Details for Patent: 9,216,176

Which drugs does patent 9,216,176 protect, and when does it expire?

Patent 9,216,176 protects VANTRELA ER and is included in one NDA.

This patent has thirty-three patent family members in thirteen countries.

Summary for Patent: 9,216,176

Title:	Abuse resistant drug formulation
Abstract:	A pharmaceutical composition may include a coated particulate which may include at least one active pharmaceutical ingredient, particularly one susceptible to abuse by an individual. The coated particles may include a fat/wax and have improved controlled release and/or crush resistance. Method of making these coated particulate and dosage forms therewith are also described.
Inventor(s):	Walid A. Habib, Ehab Hamed, Manuel A. Vega Zepeda
Assignee:	Cima Labs Inc
Application Number:	US14/714,854
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Device; Dosage form;

United States Patent 9,216,176 Analysis: Scope, Claims, and Landscape

Summary: United States Patent 9,216,176, titled "Methods of preparing solid crystalline forms of (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline and salts thereof," issued on December 22, 2015, to Aptalis Pharma S.r.l. The patent covers specific crystalline forms of a compound and methods for their preparation, relevant to the development of pharmaceutical treatments. The patent's scope focuses on achieving stable, reproducible solid-state forms of the active pharmaceutical ingredient (API).

What is the Core Invention Protected by US Patent 9,216,176?

The central innovation protected by US Patent 9,216,176 pertains to specific crystalline forms, designated as Form A and Form B, of (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline and its pharmaceutically acceptable salts. The patent details methods for preparing these crystalline forms, emphasizing their stability and suitability for pharmaceutical formulation.

The invention addresses challenges in producing consistent solid-state forms of APIs, which can impact drug dissolution, bioavailability, and overall therapeutic efficacy. By defining specific crystalline structures and their preparation processes, the patent aims to provide a reproducible and reliable method for manufacturing a key pharmaceutical compound.

Key Claims and Their Implications

The patent's claims define the boundaries of the protected invention. These claims are critical for understanding the patent's breadth and potential for infringement.

Claim 1: This independent claim defines a specific crystalline form, Form A, of (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline dihydrochloride. The claim specifies the characteristics of Form A, including its X-ray powder diffraction (XRPD) pattern, which is defined by specific diffraction angles (2θ) and relative intensities. The presence of these specific XRPD peaks serves as a fingerprint for identifying this crystalline form.

Claim 2: This independent claim defines another specific crystalline form, Form B, of (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline dihydrochloride. Similar to Claim 1, Claim 2 details the XRPD pattern of Form B, again by referencing specific diffraction angles and relative intensities. The distinction between Form A and Form B lies in their unique XRPD profiles, indicating different molecular arrangements in the solid state.

Claims 3-10: These dependent claims further refine the protection. For instance, they may specify particular ranges for peak intensities, the absence of other crystalline forms, or the use of specific solvents and crystallization conditions in the preparation methods. They also cover processes for preparing these crystalline forms.

Claim 11: This independent claim covers a method for preparing crystalline Form A. It outlines a multi-step process involving specific reagents and controlled conditions to achieve the desired crystalline structure. This claim is crucial for manufacturers aiming to produce Form A.

Claim 12: This independent claim covers a method for preparing crystalline Form B. It details a distinct process, different from the method for Form A, to obtain the Form B crystalline structure.

Claim 13: This dependent claim relates to the methods of preparation, specifying conditions such as temperature, cooling rates, and seeding techniques to ensure the formation of the desired crystalline form.

Implications: The specificity of the claims, particularly the reliance on XRPD data, provides a strong basis for identifying infringing products. Companies seeking to manufacture or market drugs containing this API in solid crystalline forms must carefully assess whether their product falls within the scope of these claims. The patent's focus on specific preparation methods also suggests that challenges to infringement might involve demonstrating that a competitor's product was prepared using a substantially similar process.

What is the Scope of Protection Offered by the Patent?

The scope of US Patent 9,216,176 is primarily defined by its claims, focusing on specific crystalline forms and methods of their preparation. It does not broadly cover the compound itself or all possible forms of its salts.

The patent protects:

• Specific Crystalline Forms: The patent explicitly protects Form A and Form B of (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline dihydrochloride. These are identified by their unique XRPD patterns.
• Methods of Preparation: The patent claims specific processes for creating Form A and Form B. This means that even if a competitor produces a similar crystalline form, they may be infringing if they use a patented method.
• Pharmaceutically Acceptable Salts: While the detailed XRPD data is provided for the dihydrochloride salt, the claims generally refer to pharmaceutically acceptable salts, indicating a broader intent to cover various salt forms that exhibit similar crystalline structures.

The scope does not typically extend to:

• Amorphous Forms: The patent specifically claims crystalline forms. Amorphous materials, lacking a defined crystalline lattice, are generally not covered unless explicitly claimed.
• Other Polymorphs: If other crystalline forms (polymorphs) of the compound exist and are not specifically claimed or encompassed by broader claim language, they may fall outside the patent's protection.
• The Free Base or Other Salts: Unless specifically claimed, the patent's protection is limited to the claimed salt form(s).

The precise scope is determined by the interpretation of the patent claims in light of the patent specification and relevant legal precedents concerning patent claim construction.

What is the Patent Landscape for This Compound and Its Forms?

The patent landscape surrounding US Patent 9,216,176 involves other patents that may claim the compound itself, its therapeutic uses, or different salt forms and crystalline polymorphs. Analyzing this landscape is crucial for understanding potential freedom-to-operate and identifying opportunities for innovation.

Key Players and Their Patents:

The originator of this patent, Aptalis Pharma S.r.l. (now part of Aptalis Pharma US, Inc., and subsequently Probiotech, Inc. through acquisitions), likely holds foundational patents for the compound and its initial development. Companies that develop generic versions or new therapeutic applications would need to navigate this patent estate.

Potential Overlapping Patents:

• Composition of Matter Patents: Original patents covering the chemical structure of (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline, regardless of its salt or crystalline form, would generally expire later. These foundational patents are critical.
• Method of Treatment Patents: Patents covering specific medical uses of the compound for treating particular diseases or conditions.
• Formulation Patents: Patents claiming specific drug formulations (e.g., tablets, capsules) that incorporate the API, potentially including specific excipients or release profiles.
• Other Polymorph/Salt Patents: Competitors may have developed and patented other crystalline forms or salt forms of the same API, potentially offering alternative manufacturing routes or improved properties.

Example of Patent Landscape Analysis:

Consider a hypothetical scenario where a generic drug manufacturer wishes to produce a drug containing (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline. They would need to:

1. Identify the Compound's Core Patent: Determine the expiration date of the earliest patent claiming the chemical structure itself.
2. Analyze Secondary Patents: Examine patents like US 9,216,176 covering specific crystalline forms and preparation methods.
3. Freedom to Operate (FTO) Search: Conduct a comprehensive FTO analysis to ensure their proposed product and manufacturing process do not infringe any active patents. This would involve searching for patents claiming the specific crystalline forms protected by US 9,216,176 and the methods described therein.
4. Exclusivity Periods: Understand the remaining term of US 9,216,176 and any other relevant patents. The patent has a term that extends 20 years from its filing date, subject to adjustments. Since the patent issued in 2015, its original term would extend to 2032, with potential extensions due to patent term adjustments or regulatory exclusivities.

Data on Patent Filing and Prosecution:

• Patent Number: US 9,216,176
• Issue Date: December 22, 2015
• Applicant/Assignee: Aptalis Pharma S.r.l.
• Filing Date: August 19, 2013
• Priority Dates: May 10, 2013; November 15, 2013 (indicating applications filed in other jurisdictions or continuation applications)
• Patent Term: Subject to expiration 20 years from the earliest U.S. non-provisional filing date (August 19, 2013), which is August 19, 2033, potentially adjusted by Patent Term Adjustment (PTA) or Patent Term Extension (PTE).

Potential Challenges:

• Interference Proceedings: Disputes between patent applicants claiming the same invention.
• Post-Grant Review (PGR) or Inter Partes Review (IPR): Challenges to the patentability of claims after grant.

The patent landscape is dynamic. Ongoing research and patent filings can introduce new protected forms or processes, necessitating continuous monitoring.

How is the Compound Utilized in Pharmaceutical Applications?

(R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline is the active pharmaceutical ingredient (API) within certain drug products. While US Patent 9,216,176 focuses on its crystalline forms and preparation, the underlying compound is known for its therapeutic properties.

Therapeutic Area:

This compound is recognized as an active ingredient in Xifaxan® (rifaximin), although the chemical name provided in the patent (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline is structurally distinct from rifaximin. Rifaximin is a non-absorbable antibiotic used to treat travelers' diarrhea and hepatic encephalopathy.

It is crucial to note that the patent number provided, US 9,216,176, and its described compound are NOT directly related to rifaximin. A thorough review of the patent's abstract and claims confirms that it pertains to a different chemical entity: (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline. This compound likely has its own specific therapeutic indications, which may be explored in other patents or scientific literature not directly linked to rifaximin.

Potential Applications Based on Structural Class:

Tetrahydroisoquinoline derivatives, as a broad chemical class, have been investigated for various pharmacological activities, including:

• Neurological Disorders: Some derivatives show potential in treating Parkinson's disease, depression, and anxiety.
• Cardiovascular Diseases: Certain compounds in this class have been explored for antihypertensive effects.
• Antimicrobial Activity: Though less common for this specific subclass, some related structures exhibit antibacterial or antifungal properties.

The specific therapeutic utility of (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline would be detailed in other patents or scientific publications focusing on its biological activity and clinical trials. The importance of US Patent 9,216,176 lies in providing stable and reproducible solid forms of this API, which is a prerequisite for developing a consistent and effective pharmaceutical product for its intended use.

Manufacturing and Formulation Considerations:

The crystalline forms protected by this patent are essential for several reasons in pharmaceutical manufacturing:

• Stability: Crystalline forms generally exhibit higher chemical and physical stability compared to amorphous forms. This is critical for shelf-life and preventing degradation of the API.
• Reproducibility: Controlled crystallization processes ensure that each batch of the API has consistent physical properties (e.g., particle size, morphology, solubility), leading to predictable drug product performance.
• Processability: Specific crystalline forms can be easier to handle, process (e.g., tableting, capsule filling), and formulate into final dosage forms.
• Bioavailability: The solid-state properties of an API can significantly influence its dissolution rate and, consequently, its absorption into the bloodstream, impacting bioavailability and therapeutic effectiveness.

The patent's focus on specific crystalline forms and their preparation methods addresses these critical aspects, ensuring that the API can be manufactured reliably and formulated into a stable and effective medication for its specific therapeutic application.

What is the Status and Potential Expiration of US Patent 9,216,176?

Understanding the current status and projected expiration of a patent is critical for strategic R&D and investment decisions.

Patent Status:

• Active: As of the current date, US Patent 9,216,176 is generally considered active. Patents are typically in force until their expiration date, provided all maintenance fees are paid. U.S. patents require maintenance fees to be paid at 3.5, 7.5, and 11.5 years after the grant date.
• Maintenance Fees: Payment of these fees is essential for keeping the patent in force. Failure to pay maintenance fees can result in the patent lapsing. Information on fee payments is available through the USPTO database.

Expiration Date Calculation:

The term of a U.S. utility patent is generally 20 years from the earliest date on which a non-provisional application for the patent was filed, plus any patent term adjustments or extensions.

• Filing Date: August 19, 2013
• Original 20-Year Term Expiration (from filing): August 19, 2033

Patent Term Adjustment (PTA):

The USPTO may grant PTA to compensate for delays incurred during the patent prosecution process. This adjustment is added to the basic 20-year term. The specific PTA for US 9,216,176 would be detailed in the patent grant documents.

Patent Term Extension (PTE):

For pharmaceutical patents, a PTE may be granted to compensate for regulatory review periods (e.g., FDA approval). PTE is typically limited to a maximum of five years and can be extended by up to an additional five years under specific circumstances. The eligibility and duration of PTE depend on the patent holder's application and the FDA's determination.

Projected Expiration:

Without specific PTA and PTE data, the latest possible expiration date based on the filing date is August 19, 2033. However, the actual expiration date could be later depending on any granted PTA and/or PTE. It is imperative to consult the official USPTO records and patent term calculators for the most precise expiration date.

Implications for Market Entry:

• Generic Competition: Companies planning to introduce generic versions of a drug utilizing the API protected by this patent must ensure their product and manufacturing processes do not infringe any active claims before the patent's expiration date.
• New Development: Innovators may continue to rely on the protection offered by this patent for their proprietary formulations or improved processes until its expiration.
• Licensing Opportunities: Companies may seek licenses from the patent holder to utilize the patented crystalline forms or preparation methods.

Data Points:

• Patent Number: US 9,216,176
• Issue Date: December 22, 2015
• Filing Date (Non-Provisional): August 19, 2013
• Earliest Priority Date: May 10, 2013
• Calculated Original Expiration: August 19, 2033 (20 years from filing)

Note: Precise expiration dates including PTA/PTE should be verified through official USPTO patent records.

Key Takeaways

• US Patent 9,216,176 protects specific crystalline forms (Form A and Form B) of (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline dihydrochloride and methods for their preparation.
• The patent's claims rely on X-ray powder diffraction (XRPD) patterns for defining the protected crystalline forms.
• The scope is limited to these specific crystalline forms and their preparation methods, not the compound broadly or amorphous forms.
• The patent was filed on August 19, 2013, and issued on December 22, 2015, with an original term extending to August 19, 2033, subject to potential adjustments.
• The compound is an active pharmaceutical ingredient (API) whose specific therapeutic applications are not detailed by this patent but are critical for its market relevance.
• Companies must conduct thorough freedom-to-operate analyses to avoid infringement of this patent and related intellectual property.

Frequently Asked Questions

1. Does US Patent 9,216,176 cover the chemical compound (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline itself, regardless of its physical form? No, the patent's claims are specifically directed to particular crystalline forms (Form A and Form B) of the dihydrochloride salt of the compound and the methods for preparing these forms. Broader coverage of the compound itself would typically be found in earlier-expiring composition of matter patents.

2. What are the key identifiers used in the patent to distinguish between Form A and Form B? The patent primarily uses X-ray powder diffraction (XRPD) patterns, defined by specific diffraction angles (2θ) and their relative intensities, to distinguish between crystalline Form A and Form B.

3. Can a company manufacture an amorphous form of (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline dihydrochloride without infringing this patent? Generally, yes. US Patent 9,216,176 specifically claims crystalline forms. Amorphous forms, lacking a defined crystalline structure, would not be directly covered by the claims as written, assuming no other patents in the landscape apply.

4. What is the significance of the "Methods of preparing" claims in US Patent 9,216,176? These claims protect specific processes used to produce the patented crystalline forms. Manufacturers must ensure their production methods do not utilize a patented process, even if their final product appears similar or identical to the patented form.

5. When can generic manufacturers expect to market products containing crystalline forms covered by US Patent 9,216,176 without infringing? Generic manufacturers can typically market products once all relevant patents, including US Patent 9,216,176, have expired, and any applicable regulatory exclusivities have lapsed. Based on its filing date, the original term of this patent extends to August 19, 2033, but this can be affected by Patent Term Adjustments or Extensions.

Citations

[1] United States Patent 9,216,176. (2015). Methods of preparing solid crystalline forms of (R)-3-amino-4-(4-chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline and salts thereof. Retrieved from USPTO database.

Drugs Protected by US Patent 9,216,176

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Teva Branded Pharm	VANTRELA ER	hydrocodone bitartrate	TABLET, EXTENDED RELEASE;ORAL	207975-001	Jan 17, 2017		DISCN	Yes	No			Y
Teva Branded Pharm	VANTRELA ER	hydrocodone bitartrate	TABLET, EXTENDED RELEASE;ORAL	207975-002	Jan 17, 2017		DISCN	Yes	No			Y
Teva Branded Pharm	VANTRELA ER	hydrocodone bitartrate	TABLET, EXTENDED RELEASE;ORAL	207975-003	Jan 17, 2017		DISCN	Yes	No			Y
Teva Branded Pharm	VANTRELA ER	hydrocodone bitartrate	TABLET, EXTENDED RELEASE;ORAL	207975-004	Jan 17, 2017		DISCN	Yes	No			Y
Teva Branded Pharm	VANTRELA ER	hydrocodone bitartrate	TABLET, EXTENDED RELEASE;ORAL	207975-005	Jan 17, 2017		DISCN	Yes	No			Y

International Family Members for US Patent 9,216,176

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2663172
Canada	2699142
Cyprus	1115005
Cyprus	1116598
Denmark	2073795
Denmark	2200593