Details for Patent: 8,076,515

Which drugs does patent 8,076,515 protect, and when does it expire?

Patent 8,076,515 protects XADAGO and is included in one NDA.

This patent has fifty-three patent family members in twenty-six countries.

Summary for Patent: 8,076,515

Title:	Process for the production of 2-[4-(3- and 2-fluorobenzyloxy) benzylamino] propanamides
Abstract:	A process for obtaining therapeutically active 2-[4-(3- and 2-(fluorobenzyloxy)benzylamino]propanamides and their salts with pharmaceutically acceptable acids with high purity degree, in particular, with a content of dibenzyl derivatives impurities lower than 0.03%, preferably lower than 0.01% by weight.The process is carried out by submitting the Schiff bases intermediates 2-[4-(3- and 2-fluorobenzyloxy)benzylideneamino]propanamides to catalytic hydrogenation in the presence of a heterogeneous catalyst in a protic organic solvent.
Inventor(s):	Elena Barbanti, Carla Caccia, Patricia Salvati, Francesco Velardi, Tiziano Ruffilli, Luigi BOGOGNA
Assignee:	Newron Pharmaceuticals SpA
Application Number:	US12/338,825
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,076,515
Patent Claim Types: see list of patent claims	Use; Formulation;

US Patent 8,076,515: Safinamide and Ralfinamide Process Claims, Scope and Patent Landscape

US Patent 8,076,515 is a Newron Pharmaceuticals manufacturing and purity patent covering processes for producing safinamide, ralfinamide, their pharmaceutically acceptable salts, selected intermediates, impurity-controlled products, formulations, and therapeutic uses. Its core protection is narrower than a composition-of-matter patent because most claims depend on a defined synthetic route or an impurity specification.

The patent’s 20-year US term is tied to its earliest claimed priority date in December 2004 and therefore reached its scheduled expiration in December 2025, subject to the USPTO’s official term calculation. The patent is not the principal remaining US patent barrier for Xadago, which has depended primarily on later safinamide treatment and formulation patents listed in the FDA Orange Book.

What does US Patent 8,076,515 cover?

The patent covers two related compounds:

• Safinamide: the 3-fluorobenzyloxy derivative.
• Ralfinamide: the 2-fluorobenzyloxy derivative.

The claims address five principal subject-matter groups.

Claim group	Claims	Main subject
Core hydrogenation process	1-7, 51-53	Catalytic reduction of a Schiff base to safinamide or ralfinamide
Upstream imine formation	8-11	Reaction of substituted benzaldehyde with L-alaninamide
Starting-material purification	12-30, 54-56	Control of benzaldehyde impurities and crystallization
Intermediates and high-purity products	31-33	Isolated Schiff bases and impurity-controlled safinamide or ralfinamide
Formulations and therapeutic methods	34-50, 57-58	Formulations and treatment using low-impurity material

The patent is therefore a process-and-quality patent with secondary product, formulation, and method-of-use claims.

What is the scope of independent claim 1?

Claim 1 is the central process claim. It requires:

1. A Schiff base intermediate corresponding to safinamide or ralfinamide.
2. Catalytic hydrogenation using hydrogen gas.
3. A heterogeneous catalyst.
4. A protic organic solvent.
5. Production of safinamide, ralfinamide, or a pharmaceutically acceptable acid salt.

The claim does not require every process detail later specified in dependent claims. It does not require palladium, platinum, methanol, ethanol, a particular pressure, a particular temperature, methanesulfonate formation, or purification of the starting aldehyde.

A process may therefore fall within claim 1 even if it uses process conditions outside claims 2-7, provided the claim 1 elements are present.

What catalysts and solvents are specifically claimed?

Claims 2-4 narrow the catalyst and solvent limitations:

• Nickel, rhodium, platinum, or palladium on an inert support.
• Lower aliphatic C1-C5 alkanols.
• Palladium or platinum.
• Wet 5% Pt/C containing 50% water.
• Wet 10% Pd/C containing 50% water.

Claims 51-53 further narrow the preferred embodiments to methanol, ethanol, isopropanol, platinum, and wet 5% Pt/C.

The practical scope is strongest against a manufacturer using the claimed Schiff-base route followed by hydrogenation in a lower alkanol with supported platinum or palladium. It is weaker against a manufacturer using:

• A different reductive amination sequence.
• A nonhydrogenative reduction.
• A homogeneous catalyst.
• A nonprotic solvent.
• A different precursor that does not pass through the claimed Schiff base.
• A process that makes the same active ingredient through a route outside the claim language.

How do claims 8-30 protect the upstream manufacturing route?

Claims 8-11 extend protection backward from hydrogenation to formation and handling of the Schiff base.

Claim 8 covers iminoalkylation of:

• 4-(3-fluorobenzyloxy)benzaldehyde for safinamide; or
• 4-(2-fluorobenzyloxy)benzaldehyde for ralfinamide,

with L-alaninamide in a protic organic solvent.

Claim 9 covers use of an L-alaninamide acid-addition salt with enough base to liberate the free amine. Claims 10 and 11 distinguish between:

• Hydrogenating the Schiff base in the same reaction mixture after precipitation; and
• Isolating the Schiff base before hydrogenation.

These claims target manufacturing integration and solvent/process control rather than the chemical identity of safinamide itself.

What starting-material impurities are covered?

Claim 12 requires the substituted benzaldehyde starting material to contain less than 0.03% by weight of a specified benzylated impurity:

• Impurity Va for the safinamide route.
• Impurity Vb for the ralfinamide route.

Claim 54 narrows the threshold to less than 0.01%.

Claims 13-30 cover the preparation and crystallization of the aldehyde starting material. Relevant limitations include:

• Alkylation of 4-hydroxybenzaldehyde.
• Use of a 3-fluorobenzyl or 2-fluorobenzyl leaving-group derivative.
• Chloride, bromide, iodide, mesylate, or tosylate leaving groups.
• Phase-transfer conditions.
• Solid-liquid or liquid-liquid phase-transfer systems.
• Quaternary ammonium or phosphonium salts and low-molecular-weight polyethylene glycols.
• Sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide.
• Toluene and n-hexane crystallization.
• Cyclohexane or diisopropyl ether crystallization.
• Cooling to approximately 10-15°C.

The upstream claims are process-dependent. They do not prevent all production of the aldehyde or all production of safinamide. They reach only processes satisfying the recited combinations.

What product and purity protection do claims 29-35 provide?

Claims 29-33 protect high-purity material defined by a low level of a specified positional benzyl impurity.

The principal thresholds are:

Claim	Product	Impurity threshold
29	Safinamide or ralfinamide, free base or salt	Less than 0.03%
30	Methanesulfonate salt	Less than 0.01%
32	High-purity safinamide or ralfinamide	Less than 0.03%
33	Methanesulfonate salt	Less than 0.01%
54	Purified aldehyde starting material	Less than 0.01% impurity

These claims are significant because they are not limited entirely to a particular manufacturing step. A commercial product meeting the defined impurity threshold may implicate a product claim even if the manufacturer uses a different process.

Their enforceability depends on claim construction and analytical proof. The patent owner would need to establish:

• The accused material is safinamide or ralfinamide, or the relevant salt.
• The specified impurity is the impurity recited in the claim.
• The impurity concentration is below the stated threshold.
• The analytical method and sampling basis reliably establish the concentration.

A high-purity claim can create freedom-to-operate risk for a manufacturer that independently develops a low-impurity process, but it does not automatically cover every high-purity safinamide product unless the claim is construed as covering the product regardless of manufacturing origin.

What formulations and method-of-use claims are included?

Claims 34-39 cover pharmaceutical formulations containing high-purity safinamide or ralfinamide.

For safinamide, the formulation claims include combinations with:

• Dopamine agonists.
• Levodopa.
• COMT inhibitors.

For ralfinamide, the claims include combinations with:

• Gabapentin.
• Pregabalin.

Claims 40-50 cover treatment methods using impurity-controlled active ingredient.

Safinamide methods include treatment of:

• Parkinson’s disease.
• Epilepsy.
• Alzheimer’s disease.
• Depression.
• Restless legs syndrome.
• Migraine.

Ralfinamide methods include treatment of:

• Pain.
• Migraine.
• Bipolar disorder.
• Depression.
• Cardiovascular disorders.
• Inflammatory disorders.
• Urogenital disorders.
• Metabolic disorders.
• Gastrointestinal disorders.

Claims 44, 48 and 49 add patient-selection or interaction limitations involving:

• Poor metabolizers.
• CYP450 drug interactions.
• hERG channel-blocking drugs.
• Bipolar disorder.

Claim 58 narrows ralfinamide treatment to chronic or neuropathic pain.

What is the practical strength of the method claims?

The method claims are narrower than the chemical claims because infringement generally requires proof that:

1. The accused product satisfies the specified impurity limitation.
2. The product is administered for a claimed disorder.
3. The treatment includes the required active agent or combination, where applicable.

Safinamide’s commercial Parkinson’s disease use creates a stronger practical relevance for claims 40-44 than the broader unapproved indications. Ralfinamide claims have materially less commercial importance because ralfinamide has not received FDA approval as a marketed US drug.

Claim 40 also contains an apparent structural-description inconsistency compared with earlier claims identifying impurity IIa. The claim recites a reversed placement of the fluorobenzyl and fluorobenzyloxy substituents. That discrepancy could create claim-construction and validity issues, particularly if the specification and prosecution history do not resolve the intended structure.

When did US Patent 8,076,515 lose exclusivity?

The patent’s scheduled US patent term ended in December 2025 based on its December 2004 priority date. The applicable term is generally 20 years from the earliest effective nonprovisional filing date under 35 U.S.C. §154, subject to patent-term adjustment, terminal disclaimers, and other statutory modifications.[2]

Milestone	Date or period
Earliest priority	December 2004
US patent grant	December 13, 2011
Scheduled 20-year term endpoint	December 2025
Patent status after scheduled endpoint	No ordinary forward enforcement for acts occurring after expiration

Expiration does not eliminate potential exposure for qualifying acts that occurred before expiration. It also does not invalidate separately issued continuation, divisional, or later-generation patents covering safinamide compositions, formulations, or treatment methods.

What is the Orange Book status of US Patent 8,076,515?

US Patent 8,076,515 is a process and purity patent rather than the primary listed patent protecting the approved Xadago product. FDA Orange Book listings are product-specific and generally identify patents submitted by the NDA holder as covering the drug substance, drug product, or approved method of use.[3]

The patent’s main Orange Book relevance is limited because:

• Its core claims cover manufacturing processes.
• Its product claims are defined by impurity content rather than by the basic safinamide molecule.
• Its listed or potentially relevant method claims extend beyond the FDA-approved indication.
• It expired in December 2025.

Xadago is safinamide mesylate, approved by FDA in March 2017 as an adjunctive treatment to levodopa/carbidopa for patients with Parkinson’s disease experiencing “off” episodes.[4] The principal commercial patent risk has therefore shifted to later patents directed to approved treatment regimens, formulations, or other approved-product characteristics.

What FDA exclusivity applies to Xadago?

FDA approved Xadago on March 21, 2017. The drug received new chemical entity exclusivity if the FDA regulatory classification treated safinamide as a new active moiety for Hatch-Waxman purposes. Standard five-year NCE exclusivity would have run approximately through March 2022, subject to the statutory rules governing ANDA submission timing.[4]

The product also obtained three years of exclusivity for the approved clinical application if FDA determined that approval relied on new clinical investigations essential to approval. That period would have been relevant to the post-approval regulatory pathway but did not create a patent term extension for US Patent 8,076,515.

Safinamide is a small molecule, not a biologic. Biosimilar pathway risk is therefore inapplicable. The relevant competitive pathway is an ANDA for safinamide tablets, not a 351(k) biosimilar application.

Which companies are challenging safinamide exclusivity?

The key competitive risk is from generic-drug companies filing ANDAs for safinamide tablets. A Paragraph IV challenge would require the ANDA filer to certify that relevant listed patents are invalid, unenforceable, or not infringed.[5]

For US Patent 8,076,515, a Paragraph IV challenge would have been commercially meaningful only before its December 2025 expiration and only if the patent was listed or otherwise asserted against the ANDA product. The strongest possible challenge theories would have included:

• Noninfringement through an alternative synthesis.
• Failure to meet the specified impurity threshold.
• Invalidity based on anticipation or obviousness.
• Lack of written description or enablement for the full safinamide/ralfinamide scope.
• Indefiniteness in the impurity and structural limitations.
• Lack of patent-eligible distinction for product claims defined only by purity, depending on claim construction and prior art.

The commercially material litigation question is the status of later Orange Book-listed Xadago patents, not merely the status of US 8,076,515.

How does the patent compare with core safinamide patents?

Issue	US 8,076,515	Core compound patent	Later Xadago patents
Main protection	Manufacturing and purity	Safinamide chemical entity	Treatment, formulation, or approved-use limitations
Ralfinamide coverage	Yes	May cover related compounds depending on claim scope	Generally less relevant commercially
Process infringement	Central	Usually secondary	Usually secondary
Product claim	Purity-defined	Chemical-structure-defined	Formulation or use-defined
Orange Book importance	Limited	Historical or expired	Primary current commercial relevance
Design-around potential	Relatively high	Low if unexpired	Depends on regimen or formulation
Market impact	API manufacturing	Fundamental molecule	Generic launch timing

US 8,076,515 is weaker than a composition-of-matter patent against a generic manufacturer using a different route. It is stronger where the manufacturer adopts the same imine-hydrogenation sequence or sells material meeting the claimed impurity specification.

How strong is the patent estate for safinamide?

The estate has a layered structure:

1. Historical composition-of-matter protection for safinamide and related compounds.
2. Process protection under US 8,076,515.
3. Regulatory exclusivity following Xadago approval.
4. Later formulation and method-of-use patents listed against Xadago.
5. Trade-secret and know-how protection for scale-up, impurity control, crystallization, and analytical methods.

US 8,076,515 had medium strength as a manufacturing patent and low-to-medium residual strength after expiration. Its strongest claims were the narrower process claims requiring:

• A specific Schiff-base intermediate.
• Supported platinum or palladium.
• Protic C1-C5 alkanol.
• Defined pressure and temperature ranges.
• Low impurity levels in the aldehyde or final API.
• Methanesulfonate salt with impurity below 0.01%.

Its broadest claim, claim 1, was vulnerable to process design-around. Claims 32 and 33 potentially created broader product exposure, but their practical value depended on proof of the impurity threshold and the legal treatment of purity-defined product claims.

What generic launch scenarios exist for safinamide?

Scenario 1: Alternative-route launch

A generic manufacturer uses a route that does not hydrogenate the claimed Schiff base in a protic organic solvent. This avoids the central process claims, assuming the final product does not independently meet an enforceable purity-defined product claim.

Scenario 2: Same-route launch before expiration

A manufacturer uses the claimed hydrogenation sequence before December 2025. This creates direct process-infringement risk, especially if the manufacturing occurs in the United States or the process is used to make a product imported into the United States under the applicable statutory provisions.

Scenario 3: High-purity product exposure

A manufacturer uses a different process but produces safinamide mesylate containing less than 0.01% of the specified impurity. Claims 30 or 33 could be asserted if the product claim is construed to cover the resulting material independent of process.

Scenario 4: Post-expiration launch

After expiration of US 8,076,515, the patent no longer blocks new manufacture or sale based solely on this patent. The generic must still address any unexpired Orange Book-listed patents and FDA regulatory requirements.

Scenario 5: Ralfinamide development

Ralfinamide has no equivalent US commercial market following FDA approval of safinamide. The ralfinamide claims are relevant mainly to pipeline development, licensing, and freedom-to-operate analysis rather than near-term generic competition.

What licensing deals affect the commercial landscape?

Newron Pharmaceuticals developed safinamide and entered into regional commercialization arrangements for Xadago, including a US collaboration with US WorldMeds. The commercial license is distinct from ownership of US Patent 8,076,515. A licensee may have rights to commercialize Xadago without owning every patent in the underlying Newron estate.[6]

Licensing analysis should separate:

• Patent ownership.
• NDA ownership.
• US commercialization rights.
• Manufacturing rights.
• Rights to prosecute or settle Paragraph IV litigation.
• Rights to later patents and improvements.
• Royalty or milestone obligations.

A generic settlement involving later Xadago patents would not necessarily provide a license under US 8,076,515 unless the settlement expressly covered it.

What manufacturing and geographic barriers remain?

The patent’s geographic protection is jurisdiction-specific. US 8,076,515 does not prevent a process used entirely outside the United States unless US statutory provisions governing importation or products made by patented processes apply. Foreign national counterparts must be assessed separately for:

• Expiration.
• Patent-term adjustment.
• Opposition or revocation history.
• Claim amendments.
• Supplementary protection certificates.
• Local infringement standards.

Manufacturing barriers after patent expiration may still include:

• Proprietary impurity-control specifications.
• Scale-up know-how.
• Catalyst handling and filtration.
• Crystallization conditions.
• Analytical methods for trace impurities.
• Validation data supporting API quality.
• Regulatory filing requirements.
• Supply-chain qualification.

These barriers are commercial and regulatory, not continuing exclusivity under US 8,076,515.

Key Takeaways

• US 8,076,515 covers processes for producing safinamide and ralfinamide through catalytic hydrogenation of defined Schiff bases.
• The patent also claims aldehyde purification, isolated Schiff bases, low-impurity products, formulations, and treatment methods.
• Claim 1 is broad within the claimed synthetic route but does not cover every process for making safinamide.
• Claims 32 and 33 create the principal product-based risk through impurity thresholds of less than 0.03% and 0.01% for methanesulfonate.
• The patent’s scheduled US term ended in December 2025.
• Safinamide is a small molecule, so biosimilar risk does not apply.
• The commercial generic barrier for Xadago depends mainly on later Orange Book-listed patents and any applicable FDA exclusivity, not solely on US 8,076,515.
• Ralfinamide claims have limited current commercial significance because ralfinamide has not become an FDA-approved marketed product.
• The patent estate is medium strength for same-route manufacturing, weaker against an alternative synthesis, and expired as a forward-looking US barrier after December 2025.

FAQs

Does US Patent 8,076,515 claim safinamide itself?

It does not claim the basic safinamide molecule in the same manner as a conventional composition-of-matter patent. It claims defined manufacturing processes and safinamide products characterized by specified impurity levels.

Can a generic manufacturer avoid US 8,076,515 by using a different process?

Potentially. An alternative synthesis that does not use the claimed Schiff-base hydrogenation route may avoid the process claims. A separate analysis is required for the purity-defined product claims.

Is ralfinamide protected by the same patent as safinamide?

Yes. The patent expressly covers both the 3-fluorobenzyloxy safinamide series and the 2-fluorobenzyloxy ralfinamide series.

Does FDA approval of Xadago create biosimilar protection?

No. Xadago contains the small-molecule active ingredient safinamide mesylate. Competition proceeds through the generic ANDA pathway rather than the biosimilar pathway.

Does expiration of US 8,076,515 permit immediate generic Xadago launch?

No. Expiration of this patent removes one potential barrier only. A generic applicant must still address any unexpired Orange Book-listed patents, applicable FDA exclusivity, patent certifications, litigation stays, and regulatory requirements.

References

1. United States Patent and Trademark Office. (2011). US Patent No. 8,076,515, Process for preparing high purity safinamide and ralfinamide. https://patents.google.com/patent/US8076515B2/en
2. United States Code. 35 U.S.C. §§ 154, 271, 282. https://uscode.house.gov/
3. U.S. Food and Drug Administration. (2025). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
4. U.S. Food and Drug Administration. (2017). FDA approves Xadago for Parkinson’s disease. https://www.fda.gov/news-events/press-announcements/fda-approves-xadago-parkinsons-disease
5. U.S. Food and Drug Administration. (2024). Paragraph IV patent certifications and 30-month stays under the Hatch-Waxman Act. https://www.fda.gov/drugs
6. Newron Pharmaceuticals S.p.A. (2012). Annual report and corporate disclosures concerning safinamide commercialization agreements. https://www.newron.com/

Drugs Protected by US Patent 8,076,515

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Mdd Us	XADAGO	safinamide mesylate	TABLET;ORAL	207145-001	Mar 21, 2017	AB	RX	Yes	No			Y	Y		ADJUNCTIVE TREATMENT TO LEVODOPA/CARBIDOPA IN PATIENTS WITH PARKINSON'S DISEASE EXPERIENCING 'OFF' EPISODES
Mdd Us	XADAGO	safinamide mesylate	TABLET;ORAL	207145-002	Mar 21, 2017	AB	RX	Yes	Yes			Y	Y		ADJUNCTIVE TREATMENT TO LEVODOPA/CARBIDOPA IN PATIENTS WITH PARKINSON'S DISEASE EXPERIENCING 'OFF' EPISODES

Foreign Priority and PCT Information for Patent: 8,076,515

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	06012565	Jun 19, 2006

International Family Members for US Patent 8,076,515

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	061510
Australia	2007263328
Brazil	PI0712936
Canada	2653012
China	101472880
China	103284984
Cyprus	1115951