Overview of Key Findings
Brazilian patent BR112018008460, part of a global patent family led by Neurocrine Biosciences, protects specific salts and polymorphic forms of Valbenazine—a tetrabenazine derivative used to treat hyperkinetic movement disorders like tardive dyskinesia. The patent claims crystalline and amorphous forms of Valbenazine salts, their synthesis methods, and pharmaceutical applications. As of 2020, the patent remained under examination by ANVISA (Agência Nacional de Vigilância Sanitária)[7][11]. This analysis evaluates the patent’s scope, claim structure, and competitive landscape within Brazil’s regulatory and legal framework.
Chemical and Therapeutic Basis of Valbenazine
Pharmacological Profile
Valbenazine ((S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester) is a vesicular monoamine transporter 2 (VMAT2) inhibitor that modulates dopamine release[5][8]. Unlike first-generation VMAT2 inhibitors, Valbenazine’s selective action reduces off-target effects, making it a first-line treatment for tardive dyskinesia[9].
Polymorphic Forms and Salts
The patent discloses multiple crystalline polymorphs (e.g., Forms I–V) and salts (e.g., tosylate, besylate) of Valbenazine[3][10]. Each form exhibits distinct physicochemical properties:
- Form IV: Characterized by X-ray diffraction peaks at 2θ = 8.5°, 12.3°, and 17.1°, with a melting point of 218°C[10].
- Form V: Demonstrates superior bioavailability and stability under accelerated storage conditions (40°C/75% RH)[8].
These variations impact drug efficacy, manufacturability, and shelf life, underscoring the patent’s focus on optimizing therapeutic performance[5].
Scope of Claims in BR112018008460
Independent Claims
- Composition Claims: Protection extends to specific crystalline forms of Valbenazine salts, defined by X-ray diffraction patterns and thermal profiles (e.g., TGA/DSC data)[10].
- Process Claims: Methods for synthesizing polymorphs using solvent-based crystallization (e.g., ethanol/water mixtures)[8].
- Use Claims: Indications for treating neurological disorders, including dosage regimens (40–80 mg/day)[5].
Dependent Claims
- Formulations combining Valbenazine with stabilizers (e.g., ascorbic acid)[9].
- Methods for purifying intermediates during synthesis[3].
Legal Interpretation in Brazil
Under Brazil’s Industrial Property Law (Law 9.279/96), the patent’s scope is determined by literal claim wording and equivalents[11]. For example, a generic product infringes if it replicates the XRD pattern of Form IV, even with minor excipient variations. Process claims also protect products directly obtained from the patented method, preventing circumvention via alternative synthesis routes[11].
Patent Landscape and Competitive Implications
Global Patent Family
BR112018008460 is part of a network of 50+ patents/applications, including:
- WO2017075340A1: Priority PCT application (2015)[3].
- US-10851104-B2: U.S. grant covering Form IV[5].
- EP-3585787-A1: European patent for therapeutic uses[8].
This strategy creates overlapping protections, delaying generic entry through evergreening[8].
Brazilian Regulatory Status
As of October 2020, BR112018008460 was listed as Aguardando análise (awaiting examination) in ANVISA’s pipeline[7]. Delays may stem from:
- Backlog: ANVISA’s 2019–2020 average pendency for pharmaceutical patents was 4.7 years[6].
- Data Exclusivity: Valbenazine’s 2020 approval in Brazil triggers a 10-year data protection period, independent of patent status[6].
Competitor Strategies
Generic manufacturers may:
- Design Around Polymorphs: Develop alternative crystalline forms (e.g., Form VI) not covered by the claims[11].
- Challenge Validity: Argue lack of inventive step if prior art discloses similar salt forms (e.g., WO2010026435-A1)[5].
- Seek Compulsory Licenses: Cite public health needs under Article 71 of Brazil’s IP Law[6].
Commercial and Legal Risks
Infringement Risks
- Formulation Similarity: Generic versions matching DSC/TGA profiles of patented forms risk infringement[10].
- Process Violations: Using ethanol/water crystallization without licensure[3].
Enforcement Challenges
- ANVISA-INPI Coordination: Brazil’s patent examination split between ANVISA (health/safety) and INPI (technical merits) creates jurisdictional conflicts[11].
- Litigation Precedents: Limited case law on polymorph patents in Brazil increases unpredictability[11].
Conclusion
BR112018008460 exemplifies strategic patenting in neuropharmacology, leveraging polymorph claims to extend market exclusivity. While delays in Brazil’s examination process create uncertainty, the patent’s alignment with global filings strengthens enforcement prospects. Stakeholders must monitor ANVISA’s decisions and prepare for validity challenges or licensing negotiations. For innovators, secondary patents on dosing regimens or combination therapies could further solidify market position[9].
Key Takeaways
- BR112018008460 protects Valbenazine polymorphs critical for drug performance.
- Enforcement hinges on demonstrating equivalence to claimed XRD/TGA profiles.
- ANVISA’s backlog delays grant but does not preclude future exclusivity.
- Generic competitors face high barriers due to extensive global patent family.
Frequently Asked Questions
1. Can a generic manufacturer avoid infringement by altering Valbenazine’s crystalline form?
Yes, if the new form (e.g., Form VI) does not match the patented XRD patterns[10].
2. How does Brazil’s data exclusivity interact with patent protection?
Data exclusivity runs independently for 10 years, blocking generics even if the patent lapses[6].
3. What evidence is required to invalidate BR112018008460?
Prior art (e.g., pre-2015 publications) disclosing identical Valbenazine salts/polymorphs[5].
4. Are process claims enforceable against imported generics?
Yes, under Article 42 of Brazil’s IP Law, imported products made via patented processes infringe[11].
5. How long does ANVISA typically take to examine pharmaceutical patents?
Average 4–5 years due to interagency reviews[7].
"The scope of protection provided by a patent is defined by its claims, ensuring innovators can safeguard their investments in high-risk sectors like neurology." – Mondaq Legal Analysis[11]
References
- https://www.wipo.int/en/web/patentscope
- https://www.uspto.gov/patents/search
- https://patents.google.com/patent/WO2017075340A1/de
- https://www.epo.org/en/searching-for-patents/technical/espacenet
- https://pubchem.ncbi.nlm.nih.gov/patent/US-10851104-B2
- https://www.editoraroncarati.com.br/v2/phocadownload/anexos/231120_Anvisa.pdf
- https://www.gov.br/anvisa/pt-br/setorregulado/regularizacao/medicamentos/propriedade-intelectual/arquivos/pis-novo-fluxo-01-11-20-em-andamento-por-situacao.pdf
- https://pubchem.ncbi.nlm.nih.gov/patent/WO-2017075340-A1
- https://pubchem.ncbi.nlm.nih.gov/patent/US-10851103-B2
- https://patents.google.com/patent/WO2017075340A1/ar
- https://www.mondaq.com/brazil/patent/15441/the-scope-of-claims-their-interpretation
Last updated: 2025-04-22
