如何在药物开发进程中战略性地开发专利组合

把握药物开发进程中的发明

每一个创新治疗药物都需要大量投资（财务、劳动力和时间）来开发。为了充分保护这种投资，必须战略性地开发专利组合。强大的专利组合通常包括范围广泛的要求保护的主题，涵盖药物的不同方面，并具有不同的保护层次。

本文将重点介绍药物公司在药物(特别是小分子药物)开发阶段可以把握并寻求专利保护的各种主题。

药物开发进程可以大致分为三个阶段：药物发现、临床前试验和临床试验。在每个阶段都有独特的可申请专利的主题。有些主题或与其他阶段有所重叠，但可能有不同的侧重点或细节。

1、药物发现阶段

药物发现阶段包括研究的早期阶段，旨在确定试验用药物并在实验室中进行初始测试。在此阶段，研究人员了解潜在药物途径并确定潜在靶标。研究人员使用各种筛选方法，确定多个候选化合物，并对其进行改进，以创造出具有优化特性的、更有效且更具选择性的候选化合物。在这些候选化合物范围内进一步探索，可获得一个或数个先导化合物，以在临床前和临床试验中推进。在这一阶段，通常进行体外和体内研究，例如酶促测定、基于细胞的测定和动物研究，以获得功效和毒性的初步证据。

在临床前阶段，测试候选药物在实验室研究和动物试验进行。在此阶段，将着重于药物对基体的影响，药物治疗疾病的功效以及药物的安全性的问题。另外，在此阶段，还必须确定如何生产足够数量的药物以用于临床试验。

3、临床试验阶段

新药的临床试验通常分为四个阶段，历时多年。I期、II期和III期临床试验通常在药物获得食品和药物管理局等监管机构批准之前进行。药物批准后，可以进行上市后的IV期试验。

I期临床试验是在一小组健康志愿者中进行的初步安全性测试。在I期研究中，将评估药物的安全性、耐受性、药代动力学和药效学。通常在此阶段将确定安全剂量范围以及副作用。II期研究在一小群患者中评估候选药物的安全性和有效性。II期临床试验旨在评估药物的疗效，并延续I期的安全性评估。III期研究通常是针对大型患者组的随机对照多中心试验，以确认安全性和有效性。此阶段会产生有关该药物的安全性、功效和整体效益-风险关系的统计显著数据。它还将为标签说明提供基础，包括潜在药物相互作用的信息和特定的剂量说明。

i）将药物与已上市的其他药物进行比较；

ii）监测该药物的长期有效性以及对患者生活质量的影响；

总之，在药物开发和临床前阶段，一家公司将会希望对最有前景的候选药物进行专利保护，特别是保护物质组成、初步制剂和一般使用方法的权利要求。随着候选药物的研发推进，公司可以根据进一步的测试和临床试验结果获得更具体的制剂或使用方法的权利要求。随着临床试验的推进，以及更多信息的收集，公司的发展计划可能会动态变化。

从专利的角度来看，公司需要能够变通，并拥有不同的选择，以覆盖最终产品和任何后续产品线。重要的是，无论多么小的创新进展都值得把握并申请专利，尽管随着药物开发过程的进行将越发难以获得专利。强大的药品专利组合的开发将取决于与研究人员的有效沟通，以及专利顾问在撰写权利要求和获得授权方面的创造力。

英文原版文章：

InventionCapture During the Drug Development Process

LiFeng, Ph.D., Kyu Yun Kim, and Lu Dai, Ph.D.

Each innovativetherapeutic drug requires a substantial investment (financial, labor, and time)to develop. To adequately protect such an investment, a patent portfolio mustbe strategically developed. A strong patent portfolio generally includes a widerange of claimed subject matters, covering different aspects of the drug, withvarying layers of protection. This article focuses on the various types ofsubject matters during the stages of drug development, especially for smallmolecule drugs, that a drug company can capture and seek patent protection.

The drug developmentprocess can be roughly divided into three stages: drug discovery, pre-clinicaltesting, and clinical trials. During each stage, there are unique subjectmatters that may be patentable. Some subject matters may overlap duringdifferent stages, but those subject matters may have a different focus ordetails.

I.              Drug Discovery

The drug discovery stageincludes the early phases of research, designed to identify an investigationaldrug and perform initial tests in the lab. During this stage, researchers learnthe underlying drug pathway and identify potential targets. Using various screeningmethods, researchers identify multiple compound candidates and refine them tocreate more potent and selective candidates with optimized properties. Thesecandidates are narrowed down to one or more lead compounds, which can be takenforward in preclinical and clinical testing. At this stage, in vitro and invivo studies, such as enzymatic assays, cell-based assays, and animal studies,are usually carried out to offer initial evidence of efficacy and toxicity.There are various subject matters available for patenting at this stage. Themultiple compound candidates including the lead compound, as well as theirsynthesis and general medical use, can be pursued for patenting. Other subjectmatters also include forms of the compounds such as salts, solvates, hydrates,enantiomers, and polymorphs. A company may also find opportunities for patentprotection relating to mechanisms of action and structure-activityrelationships.

II.           Preclinical Testing

At the preclinical stage,laboratory studies, and animal testing are performed with the drug candidate.During this stage, the drug’s impact to the bodies, the drug’s efficacy totreat the disease, and the drug’s safety are addressed. Additionally, duringthis stage, it must also be determined how to make enough quantities of thedrug to be used in clinical trials. This stage also provides variousopportunities for patent protection. One area for patent protection relates topharmacokinetic properties, such as absorption, distribution, metabolism, andexcretion profiles, of the drug candidate. Another area for patenting relatesto pharmacology studies, exploring safety and efficacy of the drugs, andtoxicology studies, concerning toxicity of the drug. Subject matter in theseareas can be generally protected in the context of method of use claims.Additionally, method of preparation, intermediates, salt and solid forms,polymorphs, formulations, and biomarkers are all areas to consider for patentprotection.

III.         Clinical Trials

Clinical trials involvingnew drugs are generally classified into four phases, which proceed over manyyears. The phase I, phase II, and phase III of clinical trials usually comebefore the drug approval by a regulatory authority, such as the Food and DrugAdministration. After the drug approval, there can be post-marketing phase IVtrials.

A phase I clinical trialis an initial safety testing in a small group of healthy volunteers. During aphase I study, the drug’s safety, tolerability, pharmacokinetics andpharmacodynamics are assessed. Generally, a safe dosing range is determined,and side effects are identified at this stage. A phase II study assesses thesafety and efficacy of a drug candidate in a small group of patients. Phase IItrials are designed to assess the efficacy of the drug as well as to continuePhase I’s safety assessment. Phase III studies are typically randomized,controlled multicenter trials on large patient groups and to confirm safety andefficacy. This phase generates statistically significant data on the safety,efficacy, and the overall benefit-risk relationship of the drug. It alsoprovides the basis for labeling instructions, including information onpotential drug-drug interactions and specific dosing instructions.

Phase I, II, and IIIstudies present additional opportunities for patent protection. For example,any optimization of the drug can be protected, including specific productformulation, strengths, specific forms of the drug including salts orpolymorphs, device for administration, and detailed method of use, such asdosage and dosing regimens. Additionally, contraindications, such as warningsor precautions, label language, and patient sub-populations can all beconsidered for patent protection.   

Phase IV studies areconducted after a drug has been approved for patient use. This phase mainlyseeks to i) compare a drug with other drugs already in the market, ii) monitora drug's long-term effectiveness and impact on a patient's quality of life;and/or iii) determine the cost-effectiveness of a drug therapy relative toother traditional and new therapies. The Phase IV study also presents anotheropportunity to determine whether there is a subject matter available forprotection, which may include different patient sub-populations, warnings orprecautions, and changes in label language.

During or after thecourse of the first generation drug development, a company may develop secondor third generation drugs. With respect to the second and third generationdrugs, the company can consider similar subject matter for patent protection tothe first generation drugs. For example, subject matters for patent protectionmay include alternative forms of the drug, such as purified isomers,polymorphs, or metabolites, different route of administration, pediatric orgeriatric use, combinations with a second active ingredient, formulations,dosages, method of treatment and production.

In summary, during thedrug discovery and preclinical stages, a company would want to secure patentprotection of the most promising drug candidate compounds, especially incomposition of matter claims, as well as claims on preliminary formulation andgeneral method of use. As the drug candidate further develops, the company canobtain more specific formulation or method of use claims based on furthertesting and clinical trial results. As the clinical process develops andadditional information is gathered, the company’s development plan may changedynamically. From the patent perspective, the company needs to be able to pivotand have different options available to cover the ultimate final drug productand any follow-on product line. It is important to note that any innovativeadvancement, no matter how small, may be worth capturing and patenting,although it may be increasingly difficult to obtain patents as the drugdevelopment process progresses. Development of a strong drug patent portfoliowould depend on effective communications with the researchers and patentcounsel’s creativity in crafting and obtaining claims.