Introduction

In current clinical practice, procalcitonin (PCT) has developed into a promising new biomarker for the early detection of systemic bacterial infections. PCT is a 116-amino acid residue first explained by Le Moullec et al. in 1984; its diagnostic significance was not recognized until 1993.[1] In 1993, Assicot et al. demonstrated a positive correlation between high serum levels of PCT and patients with positive findings for bacterial infection and sepsis (e.g., positive blood cultures). Further, they demonstrated that PCT did not elevate in viral infections and that serum levels of PCT would decrease following the administration of appropriate antibiotic therapies.[2] 

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Other inflammatory biomarkers, such as C-reactive protein, lack the specificity to accurately distinguish between bacterial and non-bacterial infections.[3] Therefore, PCT assays, with a specificity of 79%, have been developed and utilized to more accurately determine if a systemic inflammatory reaction is caused by a bacterial species.[4]

The United States Food and Drug Administration has approved using PCT assays for initiating or discontinuing antibiotics in lower respiratory tract infections (LRTIs) and for discontinuing antibiotics in patients with sepsis.[5] Numerous studies have evaluated PCT-based treatment algorithms in these settings and found them safe compared to standard care.[6] In particular, using PCT assays allows cessation of antibiotic therapy without increased morbidity and mortality. This makes PCT a potentially helpful tool for preventing the emergence of antibiotic-resistant organisms while still ensuring appropriate treatment for serious bacterial infections.[4]

PCT should not be used as the sole determinant for antimicrobial therapy.[7] The results of a PCT assay should be placed in the context of the clinical scenario considering the possible site of infection, the likelihood of bacterial infection, the severity of illness, and other pertinent clinical data.[8]

Pathophysiology

Under normal homeostasis, pre-procalcitonin undergoes initial synthesis by thyroid C cells. Later this peptide is transformed into procalcitonin via cleavage of a 25-amino acid signal sequence by endopeptidases. The end product calcitonin, the 32-amino acid hormone responsible for serum calcium regulation, is formed following conversion by the enzyme prohormone convertase.[9] Typically, physiological conditions result in very low serum PCT levels of less than 0.05 ng/mL. However, the synthesis of PCT can be increased up to 100 to 1000 fold due to circulating endotoxins or cytokines such as interleukin (IL)- 6, tumor necrosis factor (TNF)-alpha, and IL-1b, which act on various tissues.[10]

The extra-thyroid synthesis of PCT occurs in the liver, pancreas, kidney, lung, intestine, and leukocytes; notably, the synthesis of PCT is suppressed within these tissues in the absence of bacterial infection.[11] In contrast, cytokines released following viral infection, such as interferon (INF)-gamma, will lead to the down-regulation of PCT, thus highlighting another advantage of PCT assays.[12]

Specimen Requirements and Procedure

Human serum or plasma specimens can be used to determine procalcitonin (PCT). For accurate results, serum and plasma specimens should be free of fibrin, red blood cells, and other particulate matter.[13] Serum specimens from patients receiving anticoagulant or thrombolytic therapy may contain fibrin due to incomplete clot formation.[14] Using heat-inactivated specimens, pooled specimens, grossly hemolyzed specimens, specimens with obvious microbial contamination, and specimens with fungal growth is not recommended. The use of plasma is recommended for rapid turnaround of results.[15]

The PCT specimens should be free of bubbles. Remove bubbles with an applicator stick before analysis. Use a new applicator stick for each specimen to prevent cross-contamination. To ensure consistency in results, recentrifuge specimens before testing if they contain fibrin, red blood cells, or other particulate matter.[16] The EDTA plasma and serum specimens stored frozen at -70^oC or colder have demonstrated stability for up to 18 months.[17]

Diagnostic Tests

Kinetics

Procalcitonin (PCT) serum levels have been shown to increase 6 to 12 hours following initial bacterial infections and increase steadily in the two to four hours following the onset of sepsis.[18][10] The half-life of PCT is between 20 to 24 hours; therefore, when a proper host immune response and antibiotic therapy are in place, PCT levels decrease by 50% over 24 hours.[11]

Chemical Assays

In current clinical practice, several chemical assays have been developed to detect PCT serum levels at varying sensitivities, most displaying functional sensitivity around 0.06 ng/mL.[3] One of the first commercially available assays was a homogenous immunoassay that utilized time-resolved amplified cryptate emission technology.[12] The assay comprises a sheep polyclonal anti-calcitonin antibody and a monoclonal anti-katacalcin antibody which binds to the calcitonin and katacalcin amino acid sequence of PCT via the sandwich method. The assay uses 20 to 50 mL of plasma or serum and takes 19 minutes to complete; results are typically obtained within one hour following the serum draw.[19]

Testing Procedures

All currently available assays for the quantification of PCT are based on immunoassay techniques.[13] The chemiluminescent microparticle immunoassay (CMIA) technology is used to quantitatively determine PCT in human serum and plasma.[20] Samples and anti-PCT-coated paramagnetic microparticles are combined and incubated. The PCT present in the sample binds to the anti-PCT-coated microparticles. The mixture is washed. Anti-PCT acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle, pre-trigger and trigger solutions are added.[21] The resulting chemiluminescent reaction is measured as relative light units (RLUs). There is a direct relationship between the amount of PCT in the sample and the RLUs detected by the system optics.[20]

A point-of-care test for PCT  is available using an immunochromatographic technique. A colored band appears on the test strip 30 minutes after applying 200 microliters of serum or plasma; the intensity of the band is read against a reference card. The results are reported as less than 0.5, 0.5 to 2.0, 2.0 to 10, and greater than 10 μg/L.[22] However, the semi-quantitative nature of these results may limit clinical use when a change in the PCT trend is important to monitor the patient’s clinical status. It may still be valuable when quantitative measurements are unavailable within a reasonable period, such as one to three hours.[23]

Interfering Factors

Although procalcitonin (PCT) assays have shown promising results over the years, several limitations still require consideration before implementing these tests in everyday clinical practice.[13] For instance, it has been shown that PCT serum levels can also become elevated during times of noninfectious conditions, such as trauma, burns, certain carcinomas (medullary C-cell, small cell carcinoma of the lung, and bronchial carcinoid), immunomodulator therapy that increases proinflammatory cytokines, cardiogenic shock, during the first two days of life, during peritoneal dialysis treatment, and in patients with cirrhosis, particularly Child-Pugh Class C.[4] Furthermore, PCT levels may be falsely elevated in patients suffering from various degrees of chronic kidney disease, which can, in turn, alter baseline results, making the determination of an underlying bacterial infection difficult to establish.[24] Thus, the clinician needs to rule out the above scenarios to ensure no confounding issues may be obscuring the PCT measurements.[25]

The PCT assay may exhibit interference when a sample is collected from a person consuming a supplement with a high dose of biotin (also termed as vitamin B7 or B8, vitamin H, or coenzyme R).[26] It is recommended to ask all patients with an indication for PCT testing about biotin supplementation. Patients should be cautioned to stop biotin consumption at least 72 hours before collecting a sample.[27] A hook effect may occur with extremely high PCT concentrations, resulting in a much lower reported value.[28] 

The cost-effectiveness of PCT assays also needs to be considered, as overuse in the emergency setting leads to extraneous costs. The average price of the test is roughly $9.44, which is relatively inexpensive. However, this cost does not consider the amount that insurance charges, nor does it include sample acquisition costs.[29] Salinas et al. discovered that of 142,644 PCT assays performed in a calendar year, 44.1% could have been avoided based on clinical presentation and outcome, saving $594,390 annually.[30]

Within the intensive care setting, Kip et al. performed a randomized controlled trial to determine the cost-effectiveness of PCT assays among septic patients. They determined that PCT assays improved mortality rates and decreased the clinical course of antibiotics. However, they found costs for patients tested with PCT assays averaged $2704 greater than patients who did not undergo PCT testing.[31] Therefore, clinicians should exercise caution when ordering PCT assays to ensure cost-effective medical practice.[29]

Results, Reporting, and Critical Findings

Procalcitonin (PCT) has a set half-life of 20 to 24 hours which provides clinicians and researchers with a rough timeline of when levels should begin to decrease following physiological control of the systemic infection. When physiologic control is reached, PCT should decrease by approximately 50% over 24 hours.[10] The current clinical practice utilizes a variety of PCT cut-off levels to determine the initiation and discontinuation of antibiotic therapy. The clinical scenario and setting play a fundamental role in which the cut-off level should be employed. However, most research has shown that PCT levels display clinical significance in the range of 0.1 to 0.5 ng/mL.[11] Further, research has shown that PCT levels less than 0.1 ng/mL have been shown to have a high negative predictive value (96.3%) for excluding bacterial infections.[3]

The following clinical scenarios have utilized various PCT cut-off levels to determine the source of an infective process as well as when antibiotic therapy could be utilized or discontinued:[11]

Arthritis

• PCT cut-off level: 0.1 to 0.25 ng/mL

• Role of PCT: To discriminate infective (septic) arthritis from non-infective arthritis.  

• Type of Study: Observational

Bacteremic Infections

• PCT cut-off level: 0.25 ng/mL

• Role of PCT: To rule out bacteremic infections. 

• Type of Study: Observational

Blood Stream Infection (primary)

• PCT cut-off level: 0.1 ng/mL

• Role of PCT: To differentiate between true infection and a contaminated sample. 

• Type of Study: Observational

Acute Bronchitis/Chronic Obstructive Pulmonary Disease (COPD) Exacerbations

• PCT cut-off level: 0.1 to 0.5 ng/mL

• Role of PCT: To reduce (unnecessary) antibiotic exposure in the ED and inpatient setting without adverse outcomes. 

• Type of Study: Randomized controlled trial  

Infective Endocarditis 

• PCT cut-off level: 2.3 ng/mL

• Role of PCT: High diagnostic accuracy for predicting acute endocarditis. 

• Type of Study: Observational

Meningitis:

• PCT cut-off level: 0.5 ng/mL

• Role of PCT: To differentiate viral from bacterial meningitis and reduce antibiotic exposure.

• Type of Study: Before-after

Neutropenia 

• PCT cut-off level: 0.1 to 0.5 ng/mL

• Role of PCT: To identify systemic bacterial infections within neutropenic patients. 

• Type of Study: Observational

Pneumonia

• PCT cut-off level: 0.1 to 0.5 ng/mL

• Role of PCT: To reduce antibiotic exposure during hospitalization without adverse outcomes.

Postoperative Fever

• PCT cut-off level: 0.1 to 0.5 ng/mL

• Role of PCT:  To differentiate postoperative infections from non-infectious fevers. 

• Type of Study: Observational

Postoperative Infections

• PCT cut-off level: 0.5 to 1.0 ng/mL

• Role of PCT: To minimize antibiotic treatment in surgical intensive care settings without detrimental outcomes. 

• Type of Study: Randomized controlled trial

Severe Sepsis With or Without Shock

• PCT cut-off level: 0.25 to 0.5 ng/mL

• Role of PCT: To limit antibiotic treatment in intensive care settings without detrimental outcomes.

• Type of Study: Randomized controlled trial

Upper Respiratory Tract Infections

• PCT cut-off level: 0.1 to 0.25 ng/mL

• Role of PCT: To limit antibiotic treatment in intensive care settings without detrimental outcomes.

• Type of Study: Randomized controlled trial

Urinary Tract Infections

• PCT cut-off level: 0.25 ng/mL

• Role of PCT: To determine the extent of renal involvement. 

• Type of Study: Observational

Ventilator-associated Pneumonia

• PCT cut-off level: 0.1 to 0.25 ng/mL

• Role of PCT: To minimize antibiotic treatment without detrimental outcomes. 

• Type of Study: Randomized controlled trial

Once the cut-off level is established, the timing and frequency of PCT measurement to assess adequate infection control should be determined.[32] Current clinical data suggests that PCT serum levels should be remeasured after 6 to 24 hours, absent evidence of spontaneous clinical improvement such as the resolution of hemodynamic instability. Following antibiotic initiation, the recommendation is that PCT values be assessed every one to two days to ensure adequate coverage. Further, antibiotic courses should be discontinued as soon as PCT levels drop below 0.1 ng/mL or 80 to 90% below the initial measurement.[11]

Algorithms have been established for emergency and intensive care settings, providing clinicians with a quick method for determining when to initiate or discontinue antibiotics.[13] For example, an algorithm has been established to determine when to start antibiotic therapy in the emergency department for patients with respiratory tract infections.[33] Recommendations are that antibiotics be utilized when PCT levels are above 0.25 ng/mL; PCT levels should be repeated on days three, five, and seven. Antibiotics should be discontinued when PCT levels fall below 0.25 ng/mL or drop by 80 to 90%. If the PCT remains elevated, then consider new treatment options.[11]

In the intensive care unit, an algorithm has been instituted to determine when antibiotic treatment should be discontinued in patients with sepsis.[34] The algorithm recommends that antibiotic coverage be discontinued when PCT levels drop below 0.5 ng/mL or decrease 80% from the peak value. However, if PCT levels remain elevated (over 0.5 ng/mL), continuing the antibiotic course or changing the treatment entirely is advised.[11] These algorithms have been used successfully in clinical trials and have proven to reduce overall antibiotic use, thus improving antibiotic stewardship. However, further research is needed to ensure these results can be adequately repeated on a larger scale and by utilizing more clinical trials versus observational studies.[35]

Clinical Significance

It is well-documented that early diagnosis of a bacterial infection can decrease mortality and morbidity among all patients.[36] Efficient diagnosis of bacterial infections allows clinicians to initiate antibiotic therapy when deemed appropriate, thus preventing the misuse and overuse of antibiotics. As antibiotic resistance continues to rise, it has become increasingly important for clinicians to determine different algorithms and laboratory tests that help sustain current antibiotic parameters.[37]

Unfortunately, most first-line tests for determining infection, such as blood cultures and C-reactive protein, lack the efficiency and specificity needed to treat patients promptly. Therefore, procalcitonin (PCT) serum assays have been developed to provide healthcare providers with an earlier detection method to determine the origin of a systemic inflammatory response (e.g., bacterial versus non-bacterial). Early detection, in turn, limits the development of antibacterial resistance and patient exposure to antibiotics when they are no longer warranted.[11] 

The prognostic value of PCT has also shown clinical significance by providing clinicians with a positive correlation between disease severity and elevated PCT serum levels, especially within septic patients.[12] Although PCT assays have shown great promise, the cost-effectiveness of these tests continues to be debated. Current research has shown that these tests are already being overused because there are currently no adequate guidelines for when these tests should and should not be obtained.[30] Therefore, the clinical significance of these tests needs to be more thoroughly researched on a large scale and through randomized clinical trials so that guidelines can be implemented to ensure the practice of cost-effective medicine.[31]

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Quality Control and Lab Safety

For non-waived tests, laboratory regulations require, at the minimum, analysis of at least two levels of control materials once every 24 hours. If necessary, laboratories can assay QC samples more frequently to ensure accurate results. Quality control samples should be assayed after calibration or maintenance of an analyzer to verify the correct method performance.[38] To minimize QC when performing tests for which manufacturers’ recommendations are less than those required by the regulatory agency (such as once per month), the labs can develop an individualized quality control plan (IQCP) that involves performing a risk assessment of potential sources of error in all phases of testing and putting in place a QC plan to reduce the likelihood of errors.[39] Westgard multi-rules are used to evaluate the quality control runs. In case of a rule violation, proper corrective and preventive action should be taken before patient testing.[40] 

The laboratory must participate in the external quality control or proficiency testing (PT) program because it is a regulatory requirement published by the Centers for Medicare and Medicaid Services (CMS) in the Clinical Laboratory Improvement Amendments (CLIA) regulations. It is helpful to ensure the accuracy and reliability of the laboratory concerning other laboratories performing the same or comparable assays.[41] Required participation and scored results are monitored by CMS and voluntary accreditation organizations. The PT plan should be included as an aspect of the quality assessment (QA) plan and the overall quality program of the laboratory.[42]

Consider all specimens, control materials, and calibrator materials as potentially infectious. Exercise the normal precautions required for handling all laboratory reagents. Disposal of all waste material should be in accordance with local guidelines. Wear gloves, a lab coat, and safety glasses when handling human blood specimens. Place all plastic tips, sample cups, and gloves that come into contact with blood in a biohazard waste container.[43] Discard all disposable glassware into sharps waste containers. Protect all work surfaces with disposable absorbent bench top paper, discarded into biohazard waste containers weekly or whenever blood contamination occurs. Wipe all work surfaces weekly.[44]

Enhancing Healthcare Team Outcomes

As bacterial drug resistance continues to rise across the globe, it has become of utmost importance to enhance antibiotic stewardship.[37] Procalcitonin (PCT) provides healthcare providers with a more specific marker for determining the presence of bacterial infections when compared to current measures. Therefore, PCT assays can be utilized to determine if antibiotics need to be initiated, discontinued, or changed based on changing serum levels, thus decreasing the overall use or misuse of antibiotics.[4] Moreover, the assays have also been useful as a prognostic indicator for patients in the critical care setting. However, further research needs to be performed to determine if PCT assays are adequate for this purpose.[11]

PCT assays have utility in several clinical scenarios; current research suggests that PCT levels are most useful in acute exacerbations of chronic obstructive pulmonary disease (COPD) to determine when and if antibiotics should be initiated.[11] The current European Respiratory Society and American Thoracic Society guidelines state that using antibiotics in the setting of COPD exacerbations is controversial because research showing improvement in clinical outcomes is inadequate. Therefore, they recommend further effectiveness studies and the use of biomarkers to determine when antibiotics are clinically appropriate.[45] A biomarker, such as PCT, can be used to determine if antibiotics are appropriate in an acute COPD exacerbation; this improves antibiotic stewardship and reduces morbidity associated with unnecessary antibiotic use.[37] 

Overall, PCT levels provide a promising laboratory measurement for identifying bacterial infections. However, the utility of this test is limited by the clinical setting and patient population. Therefore, further research must be conducted before implementing PCT guidelines for everyday clinical practice.

Disclosure: Derrick Cleland declares no relevant financial relationships with ineligible companies.

Disclosure: Ambika Eranki declares no relevant financial relationships with ineligible companies.

Protecting your Inventions Abroad: Frequently Asked Questions About the Patent Cooperation Treaty (PCT)

INTRODUCTION

These frequently asked questions about the Patent Cooperation Treaty (PCT) outline the PCT procedure from an applicant’s perspective. For specific questions, further information and contact points, consult Question 29.

Overview of the PCT System

1) What is the Patent Cooperation Treaty (PCT)?

The PCT is an international treaty with more than 155 Contracting States.1 The PCT makes it possible to seek patent protection for an invention simultaneously in a large number of countries by filing a single “international” patent application instead of filing several separate national or regional patent applications. The granting of patents remains under the control of the national or regional patent Offices in what is called the “national phase”.

The PCT procedure includes:

Filing: you file an international application with a national or regional patent Office or WIPO, complying with the PCT formality requirements, in one language, and you pay one set of fees.

International Search: an “International Searching Authority” (ISA) (one of the world’s major patent Offices) identifies the published patent documents and technical literature (“prior art”) which may have an influence on whether your invention is patentable, and establishes a written opinion on your invention’s potential patentability.

International Publication: as soon as possible after the expiration of 18 months from the earliest filing date, the content of your international application is disclosed to the world.

Supplementary International Search (optional): a second ISA identifies, at your request, published documents which may not have been found by the first ISA which carried out the main search because of the diversity of prior art in different languages and different technical fields.

International Preliminary Examination (optional): one of the ISAs at your request, carries out an additional patentability analysis, usually on a version of your application which you have amended in light of content of the written opinion.

National Phase: after the end of the PCT procedure, usually at 30 months from the earliest filing date of your initial application, from which you claim priority, you start to pursue the grant of your patents directly before the national (or regional) patent Offices of the countries in which you want to obtain them.

2) How do I protect my invention in several countries?

Patents are territorially limited. In order to protect your invention in multiple countries you have a few options:

(a)  Direct or Paris route: you can directly file separate patent applications at the same time in all of the countries in which you would like to protect your invention (for some countries, regional patents may be available) or, having filed in a Paris Convention country (one of the Member States of the Paris Convention for the Protection of Industrial Property), then file separate patent applications in other Paris Convention countries within 12 months from the filing date of that first patent application, giving you the benefit in all those countries of claiming the filing date of the first application (consult Question 11);

(b)  PCT route: you can file an application under the PCT, directly or within the 12-month period provided for by the Paris Convention from the filing date of a first application, which has legal effect in all Contracting States of the PCT.

Comparison of Paris and PCT Route

3) Who uses the PCT?

The PCT is used by the world’s major corporations, research institutions, and universities when they seek international patent protection. It is also used by small and medium sized enterprises (SMEs) and individual inventors. The PCT Newsletter contains a yearly list of the largest PCT filers .

FILING

4) What is the effect of an international patent application?

In general terms, your international patent application, provided that it complies with the minimum requirements for obtaining an international filing date, has the effect of a national patent application (and certain regional patent applications) in or for all PCT Contracting States. Moreover, if you comply with certain formal requirements set out in the Treaty and Regulations, which are binding on all of the PCT Contracting States, subsequent adaptation to varying national (or regional) formal requirements (and the cost associated therewith) will not be necessary.

5) Who has the right to file an international patent application under the PCT?

You are entitled to file an international patent application if you are a national or resident of a PCT Contracting State. If there are several applicants named in the international application, only one of them needs to comply with this requirement.

6) Where can I file my international patent application?

You can file an international patent application, in most cases, with your national patent Office, or directly with WIPO if permitted by your State’s national security provisions. Both of those Offices act as PCT “receiving Offices”. If you are a national or resident of a country which is party to the ARIPO Harare Protocol, the OAPI Bangui Agreement, the Eurasian Patent Convention or the European Patent Convention, you may alternatively file your international patent application with the regional patent Office concerned, if permitted by the applicable national law.

7) Can I file PCT applications electronically? 

In the vast majority of cases, applicants file PCT applications electronically. You can file PCT applications electronically with any competent receiving Offices which accepts such filings. Preparing the PCT application using the WIPO web service (ePCT-filing) helps you to prepare your applications by automatically validating the entered data and drawing your attention to incorrectly or inconsistently completed parts. Moreover, it helps you to manage your applications, for example, with monitoring time limits for relevant actions. You are also entitled to certain PCT fee reductions when filing electronically. More details about PCT electronic filing can be found at www.wipo.int/pct-eservices. 

8) What are the costs associated with the filing and processing of an international application under the PCT? What are the costs for entering the national phase?

PCT applicants generally pay three types of fees when they file their international applications:

(a) an international filing fee of 1,330 Swiss francs2,

(b) a search fee which can vary from approximately 150 to 2,000 Swiss francs2 depending on the ISA chosen, and

(c) a small transmittal fee which varies depending on the receiving Office.

Because an international patent application is effective in all PCT Contracting States, you do not incur, at this stage in the procedure, the costs that would arise if you prepared and filed separate applications at national and regional Offices. Further information about PCT fees can be obtained from the receiving Offices, the dedicated PCT Fee webpage, the PCT Applicant’s Guide and the PCT Newsletter (consult Question 29).

The fees you will need to pay as you enter the national phase represent the most significant pre-grant costs. They can include fees for translations of your application, national (or regional) Office filing fees and fees for acquiring the services of local patent agents or attorneys. In several Offices however, national filing fees are lower for international patent applications than they are for direct national applications in recognition of the work already done during the international phase. You should also remember that in the case of all granted patents, whether or not the PCT is used to obtain them, you will need to pay maintenance fees in each country in order to keep the patents alive.

9) Are there any fee reductions available under the PCT? 

PCT fee reductions are available to all applicants who file electronically, based on the type of filing and the format of the application submitted (consult Question 7).

In addition, to encourage the use of the PCT System by applicants from developing countries fee reductions of 90% for certain fees, including the international filing fee, are available to natural persons, filing in their own right.3 This same 90% reduction applies to any person, whether a natural person or not, who is a national of and resides in a State that is classed as a least developed country by the United Nations. If there are several applicants, each must satisfy those criteria.

Some ISAs also provide for a reduction of the international search fee if the applicant or applicants are nationals or residents from certain countries (consult Annex D of the PCT Applicant’s Guide).

Some national or regional Offices provide for fee reductions for natural persons, universities, not-for-profit research institutes and small and medium-sized enterprises (SMEs) for the fees you will need to pay as you enter the national phase (consult respective National Chapters of the PCT Applicant’s Guide). 

10) How long does the PCT process take?

You have, in most cases, up to an additional 18 months from the time you file your international patent application (or usually 30 months from the filing date of the initial patent application of which you claim priority – consult Question 11) before you have to begin the national phase procedures with individual patent Offices and to fulfill the national requirements (consult Question 26).

This additional time can be useful for evaluating the chances of obtaining patents and exploiting your invention commercially in the countries in which you plan to pursue patent protection, and for assessing both the technical value of your invention and the continued need for protection in those countries.

It is important to note, however, that you do not have to wait for the expiration of 30 months from the earliest filing date of your patent application (“priority date”) before you enter the national phase – you can always request an early entry into the national phase.

Since, in the national phase, each patent Office is responsible for examining your application in accordance with national or regional patent laws, regulations and practices, the time required for the examination and grant of a patent varies across patent Offices.

11) What does it mean to “claim priority” of an earlier patent application?

Generally, patent applicants who wish to protect their invention in more than one country usually first file a national or regional patent application with their national or regional patent Office, and within 12 months from the filing date of that first application (a time limit set in the Paris Convention, consult Question 2), they file their international application under the PCT.

The effect of claiming the priority of an earlier patent application is that a patent shall not be invalidated by reasons of any acts accomplished in the interval, such as another filing, the publication or sale of the invention.

12) In what languages can an international patent application be filed?

You can file an international patent application in any language which the receiving Office accepts. If you file your application in a language which is not accepted by the ISA that is to carry out the international search, you will be required to furnish a translation of the application for the purposes of international search. Receiving Offices are, however, obliged to accept filings in at least one language which is both a language accepted by the competent ISA that is to carry out the international search (consult Question 13) and a “publication language”, that is, one of the languages in which international patent applications are published (Arabic, Chinese, English, French, German, Japanese, Korean, Portuguese, Russian and Spanish). You therefore always have the option of filing your international patent application in at least one language from which no translation is required for either PCT international search or publication purposes.

INTERNATIONAL SEARCH

13) Which Office will carry out the international search of my PCT application?

The following have been appointed by the PCT Contracting States as International Searching Authorities (ISAs): the national Offices of Australia, Austria, Brazil, Canada, China, Chile, Egypt, Finland, India, Israel, Japan, the Philippines, the Republic of Korea, the Russian Federation, Singapore, Spain, Sweden, Turkey, Ukraine and the United States of America, and the following regional Offices, the Eurasian Patent Office, the European Patent Office, the Nordic Patent Institute and the Visegrad Patent Institute. The availability of a particular ISA to the nationals or residents of a country is determined by the receiving Office where the international application was filed. Some receiving Offices provide a choice of more than one competent ISA. If your receiving Office is one of those, you can choose any one of them, taking into account differing requirements relating to language, fees, etc..

14) What is a PCT international search?

A PCT international search is a high quality search of the relevant patent documents and other technical literature in those languages in which most patent applications are filed (Chinese, English, German and Japanese, and in certain cases, French, Korean, Russian and Spanish). The high quality of the search is assured by the standards prescribed in the PCT for the documentation to be consulted, and by the qualified staff and uniform search methods of the ISAs, which are all experienced patent Offices. The results are published in an international search report and a written opinion of the ISA on the potential patentability of your invention (consult Questions 15 and 18). 

15) What is an international search report?

The international search report consists mainly of a listing of references to published patent documents and technical journal articles which might affect the patentability of the invention disclosed in the international application. The report contains indications for each of the documents listed as to their possible relevance to the critical patentability questions of novelty and inventive step (non-obviousness). Together with the search report, the ISA prepares a written opinion on patentability, which will give you a detailed analysis of the potential patentability of your invention (consult Question 18). The international search report and the written opinion are sent to you by the ISA.

16) What is the value of the international search report?

The report enables you to evaluate your chances of obtaining patents in PCT Contracting States. An international search report which is favorable, that is, in which the documents (prior art) cited would appear not to prevent the grant of a patent, assists you in the further processing of your application in those countries in which you wish to obtain protection. If a search report is unfavorable (for example, if it lists documents which challenge the novelty and/or inventive step of your invention), you have the opportunity to amend the claims in your international patent application (to better distinguish your invention from those documents), and have them published, or to withdraw the application before it is published.

17) Will an international search be carried out for all international applications? 

As a rule, an international search is carried out for all international applications. There are instances, however, where the ISA will not be able to carry out a search. For example, where the international application relates to subject matter which the ISA is not required to search or if the description, claims or drawings are not sufficiently clear for it to carry out a meaningful search. In such cases, the ISA will issue a declaration that no international search report will be issued.

There are also circumstances where the ISA will issue a partial search report. This can occur when, in the view of the ISA, the international application contains multiple inventions but the applicant has not paid additional search fees to cover the work required to search those additional invention(s). 

18) What is the written opinion of the International Searching Authority?

For every international application, the ISA will establish, at the same time that it establishes the international search report, a preliminary and non-binding opinion on whether the invention appears to meet the patentability criteria in light of the search report results. The written opinion, which is sent to you together with the international search report, helps you understand and interpret the results of the search report with specific reference to the text of your international application, being of special help to you in evaluating your chances of obtaining a patent. The written opinion is made available to the public at the same time as the application.

If you do not request international preliminary examination  (consult Question 23), the written opinion will form the basis of the international preliminary report on patentability (IPRP Chapter I) which will be provided, together with its English translation at the end of the international phase to the national (or regional) patent Offices;  the decision on the granting of a patent remains the responsibility of each of the national or regional Offices in which you enter the national phase;  the IPRP (Chapter I) should be considered by the Offices but is not binding on them.

SUPPLEMENTARY INTERNATIONAL SEARCH

19) What is the PCT supplementary international search?

Supplementary international search permits the applicant to request, in addition to the international search (the “main international search”), one or more supplementary international searches each to be carried out by an ISA other than the ISA which carried out the main international search. The additional search has the potential of reducing the risk of new patent documents and other technical literature being discovered in the national phase since, by requesting supplementary search the applicant can enlarge the linguistic and/or technical scope of the documentation searched.

20) What is the supplementary international search report?

The supplementary international search report is generally similar in content and appearance to the main international search report; it contains a listing of references to patent documents and other technical literature which may affect the patentability of the invention claimed in the international application. However, it does not repeat documents which have already been cited in the international search report, unless this is necessary because of new relevance when read in conjunction with other documents discovered during the supplementary international search. On occasion, the supplementary international search report may contain more detailed explanations than those in the main international search report. This is due to the fact that, unlike the main international search, no written opinion is established with the supplementary international search report, and these additional details are helpful for a full understanding of the references listed.

INTERNATIONAL PUBLICATION

21) What does international publication under the PCT consist of?

WIPO publishes the international application shortly after the expiration of 18 months from the priority date (if it has not been withdrawn earlier), together with the international search report. PCT international applications are published online on PATENTSCOPE, a powerful, fully searchable database with flexible, multilingual interfaces and translation tools to assist users and the public in understanding the content of published applications..

22) Can third parties access documents contained in the file of the international application? If so, when?

Until international publication (18 months after the priority date), no third party is allowed access to your international application unless you as applicant request or authorize it. If you wish to withdraw your application (and you do so before international publication), international publication does not take place and, as a consequence, no access by third parties is permitted. However, when international publication occurs, certain documents in the international application file are made available on PATENTSCOPE together with the published international application, for example, the written opinion of the ISA and any informal comments on the written opinion.

INTERNATIONAL PRELIMINARY EXAMINATION

23) What is international preliminary examination?

International preliminary examination is a second evaluation of the potential patentability of the invention, using the same standards on which the written opinion of the ISA was based (consult Question 18). If you wish to make amendments to your international application in order to overcome documents identified in the international search report and conclusions made in the written opinion of the ISA, international preliminary examination provides the only possibility to actively participate in the examination process and potentially influence the findings of the examiner before entering the national phase – you can submit amendments and arguments and are entitled to an interview with the examiner. At the end of the procedure, an international preliminary report on patentability (IPRP Chapter II) will be issued.

The International Preliminary Examining Authorities (IPEAs) which carry out the international preliminary examination are the ISAs mentioned above (consult Question 13). For a given PCT application, there may be one or more competent IPEAs; your receiving Office can supply details or you may consult the PCT Applicant’s Guide and the PCT Newsletter.

24) What is the value of the international preliminary report on patentability (Chapter II)? 

The IPRP (Chapter II) which is provided to you, to WIPO and to the national (or regional) patent Offices, consists of an opinion on the compliance with the international patentability criteria of each of the claims which have been searched. It provides you with an even stronger basis on which to evaluate your chances of obtaining patents, in most cases on an amended application, and, if the report is favorable, a stronger basis on which to continue with your application before the national and regional patent Offices. The decision on the granting of a patent remains the responsibility of each of the national or regional Offices in which you enter the national phase; the IPRP (Chapter II) should be considered by the Offices but is not binding on them.

NATIONAL PHASE

25) How do I enter the national phase?

It is only after you have decided whether, and in respect of which States, you wish to proceed further with your international application that you must fulfill the requirements for entry into the national phase. These requirements include paying national fees and, in some cases, filing translations of the application. These steps must be taken, in relation to the majority of PCT Contracting States’ patent Offices, before the end of the 30th month from the priority date. There may also be other requirements in connection with the entry into the national phase – for example, the appointment of local agents. More general information on national phase entry can be found in the PCT Applicant’s Guide, National Phase, and specific information concerning fees and national requirements can be found in the national chapters for each PCT Contracting State in the same Guide.

26) What happens to my application in the national phase?

Once you have entered the national phase, the national or regional patent Offices concerned begin the process of determining whether they will grant you a patent. Any examination which these Offices may undertake should be made easier by the PCT international search report and the written opinion and even more by an international preliminary examination report.

FURTHER INFORMATION

27) What is the role of WIPO in the PCT?

WIPO administers the PCT. It also serves as Secretariat to member States bodies such as the PCT Assembly, the PCT Working Group and the Meeting of International Authorities. Further, for each PCT application filed, WIPO is responsible for:

– receiving and storing all application documents;
– performing a formality examination;
– publishing the international application on WIPO’s online database PATENTSCOPE;
– publishing data about the PCT application as prescribed in the Treaty and Regulations;
– translating various portions of the PCT application and certain associated documents into English and/or French, where necessary;
– communicating documents to Offices and third parties; and
– providing legal advice on request to Offices and users.

WIPO also:

– provides overall coordination of the PCT System;
– provides assistance to existing, new and potential Contracting States and their Offices;
– provides advice on implementing the PCT in the national legislation and on setting up internal procedures in the Contracting States’ patent Offices;
– publishes the PCT Applicant’s Guide and the PCT Newsletter;
– creates and disseminates PCT information via the PCT website, webinars, and through telephone and e-mail assistance; and
– organizes and gives PCT seminars and training courses.

28) What are the advantages of the Patent Cooperation Treaty?

The PCT System has many advantages for you as an applicant, for the patent Offices and for the general public:

(a)  you have up to 18 months more than if you had not used the PCT to reflect on the desirability of seeking protection in foreign countries, to appoint local patent agents in each foreign country, to prepare the necessary translations and to pay the national fees;

(b)  if your international application is in the form prescribed by the PCT, it cannot be rejected on formal grounds by any PCT Contracting State patent Office during the national phase of the processing of the application;

(c)  the international search report and written opinion contain important information about the potential patentability of your invention, providing a strong basis for you to make business decisions about how to proceed;

(d)  you have the possibility during the optional international preliminary examination to amend the international application, enter into dialogue with the examiner to fully argue your case and put the application in order before processing by the various national patent Offices;

(e)  the search and examination work of patent Offices in the national phase can be considerably reduced thanks to the international search report, the written opinion and, where applicable, the international preliminary report on patentability that accompany the international application;

(f)  you may be able to fast-track examination procedures in the national phase in Contracting States that have PCT-Patent Prosecution Highway (PCT-PPH) agreements or similar arrangements;

(g)  since each international application is published together with an international search report, third parties are in a better position to evaluate the potential patentability of the claimed invention;

(h)  for you as an applicant, international publication online puts the world on notice of your invention. You may also highlight your interest in concluding licensing agreements on PATENTSCOPE, which can be an effective means of advertising and looking for potential licensees;

(i)  you also achieve other savings in document preparation, communication and translations because the work done during the international processing is generally not repeated before each Office (for example, you submit only one copy of the priority document instead of having to submit several copies); and

(j)  if your invention appears to be not patentable at the end of the international phase, you may abandon the PCT application and you will have saved the costs you would otherwise have incurred by directly seeking protection in foreign countries, appointing local patent agents in each foreign country, preparing the necessary translations and paying the national fees.

Ultimately, the PCT:

– brings the world within reach;
– streamlines the process of fulfilling diverse formality requirements;
– postpones the major costs associated with seeking multinational patent protection;
– provides a strong basis for patenting decisions; and
– is used by the world’s major corporations, research institutions and universities when they seek multinational patent protection.4

29) Where can I find out more about the PCT?

On the PCT website and in the various PCT publications you will find information in various language versions, including:

– PCT Applicant’s Guide;
– PCT Newsletter (monthly);
– PCT Highlights;
– Learn the PCT Video Series;
– PCT Distance Learning Course;
– Seminars; and
– PCT Webinars

If you are considering filing an international patent application under the PCT, you are advised to consult a qualified patent attorney or agent in your country, and/or your national or regional patent Office.

PCT Information Service (for general questions about the PCT):
Telephone: (41 22) 338 83 38
E-mail: pct.infoline@wipo.int

For filing international applications directly with WIPO, please contact:
World Intellectual Property Organization
PCT Receiving and Processing Section
34, chemin des Colombettes
CH-1211 Geneva 20, Switzerland
Telephone: (41 22) 338 92 22
E-mail: ro.ib@wipo.int
Website address: www.wipo.int/pct/en/filing/filing.html
ePCT
WIPO IP Portal

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