April 30, 2015
By Riley McDermid, BioSpace.com Breaking News Sr. Editor
This is the second in a two-part interview that BioSpace conducted with Kevin E. Noonan, a partner at McDonnell Boehnen Hulbert & Berghoff, a lawyer who specializes in biotechnology patent law and the issue surrounding it. Noonan particularly interested in the legal issues surrounding biosimilars, as Big Pharma braces for the effects of a recent decision by the U.S. Food and Drug Administration (FDA) to allow Novartis AG to start making the nation’s first biosimilar drug. We talked with Noonan about what he sees becoming the biggest issue for the biotech world’s new biosimilar paradigm.
An experienced biotechnology patent lawyer, Noonan brings more than 20 years of extensive work as a molecular biologist studying high-technology problems in serving the unique needs of his clients. Noonan represents biotechnology and pharmaceutical companies, from startups to Fortune 100 companies, on a myriad of issues, as well as several universities in both patenting and licensing to outside investors. He has filed amicus briefs to district courts, the Federal Circuit and the Supreme Court involving patent issues relevant to biotechnology. Noonan is a founding author of the Patent Docs weblog where he writes frequently, and was recently named Chicago’s Biotechnology “Lawyer of the Year” by Best Lawyers in America 2013 and 2014. In 2010, Noonan was interviewed on 60 Minutes about gene patenting.
3. Are there similar patent issues for biotechnology that are applicable to biosimilar law?
The patent issues for biologics have to do with the capacity for biosimilar drugs to be developed that are sufficiently different from the reference drug product to avoid infringement but sufficiently “similar” to be biosimilar under the law.
These considerations depend on how the courts apply the disclosure requirements of patent law (in Section 112) and the extent to which the FDA permits structural changes in the drugs to be biosimilar. In this regard the “Holy Grail” is the “biobetter,” which has improved properties (activity, half-life, reduced immunogenicity, etc.) while being sufficiently different structurally not to infringe. At the moment a biobetter has not been described.
Biotechnology poses two aspects that are relevant to biosimilars as well: complexity and unpredictability. Biological molecules, including biologic drugs, are much larger than traditional small molecule drugs; the difference can be as great as a molecule like omeprazole, which is made up of 43 atoms and has a molecular weight of about 354 daltons, and erythropoietin, which is comprised of 165 amino acids and has a molecular weight of about 30,000-34,000 daltons; the variability is due to modification of the protein by the attachment of sugar residues, which differs for different species. This complexity is associated with a variable extent to which a protein’s primary amino acid sequence can be altered. Although the difference between certain amino acids is small (for example, an isoleucine residue differs from a valine residue by only a single methylene group), the effects of even so small a change cannot be predicted.
Because changes in primary protein structure can affect the stability, activity, or immunogenicity of a biologic drug these changes can be significant and accordingly the FDA has not issued a Guidance document regarding the extent to which (if at all) the primary sequence of a biologic protein drug can be changed. A similar restriction on patent claiming exists, wherein proteins (at least those produced by recombinant DNA technology) are limited to their primary sequence and the Patent Office has issued its own Guidelines requiring additional disclosure to support claims to amino acid sequence variants.
These considerations are relevant to the biobetter issue, because the likelihood is that such molecules will encompass amino acid sequence differences, which on the one hand would likely permit the biobetter producer to avoid infringement but on the other might take these molecules outside the scope of what the FDA is willing to consider as a biosimilar.
4. With so many biologic medications with patents expiring before 2020, what will be on the frontline for biosimilars going forward?
The most significant biosimilar drugs will be the ones with the biggest market share – Humira, for example, as well as Herceptin, Rituxan, Enbrel and Avastin are candidates. Hospira, Inc. and Celltrion, Inc. are already pursuing a biosimilar to Remicade and companies other than Sandoz are pursuing Neupogen biosimilars. Most of these drugs are antibodies or antibody fragments, and the technology for producing them is well established, or are relatively small proteins (human growth hormone, erythropoietin and filagstrim are all 165 amino acids in length). In addition, many of these molecules have been the subject of biosimilar competition in Europe, and we can expect that these will continue to be the first ones to market in the U.S. (primarily because the biosimilar applicants can rely on the data from the European versions as Sandoz did with its recently approved biosimilar).
Also, these “first generation” drugs are all far past their regulatory exclusivity periods and most are almost off patent (with the exception of beta-interferon, which has a patent that extends another 15 years or so due to changes in how U.S. patent term is determined). But generally it is likely that FDA will continue to address the challenges associated with biosimilar products in such a way that will facilitate their entry into the marketplace, much like the Hatch-Waxman regime accelerated entry of generic small molecule drugs.
