US Patent 5,981,589: Claim Scope, Glatiramer Acetate Coverage, Expiration, and Patent Landscape

US Patent 5,981,589 covers a defined form of copolymer-1, commonly known as glatiramer acetate, having a molecular weight of approximately 5 to 9 kilodaltons and produced through a specified deprotection and purification sequence. The patent is a product-by-process claim rather than a broad composition claim. Its practical value depended on whether a competing manufacturer’s glatiramer acetate product had the claimed molecular-weight range and was made using the recited chemical sequence.

The patent was associated with Teva’s Copaxone franchise. Its US term expired in 2015, eliminating current US blocking power. The claim remains relevant as a reference point for historical Paragraph IV litigation, generic development, and the technical distinction between Copaxone and later glatiramer acetate products.

What does US Patent 5,981,589 claim?

The central claim covers:

Copolymer-1.
A molecular weight of about 5 to 9 kilodaltons.
Manufacture from protected copolymer-1.
Treatment with hydrobromic acid to form trifluoroacetyl copolymer-1.
Treatment with aqueous piperidine to form copolymer-1.
Purification of the resulting copolymer-1.

The claim is materially narrower than a claim covering all glatiramer acetate. It combines a product limitation, molecular weight, with process limitations, the HBr deprotection step, aqueous piperidine treatment, and purification.

Claim element analysis

Claim element	Scope	Commercial significance
Copolymer-1	Covers the defined random polypeptide historically used in Copaxone	Excludes unrelated synthetic polypeptides
About 5 to 9 kDa	Establishes a molecular-weight window	Requires reliable analytical measurement and interpretation of “about”
Protected copolymer-1 starting material	Requires a protected intermediate	Relevant to manufacturing route and process records
Hydrobromic acid treatment	Requires conversion to trifluoroacetyl copolymer-1	Creates a process distinction from alternative deprotection routes
Aqueous piperidine treatment	Requires a particular deprotection or conversion condition	Potential design-around point
Purification	Requires purification after formation	Broad as written because no specific purification method is recited
Resulting product	Product must possess the claimed molecular-weight characteristic	Creates a product identity issue in infringement analysis

The patent does not claim a specific dosage, injection concentration, excipient system, syringe, administration schedule, or multiple-sclerosis treatment method in the quoted claim.

What is copolymer-1 and how does it relate to glatiramer acetate?

Copolymer-1 is the synthetic polypeptide mixture used as the active ingredient in glatiramer acetate products. It is generally described as a random polymer composed of L-glutamic acid, L-alanine, L-tyrosine, and L-lysine residues. The marketed drug is supplied as the acetate salt and administered by subcutaneous injection.

Glatiramer acetate is not a single molecular species. It is a heterogeneous mixture of polypeptide chains with variable sequence and molecular weight. That heterogeneity makes molecular-weight distribution, amino-acid composition, analytical characterization, and manufacturing history important to both regulatory equivalence and patent analysis.

US 5,981,589 does not claim every molecular-weight distribution of glatiramer acetate. Its express molecular-weight limitation is approximately 5 to 9 kDa. A product outside that range could avoid literal infringement, subject to the meaning of “about” and possible application of the doctrine of equivalents.

How broad is the molecular-weight limitation?

The phrase “about 5 to 9 kilodaltons” creates a range rather than a rigid numerical boundary. Its construction would depend on the patent specification, the analytical method, the relevant technical meaning of molecular weight, and the prosecution history.

Potential measurement issues include:

Number-average molecular weight versus weight-average molecular weight.
Gel permeation or size-exclusion chromatography methodology.
Calibration standards.
Whether the reported value is an average, distribution, or batch specification.
Whether the endpoints include 5.0 and 9.0 kDa.
Batch-to-batch variability inherent in random polypeptide synthesis.

A competitor’s product specification alone may not resolve infringement. Discovery would likely focus on certificates of analysis, validated analytical methods, manufacturing batch records, regulatory submissions, and the actual process used to make the active ingredient.

Because the claim uses “about,” a product nominally reported at slightly below 5 kDa or above 9 kDa could still present a claim-construction dispute. The patent holder would need to establish the technically meaningful tolerance supported by the patent and prosecution record.

Is claim 1 a product-by-process claim?

Yes. The claim identifies a product, copolymer-1 with a molecular weight of about 5 to 9 kDa, but defines it in part by the process used to make it.

US courts generally treat process language in a product-by-process claim as relevant to infringement. A product is not necessarily infringing merely because it has the same physical characteristics if it was made by a materially different process. The Federal Circuit has emphasized that product-by-process limitations can restrict the infringement inquiry even when the product itself is difficult to distinguish analytically from a product made by another route. See Abbott Laboratories v. Sandoz, Inc., 566 F.3d 1282 (Fed. Cir. 2009); Amgen Inc. v. F. Hoffmann-La Roche Ltd., 580 F.3d 1340 (Fed. Cir. 2009).

The precise effect depends on claim construction. The claim’s use of “made by a process comprising” is important because “comprising” is open-ended. A process that includes the HBr and aqueous piperidine steps may still fall within the claim even if it contains additional operations.

Likely infringement theories

A patent holder would likely examine four theories:

The accused product has a 5 to 9 kDa molecular weight and is manufactured using the claimed sequence.
The accused process uses equivalent reagents or conditions that satisfy the claim as construed.
The accused product is imported into the United States after being made by the claimed process abroad, implicating 35 U.S.C. § 271(g).
The accused product is made by a process equivalent to the claimed process under the doctrine of equivalents.

The process limitation also creates a significant evidentiary burden. Manufacturing steps are often confidential and may require discovery from the generic applicant or active-ingredient supplier.

What manufacturing route does US 5,981,589 protect?

The claimed route begins with protected copolymer-1. Hydrobromic acid is used to generate trifluoroacetyl copolymer-1, followed by aqueous piperidine treatment to remove the protecting group and form copolymer-1. The final material is purified to produce a product in the claimed molecular-weight range.

The protection is therefore directed to a combination of:

A protected polymer intermediate.
HBr-mediated conversion.
Piperidine-mediated deprotection.
Purification.
A resulting molecular-weight window.

The patent does not, based on the quoted claim, require a particular piperidine concentration, reaction temperature, reaction time, purification resin, dialysis protocol, precipitation method, or final formulation. Those omissions expand the literal process scope but also leave potential design-around opportunities.

Potential design-around approaches

A competitor could investigate:

A different protecting group.
A different acid or deprotection reagent.
A nonaqueous piperidine system.
A different sequence of deprotection operations.
A manufacturing route that does not form trifluoroacetyl copolymer-1.
A product outside the 5 to 9 kDa range.
A process that produces the same therapeutic mixture through a materially different intermediate.

A design-around must be assessed against the full patent family, later formulation patents, method-of-use patents, regulatory requirements, and the doctrine of equivalents. Avoiding US 5,981,589 alone would not necessarily clear the Copaxone estate.

When did US Patent 5,981,589 expire?

US Patent 5,981,589 expired in 2015 under its applicable US patent term. The expiration removed the patent as a current barrier to US generic entry.

The patent’s expiration must be distinguished from:

FDA drug exclusivity.
Other Copaxone patents.
Orange Book-listed formulation patents.
Method-of-use patents.
Patent term adjustments or terminal disclaimers affecting related patents.
Foreign counterparts with different expiration dates.

The patent no longer supports a new US infringement action against a current generic product based solely on ordinary post-expiration manufacture, sale, or use.

What was the Orange Book status of US 5,981,589?

US 5,981,589 was associated with the Copaxone product and appeared in the historical patent landscape for glatiramer acetate. Orange Book listing status is product- and dosage-specific, so the relevant record depends on the Copaxone strength and FDA application.

Orange Book listing does not establish validity or infringement. It gives an NDA holder a mechanism to identify patents that may be relevant to an abbreviated new drug application. A generic applicant may respond with:

Paragraph I certification: no patent information is listed.
Paragraph II certification: the patent has expired.
Paragraph III certification: the applicant will wait until expiration.
Paragraph IV certification: the patent is invalid, unenforceable, or not infringed.

For an expired patent, Paragraph II certification is the relevant pathway. During the patent’s active term, Paragraph IV challenges to Copaxone patents generated litigation and delayed or conditioned generic launch.

Which companies challenged the Copaxone patent estate?

The principal challengers to Teva’s Copaxone estate included:

Sandoz, a Novartis company.
Momenta Pharmaceuticals.
Mylan.
Watson Pharmaceuticals, later part of Actavis.
Other ANDA applicants pursuing generic glatiramer acetate.

Sandoz and Momenta commercialized Glatopa, a generic glatiramer acetate product. Mylan also entered the glatiramer acetate market. The litigation generally involved multiple Copaxone patents, not US 5,981,589 in isolation.

The most commercially important disputes concerned later patents covering dosing regimens, formulations, and 40 mg/mL administration schedules. Those patents extended practical protection after earlier composition and manufacturing patents expired.

What patent litigation affected Copaxone and glatiramer acetate?

The central litigation pattern was Teva’s effort to enforce its Copaxone patent estate against ANDA applicants. The disputes addressed:

Whether generic glatiramer acetate infringed.
Whether the patents were invalid for anticipation or obviousness.
Whether the claims were sufficiently enabled and definite.
Whether later patents validly covered three-times-weekly dosing.
Whether formulation claims were distinct from the earlier active-ingredient claims.

Important appellate authority involving the broader Copaxone estate includes Teva Pharmaceuticals USA, Inc. v. Sandoz, Inc., 789 F.3d 1335 (Fed. Cir. 2015), and related district-court proceedings. The later 40 mg/mL disputes were commercially significant because the 40 mg/mL, three-times-weekly product became a major replacement for the original 20 mg/mL daily regimen.

Settlements and launch arrangements varied by applicant and patent. A settlement resolving particular patents did not necessarily remove other patents from the estate or establish that US 5,981,589 was valid and infringed.

How does US 5,981,589 compare with later Copaxone patents?

Patent category	Typical subject matter	Commercial role
Early composition patents	Copolymer-1 composition and use	Foundational product protection
US 5,981,589	5 to 9 kDa copolymer-1 made through HBr and aqueous piperidine processing	Manufacturing and product-by-process protection
Formulation patents	Injectable preparations, concentrations, excipients, stability	Protected commercial presentation
Method-of-use patents	Multiple-sclerosis treatment and dosing	Extended market protection
40 mg/mL regimen patents	Three-times-weekly administration	Supported lifecycle management
Device or presentation patents	Syringes, packaging, delivery systems	Narrower secondary barriers

The most important commercial patents after the early composition patents generally concerned the 40 mg/mL formulation and three-times-weekly regimen. US 5,981,589 was technically important but did not by itself protect the full commercial product lifecycle.

What was the competitive and revenue impact?

Copaxone was one of Teva’s largest products before generic erosion. Global Copaxone sales exceeded $4 billion annually at their peak, according to Teva annual reports. Sales declined materially after generic glatiramer acetate entry and the shift from the original 20 mg/mL daily regimen toward lower-cost generic products and the 40 mg/mL three-times-weekly market [Teva Pharmaceutical Industries Ltd., 2014, 2018].

The commercial exposure associated with US 5,981,589 was therefore substantial when the patent was active. Its expiration alone did not explain the entire revenue decline. The larger drivers were:

Expiration of multiple early Copaxone patents.
ANDA approvals.
Generic substitution.
Competitor access to the 40 mg/mL market.
Teva’s reliance on later formulation and dosing patents.
The absence of biosimilar regulation as the primary US entry pathway.

Did biosimilar risk apply to glatiramer acetate?

Glatiramer acetate is a synthetic polypeptide drug, not a conventional biologic manufactured through a biological expression system. Generic applicants generally pursued the ANDA pathway rather than the biosimilar pathway under the Public Health Service Act.

The FDA treated glatiramer acetate as a complex generic product requiring substantial analytical and pharmacologic characterization. The regulatory challenge was demonstrating sameness or therapeutic equivalence for a heterogeneous mixture, not establishing biosimilarity under section 351(k).

The principal competitive risk was therefore generic substitution, not a conventional biosimilar launch.

What is the current patent strength of US 5,981,589?

Current US patent strength is zero as an exclusionary right because the patent expired in 2015. Historical strength was moderate and technically focused.

Strengths

Defined a specific molecular-weight range.
Included a detailed chemical manufacturing sequence.
Could support discovery into confidential manufacturing records.
Covered a commercially relevant form of copolymer-1.
Potentially applied to imported active ingredient made by the claimed process.

Weaknesses

Did not broadly claim all glatiramer acetate.
Depended on proving the claimed manufacturing route.
Created analytical disputes over molecular weight.
Did not cover dosage, formulation, device, or administration schedule in the quoted claim.
Was vulnerable to alternative synthetic routes.
Expired before current generic competition matured.

What generic launch risks existed under the patent?

Before expiration, a generic applicant faced three primary risks:

Process discovery risk. The applicant’s manufacturing route could be exposed through ANDA certification and litigation discovery.
Molecular-weight risk. Batch data could place the product within the 5 to 9 kDa range.
Estate risk. Avoiding US 5,981,589 would not avoid later Copaxone patents covering formulation or dosing.

After expiration, the specific patent no longer presented launch risk. The remaining risk shifted to other active patents, regulatory exclusivity, manufacturing know-how, and commercial substitution dynamics.

What geographic coverage did the patent provide?

US 5,981,589 provided protection in the United States only. Foreign counterparts, if granted, required separate validity, term, and infringement analysis in each jurisdiction.

Geographic risk depended on:

Whether the patent was granted in the target country.
Local product-by-process law.
Local treatment of imported products.
National patent-term calculations.
Local Orange Book equivalents.
Regulatory approval and substitution rules.

A US expiration did not automatically terminate foreign rights.

Key Takeaways

US 5,981,589 covers copolymer-1, or glatiramer acetate, in an approximately 5 to 9 kDa molecular-weight range.
The claim requires a process involving HBr treatment, formation of trifluoroacetyl copolymer-1, aqueous piperidine treatment, and purification.
It is a narrow product-by-process claim, not a broad claim to all glatiramer acetate.
Molecular-weight measurement and confidential manufacturing records would be central to infringement analysis.
The patent expired in 2015 and has no current US exclusionary effect.
Historical Copaxone litigation involved this patent together with formulation, dosage, method-of-use, and 40 mg/mL regimen patents.
Generic glatiramer acetate entered through the ANDA pathway, not the conventional biosimilar pathway.
The principal commercial challengers included Sandoz, Momenta, Mylan, and Watson/Actavis.
Current competitive barriers depend on later patents, regulatory status, manufacturing capability, and market substitution rather than US 5,981,589.

FAQs

Does US 5,981,589 cover Copaxone 40 mg/mL?

Not by the quoted claim alone. The claim covers copolymer-1 with a molecular weight of approximately 5 to 9 kDa and a specified manufacturing process. It does not recite a 40 mg/mL concentration or three-times-weekly dosing.

Can a company infringe the patent with a different deprotection reagent?

Literal infringement would be less likely if the process does not include the claimed HBr and aqueous piperidine steps. The doctrine of equivalents could still be relevant, depending on prosecution history and the technical function of the substituted reagents.

Is glatiramer acetate a biologic for FDA patent purposes?

It is regulated as a complex synthetic drug product and has generally entered through the ANDA pathway. It is not ordinarily treated as a conventional biologic requiring a section 351(k) biosimilar application.

Does expiration of US 5,981,589 clear all Copaxone patent risk?

No. Expiration clears the specific patent only. Other patents may have covered formulations, injection concentrations, delivery systems, dosing schedules, or methods of treating multiple sclerosis.

Can a product outside 5 to 9 kDa avoid infringement?

It may avoid literal infringement of the express molecular-weight limitation, but the interpretation of “about,” the measurement method, and the doctrine of equivalents can affect the analysis.

References

Abbott Laboratories v. Sandoz, Inc., 566 F.3d 1282 (Fed. Cir. 2009).

Amgen Inc. v. F. Hoffmann-La Roche Ltd., 580 F.3d 1340 (Fed. Cir. 2009).

Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services. https://www.accessdata.fda.gov/scripts/cder/ob/

Teva Pharmaceutical Industries Ltd. (2014). Annual report 2014. https://ir.tevapharm.com/

Teva Pharmaceutical Industries Ltd. (2018). Annual report 2018. https://ir.tevapharm.com/

Teva Pharmaceuticals USA, Inc. v. Sandoz, Inc., 789 F.3d 1335 (Fed. Cir. 2015).

United States Patent and Trademark Office. (1999). United States Patent No. 5,981,589: Copolymer-1 having a molecular weight of about 5 to 9 kilodaltons. https://patents.google.com/patent/US5981589

United States Patent and Trademark Office. (2024). Patent term adjustment and patent term information. https://www.uspto.gov/patents/laws/patent-term-adjustment-patent-term-extension-reinstatement

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0762888	⤷ Start Trial	90987	Luxembourg	⤷ Start Trial
European Patent Office	0762888	⤷ Start Trial	C300096	Netherlands	⤷ Start Trial
European Patent Office	0762888	⤷ Start Trial	C300251	Netherlands	⤷ Start Trial
Austria	212857	⤷ Start Trial
Australia	1016102	⤷ Start Trial
Australia	2004202245	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,981,589

Summary for Patent: 5,981,589