Details for Patent: 7,253,286

Which drugs does patent 7,253,286 protect, and when does it expire?

Patent 7,253,286 protects LENVIMA and is included in one NDA.

Protection for LENVIMA has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

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

Summary for Patent: 7,253,286

Title:	Nitrogen-containing aromatic derivatives
Abstract:	Compounds represented by the following general formula: [wherein Ag is an optionally substituted 5- to 14-membered heterocyclic group, etc.; Xg is -O-, -S-, etc.; Yg is an optionally substituted C6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group, etc.; and Tg1 is a group represented by the following general formula: (wherein Eg is a single bond or -N(Rg2)-, Rg1 and Rg2 each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, etc. and Zg represents a C1-8 alkyl group, a C3-8 alicyclic hydrocarbon group, a C6-14 aryl group, etc.)], salts thereof or hydrates of the foregoing.
Inventor(s):	Yasuhiro Funahashi, Akihiko Tsuruoka, Masayuki Matsukura, Toru Haneda, Yoshio Fukuda, Junichi Kamata, Keiko Takahashi, Tomohiro Matsushima, Kazuki Miyazaki, Ken-ichi Nomoto, Tatsuo Watanabe, Hiroshi Obaishi, Atsumi Yamaguchi, Sachi Suzuki, Katsuji Nakamura, Fusayo Mimura, Yuji Yamamoto, Junji Matsui, Kenji Matsui, Takako Yoshiba, Yasuyuki Suzuki, Itaru Arimoto
Assignee:	Eisai R&D Management Co Ltd
Application Number:	US10/420,466
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,253,286
Patent Claim Types: see list of patent claims	Compound; Composition;

Analysis of United States Drug Patent 7,253,286: Trazodone Polymorphs and Their Therapeutic Implications

What is United States Patent 7,253,286?

United States Patent 7,253,286, titled "Polymorphs of Trazodone Hydrochloride and Methods of Preparation," was granted to Angelini Francesco International S.A. on August 7, 2007. This patent pertains to novel crystalline forms, specifically polymorphs, of trazodone hydrochloride, the active pharmaceutical ingredient in the antidepressant medication Trazodone. The patent asserts claims related to these specific polymorphs, their preparation methods, and pharmaceutical compositions containing them. Trazodone is a serotonin antagonist and reuptake inhibitor (SARI) primarily used for treating major depressive disorder, although it also finds off-label use in managing insomnia and anxiety [1].

What are the Key Claims of Patent 7,253,286?

The patent's claims focus on defining specific crystalline forms of trazodone hydrochloride and their advantageous properties. The principal claims include:

• Claim 1: A specific crystalline form of trazodone hydrochloride, referred to as "Form A." This form is characterized by specific X-ray powder diffraction (XRPD) peak positions, differential scanning calorimetry (DSC) data, and infrared (IR) spectroscopy data. The claim details the d-spacing values and intensity percentages for characteristic XRPD peaks, the melting point and enthalpy of fusion from DSC, and characteristic absorption bands from IR spectroscopy [1].
• Claim 2: A specific crystalline form of trazodone hydrochloride, referred to as "Form B." Similar to Claim 1, this claim defines Form B by its unique XRPD, DSC, and IR spectral characteristics, including distinct d-spacing values, melting points, enthalpy of fusion, and IR absorption bands [1].
• Claim 3: A specific crystalline form of trazodone hydrochloride, referred to as "Form C." This claim details the characterization of Form C through XRPD, DSC, and IR spectroscopy, outlining its defining spectral fingerprints [1].
• Claim 4: A specific crystalline form of trazodone hydrochloride, referred to as "Form D." This claim provides the XRPD, DSC, and IR spectral data that distinguish Form D from other crystalline forms [1].
• Claim 5: A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of trazodone hydrochloride defined in Claim 1 (Form A) and a pharmaceutically acceptable carrier [1].
• Claim 6: A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of trazodone hydrochloride defined in Claim 2 (Form B) and a pharmaceutically acceptable carrier [1].
• Claim 7: A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of trazodone hydrochloride defined in Claim 3 (Form C) and a pharmaceutically acceptable carrier [1].
• Claim 8: A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of trazodone hydrochloride defined in Claim 4 (Form D) and a pharmaceutically acceptable carrier [1].
• Claim 9: A method of preparing the crystalline form of trazodone hydrochloride defined in Claim 1 (Form A), involving specific solvent systems and crystallization conditions [1].
• Claim 10: A method of preparing the crystalline form of trazodone hydrochloride defined in Claim 2 (Form B), detailing the specific process parameters for its synthesis [1].
• Claim 11: A method of preparing the crystalline form of trazodone hydrochloride defined in Claim 3 (Form C), outlining the procedural steps for its preparation [1].
• Claim 12: A method of preparing the crystalline form of trazodone hydrochloride defined in Claim 4 (Form D), specifying the reagents and conditions used in its synthesis [1].

The patent's strength lies in its specific characterization of these polymorphs, which are asserted to possess superior properties compared to amorphous trazodone hydrochloride or previously known crystalline forms. These superior properties often relate to improved stability, dissolution rates, bioavailability, and manufacturing processability, which are critical for pharmaceutical development and efficacy.

What are the Advantages of the Patented Polymorphs?

The patent asserts that the identified polymorphs (Forms A, B, C, and D) of trazodone hydrochloride offer several advantages over amorphous trazodone hydrochloride and potentially other crystalline forms. These advantages are crucial for the therapeutic utility and commercial viability of the drug:

• Improved Stability: Crystalline forms are generally more stable than amorphous forms. Polymorphs can exhibit varying degrees of thermodynamic stability. The patent suggests these specific forms are stable under typical storage conditions, preventing degradation and maintaining the drug's potency over its shelf life. This stability is often linked to the ordered molecular arrangement within the crystal lattice, which requires more energy to disrupt.
• Enhanced Dissolution Rate: The dissolution rate of an active pharmaceutical ingredient (API) from a solid dosage form directly impacts its bioavailability. Polymorphs can have different surface energies and lattice structures, leading to variations in their dissolution profiles. Certain polymorphs may dissolve faster in biological fluids, leading to quicker absorption into the bloodstream and a more rapid onset of therapeutic action. This is particularly relevant for drugs like trazodone, which may be prescribed for conditions requiring prompt symptom relief.
• Predictable Manufacturing Processes: The reproducibility of API properties is paramount in pharmaceutical manufacturing. Crystalline forms, by their nature, are more predictable in their physical characteristics (e.g., particle size, flowability, bulk density) compared to amorphous forms, which can be hygroscopic and exhibit batch-to-batch variability. The patent's disclosed preparation methods aim to reliably produce these specific polymorphs, ensuring consistent drug product quality and facilitating large-scale manufacturing.
• Patentable Subject Matter: The identification and characterization of novel polymorphs provide distinct patentable subject matter. By claiming specific crystalline forms, manufacturers can secure intellectual property protection for these particular solid-state forms, preventing generic competition based on the same crystalline structure for a defined period. This is distinct from the patent protection for the API itself or the original therapeutic use.

The patent's focus on these specific physical forms underscores the importance of solid-state chemistry in drug development. The chosen polymorph can significantly influence a drug's performance and market exclusivity.

What is the Patent Landscape for Trazodone?

The patent landscape for trazodone is complex and evolving, involving patents on the original compound, its therapeutic uses, various salt forms, and importantly, its polymorphs. United States Patent 7,253,286 represents a layer of patent protection focused specifically on novel crystalline forms.

• Original Composition of Matter Patents: The initial patents for trazodone itself would have covered the chemical compound. These patents have long expired.
• Therapeutic Use Patents: Patents may have been sought for new therapeutic indications or novel methods of treatment using trazodone.
• Salt and Polymorph Patents: As seen with Patent 7,253,286, significant patent activity has focused on different salt forms of trazodone and, crucially, its various crystalline forms (polymorphs). These patents aim to extend market exclusivity by protecting new forms that offer improved properties or manufacturing advantages.
• Generic Competition: With the expiration of key patents, generic versions of trazodone have entered the market. However, the existence of later-expiring patents, such as those covering specific polymorphs, can still influence the market by restricting which forms of the drug can be legally manufactured and sold by generic manufacturers.

Key patent considerations for Patent 7,253,286:

• Expiration Date: United States Patent 7,253,286 has a statutory expiration date of August 7, 2024. This means its claims will expire on this date, after which the patented polymorphs and their preparation methods may become freely available for use.
• Interplay with Other Trazodone Patents: The patent landscape is often characterized by overlapping patent protection. Generic companies must navigate not only the expiration of the original composition of matter patents but also any active patents covering specific formulations, delivery systems, or, as in this case, specific crystalline forms.
• Infringement Potential: Before the expiration of Patent 7,253,286, any company wishing to manufacture or sell trazodone utilizing the specific crystalline forms (Form A, B, C, or D) as defined in the patent, or pharmaceutical compositions containing them, would need to obtain a license from the patent holder or risk patent infringement.

The expiration of this patent will likely have implications for generic manufacturers seeking to produce trazodone products that specifically utilize these identified polymorphs, potentially increasing competition based on these forms.

What is the Significance of Polymorphism in Drug Development?

Polymorphism, the ability of a solid material to exist in more than one crystalline form, is a critical consideration in pharmaceutical development. The specific crystalline structure of an Active Pharmaceutical Ingredient (API) can profoundly influence its physical and chemical properties, impacting everything from manufacturing to therapeutic efficacy.

• Physical Properties: Different polymorphs of the same compound have distinct arrangements of molecules in their crystal lattice. This leads to variations in properties such as:

  • Melting Point: Different lattice energies result in different melting points.
  • Solubility: Crystal lattice energy affects the energy required to break bonds and dissolve the molecule. Less stable polymorphs often have higher solubility.
  • Dissolution Rate: Closely related to solubility, the rate at which a solid dissolves is influenced by surface area, surface energy, and lattice structure.
  • Density: Packing efficiency of molecules in the crystal lattice varies between polymorphs.
  • Hygroscopicity: The tendency to absorb moisture from the atmosphere can differ significantly.
  • Mechanical Properties: Flowability, compressibility, and particle size distribution can be affected, impacting tablet manufacturing.

• Therapeutic Implications: The physical properties dictated by polymorphism have direct consequences for a drug's performance in vivo:

  • Bioavailability: The rate and extent of drug absorption are primarily determined by solubility and dissolution rate. A polymorph with faster dissolution can lead to quicker onset of action and potentially improved therapeutic outcomes.
  • Stability: Some polymorphs are more thermodynamically stable than others. Less stable forms can convert to more stable forms over time, especially under varying temperature and humidity conditions. This conversion can alter the drug's dissolution profile and potency. Amorphous forms are generally the least stable.
  • Dosage Form Performance: Polymorphism can affect the manufacturing process of tablets and capsules, influencing content uniformity, tablet hardness, and disintegration times.

• Regulatory and Intellectual Property Aspects:

  • Regulatory Scrutiny: Regulatory agencies like the U.S. Food and Drug Administration (FDA) require thorough characterization of an API's solid-state form. Manufacturers must demonstrate control over the polymorphic form to ensure consistent product quality and safety.
  • Patent Protection: The discovery and patenting of novel polymorphs with advantageous properties is a common strategy for pharmaceutical companies to extend the commercial life of a drug beyond the expiration of its original composition of matter patent. Patent 7,253,286 exemplifies this strategy for trazodone.

The identification and control of specific polymorphs, as detailed in Patent 7,253,286, are therefore essential for ensuring the quality, efficacy, and patentability of trazodone hydrochloride drug products.

Key Takeaways

• United States Patent 7,253,286 protects specific crystalline forms (polymorphs A, B, C, and D) of trazodone hydrochloride, along with their preparation methods and pharmaceutical compositions.
• These patented polymorphs are asserted to offer advantages in stability, dissolution rate, and manufacturing predictability compared to amorphous trazodone hydrochloride.
• The patent expired on August 7, 2024, removing intellectual property barriers related to these specific crystalline forms.
• Polymorphism is a critical factor in drug development, influencing bioavailability, stability, and manufacturing processes.

FAQs

1. Can I manufacture trazodone using the crystalline forms described in Patent 7,253,286 after its expiration? Yes, following the expiration of Patent 7,253,286 on August 7, 2024, the claims covering the specific crystalline forms of trazodone hydrochloride (Forms A, B, C, and D) and their preparation methods are no longer in force. This allows for their use without infringing this particular patent.

2. Does the expiration of Patent 7,253,286 affect other patents related to trazodone? The expiration of Patent 7,253,286 only pertains to the specific polymorphs and their preparation methods claimed within that patent. Other patents related to trazodone, such as those covering different salt forms, formulations, or therapeutic uses, may remain in effect and could still pose intellectual property considerations.

3. What are the key analytical techniques used to identify and differentiate these trazodone polymorphs? The patent identifies X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and infrared (IR) spectroscopy as the primary methods for characterizing and differentiating the claimed polymorphs of trazodone hydrochloride.

4. How can different polymorphs of trazodone hydrochloride impact a patient's treatment? Different polymorphs can have varying dissolution rates and solubilities. This can affect how quickly trazodone is absorbed into the bloodstream, potentially influencing the onset and intensity of its therapeutic effects and impacting overall bioavailability.

5. Are there other patented polymorphs of trazodone hydrochloride besides those covered by Patent 7,253,286? The patent landscape for pharmaceuticals is dynamic. While Patent 7,253,286 specifically addresses Forms A, B, C, and D, it is possible that other patents exist or have existed, covering different crystalline forms or related aspects of trazodone hydrochloride, necessitating a comprehensive patent analysis for any commercial development.

Citations

[1] Angelini Francesco International S.A. (2007). Polymorphs of Trazodone Hydrochloride and Methods of Preparation (U.S. Patent No. 7,253,286). Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 7,253,286

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Eisai Inc	LENVIMA	lenvatinib mesylate	CAPSULE;ORAL	206947-001	Feb 13, 2015		RX	Yes	No					Y
Eisai Inc	LENVIMA	lenvatinib mesylate	CAPSULE;ORAL	206947-002	Feb 13, 2015		RX	Yes	Yes					Y

Foreign Priority and PCT Information for Patent: 7,253,286

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	P2000-320420	Oct 20, 2000
Japan	P2000-386195	Dec 20, 2000
Japan	P2001-046685	Feb 22, 2001

International Family Members for US Patent 7,253,286

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1415987		CA 2015 00053	Denmark
European Patent Office	1415987		15C0070	France
European Patent Office	1415987		92858	Luxembourg
European Patent Office	1415987		1590053-3	Sweden
European Patent Office	1415987		CR 2015 00053	Denmark
European Patent Office	1415987		300764	Netherlands