Personalized medicine has been hailed as a

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1 34 Biotechnology Law Report 39 Number 1, 2015 # Mary Ann Liebert, Inc. DOI: /blr The Best Offense Is a Good Defense: Patent Prosecution Strategies During Personalized Medicine Drug Development By ROBERT C. MILLONIG, JR., PhD, MARSHA ROSE GILLENTINE, PhD, and REBECCA HAMMOND, PhD Dr. Millonig and Dr. Gillentine are directors in the Biotechnology/Chemical Group at Sterne, Kessler, Goldstein and Fox in Washington, DC. Dr. Hammond is an associate at Sterne, Kessler, Goldstein and Fox in Washington, DC. Correspondence should be directed to < DPETROSKY@skgf.com >. PERSONALIZED MEDICINE THE FUTURE OF THERAPEUTICS? Personalized medicine has been hailed as a revolution in human health. 1 Recently, there has been a steady increase in the number of personalized medicine therapies. As of March 2013, the Food and Drug Administration (FDA) has required approval holders to include information regarding pharmacogenomics markers, including drug exposure and clinical response variability, risk for adverse events, genotype-specific dosing, mechanisms of drug action, and polymorphic drug target and disposition genes for 119 different drugs. 2 Additionally, the FDA has approved at least nine in vitro companion diagnostic devices. 3 It is predicted that the companion diagnostic market will grow at an estimated annualized rate of 22.9% over the next 10 years. 4 Thus, therapeutics having a personalized medicine component will play an increasing role in the clinical setting over the next decade. Personalized medicine provides an individualized treatment directing the right drug to the right patient, at the right dose, at the right time. For example, a diagnostic test can be used to determine whether a patient s cancer will be susceptible to a particular therapeutic. By relying on diagnostic tests, a treatment regimen can be tailored to a specific patient s disease. This can be critical for oncology treatments, where time is often of the essence and a particular drug in a class can be ineffective upwards of 75% of the time in the general patient population. 5 In some cases, a diagnostic test can detect genetic variants before the manifestation of clinical symptoms, enabling a physician to initiate therapy much earlier than previously possible with enhanced therapeutic outcomes. In other cases, a diagnostic test can assist a physician in identifying treatments that will be more efficacious for an individual patient. The development of a strong, multi-layered fortress of patent protection surrounding a pharmaceutical product is critical to its commercial success. Because personalized medicine has an important and increasing role in patient care, patents covering such inventions are of high value. However, the nature of the technology surrounding personalized medicine presents complex legal issues and challenges for a company wishing to adequately protect their technology. Therefore, having a carefully thought-out lifecycle management strategy for personalized medicine products is imperative. 1 Francis Collins, Has the Revolution Arrived? Nature, 464: (2010). 2 Food and Drug Administration (FDA), Table of Pharmacogenomic Biomarkers in Drug Labeling, < Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ ucm htm > (last updated June 16, 2014). 3 FDA, Companion Diagnostic Devices: In Vitro and Imaging Tools, < Productsand MedicalProcedures/InVitroDiagnostics/ucm htm > (last updated May 27, 2014). 4 Companion Diagnostics Market (2nd Edition) , PRNewswire (Nov. 27, 2014). 5 Personalized Medicine Coalition, The Case for Personalized Medicine (4th ed., 2014). 39

2 40 Biotechnology Law Report Volume 34, Number 1 FILING STRATEGIES A first consideration in determining a patent strategy is the availability of data exclusivity for the product. If the product is regulated as a drug (small molecule), data exclusivity is limited to five years for a new chemical entity. However, if the product is regulated as a biologic, 12 years of data exclusivity may be available. The FDA is not permitted to approve generic or biosimilar versions of the marketed products during the period of data exclusivity. Because data exclusivity is limited, follow-on patents are important for both biologics and small molecules so that market exclusivity is extended after the expiration of data exclusivity. Maximizing patent protection, especially for a biologic compound receiving 12 years of data exclusivity, requires careful planning, with due consideration given to potential new patent filings at each stage of the development process. A timeline showing possible decision points as to when to file a patent application is shown below (Fig. 1). However, patent counsel should constantly consider whether new data, especially for a personalized medicine invention, supports a new patent application filing. INITIAL PATENT APPLICATION FILING The first patent application filing decision point normally arises upon completion of pre-clinical testing. At this stage, researchers have tested various compounds in different models, and settled on compounds they believe are likely to exhibit efficacy in treating a human disease in a clinical setting. Once promising compounds have been identified, a patentability analysis should be conducted to determine whether a patent application should be filed with claims directed to the lead compound(s) either specifically or as part of a genus and methods of treatment using this compound. An important factor to consider when determining if a patent application should be filed is whether in vitro data is sufficient to satisfy the written description and enablement requirements, especially when planning to file the patent application globally. This is a fact intensive determination that will depend on the nature of each invention. At the time of this initial invention, a determination can also be made concerning whether the efficacy of the compound will be tied to a particular biomarker. In certain circumstances, the appropriate biomarker will be apparent from the nature of the compound itself, e.g., an antagonist to a particular molecular interaction involving the biomarker. If such a link is clear and not speculative, information regarding the biomarker can be included in the initial patent filing. When drafting the first application, it is necessary to carefully consider whether coverage for the compound(s) should be broad or more narrow. A broad genus claim may provide claim coverage for all tested compounds. However, a broad genus claim may be difficult to prosecute (and costly) because it is more susceptible to lack of enablement and lack of written description attack. Moreover, the state of the prior art may also limit your ability to claim broadly. As such, it may be necessary to limit the claims to narrower classes of compounds. If broad genus claims are prosecuted, claims to the particular lead compounds should always be included. Another important consideration to keep in mind when drafting the initial patent application, is to FIG. 1. Possible decision points as to when to file a patent application.

3 Biotechnology Law Report Volume 34, Number 1 41 tailor the patent specification to the invention to be claimed. If too much detail regarding speculative methods of treatment, dosage regimens, biomarkers, patient subpopulations, salt or physical forms of the drug, formulations, recrystallization conditions, or multiple purification methods is included, subsequent patents to those types of inventions, with potentially later expiration dates, may be precluded. Therefore, unless such detail is necessary to provide an adequate description of the claimed invention, carefully consider whether this information should be included in an initial patent application. SUBSEQUENT PATENT APPLICATION FILINGS Subsequent filing decisions will arise from data generated during clinical trials conducted both pre- and post-market entry. During clinical trials, the sponsor company should obtain more information concerning a potential biomarker, the nature of a diagnostic test for the presence of the biomarker, and whether the FDA is likely to require a companion diagnostic for the biomarker upon market approval. In these situations, the filing of additional patent applications to a particular diagnostic assay, methods of treating a subpopulation of patients exhibiting the biomarker, and other inventions flowing from these studies should be considered before information from the clinical trials becomes public. For example, results from the clinical trials should be carefully reviewed for patient subpopulations in which the particular drug is more or less effective. These subpopulations may exhibit a particular genotype or may be based on other criteria such as age, sex, race, or prior treatment regimen. Additional secondary patent applications may include claims directed to specific salts, polymorphs, new formulations and/or drug delivery routes, dosing regimens, prodrugs, pharmacokinetics, subsequent approved uses, and drug combinations. For example, specific dosing regimens may be more effective for particular patient subpopulations. Depending upon the clinical trial results, data may show that such results are unexpected and therefore patentable. In reviewing results from clinical trials, the sponsor should carefully evaluate any unexpected result for patentable subject matter. Unexpected results may often be used to establish patentability. If available, include unexpected results in the specification for support that the claimed invention is non-obvious. Having comparative data in the specification is costeffective because the prosecuting attorney does not need to draft a declaration to submit the unexpected results. Additionally, some countries require that the data need to be included in the specification to be considered. When deciding whether to file a subsequent patent application, in addition to considering whether the claims are novel or non-obvious, obviousnesstype double patenting must be considered. Because a later-filed, but earlier-expiring, patent can be used as a reference patent in an obviousness-type double patenting rejection, 6 carefully consider whether the claims of a subsequently issued patent may render an earlier-issued patent invalid. DRAFTING PATENTABLE AND ENFORCEABLE CLAIMS To adequately protect personalized medicine inventions, it is necessary to obtain multiple patents directed to different inventions. For example, where the FDA would require a companion bioassay, patents directed to diagnostic assays, e.g., methods of determining the presence of a biomarker, may have significant value. Claims directed to methods of treatment, which include a companion assay may also have value. However, as these claims may be practiced by multiple entities, e.g., the diagnostic laboratory conducting the assay and the physician or patient administering the drug, these claims may have divided enforcement issues as discussed below. Moreover, the bioassays may be based on a naturally occurring material, e.g., a nucleic acid hybridization assay. As a result of tightening legal standards, protecting or establishing infringement of patents directed to each of these types of inventions has become more challenging. Recent decisions by the Supreme Court have influenced the way in which personalized medicine inventions including diagnostic steps can be patentprotected in the United States. For example, in Mayo Collaborative Services v. Prometheus Laboratories, the Court held that claims directed to correlating blood levels with dose was not patentable subject matter. 7 In Prometheus, the claim at issue was directed to: 6 Gilead Sciences, Inc. v. Natco Pharma Ltd., 753 F.3d 1208 (Fed. Cir. 2014) S. Ct (2012).

4 42 Biotechnology Law Report Volume 34, Number 1 A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising: (a) administering a drug providing 6 thioguanine to a subject having said immune-mediated gastrointestinal disorder; and (b) determining the level of 6 thioguanine in said subject having said immune-mediated gastrointestinal disorder, wherein the level of 6 thioguanine less than about 230 pmol per red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and wherein the level of 6 thioguanine greater than about 400 pmol per red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject. 8 The Court found that these method claims were not patent eligible because the relationship between metabolite concentration and optimized dosage was a law of nature. 9 This decision suggested that claims directed to diagnostic assays may not constitute patentable subject matter under certain circumstances. On March 4, 2014, the Patent and Trademark Office (PTO) issued strict examination Guidelines making it difficult to prosecute claims directed to diagnostic assays. 10 However, on November 20, 2014, the PTO indicated that revised Guidelines for inventions involving natural materials would be issued soon. 11 The public then will have 90 days to submit comments regarding the proposed revised guidelines. 12 Depending upon the revised Guidelines, prosecution of diagnostic assay claims may become easier. The Federal Circuit s decision in Classen Immunotherapies v. Biogen IDEC, although decided earlier than Prometheus, provides insight as to how diagnostic claims could be drafted to satisfy the patentable subject matter requirement of 35 U.S.C. x In Classen, the claims at issue comprised a screening step followed by an immunization step that depended on the results of the screen. The Federal Circuit likened the patent eligibility doctrine to a course filter that excludes entire areas of human inventiveness from the patent system on the basis of judge-created standards. 14 The court found that the addition of the immunization step move[d] the. claims through the coarse filter of x Therefore, based on the Federal Circuit s holding in Classen, one potential strategy to render a diagnosis claim patentable may be to add an affirmative treatment step after the correlation step, where that treatment step includes unambiguously physical acts. For example, [a] method of treating cancer comprising determining whether a person is positive for a particular gene and then administering a particular drug to such person may be patentable subject matter. However, the claims struck down in Prometheus included language that the assay results suggested a need to increase or decrease the amount of the drug administered to the subject. While it can be argued that this claim language in Prometheus is more mental than physical, the patentability of claims that add an overt treatment step, constituting a physical act, to be performed as a result of the diagnostic assay remain unclear. We must await additional case law developments to clarify. Even if claims incorporating both assay steps and treatment steps eventually are determined to constitute patent eligible subject matter, such a claim may be difficult to enforce because of the divided infringement defense. In the context of pharmaceutical patents, infringement of method of treatment claims is usually based on establishing inducement of infringement by the infringing pharmaceutical manufacturer. Reliance on inducement is necessary as the infringing manufacturer does not itself treat the disease condition, but only directs physicians and patients to do so, typically through the product insert. In Limelight Networks, Inc. v. Akamai Technologies, Inc., the Supreme Court held a defendant cannot be liable for inducing infringement if two different parties perform different steps of a method patent, i.e., divided infringement, where direction and control is not established between the two parties actually performing the method. 16 Therefore, claims and patent specifications must be carefully drafted with these divided infringement issues in mind. For example, the specification should clarify that a step directed to ascertaining the presence of a biomarker is performed by the physician who orders the test and not just by the laboratory that carries out the test. Moreover, appropriate language should be employed to ensure that the physician S. Ct. at Id. at < guidance.pdf >. 11 < = 0e90e8eb-2f a6f8-916ae39ca43c&utm_source = newsletter&utm_medium = &utm_campaign = ip >. 12 Id F.3d 1057 (Fed. Cir. 2011). 14 Id. at Id. at S. Ct. 2111, 2121 (2014).

5 Biotechnology Law Report Volume 34, Number 1 43 also performs the treatment step. Thus, claims should be drafted with an eye toward only one party performing or directing all of the recited steps. In light of the complexity in claiming diagnostic assays in view of recent case law, other claiming strategies should be employed. Claims to treating subpopulations exhibiting certain biomarkers may be a way to avoid many of these issues. Claims to diagnostic assay reagents themselves may be appropriate alternative ways to protect the assay. Moreover, the results of clinical trials may elucidate particular treatment regimens that are more effective for specific subpopulations of patients, having specified biomarkers. However, according to the Supreme Court in Association for Molecular Pathology v. Myriad Genetics, Inc., claims to an isolated DNA are not patentable because a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated. 17 Therefore, claims to the DNA sequence of interest in personalized medicine inventions may not constitute patentable subject matter itself for a companion diagnostic. However, cdnas constitute patentable subject matter, as would a potentially novel detection technique or reagent. 18 Such a detection technique or reagent wouldneedtogobeyondthethresholdof [p]urely conventional or obvious pre-solution activity [that] is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law. 19 Therefore, creative diagnostic companies can still draft claims directed to patent-eligible subject matter. Additionally, pharmaceutical companies typically do not perform the affirmative steps recited in patented method claims, e.g., administering and treating. Instead, pharmaceutical companies typically must draft claims to establish that a generic pharmaceutical company is inducing infringement. Because inducement requires a showing of intent to encourage a third party to infringe a patent, a pharmaceutical company typically relies on a generic pharmaceutical company s product label as evidence of its intent of inducing infringement of a method claim. 20 Care must be taken to draft claims that correspond to language included in the generic pharmaceutical company s product label, especially language included in the Indications and Usage and Dosage and Administration sections. 21 CONCLUSIONS Obtaining and enforcing patents directed to personalized medicine inventions has become more difficult as a result of recent case law. Patent counsel must carefully develop a life cycle management strategy that takes into account prior publications, obviousness-type double patenting, direct infringement, and patent eligible subject matter, and should reevaluate this strategy regularly as a result of developments in preclinical and clinical studies. With appropriate care, a robust patent portfolio covering personalized medicine inventions is still possible. ACKNOWLEDGMENTS N.B.: Thank you to Gaby L. Longsworth, PhD, for her thoughtful comments S. Ct. 2107, 2109 (2013). 18 See id. at Mayo, 132 S. Ct. 1289, 1298 (2012). 20 Bayer Schering Pharma AG v. Lupin, Ltd., 676 F.3d 1316 (Fed. Cir. 2012). 21 Id.