New Gene Patent Rules

New Patent Rules for Genetic Material (Adrian Neal/Stockbyte/Getty Images)The unanimous US Supreme Court ruling in Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. __ (2013) (Myriad) held that isolated, naturally occurring genes and gene fragments—a class of discoveries that has been a driver of the biotechnology industry for the last few decades—are not patent-eligible. The plaintiffs and all those who challenged the patents hailed the decision as a victory for medical research, doctors, and patients. The biotechnology industry also declared it a win because the Supreme Court limited its holding, stating only that genes and the information they encode are not patent-eligible simply because they have been isolated from the surrounding genetic material.

Biotechnology executives should closely familiarize themselves with the decision, which overturned decades of patent precedent, and its likely effects on the biotechnology industry and medical research.

BRCA1/2, Myriad Genetics, and Plaintiffs Myriad Genetics sells a genetic test that confirms the presence of a BRCA1 or BRCA2 gene mutation under the trademark BRCAAnalysis. Mutations in the BRCA1 or BRCA2 genes (collectively referred to as BRCA1/2 mutations) are responsible for the majority of hereditary breast and ovarian cancers. People with mutations in either the BRCA1 or BRCA2 genes have risks of up to 87% for developing breast cancer and up to 44% for developing ovarian cancers by age 70 (1). Individuals with the mutation who have been previously diagnosed with cancer also have a significantly increased risk of developing a second primary cancer.

Myriad had exclusive rights to provide the test in the US by virtue of at least seven patents (2), assigned or exclusively licensed from the University of Utah (3). The Myriad patents cover the genes as isolated from the human body, synthetic, or man-made genes, fragments of the genes, and use of the genes to perform screens and diagnostic tests. The company did not enforce its patents against academic researchers (3). Myriad did, however, enforce its patents against the unauthorized commercial use of its technology. Myriad, for example, sent cease and desist letters to commercial laboratories that offered the diagnostic tests (3) and enforced its patent rights through litigation (3).

In 2009, a group of patients, healthcare providers, and researchers, represented by the American Civil Liberties Union (ACLU) and the Public Patent Foundation, filed suit in federal court challenging Myriad's patents covering the BRCA1/2 technology. The ACLU argued that these patents and related technology gave Myriad an improper monopoly over the technology, which stifled research that could lead to cures and limited women's options to obtain second opinions and control their medical care (4).

Myriad argued that isolated DNA is not the same as DNA as it exists in the body (5). Myriad also noted that basic research had not been impeded by its patents and that the US Patent and Trademark Office (USPTO), after public discourse and review, has been issuing patents on isolated DNA for almost 30 years. This patented technology has fueled significant advancements in medicine, agricultural, and industrial products. Myriad also pointed out that its technology, obtained after great effort and investment, has improved individualized patient care (5).

US Patent Law and Myriad's Patents

Patents on isolated genes and gene fragments similar to the Myriad patents have been granted by the USPTO since the 1980s. The USPTO will grant a patent on discoveries or inventions if it satisfies three criteria for patentability: novelty (codified in 35 U.S.C. § 102), non-obviousness (codified in 35 U.S.C. § 103), and utility (codified in codified in 35 U.S.C. § 101). The novelty requirement ensures that the discovery is "new"—that the discovery is not a copy of an existing or prior discovery or invention. The non-obviousness requirement ensures that the discovery or invention is a significant advancement over prior known discoveries. The utility requirement ensures that the invention is useful and is of a class for which the USPTO is authorized to grant patents.

The ACLU challenged Myriad's patent claims on the ground that the subject matter of the claims (isolated genes, synthetic "man-made" genes, gene fragments, and methods for using them) should not be patented because the patent claims do not qualify for patentability under Section 101 of the Patent Act. This argument was highly unusual. Most patents are challenged on other grounds such as that patent claims are not novel (failing to satisfy Section 102 of the Patent Act) or that they do not embody a significant advancement over prior knowledge (failing to satisfy Section 103 of the Patent Act). Section 101 of the Patent Act (utility) provides that "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."

The courts have determined that certain subject matter is outside the broad scope of 35 U.S.C. § 101. Excluded subject matter includes patents on abstract ideas, laws of nature, and physical phenomena (6). While the courts had never ruled on the issue of whether human genes are excluded from patentable subject matter, the Supreme Court had decided in the seminal case of Diamond v. Chakrabarty, 447 U.S. 303 (1980) (Chakrabarty) that genetically modified bacteria were patent-eligible. The Supreme Court reasoned that the bacteria were patentable because Chakrabarty had produced "a new bacterium with markedly different characteristics from any found in nature" by introducing multiple oil-degrading plasmids into a bacterium, which itself has no capacity for degrading oil (6). The USPTO relied on this key Supreme Court precedent when it began issuing patents to isolated genes, fragments, and their uses.

The Myriad patent claims challenged by the ACLU cover the BRCA1/2 genes and certain alterations or mutations in these genes and their uses. Claims 1, 2, 5, and 6 of US Patent No 5,747,282 (the '282 Patent) are representative of the claims ultimately reviewed by the Supreme Court:

• Claim 1—An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2

• Claim 2—The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1

• Claim 5—An isolated DNA having at least 15 nucleotides of the DNA of claim 1

• Claim 6—An isolated DNA having at least 15 nucleotides of the DNA of claim 2.

Claim 1 of the '282 Patent covers the isolated human BRCA1 gene or "the DNA code that tells a cell to produce the string of BRCA1 amino acids listed in SEQ ID NO: 2" (7). Claim 2 of the patent covers an isolated synthetic form of the gene, that is manmade and does not exist in nature. This claim refers to SEQ ID NO: 1, which list only the cDNA exons in the BRCA1 gene, rather than a full DNA sequence containing both introns and exons. Claims 5 and 6 cover fragments of the genes of at least 15 nucleotides of claims 1 and 2, respectively.

On the Road to the Supreme Court

The ACLU filed suit in the US District Court for the Southern District of New York (SDNY) in May 2009 asking the court to invalidate Myriad's patents for failing to satisfy 35 U.S.C. § 101. The ACLU also challenged the diagnostic method claims but these were not appealed to the Supreme Court (8). The ACLU also argued that the USPTO's policy of granting patents on isolated human genes violated the First Amendment of the US Constitution.

Myriad sought to dismiss the suit, arguing that the patent claims were valid because the difference in the structural and functional properties of isolated DNA rendered its claims patent-eligible. Additionally, the USPTO had been granting similar patents on this technology for decades, and the biotechnology industry had relied on patents to support research and investment.

The ACLU prevailed (9). Judge Sweet of the SDNY held that Myriad's challenged patent claims were invalid. Judge Sweet opined that DNA represents the physical embodiment of biological information and that Myriad's focus on the chemical nature of DNA failed to acknowledge the unique characteristics of DNA that differentiate it from other chemical compounds. Judge Sweet concluded that the preservation of this defining characteristic of DNA in its native and isolated forms mandates the conclusion that the challenged composition of matter claims are directed to unpatentable products of nature (9).

Myriad appealed to the US Court of Appeals for the Federal Circuit, where the judges twice reversed Judge Sweet's ruling. The first appeal was returned to the district court after the Supreme Court granted ACLU's petition for certiorari, vacated the Federal Circuit's prior decision, and remanded the case to the Federal Circuit for further consideration in light of its decision in Mayo Collaborative Services v. Prometheus, Inc., 566 U.S. __, 132 S.Ct. 1289 (2012) (10).

A three-judge panel, led by Judge Lourie, held that all claims were valid but the opinions of the other judges on the panel varied with the claims. Judge Lourie opined that all appealed claims were patentable and Judge Moore agreed, but on different grounds. Judge Lourie reasoned that: "[t]he isolated DNA molecules before us are not found in nature. They are obtained in the laboratory and man-made, the product of human ingenuity. While they are prepared from products of nature, so is every other composition of matter. All new chemical or biological molecules, whether made by synthesis or decompositions, are made from natural materials" (11). Judge Lourie also cautioned that Congress, not the courts have the appropriate mandate to categorically exclude subject matter such as isolated genes from patenting. Congress, he noted, was aware of the controversial issue when it recently enacted the comprehensive patent reform act, and it is ultimately for Congress to act if it wishes to overturn case law and the long practice of the USPTO to determine that isolated DNA must be treated differently from other compositions of matter.

Judge Bryson opined that only the synthetic man-made "cDNA genes" were patent-eligible and agreed with Judge Sweet that claims to isolated naturally occurring genes and fragments are invalid. The ACLU appealed to the Supreme Court.

The Supreme Court Review

Upon accepting the case for review, the Supreme Court framed the issue as "Are human genes patentable?" The Supreme Court replied: it depends.

Justice Thomas, who delivered the unanimous opinion on June 13, 2013, held that claims to isolated, naturally occurring genes (in this case, the isolated BRCA1/2 genes, represented by claim 1 of the '282 Patent) are excluded from patentability for falling within the product of nature exception to patent-eligibility. The Supreme Court acknowledged that, although Myriad found the location of the genes, that discovery by itself, does not render the genes new compositions that are patent-eligible.

The Court explained that with respect to isolated genes: "Myriad did not create anything. To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention. Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the Section 101 inquiry" (7).

With respect to gene fragments (represented by claims 5 and 6 of the '282 Patent), the Court did not distinguish between whether the fragment was isolated from a natural source (claim 5) or synthetically made (claim 6) but focused on the chemical sequence of the gene itself rather than how it was made. Therefore, because the gene fragment of claim 6 could also describe a gene fragment isolated from a natural source, the claims were invalid.

In contrast to patenting isolated, naturally occurring genes and fragments, the Supreme Court confirmed that synthetic or altered genes remain patent-eligible (represented by claim 2 of the '282 Patent) stating that:

"[t]he technician creates something new when cDNA is made. cDNA retains the naturally occurring exons of DNA but it is distinct from the DNA from which it was derived. As a result, cDNA is not a 'product of nature' and is patent eligible under § 101, except insofar as very short series of DNA may have no intervening introns removed when creating cDNA. In that situation, a short strand of cDNA may be indistinguishable from natural DNA" (7).

The Court also emphasized that: "this case does not involve patents on new applications of knowledge about the BRCA1 and BRCA2 genes. ... Nor do we consider the patentability of DNA in which the order of the naturally occurring nucleotides has been altered. Scientific alteration of the genetic code presents a different inquiry, and we express no opinion on the application of § 101 to such endeavors. We merely hold that genes and the information they encode are not patent eligible under § 101 simply because they have been isolated from the surrounding genetic material" (7).

The Myriad Impact

The immediate impact of the Myriad decision is, of course, the loss of any patent claim that recites or describes an isolated gene or gene fragment. The ACLU, patient groups, and some researchers have hailed the decision as removing impediments to diagnostic testing and research on genes like the BRCA1/2 gene that spawned the original lawsuit. Freedom to practice this technology is predicated on the absence of any other applicable patent, such as a method of diagnosing or treating a condition using an isolated gene or gene fragment, which could expose commercial laboratories to infringement liability. Academic and medical researchers who use the isolated gene or fragment to further characterize and understand disease and/or gene function, on the other hand, are less likely to infringe diagnostic or treatment patents.

Many in the biotechnology industry were also pleased by the limited scope of the Myriad decision as it pertained to gene patents. The decision confirmed that synthetic genes and modified naturally occurring isolated genes remain patent-eligible. Thus, patents related to the recombinant production of human proteins and chemically modified gene fragments that can be used diagnostically remain patent-eligible.

The Myriad decision also expressly validated that the application of information gleaned from the isolation of the gene or a new method to isolate the gene is patent-eligible. Information obtained from analysis of patient samples and new treatments predicated upon that information, for example, such as the use of diagnostics and targeted therapies that are the core to personalized medicine, remain patent-eligible. Many believe, in fact, that the analysis of large data sets that marry information collected from diagnostic procedures and information technology is the coming phase of innovation in this area.

Interestingly, while the Supreme Court framed the issue before it in terms of whether human genes are patentable, the decision did not expressly limit its holding to human genes. The reasoning that isolation of a material from its native environment does not impart patent-eligibility to an invention, no matter how clever, could be extended to any isolated naturally occurring product. Thus, the impact of Myriad on other life-science patents, such as isolated proteins, antibiotics, viruses used as vaccines, and antisense technologies, is at this date still in question.

On the same day the Myriad decision was issued by the Supreme Court, the USPTO issued instructions to its patent examiners that any claim to an isolated gene or gene fragment that describes the gene as it exists in nature without modification should be rejected for failing to meet 35 U.S.C. § 101 (12). The USPTO also noted that in due course it will release additional guidance to US patent examiners on the further application of the Myriad decision.

While the USPTO's interpretation will be instructive to patent applicants on some level, the Myriad decision has shown that even decades of USPTO examination practice is no guarantee that the Supreme Court will not have a different opinion on what is and is not patent-eligible.

Thus, those considering or having patents in naturally occurring isolated products should review the patent claims and align them to Myriad's holding and teachings.

Antoinette Konski is a partner at Foley & Lardner, akonski@foley.com

REFERENCES

1. Myriad Gentics product information, www.myriad.com/products/bracanalysis/, accessed on June 23, 2013.

2. The seven patents referenced in the lawsuit are U.S. Patent Nos. 5,747,282; 5,837,492; 5,693,473; 5,709,999; 5,710,001; 5,753,441; and 6,033,857.

3. M. Yoon, J.Marshall Rev. Intell. Prop. L., 9; 953, 958 (2010).

4. Plaintiffs' Compliant filed in the US District Court, Southern District of New York, www.aclu.org, accessed on July 1, 2013.

5. Defendants' Memorandum in Reply to Plaintiffs' Opposition to Myriad Defendants' Motion for Summary Judgment, www.pubpat.org, accessed on July 1, 2013.

6. Bilski v. Kappos, 130 S. Ct. 3218, 3225 (2010) (citing Diamond v. Chakrabarty, 447 U.S. 303, 309 (1980)).

7. Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. __, __ (2013) (Slip Opinion at page 5).

8. C. Brinckerhoff, "A Look at the Myriad Gene Patent Claims and the USPTO Memo to Examiners on Myriad", PharmaPatents blog, June 17, 2013, www.pharmapatentsblog.com, accessed on July 1, 2013.

9. Association for Molecular Pathology v. The U.S. Patent and Trademark Office, 702 F. Supp.2d 181 (SDNY 2010).

10. Ass'n for Molecular Pathology v. Myriad Genetics, Inc., 132 S.Ct. 1794 (2012).

11. Association for Molecular Pathology v. Myriad Genetics, Inc. 689 F.3d 1303, 1325 (Fed. Cir. 2012), aff'd in part and rev'd in part, 133 S. Ct. 2107 (2013).

12. USPTO memorandum, www.uspto.gov/patents/law/exam/myriad_20130613.pdf, accessed on July 1, 2013.