Details for Patent: RE39128

Summary for Patent: RE39128

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:	US10/631,707
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

United States Drug Patent RE39128: Claim Scope, Retapamulin Coverage, and Patent Landscape

United States Patent RE39128 is a reissue patent directed to semisynthetic pleuromutilin derivatives, including retapamulin, a topical antibacterial marketed as Altabax. Its claims cover a broad chemical genus, selected individual compounds, synthesis methods, pharmaceutical compositions, nasal administration, topical dosage forms, and antibacterial treatment methods. The patent’s principal commercial relevance was retapamulin protection. The patent term has expired, and RE39128 no longer provides a live U.S. blocking right against generic or competing products.[1-3]

What drug does United States Patent RE39128 protect?

RE39128 protects derivatives of the pleuromutilin core, particularly compounds modified at the 14-position with nitrogen-containing bicyclic groups.

The principal marketed compound is retapamulin. Claim 25 expressly covers:

mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate

That structure corresponds to retapamulin, subject to the stereochemical and salt form used in the applicable product and regulatory records. Retapamulin is a topical pleuromutilin antibacterial approved by FDA for treatment of impetigo caused by susceptible strains of Staphylococcus aureus and Streptococcus pyogenes.[2]

Item	Information
Patent	U.S. RE39128
Patent type	Reissue patent
Technology	Semisynthetic pleuromutilin derivatives
Principal marketed compound	Retapamulin
Brand	Altabax
FDA product	Retapamulin ointment, 1%
Initial U.S. approval	2007
Original sponsor	GlaxoSmithKline/Stiefel commercial organization
Principal disease area	Topical bacterial skin infection
Current patent status	Expired
Biosimilar relevance	None; retapamulin is a small molecule
Generic pathway	ANDA, not biosimilar application

What are the broadest composition claims in RE39128?

Claim 1 is the primary genus claim. It covers compounds based on formula IA or IB with the following principal elements:

1. A mutilin or related pleuromutilin nucleus.
2. A 14-position substituent containing an ester-linked side chain.
3. A variable linker defined by:
   • the values of n and m;
   • the linker atom or group X; and
   • a bicyclic tertiary amine-containing group R2.
4. An R1 substituent that is vinyl or ethyl.
5. An R3 substituent that is hydrogen or hydroxyl.
6. Pharmaceutically acceptable salts.

The permitted X groups include:

• oxygen;
• sulfur;
• sulfoxide;
• sulfone;
• carbonate or ester-linked oxygen;
• amino;
• urea;
• amide; and
• a direct bond.

The R2 group is selected from several bridged or fused nitrogen-containing ring systems, including:

• quinuclidinyl;
• azabicyclo[2.2.1]heptyl;
• azabicyclo[4.3.0]nonyl;
• azabicyclo[3.2.1]octyl;
• azabicyclo[3.3.0]octyl;
• azabicyclo[2.2.2]octyl;
• azabicyclo[3.2.1]octenyl;
• azabicyclo[3.3.1]nonyl; and
• azabicyclo[4.4.0]decyl.

The claim requires attachment through a ring carbon atom. That limitation excludes structures attached through the ring nitrogen unless the relevant claim language and chemical nomenclature produce a different covered arrangement.

Claim 1 also includes an alternative side-chain construction in which the 14-position substituent is replaced by a substituted acrylic arrangement represented by RaRbC=CHCOO. This expands protection beyond simple saturated acetate linkers.

How do dependent claims narrow the chemical scope?

Claims 2 through 7 narrow claim 1 through structural selections.

Claim	Limitation
2	Substituted R2 groups bearing alkyl, alkoxy, alkenyl or related substituents
3	n = 0
4	m = 0 or 1
5	R2 is quinuclidinyl
6	Compound has formula IA
7	Long list of individually named pleuromutilin derivatives
16	X = sulfur, n = 0, and m = 0 or 1
25	Specific retapamulin compound
26	Selected compounds from the claim 7 list, generally with pharmaceutically acceptable salts

Claim 25 is the most commercially important narrow compound claim. It removes the Markush uncertainty associated with claim 1 and identifies a single retapamulin structure.

Claim 16 is also significant because it focuses on sulfur-linked derivatives with the shortest side chains. Retapamulin falls within this commercially important sulfur-linked subset.

What compounds are specifically listed in RE39128?

The individual-compound claims cover several families:

Quinuclidine derivatives

These include quinuclidin-3-yl and quinuclidin-4-yl derivatives linked through:

• sulfur;
• methylsulfur;
• oxygen;
• amino;
• carbonylamino;
• sulfoxide;
• sulfone;
• alkyl;
• alkenyl; and
• acrylate or propionate chains.

Tropane and related bicyclic amines

The claims identify compounds containing:

• 8-methyl-8-azabicyclo[3.2.1]oct-3-yl groups;
• endo and exo stereoisomers;
• azabicyclo[2.2.1]heptyl groups;
• azabicyclo[3.2.1]octyl groups; and
• azabicyclo[4.3.0]nonyl groups.

Pleuromutilin nucleus variants

The claim list includes:

• mutilin;
• 19,20-dihydromutilin;
• 1,2-didehydromutilin; and
• 2-alpha-hydroxymutilin.

This structure-specific coverage is broader than retapamulin alone. It was designed to protect a research and development series rather than only one clinical candidate.

What process claims does RE39128 contain?

Claims 8 and 9 cover methods for synthesizing the claimed pleuromutilin derivatives.

The process routes are based on two principal strategies.

Route one: acylation of protected mutilin

The first route couples mutilin or epi-mutilin, with the position-11 hydroxyl protected, to an activated derivative of a carboxylic acid having the required bicyclic amine substituent.

The activated acid may be an acid chloride or another reactive derivative. Subsequent steps may include:

• conversion of epi-mutilin to mutilin;
• removal of protecting groups;
• hydrogenation to produce the 19,20-dihydro analogue;
• hydroxylation at position 2; or
• dehydrogenation at positions 1 and 2.

Route two: substitution at the 14-position

The second route begins with a mutilin or epi-mutilin derivative having a functionalized 14-O-acyl group. A leaving group, hydroxyl group, or amino group is then reacted with the relevant:

• alcohol;
• thiol;
• amine;
• carboxylic acid; or
• acylating derivative.

Claim 9 specifies reaction classes for sulfur, oxygen, amino, amide, and ester linkages. These claims could be relevant to process infringement where a manufacturer uses the claimed coupling sequence, but they do not necessarily block every alternative process capable of making retapamulin.

What pharmaceutical formulations are protected by RE39128?

Claims 10 through 12 cover pharmaceutical compositions containing a claimed compound and a pharmaceutically acceptable carrier.

The claims expressly include:

• pharmaceutical compositions generally;
• nasal sprays;
• aqueous nasal sprays;
• topical compositions;
• ointments;
• creams; and
• lotions.

The formulation claims are platform claims. They do not recite the detailed excipient system, concentration, particle-size specification, preservative system, packaging configuration, or manufacturing parameters that often define later commercial formulation patents.

For Altabax, the commercially relevant product is a 1% topical ointment. Claim 17 covers topical administration, while claims 18 through 20 cover ointment, cream, and lotion forms. The claims therefore reach a retapamulin ointment in broad terms, but they do not necessarily cover every formulation-specific attribute of a generic product.

What method-of-use claims are included?

Claims 13 through 15 cover antibacterial and prophylactic uses.

Claim	Use
13	Treating bacterial infection
14	Reducing or eliminating nasal carriage of pathogenic organisms
15	Prophylaxis of recurrent otitis media or recurrent acute bacterial sinusitis
21	Treating bacterial infection of skin or soft tissue by topical administration
22	Gram-positive bacterial infection
23	Gram-negative bacterial infection
24	Mycoplasma infection

Claims 21 through 24 are particularly relevant to topical retapamulin. They require topical administration and cover bacterial infections of skin or soft tissue. Claims 22 and 23 extend the language to Gram-positive and Gram-negative organisms, while claim 24 identifies mycoplasma.

The FDA-approved Altabax indication is narrower than these patent claims. FDA approved retapamulin ointment for impetigo caused by susceptible S. aureus and S. pyogenes, not for every infection or prophylactic use stated in the patent.[2]

When did RE39128 lose exclusivity?

RE39128 has expired. A U.S. reissue patent does not receive a new 20-year patent term merely because the patent was reissued. The enforceable term is tied to the term of the original patent, subject to applicable patent-term adjustment or extension rules.[4]

The reissue therefore does not create current patent exclusivity for retapamulin. Any historical exclusivity associated with RE39128 ended before the present generic-entry analysis.

FDA regulatory exclusivity is separate from patent rights. Retapamulin’s original NDA approval occurred in 2007. Any five-year new chemical entity exclusivity and pediatric exclusivity associated with the product expired long before the current market date.[2,3]

What is the Orange Book status of retapamulin?

Altabax was approved under NDA 022108. The Orange Book historically listed patent information for the product, but RE39128 is no longer a live patent barrier.[3]

A current ANDA applicant would evaluate:

• whether the reference-listed drug remains active in the Orange Book;
• whether a listed patent remains unexpired;
• whether any later formulation or use patent is listed;
• whether the proposed label overlaps a patented method of use; and
• whether a Paragraph IV certification is necessary.

For an expired patent, a Paragraph IV challenge to RE39128 has no commercial value because the applicant does not need to defeat an enforceable patent to launch. A generic applicant would focus on any later, unexpired patents listed for the reference product or on non-patent regulatory requirements.

Which companies challenged or licensed retapamulin rights?

The principal commercial rights history involved GlaxoSmithKline and its dermatology business, including Stiefel. Almirall acquired Stiefel in 2016 and obtained rights to a portfolio of dermatology products, including products associated with the Stiefel business.[5]

The record for RE39128 should be distinguished from later commercial agreements. A license or asset transaction does not change the patent’s original claim scope, expiration date, or reissue status.

No biosimilar pathway applies. Retapamulin is a chemically synthesized small molecule, so a competing product would ordinarily use the ANDA pathway rather than the 351(k) biosimilar pathway.

How strong is the RE39128 patent estate?

Composition-claim strength

The estate was strong during its active term because it combined:

• a broad Markush genus;
• multiple dependent structural limitations;
• named individual compounds;
• a specific claim to retapamulin;
• pharmaceutically acceptable salt coverage; and
• related process and formulation claims.

Claim 25 was the clearest blocking claim for retapamulin. It avoided the need to prove that a commercial product fell within every alternative of the broad genus in claim 1.

Vulnerability of the genus claim

Claim 1 is more vulnerable than claim 25 because of its breadth. Potential attack points would include:

• lack of written description across the full genus;
• enablement of all combinations of R2, X, m, n, and nucleus substitutions;
• anticipation by earlier pleuromutilin derivatives;
• obviousness based on known pleuromutilin chemistry;
• indefiniteness arising from chemical terminology; and
• construction of the alternative RaRbC=CHCOO limitation.

The listed compounds and detailed synthetic examples would support the patent holder, but the strength of a broad Markush claim depends on the disclosure and prosecution history, not on the claim text alone.

Strength of the retapamulin claim

Claim 25 was commercially stronger because it identified one compound and its stereochemical configuration. A generic retapamulin product having the same active ingredient would have faced direct composition-claim exposure during the patent term, regardless of whether it used a different manufacturing process or different topical excipients.

Strength of formulation and method claims

Claims 10 through 12 and 17 through 20 are broad and potentially vulnerable to design-around strategies. A manufacturer could attempt to avoid literal infringement through:

• a different dosage form;
• a different route of administration;
• a non-ointment topical vehicle;
• a different active concentration;
• a different excipient system; or
• a label that omits patented uses.

Those strategies would not avoid a live compound claim covering retapamulin itself. They became commercially relevant only after composition protection expired or where no enforceable compound claim applied.

How does RE39128 compare with other pleuromutilin patents?

Product or class	Developer or holder	Main use	Relationship to RE39128
Retapamulin	GlaxoSmithKline/Stiefel and successors	Topical human antibacterial	Direct commercial subject of the patent
Lefamulin	Nabriva Therapeutics	Systemic human antibacterial	Separate pleuromutilin program and patent estate
Tiamulin	Veterinary pharmaceutical companies	Veterinary antibacterial	Older veterinary pleuromutilin; separate products and claims
Valnemulin	Veterinary pharmaceutical companies	Veterinary antibacterial	Separate veterinary derivative and patent history
Pleuromutilin intermediates	Multiple companies	Manufacturing and research	May create process or freedom-to-operate issues independent of RE39128

Lefamulin is the closest human therapeutic comparator by pharmacological class, but it is not a retapamulin substitute from a patent perspective. Lefamulin is administered systemically and has a separate development, regulatory, and patent history.[6]

What generic launch risks remain after RE39128 expiration?

RE39128 itself creates no current launch barrier. Residual risks may arise from:

1. Regulatory reference-product status. A generic applicant must satisfy FDA requirements for the applicable reference-listed drug and demonstrate pharmaceutical equivalence and bioequivalence where required.
2. Later formulation patents. A later patent could cover a specific ointment, excipient combination, manufacturing process, or stability profile.
3. Method-of-use patents. A later listed use patent could require a section viii statement or a Paragraph IV certification, depending on the approved labeling.
4. Trade secrets. Manufacturing know-how, impurity controls, crystallization, and process scale-up may remain commercially important even after patent expiration.
5. Supply-chain constraints. Retapamulin API production may require specialized pleuromutilin intermediates and controlled synthesis of the bicyclic amine side chain.
6. Commercial scale. The market may be limited by the size of the topical impetigo market and the availability of inexpensive topical antibacterial alternatives.

Key Takeaways

• RE39128 is a reissue patent covering semisynthetic pleuromutilin derivatives.
• Claim 25 specifically covers retapamulin, the active ingredient in Altabax.
• Claim 1 is a broad Markush genus covering multiple bicyclic amines, linkers, and pleuromutilin nucleus variants.
• Claims 8 and 9 cover selected manufacturing routes.
• Claims 10 through 12 cover pharmaceutical and nasal-spray compositions.
• Claims 17 through 20 cover topical formulations, including ointments, creams, and lotions.
• Claims 21 through 24 cover topical antibacterial treatment methods.
• The patent has expired. Reissue did not restart the patent term.
• Retapamulin is a small molecule, so biosimilar risk is irrelevant; generic risk is the applicable framework.
• A current generic entrant would focus on FDA Orange Book listings and any later unexpired formulation or method-of-use patents, not on RE39128 itself.

FAQs

Does RE39128 cover retapamulin salts?

The supplied claims include pharmaceutically acceptable salt language in the broad and selected-compound claims. The precise salt coverage depends on the applicable claim construction and the specific salt form.

Can a generic manufacturer avoid RE39128 by using a different ointment base?

During the active patent term, a different ointment base would not have avoided a claim directed to retapamulin as a compound. It could have affected formulation-claim exposure, but not direct infringement of a valid composition claim.

Is retapamulin protected by a biologic patent?

No. Retapamulin is a chemically synthesized small-molecule pleuromutilin. Its competition proceeds through generic-drug pathways, not biosimilar regulation.

Do the nasal-spray claims make RE39128 relevant to sinusitis products?

Historically, yes. Claims 11, 12, and 15 address nasal spray and recurrent sinusitis-related uses. Those claims do not establish that FDA approved retapamulin for sinusitis, and the patent has expired.

Does patent expiration eliminate all barriers to retapamulin competition?

No. Patent expiration removes the RE39128 exclusionary right. FDA approval requirements, manufacturing capability, supply of API, later patents, and commercial market conditions can still affect generic entry.

References

1. United States Patent and Trademark Office. (n.d.). U.S. Patent No. RE39,128, Pleuromutilin derivatives. https://patents.google.com/patent/USRE39128
2. U.S. Food and Drug Administration. (2007). Altabax (retapamulin) ointment prescribing information.
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
4. United States Code, 35 U.S.C. §§ 154, 251.
5. Almirall, S.A. (2016). Almirall completes acquisition of Aqua Pharmaceuticals from AstraZeneca and Stiefel assets from GSK.
6. U.S. Food and Drug Administration. (2019). Xenleta (lefamulin) prescribing information.

Drugs Protected by US Patent RE39128

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: RE39128

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 RE39128

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