Revisiting Genome Medicine Article on "Pervasive Sequence Patents" That "Cover the Entire Human Genome"

By Donald Zuhn --

Last week, we reported on an article in the current issue of Genome Medicine which contends that due to the non-specificity of sequence uniqueness across the genome and the broad scope of claims to nucleotide sequences, the Supreme Court and Congress should limit the patenting of existing nucleotide sequences (see "Genome Medicine Article Calls for Limits on Patenting of Existing Nucleotide Sequences").  The authors of the paper, Jeffrey Rosenfeld and Christopher Mason, worried that "the non-specificity of 15mer sequences creates unclear infringement liability," examined the incidence with which 15mers from a given gene matched 15mers in other genes using the Consensus Coding Sequences (CCDS) database of 18,382 high-confidence genes.  According to the authors, their analysis showed that "every gene in the CCDS database had a 15mer that matched the sequence of at least one other gene," with the "[t]he number of matching genes ranged from as few as 5 (for MTRNR2L7) or 689 (for BRCA1) to as high as 7,688 (for TTN)."  The authors also noted that 99.999% of 15mers in the human genome are repeated at least twice.

While the authors' analysis may be relevant to claims directed to 15mers, such as claims 5 and 6 of Myriad's U.S. Patent No. 5,747,282, the authors also listed claims 1 and 2 of the '282 patent when stating that in the Association for Molecular Pathology v. Myriad Genetics, Inc. case, "the broadest intellectual property rights on BRCA sequences come from several related claims in patent 5,747,282."  Claims 1, 2, 5, and 6 of the '282 patent recite:

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.

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

In support of their conclusion that "short patent sequences are extremely non-specific and that a 15mer patent claim from one gene will always 'cross-match' and patent a portion of another gene as well," the authors state that:

When we examined the amount of total sequence space in human genes that is covered by 15mers in claims from current patents (Additional file 2), we found 58 patents whose claims covered at least 10% of the bases of all human genes.  The top patent was US7795422, whose claims' sequences matched 91.5% of human genes.  Interestingly, we also observed a patent for improving bovine traits (US7468248) with explicit claims for 15mers that matched 84% of human genes.  This patent was not even aimed at any human sequence, yet covered a majority of human genes once we examined the claim's matches at the 15mer scale.

A Patent Docs reader has suggested that the claimed sequences of U.S. Patent No. 7,795,422 do not appear to "match[] 91.5% of human genes," and that U.S. Patent No. 7,468,248 does not appear to contain "explicit claims for 15mers that matched 84% of human genes," as asserted by the authors of the Genome Medicine paper.  The '422 patent, which is directed to compounds, compositions, and methods useful for modulating the expression and activity of genes involved in pathways of hypoxia inducible factor 1 (HIF1) gene expression and/or activity by RNA interference (RNAi) using small nucleic acid molecules, has five claims:

1.  A chemically modified short interfering nucleic acid (siNA) molecule, wherein: (a) the siNA molecule comprises a sense strand and an antisense strand, each strand having one or more pyrimidine nucleotides and one or more purine nucleotides; (b) each strand is independently 18 to 27 nucleotides in length, and together comprise a duplex having between 17 and 23 base pairs; (c) the antisense strand is complementary to a human Hypoxia Inducible Factor 1 (HIF1) RNA sequence comprising SEQ ID NO:567; (d) a plurality of pyrimidine nucleotides present in the sense strand are 2'-deoxy-2-fluoro pyrimidine nucleotides and a plurality of purine nucleotide present in the sense strand are 2'-deoxy purine nucleotides; and (e) a plurality of pyrimidine nucleotides present in the antisense strand are 2'-deoxy-2'-fluoro pyrimidine nucleotides and a plurality of purine nucleotides present in the antisense strand are 2'-O-methyl-puine nucleotides.

2.  The siNA molecule of claim 1, wherein the sense strand has a cap at both 5'- and 3'- ends of the sense strand.

3.  The siNA molecule of claim 1, comprising a 3'-overhang on one or both strands.

4.  A composition comprising the siNA molecule of claim 1, and a pharmaceutically acceptable carrier or diluent.

5.  The siNA of claim 1, wherein the antisense strand has a phosphorothioate internucleotide linkage at the 3'end.

Unlike claims 5 and 6 of the '282 patent, which are directed to 15mers of the BRCA1 sequence, the lone independent claim of the '422 patent is directed to a "chemically modified" double-stranded nucleic acid molecule.  It is therefore difficult to see how the claimed sequences of the '422 patent could "match[] 91.5% of human genes."  Of course, because the authors state that the "claims' sequences matched 91.5% of human genes," it is possible that they are referring to the human Hypoxia Inducible Factor 1 (HIF1) RNA sequence of SEQ ID NO:567 recited in claim 1 (the Sequence Listing for the '422 patent indicates that the RNA sequence set forth as SEQ ID NO: 567 is 3933 nucleotides in length).  However, claim 1 of the '422 patent does not claim a 17mer or 27mer of the HIF sequence, but rather claims a chemically modified siNA duplex molecule.

The '248 patent, which is also cited by the authors, and which is directed to methods, compositions, and systems for managing bovine subjects in order to maximize their individual potential performance and edible meat value, has 33 method claims, of which claims 1, 22, and 28 are the only independent claims.  These claims recite:

1.  A method for inferring a trait of a bovine subject from a nucleic acid sample of the bovine subject, comprising identifying in the nucleic acid sample, a nucleotide occurrence of a single nucleotide polymorphism (SNP) at position 300 of SEQ ID NO:21645, thereby inferring the trait, wherein the trait is marbling, tenderness, fat thickness, red meat yield, or average daily weight gain.

22.  A method for determining a nucleotide occurrence of a polymorphism in a bovine sample, comprising: a) contacting a bovine polynucleotide in the sample with an oligonucleotide that binds to a target region, wherein the target region comprises a position at position 300 of SEQ ID NO:21645 or wherein the target region is within 3000 nucleotides of a nucleotide at position 300 of SEQ ID NO:21645, and b) determining the nucleotide occurrence of a single nucleotide polymorphism (SNP) at position 300 of SEQ ID NO:21645, wherein the determination comprises analyzing binding of the oligonucleotide or detecting an amplification product generated using the oligonucleotide, thereby determining the nucleotide occurrence of the polymorphism.

28.  A method for identifying a bovine single nucleotide polymorphism (SNP) associated with a trait, comprising identifying a test SNP that is in disequilibrium with a SNP position at position 300 of SEQ ID NO:21645.

Thus, while the '248 patent recites oligonucleotides -- which the specification states "[i]n certain aspects" can be "at least 15 nucleotides in length" -- it is difficult to see how the authors can conclude that the '248 patent has "explicit claims for 15mers that matched 84% of human genes."  Again, the authors may be referring to the sequence set forth in SEQ ID NO: 21645, but the claims of the '248 patent are directed to methods of inferring a trait of a bovine subject, determining a nucleotide occurrence of a polymorphism in a bovine sample, and identifying a bovine single nucleotide polymorphism (SNP) associated with a trait, and not 15mers derived from the sequence of SEQ ID NO: 21645.

Returning to the authors' assertion that claims 1 and 2 of Myriad's '282 patent, along with claims 5 and 6 of the patent, provide "the broadest intellectual property rights on BRCA sequences," a clue as to why the authors refer to claims 1 and 2 in their Genome Medicine paper can be found in the Supplemental Declaration that Dr. Mason submitted in response to Myriad's brief and Statement of Material Facts when the Myriad case was before the District Court.  In paragraph 10 of his Declaration, Dr. Mason surprisingly states that "Claim #I and #2 of '282 are so broad that they can include up to 100% of the genes in the human genome."  As indicated above, claim 1 of the '282 patent is directed to an isolated nucleic acid encoding the amino acid sequence of SEQ ID NO: 2 (which is 1863 amino acids in length), and claim 1 is directed to an isolated nucleic acid having the nucleotide sequence of SEQ ID NO: 1 (which is 5914 nucleotides in length).  In explaining how a nucleic acid encoding a protein of 1863 amino acids or a nucleic acid of 5914 nucleotides could "include up to 100% of the genes in the human genome," Dr. Mason states in his Declaration that "[b]ecause fragments of the BRCA 1 gene can also be informative about susceptibility to disease, [Myriad] also sought claims on DNA molecules or fragments of DNA molecules with 'substantial homology.'"  Dr. Mason notes that the '282 patent discloses that "substantial homology or (similarity) exists when a nucleic acid or fragment thereof will hybridize to another nucleic acid (or a complementary strand thereof) under selective hybridization conditions," and further, that "selective hybridization will occur when there is at least about 55% homology over a stretch of at least about 14 nucleotides" (emphasis in Dr. Mason's Declaration).

Dr. Mason then declares in paragraph 12 that:

Because of this low threshold of homology, any 55% homology of 14 nucleotides is now any 8 nucleotides from BRCA1 cDNA.  Also, homology could include any 9-13 nucleotide sequence with insertions and deletions.  Utilizing the same algorithm from above, the conclusion is that 100% of the genes in the human genome have at least one 8mer from the BRCA1 cDNA.

As with the '422 and '248 patents, Dr. Mason appears to be having some difficulty ascertaining the subject matter that is actually encompassed by claims 1 and 2 of the '282 patent.  As discussed above, claims 1 and 2 of the '282 patent are directed to a nucleic acid encoding a protein of 1863 amino acids or a nucleic acid of 5914 nucleotides, and are not "so broad" that they encompass 9mers, 13mers, or 14mers derived from those nucleic acids that exhibit 55% homology and which can include insertions and deletions.  Given the authors' analysis of the '422 and '248 patents, and their "construction" of the claims in those patents, a closer examination of the "58 patents whose claims covered at least 10% of the bases of all human gene" appears to be warranted.

Professor Chris Holman's critique of the Genome Medicine paper can be found on his blog (Holman's Biotech IP Blog) (A Critique of a Recent Article Which Found That Sequence Patents Cover the Entire Human Genome").

Comments

[EG]

Don,

Once more, Professor Holman exposes the malarkey about gene patenting. Again, you need to know the law in addition to the science, and Professor Holman knows both well.

[Dan Feigelson]

Thanks Don. Any idea why was this Mason ignoramus was not cross-examined when the case was before the District Court, so as to thoroughly discredited as an "expert" opining on something about which he knows nothing?

[Bryan Rudner]

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

Don, would you like to construe this claim for us? What exactly does it cover and what does it not cover, and why? Does the term "isolation" require that no other DNA sequences be present in the composition? Does it mean 95% pure relative to other DNA sequences? Does it includes sequences greater than 100 kb in length? 500kb?

Thanks.

As you know, many of Myriad's claims (including the claim above) are breathtakingly broad and are almost certainly invalid under one or more patent statutes (besides 101). That issue should have been highlighted (here, by you guys) from the beginning of this controversy and repeated, over and over again, without ambiguity.

"While the authors' analysis may be relevant to claims directed to 15mers"

Is the analysis "relevant" or not? Why not just say so, unequivocally?

[Moocow]

Bryan,
what "exactly" a patent claim covers in the abstract is not a realistic exercise. It's much easier to sit down, look at what it is one wants to do, and then decide whether the claim covers the intended activity.

For example, if the polypeptide of SEQ ID NO:2 is the wild-type BRCA1 protein and you want to provide a "second opinion" for a patient having a deleterious mutation that results in a truncated BRCA1 protein - well, in that case there's little risk that you'll be infringing that claim. The encoded protein just doesn't have SEQ ID NO:2.

That said, there's little risk you'll be infringing that claim through any kind of sequencing anyway. The claim requires an 'isolated' DNA of at least 5.5 kb or thereabouts. Sanger sequencing works with shorter fragments. Now, it would be different if you wanted to go into the business of recombinant production of BRCA1 protein. For that, you would need to make/use a full-length sequence, like the one claimed. Actually, I would think that recombinant expression (not diagnostic testing) was what they had in mind with that claim.

I don't think that claim is necessarily invalid for other patentability reasons. It's "breathtakingly broad" only in the sense that it covers any DNA that encodes that very specific AA sequence. Change just one codon from CTT to GTT (valine to leucine) and the encoding DNA sequence is outside the scope of the claim.

Your beef is probably with Myriad's "any fragment 15 bp or longer" claim. That claim is a very uncommon type of claim, and it has patentability problems other than 101, as you point out. Notably, that kind of claim is *not* what Rosenfeld and Mason used for their analysis, maybe because it's so uncommon. The Rosenfeld paper instead identified patents on methods for predicting the juiciness and marbling of beef steaks, and I have yet to figure out what such patents have to do with this debate.

[Bryan Rudner]

Moocow: It's "breathtakingly broad" only in the sense that it covers any DNA that encodes that very specific AA sequence.

To some extent this is true of all claims written using "comprising" language. But in this case where the only known utility of the sequence at the time of filing was (1) as a probe and (2) as a tool for further research (since when is that a substantial utility?), the breadth is particularly absurd. Quadzillions of different nucleotides of different lengths are covered and only a microscopically tiny fraction were enabled for anything useful as of the filing date.

My comments are certainly more relevant to the shorter claims but they also apply to the claim I recited. You write:

"there's little risk you'll be infringing that claim through any kind of sequencing anyway. The claim requires an 'isolated' DNA of at least 5.5 kb or thereabouts."

But that's the question. What does "isolated" mean? We know from the prosecution history that it doesnt refer to the gene as it exists in the chromosome in the cell. What about when a fragment of the chromosome comprising that sequence is taken out of the cell? Is that fragment "isolated"? When does such a fragment become "isolated"? It's somewhat conspicuous that this obvious question is constantly swatted away with a glib "don't worry about it" by those who seem most invested (emotionally or financially) in the continued eligiblity and/or patentability of Myriad's claims.