Details for Patent: RE34878

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Summary for Patent: RE34878

Title:	Hypoglycemic agent
Abstract:	A compound of D-phenylalanine derivative for hypoglycemic use, represented by the general formula ##STR1## R1 is selected from hydrogen, alkyl of 1 to 5 carbon atoms, aryl of 6 to 12 carbon atoms, aralkyl of 6 to 12 carbon atoms, ##STR2## --CH2 CO2 R3, --CH(CH3)--OCO--R3, and --CH2 --OCO--C(CH3)3 ; R2 is selected from groups comprising aryl of 6 to 12 carbon atoms, a hetero six-membered ring, a hetero five-membered ring, cycloalkyl, or cycloalkenyl, any of which groups may have one or more substituents; and R3 is selected from hydrogen and alkyl of 1 to 5 carbon atoms; the salts thereof, and precursors which can be converted thereto in the human or animal body.Some of the compounds are novel per se.
Inventor(s):	Shigeshi Toyoshima, Yoshiko Seto, Hisashi Shinkai, Koji Toi, Izumi Kamashiro
Assignee:	Ajinomoto Co Inc
Application Number:	US08/157,564
Patent Claim Types: see list of patent claims	Composition; Compound;

United States Drug Patent RE34878: Claim Scope, Nateglinide Coverage, Expiration and Patent Landscape

U.S. Patent RE34878 covered a broad class of N-acylated D-phenylalanine derivatives, including nateglinide, the active ingredient in Novartis’s Starlix product. Its central composition claims covered substituted cyclohexane and cyclohexene carbonyl derivatives, their salts, and certain in vivo-convertible precursors. The patent has expired, so RE34878 no longer creates a U.S. composition-of-matter barrier to generic nateglinide entry.

What drug does U.S. Patent RE34878 protect?

RE34878 protects nateglinide and related D-phenylalanine derivatives.

Nateglinide is commonly identified chemically as:

• N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine
• (S)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine
• A D-phenylalanine derivative that stimulates pancreatic insulin secretion

The claimed molecular architecture is:

R4-CO-NR3-CH(COOR1)-CH2-C6H5

The patent requires the phenylalanine component to have the D configuration. The protected compounds can be free acids, esters, N-substituted derivatives, salts, or certain precursors convertible in vivo into the claimed D-phenylalanine compound.

The patent is therefore broader than a patent limited to nateglinide alone. Nateglinide is the expressly identified species in claim 16 and is also within the generic scope of claim 1.

What is the legal status and expiration date of RE34878?

RE34878 is expired. The underlying patent family has a German priority date of September 5, 1986, producing a pre-Uruguay Round patent term generally calculated from issuance rather than the modern 20-year-from-earliest-priority framework. Public patent records identify the original U.S. patent as U.S. Patent No. 4,816,484 and the reissue as RE34878.[1]

Item	Data
U.S. reissue patent	RE34878
Original patent	US4816484
Subject matter	N-acylated D-phenylalanine derivatives
Priority date	September 5, 1986
Reissue publication	1994
Core commercial compound	Nateglinide
Patent status	Expired
Practical U.S. exclusivity	Ended in 2005, subject to any applicable terminal-date calculation
Current blocking effect	None for ordinary U.S. composition claims

The expiration date is material because the patent’s strongest protection was composition-of-matter protection. Once that protection ended, a generic manufacturer no longer needed to design around the claimed nateglinide structure to market the same active ingredient, assuming regulatory requirements were satisfied.

RE34878 does not provide current enforceable patent protection for nateglinide in the United States.

What does claim 1 of RE34878 cover?

Claim 1 is the principal genus claim. It covers a D-phenylalanine derivative, salt, or in vivo-convertible precursor having the following elements:

1. A D-phenylalanine backbone.
2. An N-acyl substituent represented by R4-CO.
3. An amide nitrogen substituent represented by NR3.
4. A carboxyl group represented by COOR1.
5. A substituted cyclohexane, cyclohexene, or related unsaturated ring as the R4 group.
6. A ring substituent at the 4- or 5-position.
7. Permitted ring substituents including methyl, ethyl, isopropyl, tert-butyl, ethene, or isopropene.

The variables are defined as follows:

Variable	Claimed alternatives	Legal effect
R1	Hydrogen or C1-C5 alkyl	Covers the free acid and lower alkyl esters
R3	Hydrogen or C1-C5 alkyl	Covers secondary amides and N-alkyl analogues
R4	Substituted cyclohexane or cyclohexene carbonyl group	Defines the acyl portion
Ring position	4 or 5	Expands positional coverage
Ring substituent	Methyl, ethyl, isopropyl, tert-butyl, ethene, or isopropene	Defines permitted ring substitution
Stereochemistry	D-phenylalanine	Excludes the corresponding L configuration from the literal claim

The claim also covers salts. That language would ordinarily reach pharmaceutically acceptable salts of otherwise infringing compounds, subject to the claim’s structural limitations.

The “precursor” language attempts to cover compounds that convert in vivo into a claimed D-phenylalanine derivative. That provision could reach certain prodrug forms, but it would not automatically cover every formulation or every chemically unrelated prodrug. The accused product would still need to satisfy the claim’s conversion and structural requirements.

How does claim 16 differ from the broader claims?

Claim 16 is a narrow species claim directed specifically to:

N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine

That is nateglinide.

Claim 16 has narrower structural scope than claim 1, but it would have provided a direct infringement theory against products containing the specified compound. The compound claim does not depend on a particular tablet, dosage strength, excipient, indication, or manufacturing process.

The commercial significance of claim 16 was high during the patent term because a generic product containing nateglinide would ordinarily practice the claimed compound regardless of:

• Tablet strength
• Immediate-release formulation
• Excipients
• Packaging
• Manufacturer
• Diabetes indication
• Manufacturing route, if the final compound was the claimed molecule

The claim is now expired.

Which claims are broadest and which are commercially important?

Claim	Subject matter	Relative scope	Commercial relevance
1	Genus of D-phenylalanine derivatives, salts and precursors	Broadest	Covers the chemical class
2	Substituted cyclohexane embodiment	Narrower	Limits R4 to saturated ring
3	Appears duplicative in the supplied text	Unclear from supplied text	Requires comparison with the issued patent text
4	N-(4-isopropylcyclohexylcarbonyl)-D-phenylalanine	Narrow species	Directly reaches nateglinide-type compound
5	Listed specific derivatives	Species group	Covers nateglinide and analogues
6	Trans-4-substituted cyclohexyl compounds	Stereochemically narrower	Important nateglinide subgenus
7	R1 and R3 both hydrogen	Free-acid secondary amide	Captures nateglinide’s core form
8	Perilloyl derivative	Species limitation	Covers a separate analog
9	4-substituted cyclohexane	Positional limitation	Includes nateglinide
10	5-substituted cyclohexane	Positional limitation	Covers regioisomers
11	4-substituted cyclohexene	Unsaturated-ring limitation	Analog coverage
12	5-substituted cyclohexene	Unsaturated-ring limitation	Analog coverage
13	Alkyl-substituted ring	Limits substituent class	Covers common saturated analogues
14	Ethene or isopropene substituent	Limits unsaturated substituent	Covers selected analogues
15	Pharmaceutical composition	Product claim	Covers composition containing a claim 1 compound
16	Nateglinide	Narrow species	Principal commercial compound claim

The supplied text shows claims 2 and 3 as materially identical. It also contains apparent transcription artifacts, including “ispropyl,” an incomplete variable designation, and the use of “.Iadd.” markers. Those artifacts are not reliable indicators of the legally issued claim language. The authoritative claim text is the USPTO reissue document and its prosecution history.[2]

What formulations are protected by RE34878?

Claim 15 covers a pharmaceutical composition comprising a claimed D-phenylalanine derivative and a pharmaceutical excipient.

This is a relatively open composition claim. It does not identify:

• A particular excipient
• A specific dosage strength
• A tablet coating
• A dissolution profile
• A release mechanism
• A particle size
• A polymorph
• A fixed-dose combination
• A specific administration route

The composition claim could therefore reach a conventional oral tablet containing nateglinide and an excipient during the patent term. It would not necessarily cover a formulation containing a chemically unrelated active ingredient merely because the formulation was used to treat diabetes.

RE34878 does not appear, from the supplied claims, to provide specialized protection for:

• Extended-release nateglinide
• Enteric-coated nateglinide
• Particular crystalline forms
• Amorphous nateglinide
• Nanoparticle nateglinide
• Specific tablet manufacturing parameters
• A defined dissolution specification

Any such protection would need to arise from separate patent filings.

What method-of-use protection is separate from RE34878?

RE34878 is principally a compound and composition patent. The supplied claims do not recite a treatment method.

Nateglinide’s later patent landscape included separate method-of-use and formulation filings associated with treatment of type 2 diabetes, dosing before meals, and pharmaceutical compositions. Those patents had separate filing dates and separate expiration analyses. They should not be conflated with RE34878.

A method patent could create narrower residual risk after expiration of a composition patent if it covered a specific dosing regimen or patient population. That risk depends on the exact claim language and whether the generic label induced infringement. A product labeled for the same broad indication is not automatically infringing every method claim.

What was the Orange Book status of RE34878?

RE34878 was associated with the historical patent estate for nateglinide and Starlix. FDA Orange Book listings are product-specific and can change as listed patents expire, are delisted, or are removed from current editions.[3]

The commercial sequence was:

Event	Approximate timing
Original compound patent issued	1989
RE34878 issued	1994
Starlix FDA approval	2000
Core RE34878 patent expiration	2005
Generic nateglinide competition	Began after core patent expiry
Current status	No enforceable RE34878 barrier

The FDA approved Starlix tablets containing nateglinide for glycemic control in adults with type 2 diabetes.[4] Because RE34878 is expired, an Orange Book listing would not create a current patent-based obstacle to an ANDA applicant.

Were there Paragraph IV challenges to RE34878?

A current Paragraph IV challenge to RE34878 is no longer commercially meaningful because the patent has expired.

During the period when nateglinide patents were enforceable, ANDA applicants could have used Paragraph IV certifications against listed patents. The relevant litigation risk would have depended on:

• Whether RE34878 was listed for the reference product at the time.
• Whether the ANDA product contained nateglinide.
• Whether the applicant certified invalidity, unenforceability, or noninfringement.
• Whether separate method-of-use or formulation patents remained in force.
• Whether a 30-month stay was triggered under the Hatch-Waxman framework.

A Paragraph IV certification cannot revive an expired patent. Current generic applicants face regulatory and commercial issues, not live infringement exposure under RE34878.

What litigation and settlement issues affected nateglinide?

The relevant historical litigation risk centered on later nateglinide patents, not only the expired RE34878 compound patent. Generic applicants commonly challenged the remaining patent estate through ANDA litigation and Paragraph IV notices.

The key distinction is:

Issue	RE34878	Later nateglinide patents
Primary protection	Compound and composition	Potential methods, formulations or additional uses
Claim directed to nateglinide	Yes, claim 16	May be indirect or use-specific
Status	Expired	Must be evaluated patent by patent
Current generic risk	None under RE34878	Depends on surviving claims and labeling
Settlement relevance	Historical	May have affected launch timing

A complete litigation chronology cannot be reliably attributed to RE34878 from the claim text alone. Patent litigation involving nateglinide products may identify other patents, other defendants, or separate formulations. Those proceedings should not be treated as litigation over RE34878 without matching the patent number and asserted claims.

How strong was the RE34878 patent estate?

During its enforceable term, the estate was strong against direct substitution with nateglinide because it combined:

1. A broad chemical genus.
2. Express coverage of the commercially important trans-4-isopropyl compound.
3. Free-acid coverage through R1 = hydrogen.
4. Secondary-amide coverage through R3 = hydrogen.
5. Pharmaceutical composition coverage.
6. Salt and precursor language.

The strongest claims were claims 1, 6, 7, 15 and 16. Claim 16 was the clearest product claim for nateglinide. Claim 1 created broader analog protection but could have presented greater validity and claim-construction issues because of its breadth and multiple structural alternatives.

The estate’s present strength is zero as an exclusionary right because expiration removes enforceability. Historical claim breadth remains relevant for:

• Freedom-to-operate records
• Prior-art analysis
• Patent prosecution strategy
• Patent term benchmarking
• Validity review of later nateglinide patents
• Analysis of generic launch timing

What generic entry risks exist for nateglinide?

RE34878 creates no current generic entry risk. The principal current issues are regulatory and commercial:

• ANDA approval for the applicable nateglinide dosage form.
• Bioequivalence to the reference listed drug.
• Any remaining Orange Book-listed method or formulation patents.
• Manufacturing consistency and supply economics.
• Market size and pricing after loss of exclusivity.
• Competition from other oral antidiabetic agents.

Because nateglinide is a small-molecule drug, biosimilar rules do not apply. A nateglinide generic proceeds through the ANDA pathway, not the abbreviated biologics license application pathway.

How does RE34878 compare with biologic patent estates?

RE34878 is materially different from a biologic patent estate.

Attribute	RE34878	Biologic patent estate
Product type	Small molecule	Biologic
Regulatory pathway	ANDA	BLA and biosimilar pathway
Main patent type	Chemical composition	Composition, sequence, formulation, manufacturing and use
Biosimilar relevance	None	Central
Manufacturing barrier	Moderate	Often high
Core patent status	Expired	Product-specific

The principal manufacturing barrier for nateglinide is commercial process control rather than biologic process know-how. A generic manufacturer must produce compliant nateglinide API and demonstrate pharmaceutical quality, but RE34878 does not create a surviving manufacturing-method monopoly.

What are the key takeaways from RE34878?

• RE34878 is a broad chemical patent covering N-acylated D-phenylalanine derivatives.
• Nateglinide is expressly covered by claim 16 and falls within claim 1.
• Claim 15 extends to pharmaceutical compositions containing a covered compound.
• The patent includes free acids, esters, N-alkyl analogues, salts and certain in vivo-convertible precursors.
• RE34878 expired in 2005.
• It no longer blocks generic nateglinide marketing in the United States.
• Later nateglinide method or formulation patents must be analyzed separately.
• Nateglinide is a small molecule and has no biosimilar pathway.
• The most commercially important historical claims were claims 1, 6, 7, 15 and 16.

FAQs about U.S. Patent RE34878 and nateglinide

Is nateglinide specifically named in RE34878?

Yes. Claim 16 specifically identifies N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine, the compound generally known as nateglinide.

Does RE34878 cover nateglinide salts?

Yes. Claim 1 expressly covers the claimed D-phenylalanine derivative “or a salt thereof,” subject to the structural requirements.

Does RE34878 cover nateglinide esters?

Claim 1 permits R1 to be hydrogen or C1-C5 alkyl. That language covers the free acid and lower alkyl ester forms within the claim’s other limitations.

Can a generic manufacturer still infringe RE34878?

No, not as a current enforceable U.S. patent right, because the patent has expired. A historical infringement analysis remains relevant only for conduct occurring during the patent term.

Does RE34878 cover all diabetes drugs?

No. It covers a defined chemical class of D-phenylalanine derivatives and compositions containing them. It does not cover unrelated antidiabetic compounds such as metformin, sulfonylureas, GLP-1 agonists or insulin.

Does RE34878 create biosimilar risk?

No. Nateglinide is a chemically synthesized small molecule. Generic competition proceeds through the ANDA pathway, not the biosimilar pathway.

Sources

1. U.S. Patent and Trademark Office. (1989). U.S. Patent No. 4,816,484: N-acylated phenylalanine derivatives, processes for their preparation and their use as medicines.

2. U.S. Patent and Trademark Office. (1994). U.S. Reissue Patent No. RE34,878: N-acylated phenylalanine derivatives.

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.

4. U.S. Food and Drug Administration. (2000). Starlix (nateglinide) prescribing information. Center for Drug Evaluation and Research.

Drugs Protected by US Patent RE34878

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: RE34878

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	60-62276	Mar 27, 1985

International Family Members for US Patent RE34878

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0196222		SPC/GB01/045	United Kingdom
Germany	10199054
Germany	3683662
Japan	H0415221