Recent follow-on biologics legislation, the Pathway for Biosimilars Act of 2010, shines a bright spotlight on biological drugs. Biologics differ from small-molecule pharmaceutical drugs in that they are typically produced with the aid of living materials like cells, rather than synthesized in the laboratory. Because biologics come from living matter, processes for making biologics can be difficult to replicate precisely even with good manufacturing controls. In addition, in contrast to pharmaceuticals, researchers may often have a hard time proving that a biological product made by repeating other scientists’ procedures has the same structure as the original product, due to the size and complexity of most biologic drugs. For example, a small-molecule pharmaceutical like paroxetine weighs only 329.4 grams per mole, while the weight of human growth hormone, a biologic and a protein, falls in the range of 20,000 to 22,000 grams per mole depending on the degree of structural variations such as differences in glycosylation. Glycosylation is a collective term for extended sugar-type molecules attached to the amino-acid building blocks of certain proteins, and locations of these sugar groups on the amino acid backbone can often be hard to pin down.

Partly for the reasons of their complexity and party because of their biological rather than chemical origin, biological drugs typically do not fall under the provisions of the Hatch-Waxman Act. This law, after giving branded drug products several years of guaranteed exclusivity (i.e., regulatory exclusivity granted even in the absence of patent protection), allows generic drug manufacturers to forgo complex clinical trials and enter the market upon showing that the small-molecule pharmaceutical drug they have synthesized has the same structure as that of the prior drug and is bioequivalent to it (e.g., it exhibits comparable pharmacokinetics, which are rates of metabolism and clearance from the human body).  Generics manufacturers can often accelerate their market entry through patent litigation—by showing that the pioneer manufacturer’s applicable patents are invalid or unenforceable or by successfully defending the charge that the generic product infringes the patents.

Because it so difficult to demonstrate structural equivalence and bioequivalence for biologics, “generic” equivalents of biologic drugs, called “follow-on biologics,” receive very different treatment under the 2010 Act than pharmaceutical generics do under Hatch-Waxman. Most importantly, FDA clinical trial requirements for follow-on biologics are significantly more onerous than those for pharmaceutical generics. As with pharmaceuticals, patent litigation will play a crucial role in potentially shortening the pioneer drug’s exclusivity period, but the procedure for challenging and invalidating patents on biologics is significantly more complex than that in the small-molecule pharma context. Thus, the scope of claims in patents to biological products will play a very significant role in shaping the regulation of pioneer biologic drugs and follow-on biologics.

My recent paper, Limits on Hard-to-Reproduce Inventions: Process Elements and Biotechnology’s Compliance with the Enablement Requirement, 3 Hastings Sci. & Tech. L.J. 109 (2011), squarely addresses the proper way to use composition of matter claims directed to biological products. The core of the argument is simple. Given the fact that the process of their preparation can influence the composition and performance of biologic drugs, claims to biologics should in many cases contain so-called process limitations in order to comply with the enablement requirement of Section 112 of the Patent Act. Enablement requires the patent owner to teach a person of ordinary skill in the art to make and use the subject matter of the patent without undue experimentation; patent claims of overly broad scope can fail this requirement, as no amount of teaching can enable others to practice the invention across the full scope of the claim. When the structure of the biologic is not fully known and can change depending on the process by which it is made, a process limitation would rescue the claim to the composition of the biologic from invalidity under Section 112 due to the overbreadth problem. Two examples of composition-of-matter claims to biologics that include process limitations are “a non-naturally occurring glycoprotein product produced in the mammalian host cell” and “a purified and isolated polypeptide having the structure of naturally occurring erythropoietin and characterized by being the product of prokaryotic or eukaryotic expression of an exogenous DNA sequence” (the limitations are emphasized).

Process limitations significantly constrain the scope of the claims’ coverage, which may make it more difficult for pioneers to keep follow-on manufacturers out of the market through patent litigation after the pioneer’s period of guaranteed exclusivity expires. Of course, this is all contingent on the follow-on manufacturer’s ability to prove “biosimilarity” or “interchangeability” of its product relative to the pioneer biologic drug to the FDA’s satisfaction.  Because of the very difficulty of reproducing and verifying the structure and performance of biological drugs, satisfying these requirements is not an easy task. On the one hand, this state of affairs may make it fundamentally fair to require pioneers to include process limitations in their composition of matter claims—if a follow-on manufacturer made a biosimilar or interchangeable copy of the pioneer biologic by a different process and succeeded, it should be rewarded for taking this risky approach by escaping infringement of the pioneer’s claims. On the other hand, as a matter of economics and policy of encouraging investment and increasing incentives to invent, manufacturers of pioneer biologics may need the robust patent protection provided by claims lacking the limiting process elements. These broader claims would increase the chances of pioneers’ demonstrating infringement by follow-on challengers, in turn giving the branded drugs a longer exclusivity period that would help them recoup their research and development costs.

Putting the policy considerations to one side, however, one has to keep in mind that patents must first and foremost comply with the strictures of the Patent Act.  There is a strong argument to be made, which I advance in the paper, that composition of matter claims to biologics cannot, in many cases, meet the enablement requirement of Section 112 without including process limitations.

The paper is available at http://ssrn.com/author=1544643

Dmitry Karshtedt, SLS ’11, Student Fellow, CLB