An Overview of Biosimilars in the Russian Federation

Generic Drugs and Biosimilars

It is well known that the Russia Federation has a strong generic drug market. A generic medicine is defined as a medicine that contains the same active pharmaceutical ingredient (API) or a combination of the same APIs in the same dosage form as the original or innovator medicine and is introduced into circulation after an original medicine. Russian law also provides an “accelerated” marketing approval (MA) procedure for generics. Under this “accelerated procedure,” an MA Applicant submits information obtained from clinical trials of the medicine and published in specialized literature, as well as documents containing the results of bioequivalence and/or therapeutic equivalence studies of the medicine seeking MA.

While Russian law allows for the registration of biological products (Biological products are medicinal products containing a biological active substance. A “biological active substance” is a substance that is produced by or extracted from a biological source that requires for its characterization and determination of its quality a combination of physico, chemical and biological testing, along with its production process and control), it does not define a “biosimiliar,” nor does it provide a regulatory framework for the accelerated approval of biosimilars. Nonetheless, Russian legislation on the registration of medicinal products (Russian Federation Law No. 61-FZ On the Circulation of Medicines) is expected to be revised in the near future and the requirements necessary conducting clinical studies for biosimilars is under much discussion.

Because no accelerated marketing approval procedure currently exists in the Russian Federation for biosimilars, a full clinical development program must be completed. Thus, the submission of documents and timelines for biosimilars is the same as for the registration of a biological product (which is considered to be a “pharmaceutical product”). Generally, the marketing approval procedure involves the following four sequential steps:

1. Creation of a registration dossier for submission to the Ministry of Healthcare (MoH) including documents necessary for initiating clinical studies;

2. Conducting clinical trials;

3. Evaluation of the drug quality and expected benefit to possible risk ratio; and

4. Decision by the MoH.

Step 1: Registration dossier

An Applicant must submit a registration dossier to the MoH. The dossier must be submitted in Russian or translated into Russian and must contain the following six components (portions of which are submitted at different points in time during the marketing approval process):

1. Administrative documents;

2. Description of the pharmaceutical properties of the pharmaceutical product;

3. Data about the manufacturing of the pharmaceutical product;

4. Data regarding quality control of the finished pharmaceutical product;

5. Data regarding the preclinical pharmacological and toxicological studies of the pharmaceutical product; and

6. Data regarding the clinical studies of the pharmaceutical product.

All of the data required for Russian registration of a pharmaceutical product is the same information required for a European registration. Therefore, if an Applicant already has a European dossier, a separate, new dossier is not required for Russia (other than translating the European dossier into Russian). Other documents required for registration include:

1. A Certificate of Pharmaceutical Product (A WHO model certificate can be used);

2. A GMP Certificate of the finished API manufacturer; and

3. A Manufacturing License of the finished API manufacturer.

Step 2: Clinical Trials

All pharmaceutical products must undergo clinical studies during the registration process. The scope of the clinical studies depends upon: (a) pharmaceutical product type, form and route of administration (original or generic); (b) pharmacotherapeutic group and indications for use; (c) scope of clinical trials conducted abroad {Clinical studies conducted abroad do not have to be repeated; nonetheless, a manufacturer is not exempt from conducting at least one clinical study in Russia. However, the clinical studies conducted abroad influence the scope (number of patients, indications) to be conducted in Russia}; and (d) whether an international, multi-center study was conducted and whether part of the study was conducted in Russia (If Russia was included then additional studies probably will not be needed).

Specific permission must be obtained in advance from the MoH to conduct clinical studies. Specifically, an Applicant must submit a registration dossier, fee and a protocol for conducting clinical studies. The MoH will review the dossier and send it for two parallel evaluations. The first evaluation is an ethical evaluation by the Ethics Committee. The second evaluation is an evaluation for purpose of granting a clinical study by the Federal State Budgetary Institution “Scientific Center for Evaluation of Medicinal Products” (FSBI SCEMP). If a positive evaluation is received from both the Ethics Committee and FSBI SCEMP, the MoH grants permission for the Applicant to conduct clinical trials.

The length of the clinical trial period depends on the study type, duration of treatment, etc. Typically, the clinical trial period lasts at least six months although on average, it is approximately 10-18 months. During the clinical study period, the registration procedure is suspended.

Step 3: Evaluation

After completion of the clinical trials, Applicant submits a clinical trial report, a fee and an application for renewal of the registration procedure to the MoH. After the submission, registration resumes and the registration dossier is forwarded to the FSBI SCEMP for two evaluations: (a) a drug quality evaluation; and (b) an evaluation of the expected benefit to possible risk ratio. For drug quality evaluation, the FSBI SCEMP examines the Applicant’s drug quality control procedures as well as samples of the drug. Additionally, for the expected benefit to possible risk ratio, experts from the FSBI SCEMP examine the registration dossier, clinical study reports and provide an opinion (positive or negative) on the drug efficacy and safety. The FSBI SCEMP’s opinions on the drug quality and expected benefit to possible risk ratio are forwarded to the MoH.

A marketing authorization is issued for five years. After five years, the manufacturer applies for confirmation of the registration at which point the marketing authorization is issued for an unlimited amount of time.

Biosimilars Approved in Russia

Several “biosimilars” have been approved in Russia. These include epotein beta, interferon beta-1b and filgrastim. Just recently, in April 2014, Biocad Pharmaceutical Company received marketing approval from the MoH for its rituximab biosimilar, BCD-020. BCD-020 will be marketed as AcellBia and is the first monoclonal antibody biosimilar to receive approval from the MoH. As part of its dossier, Biocad supplied data from a randomized multicenter clinical study comparing the pharmacokinetics, pharmacodynamics, safety, and efficacy of BCD-020 to the innovator rituximab. Experts at the Research Center at the MoH reviewed the clinical trial efficacy and safety data in patients with B-cell lymphoma and concluded that there were no meaningful differences between BIOCAD’s rituximab biosimilar and the originator drug.

AcellBia is produced in a special economic development district outside of St. Petersburg. Biocad has reported that it us finishing clinical trials of two more monoclonal antibody biosimilars, bevacizumab and trastuzumab (biosimilars of Herceptin and Avastin by Roche), that will be produced at the same facility. On May 22, 2014, Biocad was acquired by Pharmstandard and Russian investment company Millhouse.

This post was written by Lisa Mueller and Vladislav Ugryumov of Gowlings.

An Overview of Biosimilars and the Biosimilar Pathway in India

Background

India is one of the most densely populated countries in the world. According to the World Bank (2012), 1.237 billion people live in India, accounting for about 17.5% of the world’s population. India has risen from the 15th largest pharmaceutical market in 2007 to 12th in 2011 and is expected to become the 8th largest by 2015. In fact, India’s pharmaceutical market has a compound annual growth rate of 12% post price controls. Some of this growth is driven by:

1.  Increased accessibility and affordability of prescription drugs.

2.  An increase in the diagnosis and treatment of chronic diseases.

3.  Mergers, acquisitions and partnerships with big pharma.

4.  High growth in the hospital sector. 

Health Insurance and Drug Pricing

Since its independence, India has struggled to provide its people with universal health care. India’s health industry arose in 1986. However, very few people today have health insurance. As a result, approximately 70% of Indians pay for health care expenses out of their own pockets and this is one of the important causes of poverty in the country today.

Presently, the current health insurance system comprises stand-alone health insurers along with government sponsored health insurance providers. Of the policies currently available, most only cover inpatient hospitalization and treatment in hospitals. Outpatient services are not covered. Nonetheless, over the last five years, government-sponsored healthcare schemes (GSHISs) have contributed to a significant increase in the population being covered by health insurance, scaling up at a pace possible unseen elsewhere in the world. Over 300 million people, or more than 25 percent of India’s population, gained access to some form of health insurance in 2010, up from 55 million in 2003-04. More than 180 million of these were people below the poverty line.

Given that most Indians pay for healthcare expenses out of their own pockets, drug pricing is a major concern of the government. In fact, the government believes that the prices of lifesaving drugs should not be set by market forces. As a result, the Indian government has attempted to control drug prices in several different ways. These include:

1.  Denying patent protection for certain drugs (Glivec (treatment for leukemia) – which was being supplied by Novartis free of charge to 16,000 patients – roughly 95% of those who needed it via the Novartis “Glivec International Patient Assistance Program”).

2.  Issuing compulsory licenses (e.g., Bayer’s Nexavar).

3.  The Drug Price Control Order (DPCO) of 2013. The DPCO applies to both brand name and generic drugs and lists 348 drugs as “essential” and subject to price control. The DPCO places 50% of the market under price controls, which results in a price reduction of up to 80% for these essential drugs. However, drugs that have some form of innovation that can be attributed to Indian researchers may be immune from price controls for a period of five years. Specifically, three types of innovation qualify: (a) drugs resulting from indigenous R&D; (b) improvements by an Indian company on a process for making an existing drug; and (c) development of a new drug delivery system by Indian R&D. As one government official explained, this policy “…would spur innovation and make sure the price-control regime doesn’t dissuade pharma firms from research and development.”

Rise of Similar Biologics in India

Biologics are an important component of the pharmaceutical industry and have grown exponentially in the last decade. In recent years, the pharmaceutical industry has placed greater and greater emphasis on developing biopharmaceutical-based drugs (biologics). As a result, the global biologics market is expected to reach $220 billion by 2019.

By 2020, patents on several biological products with global sales of more than US$67 billion will expire. The patent expiration dates for some of the best-selling biologics are provided in the tables 1-3.

Table 1: Humanized Antibodies

Table1

Table 2: Non-humanized Antibodies

table2

Table 3: Non-antibody Molecules

Table3

Biologics have shown huge potential in curing the unmet demand of small drug molecules. These factors have caught the attention of the global pharmaceutical industry and have polarized the industry towards biologic products. Given this, biosimilars, or “similar biologics” are expected to become an important economic and therapeutic driver of the Indian pharmaceutical market.

In India, similar biologics are regulated by the:

1.  Drugs and Cosmetics Act, 1940 (Drugs and Cosmetics Act);

2.  Drugs and Cosmetics Rules, 1945 (as amended from time to time);

3.  Rules for the Manufacture, Use, Import, Export and Storage of Hazardous Microorganisms and Genetically Engineered Organisms or Cells, 1989 (Rules 1989) notified under the Environment (Protection) Act, 1986;

4.  Recombinant DNA Safety Guidelines, 1990;

5.  Guidelines for Generating Preclinical and Clinical Data for rDNA Vaccines, Diagnostics and other Biologicals, 1999;

6.  The Central Drugs Standard Control Organization (CDSCO) Guidance for Industry, 2008 {including: (a) Submission of Clinical Trial Application for Evaluating Safety and Efficacy; (b) Requirements for Permission of New Drugs Approval; (c) Post Approval Changes in Biological Products: Quality, Safety and Efficacy Documents; and (d) Preparation of the Quality Information for Drug Submission for New Drug Approval: Biotechnological/Biological Products}; and

7.  Guidelines and Handbook for Institutional Biosafety Committees (IBSCs), 2011.

CDSCO and Department of Biotechnology (DBT) through the Review Committee on Genetic Manipulation (RCGM), approve similar biologics using an abbreviated version of the pathway applicable to new drugs. CDSCO is the highest regulatory authority in India, addresses issues and challenges for ensuring the safety and efficacy of similar biologics and establishes the appropriate regulatory pathways. Specifically, with respect to similar biologics, CDSCO is responsible for granting import/export licenses, clinical trial approvals and permission for marketing and manufacturing. The RCGM is responsible for monitoring all research scale activity and the approval of nonclinical studies. The DBT is responsible for overseeing the development and preclinical evaluation of recombinant biologics.

In 2012, CDSCO, in collaboration with the DBT, issued the Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India (Guidelines). The Guidelines detail the regulatory requirements, such as data requirements for the manufacturing, characterization, preclinical studies and clinical trials, for receiving marketing authorization of similar biologics. The Guidelines are applicable for similar biologics developed in or imported into India.

According to the Guidelines, similar biologics are developed through a sequential process designed to demonstrate the similarity, by extensive characterization studies, of the molecular and quality attributes of the similar biologic with a reference biologic. The extent of the testing of the similar biologic is likely to be less than that required for a reference biologic; however, it is essential that the testing of the similar biologic be sufficient to ensure that the product meet acceptable levels of safety, efficacy and quality to ensure public health. Generally, a reduction in data requirements is possible for preclinical and or clinical components of the development program by demonstrating comparability of the product (to the reference biologic) and consistency in the production process. If any significant differences in safety, efficacy and quality between the similar biologic and the reference biologic are identified, more extensive preclinical and clinical evaluation will be necessary. It is quite likely in this instance that the product may not qualify as a similar biologic.

Definitions

A “similar biologic” is defined as:

“A biological product/drug produced by genetic engineering techniques and claimed to be ‘similar’ in terms of safety, efficacy and quality to a reference biologic, which has been granted a marketing authorization in India by the Drug Controller General of India (DCGI) on the basis of a complete dossier, and with a history of safe use in India.”

A “reference biologic” (which is an innovator product) is defined as:

“A comparator biological product/drug used for head-to-head comparability studies with a similar biologic in order to show similarity in terms of safety, efficacy and quality. Only a biological product that was licensed on the basis of a full registration dossier can serve as reference biologic.”

Important Considerations regarding Reference Biologics 

A similar biologic can only be developed against a licensed reference biologic that has been approved using a complete data package in India. However, if a reference biologic is not authorized in India, it must have been licensed and widely marketed for at least four years (post-marketing) with significant safety and efficacy data in a country with an established regulatory framework. Nonetheless, this four year period can be waived or reduced in the event that no medicine or palliative therapy is available or in the event of a national healthcare emergency.

Other important points:

1.  The rationale for the choice of the reference biologic should be provided by the manufacturer of the similar biologic in the submissions to DBT and CDSCO.

2.  A similar biologic cannot be used as a reference biologic.

3.  The reference biologic must be used in all comparability testing.

4.  The dosage form, strength and route of administration of the similar biologic must be the same as that of the reference biologic.

5.  The active ingredient of the reference biologic and the similar biologic must be shown to be similar.

Approval Process for Similar Biologic in India 

Approval of a similar biologic is a multi-step process involving several government agencies such as CDSCO, RCGM, DCGI, IBSC, the Genetic Engineering Advisory Committee (GEAC), the Food & Drugs Control Administration (FDCA) and the Institutional Animal Ethics Committee (IAEC). The DCGI is responsible for product safety and efficacy and clinical trial and marketing approval for biotech drugs. The IBSC is responsible for training personnel on biosafety and instituting health monitoring programs for laboratory personnel. The GEAC is involved with environmental safety for large scale operations of live modified organism (LMO) based products. The FDCA approves plants and ensures current good manufacturing practices (cGMP).

The first step in the biosimilar approval process involves an Applicant submitting an application and requesting approval from RCGM and CDSCO to begin conducting studies with the similar biologic.   Upon receipt of approval, the Applicant can begin to generate the following information:

1.  Manufacturing Process Information. The manufacturing process for a similar biologic should be highly consistent and robust. If the host cell line used to produce the reference biologic is known, it is preferable to use the same cell line to manufacture the similar biologic. If such a host cell line is not available, any cell line that is adequately characterized and appropriate for intended use can be used to develop the similar biologic. The Applicant will need to describe the steps taken to minimize the potential for significant changes in critical quality attributes of the product and to avoid introduction of process related impurities that could impact clinical outcomes and cause immunogenicity issues.

The data requirements for review of the manufacturing process at the preclinical submission stage include a complete description of the manufacturing process from development and characterization of cell bands, stability of the clone, cell culture/fermentation, harvest, excipients, formulation, purification, primary packaging interactions (if different from the reference biologic), etc. and the consequences on product characteristics based on the below:

a.  Molecular biology considerations – Applicant will need to provide information regarding the host cell cultures, vectors, gene sequences, promoters, etc., used in the production of the similar biologic. Details regarding post-translational modifications, if any (e.g., glycosylation, oxidation, deamination, phosphorylation) should be explained.

b.  Fermentation Process Development – Applicant will need to supply at least three batches of reproducible fermentation data at pilot scale (batch is adequate to give enough purified product to generate preclinical data). Fermentation must be carried out in a controlled and monitored environment and details of fermentation kinetic data from a representative batch (indicating such things as cell growth, product formation, pH temperature, dissolved oxygen, major nutrient consumption pattern and agitation rate) should be provided. Additionally, an Applicant will need to supply data verifying that the specific protein yield (amount of protein per unit cell mass) remains constant for all fermentation batches. Finally, the Applicant must demonstrate that the overall productivity is reproducible and scalable.

c.  Downstream Process Development – Applicant will need to include information such as the steps involved in the purification of protein, batch size for protein purification and consistency of recovery in three consecutive batches of purification from three independent batches of fermentation. 

Additional information on the manufacturing process will be required when submitting an application for clinical trials (Phase III). Specifically, the Applicant must include a description of a well-defined manufacturing process with its associated process controls that assure that an acceptable product is produced on a consistent basis in accordance with good manufacturing practice (GMP). Data for submission should include: a detailed description of the drug substance and drug product processes, critical quality attributes of the product, manufacturing process controls, critical process parameters, stability data, comparability of the product manufactured on a commercial scale against the reference biologic and data from consistency batches and/or process validation batches, as applicable.

2.  Product Characterization Information. Characterization studies should be performed using analytical methods in order to establish product comparability for the key quality attributes of the product. State of the art analytical methods should be used to detect whether any “slight differences” exist in any of the relevant quality attributes. Such studies should involve the use of appropriately qualified reproducible and reliable assays. Such studies should include samples of the Applicant’s recombinant product, the reference biologic as a control, known positive and negative controls, when relevant. Each quantitative experience should be done at least three times and data should be represented in terms of mean and standard deviation. The Indian Pharmacopoeia Monograph should be followed, if available.

Product characterization studies which should be conducted include:

a.  Structural and Physicochemical properties: The primary and higher order structure of the product as well as other significant physicochemical properties should be determined. Specifically, the target amino acid sequence of the similar biologic should be confirmed to be the same as the reference biologic. If any post-translational modifications exist, these should be identified and quantified. In the event any significant differences exist, these should be scientifically justified and critically examined in preclinical studies and clinical trials.

b.  Biological activity: Appropriate biological assays should be used to characterize the activity and establish the product’s mechanism of action and clinical effects (in units of activity). It is important that the assays employed be calibrated against an international or national reference standard, where available and appropriate. If no standards are available, an international reference standard must be established pursuant to the ICH guidelines.

c.  Immunological Properties: Because the manufacturing process of recombinant biologics is known to affect the level of process related impurities and post-translational modifications of such products, these characteristics may affect the immunogenicity of the product. In view thereof, a comparison to the reference biologic should be made with respect to specificity, affinity, binding strength and Fc function. In addition, animal studies should be performed.

d.  Purity and Impurities: A similar biologic should be evaluated for the following: (i) product related variants (e.g., glycoforms, isomers, etc.); (ii) product related impurities (e.g., aggregated, oxidized or deaminated product); (iii) host cell related impurities (e.g., host cell protein, host cell DNA etc.); and (iv) process related impurities (residual media components, resin leachates, etc.). Any differences observed in the purity and impurity profiles of the similar biologic when compared to the reference biologic should be evaluated to assess its potential impact on safety and efficacy. If a similar biologic exhibits different impurities, those impurities should be evaluated to assess their potential impact on safety and efficacy. In contrast, if a similar biologic exhibits different impurities, those impurities should be identified and characterized, when possible. Depending on the type and amount of an impurity, preclinical and clinical studies will be used to confirm that there is no adverse impact on the safety and efficacy of the similar biologic.

e.  Specifications: Acceptance limits should be set based on reference biological data and from data from a sufficient number of batches from preclinical or clinical batches.

f.  Stability: Stability studies on the drug substance and drug product should be carried out using containers and conditions that are representative of the actual storage containers and conditions, according to relevant guidelines (e.g., ICH Q5C10, WHO TRS 82211). Side-by-side accelerated and stressed studies comparing the similar biologic to the reference biologic showing comparable degradation profiles are also useful in demonstrating the similarity of the products.

Once the Applicant generates the above information comparing the quality of the similar biologic with the reference biologic, this information is submitted along with basic clinical information and preclinical study protocols to the RCGM (using Form C3) requesting permission to conduct preclinical studies. The basic information about the reference biologic and similar biologic to be submitted may include the information contained in table 4:

Table 4:

Table4

The Applicant should also include approvals from the IBSC, IAEC, if available. Finally, the Applicant should also provide details regarding the proposed site for conducting toxicity testing and the personnel involved (e.g., the study direction, principal investigator, pathologist, other investigators and quality assurance officers at the site). The status of good laboratory practice (GLP) certification of the proposed facility should also be provided.

Once approval is received to conduct the preclinical studies, the studies should be comparative in nature and designed to detect differences, if any, between the similar biologic and reference biologic. The studies should be conducted with the final formulation of the similar biologic intended for clinical use unless otherwise justified. Additionally, the dosage form, strength and route of administration of the similar biologic should be the same as that of the reference biologic and any differences must be justified.

The following studies are required:

1.  Pharmacodynamic studies:

a.  In vitro studies:  The comparability of the similar biologic and reference biologic should be established by in vitro cell based bioassay (e.g., cell proliferation assays or receptor binding assays).

b.  In vivo studies:  In vivo evaluation of the biological/pharmacodynamic activity of the similar biologic may not be necessary if in vitro assays are available which are known to reliably reflect the clinically relevant pharmacodynamic activity of the reference biologic. If such in vitro assays are not available, then in vivo studies should be conducted.

2.  Toxicological Studies: At least one repeat in vivo toxicology study in a relevant species is required. The duration of the study should not be less than 28 days with a 14 day recovery period. However, the duration can vary depending on the dose and other parameters. The Applicant is required to provide a scientific justification for the choice of animal model used based on the data available in the scientific literature. In the event that a relevant animal species is not available but has been appropriately justified, the toxicity studies will need to be undertaken in two species (e.g., one rodent and the other non-rodent species) as per the requirements of Schedule Y of the Drugs and Cosmetics Act with due permission from the RCGM.

The dose should be calculated based on the therapeutic dose of the reference biologic. Other toxicity studies, such as safety pharmacology, reproductive toxicity, mutagenicity and carcinogenicity, are generally not required for evaluation of a similar biologic unless warranted by the results from the repeat dose toxicity studies.

Additionally, during this time, the Applicant should be collecting data comparing the antibody response of the similar biologic with the response generated by the reference biologic in a suitable animal model. Specifically, test serum samples should be tested for reaction to host cell proteins.

After completion of the preclinical studies, the final reports should reflect all aspects approved in the protocol and include the following additional sections/documents: RCGM approval of protocol and test center, IBSC approval of report, IAEC approval for animal use and for the procedures, QA statement, signatures of study director and all investigators who were involved in the study, all quality analytical reports on the test material and vehicle, animal feed and animal health certifications, protocol deviations if any, discussion of the results, individual animal data, summary data and any other data (such as computer analysis outputs, etc) and conclusions. These reports are submitted to RCGM (using Form C5) for review and consideration.

Upon successful evaluation of the preclinical study reports, the Applicant submits Form 44 (an application for grant of permission to import or manufacture a new drug or to undertake a clinical trial) to the DCGI seeking permission to conduct the appropriate phase of clinical trials (Phase III trials) and the documents required per Schedule Y of the Drugs and Cosmetics Act. Further, the Applicant should submit an application for market authorization as per the CDSCO Guidance Document for Industry, 2008. For cases where commercial manufacturing is performed either at a different scale and/or with a different process as compared to that used for manufacturing the Phase III clinical trial batches, information on the comparability of quality also needs to be submitted with appropriate justification, which are dealt with on a case-by-case basis (see, page 22 of the Guidelines, guideline 9). A manufacturing license is also needed giving the Applicant authorization to manufacture clinical trial batches of the similar biologic (along with a WHO GMP certificate). The State Licensing Authority in Form 29 issues a manufacturing license after which a “no objection” certificate is provided by the Central License Approving Authority.  Moreover, environmental clearance for clinical trials must also be received from the GEAC and RCGM (see, page 42 of http://www.cdsco.nic.in/writereaddata/CDSCO-GuidanceForIndustry.pdf).

For a similar biologic in which quality characterization, preclinical studies and clinical trials have been conducted outside India, an Applicant wishing to seek approval for the product in India must submit Form 44 to CDSCO seeking permission to conduct one or more clinical trials.

Once the necessary approvals are received, Applicant must conduct the following clinical studies:

1.  Pharmacokinetic studies (Phase I Study):  Comparative pharmacokinetic (PK) studies should be performed in healthy volunteers or patients to demonstrate the similarities in pharmacokinetic characteristics between the similar biologic and the reference biologic on a case-by-case basis. Factors that should be taken into consideration when designing a comparative PK study include: half-life, linearity of PK parameters, endogenous levels and diurnal variations of the biologic under study, conditions and diseases to be treated, route(s) of administration and indications.

In single dose comparative studies, the dose used in the PK study should be within the therapeutic dose range of the reference biologic, otherwise justification will be required. Additionally, the route of administration should be the one where the sensitivity to detect differences is the largest. Any differences in elimination kinetics between the similar biologic and reference biologic (e.g., clearance and elimination half life) should be explored.

Multiple-dose, comparative, parallel arm studies are required for a similar biologic used in a multiple dose regimen, where markedly higher or lower concentrations are expected at steady state than that expected from single dose data PK measurements and where time-dependence and dose-dependence of PK parameters cannot be ruled out.

2.  Pharmacodynamic studies (Phase I study):  Comparative, parallel or cross-over, pharmacodynamic (PD) studies in the most relevant population (patients or healthy volunteers) is required for the purpose of detecting differences between the reference biologic and similar biologic. If a PD marker is available in healthy volunteers, PD in healthy volunteers can be done. Comparative PD studies are recommended when the PD properties of the reference biologic are well characterized with at least one PD marker being linked to the efficacy of the molecule. The relationship between dose/exposure, the relevant PD marker(s) and response/efficacy of the reference biologic should be well established and used to justify the design. The parameters investigated in PD studies should be clinically relevant and surrogate markers should be clinically validated. PD studies may be combined with PK studies provided that the PK/PD relationship is characterized. Finally, a PD study can be part of a Phase III clinical trial, when applicable.

3.  Confirmatory Safety and Efficacy Studies (Phase III studies):  Comparative clinical trials to demonstrate the similarity in safety and efficacy of the similar biologic and reference biologic are required except in a few exceptions (namely recombinant human soluble insulin products for which comparative clinical safety studies are all that are required). One or more adequately powered, randomized, parallel group, blinded confirmatory clinical safety and efficacy trials are desirable based on the comparability established during preclinical and PK/PD studies. More than one safety and efficacy study may be required if the similar biologic is not comparable to the reference biologic in all preclinical evaluations conducted and/or the PK/PD studies have not demonstrated comparability.

A similar biologic can be approved without conducting a confirmatory clinical safety and efficacy trial (phase III study) if the following conditions are met:

a.  The structural and functional comparability of a similar biologic and the reference biologic is characterized to a high degree of confidence using physicochemical and in vitro techniques;

b.  The similar biologic is comparable to the reference biologic in all the preclinical evaluations conducted;

c. The PK/PD study has demonstrated comparability of the similar biologic and the reference biologic and has preferentially been done in an in-patient setting with a safety measurement (including testing for immunogenicity) for adequate period of time; and

d.  A comprehensive post-marketing risk management plan is presented (for the purpose of gathering additional safety and immunogenicity data).

However, the confirmatory clinical safety and efficacy study cannot be waived if there is no reliable and validated PD marker. Additionally, comparative pre-approval safety data including immunogenicity data, is required for all similar biologics including those for which confirmatory clinical trials have been waived. Pre-approval safety data is intended to provide assurance of the absence of any unexpected safety concerns.

Safety and efficacy data for a particular clinical indication (for which clinical studies have been conducted) of a similar biologic can be extrapolated to other clinical applications provided that the following are met:

a.  Similarity with respect to quality has been proven to the reference biologic;

b.  Similarity with respect to preclinical assessment has been proven to reference biologic;

c.  Clinical safety and efficacy is proven in one indication;

d.  Mechanism of action is the same for the other clinical indications; and

e.  The receptor(s) involved are the same for the other clinical applications.

Once all the clinical studies have been successfully completed, the Applicant submits an application for market authorization to DCGI. As described in the Guidance for Industry on Submission of Clinical Trial Application for Evaluating Safety and Efficacy, the application must contain the following five modules:

1.  Module I:  Administrative/Legal Information

2.  Module II:  Summaries

3.  Module III:  Quality Information (Chemical, Pharmaceutical and Biological)

4.  Module IV:  Non-clinical information

5.  Module V:  Clinical Information

Once the Applicant receives marketing authorization, the similar biologic can be sold in India. Once such marketing authorization is received, the Applicant is required to submit a post-marketing risk management plan. The purpose of the risk management plan is to monitor and detect known inherent safety concerns and potential unknown safety signals that may arise from similar biologics. The risk management plan must include:

1.  Pharmacovigilance Plan:  A comprehensive pharmacovigilance plan must prepared to further evaluate the clinical safety of the similar biologic in all approved indications post-approval. The plan must include the submission of periodic safety update reports (PSURs). The PSURs must be submitted every 6 months for the first two years after approval to CDSCO. After the first two years, the PSURs are submitted to DCGI.

2.  Adverse drug reaction reporting:  All cases involving serious and unexpected adverse reactions must be reported within 15 days of initial receipt.

3.  Post-marking studies:  At least one post-marketing safety and immunogenicity study (non-comparative) is required. The study must be designed to confirm that the similar biologic does not have any concerns with regards to the therapeutic consequences of unwanted immunogenicity. The post-marketing study should be submitted to CDSCO.

Biosimilars Approved in India 

According to GaBI Online, in 2000, the first “similar biologic” was approved and marketed in India for a hepatitis B vaccine. In recent years, over 50 biopharmaceutical products have been approved for marketing in India, with more than half of them being “similar biologics”. Table 5 lists some of the similar biologics approved in India.

Table 5: “Similar Biologics” Approved in India 

Table5

In addition, Bicon reported in its April 2014 investor report that it is working on biosimilar versions of Bevacizumab (Avastin), Adalimumab (Humira), Etanercept (Enbrel), Peg-filgrastim (Neulasta), rh-insulin, Glargine, Lispro and Aspart.

Litigation involving Similar Biologics: The Herceptin Battle 

Roche’s block buster drug Herceptin (trastuzumab) is used to treat HER2+ breast cancer. Generally, it is prescribed during post-surgery chemotherapy for women suffering from metastatic breast cancer and has been sold in India under the international brand name Herceptin as well as under a second off-brand name, Herclon. The cost of Herceptin in India is 15 times the per capital monthly income. The maximum price of lower cost Herclon is $75,000 rupees (US$1249.00) for a 440-mg vial.

While there is no compound patent covering trastuzumab (It was a pre-1995 compound and Indian patent law at the time did not allow product patent applications to be examined), Roche received Indian Patent No. 205534 (the ‘534 patent) claiming a formulation containing trastuzumab. The patent issued on April 6, 2007 with an expiration date of May 3, 2019. Specifically, the patent claims “a composition comprising a mixture of an anti-HER2 antibody and one or more acidic variants thereof, wherein the amount of acidic variants(s) is less than about 25%”.

Roche filed three divisional patent applications: (a) 1638/KOLNP/2005 (a divisional of the ‘534 patent) filed August 16, 2005; (b) 3272/KOLNP/2008 a divisional application off of (a) and filed February 12, 2009; and (c) 3273/KOLNP/2008, a divisional off of (a) and filed February 12, 2009.

A post-grant opposition was filed by Glenmark Pharmaceuticals. During the opposition, it came to light that Roche had failed to pay the 15th annuity on the ‘534 patent and as a result, the patent lapsed. There is speculation that Roche did not pay the annuity because the Ministry of Health was poised to issue a compulsory license for Herceptin pursuant to Section 92 of the Indian Patents Act, 1970. Roche avoided the issuance of the compulsory license by abandoning its patents and patent applications.

With respect to the divisional applications, the Controller found that a request for examination had been filed in 1638/KOLNP/2005 on March 17, 2006, one month later than the due date of February 16, 2006 (the request for examination had to be filed within 6 months of its filing date). As a result, the application was deemed to be withdrawn. With respect to the remaining two divisional applications, the Controller found that these applications had been filed after the grant of the first filed application and were not permissible. Thus, these applications were also deemed to be withdrawn.

In December 2013, Biocon announced that it had received authorization from the DCGI to market its jointly developed (with Mylan) trastuzumab similar biologic (under the name CANMAb) for the treatment of breast cancer. However, in early 2014, Roche sued Biocon and Mylan in the Delhi High Court over the impending launch of its trastuzumab similar biologic. Roche made two arguments. First, Roche argued that Biocon and Mylan were misrepresenting their drugs as “trastuzumab”, “biosimilar trastuzumab” and a “biosimilar version of Herceptin” without following the due process for their drugs being approved as biosimilars in accordance with the Guidelines issued in 2012. The second argument accused Biocon and Mylan of passing off their goods as “trastuzumab”, “biosimilar trastuzumab” and a “biosimilar version of Herceptin”. The DGCI was also made a party to the suit for giving permission to Mylan and Biocon to launch their generic versions of the drug. Moreover, Roche argued that that the approvals received by Biocon and Mylan could not have satisfied the requirements for a biosimilar drug under the Guidelines, because the protocol and design study for CANMAb was filed and approved prior to the Guidelines becoming effective. Furthermore, the approval had been granted very quickly which made a weak case for compliance with the Guidelines. 

The Court issued an injunction in early February 2014 against Biocon and Mylan stating that the companies were “not entitled to introduce or launch the drug” until they persuaded the Court that their product had undergone sufficient testing and attained requisite approvals.

This post was written by Lisa Mueller and Nidhi Anand ‎of Chadha & Chadha.

 

The Thorny Problem of Patentable Eligible Subject Matter: Update to Part 1 of the 10-Part Series: U.S.

This is an update to Part 1 of the 10-part series examining patent eligible subject matter in the U.S., BRIC and several non-BRIC countries.

In Re Roslin Institute (Edinburgh)

In part 1 of this series (which can be found here), the statutory classes of patentable subject matter in the U.S. as well as the guidance issued by the United States Patent and Trademark Office (USPTO) for evaluating subject matter eligibility (Guidance) were discussed. As an update to that discussion, provided below is a brief overview of a recent decision by the United States Court of Appeals for the Federal Circuit (CAFC) regarding patentable subject matter. In the U.S. court system, the CAFC hears appeals relating to patent law and any appeals to CAFC decisions are to the U.S. Supreme Court (Supreme Court). Specifically, the CAFC decided on May 8, 2014 in In Re Roslin Institute (Edinburgh) (Roslin) that Roslin’s clone (i.e., Dolly the Sheep) was unpatentable subject matter under Section 101.

In Roslin, the application at issue was U.S. Patent Application No. 09/225,233 (the ‘233 Application), which contained product claims to clones resulting from somatic cell nuclear transfer (i.e., a clone from an adult or differentiated cell). A representative claim is claim 155, which stated:

A live-born clone of a pre-existing, non-embryonic, donor mammal, wherein the mammal is selected from cattle, sheep, pigs, and goats.

In its opinion, the CAFC stated that “Roslin’s claimed clones are exact copies of patent ineligible subject matter [i.e., the donor mammal].” These exact copies (e.g., Dolly the Sheep), according to the CAFC, did not possess markedly different characteristics from any farm animals found in nature. The genetic information and genetic structure of the DNA used to make the clones was not created or altered by the inventors.

Additionally, while the Appellant argued that Dolly possessed distinguishable characteristics from the donor mammal (i.e., phenotype and mitochondrial DNA), the CAFC pointed out that these differences were not indicated in the claims directed to the clone. The CAFC further stated that the phenotypic differences arose independent of the inventors’ efforts and the specification of the ‘233 Application did not identify how differences in mitochondrial DNA would have influenced characteristics of the cloned mammals.

Accordingly, the CAFC concluded that the claimed clones were defined in terms of the identity of their nuclear DNA relative to the nuclear DNA of the donor mammals. The CAFC thus decided that Dolly’s genetic identity to her donor parent rendered her unpatentable subject matter, and as the claims did not describe clones that had markedly different characteristics from the donor animals of which they were copies, the claims were directed to patent ineligible subject matter under Section 101.

It should be noted that the CAFC did not comment upon what may or may not constitute a markedly different characteristic. While the characteristic considered by the CAFC here in Roslin was genetic identity (i.e., genetic information and nuclear DNA structure), does a markedly different characteristic always have to be a marked difference in structure as stated in factors a and g of the Guidance or can a markedly different characteristic be, in certain instances, differences in function, use, and the like, where no change in structure occurs? It will be interesting to see how the U.S. courts interpret the term “markedly different characteristic” in future cases in relation to the patent eligibility of product claims.

Please continue to watch the BRIC Wall for further updates on patentable eligible subject matter.

This post was written by Laura Opperman and Lisa Mueller.

The Thorny Problem of Patentable Eligible Subject Matter: Part 2 of a 10-Part Series: Canada

This is Part 2 of a 10-part series examining patent eligible subject matter in the U.S., BRIC and several non-BRIC countries. To view Part 1 (The Thorny Problem of Patentable Eligible Subject Matter: U.S.), click here

Patentable Subject Matter in Canada 

In Canada, patentable subject matter is circumscribed by the definition of “invention” contained in section 2 of the Canadian Patent Act (Patent Act): RSC 1985, c P-4, which states that an “invention” may be “any new and useful art, process, machine, manufacture or composition of matter, or any new and useful improvement in any art, process, machine, manufacture or composition of matter” (emphasis added). Therefore, to be patentable, an invention must be capable of fitting into one of the five broad categories: art, process, machine, manufacture or composition of matter. Canadian Courts and the Canadian Intellectual Property Office have generally interpreted these categories expansively. However, as will be discussed in more detail below, claims to computer software, methods of medical treatment and living organisms have each been treated with some trepidation. 

Several other sections of the Patent Act, both current and repealed, contribute to defining patentable subject matter. For example, section 27(8) provides that: “[N]o patent shall be granted for any mere scientific principle or abstract theorem.” Thus, an automated mathematical calculation (such as a computer software-implemented algorithm) is considered to be a “mere scientific principle or abstract theorem” under Section 27(8). Moreover, mental operations and processes are not the kind of processes referred to in the definition of invention contained in section 2 according to Schlumberger Canada Ltd. v Commissioner of Patents (1981), 56 CPR (2d) 204 (Fed CA). However, the practical application of a business method that incorporates software is patentable subject matter and is not considered to be captured by the prohibition in section 27(8) (see, Canada (Attorney General) v Amazon.com, Inc, 2011 FCA 328).

In addition to section 27(8), long-repealed section 41 still influences Canadian patent law. Although, ultimately repealed, Canadian Courts rely on the jurisprudence under Section 41 to justify, in part, a prohibition on certain claims for uses of compounds to treat disease. Specifically, former section 41(1) stated:

41. (1) In the case of inventions relating to substances prepared or produced by chemical processes and intended for food or medicine, the specification shall not include claims for the substance itself, except when prepared or produced by the methods or processes of manufacture particularly described and claimed or by their obvious chemical equivalents.

Section 41 was enacted for the purpose of restricting the scope of patents “relating to substances prepared or produced by chemical processes and intended for food or medicine.” In practice, this meant that all claims to compounds that could be used for food or medicine could only be claimed in conjunction with their methods or processes of manufacture. Thus, by implication, the Canadian Supreme Court extended coverage of section 41 to methods of treatment using compounds for food or medicine:

this [Section 41] necessarily implies that, with respect to such substances, the therapeutic use cannot be claimed by a process claim apart from the substance itself. Otherwise, it would mean that while the substance could not be claimed except when prepared by the patented process, its use however prepared could be claimed as a method of treatment. In other words, if a method of treatment consisting in the application of a new drug could be claimed as a process apart from the drug itself [authors’ note: meaning that the method or use can be claimed without a process limitation], then the inventor, by making such a process claim [authors’ note: a method of treatment claim without a process limitation], would have an easy way out of the restriction in s. 41(1) (see, Tennessee Eastman Co v Commissioner of Patents (Tennessee Eastman), [1974] SCR 111).

Tennesee Eastman has since been held as providing a general prohibition against claims for methods of medical treatment despite the repeal of Section 41 (see, Axcan Pharma Inc v Pharmascience Inc, 2006 FC 527; Novartis Pharmaceuticals Canada Inc v Cobalt Pharmaceuticals Company, 2014 FCA 17). Specifically, Canadian Courts have held that the critical question is whether a claim encompasses a vendible product, namely, the commercial embodiment of the invention. If the answer is in the affirmative, the claim is deemed no longer to be within the scope of methods of medical treatment (see, Janssen Inc v Mylan Pharmaceuticals ULC, 2010 FC 1123). For example, in Canada, a claim to an effective dosage range would not be permissible because such a claim would encompass the exercise of a physician’s professional skill and judgment (which is not a vendible product). Consequently, a physician would infringe such a claim when prescribing an amount of a medicine within the claimed range (see, Axcan Pharma Inc v Pharmascience Inc, 2006 FC 527; Novartis Pharmaceuticals Canada Inc v Cobalt Pharmaceuticals Company, 2014 FCA 17).

Apart from the above statutory prescriptions, a determination of what constitutes patentable subject matter is largely a matter of common law. For instance, in a series of cases, the Canadian Supreme Court first appeared to deny the patentability of life forms only to subsequently allow such patents in a limited but functionally equivalent form. Specifically, in a 5-to-4 decision in Harvard College v Canada (Commissioner of Patents) (2002 SCC 76), the Supreme Court refused the patentability of Harvard’s oncomouse because it would grow up according to the “laws of nature” rather than as a result of human intervention. Just two years later, in Monsanto Canada Inc v Schmeiser (2004 SCC 34), a slightly differently constituted Supreme Court held, again 5-to-4, that both genes, once isolated or developed, and single cells containing these genes were patentable as “compositions of matter”, notwithstanding that the cells may grow into full living organisms without human intervention. The result is that under Canadian common law, higher life forms are not patentable as such, but each cell within that life form may be patentable (see, Monsanto Canada Inc v Schmeiser, 2004 SCC 34; Re Application of Abitibi Co (1982), 62 CPR (2d) 81 (Pat App Board)).

Additionally, under common law, and wholly apart from the prohibition against patenting methods of medical treatment, the exercise of professional skill (such as those of a lawyer, accountant, architect, engineer, doctor, or patent agent) is generally not considered to be patentable subject matter (see, Lawson v Commissioner of Patents (1970), 62 CPR 101 (Ex Ct)).

New uses for known compounds (see, Shell Oil Co v Commissioner of Patents, [1982] 2 SCR 536) and selections of particularly preferred compounds from a previously disclosed or patented class of compounds also constitute patentable subject matter (see, Apotex Inc v Sanofi‑Synthelabo Canada Inc, [2008] 3 SCR 265; In the Matter of IG Farbenindustrie [1930] 47 RPC 289 (Ch D); EI Du Pont De Nemours & Co (Witsipie’s) Application [1982] FSR 303 (HL)).

Analysis of Examples under the U.S. PTO Guidance 

In view of recent U.S. Supreme Court decisions including Association for Molecular Pathology v. Myriad Genetics, Inc. (Myriad) and Mayo Collaborative Services v. Prometheus Laboratories, Inc., the U.S. Patent and Trademark Office (U.S. PTO) on March 4, 2014, issued a guidance for evaluating subject matter eligibility under Section 101 (Guidance). The Guidance superseded the June 13, 2013 memorandum issued on the day of the Myriad decision. While the Guidance was issued without public notice or opportunity for the public to comment, the U.S. PTO is holding a forum on May 9, 2014 to receive feedback from organizations and individuals regarding the Guidance. 

The Guidance is divided into 4 sections. Part I discusses the 3-part test for determining subject matter eligibility. Part II explains how to determine whether a claim (as a whole) is “significantly different”. This portion of the Guidance provides a list of 12 factors – six that weigh toward eligibility (namely, finding a significant difference) and six that weigh toward ineligibility (namely, a finding of no significant difference). Part III provides seven examples explaining the application of the factors. Part IV provides a new form paragraph for Examiners to use when rejecting claims in accordance with the guidance. 

In addition to the Guidance, the U.S. PTO prepared detailed training materials (containing 93 PowerPoint slides) for Examiners. The detailed training materials contain numerous examples not provided for in the Guidance. 

We at the BRIC Wall thought it would be insightful to examine the analysis of subject matter eligibility under Canadian patent law for several of the examples contained in the Guidance and training materials. 

Composition/Manufacture Claim Reciting A Natural Product – Example A – U.S. PTO Guidelines 

Claim 1: A stable energy-generating plasmid, which provides a hydrocarbon degradative pathway.

Claim 2: A bacterium from the genus Pseudomonas containing therein at least two stable energy-generating plasmids, each of said plasmids providing a separate hydrocarbon degradative pathway.

Background: Stable energy-generating plasmids exist within certain bacteria in nature. Pseudomonas bacteria are naturally occurring bacteria. Naturally occurring Pseudomonas bacteria containing a stable energy-generating plasmid and capable of degrading a single type of hydrocarbon are known. 

Analysis of claim 1: Patentable per se, as long as the plasmid meets novelty and inventive step requirements. According to Monsanto Canada Inc v Schmeiser, 2004 SCC 34, useful genes once developed or isolated are deemed to be patentable. 

Analysis of claim 2: Patentable provided that the addition of the second plasmid makes the bacterium novel and inventive over the known naturally occurring Pseudomonas bacteria. According to Monsanto Canada Inc v Schmeiser, 2004 SCC 34, single cells containing previously isolated or developed useful genes are individually patentable. However, a multi-cellular organism, each cell of which contains these genes, would not be patentable (see, Harvard College v Canada (Commissioner of Patents), 2002 SCC 76). Nonetheless the same result can be obtained by claiming the individual cells of the organism containing the genes. 

Composition vs. Method Claims, Each Reciting A Natural Product – Example B – U.S. PTO Guidelines 

Claim 1. Purified amazonic acid. 

Claim 2. Purified 5-methyl amazonic acid. 

Claim 3. A method of treating colon cancer, comprising: administering a daily dose of purified amazonic acid to a patient suffering from colon cancer for a period of time from 10 days to 20 days, wherein said daily dose comprises about 0.75 to about 1.25 teaspoons of amazonic acid. 

Background: The Amazonian cherry tree is a naturally occurring tree that grows wild in the Amazon basin region of Brazil. The leaves of the Amazonian cherry tree contain a chemical that is useful in treating breast cancer, however, to be effective, a patient must eat 30 pounds of the leaves per day for at least four weeks. Many have tried and failed to isolate the cancer-fighting chemical from the leaves. Applicant has successfully purified the cancer-fighting chemical from the leaves and has named it amazonic acid. The purified amazonic acid is structurally identical to the amazonic acid in the leaves, but a patient only needs to eat one teaspoon of the purified acid to get the same effects as 30 pounds of the leaves. Applicant has discovered that amazonic acid is useful to treat colon cancer as well as breast cancer, and applicant has also created a derivative of amazonic acid in the laboratory (called 5-methyl amazonic acid), which is structurally different from amazonic acid and is functionally different, because it stimulates the growth of hair in addition to treating cancer. 

Analysis of claim 1: Patentable. Because the particular cancer-fighting compound, amazonic acid, was previously unknown (only the use of Amazonian cherry tree leaves, eaten in large quantities, to treat breast cancer was known), the purified compound constitutes patentable subject matter. 

Additionally, it would be advisable to claim the use of amazonic acid for the treatment of breast and colon cancer in the form of Swiss-type claims as well as the product amazonic acid produced according to Applicant’s process of purification (namely, from leaves). 

Analysis of claim 2: Patentable. 5-methyl amazonic acid is a novel compound with the unobvious benefit of stimulating hair growth. 

Additionally, it would be advisable to claim the use of 5-methyl amazonic acid for the stimulation of hair growth in the form of Swiss-type claims as well as the product 5-methyl amazonic acid according to Applicant’s process of methylation from purified amazonic acid. 

Analysis of claim 3: Likely not patentable as drafted. This claim that would run afoul of the prohibition against claiming methods of medical treatment, since it claims both a duration and dosage range (see, Tennessee Eastman Co v Commissioner of Patents, [1974] SCR 111; Axcan Pharma Inc v Pharmascience Inc, 2006 FC 527; Novartis Pharmaceuticals Canada Inc v Cobalt Pharmaceuticals Company, 2014 FCA 17). Deciding the duration and dosage within the specified ranges would likely require the exercise of a doctor’s professional skill. 

It would be advisable to maintain this claim and to supplement it with use claims in both German and Swiss-type form. Because the use of amazonic acid for the treatment of colon cancer was previously unknown, these claims would likely not be objectionable as claiming a method of medical treatment.

E. Composition vs. Method Claims, Each Reciting Two Natural Products – Example E – U.S. PTO Guidelines 

Claim 1. A pair of primers, the first primer having the sequence of SEQ ID NO: 1 and the second primer having the sequence of SEQ ID NO: 2. 

Claim 2. A method of amplifying a target DNA sequence comprising: 

a) providing a reaction mixture comprising a double-stranded target DNA, the pair of primers of claim 1 wherein the first primer is complementary to a sequence on the first strand of the target DNA and the second primer is complementary to a sequence on the second strand of the target DNA, Taq polymerase, and a plurality of free nucleotides comprising adenine, thymine, cytosine and guanine; 

b) heating the reaction mixture to a first predetermined temperature for a first predetermined time to separate the strands of the target DNA from each other; 

c) cooling the reaction mixture to a second predetermined temperature for a second predetermined time under conditions to allow the first and second primers to hybridize with their complementary sequences on the first and second strands of the target DNA, and to allow the Taq polymerase to extend the primers; 

and repeating steps (b) and (c) at least 20 times. 

Analysis of claim 1: Patentable. According to Monsanto Canada Inc v Schmeiser, 2004 SCC 34, useful genes once developed or isolated are patentable. 

Analysis of claim 2: Patentable. Although recombinant DNA technology is well-known, if it is being used to amplify target DNA using novel primers SEQ ID NO: 1 and SEQ ID NO: 2 (which it is by reference to claim 1), it should be free of the prior art and patentable. 

It would be advisable to maintain this claim and to supplement it with use claims (such as use of SEQ ID NO: 1 and SEQ ID NO: 2 to amplify a target DNA sequence). 

Process Claims Involving A Natural Principle – Example G – U.S. PTO Guidelines 

Claim 1. A method for treating a mood disorder in a human patient, the mood disorder associated with neuronal activity in the patient’s brain, comprising: exposing the patient to sunlight, wherein the exposure to sunlight alters the neuronal activity in the patient’s brain and mitigates the mood disorder. 

Claim 2. A method for treating a mood disorder in a human patient, the mood disorder associated with neuronal activity in the patient’s brain, comprising: exposing the patient to a synthetic source of white light, wherein the exposure to white light alters the neuronal activity in the patient’s brain and mitigates the mood disorder. 

Claim 3. A method for treating a mood disorder in a human patient, the mood disorder associated with neuronal activity in the patient’s brain, comprising: providing a light source that emits white light; filtering the ultra-violet (UV) rays from the white light; and positioning the patient adjacent to the light source at a distance between 30-60 cm for a predetermined period ranging from 30-60 minutes to expose photosensitive regions of the patient’s brain to the filtered white light, wherein the exposure to the filtered white light alters the neuronal activity in the patient’s brain and mitigates the mood disorder. 

Background: It is a well-documented natural principle that white light affects a person’s mood. Exposure to white light changes neuronal activity in the brain, which changes a person’s mood. Sunlight is a natural source of white light. It is well-understood, purely conventional and routine in the art of treating mood disorders to expose a person to white light in order to alter their neuronal activity and mitigate mood disorders. 

Analysis of claim 1: Not patentable as drafted. This claim likely claims the well-documented natural principle that white light affects a person’s mood. Moreover, this claim likely violates section 27(8) which states that: “No patent shall be granted for any mere scientific principle or abstract theorem.” Additionally, as a method claim, it likely violates the rule against claiming methods of medical treatment (see, Tennessee Eastman Co v Commissioner of Patents, [1974] SCR 111; Axcan Pharma Inc v Pharmascience Inc, 2006 FC 527; Novartis Pharmaceuticals Canada Inc v Cobalt Pharmaceuticals Company, 2014 FCA 17). 

Analysis of claim 2: Not patentable as drafted for the reasons given in the analysis of claim 1, above. 

Analysis of claim 3: Not patentable as drafted for the reasons given in the analysis of claim 1, above. 

If the dosage regime of the method defined in claim 3 is inventive, it might be possible to obtain an apparatus claim which embodies the specifications of the method of claim 3, namely, a light source that emits white light, an ultra-violet (UV) ray filter and a positioning device to place the patient adjacent to the light source at a distance between 30-60 cm. The apparatus could potentially contain a timer measuring between 30-60 minutes. 

Diagnostic claim from Mayo Collaborative Services v. Prometheus Laboratories, Inc. – Examiner Training Materials 

1. A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising: 

administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and 

determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder,

wherein the level of 6-thioguanine less than about 230 pmol per 8×108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject, and 

wherein the level of 6-thioguanine greater than about 400 pmol per 8×108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject. 

Analysis of claim 1: Likely patentable if amended to remove the active step of administering the drug. Additionally, it would be advisable to supplement this claim with claims to a vendible product if possible, such as a system or kit for optimizing the blood-serum concentration of 6-thioguanine during treatment of an immune-mediated gastrointestinal disorder. 

Claim from U.S. Patent No. 6,573,103 – Examiner Training Materials 

1. A method of determining whether a pregnant woman is at an increased risk of having a fetus with Down’s syndrome, the method comprising the steps of: 

measuring the level of at least one screening marker from a first trimester of pregnancy by:

(i) assaying a sample obtained from the pregnant woman at said first trimester of pregnancy for at least one first biochemical screening marker; and/or 

(ii) measuring at least one first ultrasound screening marker from an ultrasound scan taken at said first trimester of pregnancy; 

measuring the level of at least one second screening marker from a second trimester of pregnancy, the at least one second screening marker from the second trimester of pregnancy being different from the at least one first screening marker from the first trimester of pregnancy, by: 

(i) assaying a sample obtained from the pregnant woman at said second trimester of pregnancy for at least one second biochemical screening marker; and/or 

(ii) measuring at least one second ultrasound screening marker from an ultrasound scan taken at said second trimester of pregnancy; and 

determining the risk of Down’s syndrome by comparing the measured levels of both the at least one first screening marker from the first trimester of pregnancy and the at least one second screening marker from the second trimester of pregnancy with observed relative frequency distributions of marker levels in Down’s syndrome pregnancies and in unaffected pregnancies. 

Analysis of claim 1: Possibly patentable. This claim would likely face objections relating to claiming (1) a method of medical treatment (see, Tennessee Eastman Co v Commissioner of Patents, [1974] SCR 111; Axcan Pharma Inc v Pharmascience Inc, 2006 FC 527; Novartis Pharmaceuticals Canada Inc v Cobalt Pharmaceuticals Company, 2014 FCA 17); and/or (2) an exercise requiring professional skill, since the claim requires assaying, measuring, and comparing on the part of a lab technician, an ultrasound technician, and a medical doctor respectively (see, Lawson v Commissioner of Patents (1970), 62 CPR 101 (Ex Ct)). It might be arguable that these activities do not require professional skill, if they are routine and there is no exercise of discretion. 

This post was written by Trevor Newton, Jay Zakaib and James Holtom of Gowlings (Canada) and Lisa Mueller of Michael, Best & Friedrich.