Intellectual Property Issues for Veterinary Pharmaceuticals in the USA

Keywords::

• enforcement
• exemption
• patent
• pharmaceutical
• veterinary

Patent prosecution refers to the interaction between inventors and a governmental patent office, such as the US Patent and Trademark Office (USPTO), to obtain a patent. Patent prosecution is analogous to a negotiation in which the inventors and the patent office agree on patentable subject matter or patentability. Patent enforcement relates to the right of a patent owner to exclude or prevent others from using the patented invention.

The process for obtaining and enforcing patents relating to veterinary pharmaceuticals involves similar strategies as the process for human pharmaceuticals, however, notable differences exist between the two. The issues regarding patent procurement are similar for veterinary and human pharmaceuticals; however, the enforcement of veterinary pharmaceutical patents is quite different from the enforcement of human pharmaceutical patents, especially with respect to generic products. In this article, the similarities regarding patent procurement for veterinary and human pharmaceuticals are illustrated by a discussion of the issues surrounding the patentability of gene patents and the need for exemplification for patent claims directed to vaccines, methods of treatment or prevention of disease. The differences regarding the enforcement of veterinary and human pharmaceutical patents are demonstrated by the discussion of the process of filing a new veterinary drug application and the safe harbor research exemption (also known as the Hatch–Waxman exemption).

Similar intellectual property issues affect the patenting of veterinary and human pharmaceuticals. For example, the decision in the lawsuit brought by the American Civil Liberties Union against Myriad Genetics regarding the patentability of gene patents affects both human and veterinary gene patents [1]. Not surprisingly, the Southern District of New York (SDNY) decision in the Myriad Genetics case was appealed on the Federal Circuit [2]. On 29 October 2010, the US Department of Justice (DOJ) filed an amicus brief in support of the SDNY position in the Myriad Genetics case, stating that isolated human genomic DNA is not patentable [3]. The DOJ amicus brief sides with the American Civil Liberties Union on the issue of isolated DNA and with Myriad Genetics on the patentability of scientifically manipulated DNA. Specifically, the DOJ took the position that human-engineered DNA molecules, such as cDNAs, are patent-eligible under patent law 35 USC 101, and isolated, but otherwise unmodified, genomic DNA is not patent-eligible subject matter under that law.

In the Myriad Genetics case, the patents in suit encompassed breast cancer genes BRCA1 and BRCA2. The composition claims relate to ‘isolated DNA’ containing human BRCA1/2 gene sequences. The method claims refer to diagnostic methods used to identify mutations in the BRCA1/2 genes by analyzing the sequences of the genes. The SDNY ruled that DNA’s existence in an ‘isolated’ form does not transform it into something ‘distinctly different in character’ from the nonisolated DNA contained in the human gene sequences. The SDNY was of the belief that purifying DNA did not change the underlying characteristic of the DNA, which was to convey information to express a protein. With respect to the method claims, the SDNY held that the claimed comparisons are abstract mental processes and thereby constitute unpatentable subject matter.

With respect to the application of Myriad Genetics to veterinary patents, Judge Dyk’s dissent in the Intervet versus Merial Federal Circuit decision opines that the claim relating to an isolated DNA molecule raises substantial issues of patentable subject matter under patent law 35 USC 101 [4]. According to Judge Dyk, the Federal Circuit and the Supreme Court have not yet directly decided the issue of the patentability of isolated DNA. Judge Dyk admits that the Federal Circuit has upheld the validity of several gene patents (including Amgen versus Chugai [5]); however, he believes that none of the cases have directly addressed the question of whether such patents encompass patentable subject matter under Section 101 of the Patent Act [6]. Judge Dyk’s application of the Myriad Genetics decision to a nonhuman gene is interesting because others, such as the DOJ, opined specifically on the patentability of human genes. However, Judge Dyk and the DOJ have adopted positions contrary to Federal Circuit law, as the Federal Circuit has previously upheld the patentability of gene patents (for example in Amgen versus Chugai).

Another example of a similar issue in patenting both veterinary and human pharmaceuticals is the need for exemplification for patent claims directed to vaccines, methods of treatment or methods of prevention of disease. Although it is not required by the statute and upheld by case law [7], data may be required to obtain patent claims directed to vaccines, methods of treatment or methods of prevention of disease, especially as the invention gets away from commonplace art. For example, prevention and treatment of feline immunodeficiency virus (FIV) is recognized as difficult in cats, so in vivo efficacy data may be required by the USPTO before a claim is granted that ‘prevents’ FIV infection. To illustrate this point, a series of patents directed to treatment of and immunization against FIV, stemming from Janet Yamamoto’s research at the University of Florida College of Veterinary Medicine, USA, all have therapeutic data in felines that demonstrate the efficacy of the claimed invention [101–108]. It is likely that these claims would not have been granted without experimental in vivo efficacy data in cats.

In some instances, it may be easier to patent veterinary pharmaceuticals. The availability of target animal data means that in vivo efficacy data may be available more quickly in animals than in humans. It is usually easier and faster to obtain in vivo animal data than it is to conduct clinical trials in humans.

As an example, the size of an experimental group required to demonstrate drug efficacy usually depends upon requirements as dictated by statistical methods. In order to illustrate this, guidelines established by the World Association for the Advancement of Veterinary Parasitology for evaluating the efficacy of drugs in dogs and cats indicate that a minimum of six animals per group is recommended [8]. With humans, the size of the experimental group depends upon requirements as dictated by not only statistical methods but also human group size. For example with a Lyme vaccine, statistically relevant results are obtainable in more subjects when one can infect the experimental group – more people are needed in clinical trials because one cannot be certain that all the people in the experimental group will contract Lyme disease. Furthermore, with human trials, there exists an ethical problem regarding exposing humans to conditions in which they could contract a disease, therefore, the experimental group must be substantially larger.

Another area in which there are differences between veterinary and human pharmaceutical patents is the regulatory framework. In particular, the filing of a new veterinary drug application may be an act of infringement but a human new drug application (NDA) is not necessarily an act of infringement. Furthermore, the safe harbor research exemption specifically excludes genetically manipulated veterinary products.

The safe harbor research exemption is an exemption to the rights conferred by patents, and it is especially relevant to drugs. According to this exemption, despite the patent rights, performing research and tests for preparing regulatory approval, for instance by the US FDA, does not constitute infringement for a limited period before the end of the patent term. This exemption allows generic manufacturers to prepare generic drugs in advance of the patent expiration.

In particular, 35 USC 271 subsection (e)(1) states that:

“It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention (other than a new animal drug or veterinary biological product (as those terms are used in the Federal Food, Drug, and Cosmetic Act and the Act of March 4, 1913) which is primarily manufactured using recombinant DNA, recombinant RNA, hybridoma technology, or other processes involving site specific genetic manipulation techniques) solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.”

For a human pharmaceutical product, the Supreme Court held that, according to 35 USC 271(e)(1), all uses of compounds that are reasonably related to the submission of information to the government under any law regulating the manufacture, use or distribution of the product are exempt from infringement [9]. The filing of an abbreviated new drug application (ANDA) to seek FDA approval of a generic pharmaceutical drug, therefore, may not be considered an act of infringement if the ANDA is certified under paragraphs I, II or III [10]. Certification requires the ANDA applicant to state one of the following:

• That the NDA holder submitted no patent to the FDA;

• That any patent submitted has expired;

• That the date the applicable patent expires;

• That “the patent is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of the drug product for which the abbreviated application is submitted [11].”

If an ANDA applicant certifies that a patent is invalid, unenforceable, or not infringed (a ‘paragraph IV certification’), the applicant must notify the NDA holder of the certification [12]. After being notified of paragraph IV certification, a NDA holder may sue the ANDA applicant for patent infringement by utilizing 35 USC 271 subsection(e)(2)(A) [13].

By contrast, the filing of an abbreviated new animal drug application (ANADA) for a generic new animal drug may be an act of infringement if the new generic animal drug is primarily manufactured using recombinant DNA, recombinant RNA, hybridoma technology or other processes involving site-specific genetic-manipulation techniques. Since ANADAs are used to seek approval for a generic new animal drug, which is a copy of an approved new animal drug covered by a patent or another period of exclusivity, ANADAs are not usually filed until the patent or other period of exclusivity is near expiration [201].

As with an ANDA application, the ANADA application must provide certification by the applicant that a patent does not exist, that a patent has expired or will soon expire or that a patent claimed for the approved product is invalid or will not be infringed upon by approval of the abbreviated application. In the latter case, the generic applicant or sponsor must then notify the sponsor of the approved product application and the owner of the patent that he or she has filed an abbreviated application claiming invalidity or noninfringement of the patent [202]. Similar to ANDAs, ANADAs are sometimes filed prior to the expiration of the patent and patent owners do enforce their patents. For example, Norbrook Laboratories was sued by Bayer Healthcare LLC and Boehringer Ingelheim Vetmedica for filing ANADAs directed to generic versions of Baytril^® and Metcam^®, respectively [203, 204].

All animal drugs approved for safety and effectiveness by the FDA are published in the Green Book [205]. The Green Book lists drug products, active ingredients, tradenames, new animal drug application numbers and patent information. For human drugs, the equivalent Orange Book identifies drug products approved on the basis of safety and effectiveness by the FDA and provides information on newly approved drugs, changes and revisions to current data, including therapeutic equivalence evaluations and updated patent and exclusivity data [206]. Both the Green and Orange Books provide similar information with respect to active ingredients and patent and other exclusivity data.

In summary, veterinary and human pharmaceutical patents share many similarities. In particular, the issues regarding patent procurement are similar for veterinary and human pharmaceuticals, especially regarding the issues surrounding gene patents, as well as the need for in vivo efficacy data for veterinary vaccines and the submission of an ANADA and an ANDA application. However, the enforcement of veterinary pharmaceutical patents is very different to the enforcement of human pharmaceutical patents, especially with respect to generic products. There is no safe harbor research exemption for a new animal drug or veterinary biological product primarily manufactured using recombinant DNA, recombinant RNA, hybridoma technology or other processes involving site-specific genetic-manipulation techniques.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Funding

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.