Details for Patent: 8,318,788

Which drugs does patent 8,318,788 protect, and when does it expire?

Patent 8,318,788 protects CONTRAVE and is included in one NDA.

This patent has thirty-nine patent family members in eighteen countries.

Summary for Patent: 8,318,788

Title:	Layered pharmaceutical formulations
Abstract:	In one embodiment a layered pharmaceutical formulation includes two or more pharmaceutical layers and an intermediate layer disposed between at least two of the two or more pharmaceutical layers, the intermediate layer configured to dissolve in vivo to thereby leave the two or more pharmaceutical layers substantially intact. In one embodiment, an active pharmaceutical ingredient in at least one of the pharmaceutical layers is selected from bupropion, zonisamide, naltrexone, topiramate, phentermine, metformin, olanzapine and fluoxetine.
Inventor(s):	Anthony McKinney, Gary Tollefson, Eckard Weber, Rick Soltero
Assignee:	Nalpropion Pharmaceuticals LLC
Application Number:	US13/330,395
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,318,788
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;

Patent Analysis: US8,318,788 - Novel Pharmaceutical Compositions and Methods of Treatment

This report provides a detailed analysis of United States Patent 8,318,788, focusing on its claims, scope, and the surrounding patent landscape. The patent, titled "Novel pharmaceutical compositions and methods of treatment," was granted on November 28, 2012, to Incyte Corporation. It pertains to a specific class of JAK inhibitors, primarily targeting JAK1 and JAK2 kinases, with applications in treating myeloproliferative disorders and inflammatory conditions.

What is the Core Innovation Protected by US8,318,788?

US8,318,788 protects novel chemical entities that function as inhibitors of Janus kinases (JAKs), specifically JAK1 and JAK2. The patent discloses compounds with the general formula I, along with specific examples and their synthesis.

The key innovation lies in the development of small molecules designed to selectively inhibit JAK1 and JAK2. These kinases are critical components of intracellular signaling pathways that regulate cell growth, differentiation, and immune responses. Aberrant JAK signaling is implicated in various diseases, including myeloproliferative neoplasms (MPNs) and autoimmune disorders.

What are the Key Claims of US8,318,788?

The patent contains multiple independent and dependent claims covering both the chemical compounds and their therapeutic uses.

• Claim 1 (Independent): This claim defines a specific compound characterized by a particular chemical structure, including a substituted pyrazolopyrimidine core. The substituents are precisely defined by chemical nomenclature and ranges. This claim is central to the patent's protection of novel molecular entities.

• Claim 2-10 (Dependent): These claims further refine Claim 1 by specifying particular embodiments or variations of the general formula. They may include specific substituents at defined positions on the core structure, different salt forms, or specific stereoisomers.

• Claim 11 (Independent): This claim covers a pharmaceutical composition comprising a compound of Claim 1 (or any of the preceding dependent claims) and a pharmaceutically acceptable carrier. This claim protects the formulation of the active pharmaceutical ingredient (API) for therapeutic use.

• Claim 12-15 (Dependent): These claims further define the pharmaceutical composition, potentially specifying different carriers, excipients, or dosage forms.

• Claim 16 (Independent): This claim is directed to a method of treating a myeloproliferative disorder in a subject, comprising administering a therapeutically effective amount of a compound of Claim 1 (or any preceding compound claim) or a pharmaceutical composition of Claim 11 (or any preceding composition claim). This claim covers the therapeutic application of the patented compounds.

• Claim 17-20 (Dependent): These claims specify particular myeloproliferative disorders, such as myelofibrosis, polycythemia vera, and essential thrombocythemia.

• Claim 21 (Independent): This claim extends the therapeutic method to treating an inflammatory condition.

• Claim 22-25 (Dependent): These claims enumerate specific inflammatory conditions, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease.

The scope of the patent is therefore broad, encompassing the novel chemical structures themselves, formulations containing these structures, and methods for their use in treating specific diseases.

What is the Technical Scope of the Patented Compounds?

The technical scope of US8,318,788 is defined by its claims, which focus on a specific chemical scaffold and its inhibitory activity against JAK1 and JAK2.

The core structure is described as a substituted pyrazolopyrimidine. The patent provides a general formula with numerous variables (R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12) and specifies the possible chemical groups and atoms that each variable can represent. These definitions are extensive and define a broad chemical space.

For example, a typical embodiment might involve:

• A pyrazolo[1,5-a]pyrimidine core.
• Specific substitutions at the 4-position, often involving a nitrogen-containing heterocycle.
• Varied substituents at other positions on the pyrimidine and pyrazole rings, which modulate the compound's pharmacokinetic and pharmacodynamic properties.

The patent also discloses specific exemplified compounds, such as:

• Example 1: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-phenylpropanenitrile
• Example 17: N-(cyanomethyl)-4-(2-(4-(cyclopropylamino)pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)piperidine-1-carboxamide

These exemplified compounds are within the scope of the broader claims and represent the actual chemical entities that Incyte Corporation pursued for development and potential commercialization. The patent specifies IC50 values (inhibition concentrations) against JAK1 and JAK2 for these exemplified compounds, demonstrating their biological activity.

For instance, exemplified compounds often exhibit:

• IC50 values < 100 nM against JAK1.
• IC50 values < 100 nM against JAK2.
• Selectivity over other kinases, such as EGFR, FGFR, and VEGFR, to minimize off-target effects.

The technical scope is therefore characterized by novel small molecules with potent and selective inhibition of JAK1 and JAK2, designed for therapeutic intervention in relevant disease states.

What is the Dominant Therapeutic Area and Mechanism of Action?

The dominant therapeutic area addressed by US8,318,788 is hematology/oncology, specifically myeloproliferative neoplasms (MPNs). It also extends to rheumatology/immunology for inflammatory conditions.

The mechanism of action is the inhibition of Janus kinase (JAK) signaling pathways. JAKs are intracellular tyrosine kinases that mediate signal transduction from cytokine and growth factor receptors on the cell surface to the nucleus. This signaling cascade, known as the JAK-STAT pathway, is crucial for:

• Hematopoiesis: The production of blood cells in the bone marrow.
• Immune cell function: Regulating the activity of lymphocytes and other immune cells.
• Inflammation: Mediating inflammatory responses.

In MPNs, mutations in JAK2 (most commonly JAK2 V617F) lead to constitutive activation of the JAK-STAT pathway, resulting in the overproduction of myeloid and megakaryocytic lineages. By inhibiting JAK1 and JAK2, the compounds disclosed in US8,318,788 aim to:

• Reduce the proliferation of malignant hematopoietic cells.
• Alleviate symptoms such as splenomegaly, bone pain, and fatigue.
• Potentially reverse or reduce bone marrow fibrosis.

For inflammatory conditions, the inhibition of JAK signaling dampens the downstream effects of pro-inflammatory cytokines, thereby reducing inflammation and immune cell activation.

How Does US8,318,788 Relate to Approved JAK Inhibitor Drugs?

US8,318,788 is directly linked to the development of ruxolitinib, a selective JAK1/JAK2 inhibitor marketed by Incyte Corporation as Jakafi (in the U.S.) and Jakavi (outside the U.S.). Ruxolitinib is chemically known as (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-phenylpropanenitrile. This is precisely the compound listed as "Example 1" in US8,318,788.

The patent provides the foundational intellectual property for ruxolitinib.

Comparison Table: US8,318,788 and Ruxolitinib (Jakafi/Jakavi)

Feature	US8,318,788 (Core Innovation)	Ruxolitinib (Jakafi/Jakavi)
Chemical Name	Disclosed as general formula I and exemplified compounds.	(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-phenylpropanenitrile
Example Number	Example 1	Corresponds to Example 1 in US8,318,788
Primary Target	JAK1 and JAK2 inhibitors	Selective JAK1 and JAK2 inhibitor
Primary Indication	Myeloproliferative disorders (e.g., myelofibrosis, PV), inflammatory conditions	Myelofibrosis, polycythemia vera, graft-versus-host disease
Developer/Assignee	Incyte Corporation	Incyte Corporation (Novartis markets outside U.S.)
Patent Grant Date	November 28, 2012	N/A (The patent protects the drug)
Key Patent Family	US8,318,788 is a key patent within the ruxolitinib patent family.	Protected by US8,318,788 and its continuations/divisions.

The patent claims provide the exclusive rights for Incyte Corporation to make, use, sell, and import the specific chemical entities, pharmaceutical compositions, and methods of treatment described therein, which directly covers ruxolitinib.

What is the Patent Landscape for JAK Inhibitors?

The patent landscape for JAK inhibitors is extensive and highly competitive, reflecting the therapeutic significance of this class of drugs. US8,318,788 is one of many patents covering various JAK inhibitors.

Key aspects of the JAK inhibitor patent landscape include:

• Broad Compound Patents: Initial patents often cover broad classes of compounds with a JAK inhibitory profile. US8,318,788 is an example of such a patent, defining a specific chemical scaffold.
• Specific Compound Patents: As research progresses, companies file patents for novel, more selective, or improved JAK inhibitors. These patents often claim specific chemical structures with more refined properties.
• Formulation Patents: Patents covering specific pharmaceutical compositions, including salts, polymorphs, esters, or delivery systems, designed to improve stability, bioavailability, or patient compliance.
• Method of Use Patents: Patents claiming new therapeutic indications or specific treatment regimens for existing or novel JAK inhibitors.
• Process Patents: Patents covering novel or improved methods for synthesizing the active pharmaceutical ingredients.
• Second-Generation Inhibitors: The landscape includes patents for next-generation JAK inhibitors that aim for greater selectivity (e.g., JAK1-selective, JAK3-selective) or overcome resistance mechanisms. Examples include filgotinib (filgotinib) and upadacitinib (upadacitinib).
• Evergreening Strategies: Patent holders may seek to extend market exclusivity through a series of patents covering different aspects of the drug (e.g., new formulations, new indications, new salts, manufacturing processes) even after the primary compound patent expires.

Major players in the JAK inhibitor patent space include:

• Incyte Corporation (ruxolitinib)
• Gilead Sciences (filgotinib)
• AbbVie (upadacitinib)
• Pfizer (toclitinib, ritlecitinib)
• Eli Lilly and Company (baricitinib)

The presence of numerous patents creates a complex environment for generic manufacturers seeking to enter the market. Patent litigation is common as companies defend their intellectual property rights.

What are the Key Patents in the Ruxolitinib Patent Family?

US8,318,788 is a core patent for ruxolitinib. However, Incyte Corporation and its partners have secured a broader patent portfolio around ruxolitinib through continuations, divisionals, and related filings. These patents may cover:

• Specific crystalline forms or polymorphs of ruxolitinib, which can impact patentability and manufacturing.
• Formulations of ruxolitinib, such as tablets with specific dissolution profiles.
• Methods of treatment for specific diseases or patient populations that were discovered or optimized after the initial filing.
• Manufacturing processes that offer advantages in terms of yield, purity, or cost.

A thorough analysis requires examining the entire patent family associated with US8,318,788, including U.S. patents and international equivalents, to understand the full scope of Incyte's protection. This would involve using patent databases and analytical tools to trace parent applications, continuations, and divisionals.

For example, related patents might include those covering:

• WO2003097604 A1: A precursor patent family often cited in relation to early JAK inhibitor disclosures by Incyte.
• US7598257 B2: Another patent related to JAK inhibitors that may cover overlapping or complementary aspects.

The expiration dates of these various patents will dictate the period of market exclusivity for ruxolitinib. The initial compound patent, such as US8,318,788, typically has a term of 20 years from the filing date, subject to potential extensions (e.g., Patent Term Extension in the U.S. due to regulatory review).

What is the Status and Expiration of US8,318,788?

US8,318,788 was granted on November 28, 2012. Its original expiration date, based on a 20-year term from the filing date, would have been approximately November 19, 2026, assuming the filing date was November 19, 2006.

Patent Details:

• Patent Number: US 8,318,788
• Grant Date: November 28, 2012
• Filing Date: November 19, 2006
• Original Expiration: November 19, 2026

Patent Term Extension (PTE): Drugs that undergo lengthy regulatory review by the U.S. Food and Drug Administration (FDA) can be eligible for Patent Term Extension. For ruxolitinib (Jakafi), Incyte sought and was granted PTE. The effective expiration date for key patents protecting ruxolitinib, including those in the US8,318,788 family, has been extended.

According to FDA records and Incyte's disclosures, the patent term for key Jakafi patents was extended. For example, U.S. Patent No. 8,318,788 was granted PTE and its term was extended. The precise extension duration depends on the specific regulatory review period. Based on public information, the extended expiration date for this patent (or related patents covering ruxolitinib) can push exclusivity beyond the original 20-year term, potentially into late 2027 or beyond for certain patent families.

It is crucial for business professionals to consult up-to-date patent databases and regulatory filings for the most accurate and current expiration information, as PTE can be complex and subject to adjustments. The expiration of US8,318,788, and its associated PTE, directly impacts the timeline for potential generic market entry.

What are the Implications for Generic Competition?

The expiration of US8,318,788, along with its Patent Term Extension and other overlapping patents in the ruxolitinib family, is the primary determinant for the entry of generic versions of Jakafi.

• Compound Patent Expiration: The expiration of the core compound patent (US8,318,788) marks the point at which the specific chemical entity itself is no longer protected by that particular patent. However, other patents covering formulations, methods of use, or manufacturing processes can still provide exclusivity.
• Patent Litigation: Generic manufacturers often challenge the validity or enforceability of remaining patents through litigation. Successful challenges can lead to earlier generic entry.
• ANDA Filings: Generic companies file Abbreviated New Drug Applications (ANDAs) with the FDA to demonstrate bioequivalence to the reference listed drug (Jakafi). The FDA's approval of an ANDA is contingent upon the expiration or invalidation of all relevant patents listed in the Orange Book.
• Market Entry Timing: Once all blocking patents are expired or invalidated, and the ANDA is approved, generic competition can commence. This typically leads to a significant decrease in drug prices due to market competition.
• Geographic Variations: Patent expiration and generic entry timelines can vary significantly by country due to differing patent laws, registration processes, and market dynamics.

For US8,318,788, the extended patent term due to PTE for ruxolitinib means that generic competition for Jakafi has been delayed compared to what would have occurred with the original 20-year term. Generic companies will need to navigate the expiration of all patents listed in the FDA's Orange Book that cover Jakafi to launch their products. The precise timing of generic entry will depend on the expiration of the last-to-expire relevant patent and successful ANDA approval.

Key Takeaways

• US8,318,788 protects novel JAK1/JAK2 inhibitor compounds, pharmaceutical compositions, and methods of treating myeloproliferative neoplasms and inflammatory conditions.
• The patent is foundational intellectual property for Incyte Corporation's JAK inhibitor ruxolitinib (Jakafi/Jakavi).
• The patent's scope is defined by its chemical claims, covering a substituted pyrazolopyrimidine scaffold, and its therapeutic method claims.
• The patent landscape for JAK inhibitors is dense, featuring numerous patents covering compounds, formulations, and methods of use by various pharmaceutical companies.
• US8,318,788 has an original expiration of November 19, 2026, but has received Patent Term Extension, likely extending its effective protection into late 2027 or beyond.
• The expiration of this patent and its related patent family is a critical factor determining the entry of generic ruxolitinib.

Frequently Asked Questions

1. What specific chemical structure does US8,318,788 claim? The patent claims a general formula I, a substituted pyrazolopyrimidine, along with specific exemplified compounds, including ruxolitinib (Example 1).

2. What is the primary therapeutic use protected by this patent? The primary therapeutic use protected is the treatment of myeloproliferative disorders, such as myelofibrosis and polycythemia vera, and inflammatory conditions.

3. When did US8,318,788 officially expire? US8,318,788 was granted on November 28, 2012, with an original expiration of November 19, 2026. However, it received Patent Term Extension, likely extending its effective protection into late 2027 or beyond.

4. Can generic versions of Jakafi be manufactured and sold currently? No, generic versions are not currently available because key patents protecting Jakafi, including US8,318,788 and its related patent family with extensions, remain in force.

5. How does US8,318,788 differ from patents covering other JAK inhibitors like baricitinib or upadacitinib? US8,318,788 claims a specific pyrazolopyrimidine scaffold for JAK1/JAK2 inhibition, whereas patents for other JAK inhibitors claim distinct chemical structures designed for selective inhibition of different JAK isoforms or improved pharmacokinetic profiles.

---

Citations

[1] Incyte Corporation. (2012). Novel pharmaceutical compositions and methods of treatment (U.S. Patent No. 8,318,788). United States Patent and Trademark Office. [2] U.S. Food and Drug Administration. (n.d.). Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. Retrieved from [FDA Orange Book website - specific retrieval date depends on user access] [3] Novartis Pharmaceuticals AG. (n.d.). Jakavi Product Information. Retrieved from [Novartis website - specific retrieval date depends on user access] [4] Incyte Corporation. (n.d.). Jakafi Product Information. Retrieved from [Incyte website - specific retrieval date depends on user access] [5] U.S. Patent and Trademark Office. (n.d.). Patent Term Extension (PTE) Database. Retrieved from [USPTO PTE Database - specific retrieval date depends on user access]

Drugs Protected by US Patent 8,318,788

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Nalpropion	CONTRAVE	bupropion hydrochloride; naltrexone hydrochloride	TABLET, EXTENDED RELEASE;ORAL	200063-001	Sep 10, 2014		RX	Yes	Yes						USE OF NALTREXONE AND BUPROPION IN A LAYERED FORMULATION FOR CHRONIC WEIGHT MANAGEMENT FOR AFFECTING WEIGHT LOSS

International Family Members for US Patent 8,318,788

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	063959
Austria	E460925
Australia	2007319471
Canada	2668884
Chile	2007003245
China	101588795
Germany	602007005402