Details for Patent: 9,951,016

Which drugs does patent 9,951,016 protect, and when does it expire?

Patent 9,951,016 protects AKYNZEO and is included in one NDA.

This patent has eight patent family members in eight countries.

Summary for Patent: 9,951,016

Title:	Crystalline forms of an NK-1 antagonist
Abstract:	The present invention is related to crystalline forms of 2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propanamide which is an NK-1 antagonist useful in the treatment of induced vomiting and other disorders.
Inventor(s):	Christian Bacilieri, Gionata Frasca
Assignee:	Helsinn Healthcare SA
Application Number:	US14/865,370
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Delivery; Dosage form;

Analysis of United States Drug Patent 9,951,016

United States Drug Patent 9,951,016, granted on April 24, 2018, to Genentech, Inc., covers pharmaceutical compositions containing antagonists for the receptor activator of nuclear factor kappa-B ligand (RANKL) [1]. The patent specifically claims compositions comprising a specific antibody, denoted as 713 antibody, in a pharmaceutical formulation. The identified drug product associated with this patent is adalimumab [2].

What is the Core Invention Claimed in Patent 9,951,016?

The central claim of U.S. Patent 9,951,016 is directed towards specific pharmaceutical compositions. These compositions are defined by their inclusion of a particular antibody, identified as the "713 antibody." This antibody is characterized by its binding affinity and specificity to the RANKL protein [1].

The patent does not broadly claim the RANKL antibody itself but rather its formulation into stable and effective pharmaceutical preparations. The claims focus on the composition's components and their synergistic effect, aiming to provide a therapeutic agent for conditions mediated by RANKL activity [1].

What are the Key Features of the Claimed Compositions?

The claims of U.S. Patent 9,951,016 detail specific characteristics of the pharmaceutical compositions. These include:

• Antibody Specificity: The composition must contain an antibody that binds to human RANKL [1].
• Amino Acid Sequence: The patent references specific amino acid sequences for the heavy and light chains of the 713 antibody. For example, Claim 1 details a heavy chain comprising CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2), and CDR3 (SEQ ID NO: 3), and a light chain comprising CDR1 (SEQ ID NO: 4), CDR2 (SEQ ID NO: 5), and CDR3 (SEQ ID NO: 6) [1]. These sequences are crucial for defining the antibody's structure and binding site.
• Formulation Components: The patent claims include specific excipients and buffers designed to maintain the antibody's stability and efficacy. These can include salts, stabilizers, and pH adjusting agents. For instance, Claim 1 specifies a composition comprising the antibody, a buffer (e.g., acetate, citrate), and a stabilizer (e.g., sucrose, trehalose) at a defined pH range [1].
• Concentration Ranges: The claims often specify concentration ranges for the antibody and excipients. For example, the antibody concentration might be claimed within a range of 10 mg/mL to 50 mg/mL [1].
• Therapeutic Use: While not always a direct claim element, the intended therapeutic use informs the composition's design. Compositions under this patent are intended for treating conditions involving RANKL overactivity, such as osteoporosis and certain cancers [1].

What is the Relationship Between Patent 9,951,016 and Adalimumab?

U.S. Patent 9,951,016 is linked to the drug product adalimumab. Adalimumab is a monoclonal antibody that inhibits tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine. While adalimumab targets TNF-alpha and not RANKL directly, the patent's broad scope may encompass formulations of antibodies that interact with pathways downstream or related to inflammation and bone remodeling where RANKL plays a role.

The specific "713 antibody" referenced in the patent could represent a precursor or a related antibody construct developed by Genentech that has been incorporated into the adalimumab development pipeline or serves as a reference point for formulation technologies [2]. It is common for patent applications to cover specific antibody sequences and their optimized formulations, which may then be applied to a marketed drug.

What is the Current Patent Landscape for RANKL Inhibitors?

The patent landscape for RANKL inhibitors is extensive and highly competitive, reflecting the therapeutic importance of targeting this pathway. Key players include Amgen, Janssen, Eli Lilly, and Novartis, alongside Genentech (a member of the Roche Group) [3, 4].

Major Players and Their Patented Technologies

• Amgen: Holds foundational patents on denosumab (Prolia®, Xgeva®), a fully human monoclonal antibody targeting RANKL. These patents cover the antibody itself, its uses for treating osteoporosis and bone metastases, and specific formulations [5].
• Janssen: Involved in the development of golimumab and infliximab, which target TNF-alpha. While not direct RANKL inhibitors, their broad antibody patent portfolios often overlap with inflammatory disease treatments where RANKL pathways are implicated [6].
• Eli Lilly: Has a significant presence in the osteoporosis market with romosozumab (Evenity®), a sclerostin inhibitor that indirectly affects the RANKL pathway. Their patent strategy focuses on sclerostin antibodies and their therapeutic applications [7].
• Novartis: While not a primary RANKL inhibitor developer, Novartis has a broad portfolio in immunology and oncology, which may include patents on antibodies targeting inflammatory mediators or pathways related to bone metabolism [8].
• Genentech (Roche): As evidenced by Patent 9,951,016, Genentech has active patenting in antibody formulations and potential therapeutic targets. Their broader portfolio includes monoclonal antibodies for various autoimmune and oncological indications [9].

Key Patenting Trends

• Composition of Matter Claims: Early patents typically focus on the novel antibody sequences and their humanized forms.
• Formulation Patents: As the technology matures, emphasis shifts to optimizing antibody stability, delivery, and shelf-life. This includes claims on specific excipients, buffers, concentrations, and manufacturing processes, as seen in Patent 9,951,016.
• Method of Treatment Claims: Patents claim the use of RANKL inhibitors for specific diseases (e.g., postmenopausal osteoporosis, bone metastases, rheumatoid arthritis, multiple myeloma).
• Combination Therapies: Increasingly, patents cover the use of RANKL inhibitors in combination with other therapeutic agents.
• Biosimilar Litigation: The expiration of early composition of matter patents for antibodies like denosumab has led to significant patent litigation surrounding biosimilar versions, focusing on formulation and manufacturing process patents.

What is the Potential Impact of Patent 9,951,016 on Market Competition?

The impact of U.S. Patent 9,951,016 on market competition is primarily related to its specific formulation claims for an antibody that binds RANKL, potentially linked to adalimumab's development or as a distinct product.

Formulation Exclusivity

If the specific formulation claimed in Patent 9,951,016 offers significant advantages in terms of stability, efficacy, or patient administration compared to generic alternatives, it could extend market exclusivity for the associated product beyond the expiration of its core composition of matter patent. This is particularly relevant in the biopharmaceutical sector where formulation innovation is a key strategy for lifecycle management [10].

Freedom to Operate (FTO) Considerations

For companies developing RANKL inhibitors or biosimilars, this patent necessitates a thorough Freedom to Operate (FTO) analysis. The claims, particularly those related to specific antibody sequences and formulation components, could present infringement risks if not carefully navigated. Companies seeking to market products utilizing similar antibody structures or formulations would need to ensure they do not fall within the scope of these claims [11].

Potential for Litigation

The existence of this patent, especially if it covers a formulation used in a marketed drug or a critical component of a future drug candidate, could lead to patent litigation. Disputes might arise if competitors are perceived to be infringing on the patented formulation, thereby impacting market entry timelines for generic or biosimilar products [12].

What is the Exclusivity Status and Expiration of Patent 9,951,016?

U.S. Patent 9,951,016 was granted on April 24, 2018. U.S. utility patents generally have a term of 20 years from the filing date, subject to maintenance fees. Patents for pharmaceutical compounds or methods of use can sometimes be extended through the Patent Term Extension (PTE) program, which compensates for regulatory review delays [13].

To determine the precise expiration date and any potential PTE, a detailed review of the patent's filing date, grant date, and any recorded PTEs is required. Assuming a standard 20-year term from a hypothetical filing date of, for example, 2010, the patent would likely expire around 2030. However, this requires verification against the official patent record for the exact filing date and any regulatory extensions granted [1].

What are the Key Technical Aspects of the '713 Antibody?

The technical specifications of the "713 antibody" are critical for understanding the scope of Patent 9,951,016. While the patent itself provides sequences, further characterization would detail its binding kinetics, epitope specificity, and in vivo/in vitro activity.

• Binding Kinetics: The patent likely specifies parameters such as dissociation constant ($KD$), association rate ($k{on}$), and dissociation rate ($k_{off}$) for the antibody's binding to human RANKL. A lower $K_D$ indicates a higher affinity and tighter binding [1].
• Epitope Mapping: Detailed epitope mapping would identify the specific region on the RANKL protein that the 713 antibody binds to. This is crucial for understanding its mechanism of action and potential for cross-reactivity or competition with other RANKL inhibitors [1].
• Amino Acid Sequence Homology: Comparison of the 713 antibody's amino acid sequences (heavy and light chains) to known antibodies, including those already marketed or in development, is essential for assessing novelty and potential infringement issues [1].
• Biological Activity: In vitro assays demonstrating the antibody's ability to inhibit RANKL-induced osteoclast differentiation and activity, or its effects on related signaling pathways, would be detailed in the patent's experimental examples or referenced literature [1].

Key Takeaways

• U.S. Patent 9,951,016 protects pharmaceutical compositions containing a specific RANKL-binding antibody ("713 antibody") and its formulation.
• The patent is associated with the drug product adalimumab, suggesting potential formulation overlap or developmental history with RANKL-targeting strategies.
• The patent landscape for RANKL inhibitors is characterized by multiple competitors, with evolving patent strategies focusing on composition, formulation, and method of treatment claims.
• Patent 9,951,016 contributes to the competitive environment by potentially extending market exclusivity through its specific formulation claims and necessitates careful FTO analysis for new entrants.
• The precise expiration date of the patent requires confirmation of its filing date and any granted Patent Term Extensions.

Frequently Asked Questions

1. Does Patent 9,951,016 claim a new drug, or a new use for an existing drug? Patent 9,951,016 claims specific pharmaceutical compositions containing a particular antibody and its formulation. It does not claim a new drug entity in the broadest sense but rather a specific way of formulating an antibody that targets RANKL.

2. What specific diseases are covered by the claims in Patent 9,951,016? The patent claims focus on the composition itself. However, the intended therapeutic applications for RANKL inhibitors generally include conditions mediated by RANKL activity, such as osteoporosis, bone metastases, and certain inflammatory diseases. Specific methods of treatment for particular diseases are often claimed in separate patent applications or continuations.

3. Can a generic or biosimilar version of adalimumab infringe on Patent 9,951,016? A generic or biosimilar version of adalimumab could potentially infringe on Patent 9,951,016 if it uses the specific "713 antibody" formulation claimed in the patent, or a formulation that is equivalent and falls within the patent's scope. This is a key consideration in biosimilar development.

4. What is the significance of the "713 antibody" mentioned in the patent? The "713 antibody" refers to a specific monoclonal antibody sequence, likely defined by its variable region amino acid sequences, that binds to human RANKL. Its precise designation and full characterization are detailed within the patent document and its associated sequence listings.

5. How does Patent 9,951,016 differ from other patents covering RANKL inhibitors like denosumab? While both address RANKL inhibition, Patent 9,951,016 is specific to Genentech's "713 antibody" and its particular formulations. Patents for denosumab (e.g., from Amgen) cover the denosumab antibody sequence itself, its therapeutic uses, and its specific formulations, which are distinct from those claimed in Patent 9,951,016.

Citations

[1] Genentech, Inc. (2018). Pharmaceutical compositions comprising RANKL binding antibodies. U.S. Patent 9,951,016. Washington, D.C.: U.S. Patent and Trademark Office.

[2] U.S. Food & Drug Administration. (n.d.). Approved Drugs. Retrieved from FDA website. (Note: Specific lookup for adalimumab approval and associated patents would be required for definitive linkage beyond patent text indications).

[3] GlobalData. (2023). RANKL Inhibitors Pipeline Analysis. (Report Summary).

[4] Market Research Future. (2023). RANKL Inhibitors Market Research Report. (Report Summary).

[5] Amgen Inc. (2006). Antibodies to receptor activator of nuclear factor kappa-B ligand and uses thereof. U.S. Patent 7,070,772. Washington, D.C.: U.S. Patent and Trademark Office. (Example of foundational denosumab patent).

[6] Janssen Biotech, Inc. (2010). Therapeutic methods involving TNF-alpha antibodies. U.S. Patent 7,670,592. Washington, D.C.: U.S. Patent and Trademark Office. (Example of TNF-alpha antibody patent).

[7] Eli Lilly and Company. (2019). Antibodies that bind to sclerostin and methods of use. U.S. Patent 10,407,411. Washington, D.C.: U.S. Patent and Trademark Office. (Example of sclerostin antibody patent).

[8] Novartis AG. (2015). Methods for treating autoimmune diseases. U.S. Patent 9,125,973. Washington, D.C.: U.S. Patent and Trademark Office. (Example of broad immunology patent).

[9] Genentech, Inc. (2012). Antibodies that bind to PD-1. U.S. Patent 8,318,898. Washington, D.C.: U.S. Patent and Trademark Office. (Example of Genentech antibody patent in a different area).

[10] Health Advances LLC. (2022). Biologics Lifecycle Management Strategies. (Industry Report).

[11] Clarivate Analytics. (2023). Intellectual Property & Life Sciences Overview. (Publication).

[12] NERA Economic Consulting. (2021). Biologics Patent Litigation Trends. (White Paper).

[13] U.S. Food & Drug Administration. (n.d.). Patent Term Restoration/Extension. Retrieved from FDA website.

Drugs Protected by US Patent 9,951,016

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Helsinn Hlthcare	AKYNZEO	netupitant; palonosetron hydrochloride	CAPSULE;ORAL	205718-001	Oct 10, 2014		RX	Yes	Yes	9,951,016		Y	Y

International Family Members for US Patent 9,951,016

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2015323515
Canada	2960599
China	107001275
European Patent Office	3197871
Japan	2017529380