The Pharmaceutical/Biopharmaceutical Landscape—Traversing Canada's Patent and Regulatory Regimes

General

Drug approval in Canada is, for the most part, overseen by the Minister of Health, pursuant to the requirements of the FDA and the FDR. The FDA and FDR govern the approval of drugs that contain chemical entities for human or animal use (“pharmaceuticals”), and they govern those drugs that contain biologic medicinal ingredients for human use. Approval of veterinary biologics is governed by the Health of Animals Act6 and Health of Animals Regulations7 and is under the authority of the Canadian Food Inspection Agency. Veterinary biologics are outside the scope of this paper.

An applicant seeking to sell a new drug8 must file a New Drug Submission (NDS), which contains detailed reports on safety and efficacy, including substantial evidence of the clinical effectiveness of the drug for the purpose and under the conditions of use recommended (pre-clinical, clinical, chemistry and manufacturing data).

New drug approvals also may be obtained by the filing of Abbreviated New Drug Submissions (ANDS). An ANDS is the usual vehicle for generic drug approvals: a drug that is the pharmaceutical equivalent (i.e., having identical amounts of the identical medicinal ingredients in a comparable dosage form) and that is bioequivalent to a reference product. Suitable reference products typically are those that are approved on the basis of an NDS with a complete data package. An ANDS does not need clinical data establishing safety and efficacy, but simply evidence that the generic's product is pharmaceutically equivalent and bioequivalent with the innovator's product. The ANDS pathway cannot be used for biologic drugs.

Where a manufacturer seeks to make certain changes to an already-authorized product, such as changes in manufacturing method, dosage form, formulation, indication, route of administration, and other label changes, approval must be obtained. These types of changes ordinarily require the filing of a Supplemental New Drug Submission (SNDS). Other changes, such as changes to the manufacturer's name or the brand name of the drug, usually are approved by an “Administrative” NDS.

Once the Minister is satisfied that the statutory and regulatory requirements have been met under any of the above pathways, an approval for sale, termed a Notice of Compliance (NOC), will be issued.

Between April 2011 and March 2012, the time for approval of NDSs for pharmaceuticals was a median of 350 days, with a range of 204–1,119 days; and 386 days, with a range of 350–819 days for biologics. For ANDSs, based on comparative studies, the time for approval was a median of 627 days, with a range of 266–1,156 days.

Special Case of Biologics

Biologic drugs are currently approved only by the filing of an NDS.

The FDR does not include a different pathway (such as the ANDS pathway) for the approval of a subsequent entry biologic (SEB). Although an NDS must be filed in order to obtain approval of a SEB, Health Canada will allow such an NDS to be based on a reduced clinical and non-clinical data package.9

Because SEBs are not specifically addressed in the FDA or FDR, there is no statutory definition for what can be an SEB. According to the SEB Guidance, an SEB is “a biologic product that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug.”10

Health Canada has not set out any specific classes of products that will or will not be approved as SEBs. Instead, the SEB Guidance applies to “biologic drugs that contain, as their active substances, well-characterized proteins derived through modern biotechnological methods such as use of recombinant DNA and/or cell culture.”11 A suitable SEB is one that “can be well characterized by a set of modern analytical methods,” and if the product employs a “clearly different” approach to manufacture than the reference biologic drug, then it “may not be suitable for authorization” as an SEB.12

A suitable reference biologic should be a biologic drug originally authorized for sale on the basis of a complete data package (and is not another SEB), and which has significant safety and efficacy data accumulated such that the demonstration of similarity will bring into relevance a substantial body of reliable data.13 The reference biologic drug may be one that has been authorized for sale in Canada, or it can be a non-Canadian reference biologic drug. The SEB Guidance provides a number of considerations for use of a non-Canadian reference biologic, including that the drug be a “suitable proxy for the version of the product approved in Canada,” and is “marketed by the same innovator company or corporate entity that is approved to market the medicinal ingredient in the same dosage form in Canada.”14

If, “through extensive characterization and analysis,” an SEB “can be judged similar to the reference biologic drug by meeting an appropriate set of pre-determined criteria,” then it should be approved as such. The demonstration of similarity will depend upon “detailed and comprehensive product characterization.”15

The SEB Guidance makes clear that SEBs are not “generic biologics” and that the authorization of an SEB is not a declaration of pharmaceutical or therapeutic equivalence to the reference biologic drug (this is a central issue for pharmacovigilance, and possibly reimbursement under private and public insurance plans, as discussed below).

Patent Term

Patents having a filing date on or after October 1, 1989, have a 20-year term from the filing date.16 In Canada, there are no extensions of the patent term. There is no patent term restoration similar to that in the U.S. for the time that passes between patent issuance and first marketing approval, nor is there anything similar to supplemental protection certificates in the EU.

Patent Linkage

The Patent Act includes a Bolar-type exemption to patent infringement, which is broader on its face than the related U.S. provision:

In response to this exemption, the Patented Medicines (Notice of Compliance) Regulations3 were enacted. The NOC Regulations link subsequent entry manufacturer (SEM) regulatory approval to patent status for those patents that are listed on the Patent Register.

The Patent Register, in many respects, is similar to the U.S. Orange Book. However, there are patents that may be eligible for listing on one but not the other. Further, the Patent Register permits the listing of patents pertaining to biologics.

The Minister of Health maintains the Patent Register and has delegated power to the Office of Patented Medicines and Liaison (OPML) to review each submitted patent list17 to determine whether the patent is eligible for listing against an NDS or SNDS.

There are three basic requirements for a patent to be eligible for listing on the Patent Register relating to: (1) timing; (2) relevance; and (3) subject matter.

The sponsor of the NDS/SNDS must file its patent list either: (1) at the time the related NDS or SNDS is filed; or (2) if the patent is not granted by the submission filing date, within 30 days after the grant of the patent, provided the Canadian (PCT) filing date of the patent precedes the filing date of the related NDS or SNDS.18 The deadlines are non-extendable. The sponsor may be the owner of the patent, an exclusive licensee, or a party having the consent of the patent owner to list the patent—collectively referred to in the NOC Regulations as the “first person,” but referred to below as “the innovator.”

A patent must also be relevant to the drug which is the subject of the NDS and/or SNDS against which the patent is to be listed.

A patent is eligible for listing in relation to an NDS, if the patent contains a claim for: (1) the medicinal ingredient, (2) the formulation that contains the medicinal ingredient, (3) the dosage form, or (4) the use of the medicinal ingredient and the medicinal ingredient, formulation, dosage form, or use has been approved through the issuance of an NOC in respect of the NDS. A patent may be eligible for listing in relation to an SNDS if it contains a claim for: (1) the changed formulation; (2) the changed dosage form; or (3) the changed use of that medicinal ingredient, where the changed formulation, dosage form or use has been approved through the issuance of an NOC in respect of the SNDS.19 Patents can also be carried forward from an earlier NDS or SNDS listing to another SNDS listing.20

In terms of the degree of specificity required, a patent claiming the specific medicinal ingredient, as well as patents claiming the genus encompassing the species, including when written in process-dependent form, are considered eligible for listing in relation to an NDS if the timing requirements are met. Patents claiming polymorphs—and not only the specific polymorph used in the end product—are also eligible for listing, subject to timing. Each of these basic “composition-of-matter” (COM) patents is considered eligible for listing in relation to a product comprising the COM as the sole active ingredient, as are those directed to a combination of that COM with other active agents. A higher degree of matching may be required for patents claiming formulations, dosage forms, and uses, although this will depend largely on the specific facts. It is likely worthwhile noting that drug–device combination products, such as transdermal patches, usually are considered a “dosage form” in Canada, with related patents thus being eligible for listing.21

Unless a patent includes a claim for the medicinal ingredient, a formulation, dosage form, or use thereof, it will fail to meet the subject-matter criteria. Thus, for example, patents claiming only a process for making a medicinal ingredient, an intermediate, or a metabolite would not be eligible.

Improperly listed patents can be removed from the Patent Register. Also, if the conditions for listing are no longer met, this would prompt removal. For instance, if the Drug Identification Number for a product is cancelled, a court has declared the patent invalid under the Patent Act, or the patent has expired, the patents will be deleted from the Patent Register.22

Having a patent listed on the Patent Register can effectively provide injunctive relief until patent expiry (Health Canada may be prohibited from issuing marketing approval); otherwise, an interlocutory injunction might not be available, given the difficulty in obtaining such relief in patent infringement proceedings in Canada. The details surrounding proceedings under the NOC Regulations are discussed below.

Canada

The FDR was amended in 2006 to provide effective data protection in Canada. Data protection applies to an “innovative drug,” defined as “a drug that contains a medicinal ingredient not previously approved in a drug by the Minister and that is not a variation of a previously approved medicinal ingredient such as a salt, ester, enantiomer, solvate or polymorph.”23 The data protection provisions can apply to any drug that is issued an NOC, and thus apply equally to pharmaceuticals and human biologics.

The Minister considers whether data protection is available at the time the NDS is filed. If granted, the drug will be listed on the public Register of Innovative Drugs24 on issuance of the NOC.

Data protection will not apply “if the innovative drug is not being marketed in Canada.”25

An SEM may not file a submission making a direct or indirect comparison to an innovative drug until six years after issuance of the innovator's first NOC for the innovative drug.26 There is a further 2 years of market exclusivity (2½ years if certain pediatric studies are done), which prohibits the Minister of Health from issuing a SEM NOC. Thus, the total period of protection is 8 years (or 8½ years if the pediatric extension applies) from the innovator's first NOC.27

There are no extensions for the data protection terms, including for new uses or formulations. A single active agent in a product containing a combination of active ingredients can be an “innovative drug,” and the data protection provisions would apply. There is also no additional data protection for “orphan drugs”: Canada does not currently have orphan drug legislation, although this is being considered, and may include an extended data protection term.

There have been a few judicial decisions that have considered whether a drug was “previously approved” such that the data protection provisions would not apply. For instance, sales in Canada made under the Special Access Programme (which allows a drug to be sold in Canada on compassionate grounds and without an NDS being filed) have been found not to constitute prior approval.28 But, an approval made under a much earlier version of the food and drug legislation was found to be a prior approval for the purposes of the current FDR.29 A drug that was sold in Canada as a natural health product (having a DIN and natural health product license number) was a prior approval, even though no NOC was issued.30 Also, approval of a racemate was a prior approval barring one of the individual enantiomers therein from being an “innovative drug.”31

Health Canada does not consider that a drug previously approved as a veterinary drug is a prior approval barring the same drug from being an “innovative drug” if it is to be used in humans, and vice versa.32

Proceedings Under the NOC Regulations: A Summary Procedure

Generally, prior to receiving marketing approval, a SEM must address all patents listed on the Patent Register at the time it files its drug submission making a direct or indirect comparison with, or reference to, a drug in respect of which the patents are listed.44 The SEM can (1) accept that regulatory approval will not be granted for its product until expiry of any listed patent; or (2) allege non-infringement of the listed patent, claim that the listed patent is invalid, that the patent has expired, or that the innovator incorrectly asserted its right to list the patent. These allegations are made in a Notice of Allegation (NOA).45 ANDSs trigger the NOC Regulations, but the broad language in the NOC Regulations also captures any NDS that includes a comparison or reference to a drug against which patents are listed, and thus also encompass SEB submissions.46

Within 45 days of being served with an NOA, an innovator may commence a Court proceeding under the NOC Regulations, disputing the SEM's allegations and requesting a Court order prohibiting the Minister from issuing an NOC to the SEM until patent expiry.47 The Minister is prohibited from issuing an NOC to the SEM for up to 24 months, or until the proceeding is decided, whichever is earlier.48 If the innovator is unsuccessful in the proceeding, the Minister can grant the SEM an NOC, provided the safety and efficacy requirements have been met. Once an NOC issues to the generic, in all likelihood, the innovator will not be permitted to pursue an appeal, as the issues are considered moot post-NOC grant. The SEM may, however, appeal a prohibition order.

If successful, the SEM may also sue the innovator in a separate action for damages pursuant to s. 8 of the NOC Regulations related to any delay to market entry caused by the proceeding.49 An SEM may also seek broader remedies in a provincial superior court, including an accounting of the innovator's profits; to date, no such claims have reached a decision on the merits.

A proceeding under the NOC Regulations is a summary proceeding based on a written record only, unlike an action heard by way of a trial involving live witnesses. There is no right of discovery under the NOC Regulations.

The innovator will often receive a number of NOAs, each from a different SEM, and will therefore litigate a number of separate proceedings. Once one SEM is successful on an allegation of invalidity, it will be an abuse of process for the innovator to maintain other proceedings involving the same allegation of invalidity; the series of proceedings will come to an end. However, if an innovator is successful against one SEM, it is not an abuse of process for other SEMs to continue to pursue the same allegation of invalidity;50 the series of proceedings will continue.

Both the innovator and the SEM retain their private rights of action and may sue for infringement or patent invalidity or both (as discussed below). In a proceeding under the NOC Regulations, allegations of infringement and invalidity are found to be justified or unjustified, and no decision is ultimately made relating to infringement and validity. Accordingly, a subsequent Court hearing a trial on the merits of infringement and validity is not bound by the prior decision under the NOC Regulations.51

Patent Infringement and Impeachment Actions

An action for patent infringement generally can be commenced only once the SEM has obtained its NOC and launches its product. The action may be brought either in the Federal Court of Canada or in an appropriate provincial court, although forum shopping has not been an issue in Canada, largely because of jurisdictional issues surrounding validity.

A common defense in patent infringement cases is an allegation of patent invalidity (where the patent is “impeached”). Only the Federal Court of Canada has the jurisdiction to declare a patent invalid throughout Canada, although the appropriate provincial court may declare a patent invalid as between the parties. Thus, a finding of invalidity in the Federal Court of Canada is binding on all courts and proceedings such as, for example, a proceeding under the NOC Regulations; therefore, the Federal Court tends to be the jurisdiction of choice for patent actions. Once a patent is declared invalid by the Federal Court, the OPML will delete it from the Patent Register. Any existing NOC proceeding will be rendered moot.

Any person who infringes a patent is liable for all damages sustained by the patentee after the grant of the patent by reason of the infringement. Alternatively, a successful plaintiff may request an accounting of the defendant's profits made as a result of the infringing activity, which the Court may grant as a matter of discretion.

An impeachment action may be brought by a SEM prior to market entry, and an SEM may do so instead of serving a notice of allegation under the NOC Regulations.

The Federal Court, on request, may schedule a trial in approximately two years from commencement.

The unsuccessful party may appeal the Federal Court's decision to the Federal Court of Appeal as of right.