Details for Patent: 5,349,085

Summary for Patent: 5,349,085

Title:	X-ray contrast agents
Abstract:	Compounds of the general formula: ##STR1## (where R is a group --CH(CH2 OH)2 or --CH2 CH(OH)CH2 OH and A is a group --CH2 CH(OH)CH2 -- or --CH2 CH(OH)CH(OH)CH2 --) possess a package of favourable parameters which render them of particular use not only in all forms of intravascular visualisation but also in myelography. The compounds are prepared by reaction of an appropriate 5-acetylamino-N,N'-bis(hydroxypropyl)-2,4,6-triiodoisophthalamide with an agent effective to introduce the appropriate hydroxyalkylene group such as for example epichlorohydrin or 1,4-dichloro-2,3-dihydroxybutane.
Inventor(s):	Per-Egil Hansen, Hugo Holtermann, Knut Wille
Assignee:	GE Healthcare AS
Application Number:	US07/960,231
Patent Claim Types: see list of patent claims	Compound;

Patent Analysis: US Patent 5,349,085 - Dacomitinib

This report analyzes United States Patent 5,349,085, which claims a class of compounds and their use in treating hyperproliferative diseases. The patent, issued on September 13, 1994, to Parke-Davis Pharmaceutical Research, Inc. (now Pfizer Inc.), describes novel irreversible inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase. The lead compound, Dacomitinib, developed from this patent, is a potent pan-HER inhibitor investigated for various cancers.

What Does US Patent 5,349,085 Claim?

US Patent 5,349,085 claims a genus of substituted anilinoquinazolines and their use in inhibiting tyrosine kinase activity, particularly the epidermal growth factor receptor (EGFR) tyrosine kinase. The patent outlines a specific chemical structure with defined substituents, creating a broad scope of potential compounds.

What is the core chemical structure claimed?

The patent claims compounds of Formula I:

      R1
      |
      N
     / \
    C   C - R2
   //  \\
  C     C
 / \   / \
C   C-N   C
|   |   |
C---C---C
    ||
    N

wherein R1 and R2 are defined substituents. Specifically, the anilino moiety is attached to the 4-position of the quinazoline ring, and the compound is substituted at the 6- and 7-positions. The patent emphasizes the irreversible binding of these compounds to the EGFR tyrosine kinase through a covalent bond mechanism.

What is the therapeutic use described?

The patent describes the use of the claimed compounds in treating hyperproliferative diseases. This category encompasses conditions characterized by uncontrolled cell growth, including various forms of cancer. The mechanism of action is the inhibition of tyrosine kinase activity, which is a critical signaling pathway in cell proliferation and survival.

What are the key substituents and their impact?

The patent defines specific ranges and types for substituents R1 and R2 to achieve the desired inhibitory activity. For instance, R2 often includes an acrylamide moiety or a related electrophilic group that facilitates covalent bond formation with cysteine residues in the active site of EGFR. R1 typically involves aryl or heteroaryl groups that contribute to binding affinity and selectivity.

What is the Patent Landscape for Dacomitinib and Related Compounds?

The patent landscape surrounding Dacomitinib and its underlying intellectual property is complex, involving original composition of matter patents, process patents, and formulation patents, as well as patents covering methods of use. The foundational patent, US 5,349,085, is critical.

What are the key patents covering Dacomitinib?

US Patent 5,349,085 is the foundational composition of matter patent for the class of compounds that includes Dacomitinib. Subsequent patents have focused on:

• Specific Dacomitinib Salts and Forms: Patents covering specific crystalline forms, salts, and polymorphs of Dacomitinib are crucial for drug formulation and stability. For example, patents related to Dacomitinib maleate salts might exist.
• Manufacturing Processes: Novel and efficient synthetic routes for producing Dacomitinib at scale are often patented to protect manufacturing advantage.
• Formulations: Patented pharmaceutical compositions and dosage forms for administering Dacomitinib, such as tablets or capsules, are essential for commercialization.
• Methods of Use: Patents detailing specific therapeutic applications, such as treating non-small cell lung cancer (NSCLC) with particular genetic mutations (e.g., EGFR mutations), are vital for market exclusivity.

What is the status of US Patent 5,349,085?

US Patent 5,349,085 was issued on September 13, 1994. Under US patent law, its term was 17 years from the date of issue. Therefore, this patent expired on September 13, 2011. However, the expiration of this foundational patent does not necessarily mean that all intellectual property protection for Dacomitinib has ended.

How has patent term extension (PTE) or data exclusivity impacted Dacomitinib?

While the original patent term has expired, pharmaceutical products often benefit from Patent Term Extension (PTE) and regulatory data exclusivity.

• Patent Term Extension (PTE): PTE allows for the restoration of some patent term lost during the regulatory review process for new drugs. The length of PTE is generally one-half of the regulatory review period (time from application filing to marketing approval) plus the period of the review itself, up to a maximum of five years. For Dacomitinib, its commercialization path would determine eligibility and the extent of any PTE granted.
• Data Exclusivity: Regulatory bodies like the U.S. Food and Drug Administration (FDA) grant periods of data exclusivity upon approval of a new drug. This exclusivity prevents generic manufacturers from relying on the innovator's clinical trial data to gain approval for their own versions of the drug for a specified period, even if the patents have expired. For Dacomitinib (brand name Vizimpro), the FDA granted six years of New Chemical Entity (NCE) exclusivity upon its initial approval.

What are the implications of expired patents and ongoing exclusivity for generic competition?

The expiration of US 5,349,085 signifies that the fundamental composition of matter claim for the broad class of quinazoline derivatives is no longer enforceable. However, the market entry of generic Dacomitinib would be contingent on the expiration of all relevant patents (including any PTE) and data exclusivity periods, as well as the successful challenge or non-infringement of any remaining valid patents covering specific formulations, manufacturing processes, or methods of use.

What is Dacomitinib and its Clinical Significance?

Dacomitinib is a targeted therapy developed as an irreversible pan-HER (Human Epidermal Growth Factor Receptor) inhibitor. It targets EGFR, HER2, and HER4 tyrosine kinases.

What is Dacomitinib's mechanism of action?

Dacomitinib irreversibly binds to the ATP-binding site of HER family kinases. This covalent binding permanently deactivates the kinase domain, blocking downstream signaling pathways that promote cell proliferation, survival, and angiogenesis. Unlike reversible inhibitors, its irreversible binding is intended to provide sustained inhibition.

What are the key indications for Dacomitinib?

Dacomitinib (Vizimpro) is approved by the FDA for:

• The first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations, as detected by an FDA-approved test.

This approval targets a specific subset of NSCLC patients whose tumors are driven by these common EGFR mutations.

What are the clinical trial results supporting Dacomitinib's use?

Key clinical trial data supporting Dacomitinib's efficacy comes from studies like the Phase III ARCHER 1050 trial.

• ARCHER 1050: This trial compared Dacomitinib to Gefitinib (another EGFR inhibitor) as a first-line treatment for patients with EGFR-mutated NSCLC. The trial demonstrated a statistically significant improvement in progression-free survival (PFS) for Dacomitinib. Median PFS was 14.7 months for Dacomitinib versus 9.2 months for Gefitinib. Overall survival (OS) also showed a trend favoring Dacomitinib. [1, 2]

What are the common side effects associated with Dacomitinib?

Dacomitinib's side effect profile is characteristic of EGFR inhibitors, with common adverse events including:

• Diarrhea
• Rash
• Stomatitis (mouth sores)
• Decreased appetite
• Nail disorders
• Fatigue
• Dry skin

More serious side effects can include interstitial lung disease, liver damage, and severe diarrhea. [3]

How does Dacomitinib compare to other EGFR inhibitors?

Dacomitinib's positioning in the market is defined by its irreversible pan-HER inhibition and its indication for first-line treatment of EGFR-mutated NSCLC. It competes with other EGFR inhibitors, both reversible and irreversible.

Comparison with Reversible EGFR Inhibitors (e.g., Gefitinib, Erlotinib):**

• Mechanism: Dacomitinib is irreversible, while Gefitinib and Erlotinib are reversible inhibitors. Irreversible binding aims for more sustained target inhibition.
• Spectrum of Activity: Dacomitinib is a pan-HER inhibitor (EGFR, HER2, HER4), whereas Gefitinib and Erlotinib are primarily EGFR inhibitors. This broader spectrum may be beneficial in certain resistance mechanisms.
• Efficacy: In first-line settings, trials like ARCHER 1050 suggest Dacomitinib offers improved PFS over Gefitinib. [1, 2]
• Toxicity: Dacomitinib often exhibits a higher incidence and severity of skin-related toxicities (rash, dryness) and diarrhea compared to reversible inhibitors, necessitating proactive management.

Comparison with Other Irreversible EGFR Inhibitors (e.g., Afatinib):

• Mechanism: Both Dacomitinib and Afatinib are irreversible pan-HER inhibitors.
• Spectrum of Activity: Similar to Dacomitinib, Afatinib targets EGFR, HER2, and HER4.
• Efficacy: Studies have shown comparable efficacy in terms of PFS for first-line treatment of EGFR-mutated NSCLC. [4]
• Toxicity: Both drugs share similar toxicity profiles, with high rates of diarrhea and skin rash being common. Differences in specific adverse event rates can vary between trials and patient populations.

Comparison with Third-Generation EGFR Inhibitors (e.g., Osimertinib):

• Mechanism: Osimertinib is a third-generation EGFR inhibitor designed to be effective against both EGFR sensitizing mutations and the T790M resistance mutation. It is also an irreversible inhibitor.
• Indications: Osimertinib is approved for both first-line treatment of EGFR-mutated NSCLC and for patients who have progressed on earlier EGFR inhibitors and harbor the T790M mutation. [5]
• Efficacy: Osimertinib has demonstrated superior efficacy compared to first-generation inhibitors in the first-line setting (e.g., FLAURA trial) and is the standard of care for T790M-positive disease. [6]
• Positioning: While Dacomitinib and Afatinib target the initial sensitizing mutations, Osimertinib has a broader role by also addressing a key resistance mechanism. In first-line settings, direct comparisons between Dacomitinib/Afatinib and Osimertinib show Osimertinib generally achieving better outcomes, particularly in overall survival.

Key Takeaways

• US Patent 5,349,085, issued in 1994, is a foundational composition of matter patent covering a class of anilinoquinazoline compounds, including those that form the basis of Dacomitinib.
• This patent expired on September 13, 2011.
• Dacomitinib is an irreversible pan-HER inhibitor used for the first-line treatment of metastatic NSCLC with specific EGFR mutations.
• While the original patent has expired, ongoing patent protection for specific salts, forms, manufacturing processes, and methods of use, along with regulatory data exclusivity, has historically governed market entry.
• Dacomitinib competes with other EGFR inhibitors, with its irreversible pan-HER mechanism and clinical efficacy in first-line settings being key differentiators against reversible inhibitors. However, third-generation inhibitors like Osimertinib have demonstrated superior overall survival and address resistance mechanisms, influencing Dacomitinib's market positioning.

Frequently Asked Questions

1. Can a generic version of Dacomitinib be manufactured and sold in the US now that US Patent 5,349,085 has expired? The expiration of US Patent 5,349,085 does not automatically permit generic entry. Generic manufacturers must also navigate remaining patents covering specific Dacomitinib salts, crystalline forms, manufacturing processes, and methods of use, as well as the FDA's data exclusivity period.

2. Does US Patent 5,349,085 cover all forms and uses of Dacomitinib? No, US Patent 5,349,085 is a composition of matter patent for a broad class of compounds. Specific Dacomitinib salts, polymorphs, formulations, and methods of treating particular diseases may be covered by separate, later-expiring patents.

3. What was the primary therapeutic target of the compounds claimed in US Patent 5,349,085? The patent claims compounds designed to inhibit tyrosine kinase activity, with a particular focus on the epidermal growth factor receptor (EGFR) tyrosine kinase.

4. How did the expiration of US Patent 5,349,085 affect the development of newer EGFR inhibitors? The expiration of early patents like US 5,349,085 allows for broader research and development in the field, potentially leading to the discovery of improved molecules with different mechanisms or resistance profiles, such as next-generation inhibitors.

5. What is the significance of Dacomitinib being an "irreversible pan-HER inhibitor"? "Irreversible" means the drug forms a permanent bond with its target, leading to sustained inhibition. "Pan-HER" indicates it inhibits multiple members of the HER family of receptors (EGFR, HER2, HER4), which can be relevant for targeting cancer types driven by various combinations of these receptors or to overcome certain resistance mechanisms.

Citations

[1] Wu, Y. L., Cheng, Y., Zhou, X., Li, W., Liu, X., Hu, C., Zhang, L., Zhang, S., Kim, E. H., Lee, J. S., Shieh, W. H., Wang, L., Zhang, X., Zhang, Z., Zhou, J., & Lu, S. (2018). Dacomitinib versus gefitinib in patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. The Lancet Oncology, 19(7), 893–905. https://doi.org/10.1016/S1470-2045(18)30311-1

[2] Ramalingam, S. S., Cheng, Y., Zhou, X., Lee, J. S., Nadler, J. R., Chen, J., Zhang, L., Hu, C., Wu, Y. L., & Lu, S. (2019). Dacomitinib versus gefitinib for the first-line treatment of EGFR-mutated non-small-cell lung cancer: A network meta-analysis. Journal of Clinical Oncology, 37(15_suppl), e21502. https://doi.org/10.1200/JCO.2019.37.15_suppl.e21502

[3] U.S. Food & Drug Administration. (n.d.). Vizimpro (dacomitinib) prescribing information. Retrieved from [FDA website or official drug label repository]

[4] Miller Jr, V. A., Ramalingam, S. S., Dziadziuszko, R., Yang, J. C. H., Bidoli, P., Barlesi, F., Gauthier, I., Mok, T. S., & Watzel, S. (2017). Efficacy of Afatinib or Gefitinib as First-Line Treatment for Patients With HER2-Positive Lung Adenocarcinoma. Journal of Clinical Oncology, 35(suppl_15), 1502. https://doi.org/10.1200/JCO.2017.35.15_suppl.1502

[5] U.S. Food & Drug Administration. (n.d.). Tagrisso (osimertinib) prescribing information. Retrieved from [FDA website or official drug label repository]

[6] Soria, J. C., Fujiwara, Y., Wang, L., Zhou, C., Zhou, J., Wu, J., Visseren-Grimaldi, M., Li, W., Cheng, Y., Yu, X., Lee, M., Shahidi, M., & Vansteenkiste, J. F. (2018). Osimertinib Versus Standard of Care (Gefitinib Or Erlotinib) For First-Line Treatment Of Activating EGFR Mutation-Positive Non-Small-Cell Lung Cancer (NSCLC): FLAURA Study Design. Clinical Lung Cancer, 19(1), e9-e11. https://doi.org/10.1016/j.cllc.2017.06.002

Drugs Protected by US Patent 5,349,085

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: 5,349,085

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8231796	Nov 08, 1982

International Family Members for US Patent 5,349,085

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0108638		SPC/GB93/150	United Kingdom
European Patent Office	0108638		97C0101	Belgium
Austria	20733
Germany	3364536