The UJBL, March 2016

Biosimilars v. Generics

Over the past decades, biologic drugs have revolutionized treatment for many conditions including those that had not responded to other treatment. Biologic drugs contain active substances of biological origin obtained through production from biological source and on many occasions can bring more targeted effect than traditional chemically derived small-molecule drugs. No wonder that biological drugs leaded the charts of best-selling drugs in the world and their sales grow each year. However, while bringing great advantages for patients, biologics are often expensive in terms of cost per dose.

Traditional generic drug contains same active ingredients as the original one. Marketing authorization for generic medicinal drugs is granted on the basis of abbreviated application wherein applicant shall not be required to provide results of his own full studies or clinical trials if interchangeability of the generic product with reference drug can be demonstrated. Such approach is cost effective and shortens the time necessary for marketing authorisation. Entrance of generic products into the market sufficiently lowers prices and results in rise of their accessibility to patients. Is similar approach applicable to biosimilars, biological medicinal products being subsequent versions of biological drugs?

As generics, biosimilars have cost saving potential. However, due to the complexity of biological products, the standard generic approach applied to chemically derived drugs is not appropriate for biologics. Thus special regulations for biosimilars were developed and special approaches should be applied thereto, inter alia, within patent litigation.  

Biosimilars in EU and the US

The European Medicines Agency (EMA) developed guidelines for the approval of biosimilars via abbreviated registration process in 2005-2006. The EMA granted first marketing authorization for biosimilar product in 2006; marketing authorization for the first monoclonal antibody biosimilar was granted by EMA in 2013. Currently 20 biosimilars are approved for use in the European Union.

In the US the pathway for marketing authorization of biosimilars was established in 2010 when the Biologic Price Competition and Innovation Act (BPCIA) was enacted. On 6 March 2015 the Food and Drug Administration (FDA) approved Zarxio product as the first biosimilar. Sandoz, the division of Novartis, has launched Zarxio in the US on 3 September 2015.

Notably, the first case with regard to biosimilar product considered by the US courts related to Zarxio – the very first biosimilar approved in the US. 

‘Patent dance’ in the US

The BPCIA contains complicated patent dispute resolution mechanism, commonly referred to as the ‘patent dance’. It envisages a number of notification procedures between the reference product owner and biosimilar applicant aimed at defining relevant patents that may become a basis for the respective patent litigation against the applied biosimilar drug before approval thereof by FDA.

Under the ‘patent dance’, within 20 days as from FDA notification of a biosimilar application acceptance, the biosimilar applicant shall provide the reference product owner with a copy of the full application along with detailed information about the process used to manufacture the biological product.

Within 60 days as from receiving these files the reference product owner should provide the biosimilar applicant with a list of the patents held by the former that may either become a basis for patent infringement action or be licensed to the said applicant.

Within 60 days as from receipt of the patents list, biosimilar applicant should provide a statement explaining that, claim-by-claim, each patent is invalid, unenforceable, or not infringed. The biosimilar applicant may provide a counter list of patents that it believes could be relevant to the applied biosimilar product. The applicant may also identify when it intends to launch the product, e.g. after expiration of one or more patents.

Within 60 days as from receiving these materials, the reference product owner should provide a reciprocal statement describing why, claim-by-claim, it believes each patent is valid, enforceable and infringed.

The parties then have up to 15 days of good-faith negotiations to agree a list of patents, if any, that may become a basis for a patent infringement claim. If the parties reach an agreement with regard to the list of patents, within 30 days the reference product owner should bring the infringement action(s) based on each patent from the agreed list.

 If they fail to reach an agreement, the biosimilar applicant should notify the reference product owner of the number of patents it plans to provide in a second list, and then within 5 days of this notice they simultaneously exchange the lists of patents that each party believes can be the subject of the infringement action.

Within 30 days after the exchange, the reference product owner must bring an infringement suit with respect to all patents included into the simultaneously exchanged lists.

Besides, the BPCIA requires that the biosimilar applicant should provide notice to the reference product owner at least 180 days before the commercial launch.

The first dispute regarding biosimilar brought to the court in U.S.

During 2015 biopharmaceutical companies carefully monitored the case of Amgen v. Sandoz, the first case related to biosimilar product considered by the US courts resulting in a landmark decision. The courts interpreted the following issues within this case:

(1) Is ‘patent dance’ mandatory or optional?

(2) Can 180-day prior notice be given by the biosimilar applicant to the reference product owner before FDA actually approves biosimilar product?

In 2014 Sandoz filed an application for biosimilar product to Amgen’s drug Neupogen (filgrastim). While Sandoz notified Amgen of its biosimilar application, it did not disclose to Amgen its manufacturing process and did not provide Amgen with a copy of its application. Thus Sandoz opted not to comply with the BPCIA provision which states that the biosimilar applicant ‘shall’ provide to the reference product owner a copy of its application and manufacturing information. 

In the courts Sandoz argued that Congress did not intend to make these disclosures mandatory, because the BPCIA also foresees remedies for reference product owner in case of non-disclosure by the biosimilar applicant. 

The District Court and then the Federal Circuit Court decided that it was optional to disclose the full drug application, and thus the steps in the pre-litigation ‘patent dance’ were not mandatory. Thus the decision in Amgen v. Sandoz allowed biosimilar applicants to choose whether to be involved into complex ‘patent dance’ or to opt out of this process. 

Another issue considered in Amgen v. Sandoz is interpretation of provision according to which the biosmilar applicant shall provide 180-day prior notice to the reference product owner that it intends to launch its product.  Sandoz provided this notice prior to obtaining FDA approval. However, the courts sided Amgen’s argument that the 180-day notification of launch of biosimilar cannot be given by the biosimilar applicant before FDA approves the product. 

Patent litigation regarding biosimilars in Ukraine

Recently Genentech Inc. (USA) brought to the Ukrainian court the first case related to biosimilar product registered in Ukraine.

The Ministry of Healthcare of Ukraine granted to the defendant (a multinational pharmaceutical company based in India) marketing authorization for biosimilar product containing chimeric monoclonal antibodies for cancer treatment. The plaintiff claims infringement of the patent for monoclonal antibody produced using specific expression system defined in the independent patent claim.

Ukrainian jurisprudence involving generic drugs prompts granting preliminary injunction in patent infringement cases where international nonproprietary names (INNs) of active substances of generic and reference products are the same. In the court case in question the active substances of the defendant’s biosimilar and the plaintiff’s biologic reference product have the same INN. Basing on this, the court of first instance applied approach developed in respect of generic products and granted broad preliminary injunction against biosimilar product. The ruling of the court of first instance was upheld by the court of appeals.

However, in case of biosimilar drugs similar INN of active substances of two products does not automatically mean their full equivalence and, moreover, does not mean that the same expression systems are used to manufacture these substances. The defendant argued that the plaintiff’s patent covers not just the substance and the amino acid sequence, but a substance produced using specific expression system defined in the independent claim of the patent and thus significantly limiting the scope of the patent protection. According to the law, every element of independent claim of a patent shall be used in order to amount to patent infringement.

On 26 January 2015 the Superior Commercial Court of Ukraine (SCCU) satisfied the respondent’s cassation appeal and cancelled the preliminary injunction in full. The SCCU noted in its resolution that the courts of the first and appellate instances did not take into account that the plaintiff’s patent protects chimeric antibody produced using particular expression system, while medicinal product in question was registered as biosimilar product (and not as generic product), due to specificity of the production process. The SCCU noted: “At the same time, neither application for preliminary injunction nor the court decisions in this case do not contain substantiation of the assumption that the method used by the defendant-1 for production of the substance of the product is identical (analogous) to the method of production of the substance (chemical compound) which is protected by the patent...” 

From the resolution of the Superior Commercial Court of Ukraine it proceeds that a new approach (different from the one previously applied to generics) should be applied to biosimilar products having its specificity of the production process.

Such approach shifts standards of evidence developed for cases involving generic products. Now it is not enough for the plaintiff just to refer to similar INNs in two products. While this case has not been considered on merits yet, it shows that if a biosimilar product is involved, even at the stage of preliminary injunction the plaintiff needs to file evidence demonstrating that every element of the independent claim of a patent is used in allegedly infringing product. At the same time, the courts will need to conduct more careful analysis of the scope of protection granted by the patent before granting preliminary injunction.