From Roche To Momenta: The Safe Harbor And The Current Landscape Of Biosimilars

Editor: Please tell us about your professional background.

Weiswasser: My scientific training is in biochemistry and molecular biology, and I focus my patent litigation and counseling practice on the biotech and pharmaceutical industries. Over the years I have worked extensively with biotechnology and pharmaceutical companies on patent-related issues, including issues arising at the regulatory interface of patent law.

Editor: Would you please outline for us the statutory context of the Federal Circuit’s decisions in the recent Classen and Momenta cases?

Weiswasser: The Federal Circuit’s Classen and Momenta decisions concern what is called the “safe harbor” provision of the Hatch-Waxman Act. The safe harbor was enacted as part of the 1984 Hatch-Waxman legislation and served as a key provision of the compromise that the Act embodied. The safe harbor provision was designed specifically to overrule a 1984 Federal Circuit decision, Roche v. Bolar, a controversial decision that held it was an act of infringement to test patented drugs prior to patent expiration, even if the purpose of the testing was to develop data for obtaining FDA approval of the drug. Regarded as creating a distortion in the patent regime, Roche was regarded as effectively lengthening the patent term for pharmaceutical drug products because generic competitors couldn’t come on the market when the patent expired.

The safe harbor is part of section 271 of the Patent Act – an exception to the definition of infringement. The statutory language of the safe harbor is framed in terms of what shall not be an act of patent infringement. Here, it shall not be infringement to use patented technology “solely for uses reasonably related to the development and submission” of information for the FDA.

Editor: You mentioned a “compromise” – please explain what you mean.

Weiswasser: The Hatch-Waxman Act embodied a compromise between the pioneer and generic industries, and that underlying compromise can be highly relevant to understanding and evaluating the scope of the safe harbor. Prior to Hatch-Waxman, there were two so-called distortions to the patent term of pioneer drug developers, and these distortions stemmed from the requirement that drug manufacturers – pioneer and generic – were required to establish that new drugs were safe and effective. First, the pioneer developer was caught in the FDA approval process during the initial part of its patent term and was not able to sell its drug throughout the entire exclusivity period. That resulted in a de facto shortening of patent term on the front end. Second, generic manufacturers were required to obtain FDA approval, but under Roche “use” of patented product for testing was held to be patent infringement during the term of the brand holder patents. That resulted in a de facto extension of the patent term on the back end. So Hatch-Waxman was compromise legislation between generic and innovator interests, which created patent term extensions for time lost at the beginning of the patent term and a safe harbor for generic manufacturers to test their drugs at the end of the patent term. It also relaxed the requirements for generic manufacturers to obtain approval of their products by allowing for an abbreviated new drug application.

Editor: How did the two Supreme Court safe harbor cases set the stage for Classen and Momenta?

Weiswasser: This provision has enjoyed more than its fair share of Supreme Court attention – the Court has taken and decided two cases on questions about the scope of the provision. In the 1990 Eli Lilly v. Medtronic case, the Supreme Court held that medical devices could be protected under the safe harbor and also provided an important doctrinal framework for analyzing safe harbor questions of scope. Justice Scalia focused on the legislative purpose of the Act to rectify “two unintended distortions” of the patent term and held that it is key to balance patent term restoration with safe harbor protection.

In the next case, about 15 years later, the Court addressed a different but quite significant issue. In Merck v. Integra, the facts involved the use of patented molecules in basic research when it was merely possible that some of them could be used to develop a drug that would ultimately be the subject of an FDA application. The data developed, however, was not ultimately included in the FDA submission. The Federal Circuit had held no safe harbor protection for basic research; it wasn’t “reasonably related” to a regulatory submission. The Supreme Court reversed with an opinion again written by Justice Scalia, who focused on the “reasonably related” language of the statute and emphasized the practical realities of research directed to developing therapeutics, where researchers cannot know when they undertake their research what subjects and work will ultimately be the subject of a request for FDA approval. To account for those realities, the Court held that the safe harbor protects research using patented technology if there is a “reasonable basis for believing that the experiments will produce the types of information that are relevant to an IND or NDA” submission to the FDA. There is no requirement that the information developed from the research actually be a part of any ultimate FDA submission. I think that this relatively broad interpretation of the statute set the stage for where the Classen and Momenta cases come up.

Editor: So where do Classen and Momenta come into play?

Weiswasser: These cases both addressed questions of FDA-related activities undertaken by defendants after the defendants’ drugs had already been approved by the FDA. We are well outside the Roche v. Bolar fact pattern now because the patented technology is not being used to obtain FDA approval; that approval has already been obtained and the defendant is using patented technology for work that is after FDA approval.

Classen involved patents relating to certain immunization methods and an allegation of patent infringement based on post-FDA approval studies by the defendant involving vaccination schedules. A split panel of the Federal Circuit held no protection. Joined by Chief Judge Rader, Judge Newman wrote the majority opinion and held that the safe harbor does not cover activities that occur after FDA approval. This decision was driven by a narrow reading of the statute as limited to covering a narrow range of activities centered on testing drugs to obtain FDA approval in the first instance.

Momenta then comes along and presents a similar question of post-approval activities. That case involved generic enoxaparin and the defendant’s post-approval drug testing practices that were covered by a patent owned by Momenta. This time, though, the majority of the panel, in an opinion authored by Judge Moore, held that such post-approval activities could be protected provided the post-approval studies are reasonably related to FDA-related activities. There was an effort to reconcile the ruling with the Classen decision on the ground of whether the submissions to FDA were required to maintain approval. Chief Judge Rader’s dissent is quite notable for its forcefulness. He recounted the legislative history of the provision and strongly expressed the view that the scope of the safe harbor should be limited to the Roche v. Bolar situation – the decision that the safe harbor overrules.

There was a lot of speculation that these conflicting decisions might interest the Supreme Court to take a third safe harbor case, but the Court recently denied a cert petition in the Classen case. Momenta issued a press release recently that it plans to file this month a cert petition so we’ll have to see how that plays in terms of potential Supreme Court review.

Editor: Moving on to biosimilars: do you think FDA regulations will come out this year?

Weiswasser: We can only surmise. It would not be unfair to say that FDA’s implementation of the biosimilar legislation is moving at a quite slow pace. But that’s understandable and not surprising, given the scientific and practical complexities of the issues in play. Next month will mark the three-year anniversary of the legislation embodying the abbreviated licensure pathway for biologics that are shown to be biosimilar or interchangeable with an approved product. FDA appears to have been working diligently since then to implement the statue but progress has been very slow. The FDA has issued guidance documents, had hearings and received feedback and comments. I would be reading tea leaves as to whether we are actually going to see regulations this year.

Editor: Were the 2012 FDA guidance documents helpful?

Weiswasser: Yes, I think that they are helpful, but they are laden with controversy and open issues and FDA seems to acknowledge that. About a year ago the FDA published draft guidance on the development of biosimilar products and following that publication the FDA took comments on its drafts and then held a hearing in May. For example, one of the FDA documents was intended to provide guidance to industry around scientific considerations in demonstrating biosimilarity of a proposed therapeutic protein product to a reference product – a product that is also approved/licensed. In that guidance the FDA says that it will be considering the totality of the evidence provided by a sponsor to show biosimilarity and intends to pursue a stepwise approach to determining biosimilarity.

The questions that FDA is grappling with are very challenging from safety and scientific perspectives. That isn’t surprising given the complexity of the biologic molecules involved. Consider the contrast between protein therapeutics and small molecule therapeutics. Biologics tend to be massive protein molecules that have extensive complexity in all aspects of its structure – primary amino acid sequencing, post-translational modifications such as glycosylation, as well as very complex, specific and highly important tertiary structures, such as how the protein folds. This underscores why it is so challenging to figure out what biosimilar means for these complex molecules. Compare this to small molecules, which tend to be relatively simple chemicals that are straightforward to replicate.

The FDA is appropriately focused on these differences. For example, in its guidance on biosimilars, FDA emphasizes the complexities of protein products as compared to small molecule drugs and discusses the potential implications that can occur in terms of safety and effectiveness when any changes are made.

Editor: What are you watching in the biotech area?

Weiswasser: Certainly we have to watch the Myriad case. The Supreme Court has granted cert on one question – whether human genes are patentable subject matter. Clearly that’s a key issue for the industry. I’m also watching the Bowman case in the Supreme Court, which addresses the issue of exhaustion in the context of bio-related inventions. The Court recently heard oral argument in that case, and we’re watching for how the Supreme Court resolves those issues. And of course, as I mentioned, the issue of biosimilars will remain front and center as the FDA and industry continue to grapple with the standards for determining biosimilarity and interchangeability.

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