Details for Patent: RE43390

Summary for Patent: RE43390

Title:	Pleuromutilin derivatives as antimicrobials
Abstract:	The present invention relates to pleuromutilin derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medical therapy, particularly antibacterial therapy.
Inventor(s):	Valerie Joan Berry, Steven Dabbs, Colin Henry Frydrych, Eric Hunt, Francis Dominic Sanderson, Gary Woodnutt
Assignee:	Almirall SA , SmithKline Beecham Ltd , GlaxoSmithKline LLC
Application Number:	US13/102,156
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

United States Patent RE43390 (mutilin 14-Quinuclidinyl/azabicyclicthiooxy-acetate family): claim scope, process coverage, and US patent landscape

RE43390 is a US reissue covering a broad genus of “mutilin” derivatives defined by a general formula (IA)/(IB), with substituent controls at the 14-position, plus downstream coverage for pharmaceutical compositions and multiple antibacterial use methods (systemic and nasal carriage reduction, plus topical skin/soft tissue treatment). The claims also include manufacturing-process pathways built around coupling at the 14-position using acyl/O-acyl intermediates and active derivatives (e.g., acid chlorides), enabling route-based infringement theories against generic or follow-on applicants that practice the claimed intermediates or coupling schemes.

Below is a structured read on what RE43390 claims, what it likely blocks (and where design-around pressure exists), and how the broader US patent landscape typically interacts with such a reissue.

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What is United States Patent RE43390 and what does it claim?

Short answer: RE43390 claims a genus of mutilin 14-substituted derivatives where the 14 substituent includes an azabicyclic or quinuclidinyl-containing group linked through specified linkers X (O, S, S(O), SO2, carbonate-type, amide-type, etc.), with constraints on the presence and size of methylene spacers (n, m) and with alternatives that replace the spacer-terminated moiety by a vinyl-like acrylic acid (RaRbC=CHCOO) pattern. It also claims multiple drug-product forms and antibacterial treatment and prophylaxis methods, plus processes for preparing the 14-substituted compounds via coupling of protected mutilin or epi-mutilin intermediates.

Claim set overview (independent vs dependent coverage)

The independent anchor is claim 1, with a tight chemical definition plus an “or” structure that allows different linker/spacer architectures. From there, the patent expands along three axes:

1. Chemical genus refinement (claims 2, 3, 4, 5, 6)
2. Explicit compound list / narrowed examples (claims 7, 25–27, and the multiple entries embedded in claim 26)
3. Manufacturing routes (claims 8–9)
4. Formulation + route of administration (claims 10–12, 17–20)
5. Therapeutic uses and prophylaxis (claims 13–15, 21–24)

What chemical “core” is being claimed (14-position mutilin derivatives)

Claim 1 requires:

• A compound of formula (IA) or (IB)
• Variables: n and m independently in {0, 1, 2}
• Linker X selected from:
  • —O—, —S—, —S(O)—, —SO2—
  • —CO.O—, —NH—, —CONH—, —NHCONH—
  • or a bond
• A special case: if n is 1 or 2 and m is 2, then X is —S—
• Substituent R1 is vinyl or ethyl
• Substituent R2 is optionally substituted quinuclidinyl or multiple azabicyclic ring systems (including several numbered bicyclic templates), attached through a ring carbon atom
• R3 is H or OH
• Another special case: if the 14-position moiety R2(CH2)mX(CH2)nCH2COO is altered, the claim allows replacement by RaRbC=CHCOO where one of Ra/Rb is H and the other is R2 or both together form R2
• Coverage extends to pharmaceutically acceptable salts

Practical read on the medicinal chemistry scope

• The patent is built around a conserved “mutilin” skeleton with a 14-position functionalization handle.
• The linker X list is broad enough to cover oxy-, thio-, sulfoxide/sulfone-like, and multiple nitrogen-containing connectivity patterns.
• Spacer flexibility via n/m in 0–2 supports multiple homologs.
• The inclusion of an alternative acrylate-type pattern (RaRbC=CHCOO) expands beyond pure saturated spacers into an unsaturated acid linkage architecture.

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How broad are RE43390 claim 1’s genus boundaries and what combinations are actually in-scope?

Short answer: Claim 1 covers many combinations of spacer length (n,m), linkage type (X), and R2 ring selection (quinuclidinyl and specified azabicyclics), with additional constraints for particular spacer/linker combinations and with allowance for substituent R3 (H/OH). It also adds an alternative “vinyl/alkene acid” variant at the 14 position.

Spacer-length logic (n,m) and special constraint

• Default: n ∈ {0,1,2}, m ∈ {0,1,2} independently.
• Special constraint: if n ∈ {1,2} and m = 2, then X must be —S—.
  • This matters for design-around: an applicant using longer methylene (m=2) with oxygen or amide linkers can fall outside that narrowed subspace.

R2 attachment point

• R2 attaches through a ring carbon atom.
  • This limits N-attachment variants (e.g., where the substituent attaches through the nitrogen of quinuclidine) unless they still satisfy the claim’s “attached through ring carbon atom” requirement.

R3

• R3 is H or OH, enabling at least two stereochemical or oxidation-state variants to remain in scope.

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Which specific compounds does RE43390 explicitly list, and why does that matter?

Short answer: The reissue includes a long enumerated list of specific mutilin 14-substituted acetates and ester/acrylate/propionate/butyrate analogs with particular quinuclidinyl and azabicyclic substituents (including exo/endo stereochemical labels and multiple ring-numbered azabicycles). Those enumerations reduce ambiguity about coverage of at least those exemplified members and can strengthen infringement arguments against products that match the listed structures.

Explicit compound list content (claims 7 and 26)

Claim 7 and claim 26 include extensive examples such as:

• mutilin 14-(quinuclidin-4-yl-sulfanyl)-acetate
• 19,20-dihydro analogs
• mutilin 14-(quinuclidin-3-yloxy)-acetate
• mutilin 14-(quinuclidin-3-ylsulfonyl)-acetate
• various quinuclidinyl-position isomers (3-yl, 4-yl)
• azabicyclo substituent variants (including multiple bicyclic ring classes)
• stereochemical labels such as (3R,4R), (3S,4R), and exo/endo descriptors
• salts included by reference

Claim 25–27 further narrow to:

• Claim 25: mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate
• Claim 27: same compound or pharmaceutically acceptable salt

Why enumeration matters legally

• If a competitor’s product structure matches one of the explicitly listed members, a plaintiff can use those as “anchor” constructions to argue that the asserted compound falls within both (i) the genus definition and (ii) the specifically claimed species set.
• Enumeration can also affect validity by demonstrating enablement and representative possession of the genus, depending on the original filing and the reissue history.

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What is the manufacturing-process claim scope in RE43390, and how can it drive IP risk for generics?

Short answer: RE43390 claims process steps that couple protected mutilin or epi-mutilin with a carboxylic acid derivative representing the R2A-(CH2)m-X-(CH2)n-CH2CO2H fragment, and alternative steps that couple a 14-O-acyl-(epi) mutilin derivative with an R2A(CH2)mXH fragment. These route claims can be used even if a defendant argues different end-form synthesis details, provided the defendant practices the core coupling/intermediate scheme and meets the defined intermediate patterns.

Claim 8: two process pathways

Claim 8 provides process coverage via:

Path (a): coupling protected mutilin/epi-mutilin with an acid-derivative

• Start: mutilin or epi-mutilin with a protected hydroxy group at position 11
• Coupling partner: an active derivative (example given: acid chloride) of:
  • R2A—(CH2)m—X—(CH2)n—CH2CO2H
• R2A is R2 as defined in claim 1 or convertible thereto
• “If necessary” convert epi-mutilin to mutilin
• “If necessary or desired,” modify the mutilin nucleus to introduce:
  • 2-OH
  • 19,20-dihydro
  • or 1,2-dehydro substituents

Path (b): coupling using a 14-O-acyl-(epi) mutilin intermediate

• Provide a mutilin or epi-mutilin derivative having:
  • (CH2)nCH2CO as an O-acyl group at position 14
• The O-acyl substituent is substituted with:
  • RL which is leaving group, OH, or NH
• Then couple the 14-O-acyl-(epi) derivative with:
  • R2A(CH2)mXH or an active derivative thereof
• Again, optionally convert epi-mutilin configuration to mutilin and optionally introduce modifications (2-OH, 19,20-dihydro, 1,2-dehydro)

Claim 9: specific reagent mapping by X

Claim 9 breaks down process variants based on X:

• When X is O, S, or NH:

  • RL is a leaving group
  • React with:
    • alcohol R2—(CH2)m—OH
    • thiol R2—(CH2)m—SH
    • amine R2—(CH2)m—NH2

• When X is CONH:

  • RL is amino
  • React with acid R2A—(CH2)m—CO2H or acylating agent derived therefrom

• When X is CO.O:

  • RL is hydroxy
  • React with acylating agent derived from acid R2A—(CH2)m—CO2H

Process-claim strategic implication

For a follow-on manufacturer, risk increases if their chemistry:

• Uses protected hydroxy at position 11 as a coupling platform
• Uses an acid chloride (or equivalent “active derivative”) matching the defined R2A-(CH2)m-X-(CH2)n-CH2CO2H fragment
• Uses 14-O-acyl intermediates with RL as leaving group/OH/NH and then couples to the R2A(CH2)mXH nucleophile types in the claim’s matrix

Even if an end compound is within claim 1, process claims add an additional infringement hook if end-to-end documentation aligns with the claimed intermediates.

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What formulation and delivery claims are in RE43390 (and what do they cover commercially)?

Short answer: RE43390 claims pharmaceutical compositions containing the claimed compound, including:

• generic “composition + carrier”
• a nasal spray (aqueous spray)
• topical administration forms including ointment, cream, and lotion These provide straightforward coverage against product forms that match the claimed compositions and routes.

Compositions and dosage forms

• Claim 10: pharmaceutical composition comprising compound + pharmaceutically acceptable carrier
• Claim 11: spray adapted for nasal cavity
• Claim 12: spray is an aqueous spray
• Claim 17: pharmaceutical composition adapted for topical administration
• Claims 18–20: ointment, cream, lotion

Commercial implication: A defendant selling the active with a carrier in an aqueous nasal spray and/or a topical formulation aligned with these categories faces direct product-form coverage, independent of method-of-use.

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What therapeutic and prophylaxis methods are claimed in RE43390?

Short answer: The patent claims multiple antibacterial uses:

• treating bacterial infection via administration of claim 1 compounds
• reducing/eliminating nasal carriage of pathogenic organisms
• prophylaxis of recurrent otitis media or recurrent acute bacterial sinusitis
• topical treatment of skin/soft tissue bacterial infections, with further dependent claims by organism type: Gram-positive, Gram-negative, and mycoplasma

Systemic/nasal methods

• Claim 13: method of treating bacterial infection
• Claim 14: method of reducing/eliminating nasal carriage
• Claim 15: prophylaxis of recurrent otitis media or recurrent acute bacterial sinusitis

Topical methods

• Claim 21: treating bacterial infections of skin or soft tissue via topical administration
• Claim 22: caused by Gram-positive bacteria
• Claim 23: caused by Gram-negative bacteria
• Claim 24: caused by mycoplasma

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How does RE43390’s claim structure shape design-around strategies?

Short answer: The biggest design-around levers are at (i) the 14-position linker architecture (X and its allowed set), (ii) spacer lengths n/m, (iii) R2 connectivity rules (attachment through ring carbon atom), and (iv) the nature of the acid component at the 14 group (including whether it follows saturated R2(CH2)mX(CH2)nCH2COO vs the RaRbC=CHCOO alternative).

High-sensitivity claim elements

• X selection: O vs S vs sulfoxide/sulfone-like vs amide connectivity vs bond
• m and n combination: especially when m=2 and n=1 or 2 forces X=—S—
• R2 attachment point: ring carbon attachment
• R1: vinyl or ethyl
• R3: H vs OH

Process design-around

• Avoid intermediates that map to the claimed O-acyl-(epi) mutilin at position 14 with RL leaving group/OH/NH coupled to R2A(CH2)mXH under the claim’s matrix.
• Use alternative coupling logic that does not practice the claimed pairing of intermediate patterns.

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What is the patent landscape around RE43390 in the US (what else typically matters)?

Short answer: RE43390 is a reissue; as such it sits within a chain that usually includes:

• an original composition/compound patent family (with priority to an earlier non-reissue filing),
• continuation/divisional or related patents covering related species, alternative substituent patterns, additional formulations, and/or additional manufacturing methods,
• and potentially later patents asserting improvements (additional linkers, specific species, or additional dosage forms).

However, this response cannot complete an accurate landscape map (other US patent numbers, assignees, expiration dates, Orange Book listings, or litigation dockets) from the data provided. The only actionable item supplied is RE43390 claim language, which is sufficient for claim-scope analysis but not for an evidentiary landscape with named competitors, caselaw, or expiry timelines.

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Key claim-scope conclusions for business decisions

1. Compound coverage is genus-heavy but structurally tethered
   Claim 1’s enumerated X types, spacer constraints (n,m ∈ {0,1,2} with a special m=2 limitation), R1 (vinyl/ethyl), and defined R2 ring inventory create a wide but not unconstrained claim set. A product outside those structural constraints is the primary escape route.

2. The 14-position is the infringement center of mass
   Most product members in claims 7 and 26 are 14-substituted acetates and related esters/acrylate analogs, so a design-around that preserves the core mutilin but changes the 14-linker architecture is the likely strategy tested.

3. Route-of-synthesis claims create additional risk even with formulation differences
   Claims 8–9 can be asserted against manufacturers whose process uses the protected 11-hydroxy coupling and the 14-O-acyl intermediate coupling logic.

4. Multiple administration routes are covered
   Nasal aqueous spray and topical semisolids/liquids are claimed. A competitor cannot rely solely on “different dosage form” if the claimed dosage form classes are used.

5. Method-of-use coverage includes both treatment and prophylaxis
   That matters for label strategy and for post-approval enforcement targeted at patient selection and indications.

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Key Takeaways

• RE43390 is a reissue-style patent with genus claims to mutilin 14-substituted derivatives plus process claims and formulation/method-of-use claims across systemic, nasal carriage, prophylaxis (otitis media/sinusitis), and topical skin/soft tissue antibacterial indications.
• The strongest claim leverage is claim 1 (structural definition of substituents via X, n/m, R1, R2) plus species lists (claims 7 and 26) and manufacturing routes (claims 8–9).
• Practical infringement risk concentrates on products that:
  • match the claim 1 14-position architecture, and
  • are made using the claimed coupling/14-O-acyl intermediate schemes, and
  • are marketed/formulated as nasal aqueous spray and/or topical ointment/cream/lotion, and
  • are used for the claimed bacterial treatment, nasal carriage reduction, prophylaxis, or topical treatment indications.

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FAQs

1. Can a compound avoid RE43390 by changing X from oxygen to carbon?
   Claim 1 does not list —C— as a linker; the allowed X set is enumerated (O/S/S(O)/SO2/amide-like/ether-like/carbonyl-oxygen variants/bond), so removing X from those categories is a primary route-out.

2. Does the special m=2 rule narrow only oxygen and nitrogen linkers?
   Yes. The special constraint applies when n is 1 or 2 and m is 2, forcing X to be —S—, which tightens freedom for other X types in that parameter band.

3. Does RE43390 cover both epi-mutilin and mutilin manufacturing?
   Yes. Claim 8 uses “mutilin or epi-mutilin,” with optional conversion steps, so epi-to-mutilin or using mutilin directly remains in-scope.

4. Are nasal carriage and prophylaxis claims independent of formulation?
   The method claims cover administration regardless of composition claims, while formulation claims cover product forms. A product can still face method-of-use exposure if the clinical use matches claims 13–15.

5. Do explicit species in claims 7 and 26 expand enforceability beyond the genus?
   Yes. Enumerated species reduce ambiguity for infringement analysis and support enforcement against products that match the listed 14-substituted mutilin structures exactly.

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References (APA)

1. United States Patent and Trademark Office. RE43390 (reissue patent). Patent claims as provided in the prompt.

Drugs Protected by US Patent RE43390

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

Foreign Priority and PCT Information for Patent: RE43390

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9722817	Oct 29, 1997
United Kingdom	9813689	Jun 25, 1998

PCT Information
PCT Filed	October 27, 1998	PCT Application Number:	PCT/GB98/03211
PCT Publication Date:	May 06, 1999	PCT Publication Number:	WO99/21855

International Family Members for US Patent RE43390

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1028961		CA 2007 00052	Denmark
European Patent Office	1028961		91372	Luxembourg
European Patent Office	1028961		SPC042/2007	Ireland
European Patent Office	1028961		07C0057	France
European Patent Office	1028961		SPC/GB07/061	United Kingdom
European Patent Office	1028961		306	Finland
European Patent Office	1028961		C01028961/01	Switzerland