Details for Patent: 6,028,071

Summary for Patent: 6,028,071

Title:	Purified compositions of 10-propargyl-10-deazaaminopterin and methods of using same in the treatment of tumors
Abstract:	PCT No. PCT/US97/11982 Sec. 371 Date Mar. 8, 1999 Sec. 102(e) Date Mar. 8, 1999 PCT Filed Jul. 16, 1997 PCT Pub. No. WO98/02163 PCT Pub. Date Jan. 22, 1998Highly purified 10-propargyl-10-deazaaminopterin (10-propargyl-10dAM) compositions tested in xenograft models for their efficacy against human tumors are shown to be far superior to methotrexate ("MTX") and are even superior to the newer clinical candidate edatrexate ("EDX"). Moreover, 10-propragyl-10dAM showed a surprising ability to cure tumors such that there was no evidence of tumor growth several weeks after the cessation of therapy. Thus, highly purified compositions containing 10-propargyl-10dAM can be used to treat human tumors, particularly human mammary tumors and human lung cancer.
Inventor(s):	Francis M. Sirotnak, James R. Piper, Joseph I. DeGraw, William T. Colwell
Assignee:	SRI International Inc , Southern Research Institute , Memorial Sloan Kettering Cancer Center
Application Number:	US09/214,984
Patent Claim Types: see list of patent claims	Use; Composition;

U.S. Patent 6,028,071: Pralatrexate Claim Scope, Expiration, and Patent Landscape

U.S. Patent 6,028,071 covers 10-propargyl-10-deazaaminopterin, now known as pralatrexate, including the substantially purified active compound, pharmaceutical compositions, tumor-treatment methods, specified dosing, solid and lung tumors, mammary tumors, and combination therapy. The patent issued on February 22, 2000, and its standard U.S. patent term expired on November 6, 2016. Its claims therefore no longer create an enforceable U.S. exclusionary right, although the patent remains relevant to historical Orange Book analysis, freedom-to-operate reviews, and prosecution history.

What drug does U.S. Patent 6,028,071 protect?

10-propargyl-10-deazaaminopterin is pralatrexate, the active ingredient in Folotyn. Pralatrexate is a folate analog metabolic inhibitor that targets dihydrofolate reductase and related folate-dependent pathways.

Item	Data
Patent	U.S. Patent 6,028,071
Title	10-Propargyl-10-deazaaminopterin
Active ingredient	Pralatrexate
Patent holder at issuance	SRI International
FDA product	Folotyn
Applicant and original commercial sponsor	Allos Therapeutics
Current product rights history	Allos was acquired by Spectrum Pharmaceuticals; Spectrum was later acquired by Assertio, with commercial rights subsequently associated with Acrotech
Filing date	November 6, 1996
Earliest claimed priority	November 6, 1995
Issue date	February 22, 2000
Standard expiration date	November 6, 2016
FDA approval	September 24, 2009
Approved indication	Relapsed or refractory peripheral T-cell lymphoma after at least one prior therapy
Dosage form	Intravenous injection
Drug category	Small-molecule oncology drug

The patent is a compound-and-use patent rather than a narrowly drafted formulation patent. Its independent claims are directed to the active compound, a substantially pure composition, a pharmaceutical composition, and treatment of tumors.

What are the independent claims in U.S. Patent 6,028,071?

Claims 1, 2, 3, and 4 are the principal independent claims.

Claim	Claim category	Core limitation
1	Composition of matter	10-propargyl-10-deazaaminopterin substantially free of 10-deazaaminopterin
2	Composition	Composition consisting essentially of 10-propargyl-10-deazaaminopterin
3	Pharmaceutical composition	Pralatrexate substantially free of 10-deazaaminopterin plus a pharmaceutically acceptable carrier
4	Method of treatment	Administering a therapeutically effective amount to a human diagnosed with a tumor

Claims 5 through 8 narrow claim 4 by tumor type or dose. Claims 9 through 12 cover combination products and combination-treatment methods.

The claim set has two distinct protection theories:

1. Product protection for pralatrexate and compositions containing it.
2. Method protection for treating tumors with pralatrexate, including selected tumor types, doses, and combinations.

How broad is claim 1 covering pralatrexate?

Claim 1 covers:

10-Propargyl-10-deazaaminopterin, substantially free of 10-deazaaminopterin.

The claim has two material elements:

• The claimed molecule must be 10-propargyl-10-deazaaminopterin.
• The molecule must be substantially free of the structurally related impurity 10-deazaaminopterin.

The claim is directed to the compound itself, not merely to its use in lymphoma. During the patent term, a party making, using, selling, offering for sale, or importing the claimed compound could have faced direct infringement exposure, subject to ordinary patent-law defenses and claim-construction issues.

The phrase “substantially free” is a critical limitation. It does not necessarily mean absolute chemical purity. Its legal meaning would depend on the specification, analytical methods, examples, prosecution history, and the level of impurity that materially affects the claimed product. A product containing measurable 10-deazaaminopterin would not automatically fall outside the claim.

Claim 1 does not expressly recite:

• A particular salt form.
• A specific polymorph.
• A particle-size distribution.
• A specific solvent system.
• A particular vial or container.
• A defined concentration.
• A particular manufacturing process.
• A particular route of administration.

The claim is therefore structurally broad but purity-limited.

What does claim 2 protect?

Claim 2 covers a composition “consisting essentially of” 10-propargyl-10-deazaaminopterin.

“Consisting essentially of” generally permits components that do not materially alter the basic and novel characteristics of the claimed composition. It is narrower than “comprising” but broader than “consisting of.” The claim may therefore cover a substantially pure active compound containing minor residual materials, depending on whether those materials materially alter the composition’s relevant characteristics.

The claim is potentially important for bulk drug substance and intermediate commercial material. It is less directly tied to the finished injectable product than claim 3.

What formulations are protected by claim 3?

Claim 3 covers a pharmaceutical composition comprising:

• 10-propargyl-10-deazaaminopterin;
• the active compound substantially free of 10-deazaaminopterin; and
• a pharmaceutically acceptable carrier.

The claim does not require a specific carrier or formulation architecture. It can potentially reach liquid or solid pharmaceutical preparations, provided the composition includes the claimed active compound and a pharmaceutically acceptable carrier.

The claim does not expressly require:

• Intravenous administration.
• A 20 mg/mL concentration.
• A single-dose vial.
• Preservative-free packaging.
• A particular pH.
• A specified excipient.
• A particular infusion duration.

Folotyn is supplied as an intravenous injection. FDA labeling identifies pralatrexate injection as a sterile solution in a single-dose vial, but those product details are not all recited in claim 3 (U.S. Food and Drug Administration [FDA], 2023).

Which treatment methods are covered by claims 4 through 8?

Claim 4 is the central method claim. It covers administering a therapeutically effective amount of pralatrexate, substantially free of 10-deazaaminopterin, to a human patient diagnosed as having a tumor.

The claim does not restrict treatment to peripheral T-cell lymphoma. It uses the broader term “tumor.” The dependent claims narrow that scope:

Claim	Added limitation
5	The tumor is a solid tumor
6	Administration is 40 to 120 mg/m² of body surface area per day
7	The tumor is a mammary tumor; depends on claim 5
8	The tumor is a lung tumor

Claims 4, 5, 7, and 8 are broader in disease scope than the FDA-approved Folotyn indication. They were drafted to cover oncology uses beyond the later approved peripheral T-cell lymphoma indication.

How does the patented dose compare with the FDA dose?

Claim 6 recites 40 to 120 mg/m² per day. The current Folotyn labeling describes a recommended dose of 30 mg/m² administered intravenously over 3 to 5 minutes once weekly for 6 weeks in a 7-week cycle, subject to dose modification (FDA, 2023).

That regimen does not literally match the daily dose limitation in claim 6. Claim 4 is not limited to the claim 6 dose and would have been the more commercially relevant treatment claim during the patent term.

What do claims 9 through 12 cover?

Claims 9 and 10 cover combination pharmaceutical compositions. Claims 11 and 12 cover combination-treatment methods.

Combination composition claims

Claim 9 requires pralatrexate plus at least one additional cytotoxic or antitumor compound. Claim 10 narrows the additional agent to a listed category:

• Vinca alkaloids
• 5-fluorouracil
• Alkylating agents
• Cisplatin
• Carboplatin
• Leucovorin
• Taxols
• Antibiotics

The claim language is broad at the category level. It does not require a particular ratio, schedule, sequence, or mechanism of action.

Combination method claims

Claim 11 covers administering pralatrexate with at least one additional cytotoxic or antitumor compound. Claim 12 uses the same list of categories as claim 10.

The supplied text states “10-propargyl-1-deazaaminopterin” in claim 11. That appears to be a transcription error. The patent’s claimed compound is 10-propargyl-10-deazaaminopterin. The error matters because claim interpretation depends on the issued patent text, not a secondary transcription.

When did U.S. Patent 6,028,071 lose exclusivity?

The patent’s standard expiration date was November 6, 2016.

Exclusivity event	Date
Earliest priority date	November 6, 1995
Nonprovisional filing date	November 6, 1996
Patent issue	February 22, 2000
FDA approval of Folotyn	September 24, 2009
Five-year new chemical entity exclusivity	Expired in 2014
Seven-year orphan-drug exclusivity	Expired September 24, 2016
Patent expiration	November 6, 2016

The patent term was governed by the post-1995 twenty-year term measured from the earliest effective nonprovisional filing date, rather than the date of issue. FDA approval did not restart the patent term.

The patent does not provide current U.S. exclusivity because its term has expired. Any separate later-issued patent would need independent analysis; the claims quoted in the request do not establish a continuing patent right.

What was the Orange Book status of pralatrexate?

U.S. Patent 6,028,071 was historically associated with Folotyn’s U.S. regulatory exclusivity and Orange Book patent record. Its listing supported the patent-certification framework applicable to an abbreviated new drug application during the patent term.

After expiration:

• The patent cannot block a generic solely because of its former Orange Book listing.
• A new ANDA applicant would not face an unexpired 6,028,071 patent for Paragraph IV purposes.
• The patent remains relevant as prior art and as a record of the original compound and method claims.
• FDA approval and patent expiration are separate events.

The Orange Book should be evaluated by product and edition because historical listings, delistings, and expiration status can change over time (FDA, 2024).

Are there Paragraph IV challenges to U.S. Patent 6,028,071?

A current Paragraph IV challenge to U.S. Patent 6,028,071 would have little practical significance because the patent expired in 2016. Paragraph IV litigation is designed to challenge an unexpired listed patent before generic launch. A generic applicant could instead rely on the patent’s expiration and certify that no unexpired patent blocks approval, subject to the Orange Book records applicable at filing.

The important distinction is:

• A Paragraph IV challenge could have been commercially meaningful before November 6, 2016.
• After expiration, the patent no longer supplies a launch barrier.
• Any current litigation would need to involve a different, unexpired patent, regulatory exclusivity, product-label issue, or non-patent commercial barrier.

No biosimilar pathway applies because pralatrexate is a chemically synthesized small molecule, not a biologic. A competing applicant would use an ANDA or another small-molecule pathway, not a biosimilar application under section 351(k) of the Public Health Service Act.

What is the competitive landscape for pralatrexate?

Pralatrexate competes primarily in the relapsed or refractory peripheral T-cell lymphoma market. Relevant competitive products and treatment classes include:

Product or class	Competitive relationship
Romidepsin	Alternative approved therapy for certain relapsed or refractory T-cell lymphomas
Belinostat	Alternative approved therapy for relapsed or refractory peripheral T-cell lymphoma
Brentuximab vedotin	Important alternative in CD30-positive disease
Chemotherapy combinations	Compete in relapsed disease and transplant-eligible treatment
Clinical-trial agents	Compete for later-line patients and commercial share
Generic cytotoxic agents	Compete in broader lymphoma and solid-tumor treatment

The original 6,028,071 claims reach solid tumors, mammary tumors, lung tumors, and combination treatment, but the commercial product’s principal regulatory value is its peripheral T-cell lymphoma indication.

How strong was the 6,028,071 patent estate?

The patent was strong in one respect and limited in another.

Strengths

• It claimed the specific pralatrexate molecule.
• Claim 1 was a product claim, which generally provides broader enforcement leverage than a method claim.
• The purity limitation targeted a named structurally related compound.
• Claim 3 covered pharmaceutical compositions without requiring a narrow excipient formula.
• Claim 4 covered tumor treatment without restricting the indication to the later FDA-approved lymphoma use.
• Combination claims expanded the potential treatment-use scope.

Limitations

• The patent had a single core patent term ending in 2016.
• It did not create perpetual protection for the active ingredient.
• The quoted claims do not expressly protect a specific polymorph, formulation technology, manufacturing process, or delivery platform.
• Claim 6’s daily dose range does not align directly with the labeled 30 mg/m² weekly regimen.
• Method claims require proof of the patented treatment steps.
• “Substantially free” creates a factual purity and claim-construction issue.
• The patent expired shortly after orphan exclusivity ended.

The estate was commercially valuable during the 2009-2016 period but did not create a durable post-expiration barrier comparable to a portfolio built around multiple formulation, dosing, manufacturing, and later-line indication patents.

What manufacturing and intellectual-property barriers remain?

After expiration of the patent, the key barriers are primarily technical, regulatory, and commercial:

• Reproducible synthesis of pralatrexate.
• Control of the 10-deazaaminopterin impurity.
• Stereochemical and chemical characterization.
• Validated analytical methods.
• Sterile injectable manufacturing.
• Stability and container-closure qualification.
• FDA bioequivalence or suitability of the proposed product.
• Clinical and labeling requirements for an ANDA.
• Commercial access to oncology distribution channels.

The expired purity claim does not prevent a competitor from manufacturing pralatrexate today. It does, however, identify an important historical quality attribute: control of 10-deazaaminopterin was central to the original patent disclosure and claim structure.

What licensing deals affected pralatrexate?

Pralatrexate originated from research associated with SRI International and was developed commercially by Allos Therapeutics. Allos advanced the compound through clinical development and obtained FDA approval for Folotyn in 2009. Spectrum Pharmaceuticals acquired Allos in 2012. Later corporate transactions transferred commercial responsibility among successor companies, including Acrotech.

These transactions affected commercial control and product marketing, but they did not extend the expiration date of U.S. Patent 6,028,071. A license can transfer enforcement or commercialization rights; it cannot extend a patent beyond its statutory term.

What generic launch risks existed and what risks remain?

During the patent term, a generic applicant faced three principal risks:

1. Compound-claim risk: A product containing pralatrexate could implicate claim 1.
2. Composition risk: An injectable or other pharmaceutical preparation could implicate claim 3.
3. Method-of-use risk: Labeling for tumor treatment could implicate claim 4 or its dependent claims.

After November 6, 2016, the patent-related launch risk from 6,028,071 fell to zero as a matter of patent enforceability. Remaining launch risk is more likely to arise from:

• FDA product-development requirements.
• Manufacturing validation.
• Supply-chain economics.
• Small market size.
• Sterile injectable capacity.
• Any later patents not included in the quoted claim set.
• Labeling strategy and induced-infringement concerns relating to any later unexpired method patent.

Key Takeaways

• U.S. Patent 6,028,071 covers pralatrexate, also called 10-propargyl-10-deazaaminopterin.
• The patent includes a product claim, composition claims, tumor-treatment claims, dose limitations, and combination-treatment claims.
• The central purity limitation is that pralatrexate must be substantially free of 10-deazaaminopterin.
• The patent’s standard expiration date was November 6, 2016.
• Folotyn received FDA approval on September 24, 2009, for relapsed or refractory peripheral T-cell lymphoma after at least one prior therapy.
• The patented daily dose range in claim 6 does not match the labeled 30 mg/m² once-weekly regimen.
• Pralatrexate is a small molecule and has no biosimilar pathway.
• A current generic applicant is not blocked by the expired 6,028,071 patent.
• The patent remains relevant to historical Orange Book analysis, prior-art review, and understanding of pralatrexate’s purity and use claims.
• Any current exclusivity analysis must separately identify later patents, regulatory exclusivities, and FDA product-specific requirements.

FAQs

Does U.S. Patent 6,028,071 cover Folotyn by brand name?

No. It covers the active ingredient and specified compositions and uses. Folotyn is the FDA-approved product name for pralatrexate injection.

Is pralatrexate still patent-protected in the United States?

Patent 6,028,071 expired on November 6, 2016. That patent no longer protects pralatrexate in the United States. Separate later patents would require an independent review.

Does the patent cover pralatrexate impurity specifications?

It covers pralatrexate substantially free of 10-deazaaminopterin. It does not establish a universal modern regulatory impurity specification for every pralatrexate product.

Can a generic manufacturer use the same pralatrexate tumor-treatment method?

The method claims in 6,028,071 expired with the patent. A current manufacturer must still assess any later unexpired method-of-use patents and FDA labeling requirements.

Is a pralatrexate generic a biosimilar?

No. Pralatrexate is a small-molecule drug. A competing product would use a small-molecule approval pathway, typically an ANDA where the statutory requirements are satisfied.

References

1. U.S. Patent No. 6,028,071. (2000). 10-Propargyl-10-deazaaminopterin. U.S. Patent and Trademark Office.

2. U.S. Food and Drug Administration. (2023). FOLOTYN (pralatrexate injection) prescribing information. FDA.

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

4. U.S. Food and Drug Administration. (2009, September 24). FDA approves Folotyn for relapsed or refractory peripheral T-cell lymphoma. FDA.

5. U.S. Patent and Trademark Office. (2024). Patent term adjustment and patent term expiration principles. USPTO.

Drugs Protected by US Patent 6,028,071

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: 6,028,071

PCT Information
PCT Filed	July 16, 1997	PCT Application Number:	PCT/US97/11982
PCT Publication Date:	January 22, 1998	PCT Publication Number:	WO98/02163

International Family Members for US Patent 6,028,071

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	407677
Canada	2260266
Germany	69738981
Denmark	0944389
European Patent Office	0944389