Introduction
The development of antivirals as in vivo therapeutics has resulted in a huge upsurge in the number of granted US patents (see Table 1). However, patentability concerns have always surrounded antivirals. In the event of an epidemic, even upon grant of a US patent, public policy may favor the federal government exercising eminent domain to seize an antiviral patent.
The subtleties surrounding application of US patent statutes 35 USC, sections 102 (novelty), 103 (nonobvious subject matter) and 112 (enablement, written description and best mode requirements) greatly affect the patentability of antivirals. Generally, antiviral patent applications are initially rejected for a lack of enablement and as being obvious in view of the state of the art.
Enablement
"The enablement requirement refers to the requirement of 35 USC 112, first paragraph that the specification describe how to make and how to use the invention"1. "The determination of what constitutes undue experimentation in a given case requires the application of a standard of reasonableness, having due regard for the nature of the invention and the state of the art"2. Antivirals are generally viewed to be an unpredictable art; however, the state of the art (virology) and one of skill in the art (e.g., scientists with advanced degrees in virology, biochemistry or molecular biology) is regarded to be quite high. "In unpredictable art areas, this court [the Federal Circuit] has refused to find broad generic claims enabled by specifications that demonstrate the enablement of only one or a few embodiments and do not demonstrate with reasonable specificity how to make and use other potential embodiments across the full scope of the claim"3.
For example, the Board of Patent Appeals and Interferences (BPAI) agreed with an examiner who "suggested that, in view of the state of the art of retroviral inhibition and the persistent difficulty in treating viral infections, such as AIDS, that more than screening tests are necessary to support the method claims directed to in vivo use"4. The BPAI has also found that in vitro activity of a single strain of a single retrovirus (e.g., HIV-1 strain RF) is not reasonably predictable of activity against all retroviruses or even all strains of HIV as "[i]t is accepted in the field of antiviral therapy that observation of activity against one virus, or even two viruses, is an insufficient basis on which to reasonably predict broad spectrum antiviral activity, or even activity against related viruses"5. However, when inventors "presented evidence supporting their assertion that PCV [an acylic nucleoside that inhibits the viral DNA polymerase of herpesviruses] is 'moderately to highly active against HSV-1 [herpes simplex], HSV-2, CMV [cytomegalovirus], VZV [varicella zoster] and EBV [Epstein-Barr virus]' ... and 'three of six animal herpesviruses against which it was tested' ... in vitro, and also 'that in vitro activity of the acyclic nucleosides [ACV (aciclovir) and GCV (ganciclovir)] correlates with in vivo activity against the herpesviruses' with respect to production of infectious virus," the BPAI was convinced that the disclosure satisfied the enablement requirement6.
For a specification to satisfy the enablement requirement with respect to antivirals, working examples are essential to support the claims directed to antivirals and methods of use. In vivo data are preferable to in vitro data and data demonstrating the efficacy of an antiviral against several related viruses are preferable to those for a single virus. In some instances, depending on the unpredictability of the specific antiviral, an animal model may not necessarily extrapolate to humans.
Obviousness
"To reach a proper determination under 35 USC 103, the examiner must step backward in time and into the shoes worn by the hypothetical 'person of ordinary skill in the art' when the invention was unknown and just before it was made. In view of all factual information, the examiner must then determine whether the claimed invention 'as a whole' would have been obvious at that time to that person"7. According to the Graham v. Deere analysis for making an obviousness determination, "the scope and content of the prior art are to be determined; differences between the prior art and the claims at issue are to be ascertained; and the level of ordinary skill in the pertinent art resolved. Against this background, the obviousness or nonobviousness of the subject matter is determined. Such secondary considerations as commercial success, long-felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented"8.
In KSR International Co. v. Teleflex Inc., the US Supreme Court rejected the teaching, suggestion and motivation (TSM) test, as well as an "obvious to try" analysis: "[w]hen there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. ... Rigid preventative rules that deny factfinders recourse to common sense, however, are neither necessary under our case law nor consistent with it"9.
The KSR decision is already affecting the patentability of antivirals10. For example, a request for a preliminary injunction to prevent the launch of a generic famciclovir (an oral antiviral against herpes) was recently denied in the ongoing litigation of Novartis Pharmaceuticals Corporation v. Teva Pharmaceuticals USA, Inc.11. The District Court found, in part, that the patent may be obvious in view of the prior art. The obviousness question centers on whether the prior art taught penciclovir (the active compound in famciclovir) and whether it was obvious to create a prodrug of penciclovir. The District Court found that "penciclovir was one of only a few compounds that would act as an effective lead compound. ... In this case, the 'prior art as a whole' would have motivated Beecham [the applicants] to pursue penciclovir as one of the 'known options' within their 'technical grasp'. Specifically, a person of ordinary skill would have pursued working with acyclic guanine nucleosides like penciclovir—not other classes of compounds—because they had proven very effective antiviral agents"12. Thus, the District Court has applied the "common sense" approach to obviousness advocated in KSR.
The ongoing Novartis Pharmaceuticals Corporation v. Teva Pharmaceuticals USA, Inc. also provides insight regarding references that teach away from an invention. For example, a "Tippie article did teach away from penciclovir, but the 'prior art as a whole' did not teach away from using penciclovir as a lead compound." Even though "the prior art produced some conflicting results about the effectiveness and toxicity of penciclovir ... [t]here are far greater references teaching that penciclovir would act as a powerful antiviral agent"13. Accordingly, it appears that the burden is on the applicants to survey the state of the art prior to relying on a single reference that suggests that the claimed invention is not possible, or that 'teaches away' from the claimed invention. Instead, it would be advantageous to identify a majority of references that teach away from a claimed invention to convince a patent examiner or a court.
Eminent domain
Even if an antiviral patent survives litigation, it is not immune to further challenges. For example, if a viral epidemic occurs, the patent directed to the antiviral may be seized by the federal government under eminent domain power. The potential of an avian influenza, or bird flu, outbreak "has heightened public interest regarding the availability and affordability of influenza antiviral medications such as Tamiflu"14. Tamiflu is the brand name of oseltamivir phosphate, which is not a bird flu vaccine but rather the most efficient antiviral treatment against the H5N1 and human virus strains. According to Roche, the exclusive manufacturer of Tamiflu, making Tamiflu is a time-consuming and complicated process that requires scarce raw materials, such as shikimic acid, which is extracted from star anise. Because of the difficulty in manufacturing Tamiflu, there have been pressures on Roche to allow the manufacture of generic oseltamivir. Roche has agreed to potentially sublicense to countries and companies interested in producing generic oseltamivir, but only if the countries and companies can realistically produce sufficient amounts for emergency pandemic use.
Eminent domain power, derived from the Takings Clause of the Fifth Amendment, authorizes the federal government to seize private property, including intellectual property, for public use15. And 28 USC §1498(a) allows the federal government to seize a patent and is subject to reasonable compensation to be paid to the patent owner16. "By exercising this statutory authority, the federal government declares a 'compulsory license' that allows third-party use of a patented invention without the authorization of the patent holder"14. Not surprisingly, the possibility of seizure of the Tamiflu patent has caused controversy. The pharmaceutical industry fears that such a compulsory license would remove incentives towards research and innovation. Conversely, there may not be enough Tamiflu for emergency needs if Roche remains the sole manufacturer. In view of Roche's willingness to sublicense, it seems unlikely that the government will not issue a compulsory license for Tamiflu.14
Conclusions
The standard for obtaining an antiviral patent has been raised due, in part, to more stringent requirements set forth by the US Patent and Trademark Office. Even though working examples are not necessary to satisfy the enablement requirement per se17, a lack of examples will likely bar an applicant from obtaining broad antiviral claims. The KSR decision has already affected the patentability of antivirals by applying a 'common sense' approach to obviousness.
Even though government seizure of a patent is a worst-cast scenario, it remains a distinct possibility. Previous arguments for overriding the rights of patent owners were advanced for the HIV/AIDS epidemic in developing countries as well as during the anthrax scare of 2001 (ref. 13). The balance between respecting the rights of patent holders and public policy advocating readily available antivirals in anticipation of an epidemic remains tenuous.