Using intellectual property laws to secure physical form patents for new drugs first made headlines some thirty years ago. These attention-grabbing lawsuits centered around paroxetine (Paxil), ranitidine (Zantac), and other blockbuster drugs. Generics were attempting to secure exclusive FDA approval for their Abbreviated New Drug Application (ANDA) without invalidating or infringing on the patent holder’s intellectual property.
While patenting physical forms first became big news in the 1990s, the issue has only grown more complex in the intervening decades. In order to protect their investments, developers rely on intellectual property laws during both drug discovery and development.
Questions of intellectual property can arise at the earliest points in the drug discovery process.
In preclinical drug development, the lead optimization (LO) stage is characterized by the discovery team’s efforts to alter the chemicals structure of lead molecules in order to develop a drug candidate with the ideal profile to advance into clinical studies. As many as 250 molecules may initially be considered for candidate selection at the start of LO, with as few as 4 progressing to the clinical trial process.
The optimal drug candidate possesses two qualities: the potential for scale-up as a commercial product, and an effective combination of Absorption, Distribution, Metabolism, Excretion, and toxicological (ADMET) properties. At this stage, the developers must decide if the compound can be crystalline or if it should be enabled through cocrystal formation, amorphous solid dispersion, or salt.
As discovery progresses, the candidate must also be successfully synthesized at mg to gram-scale quantity multiple times over. Once these discovery synthetic routes are established, the candidate undergoes toxicology studies.
These in vivo trials are administered on animals at far greater doses per body weight than what will ever be released as a commercial drug for human consumption. The dosage forms may vary as well, including suspensions/oral gavage. These trials are intended to establish a margin of safety (MOS) for the candidate.
If toxicological effects are observed in blood levels that are less than 10 to 100-times greater than the expected blood levels of human patients, the candidate may no longer be viable. Further formulations or enabling forms can be utilized to produce the necessary blood levels to establish MOS and secure the safety of the FHD (first human dose).
With this goal in mind, discovery teams will often select physical forms with the highest solubility, reasoning that alterations can always be made later in the process if scale-up and commercialization demands it. Due to the ubiquity of oral dosage forms on the market, it is usually assumed that this will be the administration route.
Candidates are duly prepared in solid forms that will remain chemically stable even in formulation. Stability is all important in drug discovery, and before candidate selection (CS) can progress the solution-state chemical stability toward oxidation, pH and water and/or biorelevant fluids must all be assayed.
The actual stability of a compound in process solvents and its eventual commercial formulation can only be determined once the synthetic route is defined, the recommended dose is established, scale-up occurs, and the final formulation is developed.
It is at this point in the discovery process that intellectual property enters the equation. The innovator typically files a composition of matter patent for both the lead molecule and any tertiary molecules that may also prove viable candidates. The FDA’s average timeline for approving Investigational New Drug (IND) applications for clinical trials ranges from one to two years.
Composition of matter patents require meticulous documentation, and failure to disclose all the necessary details may invalidate the patent entirely. One of the core requirements is that the patent lays out the best mode of practicing said invention.
Sufficient details must be included to allow others to practice the invention for themselves. If the inventor does not volunteer a preference that directly impacts the creation or employment of the invention, the best mode requirement is considered in breech.
Whether the best mode disclosure requirement includes the physical form that is isolated in the examples is debatable, as much of the material’s data remains unknown at this juncture. But by producing a solid-state characterizations of the physical form in the example of the composition of matter patent, a precedent of “prior art” can be established.
To ensure later developments are not conflated with the original material, this “prior art” form should be included in the patent materials. The presiding patent attorney will have strong opinions on what ought to be expressly written into the patent and what data should be stored in the composition of matter file. Once the composition of matter patent is ready to be filed there is typically 30mgs or more of material, which is sufficient to gather solution NMR, an XRPD pattern, and Thermogravimetric Analysis (TGA) data.
In the event that TGA reveals a marked loss, studies should be conducted to identify whether is water or solvent of recrystallization. Failure to address the issue promptly can lead to serious issues, as it is both expensive and time-intensive to recreate the synthesis and isolation in order to confirm which isolated form was present in the patent examples and thus “prior art” for new physical form patents.
Replicating the conditions in place when the initial examples of the composition of matter patent were performed and other attempts at reconstruction are unlikely to benefit the applicants of new physical form patents. Their newer material will in all probability be purer, altering its Crystallization tendencies. Indeed, the entire related substance profile may be demonstrably different.
Crystalline forms are especially intriguing, as the discovery of a new one spawns nuclei of a heretofore unseen substance. After these new forms come into existence, recreating the previous form can be almost impossible. Hence the paramount importance of characterizing the form developed in the composition of matter patent: to legally establish the identity of the prior art form.
Patenting or disclosing viable forms during drug discovery ensures freedom to operate.
The years-long journey of process, formulation, and product development provides ample fodder for innovation. When various issues cause an impediment in the process, an alternate physical form that was used in discovery may provide a solution.
Frequently, different forms are identified via a polymorph screen. To learn the most appropriate crystallization method for kilo-lots in GLP toxicology and FHD studies, solvent-solubility screens may be conducted. Oftentimes the purity of these lots surpases that of the discovery lots. However, the ultimate commercial process will still have differences.
Solvates (hydrates) and additional physical forms (polymorphs) may be discovered during GLP toxicology and FHD studies. When these additional forms found during screening prove to be useful, it is advisable to either file a patent or publicly disclose them. Patenting or disclosing helps to prevent other parties from obstructing your operation.
Forced degradation studies take place in tandem with screening. These studies seek to establish the existence of any considerable impurities occuring during drug decomposition. Once identified, the compounds are checked for potential toxicity or mutagenic properties.
Stability of the formulation is carefully studied before administration of the FHD. Following the FHD, enough data is collected and analyzed to determine some key pieces of the puzzle: safe but effective dosage along with necessary blood concentration for therapeutic effect.
At this point, the process for synthesis is specified, commercial crystallization methods are developed ahead of important trials, and the scope of commercial development broadens.
Investigation of the API’s processing qualities via established crystallization solvents and conditions leads to increased material availability. In an optimal situation, the crystal form used in screening can go on to be used in the final product.
Tests must be conducted, however, to determine compressibility, particle size, filtration and drying rates, flow characteristics, and crystal morphology in order to rule out any objectionable properties. In that event, alternative forms are sought for easier development. Finally, an advantageous go-to-market strategy is selected.
Often, additional useful forms are discovered as a result of the development process. When this occurs, choosing to patent or disclose the forms protects your ability to operate in further trials as different patient groups and drug delivery methods come into play.
During the Phase 3 clinical trial stage, and sometimes sooner, other drug developers will be keen to examine information regarding your novel therapy. Due to the Hatch-Waxman act, there are potential routes for others to develop and market a generic based on their study of your new physical form.
A developer who broadcasts clinical trial success can grow the awareness of their new chemical entity (NCE) that attracts other companies to study the novel product. The more renown an NCE receives from favorable clinical trials, the more likely it is to be referenced in trade journals. This popularity almost assuredly leads to competitor investigation.
Popularity is not the only means for those with an interest in drug discovery to learn about your NCE, though. Simply following publication of clinical trial results can be enough to spark interest.
Following the lead of more modest biotech firms, it is advisable to use specific databases and websites for simple disclosure to establish intellectual property. This process helps to avoid any impediment to utilize additional physical forms in later work.
These IP repositories include the International Centre for Diffraction Data’s (ICDD’s) Powder Diffraction File and IP.com. Uploading detailed information to these databases can help you avoid costly patent filing and lengthy submissions for publication in peer-reviewed journals.
Industry-wide, the significance of alterations in physical properties, as well as the consequence of physical form discovery, are well understood. Industry professionals recognize the value of physical form patents for the preservation of a developer’s future operations as well as ensuring they reap the greatest value from their NCE in the face of competition for generic manufacture.