Details for Patent: 5,317,016

Summary for Patent: 5,317,016

Title:	Pyrrolidylthiocarbapenem derivative
Abstract:	A pyrrolidylthiocarbapenem derivative represented by Formula I is provided: ##STR1## wherein R1 is hydrogen or lower alkyl; R2, R3 and R4 are hydrogen, lower alkyl which can be substituted or an amino protecting group independently, or R2 and R3 together with a nitrogen atom to which R2 and R3 are bonded form a saturated or unsaturated cyclic group, or R2 and R4, or R3 and R4 together with two nitrogen atoms and one sulfur atom in the sufamide group form a saturated or unsaturated cyclic group; each cyclic group can further include at least one atom selected from the group consisting of oxygen, sulfur and nitrogen, and each cyclic group can be substituted; X1 is hydrogen or a hydroxy protecting group; X2 is hydrogen, a carboxy protecting group, an ammonio group, an alkali metal or an alkaline-earth metal; and Y2 is hydrogen or an amino protecting group.
Inventor(s):	Yasuhiro Nishitani, Tadashi Irie
Assignee:	SHIONGI SEIYAKU KK , Shionogi and Co Ltd
Application Number:	US07/929,961
Patent Claim Types: see list of patent claims	Use;

US Drug Patent 5,317,016: Scope, Claims, Doripenem Relevance, and Patent Landscape

US Patent No. 5,317,016 covers a broad genus of pyrrolidylthiocarbapenem derivatives, including the carbapenem antibiotic doripenem and closely related intermediates, protected derivatives, salts, and formulations. The patent issued on May 31, 1994, and its ordinary pre-URAA term would have ended on May 31, 2011. The patent received patent-term extension associated with doripenem, with the FDA Orange Book listing an expiration date of November 2, 2014.[1][2]

The strongest commercial claims are claims 1, 4, 5, and 11. They cover the active carbapenem structure, selected substituent patterns, the unprotected active form, and the stereochemical configuration of the pyrrolidine ring. Claims 12 through 15 cover antibacterial compositions containing the compounds. Claim 16 covers antibacterial-use methods.

What drug does US Patent 5,317,016 protect?

US 5,317,016 is principally associated with doripenem, marketed in the United States as Doribax. Doripenem is a 1-beta-methyl carbapenem with a substituted pyrrolidine-thio side chain and was approved by the FDA for selected serious bacterial infections in 2007.[2][3]

The patent is not limited to doripenem by name. Its independent composition claim covers a chemically broad genus defined through Formula I and variable substituents R1 through R4, X1, X2, and Y2.

Item	Description
Patent	US 5,317,016
Title	Pyrrolidylthiocarbapenem derivatives
Grant date	May 31, 1994
Principal technology	Pyrrolidylthiocarbapenem antibacterial compounds
Commercial drug associated with patent	Doripenem
US brand	Doribax
FDA approval	2007
Standard patent expiration	May 31, 2011
Listed PTE expiration	November 2, 2014
Product type	Small-molecule antibacterial
Biosimilar pathway	Not applicable
Primary regulatory pathway	Abbreviated New Drug Application for generics

The patent’s commercial value came from its composition coverage rather than from a narrow product-by-name claim. A compound that falls within Formula I and satisfies the specified stereochemical and substituent limitations can infringe claim 1 even if it is not identified as doripenem in the patent.

What is the scope of claim 1 of US 5,317,016?

Claim 1 is a genus claim covering pyrrolidylthiocarbapenem derivatives represented by Formula I. It defines the core carbapenem scaffold and permits substantial variation in the side-chain and protecting-group architecture.

The claim has six principal structural control points:

1. R1 may be hydrogen or lower alkyl.
2. R2, R3, and R4 may be hydrogen, substituted or unsubstituted lower alkyl, or amino-protecting groups.
3. R2 and R3 may jointly form a cyclic group with the attached nitrogen.
4. R2 and R4, or R3 and R4, may jointly form a ring involving two nitrogen atoms and one sulfur atom in the sulfamide group.
5. X1 may be hydrogen or a hydroxy-protecting group.
6. X2 may be hydrogen, a carboxy-protecting group, ammonium, an alkali metal, or an alkaline-earth metal.

The claim also permits cyclic groups containing oxygen, sulfur, or nitrogen and allows those rings to be substituted. This language materially expands the genus beyond one marketed compound.

What chemical subject matter falls within claim 1?

Claim 1 potentially covers four commercial and synthetic categories:

Category	Examples under the claim
Active drug forms	Free-acid carbapenems and alkali-metal salts
Protected intermediates	Silyl-protected hydroxyl groups and protected carboxyl groups
Protected amino derivatives	Boc, allyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, and diazo-related protection
Cyclic sulfamide derivatives	Saturated or unsaturated ring systems involving R2-R4 and the sulfamide atoms

The inclusion of protected intermediates is significant. A generic manufacturer could potentially encounter claim coverage during synthesis even if the final active pharmaceutical ingredient were outside a narrower product claim. A complete freedom-to-operate analysis therefore must examine manufacturing intermediates, not only the final drug substance.

How do dependent claims narrow the patent?

Claims 2 through 11 progressively narrow the broad genus.

Claim	Principal limitation	Commercial or legal relevance
2	R1 is methyl	Captures the 1-beta-methyl carbapenem subclass associated with doripenem
3	R4 is hydrogen	Narrows the sulfamide substitution pattern
4	X1 and Y2 are hydrogen; X2 is hydrogen or alkali metal	Targets unprotected active drug and salt forms
5	Specific R2/R3 patterns	Covers hydrogen, methyl, dimethyl, and 2-hydroxyethyl combinations
6	R2 and R4 form an ethylene bridge	Covers a constrained cyclic sulfamide structure
7	R2 and R4 form a propylene bridge	Covers a larger cyclic sulfamide structure
8	Specified amino-protecting groups	Covers protected synthetic intermediates
9	Specified hydroxy-protecting groups	Covers trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl derivatives
10	Specified carboxy-protecting groups and salts	Covers sodium, potassium, tert-butyl, allyl, p-nitrobenzyl, p-methoxybenzyl, and diphenylmethyl forms
11	(3S,5S) pyrrolidine configuration	Defines the key stereochemical configuration

Claims 4, 5, and 11 have the clearest relevance to doripenem because they combine the 1-methyl carbapenem, unprotected active form, selected sulfamide substitution, and the (3S,5S) pyrrolidine configuration.

What is the significance of the stereochemical limitation in claim 11?

Claim 11 requires the pyrrolidine ring to have the (3S,5S) configuration. This is a meaningful limitation because carbapenem antibacterial activity depends heavily on three-dimensional structure.

An accused compound with the same constitution but a different pyrrolidine stereochemistry would not literally satisfy claim 11. It could still fall within claim 1 if claim 1 does not independently require the (3S,5S) configuration. The difference creates a claim-selection issue:

• Claim 1 provides broader genus coverage.
• Claim 11 provides narrower stereochemical coverage.
• Claims 12 through 15 may incorporate the relevant composition limitations through dependency.
• Claim 16 uses claim 1 as its compound reference and therefore does not automatically require the claim 11 stereochemistry.

This structure gives the patent layered protection. Invalidity or noninfringement of the narrow stereochemical claim would not necessarily eliminate the broader genus claim.

What formulations are protected by US 5,317,016?

The patent claims antibacterial agents comprising an effective amount of a claimed pyrrolidylthiocarbapenem derivative. Claims 12 through 15 are composition claims, but they are not detailed pharmaceutical formulation claims.

They do not expressly require:

• A particular vial or container;
• A specified concentration;
• A particular pH;
• A defined buffer system;
• A stabilizer;
• A lyophilized cake;
• A reconstitution solvent;
• A particular injection route; or
• A specific excipient combination.

The composition claims may cover a pharmaceutical antibacterial composition containing a claimed compound, but later formulation patents could provide narrower protection for stability, lyophilization, reconstitution, dosing, or intravenous administration. US 5,317,016 should therefore be classified as a compound and broad antibacterial-composition patent, not as a detailed formulation patent.

Does claim 16 cover a method of treatment?

Claim 16 covers a method for inhibiting growth of bacteria sensitive to the claimed compound by contacting the bacterium with an effective amount of the compound.

The claim is drafted as an antibacterial-use method rather than as a conventional human method-of-treatment claim. Its operative elements are:

1. A bacterium sensitive to the compound;
2. Contact between the bacterium and the compound; and
3. An effective amount of the compound.

The claim does not expressly specify:

• Human administration;
• A disease indication;
• A dose;
• A dosing interval;
• Intravenous administration;
• A patient population; or
• A treatment duration.

This language can be relevant to infringement analysis involving in vitro testing, antimicrobial susceptibility testing, manufacturing controls, and therapeutic use. Direct infringement of a method claim generally depends on performance of every required step. Regulatory approval alone does not establish infringement, although a proposed generic label can be relevant to inducement analysis.

When did US 5,317,016 lose exclusivity?

The patent’s ordinary term ended in 2011, but the patent received term extension linked to the regulatory approval of doripenem.

Exclusivity event	Date
Patent grant	May 31, 1994
Ordinary 17-year expiration	May 31, 2011
Doripenem FDA approval	2007
Five-year new chemical entity exclusivity	Approximately 2012
Listed patent-term-extension expiration	November 2, 2014

The patent-term extension was more important than the five-year NCE exclusivity because the extension maintained patent-based exclusion after the ordinary patent expiration date. After November 2, 2014, US 5,317,016 no longer blocked generic entry on its own.[1][2]

The exact commercial launch date for a generic depended on other listed patents, regulatory review, Paragraph IV litigation, settlements, and the applicant’s product-specific approval status.

What was the Orange Book status of US 5,317,016?

US 5,317,016 was listed in the FDA Orange Book for Doribax, the doripenem injection product. The listing identified the patent as relevant to the approved product and carried a patent expiration date reflecting the patent-term extension.[2]

The Orange Book listing had three practical consequences:

• An ANDA applicant had to address the listed patent.
• A Paragraph IV certification could trigger statutory patent litigation.
• A timely patent lawsuit could impose a 30-month stay of approval under the Hatch-Waxman framework.

The listing did not mean that every doripenem formulation or manufacturing process was covered by every claim. Orange Book listing is a regulatory notice mechanism, not an adjudication of claim scope or validity.

Which companies challenged doripenem exclusivity?

Publicly reported doripenem competition centered on generic ANDA activity after the core patent-term extension expired. The principal commercial rights holders included Shionogi and its US commercialization partners, while generic competition developed through the ANDA pathway.

No biosimilar challenge applies. Doripenem is a chemically synthesized small molecule, so competitors file ANDAs rather than biosimilar applications under section 351(k) of the Public Health Service Act.

For US 5,317,016 specifically, the key legal point is timing. A Paragraph IV challenge filed before November 2, 2014 could have confronted the patent-term-extended listing. A post-expiration ANDA would generally face no enforceable exclusion from this patent, although the applicant could still need to address other listed patents or regulatory requirements.

What patent litigation affects US 5,317,016?

The relevant litigation risk would have arisen from an ANDA applicant making one of four certifications:

• Paragraph I: no patent information was filed;
• Paragraph II: the patent had expired;
• Paragraph III: the applicant would wait until expiration; or
• Paragraph IV: the patent was invalid, unenforceable, or would not be infringed.

For this patent, Paragraph IV risk was concentrated before November 2, 2014. After that date, litigation concerning US 5,317,016 would generally have limited commercial value unless it involved damages for pre-expiration activity or a dispute over the accuracy of the patent-term-extension date.

A generic applicant could have pursued several noninfringement positions:

• The final compound falls outside Formula I.
• The pyrrolidine ring has a different configuration.
• The R2-R4 or R3-R4 ring arrangement does not satisfy the claim.
• The product lacks the required 1-methyl substitution.
• The product does not contain the claimed salt or protecting-group form.
• The accused process does not make or use a claimed intermediate.
• The proposed label does not induce performance of claim 16.

Potential invalidity positions would include written description, enablement, anticipation, obviousness, indefiniteness, and double patenting. The breadth of claim 1 creates the principal validity pressure. The narrower claims may be more defensible structurally but provide less coverage.

How strong is the patent estate for doripenem?

The patent estate was strong during the period when US 5,317,016 remained enforceable because it combined broad composition coverage with narrower fallback claims.

Strengths

• Broad genus coverage in claim 1;
• Specific coverage for 1-methyl carbapenems;
• Protection for the (3S,5S) pyrrolidine configuration;
• Coverage of active forms, salts, and protected intermediates;
• Composition claims covering antibacterial agents;
• Method coverage for bacterial growth inhibition;
• Regulatory patent-term extension linked to doripenem.

Weaknesses

• The patent is an early-generation composition patent with a broad Markush structure.
• Broad genus claims can face written-description and enablement challenges.
• Claims 12 through 15 do not define a detailed commercial formulation.
• Claim 16 lacks detailed dosing or disease limitations.
• The patent expired, including its extension, in 2014.
• Later generic applicants could design around selected dependent claims while challenging only the broadest relevant claim.

The estate’s current value is historical rather than exclusionary. The patent may remain relevant to diligence concerning pre-expiration conduct, historical licensing, litigation reserves, and patent-family development, but it does not provide current US market exclusivity.

What licensing deals affected doripenem commercialization?

Doripenem was developed by Shionogi and commercialized in the United States through a partnership structure involving Peninsula Pharmaceuticals and Johnson & Johnson’s Ortho-McNeil organization. The commercial arrangement gave the US product a separate licensing and commercialization history from the underlying patent ownership.[3][4]

Licensing analysis should distinguish among:

• Ownership of US 5,317,016;
• Rights to develop doripenem;
• Rights to commercialize Doribax in the United States;
• Rights to supply the active ingredient;
• Rights to use manufacturing know-how; and
• Rights to prosecute or settle patent litigation.

A license to commercialize Doribax would not necessarily transfer ownership of the patent or control over patent enforcement.

What generic launch scenarios existed for doripenem?

The principal launch scenarios were:

Scenario	Consequence
Paragraph III certification before patent expiration	Approval deferred until the applicable expiration date
Paragraph IV certification before November 2, 2014	Potential patent suit and 30-month stay
ANDA filed after patent expiration	US 5,317,016 no longer independently delays approval
Design-around product	Reduced exposure to narrower dependent claims
Alternative manufacturing route	Could avoid process or intermediate claims in later patents
Post-expiration approval delayed by regulatory review	Commercial entry may occur after patent expiry for non-patent reasons

Because doripenem is an injectable carbapenem, commercial entry also depends on sterile manufacturing capacity, validated aseptic processing, supply reliability, hospital contracting, and demand in the hospital anti-infective market. Those barriers are commercial and manufacturing barriers, not continuing exclusivity under US 5,317,016.

How does US 5,317,016 compare with a modern generic patent strategy?

US 5,317,016 uses a classic early pharmaceutical strategy:

1. Broad chemical genus;
2. Preferred substituent subclasses;
3. Stereochemical limitation;
4. Protected intermediates;
5. Active pharmaceutical compositions; and
6. Antibacterial-use methods.

Modern portfolios often divide these functions across multiple patents covering:

• The active ingredient;
• Crystalline or amorphous forms;
• Hydrates and solvates;
• Injectable formulations;
• Stability systems;
• Manufacturing processes;
• Purification methods;
• Dosing regimens; and
• Specific clinical indications.

The 1994 patent is broad in chemical scope but comparatively limited in formulation detail. Its commercial protection depended heavily on the strength of the compound claims and regulatory patent-term extension.

What is the current geographic coverage?

US 5,317,016 provides US rights only. Equivalent protection would have depended on separately granted national patents and the applicable patent terms in each jurisdiction.

The international landscape for doripenem could include:

• Japanese priority and national filings;
• European patent protection;
• Other national patents in major pharmaceutical markets;
• Separate formulation and process patents;
• Regulatory exclusivity under each jurisdiction’s local framework.

Expiration dates cannot be assumed to match the US date. Patent term, supplementary protection certificates, pediatric extensions, terminal disclaimers, and national prosecution history must be assessed country by country.

Key Takeaways

• US 5,317,016 is a broad pyrrolidylthiocarbapenem composition patent associated with doripenem.
• Claim 1 covers a wide Markush genus, including active compounds, salts, protected forms, and structurally constrained sulfamide derivatives.
• Claims 2 through 7 narrow the genus toward 1-methyl and selected cyclic or acyclic substituent patterns.
• Claim 11 requires the (3S,5S) pyrrolidine configuration.
• Claims 12 through 15 cover antibacterial compositions, but they do not provide detailed formulation protection.
• Claim 16 covers bacterial-growth inhibition using a claimed derivative.
• The patent issued May 31, 1994.
• Its ordinary expiration was May 31, 2011.
• The FDA-listed patent-term-extension expiration was November 2, 2014.
• Doripenem is a small molecule, so biosimilar risk does not apply.
• Current US exclusivity cannot be based on US 5,317,016.
• Later generic risk depends on other patents, ANDA certifications, manufacturing capability, and regulatory approval timing.

FAQs

Was US 5,317,016 the basic compound patent for doripenem?

Yes. It is the principal early US compound patent associated with doripenem and covers a broad genus that includes the marketed active ingredient.

Did US 5,317,016 cover meropenem?

The claims are directed to pyrrolidylthiocarbapenem derivatives with specific sulfamide and pyrrolidine structures. Meropenem has a different side-chain architecture and is not treated as the principal commercial compound covered by this patent.

Could a generic manufacturer avoid US 5,317,016 by changing the salt?

Potentially, but only if the resulting compound falls outside all relevant claims. Claim 10 expressly covers several salts and protected carboxyl forms, while claim 1 includes hydrogen, ammonium, alkali-metal, and alkaline-earth-metal options.

Did the patent protect doripenem manufacturing processes?

It protects certain protected derivatives and intermediates through claims 8 through 10. Those claims are not equivalent to a comprehensive process patent and do not necessarily cover every manufacturing route.

Is US 5,317,016 still relevant to a doripenem freedom-to-operate review?

Yes, for historical infringement, pre-expiration activity, licensing diligence, and patent-family analysis. It does not create current US market exclusivity because its listed term ended in 2014.

References

1. United States Patent and Trademark Office. (1994). Pyrrolidylthiocarbapenem derivatives (U.S. Patent No. 5,317,016).

2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations (Orange Book), Doribax (doripenem).

3. U.S. Food and Drug Administration. (2007). FDA approves Doribax for treatment of certain serious bacterial infections.

4. Shionogi & Co., Ltd. (2007). Doripenem development and commercialization materials.

Drugs Protected by US Patent 5,317,016

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: 5,317,016

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	3-207972	Aug 20, 1991
Japan	4-35366	Feb 21, 1992

International Family Members for US Patent 5,317,016

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0528678		CA 2009 00003	Denmark
European Patent Office	0528678		91519	Luxembourg
European Patent Office	0528678		300374	Netherlands
European Patent Office	0528678		09C0005	France
European Patent Office	0528678		SPC/GB09/006	United Kingdom
European Patent Office	0528678		C00528678/01	Switzerland