Federal Circuit Finds Claims Directed to DNA Primers and Methods of Use Unpatentable

Myriad first argued that the primers are patentable because the sequences are synthetically replicated but, citing its own and the Supreme Court's prior Myriad decisions, the Federal Circuit noted that “isolated DNA is routinely synthetically created” and can originate from inside a cell or be synthesized by an extracellular process. Then, Myriad argued that the primers are not naturally occurring because single-stranded DNA does not occur in the human body. Unpersuaded, the Federal Circuit again cited to Myriad where the Supreme Court held ineligible claims directed to segments as short as 15 nucleotides, the same length as the primers claimed here. Thus, even short single strands of nucleotides are not patent eligible if that same sequence occurs in nature. Myriad further argued that the sequences, once isolated as primers, have a fundamentally different function than when they are part of a DNA strand. Myriad claimed that instead of functioning to store the biological information used in the development and functioning of living organisms, primers function as starting material for PCR. However, the court reasoned that primers utilize one of the primary functions of DNA's structure in nature ' that complimentary nucleotide sequences bind. Finding that a primer binds at the part of the DNA where its sequence is directly complimentary and thus identifies the relevant part of the DNA for the polymerase reaction to start, the court held that primers function just as in nature utilizing DNA's innate ability to bind to itself. Furthermore, the Federal Circuit noted that “a DNA structure with a function similar to that found in nature can only be patent eligible as a composition of matter if it has a unique structure, different from anything found in nature.”

Turning to the two asserted method claims.

Claim 7 recites:

A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequence of the BRCA1 gene,BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject[,] wherein a germline nucleic acid sequence is compared by hybridizing a BRCA1 gene probe which specifically hybridizes to a BRCA1 allele to genomic DNA isolated from said sample and detecting the presence of a hybridization product wherein a presence of said product indicates the presence of said allele in the subject.

Claim 8 recites:

A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequence of the BRCA1 gene,BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject[,] wherein a germline nucleic acid sequence is compared by amplifying all or part of a BRCA1 gene from said sample using a set of primers to produce amplified nucleic acids and sequencing the amplified nucleic acids.

Ambry argued that both claims are ineligible under the Supreme Court's Mayo v. Prometheus Labs., 132 S.Ct. 1289 (2012) decision where claims to measuring a metabolite and coordinating that measurement with a dosage regimen were held patent ineligible. There, the Court held that bare recitation of a natural law was not patentable. Ambry argued that Myriad's method claims simply compared wild-type sequences to the patient's BRCA1 sequence by applying conventional techniques. But the Federal Circuit did not reach the issue of whether Mayo was on point. Rather, the court held that the claims recite abstract ideas and, as such, are patent ineligible under Alice Corp. v. CLS Bank Int'l, 134 S.Ct. 2347 (2014).

In Alice, the Court reiterated its two-step test to determine patent eligibility for claims containing abstract ideas: first, determine whether the claims at issue are directed to a patent ineligible concept and, if they are, ask whether the remaining elements, either in isolation or in combination with the non-patent-ineligible elements, are sufficient to “transform the nature of the claim into a patent-eligible application.” Id. at 2355. In other words, “there must be a further inventive concept to take the claim into the realm of patent eligibility.” Id.

In Ambry Genetics, the Federal Circuit treated separately the first paragraphs of claims 7 and 8, which correspond to the first step of the Alice analysis, and the second paragraphs of the claims, which correspond to the second step of the analysis. The court found that the comparisons described in the first paragraphs are “patent-ineligible abstract ideas of comparing the BRCA sequences and determining existing alterations.” The court also noted that because of their breadth, each comparison step would also cover yet undiscovered alterations and that “it is antithetical to the patent law to allow these basic building blocks of scientific research to be monopolized.”

Having determined that the comparison steps are abstract ideas, the court moved on to determine whether there was a further inventive concept in the second paragraphs of the claims. Myriad argued that claims 7 and 8 are similar to claims Judge Bryson had suggested may be patentable in the court's prior Myriad case. There, Judge Bryson had suggested, and the Supreme Court agreed, that “as the first party with knowledge of the BRCA1 and BRCA2 sequences, Myriad was in an excellent position to claim applications of that knowledge.” Myriad, 133 S.Ct. at 2120. But the Federal Circuit in Ambry noted that the claims discussed in Myriad were limited to the particular mutations that the inventors discovered, while claims 7 and 8 at issue are “significantly broader and more abstract, as they claim all comparisons between the patient's BRCA genes and the wild type BRCA genes.” The court determined that the second paragraphs “do nothing more than spell out what practitioners already knew ' how to compare gene sequences using routine, ordinary techniques.”

Thus, all of the asserted claims were deemed directed to patent ineligible subject matter in violation of 35 U.S.C. '101 and the district court's denial of Myriad's motion for a preliminary injunction was affirmed. But this is not likely to be the end of the Myriad-BRCA genes story ' not when the Amended Complaint in this case alone alleges infringement of 66 claims across 15 patents.

Veronica Mullally Munoz is a partner with Pearl Cohen Zedek Latzer Baratz in New York. A member of the Board of Editors of this newsletter, she concentrates her practice on patent litigation in the life sciences. She can be reached at [email protected].

The Federal Circuit's decision in Univ. of Utah Research Found. v. Ambry Genetics Corp., 2014-1361, -1366 (Fed. Cir. Dec. 17, 2014) is the latest in the series of Myriad cases dealing with the patentability of genetic material. The U.S. Supreme Court in Association for Molecular Pathology v. Myriad Genetics, Inc., 133 S.Ct. 2107 (2013), held that claims drawn to isolated DNA were patent-ineligible subject matter. Ambry Genetics (Ambry) began offering BRCA1 and BRCA2 diagnostic testing kits following that decision. In July 2013, Myriad Genetics, the University of Utah Research Foundation, the Trustees of the University of Pennsylvania, HSC Research and Development LP, and Endorecherche, Inc. (collectively “Myriad” hereinafter) sought to, inter alia , enjoin Ambry and asserted infringement of six claims (from three patents) that had not previously been considered by the Federal Circuit or the Supreme Court. The Utah District Court denied Myriad's motion for a preliminary injunction and the Federal Circuit panel, Prost, Clevenger and Dyk affirmed. Circuit Judge Dyk delivered the opinion of the court.

The four composition of matter claims on appeal are directed to primers which are short, synthetic, single-stranded DNA molecules that bind complimentary target DNA and enable synthesis of DNA having all or part of the sequence of a BRCA gene in a DNA polymerase chain reaction (PCR). The two method claims on appeal involve comparison of wild-type BRCA gene sequences with the patient's BRCA gene sequence. The lower court held all six claims patent ineligible as claiming naturally occurring DNA sequences and/or abstract ideas.

The Federal Circuit found no difference between the isolated DNA considered patent ineligible by the Supreme Court in Myriad and the primers at issue noting that the primers necessarily contain the identical sequence of the BRCA sequence directly opposite to the strand to which they are designed to bind.

Myriad first argued that the primers are patentable because the sequences are synthetically replicated but, citing its own and the Supreme Court's prior Myriad decisions, the Federal Circuit noted that “isolated DNA is routinely synthetically created” and can originate from inside a cell or be synthesized by an extracellular process. Then, Myriad argued that the primers are not naturally occurring because single-stranded DNA does not occur in the human body. Unpersuaded, the Federal Circuit again cited to Myriad where the Supreme Court held ineligible claims directed to segments as short as 15 nucleotides, the same length as the primers claimed here. Thus, even short single strands of nucleotides are not patent eligible if that same sequence occurs in nature. Myriad further argued that the sequences, once isolated as primers, have a fundamentally different function than when they are part of a DNA strand. Myriad claimed that instead of functioning to store the biological information used in the development and functioning of living organisms, primers function as starting material for PCR. However, the court reasoned that primers utilize one of the primary functions of DNA's structure in nature ' that complimentary nucleotide sequences bind. Finding that a primer binds at the part of the DNA where its sequence is directly complimentary and thus identifies the relevant part of the DNA for the polymerase reaction to start, the court held that primers function just as in nature utilizing DNA's innate ability to bind to itself. Furthermore, the Federal Circuit noted that “a DNA structure with a function similar to that found in nature can only be patent eligible as a composition of matter if it has a unique structure, different from anything found in nature.”

Turning to the two asserted method claims.

Claim 7 recites:

A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequence of the BRCA1 gene,BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject[,] wherein a germline nucleic acid sequence is compared by hybridizing a BRCA1 gene probe which specifically hybridizes to a BRCA1 allele to genomic DNA isolated from said sample and detecting the presence of a hybridization product wherein a presence of said product indicates the presence of said allele in the subject.

Claim 8 recites:

A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequence of the BRCA1 gene,BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject[,] wherein a germline nucleic acid sequence is compared by amplifying all or part of a BRCA1 gene from said sample using a set of primers to produce amplified nucleic acids and sequencing the amplified nucleic acids.

Ambry argued that both claims are ineligible under the Supreme Court's Mayo v. Prometheus Labs., 132 S.Ct. 1289 (2012) decision where claims to measuring a metabolite and coordinating that measurement with a dosage regimen were held patent ineligible. There, the Court held that bare recitation of a natural law was not patentable. Ambry argued that Myriad's method claims simply compared wild-type sequences to the patient's BRCA1 sequence by applying conventional techniques. But the Federal Circuit did not reach the issue of whether Mayo was on point. Rather, the court held that the claims recite abstract ideas and, as such, are patent ineligible under Alice Corp. v. CLS Bank Int'l, 134 S.Ct. 2347 (2014).

In Alice, the Court reiterated its two-step test to determine patent eligibility for claims containing abstract ideas: first, determine whether the claims at issue are directed to a patent ineligible concept and, if they are, ask whether the remaining elements, either in isolation or in combination with the non-patent-ineligible elements, are sufficient to “transform the nature of the claim into a patent-eligible application.” Id. at 2355. In other words, “there must be a further inventive concept to take the claim into the realm of patent eligibility.” Id.

In Ambry Genetics, the Federal Circuit treated separately the first paragraphs of claims 7 and 8, which correspond to the first step of the Alice analysis, and the second paragraphs of the claims, which correspond to the second step of the analysis. The court found that the comparisons described in the first paragraphs are “patent-ineligible abstract ideas of comparing the BRCA sequences and determining existing alterations.” The court also noted that because of their breadth, each comparison step would also cover yet undiscovered alterations and that “it is antithetical to the patent law to allow these basic building blocks of scientific research to be monopolized.”

Having determined that the comparison steps are abstract ideas, the court moved on to determine whether there was a further inventive concept in the second paragraphs of the claims. Myriad argued that claims 7 and 8 are similar to claims Judge Bryson had suggested may be patentable in the court's prior Myriad case. There, Judge Bryson had suggested, and the Supreme Court agreed, that “as the first party with knowledge of the BRCA1 and BRCA2 sequences, Myriad was in an excellent position to claim applications of that knowledge.” Myriad, 133 S.Ct. at 2120. But the Federal Circuit in Ambry noted that the claims discussed in Myriad were limited to the particular mutations that the inventors discovered, while claims 7 and 8 at issue are “significantly broader and more abstract, as they claim all comparisons between the patient's BRCA genes and the wild type BRCA genes.” The court determined that the second paragraphs “do nothing more than spell out what practitioners already knew ' how to compare gene sequences using routine, ordinary techniques.”

Thus, all of the asserted claims were deemed directed to patent ineligible subject matter in violation of 35 U.S.C. '101 and the district court's denial of Myriad's motion for a preliminary injunction was affirmed. But this is not likely to be the end of the Myriad-BRCA genes story ' not when the Amended Complaint in this case alone alleges infringement of 66 claims across 15 patents.

Veronica Mullally Munoz is a partner with Pearl Cohen Zedek Latzer Baratz in New York. A member of the Board of Editors of this newsletter, she concentrates her practice on patent litigation in the life sciences. She can be reached at [email protected].