Details for Patent: RE38743

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Summary for Patent: RE38743

Title:	Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events
Abstract:	Heterogeneous intimate admixtures of sulfated heparinic polysaccharides, well suited for the prophylaxis/treatment of acute thrombotic episodes in a human patient, comprise immixture of sulfated polysaccharides having a weight average molecular weight less than that of heparin and which include from 9% to 20% of polysaccharide chains having a molecular weight less than 2,000 daltons and from 5% to 20% of polysaccharide chains having a molecular weight greater than 8,000 daltons, the ratio between the weight average molecular weight and the number average molecular weight thereof ranging from 1.3 to 1.6.
Inventor(s):	Roger Debrie
Assignee:	Aventis Pharma SA
Application Number:	US10/430,435
Patent Claim Types: see list of patent claims	Use; Composition;

United States Drug Patent RE38743: Claim Scope, Expiration, Litigation Risk, and Parnaparin Patent Landscape

U.S. Patent RE38743 protected a low-molecular-weight heparin mixture corresponding to parnaparin sodium, including defined molecular-weight distribution, anti-Xa activity, purity, and manufacturing parameters. The reissue did not create a new patent term. The patent is expired, and it does not provide current U.S. exclusivity for parnaparin or an FDA-approved parnaparin product.

What drug does U.S. Patent RE38743 protect?

RE38743 covers a heterogeneous low-molecular-weight sulfated heparin mixture rather than a single molecular entity. The claimed profile is consistent with parnaparin sodium, commercially associated with the Fluxum product outside the United States.

The core product limitations are:

Parameter	Claimed range
Average molecular weight	Approximately 3,500-5,500 daltons
Chains below 2,000 daltons	9%-20%
Chains from 2,000-8,000 daltons	60%-86%
Chains above 8,000 daltons	5%-20%
Weight-average/number-average molecular-weight ratio	1.3-1.6
Dermatan sulfate	Less than 2% in dependent claims
Anti-Xa activity	About 90 IU in claim 4; about 100 IU/mg in claim 28
Source	Porcine or bovine heparin
Functional property	Bioavailability and antithrombotic activity greater than heparin

The patent therefore protects a defined molecular-weight distribution and impurity profile. It does not broadly cover every low-molecular-weight heparin.

The functional language requiring bioavailability and antithrombotic activity greater than heparin narrows the claim and creates potential evidentiary issues. A product may satisfy the structural parameters but still require proof that the claimed comparative biological performance is met.

What are the independent claims of RE38743?

The principal independent claims are claims 1, 7, 23, 24, 25, 27, 29, 30, 31, and 32.

Product claims

Claims 1 and 31 cover the heterogeneous sulfated polysaccharide admixture. Claim 1 uses "consisting essentially of," while claim 31 uses "comprising."

That distinction matters:

• Claim 1 excludes additional components that materially affect the basic and novel characteristics of the mixture.
• Claim 31 is potentially broader because it permits additional components, provided the claimed molecular-weight distribution and other limitations remain satisfied.
• Claim 31 expressly incorporates the less-than-2% dermatan sulfate limitation.
• Claim 32 combines the product limitations with a defined manufacturing process.

The central product claim is not merely a molecular-weight claim. It requires the interaction of:

1. Chain-distribution percentages.
2. Average molecular weight.
3. Polydispersity ratio.
4. Comparative biological performance.
5. In some claims, dermatan sulfate purity.
6. In some claims, anti-Xa activity.

Process claims

Claim 7 is the primary process claim. It requires:

1. Salifying heparin with a long-chain quaternary ammonium salt in an aqueous medium.
2. Esterifying the resulting salt to a 9.5%-14% degree of esterification.
3. Depolymerizing the ester.

Claims 8-22 add process controls involving:

• Chloroform or methylene chloride.
• Benzyl chloride.
• Benzethonium chloride.
• Temperature of 25-45°C for esterification.
• A heparin-to-benzyl-chloride-to-solvent ratio.
• Strong-base depolymerization.
• Base-to-ester ratio of 0.05-0.2.
• Water-to-ester ratio of 15-30.
• Depolymerization at 50-70°C for 30 minutes to three hours.
• Alcohol-precipitated starting heparin.

These claims are materially narrower than the product claims. A competitor could avoid direct infringement of claim 7 by using a different depolymerization chemistry, a different protecting group, enzymatic processing, oxidative cleavage, or another process that produces a non-infringing molecular-weight distribution.

How broad is the molecular-weight protection?

The molecular-weight limitations define the commercial identity of the claimed mixture.

The three chain fractions are not independent alternatives. They must collectively satisfy the claimed distribution:

• 9%-20% below 2,000 daltons;
• 60%-86% between 2,000 and 8,000 daltons; and
• 5%-20% above 8,000 daltons.

The ranges collectively allow some mathematical flexibility, but the claimed composition must still have an overall average molecular weight of approximately 3,500-5,500 daltons and a weight-average-to-number-average ratio of 1.3-1.6.

The claim language creates several potential design-around routes:

• Reduce the fraction below 2,000 daltons below 9%.
• Increase the fraction above 8,000 daltons above 20%.
• Shift the average molecular weight outside 3,500-5,500 daltons.
• Produce a polydispersity ratio below 1.3 or above 1.6.
• Exceed the dermatan sulfate limitation.
• Use a product that does not meet the comparative biological limitation.

Because low-molecular-weight heparins are heterogeneous mixtures, analytical methodology is important. Gel permeation chromatography, high-performance liquid chromatography, electrophoretic methods, anti-Xa testing, and impurity assays may produce different measurements. A patent dispute would likely focus on validated test methods, batch specifications, sampling, and whether the claim percentages are calculated by mass, number, or another convention.

What formulations are protected by RE38743?

Claims 27 and 30 cover therapeutic compositions containing the claimed polysaccharide mixture and a pharmaceutically acceptable carrier or diluent.

These claims do not appear to require a particular dosage form, container, preservative, stabilizer, route of administration, or injection device. They can therefore reach injectable compositions containing the claimed active mixture, subject to the product limitations.

The patent does not establish a separate formulation patent estate for:

• Prefilled syringes.
• Multidose vials.
• Specific concentrations.
• Particular excipients.
• Needle-safety systems.
• Autoinjectors.
• Packaging.
• Device combinations.

Those features would require separate patent claims. RE38743 is primarily a composition, process, and therapeutic-use patent.

What methods of use are protected?

Claims 24-26 and 29 cover therapeutic use.

Claim	Use
24	Prevention of thrombotic episodes
25	Prevention of postoperative venous thrombosis
26	Prevention in a human at risk of myocardial infarction
29	Treatment of thrombotic episodes

Claims 27 and 30 protect compositions for prevention and treatment, respectively.

The method claims are narrower than a general anticoagulant claim because they require administration of the claimed heterogeneous polysaccharide mixture. A product containing a different low-molecular-weight heparin would not fall within these claims merely because it is used for the same indication.

When did U.S. Patent RE38743 lose exclusivity?

RE38743 is expired. The reissue did not restart the patent term.

The patent was a reissue of an earlier U.S. patent, and the operative term was governed by the predecessor patent's statutory term. Under U.S. patent law, a reissue patent has the same enforceable term as the original patent and cannot extend the original patent's duration. 35 U.S.C. §§ 154, 251.

Public patent records identify the expiration of the RE38743 patent term as February 14, 2012. The patent therefore does not create a current U.S. blocking right against manufacture, importation, sale, or use of a qualifying parnaparin product. (U.S. Patent No. RE38,743, 2004; U.S. Patent No. 5,389,618.)

Event	Date or status
Original U.S. patent	U.S. Patent No. 5,389,618
Reissue patent	RE38,743
Reissue issue date	February 17, 2004
Patent-term endpoint	February 14, 2012
Current status	Expired
Current U.S. patent exclusivity	None from RE38743

Any later patent would need to be analyzed separately. RE38743 itself cannot support a current infringement action.

What is the Orange Book status of parnaparin and RE38743?

RE38743 is not an Orange Book patent for an FDA-approved parnaparin product.

The FDA Orange Book lists patents associated with approved drug applications. Parnaparin is not an FDA-approved U.S. drug product with an approved new drug application listed in the Orange Book. As a result:

• RE38743 is not an active Orange Book-listed patent for parnaparin.
• There is no current Orange Book expiration date tied to RE38743.
• There is no U.S. regulatory exclusivity period for parnaparin based on this patent.
• A generic sponsor would not use a Paragraph IV certification against RE38743 in an ANDA directed to an FDA-approved parnaparin reference product.

The absence of an FDA-approved reference product is a larger U.S. market barrier than the expired patent. A sponsor would need to establish an FDA regulatory pathway, product characterization, manufacturing controls, clinical or bridging evidence, and appropriate reference-product support.

Were there Paragraph IV challenges or U.S. litigation?

RE38743 is expired, so it no longer presents a viable basis for a current Paragraph IV challenge or patent injunction.

The supplied patent record does not establish a reported U.S. Paragraph IV litigation campaign, settlement agreement, or active infringement action involving RE38743. The expiration date also eliminates present-day litigation risk based solely on this patent.

A historical litigation search would need to distinguish:

• Litigation involving the original patent.
• Litigation involving the reissue.
• Product-liability or regulatory proceedings.
• Foreign litigation involving parnaparin or related low-molecular-weight heparins.
• Disputes involving later process, formulation, or manufacturing patents.

Those categories do not change the expired status of RE38743.

How does RE38743 compare with competing low-molecular-weight heparins?

RE38743 is narrower than a platform patent covering all low-molecular-weight heparins. It is directed to a specific heterogeneous mixture and preparation route.

Product	Active substance	General molecular-weight profile	U.S. regulatory position
Parnaparin	Low-molecular-weight heparin mixture	Approximately 3,500-5,500 daltons under the claimed profile	No established FDA-approved U.S. product
Enoxaparin	Low-molecular-weight heparin mixture	Distinct molecular and structural specifications	FDA-approved; generic competition exists
Dalteparin	Low-molecular-weight heparin mixture	Separate molecular-weight and activity profile	FDA-approved
Tinzaparin	Low-molecular-weight heparin mixture	Separate molecular-weight and activity profile	FDA-approved
Fondaparinux	Synthetic pentasaccharide	Single defined synthetic anticoagulant structure	FDA-approved; not a heparin mixture

The existence of approved enoxaparin, dalteparin, and tinzaparin products does not establish infringement of RE38743. Each product must be tested against the specific composition, impurity, molecular-weight, and process limitations.

Is there biosimilar risk for RE38743?

Traditional biosimilar analysis does not apply directly. Parnaparin is a complex polysaccharide mixture, not a protein biologic subject to the principal biosimilar framework under the Public Health Service Act.

The relevant competitive risk is a complex-generic or follow-on anticoagulant risk. The main barriers are:

• Batch-to-batch molecular-weight control.
• Source-animal material qualification.
• Viral and prion safety controls.
• Control of dermatan sulfate and other impurities.
• Reproducible anti-Xa and anti-IIa activity.
• Structural characterization of heterogeneous chains.
• Demonstration of pharmaceutical equivalence or appropriate clinical comparability.
• Establishment of a U.S. regulatory pathway.

These manufacturing and regulatory barriers may be commercially significant even though the RE38743 patent has expired.

What manufacturing and IP barriers remain?

The expired process claims do not block the use of their disclosed chemistry. They remain relevant as technical disclosure and as a benchmark for product quality, but they do not provide current patent exclusivity.

A modern competitor would still face non-patent barriers:

1. Reliable sourcing of pharmaceutical-grade porcine or bovine heparin.
2. Control of molecular-weight distribution after depolymerization.
3. Consistent anti-Xa potency.
4. Removal or control of dermatan sulfate.
5. Validation of analytical methods for heterogeneous polysaccharides.
6. Scale-up of esterification and depolymerization.
7. Regulatory qualification of animal-derived materials.
8. Demonstration of clinical comparability.

New patents could potentially protect later process improvements, purification systems, formulations, delivery devices, or analytical controls. Such patents would need separate identification and cannot be inferred from RE38743.

What is the commercial and licensing exposure?

RE38743 creates no current U.S. royalty or blocking exposure because it expired in 2012. Its historical commercial significance was tied to the composition and process associated with parnaparin, not to the broader low-molecular-weight heparin market.

The U.S. commercial opportunity is constrained by the absence of an established FDA-approved parnaparin reference product. The main current risks are regulatory development cost, manufacturing reproducibility, and market competition from approved anticoagulants rather than infringement liability under RE38743.

The supplied record does not establish an active license, settlement, or royalty obligation that remains enforceable after patent expiration.

Key Takeaways

• RE38743 covers a parnaparin-like low-molecular-weight heparin mixture.
• Its strongest protection is the combination of molecular-weight distribution, average molecular weight, polydispersity, impurity limits, and anti-Xa activity.
• Claims 7-22 protect a specific esterification and depolymerization process.
• Claims 24-30 cover thrombotic prevention, treatment, and related compositions.
• RE38743 expired on February 14, 2012.
• The reissue did not extend the original patent term.
• RE38743 is not a current Orange Book barrier.
• No current Paragraph IV challenge is required against an expired patent.
• Biosimilar terminology is not the best fit; parnaparin presents complex-polysaccharide generic and regulatory risks.
• Current U.S. barriers are regulatory, analytical, manufacturing, and commercial rather than patent-based.

FAQs About U.S. Patent RE38743 and Parnaparin

Is RE38743 still enforceable against a parnaparin manufacturer?

No. RE38743 expired on February 14, 2012 and cannot support a current infringement injunction or damages claim for post-expiration activity.

Does RE38743 cover enoxaparin?

Not automatically. Enoxaparin would need to satisfy every applicable limitation of an asserted claim, including the specified molecular-weight distribution, polydispersity, impurity, and functional requirements.

Can a company design around RE38743 by changing the depolymerization process?

Yes, in principle. A different process may avoid the process claims, although the resulting product would still need to be evaluated against the composition claims.

Is parnaparin eligible for an ANDA in the United States?

The patent does not determine eligibility. Because parnaparin lacks an established FDA-approved U.S. reference product, the sponsor would need to establish the appropriate FDA regulatory pathway rather than rely solely on an ordinary ANDA strategy.

Does the less-than-2% dermatan sulfate limitation apply to every claim?

No. It is expressly included in claims 2 and 31. It is not stated as an independent limitation in claim 1, although other claims may incorporate claim 1 and add separate limitations.

References

1. U.S. Patent and Trademark Office. (2004). U.S. Patent No. RE38,743: Low molecular weight heparins and process for preparing same.

2. U.S. Patent and Trademark Office. (1995). U.S. Patent No. 5,389,618: Low molecular weight heparins and process for preparing same.

3. United States Code. (2023). 35 U.S.C. § 154: Contents and term of patent; provisional rights.

4. United States Code. (2023). 35 U.S.C. § 251: Reissue of defective patents.

5. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.

6. U.S. Food and Drug Administration. (2024). Abbreviated new drug application submissions: Refuse-to-receive standards. FDA.

Drugs Protected by US Patent RE38743

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: RE38743

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
France	90 08013	Jun 26, 1990

International Family Members for US Patent RE38743

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	398976
Austria	A128191
Australia	643531
Australia	7928891