Details for Patent: 5,998,581

Summary for Patent: 5,998,581

Title:	Reductive alkylation of glycopeptide antibiotics
Abstract:	This invention is concerned with improved processes for reductive alkylation of glycopeptide antibiotics. The improvement residing in providing a source of copper which results in the initial production of a copper complex of the glycopeptide antibiotic. Reductive alkylation of this complex favors regioselective alkylation and increased yields. Copper complexes of the glycopeptide antibiotic starting materials and of the alkylated products are also part of the invention.
Inventor(s):	Richard Alan Berglund, Nancy Anne Lockwood, Howard Eugene Magadanz, Hua Zheng
Assignee:	Eli Lilly and Co
Application Number:	US09/290,204
Patent Claim Types: see list of patent claims	Use;

United States Patent 5,998,581 (N4 reductive alkylation of glycopeptides with soluble copper complexes): scope, enforceable claim boundaries, and US patent landscape

US Patent 5,998,581 is directed to making N4 reductively alkylated glycopeptide antibiotics by reacting an N4 amine-bearing glycopeptide with a ketone or aldehyde under specific reductive conditions mediated by a soluble copper complex, then isolating the copper complex and finally “freeing” the alkylated glycopeptide via aqueous treatment at pH ≤4. The independent claim 1 is process-focused, with a defined sequence (copper complex formation, isolation, decomplexing) and a defined catalyst/reductant selection. Dependent claims narrow solvent, stoichiometry, complex stoichiometry (1:1 with A82846B), a specific aldehyde (4’-chloro-4-biphenylcarboxaldehyde), and pH bands for preparation and decomplexing.

A complete and accurate patent-landscape analysis for the full US estate and litigation posture cannot be produced from the claim text alone because it requires docket-specific data: the patent’s bibliographic record (application number, publication history, continuations), the full claim set as granted, assignment and prosecution history, and the Orange Book/FDA regulatory record for the covered drug substance(s). Without those, the scope-to-landscape mapping risks material error.

What does US Patent 5,998,581 claim: N4 alkylated glycopeptide antibiotics made via soluble copper complex and reductive alkylation? (claim construction)

Executive scope statement (what claim 1 covers)

Claim 1 covers preparation of an N4 alkylated glycopeptide antibiotic by a three-step sequence:

1. React a soluble copper complex of a glycopeptide antibiotic having an amine-containing saccharide at N4 with a ketone or aldehyde, using a specific reducing agent chosen from:

   • sodium cyanoborohydride, or
   • pyridine.borane complex, to form a copper complex of said N4 alkylated glycopeptide antibiotic.

2. Isolate the resulting copper complex.

3. Decomplex (“free”) the N4 alkylated glycopeptide by aqueous treatment at pH ≤ 4.

The claim is framed as “prepared by the steps,” so infringement analysis will hinge on whether an accused manufacturing process performs each claimed step as set out, including the selected reductant and the pH decomplexing condition.

Step-by-step claim boundaries that matter in practice

Step (i): “reacting a soluble copper complex … with a ketone or aldehyde in the presence of a reducing agent selected from…”

Key enforceability levers:

• Copper mediation is required. The starting point must be a soluble copper complex of the N4-amine glycopeptide. Processes that directly reductively alkylate without a copper-complex intermediate fall outside claim 1 as written.

• Substrate must be a glycopeptide antibiotic with an N4 amine-containing saccharide. The claim does not say “only,” but infringement would require an actual N4-amine saccharide glycopeptide as the starting material.

• Electrophile scope is ketone or aldehyde. It includes both aldehydes and ketones, but dependent claims then single out a specific aldehyde.

• Reducing agent is limited to two named classes/reagents. “Selected from the group consisting of…” narrows to:

  • sodium cyanoborohydride variants as sodium cyanoborohydride specifically, and
  • pyridine.borane complex.

  Replacing with other borohydrides (even if reductively alkylating) can be a design-around if it does not use one of these specific reducing agents.

• Copper complex of the alkylated product is required. Step (i) ends by forming a copper complex of the alkylated glycopeptide. If a process forms a free alkylated glycopeptide directly, it may not meet the “form a copper complex …” language.

Step (ii): “isolating said copper complex”

This is a structural/process checkpoint. It requires isolation of the intermediate copper complex before decomplexing.

• A process that keeps copper complex in solution and proceeds immediately to decomplexing without isolation may still be argued as “isolating” depending on claim construction, but isolation is a meaningful boundary for infringement risk.

Step (iii): “freeing … by aqueous treatment at a pH ≦ 4”

• pH ≤ 4 is a hard parameter. This is one of the clearest infringement triggers. A process that performs decomplexing at pH > 4 can be a strong non-infringing alternative if everything else is matched.

• The claim ties this decomplexing step to aqueous treatment, not solvent-only washing or non-aqueous quenching.

Does claim 1 protect the end product or just the process?

Claim 1 is a method claim. It covers the act of preparing, not a product claim with explicit structural features independent of process. However, the claim is “An N4 alkylated glycopeptide antibiotic prepared by the steps…” which can be used to argue that producing that product by those steps infringes, even if product is similar. Still, enforcement typically tracks performance of the claimed steps.

How broad is the “ketone or aldehyde” and “N4 alkylation” scope in US 5,998,581? (electrophile and alkyl group coverage)

What the claim says vs what it does not say

• Says: use a ketone or aldehyde to alkylate at N4.
• Does not specify: which ketone/aldehyde substituents; which alkyl group identity; chain length; aromatic vs aliphatic; or whether the reaction installs a single alkyl group vs more complex adducts.

So, independent claim 1 is broad on electrophile identity (as a class) and on resulting alkyl substitution, constrained by (a) N4 amine substrate and (b) reductive system (copper complex and selected reducing agent).

Dependent claims that narrow electrophile identity (critical for freedom-to-operate)

Your provided dependent claims include a specific aldehyde:

• Claim 6: aldehyde is 4’-chloro-4-biphenylcarboxaldehyde.
• Claim 12: copper-antibiotic complex of claim 11 where aldehyde is the same.
• Claim 15: same narrowing for the A82846B instance.

These dependent claims likely correspond to a specific commercial or research target (the A82846 family is explicitly named). That narrows some marketed embodiments and also helps infer typical invention exemplars.

Which glycopeptide antibiotic backbones are covered: A82846A/B/C and orienticin A in claim 13? (substrate scope)

Named candidates in dependent claims

• Claim 13: N4 amine saccharide glycopeptide antibiotic is selected from:
  • A82846A, A82846B, A82846C, and orienticin A.
• Claim 14: the N4 substrate is A82846B.
• Claim 15: aldehyde is 4’-chloro-4-biphenylcarboxaldehyde, and the substrate is A82846B.

Practical implication for infringement and design-around

Independent claim 1 does not limit to those named glycopeptides, but infringement requires an N4 amine saccharide glycopeptide antibiotic that fits the glycopeptide antibiotic class used in the claim. The dependent claims give the cleanest “known” embodiments. If an accused process uses a different glycopeptide backbone, it may still fall within claim 1 if it meets the “glycopeptide antibiotic having an amine-containing saccharide at N4” requirement, but it avoids the narrower dependent claim path that locks to A82846/orienticin A.

What copper complex stoichiometry and composition requirements apply: “1:1 copper complex with A82846B” in claim 5?

Scope in claim 5

• Claim 5: soluble copper complex in step (i) is a 1:1 copper complex with A82846B.

This imposes an explicit stoichiometry for the intermediate. A process using different copper:ligand ratios, different copper salts not giving the same complex ratio, or forming non-1:1 complexes would be harder to map to claim 5. But claim 1 itself does not require 1:1.

Relation to claim 11 (“copper-antibiotic complex consisting essentially of copper and …”)

• Claim 11: a copper-antibiotic complex consisting essentially of copper and … a reductively alkylated glycopeptide antibiotic prepared by the defined reaction.

“Consisting essentially of” allows incidental components that do not materially affect the basic and novel characteristics, which often creates a broader allowable impurity/composition envelope than “consists of,” while still excluding major additional metals or structurally distinct complexing ligands as a matter of claim scope.

What reducing systems and solvents are covered: sodium cyanoborohydride vs pyridine.borane, and methanol in claim 2?

Reducing agent choice narrows independent claim 1

Only two reducing agents are in claim 1’s closed list:

• sodium cyanoborohydride
• pyridine.borane complex

If an accused process uses, for example, NaBH4 directly or other borane sources without forming a pyridine.borane complex, it may avoid the literal language.

Solvent narrowing via dependent claim 2

• Claim 2: prepared in methanol.

This is a specific process parameter. Many manufacturing routes use mixed solvents; whether they are “prepared in methanol” depends on claim construction and process records. Claim 1 has no solvent limitation in the provided text, so methanol is a narrower embodiment.

What pH windows are required: decomplexing at pH ≤4 and preparation pH 6–8 (claims 1 and 7–8)?

Claim 1: decomplexing constraint is decisive

• Aqueous treatment at pH ≤ 4 to free the N4 alkylated glycopeptide.

Dependent claims 7 and 8: preparation pH windows

• Claim 7: prepared at pH between 6 and 8.
• Claim 8: pH between 6.3 and 7.0.

Important nuance: Claim 1 already includes pH ≤4 in step (iii). Claims 7–8 appear to address “prepared at” pH, which likely refers to the reaction step conditions rather than the decomplexing step. If a process uses reaction pH 6–8 but decomplexes at pH ≤4, it could satisfy both.

What happens if a process uses excess aldehyde/ketone or different stoichiometry: slight excess and equimolar limits (claims 3–4)?

• Claim 3: aldehyde or ketone is present in slight excess.
• Claim 4: reducing agent present in at least equimolar amount.

These narrow embodiments. A process that uses limiting reagent ratios or different equivalents could avoid those dependent claims while still potentially infringing claim 1 if the core steps and reductant/copper system are followed.

What product-type protection is present via claim 11 copper-antibiotic complexes? (composition-of-matter vs process)

Claim 11 is for a copper-antibiotic complex consisting essentially of:

• copper, and
• a reductively alkylated glycopeptide antibiotic, prepared by the defined reaction.

This creates a potential route to enforce intermediate/composition products. If a third party sells or uses the copper-antibiotic complex as isolated product, claim 11 can be relevant even if their final decomplexing differs. Claim 11 still ties the complex to being prepared by the specific reductive system and N4 alkylation conditions.

What broader US patent landscape should surround 5,998,581: glycopeptide N4 modification, reductive alkylation, and copper-complex mediated chemistry?

A reliable landscape requires citation-level patent mapping to show:

• continuations and divisionals from the same family,
• other US patents in the same chemistry family (different electrophiles, reductants, decomplexing conditions, solvents, or glycopeptide substrates),
• related patents on glycopeptide N4 alkylated analogs (including any structural analogs derived from the A82846 or orienticin A frameworks),
• any later-arising improvements (alternative reductants, alternative metal complexes, alternative decomplexing agents, purification steps).

From the information provided here, only the subject patent number and your extracted claim set are available. Without bibliographic family data, prosecution history, or citations/forward citations, an “accurate” landscape cannot be produced.

When does US 5,998,581 lose exclusivity: expiration and patent term basics?

Accurate exclusivity timelines require the application filing date, non-provisional status, and whether any PTA (patent term adjustment) or terminal disclaimers apply. The claims text does not include those dates. Without the bibliographic record, any expiration statement would risk being wrong.

What generic entry risks exist for N4 reductively alkylated glycopeptide antibiotics covered by 5,998,581? (Paragraph IV and FDA posture)

A generic or biosimilar entry risk analysis depends on whether the protected compound is:

• an FDA-approved drug product (and which NDA/ANDA),
• listed in the Orange Book with this patent,
• the route of manufacture likely uses the claimed copper-mediated reductive alkylation and decomplexing pH step,
• and whether there are active Hatch-Waxman 505(b)(2)/505(j) competitors pursuing Paragraph IV certifications.

Those determinations require the FDA regulatory identity and Orange Book listing of 5,998,581, which are not provided in your prompt.

Key takeaways

• Claim 1 is a process claim requiring: (i) a soluble copper complex intermediate of an N4-amine glycopeptide, (ii) reductive alkylation with a ketone/aldehyde using one of two specified reductants, (iii) isolation of the copper complex of the alkylated product, and (iv) aqueous decomplexing at pH ≤4.
• The claim is broad on ketone/aldehyde identity in independent scope but narrow in dependent embodiments (notably 4’-chloro-4-biphenylcarboxaldehyde) and narrow on reductants (closed list).
• Dependent claims introduce meaningful infringement levers around: methanol solvent, aldehyde/ketone excess, reductant equivalents, 1:1 copper complex with A82846B, and reaction pH 6–8 (or 6.3–7.0).
• Claim 11 adds protection for a copper-antibiotic complex composition “consisting essentially of” copper and the reductively alkylated glycopeptide, tethered to the same reductive-copper preparation sequence.
• A complete US patent landscape (family members, forward citations, litigation, Orange Book status, expiration, and generic entry scenarios) cannot be produced from claim text alone without bibliographic and regulatory record inputs.

FAQs

1. Would using sodium borohydride instead of sodium cyanoborohydride avoid claim 1?
2. If a process decomplexes at pH 5 instead of pH ≤4, does it avoid claim 1?
3. Does claim 5 require a strict 1:1 Cu:A82846B ratio for infringement of dependent claim 5?
4. Can a competitor infringe claim 11 by selling or using the copper-antibiotic complex even if their final product is decomplexed differently?
5. How do claim 7–8 reaction pH windows interact with claim 1’s decomplexing pH ≤4 requirement?

References

1. United States Patent 5,998,581 (claim text provided in prompt).

Drugs Protected by US Patent 5,998,581

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,998,581

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	010621
Austria	286910
Australia	5449798