After Myriad: A Herd of Elephants in the Room

Guest Post by Sean Brennan --

As we all know by now, the Supreme Court last month decided that isolated genes are not eligible for patenting.  Although seemingly drawing a clear-cut distinction between DNA molecules having the same sequence as that which occurs in nature (genes), and DNA molecules having different sequences from those that occur in nature (cDNA) (see Patent Docs posts here and here), the decision leaves a host of unsettled questions about the patent-eligibility of numerous biologicals.  Although ostensibly concerned with human genes, the reasoning supporting the decision could be used to call into question the patent-eligibility of compositions ranging from purified metabolites (such as antibiotics) to isolated proteins to procaryotic genes.

Non-human genes

Although the question addressed by the Court was "Are human genes patentable?", in its decision the Court couldn't seem to decide whether its decision applied strictly to human genes or to genes in general.  In framing the question, the Court stated that the case "requires us to resolve whether a naturally occurring segment of . . . DNA is patent eligible . . . by virtue of its isolation from the rest of the human genome."  (Slip. Op. at 1, emphasis added).  But in announcing its decision, the Court appeared to have lost sight of the "human" limitation when it stated:  "we hold that a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated" (Id.); "separating [a] gene from its surrounding genetic material is not an act of invention" (Id. at 12); and "[w]e 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" (Id. at 18).

Thus, the decision leaves open the question of whether it is only human genes that are not patent-eligible (i.e., did the Supreme Court buy the "you can't patent my body" argument?) or is any gene, from any organism, barred from patent eligibility?  It is difficult to understand how the Court could justify one standard for human genes and another for genes of other species.

This being the case, the decision would seem to doom the patent-eligibility of procaryotic genes; the vast majority of which do not contain introns.  Although it is possible to reverse-transcribe a procaryotic mRNA molecule to generate a cDNA from a procaryotic gene, such a nucleic acid molecule would not have a sequence different from the sequence of the gene as it occurs in nature.

This result would be unfortunate, since new bacterial species are being discovered every day, and many of these contain genes encoding proteins that are useful for processes such as pesticide production and bioremediation.  It would also set up a technology-specific distinction between biotechnological and pharmaceutical practice, in which it is typical to obtain composition claims for the first disclosure of a new compound.

Vectors

If it is no longer possible to claim an isolated gene per se, might we still be able to claim a gene sequence as a component of a vector?  Unfortunately, the decision provided no guidance on this point, because none of Myriad's claims reciting BRCA genes as components of a vector or expression system (e.g., claims 8-11 of U.S. Patent No. 5,747,282) were at issue.  Although it is undisputed that the combination of a gene with one or more of a heterologous promoter, termination site, regulatory sequence(s), replication origin, or antibiotic resistance marker is a composition that does not occur in nature; I worry that, given the current judicial climate (see Mayo v. Prometheus), addition of heterologous sequences to a newly isolated gene will be dismissed as "insignificant post-solution activity."  After all, cloning vectors and expression vectors are standard materials that can be purchased from any one of a dozen or more suppliers.  Then again, it could turn out that certain vectors (and/or heterologous sequences) will be considered standard and others not, so that the patent eligibility of a gene might end up depending upon what other sequences are attached to it.  A good deal of biotech practice over the next few years may well involve figuring out how much we need to "dress up" a gene before it can be "taken out" into the realm of patent-eligibility.

Informational content

The Court seemed to imply that identity of informational content between a cloned gene and a naturally-occurring gene is what renders gene sequences patent-ineligible; and not the (supposed) identity of chemical structure between the two:  "Myriad's claims are simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA.  Instead, the claims understandably focus on the genetic information encoded in the BRCA1 and BRCA2 genes." (Slip Op. at 14-15).  "Myriad . . . is concerned primarily with the information contained in the genetic sequence, not with the specific chemical composition of a particular molecule."  (Id. at 15, emphasis in original).

If this is the case, I wonder why even cDNA was found to be patent-eligible.  Inasmuch as the informational content of most DNA molecules resides in their ability to encode a polypeptide sequence, a cDNA is no different in this respect from the intron-containing gene sequence from which it is derived.

At the risk of presenting a somewhat far-fetched example to make another point, I note that it is possible to create recombinant gene sequences that do not have the same chemical structure, but nonetheless contain the same informational content, as a naturally-occurring gene.  For instance, certain bacteriophages contain hydroxymethyluracil (HMU) instead of thymine in their DNA.  Imagine an enterprising geneticist who develops a cloning system, based on this bacteriophage, that generates cloned DNA containing HMU instead of thymidine.  The cloned gene now has a structure that does not occur in the natural gene -- is it patent eligible?  It would seem to depend on whether the criterion is a different chemical structure or a different information content.  Unfortunately the decision, while leaning toward informational content, failed to provide a clear criterion.

Another biological fact that seemed to get lost in the Myriad case is that naturally occurring DNA sequences contain epigenetic informational content (the most well-known example being methylation of cytosine residues) that is generally not present in an isolated cloned gene.  Consequently, there are both structural (e.g., methyl groups) and informational (gene methylation generally signals transcriptional repression) differences between certain isolated genes and their naturally-occurring counterparts.  This being so, whatever the Court's criterion for eligibility (structural difference or informational difference), it would appear that at least some isolated DNA molecules remain patent-eligible.

What is a mutant?

The Court punted on the question of whether mutated sequences are patent-eligible and, to make matters worse, provided scant guidance as to what types of sequences they considered mutant and, thereby, at least potentially patent-eligible.  The decision failed to comment specifically on claims that recited naturally-occurring mutant BRCA sequences (claim 7 of the '282 patent and claim 1 of U.S. Patent No. 5,693,473).  But following the Court's "product of nature" reasoning would lead to the conclusion that naturally-occurring alleles of a gene (some of which might be "mutants" in the classical sense of encoding a gene product with altered function) would not be patent-eligible.

On the other hand, isolated genes whose sequences have been altered in the laboratory would appear to escape at least the "product of nature" barrier to eligibility.  The question then arises as to whether a gene with a change in a single nucleotide (that does not alter the amino acid sequence of the encoded polypeptide) would be considered a "mutant."  What about a single nucleotide change that did result in an amino acid change?  Would it make any difference if the new amino acid encoded by the mutant sequence was a conservative or a non-conservative substitution?  Eventually, we may need to know how large or significant a change in sequence is necessary to confer "mutant" status on an isolated nucleic acid.

A further complication is that assessing whether a laboratory-altered sequence is different from a naturally-occurring sequence can present the patent applicant with a moving target.  Consider the hypothetical heartbreaker in which an applicant constructs a mutant sequence in vitro that is found to be both patent-eligible and patentable.  Years after the patent is granted, the same sequence is discovered in nature.  Does the patentee's claimed mutant sequence become retroactively ineligible?

Transformed cells

What about a claim to a gene sequence that has been introduced into a heterologous cell?  Surely, this is a composition that does not occur in nature.  Although such claims (e.g., claims 12 and 13 of the '282 patent) were not at issue in Myriad, it was just such a composition that was validated as patent eligible by the Supreme Court in Chakrabarty (albeit the cell in that case comprised more than one heterologous nucleic acid), which was cited favorably by the Myriad Court.  It's possible that, in the end, this may be as close as we'll be able to get to a composition claim to a newly-isolated gene.  In many cases, this may be good enough, since the principal use for most cloned genes is to express their gene product and, in order to do so, the gene is often placed into a heterologous cell for expression.

Proteins

The Court's proscription of naturally-occurring substances would also seem to rule out patent eligibility for isolated polypeptides.  In most cases, the amino acid sequence of a purified protein is exactly the same as the amino acid sequence of the naturally-occurring protein.  One normally doesn't even have to break any chemical bonds to purify a protein (thus failing the test for eligibility set forth by Judge Lourie in the decision below).  In the same way that "Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes" and "[t]he location and order of the nucleotides existed in nature before Myriad found them"; the amino acid sequence of a protein exists in nature before that protein is purified, and it is generally not altered by the purification procedure.

Does this mean that isolated proteins are also no longer patent-eligible?  Maybe not, since, in some cases, there are structural differences between isolated and naturally-occurring proteins (assuming structural distinction is sufficient for eligibility -- see above).  For example, if an isolated protein is obtained through expression of a recombinant nucleic acid, it often lacks certain naturally-occurring post-translational modifications, such as glycosylation or phosphorylation.  This is particularly true of a eukaryotic protein expressed in a procaryotic host cell.  Thus, it may be possible to obtain a claim to a polypeptide that lacks certain post-translational modifications, or contains additional modifications not present on the naturally-occurring protein.  Whether such a claim will have any value will depend, of course, on whether the isolated protein, containing more or fewer post-translational modifications than its naturally occurring counterpart, functions effectively for its intended purpose.

Antibiotics and other naturally-occurring compounds

Denial of patent-eligibility to an isolated biological molecule, based on identity to its naturally-occurring counterpart, will have repercussions well beyond the field of molecular biology.  As other commentators have already pointed out, the Myriad decision could sound the death knell for patent eligibility of all purified naturally-occurring substances (such as antibiotics, certain chemotherapeutics, and bacterial metabolites).  In a worst-case scenario, even chocolate chip cookies and baseball bats could become patent-ineligible.

Conclusion

The Myriad decision leaves me with a lot to be pessimistic about.  But on the bright side, keeping my expectations low will at least minimize the chance that I'll be disappointed.  I give the Court credit for trying to limit the breadth of its decision.  Presumably, they wanted to come-up with a clear-cut answer to a clear-cut question and thought they had done so by accepting the Solicitor's and Judge Bryson's distinction between genomic DNA and cDNA.  But in so doing, the Court let not just one, but a whole herd of elephants into the room.  I have a feeling we'll be shoveling for quite a while.

Dr. Brennan is a Patent Agent with Brennan IP Services.  He received a Ph.D. in Molecular Biology from the University of California, San Diego in 1982, and prior to becoming a patent practitioner, Dr. Brennan was a faculty member at the University of Connecticut School of Medicine and the University of Southern California.

Comments

[Skeptical]

Dr. Brennan,

It is as if you are trying very hard NOT to understand the law of 101 and the judicial exceptions.

The law was applied to the facts of this case to reach a decision for this case. The law is, was, and remains, a product of nature belongs to the warehouse of all men and is thus outside the bounds of patent law.

[Bob Cook-Deegan]

Completely agree these are unresolved questions, centering on "how much" needs to be done to alter a molecule to make it patent-eligible. We now know "isolating" a "gene" does not qualify, but reverse transcribing it does. Isn't it *much* better that the court did not address the other kinds of molecules that were not before it; they had their hands full with what was already on the table. But we do have a strong clue from both the decision and from the oral arguments that the Court was very concerned to preserve patent incentives for inventions to induce private R&D, and all the categories of uncertainty you note seem likely to fall on the invention side of the invention-v-discovery line, esp. if claims are not so broad they cover all uses of molecules used extensively in research.

I actually think the Court was deliberately focused on just addressing the arguments before it in the Solicitor General's brief, and that was wise. Credit to Team Thomas and the Solicitor General's office.

[HomelyInHouse]

Agree with the prior. Thomas is well known for looking at nothing, absolutely nothing, except the argument before him. This means that the broader implications were not considered. The on broader consideration was his prior holding in JEM Ag Supply v Pioneer and he differentiated it and upheld it.

All this means to me that little has changed, no more "isolated" recitations but the Fed.Cir will soon take a bunch of 101 cases and make everything else patent eligible. The Fed.Cir. understands that bad facts make bad law, and these were bad facts.

Hopefully not just a hope, but a reality based dream on my part.

[Kevin E. Noonan]

Dear Bob:

I totally agree that the Court was wise in not entering these waters outside DNA, but the Court's penchant for broad stroke legal pronouncements certainly supports the trepidation many now feel about the patent eligibility of anything having a natural source.

And the effort and uncertainty that will be occasioned by determining on what side of the line any particular invention falls is both unnecessary and wasteful, and will likely inhibit rather than promote progress.

Sometimes I think it would have been better if the Court had followed the district court and said that human DNA is special (for religious, moral or philosophical reasons) and left it at that.

Thanks for the comment

[Rao Vepachedu]

Now that any gene mutations to diagnose or predict any diseases are not patentable, we may have effectively killed a golden goose that lays golden eggs.

[Sean Brennan]

Skeptical, thanks for the tutorial, but I think the issue is simply that you and I disagree on whether isolated DNA is a product of nature. I provided several reasons in my post why I think it is not. And I'll add that although my post contains a fair amount of speculation, I don't believe any of it is groundless.

[Skeptical]

Dr. Brennan,

It's not me that your disagreement with matters.

As I pointed out, the court used its rule of law to the specific facts at hand.

This is not all that complicated. You are stuck seeing the bio trees and missing the forest.

[Ron]

Thanks for the very interesting post, especially the thoughts about informational content of DNA; I wasn't quite sure what to make of that in the opinion. It's quite weird to be going through patents trying to figure out whether a particular sequence contains/contained an intron and thus passes the Myriad test.

[doofustimesagoogaplex]

Skeptical: Do you have any practical point to offer apart from some lofty citation of a legal principle that you continue to rehash. Most of us DO work with the trees on a daily basis - as these are practical issues that matter to our clients.

[Skeptical]

The forest should be every bit as important to you and your clients d.

The practical point is to not get so caught up in the technical aspect that you cannot recognize the rule of law being applied.

And some of us serve clients in more than one technical space - wherein the understanding of that larger picture prevails.

Thanks for the comment.

[lulu393]

Of course patent laws are applied differently to humans, as made clear by the AIA: "Not withstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism."(112-29, sec 33(a), 125 Stat. 284)

While the case at hand deals with isolated human genes, not human organisms, the fact that the isolated gene has no new properties and was not transformed into something different weighs against patent eligibility when determining whether the gene is different than that found in nature. Where was the hand of man in all this? In the PROCESS not the product. Thus, it's not the end of the world if one can't patent a product when one can still patent a process of its making.

[Skeptical]

While what you say may be true lulu393, be aware that such was not the rule of law being used by the Court.

Quite in fact, having too much consideration of this non-used law can (and apparently does) cloud the understanding of the actual rule of law used. In that sense, this consideration may be decidedly UNhelpful.

[GD]

"I wonder why even cDNA was found to be patent-eligible."

I was wondering exactly the same thing. There are now good arguments to say that nothing simply purified from nature is patentable. Maybe it always was that way. Natural products are just laws of nature, information content or whatever other metaphysics the justices choose to call it. A decade or so of fresh litigation will be needed to clarify this fouled palate.

Although some argue that Myriad represented nothing new and simply reaffirmed old law, it didn't seem to be that simple. At the very least, the CAFC thought for decades that natural DNA sequences were patentable. Why didn't every defendant bring this up in every court every time a DNA case was argued? Were they all daft? Why did the PTO issue those claims for decades? And, for those same decades the supreme court let the whole "fantasy" continue. Where were the supremes all that time? Why did it take them so long to merely restate the obvious?

One defensible answer is that is wasn't obvious. Apparently, something in society has changed and that sensibility somehow got factored into Myriad and what is now the metaphysical law of section 101 with its fun filled elements of 102, 103 and maybe even 112. Maybe we are even back to the flash of genius test and all the good stuff that engenders, e.g., negating patentability by certain manners in which a patent was made. (Maybe that line belongs in section 101 since it has no obvious impact residing in section 103.)

Whatever. So much for settled expectations. Arguably for patents at least, settled law is now a rare beast. As Clarence Thomas put it a few years back in a speech when asked about stare decisis (paraphrasing his response): 'Yeah sure, I believe in it, except of course when I disagree with the underlying law or interpretation thereof.'

Dogs really are sleeping with cats. These are strange days indeed.

[Tobias Guenther]

Great post, Sean. Thank you for putting most (all?) of the glaring issues in one comment for all to see. I expect each of these will be addressed in the near future by the PTO and then by the Federal Circuit and ultimately another visit to the Supreme Court to revisit what easily could (and should) have been addressed clearly the first time around.

Skeptical: "the practical point is to not get so caught up in the technical aspect that you cannot recognize the rule of law being applied."

Shorter Skeptical: "I have nothing to add except lofty pronouncements."

As Sean points out, the Myriad decision applies bafflingly opaque reasoning to reach a highly technical and nuanced result: a claim to an isolated (and therefore non-natural) polynucleotide is eligible if the polynucleotide has the identical information content as a naturally spliced RNA molecule found in that same cell *unless* the sequence of the claimed polynucleotide is also found somewhere else in the (human?) genome.

[Skeptical]

Tobias,

Sorry that you feel that this decision has 'baffingly opaque reasoning' as it has the most clear reasoning of any 101 decision since Chakrabarty itself.

What you may view as 'lofty' is simply a clear cut 10,000 foot view that is quite easy to understand.

[Tobias Guenther]

Skeptical: "it has the most clear reasoning of any 101 decision since Chakrabarty itself."

What was this "clear reasoning"? The Court recognizes that the claimed isolated DNA is non-natural but it's ineligible for patenting because ... why? What's the analysis?

Maybe you can explain how the Court manages to find that the claimed composition differs chemically from the naturally occuring composition, and yet also seems to believe "Myriad's claims are simply not expressed in terms of chemical composition"? How does that work?

Likewise with this point raised by Sean:

"Another biological fact that seemed to get lost in the Myriad case is that naturally occurring DNA sequences contain epigenetic informational content (the most well-known example being methylation of cytosine residues) that is generally not present in an isolated cloned gene. Consequently, there are both structural (e.g., methyl groups) and informational (gene methylation generally signals transcriptional repression) differences between certain isolated genes and their naturally-occurring counterparts."

Given that the decision is so clear to you, it should be straitforward for you to apply the "clear reasoning" to a claim directed to a specific isolated 100 base nucleotide with a single modified cytosine. Would such a claim be eligible if it was shown by an accused infringer that an identical (but non-isolated) sequence with the modified cytosine could be found in the chromosome of an old, highly engineered laboratory strain of E. coli? Explain the analysis.

I suspect one problem with your 10,000 foot view is that there isn't much oxygen up there.

[lxf001]

I agree on the cDNA aspect. The Court thinks the informational content is relevant for a gene (rendering it the same as what is found in the human body), but when faced with cDNA, the Court reverts to the chemical structure of cDNA being different than genomic DNA. So, what is relevant - chemical structure or informational content? Oh, I get it, they know it when they see it. Playing both sides, seems to me.

[Skeptical]

Tobias - quite simple: you cannot have a patent on an item that is a product of nature.

(You can even say this while holding your breath in case of your concern about lack of oxygen at 10,000 feet).

[Igor Faynshteyn, Esq.]

LOL - what a tour I had of Mr. Skeptical, the clown-troll, in just a couple of days on this great blog.

When I first made my comment on this blog, in the most recent post on this subject, and Skeptical replied, I actually didn't know who he was and took him seriously. But after reading his automated responses, which display an absolute lack of knowledge in anything that has to do with patent law and science, I realized that he is actually a troll.

So, please don't mind him. Let the important conversation about this topic continue uninterrupted.

[Igor Faynshteyn, Esq.]

I agree with you, lxf001. The Court couldn't seem to decide what mattered more - the genetic informational content, or the chemical structure/composition.

The Court at least recognized that a broad decision would have significant and negative consequences for the biotech industry, while also understanding that patenting DNA itself could have significant impact on the cost of healthcare.
So they were left with drawing lines in an area of law where it's difficult, if not impossible, to do. In that sense, I agree with Dr. Noonan's sarcastic comment that better to just say it's immoral to patent human DNA.

This is what happens when a bunch of jurists are deciding questions better left to the scientists, or better still to the Federal Circuit, which was created for the very purpose of establishing stability in patent law, and otherwise making more informed decisions in areas where clear lines cannot be drawn.

I think this decision is essentially like Bush-Gore - non-precedential. When CAFC gets their hands on new cases dealing with patent eligibility questions, they will be sure to narrow the Myriad decision to the facts of that case.