By Kevin Noonan
Treatment using cell-based therapies is a rapidly advancing area of clinical research and development. It is also one that involves significant investment and, therefore, can be expected to have concomitantly significant costs to patients and their insurers. Accordingly, patent exclusivity will be important to defray high development and regulatory compliance costs. The nature of such therapies, and recent patent law trends regarding natural products and methods relating to the practice of medicine, suggest these therapies may not be given the type of robust patent protection conventionally available for small-molecule drugs. Even method-of-treatment claims, which are less prone to impediments in patent procurement occasioned by these recent legal trends, or invalidation even after grant, may not provide sufficient protection in light of statutory “safe harbors” enacted almost a quarter century ago against infringement liability enjoyed by medical professionals. In addition, cell-based therapies may be patient-specific (e.g., based on idiopathic antigenic reactivities for oncogenic immunotherapies) and be unable to satisfy the disclosure requirements of the patent statute or to have claims that would apply broadly to therapies for heterogeneous patient populations. Indeed, it may be the case that regulatory exclusivity—analogous to the 12-year market exclusivities for biologic drugs provided by the Biologics Price Competition and Innovation Act (BPCIA)—will be more relevant than patenting to development of cell-based therapies. The prospects for the impact of these patent considerations will be discussed.
The history of biomedical advances over the past 50 years has focused predominantly of increasing complexity, from small-molecule therapeutics to antibodies, cytokines, blood-clotting factors, and protein hormones such as insulin and erythropoietin. The next great advance is cell-based therapies, which have the potential to provide more targeted therapies for diseases of aging (Parkinson’s disease, ALS, stroke, and a variety of bone and joint disabilities), autoimmune diseases (diabetes, Crohn’s disease), and cancer (through patient-specific activated T cells and other engineered hematopoietic cells). These treatments are one of the most rapidly advancing areas of clinical research and development. However, as was the case with earlier, high-complexity therapies, the path forward is uncertain; development requires significant investment and can be expected to have similarly significant costs to patients and their insurers at a time when these costs are political liabilities. Nevertheless, if these investments are to be made, exclusivity—particularly patent exclusivity—will be crucial. The present patent landscape in the United States provides little comfort that these exclusivities will be available to sufficiently protect investment in this technology.
Technology background
Cell-based therapies come in several overlapping varieties. On the one hand, therapeutic cells can be autologous to the individual; the cells used for therapy are isolated and/or derived from a patient, concentrated, modified, or otherwise manipulated and then returned to the patient. Examples of current technologies using autologous cells include hematopoietic stem cells isolated from bone marrow or umbilical cord blood. There has been some thought that cord-blood stem cells could eventually be routinely stored for use during an infant’s lifetime as needed. Other, more nascent sources of autologous cells include adult stem cells isolated from tissues; these include mesenchymal and neural stem cells derived from adult tissue or stimulated to differentiate from embryonic stem cells.
In the other broad category are allogeneic cells, derived from anyone other than the patient. Such cells have the advantage of being capable of mass production and being available off-the-shelf and, to some extent, standardized with regard to biochemical, metabolic, and antigenic properties. Disadvantages include the possibility that for any particular patient, immunological rejection may be triggered. These cells include cells having the broadest applicability, such as human embryonic stem cells and induced pluripotent cells, which can be generated by introducing four well-defined genes (Oct3/4, Sox2, c-Myc, and Klf4) into cells from appropriate tissues. Human embryonic stem cells have the broadest potential applicability because they are the most pluripotent, but their use can raise ethical issues, whereas iPSCs are less robust but also less ethically challenging. Another distinction is whether the cells are isolated, purified, and usually concentrated, or if the cells are modified either by how they are cultured or—more generally—by genetic engineering.
Many groups worldwide are developing cell-based therapies for a variety of diseases; most of those (87%) in clinical trials are being conducted in Phase I or II. Half of such trials are in the US with another one-quarter in Asia (1). About one-third of these trials include mesenchymal stem cells; 17% utilize hematopoietic cells, and only 5% involve embryonic stem cells (2). These trials are directed to a wide variety of diseases: 17% to cardiovascular diseases, 12% for neurological disorders, 11% for autoimmune disease, and 8% for skeletal or joint injuries (2).
The effects of cell-based therapies also vary. For neurological diseases, it is thought that treatments are neuroprotective for existing cells and tissue rather than providing neural cell replacement. For example, the NurOwn cell therapy product (Brainstorm Cell Therapeutics, Inc.) is comprised of autologous mesenchymal stem cells (MSCs) modified to express neurotrophic factors, shown to promote motor nerve survival (1). Conversely, cell therapy for ischemic stroke is focused on cell replacement as well as neuroprotection and angiogenesis induction by using a combination of bone marrow-derived mesenchymal stem cells, neural stem cells, and other stem cell types (1).
Cell-based cancer therapies rely on different approaches including genetically engineered cells, particularly chimeric antigen receptor (CAR) T cells, exemplified by US Patent No. 7,446,190; claim 1 is representative:
“1. A nucleic acid polymer encoding a chimeric T cell receptor, said chimeric T cell receptor comprising (a) a zeta chain portion comprising the intracellular domain of human CD3 ζ chain, (b) a costimulatory signaling region, and (c) a binding element that specifically interacts with a selected target, wherein the costimulatory signaling region comprises the amino acid sequence encoded by SEQ ID NO:6” (3).
These cells are generally autologous, and provide cells capable of specifically targeting malignant cells that have escaped a patient’s native immune surveillance. Several companies (Juno Therapeutics, KITE Pharma) are actively pursuing these therapeutic modalities (4).
Patent protection prospects
Despite the bright therapeutic potential of cell-based therapies, the nature of such therapies and recent patent law trends regarding natural products and methods relating to the practice of medicine suggest these therapies may not be given the type of robust patent protection conventionally available for small-molecule drugs. The principal challenge in the US stems from recent developments in the law of subject matter eligibility, codified as Section 101 of the Patent Act:
“Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title” (5).
Until recently, this section has been interpreted broadly by the courts, including the Supreme Court’s decision in Diamond v. Chakrabarty (6) that a genetically manipulated bacterium was eligible to be patented. Beginning in 2012, however, the Supreme Court began retrenching on the decades-old nostrum that “everything under the sun made by man” should be patent-eligible, and began to reemphasize the notion that there are exceptions to patent eligibility. These are usually defined (albeit loosely and rather indefinitely) by the Court as “laws of nature, natural phenomena, and abstract ideas” (7).
Relevant to cell-based therapies is the Supreme Court’s 2013 decision in Association for Molecular Pathologists v. Myriad Genetics (“Myriad”) (8), in which the Court deemed patent ineligible DNA isolated from nature (while at the same time deciding that cDNA, made from mRNA converted by the viral enzyme reverse transcriptase, was patent eligible). The decision was expressly limited to the question before the Court—“was a human gene patentable?”—freighted with all the social, moral, and political weight this characterization could bring to bear. It was the Court’s rationale, however, that has resonated negatively with regard to patenting natural products (as many of the cell-based therapies certainly are). This rationale was that “mere” isolation of a portion of human DNA (a “gene”) from a chromosome was not enough to render the isolated DNA patent eligible. There must be “something more” (a concept taken from an even more troublesome Supreme Court decision involving diagnostic method claims, Mayo Collaborative Services v. Prometheus Laboratories) (9), which has been interpreted to mean a structural difference. In a stroke, the decision put in question and jeopardy all natural products that were “merely” isolated from nature.
While there have been relatively few court cases (and in particular, no traditional pharmaceutical cases) testing the principle, the US Patent and Trademark Office (USPTO) has in various attempts to apply these rubrics emphasized structural variants or differences between a natural product as it exists in nature and how it is claimed when deciding patent eligibility. The Court was careful in its Myriad decision not to overrule Chakrabarty, and thus genetically engineered or otherwise modified cells likely remain patent eligible. However, other types of cells used in cell-based therapies (e.g., hematopoietic cells, embryonic and adult stem cells, and products of such cells such as dermal sheets used to treat burn victims) are clearly at risk with regard to whether patent protection is or will be available.
Paradoxically, methods for making such cells seem to remain eligible for patenting. This status stems from language in the Court’s Myriad decision itself, as well as how the Court of Appeal for the Federal Circuit (having jurisdiction over all US patent questions) has interpreted the patent statute. In Rapid Litigation Management Ltd. v. Cellzdirect, Inc. (10), the Federal Circuit reversed a district court decision that claims to methods for culturing human hepatocytes were patent-ineligible for relying on a law of nature. The invention was directed to methods for producing pure cultures of mature hepatocytes to be used for testing, diagnostic, and treatment purposes. Hepatocytes in the prior art were disadvantageous for these purposes because they were only available from liver resections or non-transplantable livers of organ donors. This type of cell has a short lifespan that resulted in erratic supply as well as limited and unreliable availability.
The inventors found, contrary to the understanding in the prior art, that certain hepatocytes in a hepatocyte population could be frozen and thawed multiple times and retain viability. The appellate panel found that the claims for such methods were not directed to a patent-ineligible “law of nature” but to an application of such a law, “a new and useful laboratory technique for preserving hepatocytes.” Viewed in this way, the court held that the claimed method was “precisely the type of claim that is eligible for patenting.” Similar logic may apply to methods for producing cells for cell-based therapies, particularly insofar as such methods overcome the types of challenges commonly faced in the development of cell-based therapies. Although the district court’s initial invalidation was an example of the risk even method claims can be subject to when a district court applies prevailing Supreme Court precedent, this recent Federal Circuit case suggests that methods that result in useful compositions can be patent eligible.
Even if patent-eligible, however, other applications of the patent statute may pose impediments to sufficiently robust patent protection for cell-based therapies (albeit to a lesser degree and in a less categorical manner). Cell-based therapies can be patient-specific (e.g., based on idiopathic antigenic reactivities for oncogenic immunotherapies) and be unable to satisfy the disclosure requirements of the patent statute or to have claims that would apply broadly to therapies for heterogeneous patient populations. For example, in the Federal Circuit decision, In re Alonso (11), the claimed invention was directed to antibody reagents and methods for treating neurofibrosarcomas using a monoclonal antibody idiotypic to each patient’s cancer. The evidence in the specification showed that infusion of a human patient with 100 mg of an expressly disclosed monoclonal antibody resulted in clearance of lung metastases within 24 hours and regression of the primary brain tumor within seven days. The USPTO rejected claims to such antibodies (and the Federal Circuit affirmed) based on failure to satisfy Section 112(a) of the patent statute (12), which requires an adequate written description sufficiently explicit and detailed that the skilled worker could make and use the claimed invention. In this case, the patent applicant was unable to satisfy that provision, due to the unavoidable idiotypic (and idiosyncratic) characteristics of the claimed antibodies. Similarly, cell-based therapies that rely on such characteristics (particularly, for example, those using autologous cells) may suffer the same fate and be denied patent protection.
Finally, even method-of-treatment claims, which are less prone to impediments in patent procurement occasioned by these recent legal trends, may not provide sufficient protection in light of statutory “safe harbors” enacted almost a quarter century ago against infringement liability enjoyed by medical professionals (13).
Conclusion
Cell-based therapies represent in many ways the cutting edge of medicine, promising to provide treatments for diseases that cannot be treated (at least adequately) using conventional pharmaceutical agents or even complex biologic drugs. Recent trends in US patent law, however, make it likely that many such therapies, or aspects thereof, will not have the kind of patent exclusivities available that would justify the massive expenditures necessary to bring them to market. In these circumstances, it may be necessary for developers to rely on regulatory exclusivity analogous to the 12-year market exclusivities for biologic drugs provided by the BPCIA, whether extant or provided by Congress in response to the need for these therapies. The nascent nature of these therapeutics have not brought these considerations to the fore with policymakers as yet, but it does not take extraordinary vision to see that the current patent and regulatory landscape is not favorable to expeditious development of such therapies at a time when science has provided the means and the public has the need for them.
Kevin Noonan is partner at McDonnell Boehnen Hulbert & Berghoff LLP and chair of the firm’s biotechnology and pharmaceuticals practice group.
References
1. E. Buzhor et al., Regen. Med. 9 (5), https://doi.org/10.2217/rme.14.35 (Nov. 5, 2014).
2. T.R. Heathman et al., Regen. Med. 10 (1), 49-64 (2015).
3. M. Sadelain, et al., “Nucleic acids encoding chimeric T cell receptors,” US Patent 7,446,190, Nov. 2008.
4. June Therapeutics, “Juno Therapeutics Defeats Kite Pharma’s Challenge to CAR T-Cell Patent,” Press Release (Seattle, WA, Dec. 19, 2016).
5. Leahy-Smith America Invents Act, Public Law 112-29, § 33, 125 Stat. 284 (Sept. 16, 2011).
6. Diamond v. Chakrabarty, 447 U.S. 303 (1980).
7. Funk Bros.Seed Co. v. Kalo Inoculant Co., 333 U.S. 127 (1948).
8. Association for Molecular Pathologists v. Myriad Genetics, 133 S. Ct. 2107 (2013).
9. Mayo Collaborative Services v. Prometheus Laboratories Inc., 132 S. Ct. 1289 (2012).
10. Rapid Litigation Management Ltd. v. Cellzdirect, Inc., 827 F.3d 1042 (Fed. Cir. 2016).
11. In re Alonso, 545 F.3d 1015, 1019 (Fed. Cir. 2008).
12. Leahy-Smith America Invents Act, Public Law 112–29, § 4(c), 125 Stat. 296 (Sept. 16, 2011).
13. Leahy-Smith America Invents Act, Public Law, 112–29, §§ 3(g)(2), 16(a)(1), 20(i)(4), (j), 125 Stat. 288, 328, 335 (Sept. 16, 2011).
1. E. Buzhor et al., Regen. Med. 9 (5), https://doi.org/10.2217/rme.14.35 (Nov. 5, 2014).
2. T.R. Heathman et al., Regen. Med. 10 (1), 49-64 (2015).
3. M. Sadelain, et al., “Nucleic acids encoding chimeric T cell receptors,” US Patent 7,446,190, Nov. 2008.
4. June Therapeutics, “Juno Therapeutics Defeats Kite Pharma’s Challenge to CAR T-Cell Patent,” Press Release (Seattle, WA, Dec. 19, 2016).
5. Leahy-Smith America Invents Act, Public Law 112-29, § 33, 125 Stat. 284 (Sept. 16, 2011).
6. Diamond v. Chakrabarty, 447 U.S. 303 (1980).
7. Funk Bros.Seed Co. v. Kalo Inoculant Co., 333 U.S. 127 (1948).
8. Association for Molecular Pathologists v. Myriad Genetics, 133 S. Ct. 2107 (2013).
9. Mayo Collaborative Services v. Prometheus Laboratories Inc., 132 S. Ct. 1289 (2012).
10. Rapid Litigation Management Ltd. v. Cellzdirect, Inc., 827 F.3d 1042 (Fed. Cir. 2016).
11. In re Alonso, 545 F.3d 1015, 1019 (Fed. Cir. 2008).
12. Leahy-Smith America Invents Act, Public Law 112–29, § 4(c), 125 Stat. 296 (Sept. 16, 2011).
13. Leahy-Smith America Invents Act, Public Law, 112–29, §§ 3(g)(2), 16(a)(1), 20(i)(4), (j), 125 Stat. 288, 328, 335 (Sept. 16, 2011).