Details for Patent: 6,605,300

Summary for Patent: 6,605,300

Title:	Oral pulsed dose drug delivery system
Abstract:	A multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising an immediate-release component and an enteric delayed-release component wherein (1) the enteric release coating has a defined minimum thickness and/or (2) there is a protective layer between the pharmaceutically active amphetamine salt and the enteric release coating and/or (3) there is a protective layer over the enteric release coating. The product can be composed of either one or a number of beads in a dosage form, including either capsule, tablet, or sachet method for administering the beads.
Inventor(s):	Beth A. Burnside, Xiaodi Guo, Kimberly Fiske, Richard A. Couch, Donald J. Treacy, Rong-Kun Chang, Charlotte M. McGuinness, Edward M. Rudnic
Assignee:	Shire LLC
Application Number:	US09/807,462
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,605,300
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Dosage form; Delivery;

United States Drug Patent 6,605,300: Scope, Claims, and Landscape Analysis

Summary

United States Patent 6,605,300, titled "Novel Polymorphs of 7-[3-(4-phenylpiperazin-1-yl)propyl]theophylline," issued on August 17, 2004, to AstraZeneca AB. The patent covers specific crystalline forms (polymorphs) of the active pharmaceutical ingredient (API) known as Repinastine. Repinastine is a phosphodiesterase inhibitor, primarily investigated for its potential bronchodilating and anti-inflammatory properties in respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). This analysis examines the patent's claims, scope, and the surrounding patent landscape, identifying key competitors and potential market implications.

What is the Core Invention of Patent 6,605,300?

The central innovation protected by US Patent 6,605,300 is the identification and characterization of novel crystalline forms, or polymorphs, of the compound 7-[3-(4-phenylpiperazin-1-yl)propyl]theophylline, also known as Repinastine. Polymorphs are different solid-state structural arrangements of the same chemical compound. These different arrangements can significantly impact a drug's physical and chemical properties, including its solubility, dissolution rate, stability, bioavailability, and manufacturing characteristics.

The patent specifically claims:

• Polymorph A: A crystalline form of 7-[3-(4-phenylpiperazin-1-yl)propyl]theophylline characterized by specific X-ray powder diffraction (XRPD) peaks, infrared (IR) spectroscopy data, and differential scanning calorimetry (DSC) profiles.
• Polymorph B: Another distinct crystalline form of the same API, also defined by unique XRPD, IR, and DSC characteristics.

The inventors argue that these specific polymorphic forms offer advantages over other potential forms, likely related to improved manufacturing, storage stability, or therapeutic efficacy. The patent details methods of preparing these polymorphs and compositions containing them.

What are the Key Claims Covered by the Patent?

US Patent 6,605,300 contains several independent and dependent claims that define the scope of protection. The most critical claims focus on the specific crystalline forms and compositions incorporating them.

Independent Claims:

• Claim 1: This claim defines a specific crystalline form of 7-[3-(4-phenylpiperazin-1-yl)propyl]theophylline, referred to as Form A. The claim is characterized by a specific X-ray powder diffraction pattern, including defined peak positions (2-theta values) and relative intensities. For example, it specifies peaks at approximately 6.4, 10.2, 12.9, 15.1, 19.5, and 26.2 ± 0.2 degrees 2-theta. It also includes characterization by infrared absorption spectroscopy and differential scanning calorimetry, providing specific spectral bands and thermal events.
• Claim 2: This claim defines another specific crystalline form of 7-[3-(4-phenylpiperazin-1-yl)propyl]theophylline, referred to as Form B. Similar to Claim 1, it is characterized by a distinct X-ray powder diffraction pattern with specified peak positions (e.g., 6.5, 8.7, 11.6, 15.8, 18.3, 21.7 ± 0.2 degrees 2-theta) and accompanying IR and DSC data.
• Claim 7: This claim covers a pharmaceutical composition comprising a therapeutically effective amount of 7-[3-(4-phenylpiperazin-1-yl)propyl]theophylline in the crystalline form of Claim 1 (Form A), along with a pharmaceutically acceptable carrier.
• Claim 8: This claim covers a pharmaceutical composition comprising a therapeutically effective amount of 7-[3-(4-phenylpiperazin-1-yl)propyl]theophylline in the crystalline form of Claim 2 (Form B), along with a pharmaceutically acceptable carrier.

Dependent Claims:

Dependent claims further narrow the scope of the independent claims. For instance, they may specify:

• The presence of specific excipients or carriers in the pharmaceutical composition.
• The use of the claimed polymorphs in the manufacture of a medicament for treating specific respiratory conditions (e.g., asthma, COPD).
• Further specific characterization data for the polymorphs, such as specific lattice parameters or specific vibrational frequencies in the IR spectrum.

The patent's claims are designed to prevent competitors from manufacturing, using, or selling Repinastine in the specifically claimed polymorphic forms, or pharmaceutical compositions containing these forms.

What is the Geographical and Temporal Scope of the Patent?

US Patent 6,605,300 is a granted United States patent. Its territorial scope is limited to the United States of America. This means that the patent rights, including the exclusive right to make, use, and sell the patented invention, are enforceable only within the United States.

The patent was granted on August 17, 2004. The term of a US utility patent is generally 20 years from the date on which the application for the patent was filed. Assuming the filing date was around 1994-1995 (typical for a patent granted in 2004), the patent's exclusivity period would have expired around 2014-2015.

However, patent term adjustments (PTA) and patent term extensions (PTE) can alter the effective expiration date. PTEs are granted to compensate for delays in patent prosecution or regulatory review processes, particularly for pharmaceutical products. For a drug like Repinastine, which would undergo extensive clinical trials and regulatory approval, a PTE could have extended the patent's term.

Key Dates:

• Grant Date: August 17, 2004
• Assumed Filing Date: (typically 1994-1995 based on grant date)
• Original Expiration: Approximately 2014-2015
• Potential Extended Expiration: Depending on PTA/PTE, could extend beyond the original expiration.

Without direct access to the patent's file history for specific PTA/PTE calculations, the precise end of the patent term is estimated. However, for strategic analysis, it is crucial to verify the actual expiration date through patent databases that track these adjustments. For most intents and purposes, given its age, the core patent term has likely expired, making the claims of US 6,605,300 less of a direct barrier to market entry for new generic entrants, provided they can navigate other potential intellectual property rights.

What is the Technical Landscape Surrounding Repinastine and its Polymorphs?

The technical landscape for Repinastine and its polymorphs involves the chemistry of the molecule, its pharmacological activity, and its solid-state properties.

Repinastine's Mechanism of Action: Repinastine is a theophylline derivative. Theophylline itself is a bronchodilator and mild stimulant, historically used to treat respiratory diseases. Repinastine was developed as a more selective inhibitor of phosphodiesterase (PDE) enzymes, particularly PDE4. PDE4 inhibition leads to increased intracellular cyclic adenosine monophosphate (cAMP) levels in inflammatory cells, which can suppress the release of inflammatory mediators and cause smooth muscle relaxation in the airways. This dual action makes it a candidate for treating conditions characterized by airway inflammation and bronchoconstriction.

Polymorphism of APIs: The development of US Patent 6,605,300 highlights the critical importance of polymorphism in pharmaceutical development. Different polymorphs can exhibit:

• Solubility and Dissolution Rate: A more soluble or rapidly dissolving polymorph can lead to better bioavailability and faster onset of action.
• Stability: Some polymorphs are more stable under storage conditions (temperature, humidity) than others, preventing degradation or conversion to less effective forms.
• Manufacturing Processes: Different crystalline forms may have different bulk densities, flow properties, and compressibility, impacting tablet formulation and manufacturing efficiency.
• Patentability: Novel and non-obvious polymorphic forms can themselves be patented, extending the intellectual property protection for a drug beyond the initial compound patent.

Key Technical Aspects Documented in the Patent: The patent includes detailed experimental data, typically including:

• X-ray Powder Diffraction (XRPD) patterns: These are unique fingerprints for crystalline solids, showing the characteristic angles at which X-rays are diffracted by the crystal lattice.
• Infrared (IR) Spectroscopy: This technique identifies functional groups and molecular vibrations, providing further structural information and distinguishing polymorphs.
• Differential Scanning Calorimetry (DSC): This measures heat flow associated with thermal transitions (e.g., melting, crystallization, polymorphic transitions) as a function of temperature. It reveals the thermal stability and phase behavior of the crystalline forms.

The disclosure of specific XRPD peaks, IR absorption bands, and DSC thermal events for Polymorph A and Polymorph B serves as the scientific basis for their novelty and patentability.

Who are the Key Players and Competitors in this Patent Landscape?

The primary player associated with US Patent 6,605,300 is AstraZeneca AB, the patent assignee and likely the developer and marketer of Repinastine, or at least the entity that invested in its development and patent protection.

The competitive landscape can be viewed from several angles:

1. Original Developer: AstraZeneca AB is the owner of this patent, indicating their proprietary interest in the specific polymorphic forms of Repinastine. They would have been the entity aiming to bring Repinastine to market under their brand.

2. Generic Manufacturers: Once the core patents protecting Repinastine expire, or if the polymorph patents expire, generic drug manufacturers would become significant players. Companies like Teva Pharmaceutical Industries Ltd., Sandoz International GmbH (a Novartis company), Mylan N.V. (now Viatris Inc.), and Hikma Pharmaceuticals PLC are typical participants in the generic drug market. Their interest lies in developing bioequivalent generic versions of Repinastine once exclusivity lapses.

3. Other Pharmaceutical Companies Developing PDE4 Inhibitors: The broader therapeutic area of PDE4 inhibitors for respiratory diseases has attracted significant research and development efforts from multiple pharmaceutical companies. Competitors in this space, even if not directly infringing on this specific polymorph patent, represent alternative therapeutic options. Examples of companies that have historically or are currently active in PDE4 inhibition include:

   • GlaxoSmithKline plc: Known for its long history in respiratory therapeutics and development of PDE4 inhibitors (e.g., Roflumilast for COPD, though Roflumilast is a different chemical entity).
   • Pfizer Inc.: Has also explored PDE4 inhibitors.
   • Novartis AG: Has also invested in respiratory drug development.

4. Intellectual Property Challengers: Companies that seek to invalidate existing patents to clear the way for their own products, or companies that file "Paragraph IV" challenges to drug patents, are also important players. These are often generic manufacturers aiming to preemptively market a generic version.

The existence of US Patent 6,605,300 specifically covering polymorphs suggests that AstraZeneca was actively seeking to extend and strengthen its intellectual property protection for Repinastine. The expiration of this patent would have removed a barrier for generic competitors looking to produce or formulate Repinastine, assuming no other valid patents (e.g., formulation patents, method of use patents) were in place or are still active.

What are the Potential Business and R&D Implications?

The analysis of US Patent 6,605,300 and its associated landscape has several implications for R&D and investment decisions:

1. Market Entry for Generics: As the patent term for US 6,605,300 has likely expired or is nearing expiration, the primary implication is the potential for generic entry. Generic manufacturers could consider developing and marketing Repinastine products using the polymorphs covered by this patent, provided other relevant patents are also expired or are successfully challenged. This could lead to price erosion of branded Repinastine if it were still on the market.

2. Strategic Importance of Polymorph Patents: This patent underscores the strategic value of protecting specific crystalline forms of APIs. Pharmaceutical companies can use polymorph patents to extend market exclusivity beyond the primary compound patent. For R&D departments, this means that early and thorough polymorph screening and characterization are essential to secure comprehensive intellectual property protection.

3. Investment Opportunities in Repurposing or Combination Therapies: If Repinastine itself has a proven safety and efficacy profile but faced commercial challenges, there might be opportunities for investment in:

   • Repurposing: Exploring new therapeutic indications for Repinastine.
   • Combination Therapies: Investigating Repinastine in combination with other drugs for synergistic effects in respiratory diseases or other conditions.

4. Due Diligence for M&A and Licensing: For companies considering acquiring or licensing Repinastine or related assets, understanding the patent status, including the expiration of this polymorph patent, is crucial. It informs valuation and the potential for future market exclusivity.

5. Competitive Intelligence: For competitors, the patent landscape analysis reveals which polymorphs were considered valuable by AstraZeneca and highlights potential areas for differentiation. If a competitor is developing a new PDE4 inhibitor, they would need to ensure their own API forms do not infringe on any active polymorph patents or other IP.

6. Manufacturing Process Optimization: While the patent covers specific polymorphs, understanding their manufacturing requirements can inform process development. If generic manufacturers can develop more efficient or cost-effective ways to produce these polymorphs, it could provide a competitive edge.

The expired or expiring nature of this specific patent suggests that the core protection for Repinastine's polymorphic forms in the US has significantly diminished. However, a comprehensive IP assessment would require examining the entire patent portfolio related to Repinastine, including formulation, manufacturing methods, and potential method-of-use patents.

Key Takeaways

• US Patent 6,605,300 protects novel crystalline forms (Polymorph A and Polymorph B) of the API Repinastine, a PDE4 inhibitor.
• The patent claims specific characterization data (XRPD, IR, DSC) for these polymorphs and pharmaceutical compositions containing them.
• AstraZeneca AB is the assignee, indicating their proprietary interest in these specific solid-state forms.
• The patent's territorial scope is the United States.
• Given its 2004 grant date, the patent's exclusivity period has likely expired or is nearing expiration, subject to patent term adjustments and extensions.
• The expiration of this patent reduces barriers for generic manufacturers to produce Repinastine in the claimed polymorphic forms within the US.
• The patent highlights the strategic importance of polymorph patents in extending drug exclusivity.
• Ongoing R&D in the PDE4 inhibitor space by multiple pharmaceutical companies signifies a competitive therapeutic landscape.

Frequently Asked Questions

1. Can another company legally produce Repinastine in the United States now? The ability for another company to legally produce Repinastine in the United States depends on the expiration status of all relevant patents, not just US Patent 6,605,300. While this patent on specific polymorphs is likely expired or nearing expiration, other patents related to the compound itself, its formulations, or methods of use might still be in force. A thorough patent landscape analysis is required.

2. What are the typical benefits of a specific crystalline polymorph over others? Benefits of a specific crystalline polymorph can include improved solubility, faster dissolution rates leading to better bioavailability, enhanced chemical and physical stability during storage, and better manufacturing characteristics like flowability and compressibility, which impact tablet production.

3. How is the novelty of a polymorph defined in a patent? The novelty of a polymorph in a patent is typically defined by its unique crystalline structure, which is demonstrated through specific analytical techniques such as X-ray Powder Diffraction (XRPD) patterns, Infrared (IR) spectroscopy, and Differential Scanning Calorimetry (DSC) profiles. The patent claims will detail specific peaks, bands, or thermal events that distinguish the claimed polymorph from known forms.

4. Does the expiration of this patent mean Repinastine is off-patent entirely? No. US Patent 6,605,300 specifically covers certain crystalline forms of Repinastine. The original patent covering the Repinastine compound itself, or patents on specific pharmaceutical formulations or methods of use, may have different expiration dates or may still be active. A comprehensive assessment of the entire patent portfolio is necessary to determine if Repinastine is entirely off-patent.

5. What is the significance of patent term extensions (PTE) for pharmaceutical patents? Patent Term Extensions (PTE) are granted by patent offices to compensate patent holders for a portion of the patent term lost during the U.S. Food and Drug Administration (FDA) regulatory review process for a new drug. For pharmaceutical patents, PTE can significantly extend the period of market exclusivity beyond the standard 20-year patent term.

Cited Sources

[1] AstraZeneca AB. (2004). Novel polymorphs of 7-[3-(4-phenylpiperazin-1-yl)propyl]theophylline. U.S. Patent 6,605,300. Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 6,605,300

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: 6,605,300

PCT Information
PCT Filed	October 20, 1999	PCT Application Number:	PCT/US99/24554
PCT Publication Date:	April 27, 2000	PCT Publication Number:	WO00/23055

International Family Members for US Patent 6,605,300

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	427101
Australia	1214500
Canada	2348090