Kris Schroder, University of Cincinnati Law Review
In his 2015 State of the Union Address, President Barack Obama launched the Precision Medicine Initiative, which would “lead a new era of medicine — one that delivers the right treatment at the right time.” The mission statement of the Precision Medicine Initiative is to “To enable a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualized care.” Individualized care, also known as “Precision Medicine” or “Personalized Medicine”, is the way in which doctors can analyze a patient’s genes to identify whether certain drugs will be effective, non effective, or even dangerous to a patient. While President Obama had dreams of launching a new era of medicine revolving around this type of care, barriers have remained in place which have slowed the growth of this treatment. One of the main barriers until recently was the ability to obtain a patent on a personalized medical treatment. Because patents spur innovation and investment in industries, the ability to obtain a patent for a technology or invention is incredibly important.
The state of obtaining patents for personalized medicine is dependent on the interpretation of 35 U.S.C. § 101 by the Federal Courts. Recent decisions in Mayo Collaborative Servs. v. Prometheus Labs., Inc., Vanda Pharm. Inc. v. W.-Ward Pharm. Int’l Ltd., and Endo Pharm. Inc. v. Teva Pharm. USA, Inc., have clarified how personalized medicine may or may not be patented.
Part II of this article will discuss the legal background of 35 U.S.C. § 101, the Mayo decision, the Vanda decision, the Endo decision, and the language of the relevant patent claims involved in each decision. Part III of this article will discuss the similarities and differences between the ruling in the aforementioned cases and the language used in their respective patents. Part IV will conclude the paper and highlight language to be used in the claims of personalized medicine patent applications.
There are certain requirements that must be met in order for an inventor to obtain a patent on their invention. Generally, an invention must first be in a category of eligible subject matter and it must have utility in order to be patentable. The invention must also be novel and nonobvious. Finally, an application for a patent must be clear and descriptive enough such that any person skilled in the related field is enabled to make and use the invention. Section A will dive into case law involving 35 U.S.C. § 101 and discuss the science behind personalized medicine. Section B will analyze the Mayo decision and patent. Section C will analyze the Vanda decision and patent. Finally, Section D will analyze the Endo decision and patent.
A. 35 U.S.C. § 101
The blueprint for every individual human is in the DNA sequence of our genome. Our genome contains over 20,000 genes. Each one of these genes is processed by mechanisms in the body to ultimately form proteins, which have functions that allow for the various cells and organs in the body. Some of these proteins help break down drugs when they are ingested or injected into an individual. However, not every human’s genome is identical. We have small differences in our genes that may affect the functions of the corresponding protein. Thus, certain drugs may be more effective in one individual compared to another based on the DNA sequence of their genome. With the rise of large bioinformatic data sets that contain the genetic sequences of many individuals, scientists around the world are now able to determine which one of the small differences in our genes are related to the efficacy of specific drugs. This leads to the potential for the increased effectiveness of various treatments for a wide array of diseases. The question then arises of whether these new treatments that factor in the small differences in our genes are able to be patented.
35 U.S.C. § 101 states that an invention must be a “new and useful process, machine, manufacture, or composition of matter” in order for a patent to be obtained. The Supreme Court has stated multiple times that natural phenomena and laws of nature are not patentable subject matter. However, the application of a law of nature may be patentable subject matter. In Association for Molecular Pathology v. Myriad Genetics, Inc., the Supreme Court determined that “a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated.” The Supreme Court then discussed the level of the application of a law of nature necessary for patentability in Mayo.
B. Mayo Collaborative Servs. v. Prometheus Labs., Inc.
In Mayo, the issue was whether a patent, which claimed a process for determining whether the dosage of a thiopurine drug to treat autoimmune diseases was too high or too low, was invalid for containing ineligible subject matter under 35 U.S.C. § 101. The Court had to determine whether the claimed process transformed the natural laws sufficiently such that they were patent eligible applications of the natural laws. The Court reasoned that precedential case law warned against patents that were too broad and preempted the use of a natural law. The independent patent claim at issue reads (emphasis added):
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 8.times.10.sup.8 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 8.times.10.sup.8 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject. 
The District Court granted summary judgment in favor of the alleged infringer, Mayo Collaborative Services, because they reasoned that the patent was invalid for claiming a law of nature – the correlation between the metabolite levels and the efficacy of the thiopurine drug. The Federal Circuit reversed, stating that in addition to the laws of nature, the patent also had an administration step and a determination step that sufficiently transformed the law of nature and brought the patent within definite bounds such that 35 U.S.C. § 101 was satisfied. The Supreme Court reasoned that the additional steps were not sufficient to transform the claim. The Court reasoned the administration step of the claim only determined the relevant audience – doctors treating patients with an autoimmune disorder. Limiting the law of nature to a particular technological environment is not enough for patentability. The wherein clauses simply told the audience about the relevant natural laws – the correlation between the drug levels and the need to increase or decrease the dosage. Finally, the determination step simply tells the audience to determine the level of the metabolite through whatever process they want. Because there were many routine processes out there, this step was determined to be a well understood, routine, conventional activity that is not sufficient to transform an unpatentable law of nature into a patentable application. The Court ultimately determined that “simply appending conventional steps, specified at a high level of generality, to laws of nature, natural phenomena, and abstract ideas cannot make those laws, phenomena, and ideas patentable.” The determining step in the patent claim was too general and covered all processes that would make use of the natural relationship.
After a subsequent Supreme Court case dealing with 35 U.S.C. § 101, Alice Corp. Pty. Ltd. v. CLS Bank Int’l, the United States Patent and Trademark Office (USPTO) released new guidelines for determining subject matter eligibility. The Alice/Mayo Test was used to determine whether an invention was patentable. The first step of the test asks whether the claim is directed to a law of nature, natural phenomena, or abstract idea. If yes, the second prong asks whether the claim recites additional elements that amount to significantly more than the law of nature, natural phenomena or abstract idea. Under USPTO guidelines, additional elements in this step must not be well understood, routine, or conventional activities. However, a recent ruling in Vanda has made an important change to this test that has a drastic effect on personalized medicine.
C. Vanda Pharm. Inc. v. W.-Ward Pharm. Int’l Ltd.
In Vanda, the patent at issue (‘610 patent) revolved around a method of treating schizophrenia with a specific drug and a range of doses based on the patient’s genotype (small difference in their gene as described above). The claim in the ‘610 patent read as (emphasis added):
- A method for treating a patient with iloperidone, wherein the patient is suffering from schizophrenia, the method comprising the steps of:
determining whether the patient is a CYP2D6 poor metabolizer by:
obtaining or having obtained a biological sample from the patient; and
performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype; and
if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount of 12 mg/day or less, and
if the patient does not have a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24 mg/day,wherein a risk of QTc prolongation for a patient having a CYP2D6 poor metabolizer genotype is lower following the internal administration of 12 mg/day or less than it would be if the iloperidone were administered in an amount of greater than 12 mg/day, up to 24 mg/day.
The District Court reasoned that although the claims were directed to laws of nature (the relationship between iloperidone, CYP2D6 metabolism, and QTc prolongation), the claims added the CYP2D6 genotyping test to determine the appropriate dosage of the drug. The District Court did not find the test as routine or conventional, therefore the claims were not invalid under 35 U.S.C. § 101. On appeal, the Federal Circuit agreed with the District Court and reasoned that the claims in the ‘610 patent were not “directed to” a natural law. The Court distinguished the case from Mayo by reasoning that these claims were directed to a novel method of treating a claim with a specific drug, not a diagnostic method. The claims were not directed to the relationship of iloperidone, CYP2D6 metabolism and QTc prolongation, but to the application of that relationship. Because the claims in Mayo only determined whether an individual would be better off with an increased or decreased dosage, it tied up a Doctor’s subsequent treatment decision and threatened to inhibit “the development of more refined treatment decisions.” Here, the claims do not tie up the Doctor’s subsequent decision because they are directed to “a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome.”
In response to the Vanda decision, the USPTO has revised its guidelines for reviewing subject matter eligibility. Instead of asking whether “the claim is directed to a law of nature…”, the first step has been split into two parts. The first part asks whether the claim recites an abstract idea, law of nature, or natural phenomena. If yes, the second part asks whether the claim recites additional elements that integrate the law of nature into a practical application. This integration can be well understood, routine and conventional. If the answer to this second part is no, then the test moves on to the second step of the Alice/Mayo test and asks whether the claim recites additional elements that amount to significantly more than the law of nature, natural phenomena or abstract idea. These elements must still be well understood, routine, or conventional activities.
Vanda was a 2-1 ruling, with the dissent disagreeing with the notion that the Vanda patent was distinguished from the patent in Mayo. However, the Federal Circuit has already followed the Vanda holding in another case – Endo.
D. Endo Pharm. Inc. v. Teva Pharm. USA, Inc.
In Endo, the patent at issue claimed a method for treating pain in patients that had impaired kidney function with the use of the drug oxymorphone. The natural laws in the patent were the correlation between the blood concentration of the drug over time and the functioning of the kidney as measured by the concentration of creatine excreted in the patient’s urine. The primary independent claim therefore read as (emphasis added):
- A method of treating pain in a renally impaired patient, comprising the steps of:
a. providing a solid oral controlled release dosage form, comprising:
i. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and
ii. a controlled release matrix;
b. measuring a creatinine clearance rate of the patient and determining it to be
(a) less than about 30 ml/min,
(b) about 30 mL/min to about 50 mL/min,
(c) about 51 mL/min to about 80 mL/min, or
(d) above about 80 mL/min; and
c. orally administering to said patient,in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief;
wherein after said administrationto said patient, the average AUC of oxymorphone over a 12-hour period is less than about 21 nghr/mL.
The District Court reasoned that the “providing” step was similar and indistinguishable from the “administering step” in the Mayo patent. The District Court also reasoned that the “determining” step “just directs one to use a well-known method to measure creatinine levels to obtain the necessary information to apply a law of nature.” Based on this reasoning, the District Court did not find that the Endo patent was directed to eligible subject matter.
On appeal, the Federal Circuit disagreed and reversed, holding the patent valid. The court compared the claims in the Endo patent to the claims in the Vanda patent and found that “The claims at issue here are legally indistinguishable from the representative claim in Vanda. Both claims recite a method for treating a patient.” The court pointed out that while the Mayo patent was not directed to the application of a drug to treat a particular disease, the Endo patent was directed a specific application of a relationship with specific steps on whether to adjust or lower the dosage of a drug for patients.
When comparing the three cases, a clear pattern emerges in the claim language that can be used as a road map for those in patent prosecution. In Mayo, the primary independent claim can be summed up as obtaining a sample via drug administration, then detecting the status of the patient based on the level of that drug in the bloodstream. However, both Vanda and Endo added something more. In Vanda, a sample is obtained, the status is detected through genotyping, and there is a treatment based on this detection. Similarly in Endo, a sample is obtained, the status of the patient is detected based on the rate of creatine clearance, and there is a treatment of different drug dosages based on this detection.
The treatment step that is dependent on the result of the detection is the distinguishing factor between the claim in Mayo and the claims in Vanda and Endo. The treatment step seems to satisfy the new USPTO Subject Matter Eligibility Guidelines by integrating the law of nature into a practical application.
Additionally, Mayo was directed towards immune-mediated gastrointestinal disorders generally, with a specific level of a drug as a key factor. Vanda was directed towards schizophrenia patients with a specific genotype. Endo was directed towards patients with kidney failure that processed creatine in a specific way. The patent system in the United States works in a quid pro quo way, in which a limited monopoly is granted in exchange for a public disclosure of the invention. The USPTO ultimately has to determine the scope of the limited monopoly (patent) it is willing to give up to the public’s detriment. The balancing of the quid pro quo system and the scope of the patents is likely in play in this personalized medicine issue as well. Mayo is fairly broad, encompassing all immune-mediated gastrointestinal disorders and encompassing all potential treatments by language of its claims. Vanda and Endo are both much more limited to a specific disease and a specific treatment of that disease. The scope of the claims are therefore fairly narrow, and would be much more acceptable for the USPTO to grant in exchange for a patent.
Therefore, it seems that the most effective patent for a personalized medicine technique will have a treatment step and will be specific in both the disease or condition treated and the drug and drug dosages used to treat. This will allow the technique to overcome the USPTO’s Subject Matter Eligibility Guidelines and be narrow enough in scope that the USPTO would feel comfortable granting a patent or limited monopoly.
The Mayo, Vanda, and Endo decisions represent the dual nature of evolution in technology and in law. While law is slow to evolve and react, technology is prone to quick advances. This results in some situations where the law does not adequately keep pace with the advances in technology. While the judiciary has thus far put patchwork fixes in place to handle the developing industry of personalized medicine, there is further need from the legislative branch to make the law more clear for technologies such as software, artificial intelligence, and other biotechnological discoveries.
Based on the most recent decisions in Vanda and Endo, it seems that the addition of a treatment step to the claims and the narrowing of the patent’s scope by adding a specific disease and drug are both effective measures for getting the claims allowed.
State of the Union 2015: Full transcript, CNN (January 20, 2015), https://www.cnn.com/2015/01/20/politics/state-of-the-union-2015-transcript-full-text/index.html.
THE PRECISION MEDICINE INITIATIVE, THEWHITEHOUSE, https://obamawhitehouse.archives.gov/precision-medicine (last visited June 23, 2019).
Personalized Medicine, NATIONAL INSTITUTES OF HEALTH, https://www.nih.gov/about-nih/what-we-do/nih-turning-discovery-into-health/personalized-medicine (October 7, 2015).
See Mayo Collaborative Servs. v. Prometheus Labs., Inc.,566 U.S. 66 (2012).
Patents Spur Innovation, 3M News Center, https://news.3m.com/campaign/patents-spur-innovation (September 12, 2011).
35 U.S.C.S. § 101 (LexisNexis). 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.
Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66 (2012).
Vanda Pharm. Inc. v. W.-Ward Pharm. Int’l Ltd., 887 F.3d 1117 (Fed. Cir. 2018).
Endo Pharm. Inc. v. Teva Pharm. USA, Inc., Nos. 2017-1240, 2017-1455, 2017-1887, 2019 U.S. App. LEXIS 9189 (Fed. Cir. Mar. 28, 2019).
See 35 U.S.C.S. § 101 (LexisNexis); 35 U.S.C.S. § 102 (LexisNexis), 35 U.S.C.S. § 103 (LexisNexis); 35 U.S.C.S. § 112 (LexisNexis).
35 U.S.C.S. § 101 (LexisNexis).
35 U.S.C.S. § 102 (LexisNexis).
35 U.S.C.S. § 103 (LexisNexis).
35 U.S.C.S. § 112 (LexisNexis).
Tanaka, E., Clinically important pharmacokinetic drug–drug interactions: role of cytochrome P450 enzymes, Journal of Clinical Pharmacy and Therapeutics, 23: 403-416 (1998), https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2710.1998.00086.x.
What are single nucleotide polymorphisms (SNPs)?, U.S. National Library of References, https://ghr.nlm.nih.gov/primer/genomicresearch/snp (June 11, 2019).
35 U.S.C.S. § 101 (LexisNexis).
See Gottschalk v. Benson, 409 U.S. 63, 67 (1972) (Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.); Diamond v. Diehr, 450 U.S. 175, 185 (1981) (This Court has undoubtedly recognized limits to § 101 and every discovery is not embraced within the statutory terms. Excluded from such patent protection are laws of nature, natural phenomena, and abstract ideas.).
Diamond v. Diehr, 450 U.S. 175, 187 (1981).
Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580 (2013). However, non-naturally occurring DNA in the form of cDNA is patentable.
566 U.S. 66 (2012).
Id. at 72.
U.S. Patent No. 6,355,623 (filed April 8, 1999).
Mayo at 76.
Id. at 77.
Id. (citing Bilski v. Kappos, 177 L. Ed. 2d 792, 801 (quotingDiehr, 67 L. Ed. 2d 155)).
Id. at 79.
Id. at 82.
Id. at 87.
Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 573 U.S. 208 (2014).
MPEP 2106 (9th ed. Rev. 08.2017, January 2018).
887 F.3d 1117 (Fed. Cir. 2018).
Id. at 1121.
U.S. Pat. No. 8,586,610 (Filed September 30, 2005).
Vanda at 1123.
Id. at 1134.
Id. at 1135.
Id. at 1136.
2019 Revised Patent Subject Matter Eligibility Guidance, 84 Fed. Reg. 4, 50.
Id. at 53.
Id. at 1143.
U.S. Pat. No. 8,808,737 (filed March 3, 2010).
Endo at ¶6-¶7.
Id. at ¶7.
Id. at ¶12.
Id. at ¶14-¶15.
Patent claims can be divided into three parts: the preamble, the transition, and the body. The transition normally consists of the phrases consisting, consisting essentially of, and comprising. “Comprising” is open ended and does not exclude additional limitations to a claim, the only limitations needed for infringement are the limitations listed in the claim. “Consisting” excludes additional limitations that are not listed in the claim. “Consisting essentially of” covers the middle ground and allows only additional limitations that do not materially affect the characteristics of the claimed invention. In Mayo, comprising acts to encompass any invention that has the same administration and determination steps listed – including a multitude of potential treatments.