By Irah H. Donner, author of Bloomberg BNA's Patent Prosecution: Law, Practice, and Procedure, Eighth Edition and Constructing and Deconstructing Patents

In Association for Molecular Pathology v. Myriad Genetics (formerly v. U.S. Patent & Trademark Office), the Court held that isolated deoxyribonucleic acid (DNA) is an unpatentable product of nature, while cDNA is a non-naturally occurring genetic sequence, and is patent eligible. Isolated DNA (or isolated genomic DNA) is DNA taken from a part of the entirety of an organism's hereditary information or chromosomes. Complementary DNA (cDNA) is DNA that is artificially synthesized from messenger RNA, which is genetic material transcribed from genomic DNA that becomes proteins.

Myriad Genetics, Inc. and the Directors of the University of Utah Research Foundation (collectively, Myriad) originally appealed from the decision of the U.S. District Court for the Southern District of New York granting summary judgment that all of the challenged claims were drawn to nonpatentable subject matter under 35 U.S.C. §101.^[1]

The composition claims covered two "isolated" human genes, BRCA1 and BRCA2, and certain alterations, or mutations, in these genes associated with a predisposition to breast and ovarian cancers. Representative composition claims included claims 1, 2, and 5 of the '282 patent:

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

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

5. An isolated DNA having at least 15 nucleotides of the DNA of
claim 1.^[2]

SEQ ID NO:2 depicted the amino acid sequence of the BRCA1 protein, and SEQ ID NO: 1 depicted the nucleotide sequence of the BRCA1 DNA coding region. All but one of the challenged method claims covered methods of analyzing or comparing a patient's BRCA sequence with the normal, or wild-type, sequence to identify the presence of cancer-predisposing mutations.^[3]

Representative method claims included claim 1 of the '999 patent, which recited:

1. A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1.^[4]

Representative method claims also included claim 1 of the '001 patent, which recited:

1. A method for screening a tumor sample from a human subject for a somatic alteration in a BRCA1 gene in said tumor which comprises [] comparing a first sequence selected from the group consisting of a BRCA1 gene from said tumor sample, BRCA1 RNA from said tumor sample and BRCA1 cDNA made from mRNA from said tumor sample with a second sequence selected from the group consisting of BRCA1 gene from a nontumor sample of said subject, BRCA1 RNA from said nontumor sample and BRCA1 cDNA made from mRNA from said nontumor sample, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA from said tumor sample from the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA from said nontumor sample indicates a somatic alteration in the BRCA1 gene in said tumor sample.^[5]

The final method claim challenged by plaintiffs was directed to a method of screening potential cancer therapeutics. Specifically, claim 20 of the '282 patent read as follows:

20. A method for screening potential cancer therapeutics which comprises:

growing a transformed eukaryotic host cell containing an altered BRCA1 gene causing cancer in the presence of a compound suspected of being a cancer therapeutic, growing said transformed eukaryotic host cell in the absence of said compound,

determining the rate of growth of said host cell in the presence of said compound and the rate of growth of said host cell in the absence of said compound and comparing the growth rate of said host cells, wherein a slower rate of growth of said host cell in the presence of said compound is indicative of a cancer therapeutic.^[6]

The challenged claims thus related to isolated gene sequences and diagnostic methods of identifying mutations in those sequences.

The invention related to the human genome, which contains approximately 25,000 genes forming the basis of human inheritance. The majority of genes act by specifying polypeptide chains that form proteins. Proteins in turn make up living matter and catalyze all cellular processes.^[7]

Chemically, the human genome is composed of deoxyribonucleic acid (DNA). Each DNA molecule is made up of repeating units of four nucleotide bases-adenine (A), thymine (T), cytosine (C), and guanine (G)-which are covalently linked or bonded together via a sugarphosphate, or phosphodiester backbone. Covalent bonds are chemical bonds that share electrons between atoms in a molecule. DNA generally exists as two DNA strands intertwined as a double helix in which each base on a strand pairs, or hybridizes, with a complementary base on the other strand: A pairs with T, and C with G.^[8]

The linear order of nucleotide bases in a DNA molecule is referred to as its sequence. The sequence of a gene is denoted by a linear sequence of As, Ts, Gs, and Cs. DNA sequencing or gene sequencing refers to the process by which the precise linear order of nucleotides in a DNA segment or gene is determined. A gene's nucleotide sequence, in turn, encodes for a linear sequence of amino acids that comprise the protein encoded by the gene, e.g., the BRCA1 gene encodes for the BRCA1 protein. Most genes have both exon and intron sequences. Exons are DNA segments that are necessary for the creation of a protein, i.e., that code for a protein. Introns are segments of DNA interspersed between the exons that, unlike exons, do not code for a protein.^[9]

The creation of a protein from a gene comprises two steps: transcription and translation. First, the gene sequence is transcribed into a different nucleic acid called ribonucleic acid (RNA). RNA has a chemically different sugar-phosphate backbone than DNA, and it utilizes the nucleotide base uracil (U) in place of thymine (T). For transcription, the DNA double helix is unwound and each nucleotide on the non-coding, or template DNA strand is used to make a complementary RNA molecule of the coding DNA strand, i.e., adenine on the template DNA strand results in uracil in the RNA molecule, thymine results in adenine, guanine in cytosine, and cytosine in guanine. The resulting pre-RNA, like the DNA from which it was generated, contains both exon and intron sequences. Next, the introns are physically excised from the pre-RNA molecule, in a process called splicing, to produce a messenger RNA (mRNA).^[10]

Following transcription, the resulting mRNA is translated into the encoded protein. Genes, and their corresponding mRNAs, encode proteins via three-nucleotide combinations called codons. Each codon corresponds to one of the twenty amino acids that make up all proteins or a stop signal that terminates protein translation. The relationship between the 64 possible codon sequences and their corresponding amino acids is known as the genetic code.^[11]

Changes or mutations in the sequence of a human gene can alter the structure as well as the function of the resulting protein. Small-scale changes include point mutations in which a change to a single nucleotide alters a single amino acid in the encoded protein. Larger variations include the deletion, rearrangement, or duplication of larger DNA segments, ranging from several hundreds to over a million nucleotides, and result in the elimination, misplacement, or duplication of an entire gene or genes. While some mutations have little or no effect on the body's processes, others result in disease or an increased risk of developing a particular disease. DNA sequencing is used in clinical diagnostic testing to determine whether a gene contains mutations associated with a particular disease or risk of a particular disease.^[12]

Nearly every cell in the human body contains an individual's entire genome. DNA in the cell, called native or genomic DNA, is packaged into twenty-three pairs of chromosomes. Chromosomes are complex structures of a single DNA molecule wrapped around proteins called histones. Humans have twenty-two pairs of autosomal chromosomes, numbered one to twenty-two according to size from largest to smallest, and one pair of sex chromosomes, two X chromosomes in females and one X and one Y chromosome in males.^[13]

Genomic DNA can be extracted from its cellular environment using a number of well-established laboratory techniques. A particular segment of DNA, such as a gene, can then be excised or amplified from the DNA to obtain the isolated DNA segment of interest. DNA molecules can also be synthesized in the laboratory. One type of synthetic DNA molecule is complementary DNA (cDNA). cDNA is synthesized from mRNA using complementary base pairing in a manner analogous to RNA transcription. The process results in a double-stranded DNA molecule with a sequence corresponding to the sequence of an mRNA produced by the body. Because it is synthesized from mRNA, cDNA contains only the exon sequences, and thus none of the intron sequences, from a native gene sequence.^[14]

Mutations in the BRCA genes correlate with an increased risk of breast and ovarian cancer. The average woman in the United States has around a 12-13 percent risk of developing breast cancer in her lifetime. Women with BRCA mutations, in contrast, face a cumulative risk of 50-80 percent of developing breast cancer and a cumulative risk of ovarian cancer of 20-50 percent. Diagnostic genetic testing for the existence of BRCA mutations is therefore an important consideration in the provision of clinical care for breast or ovarian cancer. This testing provides a patient with information on her risk for hereditary breast and ovarian cancers, and thus aids in the difficult decision regarding whether to undertake preventive options, including prophylactic surgery. Diagnostic results can also be an important factor in structuring an appropriate course of cancer treatment, since certain forms of chemotherapy are more effective in treating cancers related to BRCA mutations.^[15]

The invention of the patents-in-suit identified the genetic basis of BRCA1- and BRCA2-related cancers using an analysis called positional cloning. Relying on a large set of DNA samples from  families with inherited breast and ovarian cancers, the invention correlated the occurrence of cancer in individual family members with the inheritance of certain marker DNA sequences. This allowed the physical location of the BRCA genes to be identified or mapped within the human genome in order to isolate the BRCA genes and determine their exact nucleotide sequences. This in turn allowed Myriad to provide BRCA diagnostic testing services to women.^[16]

Myriad filed the first patent application leading to the patents-in-suit in August 1994. This application covered isolated BRCA1 DNA and associated diagnostic methods. The resulting patent, U.S. Patent No. 5,693,473, issued on December 2, 1997. Myriad filed the first application covering isolated BRCA2 DNA and associated diagnostic methods in December 1995, and the resulting patent, U.S. Patent No. 5,837,492, issued on November 17, 1998.^[17]

Myriad initiated several patent infringement actions against entities providing clinical BRCA testing, filing suit against Oncormed, Inc. in 1997 and again in 1998,^[18] and against the University of Pennsylvania in 1998.^[19] Both lawsuits were later dismissed without prejudice after each defendant agreed to discontinue all allegedly infringing activity.^[20]

Some of the plaintiffs in the instant case were researchers and medical organization members who claimed that Myriad's vigorous enforcement of its patent rights against others stopped them from engaging in clinical BRCA genetic testing even though they had the personnel, expertise, and facilities as well as the desire to provide such testing. The plaintiffs moved for summary judgment on the merits of their challenge to Myriad's patent claims as not being eligible for patent protection. The district court held for the plaintiffs, concluding that the 15 challenged claims were drawn to nonpatentable subject matter and thus invalid under 35 U.S.C. §101. Regarding the composition claims, the district court held that isolated DNA molecules fell within the judicially created products-of-nature exception to Section 101 because such isolated DNAs were not markedly different from native DNAs. The district court relied on the fact that, unlike other biological molecules, DNAs are the physical embodiment of information, and that this information is not only preserved in the claimed isolated DNA molecules, but is also essential to their utility as molecular tools.^[21]

The district court also held the method claims patent ineligible, finding that they covered analyzing or comparing DNA sequences by any method and thus covered mental processes independent of any physical transformations. The district court held that the method claim to comparing the growth rate of cells claimed a basic scientific principle and that the transformative steps amounted only to preparatory data gathering.^[22]

Myriad appealed, and the Federal Circuit affirmed in part and reversed in part.

The Federal Circuit noted that the Supreme Court has consistently held that Section 101, although broad, is not unlimited: the three judicially created exceptions to Section 101's broad patent-eligibility principles include laws of nature, physical phenomena, and abstract ideas. These exceptions, in turn, preclude the patenting of phenomena of nature, mental processes, and products of nature.^[23]

On appeal, Myriad argued that the composition claims to isolated DNAs covered patent-eligible compositions of matter within the meaning of Section 101. According to Myriad, the district court came to a contrary conclusion and erred by (1) misreading Supreme Court precedent as excluding from patent eligibility all products of nature unless markedly different from naturally occurring ones; and (2) incorrectly focusing on the informational content similarities between isolated and native DNAs. According to Myriad, isolated DNA does not exist in nature, and isolated DNAs, unlike native DNAs, can be used as primers and probes for diagnosing cancer.^[24]

Plaintiffs responded that claims to isolated DNA molecules failed to satisfy Section 101 because such claims covered natural phenomena and products of nature. Plaintiffs asserted that to be patent eligible a composition of matter must also have a distinctive name, character, and use, making it markedly different from the natural product. Plaintiffs argued that because isolated DNAs retained the same nucleotide sequence as native DNAs, they did not have any markedly different characteristics. Furthermore, according to plaintiffs, the isolated DNA claims also preemptively excluded anyone from working with the BRCA genes.^[25]

The government as amicus curiae argued that DNA molecules engineered by man, including cDNAs, are patent-eligible compositions of matter because, with rare exceptions, they do not occur in nature, either in isolation or as contiguous sequences within a chromosome. In contrast, the government asserted, isolated and unmodified genomic DNAs are patent-ineligible products of nature because their nucleotide sequences exist because of evolution, not man.^[26]

Although the parties and the government appeared to agree that isolated DNAs are compositions of matter, they disagreed on whether and to what degree such molecules fell within the exception for products of nature. The Federal Circuit concluded "that the challenged claims to isolated DNAs, whether limited to cDNAs or not, are directed to patent-eligible subject matter under §101."^[27] According to the Federal Circuit:

The distinction, therefore, between a product of nature and a human-made invention for purposes of §101 turns on a change in the claimed composition's identity compared with what exists in nature. Specifically, the Supreme Court has drawn a line between compositions that, even if combined or altered in a manner not found in nature, have similar characteristics as in nature, and compositions that human intervention has given "markedly different," or "distinctive," characteristics. … [W]e conclude that the challenged claims are drawn to patentable subject matter because the claims cover molecules that are markedly different-have a distinctive chemical identity and nature-from molecules that exist in nature.^[28]

The Federal Circuit observed that it was undisputed that Myriad's claimed isolated DNAs existed as distinctive chemical molecules from DNAs in the human body, i.e., native DNA. According to the court:

Isolated DNA, in contrast, is a free-standing portion of a native DNA molecule, frequently a single gene. Isolated DNA has been cleaved (i.e., had covalent bonds in its backbone chemically severed) or synthesized to consist of just a fraction of a naturally occurring DNA molecule. … Accordingly, BRCA1 and BRCA2 in their isolated state are not the same molecules as DNA as it exists in the body; human intervention in cleaving or synthesizing a portion of a native chromosomal DNA imparts on that isolated DNA a distinctive chemical identity from that possessed by native DNA.^[29]

The Federal Circuit noted that isolated DNA was not purified DNA. Purification makes pure what was the same material, but was previously impure. Although isolated DNA must be removed from its native cellular and chromosomal environment, "it has also been manipulated chemically so as to produce a molecule that is markedly different from that which exists in the body. It has not been purified by being isolated."^[30]

The court explained that the claimed isolated DNA molecules do not exist as in nature within a physical mixture to be purified. Isolated DNA have to be chemically cleaved from their chemical combination with other genetic materials.

In other words, in nature, isolated DNAs are covalently bonded to such other materials. Thus, when cleaved, an isolated DNA molecule is not a purified form of a natural material, but a distinct chemical entity. In fact, some forms of isolated DNA require no purification at all, because DNAs can be chemically synthesized directly as isolated molecules.

*  *  *

But a covalent bond is the defining boundary between one molecule and another.  The covalent bonds in this case separate one chemical species from another.^[31]

Plaintiffs argued that because the claimed isolated DNAs retain the same nucleotide sequence as native DNAs, they do not have any markedly different characteristics. The Federal Circuit criticized this approach because it only looked at the one similarity with respect to the information content contained in isolated and native DNAs' nucleotide sequence. "We disagree," the court stated,

as it is the distinctive nature of DNA molecules as isolated compositions of matter that determines their patent eligibility rather than their physiological use or benefit. Uses of chemical substances may be relevant to the non-obviousness of these substances or to method claims embodying those uses, but the patent eligibility of an isolated DNA is not negated because it has similar informational properties to a different, more complex natural material that embodies it. The claimed isolated DNA molecules are distinct from their natural existence as portions of larger entities, and their informational content is irrelevant to that fact. We recognize that biologists may think of molecules in terms of their uses, but genes are in fact materials having a chemical nature and, as such, are best described in patents by their structures rather than their functions.^[32]

The Federal Circuit therefore rejected the district court's categorical exclusion of isolated DNA molecules. The Federal Circuit then addressed the suggestion that holding isolated DNAs patent eligible opens the door to claims covering isolated chemical elements, like lithium; minerals found in the earth, like diamonds; and even organs, like a kidney. The court observed that none of these examples presented the case of a claim to a composition having a distinctive chemical identity from that of the native element, molecule, or structure. "In contrast, a portion of a native DNA molecule-an isolated DNA-has a markedly different chemical nature from the native DNA. It is, therefore, patentable subject matter."^[33]

Finally, the Federal Circuit noted the Patent Office's longstanding position that isolated DNA molecules are patent eligible. Specifically, the Patent Office has issued patents directed to DNA molecules for almost 30 years, and Congress has not indicated that the PTO's position was inconsistent with Section 101. "If the law is to be changed, and DNA inventions excluded from the broad scope of §101 contrary to the settled expectation of the inventing community, the decision must come not from the courts, but from Congress."^[34]

Regarding Myriad's method claims, however, the Federal Circuit  concluded that all but one were directed to patent-ineligible, abstract mental processes, and and that they failed the machine-or-transformation test.^[35]

Myriad argued that its claims to methods of "comparing" or "analyzing" BRCA sequences satisfied the machine-or-transformation test because each required a transformation-extracting and sequencing DNA molecules from a human sample-before the sequences could be compared or analyzed. According to Myriad, the district court failed to recognize the transformative nature of the claims by misconstruing the claim term "sequence" as mere information, rather than a physical molecule; and by erroneously concluding that Myriad's proposed transformations were mere data-gathering steps.^[36]

Plaintiffs responded that these method claims were drawn to the abstract idea of comparing one sequence to a reference sequence and preempted the phenomenon of nature of correlation of genetic mutations with a predisposition to cancer.^[37]

The Federal Circuit concluded that Myriad's claims to "comparing" or "analyzing" two gene sequences were outside the scope of Section 101 because they claimed only abstract mental processes.  The claims recited, for example, a "method for screening a tumor sample," by "comparing" a first BRCA1 sequence from a tumor sample and a second BRCA1 sequence from a non-tumor sample, wherein a difference in sequence indicates an alteration in the tumor sample. These claims therefore recited "nothing more than the abstract mental steps necessary to compare two different nucleotide sequences."^[38]

Although the application of a formula or abstract idea in a process may be patent-eligible subject matter, Myriad's claims did not apply the step of comparing two nucleotide sequences in a process. "Rather, the step of comparing two DNA sequences is the entire process claimed."^[39] The Federal Circuit noted that the claims did not specify any action prior to the step of "comparing" or "analyzing" two sequences: "[N]either comparing nor analyzing means or implies 'extracting' or 'sequencing' DNA or otherwise 'processing' a human sample."^[40] Myriad argued that the specification showed that the claim term "sequence" referred not to information but to a physical DNA molecule, whose sequence would then have to be determined before it could be compared. The Federal Circuit disagreed, noting that the patent specifications made clear that "sequence" did not exclusively specify a DNA molecule, but referred more broadly to the linear sequence of nucleotide bases of a DNA molecule. Therefore, the comparison between the two sequences could be accomplished by mere inspection alone. Accordingly, Myriad's claimed methods of comparing or analyzing nucleotide sequences were directed to the abstract mental process of comparing two nucleotide sequences. The claims thus failed to claim a patent-eligible process under Section 101.^[41]

The only one of Myriad's method claims upheld by the Federal Circuit was that directed to a method for screening potential cancer therapeutics via changes in cell growth rates. Plaintiffs challenged this claim as directed to the abstract idea of comparing the growth rates of two cell populations. In addition, plaintiffs argued that this claim preempted the basic scientific principle that a slower growth rate in the presence of a potential therapeutic compound suggested that the compound was a cancer therapeutic. The Federal Circuit disagreed.^[42]

The Federal Circuit explained that the claim recited a method that comprised the steps of (1) "growing" host cells transformed with an altered BRCA1 gene in the presence or absence of a potential cancer therapeutic, (2) "determining" the growth rate of the host cells with or without the potential therapeutic, and (3) "comparing" the growth rate of the host cells. The claim thus included more than the abstract mental step of looking at two numbers and "comparing" two host cells' growth rates. The claim included the steps of "growing" transformed cells in the presence or absence of a potential cancer therapeutic, "an inherently transformative step involving the manipulation of the cells and their growth medium."^[43] The claim also included the step of "determining" the cells' growth rates, a step that also necessarily involves physical manipulation of the cells.^[44]

In addition, the Federal Circuit found the claim not so manifestly abstract as to claim only a scientific principle, and not a patent-eligible process. The claim did not cover all cells, all compounds, or all methods of determining the therapeutic effect of a compound. Instead, the claim was tied to specific host cells transformed with specific genes and grown in the presence or absence of a specific type of therapeutic. Moreover, the claim was tied to measuring a therapeutic effect on the cells solely by changes in the cells' growth rate. Accordingly, the Federal Circuit held that claim 20 of the '282 patent claimed patentable subject matter under Section 101.^[45]

Accordingly, the Federal Circuit reversed the district court's grant of summary judgment with regard to Myriad's composition claims to isolated DNAs, affirmed the district court's grant of summary judgment with regard to Myriad's method claims to comparing or analyzing gene sequences, and reversed the district court's grant of summary judgment with regard to Myriad's method claim to screening potential cancer therapeutics via changes in cell growth rates.^[46]

Judge Moore concurred with the majority that isolated DNA was patentable, but disagreed with the majority's methodology for determining when an isolated compound was sufficiently man-made to no longer be considered a natural phenomenon or product of nature. According to Judge Moore:

I join the majority opinion with respect to standing and the patentability of the method claims at issue. I believe, however, that claims directed to isolated DNA sequences present a different set of issues. I join the majority with respect to claims to isolated cDNA sequences, and concur in the judgment with respect to the remaining sequences. I write separately to explain my reasoning.^[47]

Judge Moore analyzed the isolated DNA claims to determine whether they had markedly different characteristics with the potential for significant utility. According to Judge Moore:

Even though an invention did not previously exist in nature in exactly the claimed state, however, does not automatically mean it is patentable subject matter. … 

*  *  *

Even if the invention was based on nature, and resulted in a living organism, it may fall within the scope of section 101. … 

*  *  *

Instead, each applies a flexible test to the specific question presented in order to determine whether the claimed invention falls within one of the judicial exceptions to patentability. … 

*  *  *

As illustrated by these examples, courts have long applied the principles … to different factual scenarios in order to determine whether an invention, as claimed, falls into the laws of nature exception. I see no reason to deviate from this longstanding flexible approach in this case. Keeping these principles in mind, I analyze the isolated DNA claims below, to determine whether they have markedly different characteristics with the potential for significant utility, e.g., an "enlargement of the range of … utility" as compared to nature.^[48]

Judge Bryson concurred in part, but dissented on the issue of whether an isolated human DNA molecule should not be patentable:

I concur with the portions of this court's judgment that are directed to standing, the patentability of the cDNA claims, and the patentability of the method claims. I respectfully dissent, however, from the court's holding that Myriad's BRCA gene claims and its claims to gene fragments are patent-eligible. In my view, those claims are not directed to patentable subject matter, and if sustained the court's decision will likely have broad consequences, such as preempting methods for whole-genome sequencing, even though Myriad's contribution to the field is not remotely consonant with such effects.^[49]

Judge Bryson summarized his views as follows:

In sum, the test employed by the Supreme Court … requires us to focus on two things: (1) the similarity in structure between what is claimed and what is found in nature and (2) the similarity in utility between what is claimed and what is found in nature. What is claimed in the BRCA genes is the genetic coding material, and that material is the same, structurally and functionally, in both the native gene and the isolated form of the gene.

The structural differences between the claimed "isolated" genes and the corresponding portion of the native genes are irrelevant to the claim limitations, to the functioning of the genes, and to their utility in their isolated form. The use to which the genetic material can be put, i.e., determining its sequence in a clinical setting, is not a new use; it is only a consequence of possession. In order to sequence an isolated gene, each gene must function in the same manner in the laboratory as it does in the human body. Indeed, that identity of function in the isolated gene is the key to its value. … The naturally occurring genetic material thus has not been altered in a way that would matter . … For that reason, the isolation of the naturally occurring genetic material does not make the claims to the isolated BRCA genes patent-eligible.^[50]

On appeal,^[51] the Supreme Court granted the petition for a writ of certiorari, vacated the judgment and remanded the case to the Federal Circuit for further consideration in light of Mayo Collaborative Services v. Prometheus Laboratories, Inc.^[52]

On remand, the Federal Circuit once again held that Myriad's composition claims directed to isolated  DNA molecules, whether limited to complementary DNAs (cDNAs) or not, were patent-eligible subject matter under 35 U.S.C. §101. The decision essentially follows the previous Federal Circuit opinion. According to the Federal Circuit: 

The principal claims of the patents before us on remand relate to isolated DNA molecules. Mayo does not control the question of patent-eligibility of such claims. They are claims to compositions of matter, expressly authorized as suitable patent-eligible subject matter in §101. As to those claims, the issue of patent-eligibility remains, as it was on the first appeal to this court, whether they claim patent-ineligible products of nature. We hold that they do not. The isolated DNA molecules before us are not found in nature. They are obtained in the laboratory and are 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 decomposition, are made from natural materials. . . . But, as such, they are different from natural materials, even if they are ultimately derived from them. The same is true of isolated DNA molecules.^[53]

In addition, the Federal Circuit affirmed the district court's decision that Myriad's method claims directed to comparing and analyzing DNA sequences were not patent eligible because similar claims were held to be unpatentable in Prometheus ^[54]:

We renew our conclusion that Myriad's claims to "comparing" or "analyzing" two gene sequences fall outside the scope of §101 because they claim only abstract mental processes. . . . The claims recite, for example, a "method for screening a tumor sample," by "comparing" a first BRCA1 sequence from a tumor sample and a second BRCA1 sequence from a non-tumor sample, wherein a difference in sequence indicates an alteration in the tumor sample.  '001 patent claim 1. This claim thus recites nothing more than the abstract mental steps necessary to compare two different nucleotide sequences: one looks at the first position in a first sequence; determines the nucleotide sequence at that first position; looks at the first position in a second sequence; determines the nucleotide sequence at that first position; determines if the nucleotide at the first position in the first sequence and the first position in the second sequence are the same or different, wherein the latter indicates an alteration; and repeats the process for the next position.

Limiting the comparison to just the BRCA genes or, as in the case of claim 1 of the '999 patent, to just the identification of particular alterations, fails to render the claimed process patent-eligible. . . .  Although the application of a formula or abstract idea in a process may describe patent-eligible subject matter, id. at 3230, Myriad's claims do not apply the step of comparing two nucleotide sequences in a process. Rather, the step of comparing two DNA sequences is the entire process that is claimed.^[55]

The Federal Circuit also reversed the district court's conclusion that Myriad's claimed method of screening potential cancer therapeutics was not patent-eligible subject matter, finding instead that the method involved the creation of transformed host cells, and therefore was patent eligible:

Lastly, we turn to claim 20 of the '282 patent, directed to a method for screening potential cancer therapeutics via changes in cell growth rates of transformed cells. The parties agree that those transformed cells arose from human effort; i.e., they are not natural products. . . .

Claim 20 recites a method that comprises the steps of (1) growing host cells transformed with an altered BRCA1 gene in the presence or absence of a potential cancer therapeutic, (2) determining the growth rate of the host cells with or without the potential therapeutic, and (3) comparing the growth rate of the host cells. Claim 20 thus recites a screening method premised on the use of "transformed" host cells. Those cells, like the patent-eligible cells in Chakrabarty, are not naturally occurring. Rather, they are derived by altering a cell to include a foreign gene, resulting in a man-made, transformed cell with enhanced function and utility. . . .

*    *    * 

Here, claim 20 . . . does not simply apply a law of nature. Of course, all activity, whether chemical, biological, or physical, relies on natural laws. But, more to the point here is that claim 20 applies certain steps to transformed cells that, as has been pointed out above, are a product of man, not of nature. . . . By definition, however, performing operations, even known types of steps, on, or to create, novel, i.e., transformed subject matter is the stuff of which most process or method invention consists. All chemical processes, for example, consist of hydrolyzing, hydrogenating, reacting, etc. In situations where the objects or results of such steps are novel and nonobvious, they should be patent-eligible. It is rare that a new reaction or method is invented; much process activity is to make new compounds or products using established processes. . . . The transformed, man-made nature of the underlying subject matter in claim 20 makes the claim patent-eligible. The fact that the claim also includes the steps of determining the cells' growth rates and comparing growth rates does not change the fact that the claim is based on a man-made, non-naturally occurring transformed cell-patent-eligible subject matter.^[56]

            Judge Moore concurred in part, and again agreed that an isolated DNA molecule is patent eligible, but provided different reasons:

The isolated DNA claims of the patents in suit fall into two categories. The first category of claims is directed to isolated sequences that are identical to naturally occurring gene sequences. These include claims encompassing both the isolated full length gene sequence (e.g. claim 1 of '282 patent), which are thousands of nucleotides, and claims to shorter isolated DNA strands, with as few as fifteen nucleotides, whose nucleotide sequence is found on the chromosome (e.g. claim 5 of '282 patent). The second category of claims is directed to isolated DNA sequences that are different from the naturally occurring gene sequences. These include claims to isolated cDNA molecules (e.g. claim 2 of the '282 patent), which differ from the natural gene sequence in that the introns are removed, and are the opposite (complementary) sequence of the naturally occurring RNA.

The cDNA claims present the easiest analysis. . . . cDNA sequences thus have a distinctive character and use, with markedly different chemical characteristics from either the naturally occurring RNA or any continuous DNA sequence found on the chromosome. The claimed isolated cDNA sequences are the creation of man, made using biological tools and the naturally occurring mRNA as a template. . . . I decline to extend the laws of nature exception to reach entirely manmade sequences of isolated cDNA, even if those sequences are inspired by a natural template. I therefore join the majority opinion with respect to the claims to cDNA sequences.

DNA sequences that have the same pattern of DNA bases as a natural gene, in whole or in part, present a more difficult issue. Unlike the isolated cDNA molecules, whose sequence is not present in nature, the isolated DNA claims include nucleotide sequences which are found in the human body, albeit as part of a much larger molecule, the chromosome. To the extent the majority rests its conclusion on the chemical differences between genomic and isolated DNA (breaking the covalent bonds), I cannot agree that this is sufficient to hold that the claims to human genes are directed to patentable subject matter. I agree that isolated genes are a different molecule and are therefore not squarely analogous to unpatentable minerals, created by nature without the assistance of man. The claimed isolated DNA molecules, which are truncations (with different ends) of the naturally occurring DNA found as part of the chromosome in nature, are not naturally produced without the intervention of man.^[57]

            Judge Bryson dissented in part, arguing that neither the isolation of the naturally occurring material nor the resulting breaking of covalent bonds made the claimed molecules patentable. Judge Bryson reasoned that isolated genes were not materially different from the native genes, and that extracting a gene was like snapping a leaf from a tree:

I concur with the portions of this court's judgment that are directed to . . . the patentability of the cDNA claims, and the patentability of the method claims. I respectfully dissent from the court's holding that Myriad's BRCA gene claims and its claims to gene fragments are patent-eligible. In my view, those claims are not directed to patentable subject matter, and the court's decision, if sustained, will likely have broad consequences, such as preempting methods for whole-genome sequencing, even though Myriad's contribution to the field is not remotely consonant with such effects.

In its simplest form, the question in this case is whether an individual can obtain patent rights to a human gene. From a common-sense point of view, most observers would answer, "Of course not. Patents are for inventions. A human gene is not an invention." The essence of Myriad's argument in this case is to say that it has not patented a human gene, but something quite different-an isolated human gene, which differs from a native gene because the process of extracting it results in changes in its molecular structure (although not in its genetic code). We are therefore required to decide whether the process of isolating genetic material from a human DNA molecule makes the isolated genetic material a patentable invention. The court concludes that it does; I conclude that it does not.^[58]

Judge Bryson further explained:

Myriad's claims to the isolated BRCA genes seem to me to fall clearly on the "unpatentable" side of the line the Court drew in Chakrabarty. Myriad is claiming the genes themselves, which appear in nature on the chromosomes of living human beings. The only material change made to those 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.^[59]

After the Federal Circuit decision on remand, the Supreme Court again granted certiorari and vacated the judgment on November 30, 2012.^[60]

On appeal to the Supreme Court, in a substantially unanimous opinion, the Court held that isolated deoxyribonucleic acid (DNA) is an unpatentable product of nature, while cDNA is a non-naturally occurring genetic sequence, and is patent eligible.^[61] Isolated DNA (or isolated genomic DNA) is DNA taken from a part of the entirety of an organism's hereditary information or chromosomes. Complementary DNA (cDNA) is DNA that is artificially synthesized from messenger RNA, which is genetic material transcribed from genomic DNA that becomes proteins.

The Court framed the issue and summarized their holding as follows:

This case involves claims from three of them and requires us to resolve whether a naturally occurring segment of deoxyribonucleic acid (DNA) is patent eligible under 35 U.S.C. §101 by virtue of its isolation from the rest of the human genome. We also address the patent eligibility of synthetically created DNA known as complementary DNA (cDNA), which contains the same protein-coding information found in a segment of natural DNA but omits portions within the DNA segment that do not code for proteins. For the reasons that follow, we hold that a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but that cDNA is patent eligible because it is not naturally occurring. We, therefore, affirm in part and reverse in part the decision of the United States Court of Appeals for the Federal Circuit.^[62]

The Court noted that it was undisputed that Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes. The location and order of the nucleotides existed in nature before Myriad found them. Nor did Myriad create or alter the genetic structure of DNA. The Court explained:

Instead, Myriad's principal contribution was uncovering the precise location and genetic sequence of the BRCA1 and BRCA2 genes within chromosomes 17 and 13. The question is whether this renders the genes patentable. . . . This case, by contrast, 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 §101 inquiry.^[63]

The Court further noted that Myriad's claims were not saved by the fact that isolating DNA from the human genome severed the chemical bonds and thereby created a nonnaturally occurring molecule. Myriad's claims were not expressed in terms of chemical composition, nor did they rely in any way on the chemical changes that result from the isolation of a particular section of DNA. Instead, the claims recited the genetic information encoded in the BRCA1 and BRCA2 genes. With regard to the cDNA, the Court did not have the same difficulty:

cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments. As already explained, creation of a cDNA sequence from mRNA results in an exons-only molecule that is not naturally occurring. Petitioners concede that cDNA differs from natural DNA in that "the non-coding regions have been removed." Brief for Petitioners 49. They nevertheless argue that cDNA is not patent eligible because "[t]he nucleotide sequence of cDNA is dictated by nature, not by the lab technician." Id., at 51. That may be so, but the lab technician unquestionably 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 to remove when creating cDNA. In that situation, a short strand of cDNA may be indistinguishable from natural DNA.^[64]

Finally, the Court explained that it was important to emphasize what was not implicated by this decision:

First, there are no method claims before this Court. Had Myriad created an innovative method of manipulating genes while searching for the BRCA1 and BRCA2 genes, it could possibly have sought a method patent. . . . Similarly, 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 about 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.^[65]