[author: Kevin E. Noonan]

Dr. Christopher Holman, Associate Professor of Law at the University of Missouri-Kansas City, filed an amicus curiae brief in AMP v. USPTO (the Myriad case) that addresses some of the factual and scientific inaccuracies that have been rampant in commentary and advocacy of this case at both the District Court and Federal Circuit, and within at least parts of the Executive Branch.

Dr. Holman (at right) makes three arguments:

I.  Isolated DNA is not simply DNA that has been cleaved and extracted from native chromosomal DNA

II.  The DNA of claims 1 and 2 of the '282 patent is not fundamentally different to an extent that would justify different patent eligibility

III.  There are several "unfounded assumptions":

a.  Regarding the utility of isolated genomic DNA

b.  As to the impact of isolated DNA patents on genetic testing and whole genome sequencing (WGS)

As an introduction, Dr. Holman discusses the "unusual posture" of the case, wherein there has been no allegation that "any particular technology infringes any of the challenged [composition of matter] claims [because, after all, the basis for standing in the case is that Myriad did threaten Dr. Harry Ostrer's former employer, New York University Medical Center, with a patent infringement lawsuit based on the method claims].  Dr. Holman reminds the Court that his own, independent research found "that no US court has addressed the question of whether an isolated DNA claim would be infringed by any form of DNA sequencing or diagnostic testing, citing his own paper in Science 322: 198-9 (2008) (see "Science Article Should Help Allay Gene Patenting Fears").  And he makes a point made previously, that "the claims [at issue] have yet to be adequately construed, and their purported preemptive effect remains entirely speculative."

Turning to his first argument, Dr. Holman references "[s]tatements in [the Federal Circuit's now-vacated earlier decision,] Myriad I, [that] suggest that some members of th[e] Court are under the impression that the claims encompass native genomic DNA that as been simply 'cleaved' from the chromosome and 'extracted' from the cell, in a process analogous to separating cotton fiber from cottonseed, or purifying human adrenaline from human tissue."  Dr. Holman quickly disabuses any members of the Court from this notion, reminding the Court that these conceptions are mere "imagery" that "might serve as a useful metaphor."  He also reminds the Court of a useless metaphor, the Department of Justice's "magic microscope," which he rightly characterizes as "misrepresent[ing] the biology and obscure[ing] the very real distinction between the claimed DNA and native chromosomal DNA."  Contrary to these simplistic misrepresentations, Dr. Holman construes the claims properly as being limited to "synthetic DNA molecules that are structurally and functionally distinguishable from their native counterparts."

Here, Dr. Holman makes a distinction opposite to, but in the same spirit as, Judge Sweet's attempt to separate DNA into its own category of biomolecule (albeit with much greater accuracy and less sophistry).  He ties the "fundamental[] differen[ce] between DNA and other biomolecules to their unique capacity to self-replicate.  Proteins and other biomolecules, not having any self-replicative capacity, must be separated from "other protein and cellular constituents, resulting in a purified preparation of protein molecules originating from a native source."  While this distinction is patently correct, it treads into the same dangerous waters as Judge Lourie's majority opinion in Myriad I, because in attempting to salvage patent-eligibility for DNA molecules it could lead to a determination that "merely" isolating a biomolecule is not enough (to use the Mayo v. Prometheus language) to render such other biomolecules patent eligible.  Here, Dr. Holman's brief goes on to explain the process by which a DNA molecule encoding a protein, like the BRCA1/2 molecules at issue here, is actually isolated (including the classical creation of a (entirely synthetic, man-made) genomic DNA library that is screened (again, an activity evincing the "hand of man") to identify and isolate the DNA molecule that can then be claimed.  For the uninitiated, and to illustrate how Dr. Holman eloquently explains a process that would require a description in excess of the 15-page amicus brief limit, that description is as follows:

A biologist seeking to isolate a human genomic gene begins by extracting chromosomal DNA from a sample of human cells, and then cleaving the long chromosomal DNA strands into shorter fragments.  These DNA fragments are then inserted into DNA vectors capable of replication in a host cell.  The vectors are subsequently introduced into cells, typically bacterial or yeast, which can be grown in culture.  The cells multiply, and as they do the recombinant vector DNA, including the fragment originating from the human chromosome, is replicated.

The resulting collection of vector-containing cells is referred to as a "genomic DNA library."  The cells comprising the library contain DNA that retains the primary sequence of genomic DNA, but the DNA molecules themselves did not originate in the human chromosome, but instead were synthesized as copies outside the body.  Single cells can be isolated from this mixture, and used to create a culture of cells that all comprise the same fragment of genomic DNA.  To isolate a gene of interest, a biologist screens the library to identify and isolate a pure cell culture that comprises a DNA fragment that includes the gene.

Once the DNA sequence of a gene has been determined, there is generally little reason to go back and repeat this process, since the sequence information of the DNA can be used to synthesize further copies by more convenient means.  For example, as described in a brief I submitted in the first iteration of this case, conventional BRCA genetic testing involves using techniques such as PCR to amplify DNA molecules representing fragments of a patient's full-length BRCA gene.  Brief of Amici Curiae Christopher M. Holman and Robert Cook-Deegan in Support of Neither Party, 2010 WL 4853323,*16.  In short, genetic testing does not involve cleaving the BRCA gene out of a native chromosome, but rather synthetic copies produced outside the body.

Dr. Holman then explains the relevance of this disquisition to the case at hand:  the isolation of the BRCA1 gene as described in U.S. Patent No. 5,747,282 (the '282 patent" employs the general methodologies described above," citing the appropriate portions of the '282 specification).  The process that was the focus of the inapt analogies by Plaintiffs and certain amici, isolating chromosomal DNA from a cell and cleaving that DNA into fragments, certainly occurred, Dr. Holman states, but "these are merely intermediate steps in the preparation of the genomic DNA library, from which the genes were actually isolates," and reminding the Court that said isolated and fragmented DNA preparation "would not [itself] fall within a reasonable construction of the claims."  In this he refutes the scientifically challenged argument that a "literal" reading of the claims would include such a fragmented chromosomal preparation (because it would "inherently include a BRCA gene") by reminding the Court that such an interpretation of the claim would clearly encompass the prior art.

Dr. Holman then cites additional distinctions between native DNA and the DNA as claimed:  that the isolated DNA has "distinct functional and structural characteristics," including epigenetics (such as DNA methylation) which is lost when DNA is isolated.

In his second argument, Dr. Holman challenges the government's argument that isolated genomic DNA and cDNA are "so fundamentally different . . . that the two forms of DNA should be treated differently for purposes of patent eligibility" as well as the appearance that members of the Court "have to some extent accepted this argument."  Dr. Holman states that the methods used to produce cDNA are "entirely analogous" to the methods he describes earlier in the brief for producing genomic DNA, and then once again explains for the Court how that is done:

As a first step, messenger RNA (mRNA) is extracted from human cells.  This collection of mRNA molecules will comprise many different sequences, generally representing all of the proteins that are being expressed by the cells.  The extracted mRNA is analogous to the extracted genomic DNA described above.  mRNA is structurally very similar to DNA, and contains the sequence information of the gene.  However, mRNA is a single-stranded molecule that cannot self-replicate like DNA and is less chemically stable.

To address these issues, scientists use the extracted mRNA molecules as templates to synthesize double-stranded cDNA molecules retaining the sequence information of mRNA, but which are more stable and can self-replicate.  These double-stranded cDNA molecules are inserted into vectors which are then introduced into cells, resulting in a cDNA library entirely analogous to a genomic DNA library as described above.  This library can be screened to isolate a cDNA corresponding to a gene of interest, e.g., a cDNA encoding a BRCA protein.

Significantly, the resulting isolated cDNA is entirely analogous to the claimed isolated genomic DNA.  In both cases the DNA did not actually originate in the cell, but it retains the informational content of a native polynucleotide sequence.  In the case of cDNA, the sequence of an mRNA molecule, and in the case of isolated genomic DNA, the sequence of genomic DNA.

While correct, it must be recognized that this explanation could just as easily be used as the basis for denying patent eligibility to cDNA as well as genomic DNA to those focused on the information content and blind to the chemical properties and characteristics Dr. Holman takes such pains to clearly explain.  This risk is exacerbated by Dr. Holman's argument that "a cDNA is nothing more than a rote copy of a naturally occurring mRNA molecule.  The 'engineering' to exclude introns and other regulatory regions is accomplished entirely within the cell, by natural processes, without any human intervention."  And in correcting some of the factually incorrect statements by Judge Moore in her concurring opinion (and taking several paragraphs of his limited space in the brief to explicate these errors), scientific correctness may have trumped effective advocacy.

Dr. Holman then discusses the "unfounded assumptions" that underlie the grounds in Myriad I for finding that the claimed DNA "had markedly different utility than its naturally occurring counterpart."  Here he again corrects Judge Moore's statements regarding the utility of isolated DNA for use as primers and probes, correctly stating that "the single most important category of biotechnology products" have been therapeutic proteins like erythropoietin and insulin, which required isolation of the human gene encoding them to enable production of sufficient quantities (using recombinant DNA technology) to be useful as the first biologic drugs.  However, Dr. Holman is entirely correct when he states that "[i]t would be unwise for the court to dismiss this important use of isolated DNA as insufficient to warrant patent eligibility, particularly when the parties who would most affected by this, biotechnology companies that produce biotech drugs (as well as patients that might benefit) are not parties to the litigation" (ironically, the BRCA-encoding DNA does not appear to have any such commercial utility).  In a further irony, Dr. Holman also corrects Judge Bryson's apprehension of the distinction between genomic and cDNA, that the latter can be "attached to a promoter and inserted into a non-human cell to drive protein expression," on the grounds that genomic DNA has the same utility (provided that the protein is made in a eukaryotic cell).

Finally, Dr. Holman discussed other "unfounded assumptions" relating to the impact of "gene patents" on genetic diagnostic testing and whole genome sequencing, focusing on the concerns in this regard contained in Judge Bryson's dissenting opinion in Myriad I.  Citing Judge Rich that "the name of the game is the claim," Dr. Holman challenges those "many critics of gene patents [who] incorrectly assume that any patent claim that recites a gene sequence necessarily forecloses any research or diagnosis relating to that gene."  Citing his earlier amicus brief with Dr. Robert Cook-Deegan, he again asserts that "there is no basis for assuming that all forms of DNA sequencing, especially next-generation single molecule methods, would necessarily entail the production of isolated DNA falling within the scope of the properly construed claims" and that "[c]laims reciting the full-length gene would not be infringed by conventional BRCA testing, for example, which is based on the amplification and analysis of fragments of the gene."  He concedes that the fragment claims are less certain in this regard, but reminds the Court that these claims may be invalid on other grounds (see "Caught in a Time Warp: The (In)validity of BRCA1 Oligonucleotide Claims").  He also challenges the assumption that progress in genetic testing will be impeded by "thousands of gene patents," citing his study (Holman, "Debunking the Myth That Whole Genome Sequencing Infringes Thousands of Gene Patents," 30 Nature Biotechnology 240 (2012)) debunking the oft-repeated and "widespread perception that 20% of human genes are patented," calling this "a myth based upon the misreading of a single 'Policy Perspective' article published in Science."

Dr. Holman's brief concludes with a most succinct and eloquent description of what is at stake in this case:

A determination by this court that any of the challenged isolated DNA claims is patent ineligible could cause serious unintended collateral damage to biotechnology, and should not be made cavalierly based on an overly simplistic and imprecise interpretation of the claims and speculation as to their potential preemptive effect.

For additional information regarding this topic, please see:

• "U.S. Government: Mayo Decision Supports Prior Argument That Isolated Genomic DNA Is Not Patent Eligible," July 10, 2012
• "IPO Amicus Brief Argues for Patent Eligibility of Myriad's Isolated DNA Claims and Method Claim 20," July 9, 2012
• "Eli Lilly & Co. File Amicus Brief in AMP v. Myriad," June 27, 2012
• "Parties and Amici File Briefs in Myriad Case," June 17, 2012