Myriad: Isolated DNA claims from “ball bats in trees,” and “kidneys” to “magic microscopes”

The July 29, 2011 Federal Circuit decision in Assoc. for Molecular Pathology et al. v. U.S.P.T.O. and Myriad Genetics, 2010-1406 (2011), has been eagerly awaited by the biotechnology community and by persons concerned with the ethical implications of DNA technology. Although a significant part of the decision involved standing to sue, I will only discuss the scientific portions of the decision that deals with the very real ethical question of whether human genes and/or gene sequences should be patented.

The decision in Myriad was written by Judge Alan Lourie with concurrences-in-part by Judges Moore and Bryson. Judge Bryson also filed a dissent-in-part. Judge Lourie, who has a Ph.D. in chemistry, is well suited to understand all the issues associated with genetic sequence cases and has written some key biotechnology decisions, such as the Regents of the University of California v. Eli Lilly, 119 F.3d 1559 (Fed. Cir. 1997) (Cloned human insulin product did not infringe patented rat insulin.) and In re Deuel , 51 F.3d 1552 (Fed. Cir. 1995) (Settled an issue of obviousness between genetic sequences). Judge Bryson was also part of the Lily decision.

To even begin to understand the issues at stake, beyond the news headlines, the DNA principles behind the technology need to be explained. Genes, the hereditary components of organisms, are made up of four nucleic acid molecules, called “bases”, (adenine (A), guanine (G), cytosine (C), and thymdine (T)) which form chains of polymers with varying sequences of the nucleic acids. One chain of the DNA polymer will bind a complementary chain in that only a C will bind with a G, and a T will only bind with an A. An example:

G-T-A-T-C-A-G-G-T  Strand
|   |   |   |   |   |   |   |   |   
C-A-T-A-G-T-C-C-A  Complementary Strand

The two strands occur most frequently as a double helix wrapped around other components in the nucleus to prevent tangling such as occurs with the old coiled telephone cords. The DNA can then be “translated” into proteins using cellular machinery that creates complimentary 3 base RNA molecules that then carry the message to the ribosomes in the cell that use each three-base message to link an amino acid onto a growing protein chain. Thus, all the proteins in our body, from hair to stomach enzymes are translated from the DNA template to form proteins using a “program” that is encoded in the DNA of the nucleus of each cell. Each different type of cell uses different parts of the DNA to make proteins unique to that cell. The unused DNA is shut off. The technology was well explained by Judge Lourie in the Lily case:

DNA functions as a blueprint of an organism's genetic information. It is the major component of genes, which are located on chromosomes in the cell nucleus. Only a small part of chromosomal DNA encodes functional proteins.

Messenger ribonucleic acid ("mRNA") is a similar molecule that is made or transcribed from DNA as part of the process of protein synthesis. Complementary DNA ("cDNA") is a complementary copy ("clone") of mRNA, made in the laboratory by reverse transcription of mRNA. Like mRNA, cDNA contains only the protein-encoding regions of DNA. Thus, once a cDNA's nucleotide sequence is known, the amino acid sequence of the protein for which it codes may be predicted using the genetic code relationship between codons and amino acids.

Judge Lourie provided some nice diagrams in both the Lily and the Myriad cases which further describe the process.

The basic argument in Myriad is whether DNA that is isolated from the chromosomes is statutory subject matter, or whether it is a product of nature. The stakes are high in the Myriad case, since the isolated DNA claimed by Myriad encodes mutated BRCA1 and BRCA2 proteins that can be used to detect breast cancer. Myriad has the only test offered in the United States because of its aggressive enforcement of its several patents. The numerous plaintiffs in the case speak to the core of the patent versus non-patent debate: whether patents actually “promote the progress of science and useful arts” as required in the U.S. Constitution. Myriad and other companies heavily reliant on biotechnology patents, would support the argument that strong patent enforcement allows companies which have invested millions or billions in assay or drug development for clinical use to recoup their investment and provide a return for investors. The plaintiffs would argue that such patents not only hinder the useful arts, but also endanger lives and/or drives up the cost of providing potentially life-saving testing and treatment. The anti-patent argument is beyond the scope of this writing, but lies at the core of the plaintiffs’ arguments.

Biotech and DNA patents in particular, evoke strong public and personal sentiment because the genetic material which is built from DNA building blocks encodes who and what we are. DNA is the material that makes up the “genes” that we pass on to future generations and determines that we are human, and not “rat” as aptly demonstrated by the Federal Circuit decision in Eli Lily. The lead biotech case was Diamond v. Chakrabarty, 447 U.S. 303 (1980), a lab-created bacterium that broke down crude was found to be patentable subject matter under 35 U.S.C. 101. The decision, written by U.S. Supreme Court Justice Burger held that “Congress plainly contemplated that the patent laws would be given wide scope” and concluded that Congress had intended patentable subject matter to “include anything under the sun that is made by man.”

Gregory Castanias of Jones Day argued for Myriad and in line with Chakrabarty, asserted that “isolated DNA” is patentable because it is “a non-naturally occurring composition of matter.” To support their contention that isolated DNA sequences are distinct from sequences found in the body, the Myriad attorney used an analogy that a baseball bat is patent-eligible even though the tree it comes from is a product of nature and ineligible under 35 U.S.C. 101. Judge Moore stated that in both the baseball bat and an isolated DNA, man decides what is to be kept and what is to be discarded, and thus both are patentable. This was the first of odd analogies in the colorful exchange between counsel and members of the three judge panel.

Chris Hansen of the ACLU argued that isolated DNA is no more patentable than a kidney removed from his body or that the use of a scalpel is no different than any chemicals used to remove the isolated DNA from a body. Judge Lourie disagreed and pointed out that breaking covalent bonds can result in a compound that has different characteristics and alters the chemical identity of the substance that has been isolated; that DNA wrapped up in a body cannot be tested. Judge Moore in her concurring decision pointed out that diagnostic testing is beyond what nature does with DNA in the body. Judge Bryson stated that merely breaking bonds does not render DNA patentable, whereas Judge Lourie held that the new bonds created a new chemical entity. Judge Lourie distinguished from the dissent by saying that “a covalent bond is the defining boundary between one molecule and another”. Quoting Linus Pauling, she said that the covalent bond is a means to determine an “independent molecular species.” Further, Judge Moore assailed the government’s proposed “chemical alteration” test, which would render a claim patentable under 35 U.S.C. 101 if a chemical alteration of a bioactive molecule” leads to different properties, such as better absorption in the body.” She pointed out that isolation of DNA sequences is not sorting wheat from chaff, but creating a new DNA molecule. She also cautioned that the tests proposed by the government are not limited to just DNA, but could also encompass far broader technologies.

The hypotheticals continued with Mr. Hansen stating that “gold in a mountain” cannot “be made into jewelry”, at which point Judge Louire countered that gold in a mountain is the same mineral as when extracted, but that an isolated DNA is a different chemical composition. Judge Lourie, being the consummate chemist, reminded Mr. Hansen that a 50 base pair DNA sequence is a totally different molecule than a 100 base pair sequence.

Not to be outdone by others in the hypothetical war, the U.S. Department of Justice Acting Solicitor General, Neal Katyal suggested a “magic microscope” test that could “see” into the gene; if the sequence was the same as one found in the body, then the sequence is not patentable. The DOJ position is particularly troubling since the position is in direct opposition to the Patent Office position for over 35 years of issuing such patents and as outlined in the 2001 Utility Examination Guidelines, a point not lost on Judge Moore, who repeatedly questioned Mr. Katyal about the discrepancy with the PTO long standing policy and questioned why the government is not speaking with one voice; later calling the magic microscope test, “kitschy.” Mr. Katyal responded that he thought the position of the Patent Office was “wrong.” It appears that even after the long “high level” discussions that Mr. Katyal indicated occurred between DOJ and the PTO about the allowability of isolated DNA claims, and given that the U.S.P.T.O. did not appeal, the conclusion can be readily drawn that the current administration views isolated DNA as not patentable, except for limited circumstances, such as cDNA.

Judge Moore, in her concurring decision, likewise agreed that a “gene” should not be patentable subject matter, since gene sequences are actually found in the body and she reasoned, genes have no utility for diagnostic assays. However, she continues, since “settled expectations” have arisen from both Congressional action and the “thousands of patents with claims to isolated DNA sequences” then patentability of such claims should not be overturned by the courts. However, science has not yet decided what a “gene” is. A general definition is that one gene encodes one peptide, or protein sequence. However, a publication in 2007 in Genome Research by Mark B. Gerstein of Yale University states that, “A gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products. Our definition sidesteps the complexities of regulation and transcription by removing the former altogether from the definition and arguing that final, functional gene products (rather than intermediate transcripts) should be used to group together entities associated with a single gene.” (emphasis added). The definition, also does not discuss non-genomic regulation of the DNA, such as binding of inhibitors or enhancement factors to the DNA chain that occurs during transcription in the body, but not in a test tube. The difficulty in determining the scope of a claim or any party’s position on patenting of “genes” is uncertain given this definition; an uncertainty which is well-known in the biotech examining corps.

However, in a statement that was woven throughout the Myriad discussions, Justice Burger wrote in Chakrabarty that, “[w]e have cautioned that courts "should not read into the patent laws limitations and conditions which the legislature has not expressed,” which seems to be consistent with Judge Moore’s position. Judge Bryson, while agreeing with the majority on the patentability of cDNA and method claims, dissented on the patentability of gene sequences. Judge Bryson limits Chakrabarty only to “a nonnaturally occurring manufacture or composition of matter,” (citations removed), which was fulfilled with an engineered bacterium not found in nature, but not for genes, since “[t]he only material change made to those [BRCA1 and BRCA2] genes from their natural state is the change that is necessarily incidental to the extraction of the genes from the environment in which they are found in nature.” Bryson then compared an isolated gene to a new mineral discovered in the earth or new plant found in the wild as only being useful once extracted.

Judge Moore bluntly stated that the “Executive’s” position recited by the Solicitor General would “destroy existing property rights.” Judge Moore additionally states that , “[w]e cannot, after decades of patents and judicial precedent, now call human DNA fruit from the poisonous tree, and punish those inquisitive enough to investigate, isolate, and patent it.” Well said, Judge Moore!

The ACLU requested reconsideration of the decision by the same panel based on assertions that Judge Lourie’s explanation of covalent bonds resulting in a distinct DNA molecule was an error because neither side had presented the argument. The ACLU Petition was denied on September 13, 2011 and Myriad’s Petition was denied on September 16. Since an en banc rehearing was not requested by the ACLU, it is waived. It appears that cert. by the Supreme Court is the only option for both parties at this point