United States Drug Patent RE37035: Claim Scope, Repaglinide Coverage, Expiration, and Patent Landscape

US Reissue Patent RE37,035 is the core composition-of-matter patent covering repaglinide and a broad family of related benzoic-acid derivatives. Claims 1-7 define the chemical genus and progressively narrow it. Claims 8-13 identify individual compounds, including repaglinide-related structures and crystalline forms. Claim 14 covers the S-enantiomer across the preceding claims. Claim 15 covers pharmaceutical compositions containing a claimed compound.

The patent was reissued from US Patent 5,312,924. Its commercial relevance was principally tied to Prandin, Novo Nordisk's repaglinide product. The US patent term, including the applicable patent-term adjustment or extension reflected in FDA patent records, ended in 2012. RE37,035 no longer blocks US generic repaglinide entry.

What drug does US RE37035 protect?

RE37,035 protects repaglinide and structurally related insulin secretagogues in the meglitinide class.

Repaglinide is the active ingredient in:

Prandin tablets;
generic repaglinide tablets; and
Prandimet, the repaglinide/metformin combination product, although combination-product protection involved separate patent and regulatory issues.

The repaglinide structure corresponds to the compound identified in claim 9:

2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoic acid.

The marketed active moiety is generally identified as the S-enantiomer of repaglinide. Claim 14 expressly narrows the earlier claims to the S-enantiomer and its salts.

The patent is a small-molecule composition patent, not a biologic patent. Biosimilar provisions under the Biologics Price Competition and Innovation Act do not apply. Any follow-on product is regulated through the abbreviated new drug application pathway for generics.

What is the patent history of US RE37035?

Item	Detail
Reissue patent	US RE37,035
Original patent	US 5,312,924
Patent subject	Benzoic-acid derivatives, pharmaceutical compositions, and hypoglycemic use
Commercial compound	Repaglinide and related analogs
Original assignee lineage	Boehringer Mannheim group, later associated with the Novo Nordisk commercial program
Reissue date	2001
Principal product	Prandin
US regulatory approval	Prandin NDA approved in 1997
US patent-term end	2012, as reflected in FDA Orange Book patent records
Current blocking effect	None for ordinary US generic repaglinide entry

A reissue patent does not create a new statutory patent term. The reissue corrected or restated patent rights associated with the original patent; it did not reset the expiration clock.

How broad are claims 1 through 7?

Claims 1 through 7 use a nested Markush structure. Each dependent claim removes chemical alternatives and increases structural specificity.

Claim 1: broad chemical genus

Claim 1 covers compounds having:

an aromatic core bearing the relevant substituted benzamide side chain;
R1 as a four- to six-carbon cyclic amino group, including piperidino-type systems;
R2 as hydrogen, halogen, methyl, or methoxy;
R3 as a broad range of alkyl, aryl, substituted alkyl, alkenyl, alkynyl, carboxy, or alkoxycarbonyl groups;
R4 as hydrogen, methyl, ethyl, or allyl; and
W as a broad range of alkyl, hydroxymethyl, formyl, carboxyl, ester, nitrile, and substituted carbon-chain groups.

The claim also reaches:

enantiomers;
diastereomers;
racemic mixtures;
non-toxic base salts where W is carboxyl; and
acid-addition salts at the cyclic amino group.

Claim 1 is therefore a compound genus claim with substantial substituent breadth. Its commercial significance depends on whether a specific product falls within the claimed scaffold and substitution pattern, not merely whether it has hypoglycemic activity.

Claim 2: defined ring and substituent options

Claim 2 narrows R1 to named cyclic amines, including:

pyrrolidino;
piperidino;
3-methylpiperidino;
4-methylpiperidino;
3,3-dimethylpiperidino;
3,5-dimethylpiperidino; and
hexamethyleneimino groups.

R2 is limited to hydrogen, fluorine, or chlorine. Claim 2 retains numerous R3 and W alternatives, making it a substantial intermediate genus.

Claim 3: piperidino subgroup

Claim 3 is more commercially relevant because it limits:

R1 to piperidino;
R2 to hydrogen;
R3 to selected alkyl, alkenyl, phenyl, tetrahydropyranylmethyl, cyclopropylmethyl, or cyclohexylmethyl groups;
R4 to methyl, ethyl, or allyl; and
W to carboxyl, methoxycarbonyl, ethoxycarbonyl, or cyanomethyl.

This claim captures the structural neighborhood containing repaglinide.

Claim 4: carboxylic-acid subgroup

Claim 4 narrows W to carboxyl and limits R3 principally to:

C3-C6 alkyl;
C3-C4 alkenyl;
phenyl;
cyclopropylmethyl; or
cyclohexylmethyl.

This claim is directed to the free-acid compounds and their permitted salts.

Claims 5 through 7: increasingly specific alkyl series

Claim 5 identifies selected C3-C6 alkyl and cycloalkylmethyl analogs. Claim 6 lists specific R3 groups, including n-propyl, n-butyl, isobutyl, sec-butyl, n-pentyl, and cyclohexylmethyl. Claim 7 further focuses on the straight and branched alkyl series, excluding some alternatives present in claim 6.

These claims are important because they provide fallback positions if the broader genus were challenged for written description, enablement, novelty, or obviousness.

Which claims cover repaglinide?

Repaglinide is principally covered by claim 9 and the claims from which it depends.

Claim	Relationship to repaglinide
Claim 1	Broad genus covering the underlying chemical architecture
Claim 3	Narrower piperidino and carboxylic-acid subgroup
Claim 4	Selected alkyl, alkenyl, aryl, and cycloalkylmethyl acid analogs
Claim 5	Includes the 3-methylbutyl substitution pattern
Claim 6	Identifies the relevant branched-butyl series
Claim 7	Includes the 3-methylbutyl-related alkyl class to which repaglinide belongs
Claim 9	Specifically identifies repaglinide's principal constitutional structure
Claim 14	Covers the S-enantiomer of claim 9
Claim 15	Covers a hypoglycemic pharmaceutical composition containing a claim 1 compound

The strongest product-specific protection is in claim 9, read with claim 5 and the applicable enantiomer language in claim 14. Claims 10-12 separately address solid-state forms of the compound identified in claim 9.

What do claims 8 through 13 protect?

Claim 8: n-butyl analog

Claim 8 covers:

2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]benzoic acid.

This is a specific analog with an unbranched butyl substituent at the chiral center. It is distinct from the 3-methylbutyl structure of repaglinide.

Claim 9: repaglinide-related compound

Claim 9 covers:

2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoic acid.

This is the key individual-compound claim for repaglinide. It includes the enantiomers and mixtures, salts, and acid-addition salts described in the claim.

Claims 10-12: crystalline or solid-state forms

Claims 10, 11, and 12 identify forms A, B, and C of the compound in claim 9 by recrystallization solvent and melting point.

Claim	Form	Recrystallization	Reported melting point
10	Form A	Acetone/petroleum ether	90-92°C
11	Form B	Ethanol/water	140-142°C
12	Form C	Methanol	74-85°C

These claims are narrower than the parent compound claim. A commercial product would infringe them only if the material supplied or administered had the claimed solid-state characteristics and the claim construction treated those characteristics as defining limitations.

The forms are not formulation claims. They do not claim a tablet, excipient system, dissolution profile, coating, or manufacturing process. They are product-form claims directed to specific physical forms of the active ingredient.

Claim 13: cyclohexylmethyl analog

Claim 13 covers a separate individual compound containing an alpha-cyclohexylmethyl substituent. It is a chemical analog, not repaglinide itself.

What does claim 14 add?

Claim 14 covers the S-enantiomer of a compound in claims 1 through 13, together with applicable salts.

This claim is commercially important because repaglinide activity and product identity are associated with the S-enantiomer. Enantiomer claims can be more valuable than racemic claims where:

the marketed product contains a single stereoisomer;
the stereoisomer has superior pharmacology or safety;
the original disclosure supports the specific stereochemical form; and
the generic applicant seeks to market the same stereochemical active ingredient.

Claim 14 does not independently cover every S-enantiomer in the abstract. It depends on the compounds defined by the earlier claims.

What does claim 15 protect?

Claim 15 covers a hypoglycemic pharmaceutical composition consisting essentially of:

an inert pharmaceutical carrier; and
an effective hypoglycemic amount of a claim 1 compound.

The phrase "consisting essentially of" generally permits conventional components that do not materially alter the claimed invention, while excluding material ingredients that would change the basic character of the composition.

Claim 15 is broad at the functional level but remains tethered to a compound within claim 1. It does not expressly require:

a particular tablet strength;
a specific excipient;
a specific dissolution rate;
immediate release;
modified release;
a particular dose regimen; or
a specific indication beyond hypoglycemic activity.

It is weaker as a standalone formulation claim than a claim directed to a defined excipient matrix or manufacturing process.

What patents protected repaglinide beyond RE37035?

The repaglinide estate included later patents directed to formulation, combination therapy, and product-specific or regulatory uses. The relevant categories were:

Patent category	Typical subject matter	Commercial relevance
Composition of matter	Repaglinide and analogs	Primary protection; RE37,035
Stereochemistry	S-enantiomer	Supports marketed active ingredient
Solid state	Polymorphic or crystalline forms	Potential process and product defenses
Formulation	Tablets and excipient systems	Can delay or complicate generic substitution
Combination therapy	Repaglinide with metformin	Relevant to Prandimet
Method of use	Glycemic control and dosing	Relevant only to labeled or induced-use theories

Public FDA records identified additional Prandin and Prandimet-related patents, including US 6,143,769 and US 6,750,238. Those later patents should be analyzed separately because their claims, expiration dates, Orange Book status, and products differ from RE37,035. A later formulation or combination patent would not revive the expired composition patent.

What was the Orange Book status of RE37035?

RE37,035 was listed in FDA Orange Book records for repaglinide products during the period when Prandin faced generic competition.

The legal effect of an Orange Book listing was product-specific:

a Paragraph IV certification could trigger a 30-month stay if the NDA holder or patent owner filed suit within the statutory period;
a Paragraph III certification could defer approval until patent expiration;
a patent listing did not itself prove infringement or validity; and
an expired listing no longer created a Hatch-Waxman approval bar.

For repaglinide, the principal composition patent protection expired in 2012. Subsequent generic approvals demonstrate that the expired RE37,035 patent was no longer a durable barrier to ordinary generic repaglinide tablets.

When did repaglinide lose US exclusivity?

Repaglinide lost practical US market exclusivity in stages.

Event	Approximate timing
Prandin FDA approval	1997
Initial branded exclusivity period	Expired before composition-patent expiry
Core composition patent term	Ended in 2012
Generic repaglinide entry	2012 period
Current status	Generic competition established

The key distinction is between FDA regulatory exclusivity and patent exclusivity. FDA exclusivity controls the timing of ANDA approval in specific circumstances. Patent expiry controls whether a valid listed patent remains an approval or litigation barrier. Neither form of exclusivity remains an obstacle for ordinary US repaglinide products.

Were there Paragraph IV challenges and settlements?

Repaglinide was subject to the normal ANDA challenge environment for an aging small-molecule product. Generic applicants could certify that listed patents were invalid, unenforceable, or not infringed under Paragraph IV.

The principal strategic issue was whether an applicant could:

challenge the broad composition patent;
carve out patented uses;
avoid later formulation or combination patents;
market repaglinide tablets after the core patent expired; or
rely on a Paragraph III certification for later-expiring listed patents.

No continuing US market-exclusion effect remains from RE37,035. Any historical Paragraph IV litigation or settlement must be evaluated against the specific defendant, NDA product, patent claims, and agreement date. A settlement involving a later Prandimet or formulation patent would not establish continuing enforceability of RE37,035.

How strong was the patent estate?

Composition protection

The estate was strong during its effective term because claims 1-7 created multiple fallback layers around the same scaffold, while claims 8, 9, and 13 identified individual compounds.

Product-specific protection

Claims 9 and 14 were more commercially significant than the broad genus claims because they mapped closely to repaglinide and its S-enantiomer.

Solid-state protection

Claims 10-12 could have supported a crystallinity or polymorph position, but their scope was materially narrower. They required the relevant form and did not automatically cover every repaglinide tablet.

Formulation protection

Claim 15 was broader than a conventional narrow formulation claim but required a claimed chemical compound and an effective hypoglycemic amount. Later patents were more likely to carry formulation-specific value.

Current strength

The current enforceability value of RE37,035 is effectively zero because the US patent term has ended. Its historical strength remains relevant to:

prior-art analysis;
freedom-to-operate opinions for earlier development periods;
patent prosecution history;
validity comparisons with later repaglinide patents; and
due diligence concerning historical generic settlements.

What generic entry risks existed?

During the protected period, a generic applicant faced four principal risks:

Direct composition infringement. A product containing repaglinide could fall within claims 9 and 14.
Stereochemical infringement. The marketed S-enantiomer could create direct exposure under claim 14.
Solid-state infringement. A generic using one of the claimed forms could face claims 10-12.
Later patent exposure. Formulation or combination-product patents could remain relevant after the core compound patent expired.

After 2012, the first risk disappeared for US commercial launch. Remaining risks depended on separate, later patents and the precise product configuration.

How does RE37035 compare with competing diabetes-drug patents?

Product	Drug class	Patent type	Biosimilar risk
Repaglinide	Meglitinide	Small-molecule composition, stereochemical, formulation, combination	None
Nateglinide	Meglitinide	Small-molecule composition and formulation	None
Metformin	Biguanide	Older small-molecule and formulation patents	None
Sulfonylureas	Insulin secretagogues	Mostly expired small-molecule estates	None
Insulin analogs	Biologic	Composition, formulation, device, method patents	Biosimilar or interchangeable-biologic pathway may apply

Repaglinide's main competitive weakness was not biosimilar substitution. It was the relatively mature small-molecule market, low generic manufacturing barriers, and competition from metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 products, and insulin therapies.

What manufacturing and geographic barriers remain?

RE37,035 did not claim a manufacturing process in the claims provided. It therefore did not create a process-specific manufacturing barrier after expiration.

The patent's geographic effect was also jurisdiction-specific:

US protection depended on the US original and reissue patents;
European protection depended on corresponding national or European patents;
other jurisdictions required separate validity and expiration analysis;
US expiration did not automatically terminate foreign rights; and
foreign rights would have been affected by local patent-term rules, supplementary protection certificates, and national prosecution history.

For current US generic supply, practical barriers are more likely to involve API quality, impurity controls, bioequivalence, manufacturing scale, and regulatory compliance than RE37,035.

Key Takeaways

RE37,035 is the reissue of US 5,312,924 and the principal historical composition patent for repaglinide.
Claim 1 covers a broad Markush genus of substituted benzoic-acid derivatives.
Claims 3-7 narrow the genus to piperidino compounds and selected alkyl or cycloalkylmethyl analogs.
Claim 9 identifies the repaglinide constitutional structure.
Claim 14 covers the S-enantiomer, which is commercially relevant to the marketed drug.
Claims 10-12 cover three specified solid-state forms.
Claim 15 covers a hypoglycemic composition containing a claim 1 compound.
The US patent term ended in 2012, so RE37,035 is no longer a generic-entry barrier.
Repaglinide is a small molecule and has no biosimilar pathway exposure.
Later formulation and combination patents, particularly those associated with Prandin or Prandimet, required separate analysis.
Current US commercial risk centers on later patents, regulatory compliance, and manufacturing economics rather than RE37,035.

FAQs

Is RE37035 still enforceable against generic repaglinide?

No. The US patent term ended in 2012. The patent remains relevant as a historical document but does not currently block ordinary US generic repaglinide marketing.

Does claim 9 cover the active ingredient in Prandin?

Yes. Claim 9 identifies the repaglinide-related compound corresponding to the active pharmaceutical ingredient used in Prandin, subject to the claim's stereochemical and salt language.

Are claims 10, 11, and 12 separate repaglinide polymorph patents?

They are dependent claims to specified forms of the compound in claim 9. They are narrower solid-state claims, not independent broad polymorph patents covering every crystalline or amorphous form.

Could a generic avoid RE37035 by using a repaglinide salt?

Not during the patent term if the salt fell within the claim language. The claims expressly address non-toxic salts where W is carboxyl and acid-addition salts at the amino function. The issue is moot for current US entry because the patent has expired.

Does RE37035 cover repaglinide manufacturing processes?

The claims provided do not claim a manufacturing process. They principally claim compounds, stereoisomers, salts, solid-state forms, and a pharmaceutical composition.

References

U.S. Patent and Trademark Office. (1994). U.S. Patent No. 5,312,924: Benzoic acid derivatives, process for their preparation and their use as medicaments.
U.S. Patent and Trademark Office. (2001). U.S. Reissue Patent No. RE37,035: Benzoic acid derivatives, process for their preparation and their use as medicaments.
U.S. Food and Drug Administration. (1997). Prandin (repaglinide) tablets: Initial approval package and prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Orange Book.
U.S. Patent and Trademark Office. (2024). Patent Center and Patent Examination Data System records for U.S. Patent Nos. 5,312,924, RE37,035, 6,143,769, and 6,750,238.
Novo Nordisk A/S. (Various years). Annual reports and product-history disclosures concerning repaglinide and Prandin.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	3347565	Dec 30, 1983
Germany	3522604	Jun 25, 1985
Germany	3523466	Jul 01, 1985

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0147850	⤷ Start Trial	SPC/GB98/042	United Kingdom	⤷ Start Trial
European Patent Office	0147850	⤷ Start Trial	99C0002	Belgium	⤷ Start Trial
Austria	44027	⤷ Start Trial
Austria	52255	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: RE37035