependent claim specimen lists (15–17) indicate that multiple specific embodiments were contemplated, but strength against validity attacks (102/103, enablement, written description, indefiniteness) cannot be evaluated without the specification and the prosecution record.

Where the claim can be attacked (structural-genus typical issues)

Common attack vectors for genus claims of this style include:

• whether the specification enables the full range of R1/R4/R5/R6-R9 permutations without undue experimentation,
• whether the inventors possessed the full breadth claimed,
• whether certain terms are indefinite in context,
• whether prior art discloses the same core scaffold with obvious substitutions.

A precise “strength” view requires claim-construction history and cited prior art, neither of which is in the prompt.

Which composition and method claims extend protection beyond compounds?

Short answer: Claims 18–21 extend protection to (a) compositions including a pharmaceutically acceptable carrier and an effective amount of the claim 1 compound to inhibit KSP activity, (b) combinations with at least one additional cancer agent, and (c) methods of inhibiting KSP activity via administration of the composition.

Claim 18: KSP-inhibiting composition

• Covers a broad formulation product: carrier + effective amount of any Claim 1 compound.

Claim 19–20: combination therapy

• Claim 19 requires at least one additional cancer agent.
• Claim 20 lists a set of standard oncology actives (irinotecan, topotecan, gemcitabine, imatinib, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, trastuzumab).

This is a substantial risk amplifier because it can capture broad combination regimens if a competitor studies or markets a fixed or flexible combination that includes the claimed KSP inhibitor.

Claim 21: method-of-use

• Covers administering the composition to inhibit KSP activity in human or animal subjects.

For design-around, method claims are less about molecule modification and more about whether the same pharmacological effect is pursued and how the clinical protocol is defined.

How does this patent compare with typical KSP inhibitor competitor patent estates?

Short answer: The claim language indicates a chemotype that is scaffold-centric with amine-containing linkers and benzamide caps. Many KSP programs in oncology target Eg5 and feature:

• heteroaromatic cores,
• flexible linker and basic side chain for potency/PK,
• substituted phenyl/carboxamide motifs.

Competitor overlap tends to be highest when:

• the core class is the same (pyrido[1,2-a]pyrimidin-4-one type),
• the side-chain architecture is the same (L-R13 aminopropyl-type),
• the terminal functionality is the same (benzamide or related carbonyls).

A formal comparison requires known competitor compounds and their patent families, which are not provided here.

Commercial exposure: what revenue streams would be at risk if Claim 1 is asserted?

Short answer: Commercial exposure cannot be mapped to actual US products without identifying the drug candidate linked to US 7,326,711 and its FDA status.

What can be stated from the claim set:

• The method and combination claims align with oncology cash-flow profiles where KSP inhibitors are developed as monotherapy and in combination with cytotoxics and targeted agents.
• The breadth of listed combination partners in Claim 20 can increase the number of viable clinical trials that could trigger method/combination infringement arguments if the KSP inhibitor is used in those regimens.

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Key Takeaways

• US 7,326,711 Claim 1 is a broad structural-genus claim for substituted pyrido[1,2-a]pyrimidin-4-one type KSP inhibitors with extensive latitude in aromatic substitution (R6–R9), side-chain architecture (R4 via L-R13), and terminal functional groups (R5 via COR10/CONR11R12/S(O)mR10/SO2NR11R12).
• Dependent claims 4, 5, and 8–9 focus on benzyl (R1=benzyl) and aminopropyl-type linkers (R4=L-R13 where L-R13 is aminoalkyl, including aminopropyl), which are common SAR “hotspots” that reduce competitor escape options.
• Claims 18–21 extend protection from compounds to compositions, combination regimens with a broad list of cancer agents, and administration methods for inhibiting KSP activity.
• A complete US patent landscape (specific overlapping patents, expiry windows, Paragraph IV equivalents, litigation history, and FDA/Orange Book status) cannot be produced accurately from the claim text alone because the prompt omits the patent’s bibliographic data, family members, assignee, priority dates, and the associated FDA product linkage.

FAQs

1. Does US 7,326,711 cover salts, stereoisomers, and tautomers?
   Yes. Claim 1 explicitly includes “stereoisomer, tautomer, pharmaceutically acceptable salt, or ester thereof.”

2. Which dependent claims most directly target aminopropyl-containing KSP inhibitors?
   Claim 5 (R4 is L-R13), Claim 8 (L-R13 is aminoalkyl), and Claim 9 (L-R13 is aminopropyl).

3. How do the claims treat benzamide-like functional groups for the terminal cap?
   Claim 10 sets R5=COR10, and Claim 12 limits R10 to substituted phenyl or substituted pyridyl, with Claim 13 further restricting substituted phenyl to alkyl- or halo-substituted phenyl.

4. Do the patent claims extend to combination cancer regimens?
   Yes. Claims 19–20 cover combinations of the KSP inhibitor composition with at least one additional cancer agent selected from a listed set including irinotecan, gemcitabine, platinum agents, taxanes, anthracyclines, and monoclonal antibodies such as rituximab and trastuzumab.

5. Is method-of-use protection included, or only compound protection?
   Both. Claim 21 covers administering the claimed composition to inhibit KSP activity in human or animal subjects.

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References

1. US Patent 7,326,711 (claims provided in prompt).

Details for Patent 7,326,711

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	November 26, 1997	7,326,711	2024-06-17
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	February 19, 2002	7,326,711	2024-06-17
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	September 25, 1998	7,326,711	2024-06-17
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	February 10, 2017	7,326,711	2024-06-17
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	June 22, 2017	7,326,711	2024-06-17
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	February 28, 2019	7,326,711	2024-06-17