Supreme Court: Natural Isolated DNA Not Patentable, Synthetic DNA Is [pdf] | Hacker News Reader

Supreme Court: Natural Isolated DNA Not Patentable, Synthetic DNA Is [pdf]

supremecourt.gov

372 pointsjakewalker165 comments

Does this mean that someone born with synthetic DNA is guilty of infringement if they have children? Do they need to buy a licence to keep living? Perhaps as a compromise, the court can decide that they count as three fifths of a person.

Once you are born with synthetic DNA, is it not "existing in nature?" An interesting point, but cloning is not very popular among bioethicists.

Why cloning? In vitro fertilisation is common.

IVF doesn't actually change the genetic makeup of the sperm or egg in question. To do so would create a genetically altered human.

The parents would have bought the license for their child when they agreed to have the DNA modified. By the time that child has children, the patent would have expired.

Unless they change that, and keep on extending it, as it has been done with copyrights.

That's true... but I imagine if they extended it that far, reproduction rights of the child would be included in the license. Unlike corn, I can't imagine many parents would agree to sterilize their children just to include some synthetic DNA sequence. Even if the parents were very desperate (because of some genetic problem), they would still want their child to be able to reproduce.

assuming the parents understand the contract in which they are entering.

They wouldn't need to sterilize the children, nor would the corporation be interested in that. Just think of the recurring revenue!

So... expect numerous patent lawsuits in Kentucky?

Another possibility: the kid is a teen parent...

A historical correction to the misplaced tone of your 3/5ths reference, the 3/5ths compromise was by the anti-slavery republican north to prevent the southern democratic slavers from dominating the House of Representatives and the electoral college.[1]

[1] http://www.redstate.com/jeffdunetz/2010/07/18/were-our-found...

I know you meant well with your comment, but in general, it's best to avoid well-actually comments. This is one of Hacker School's core rules; they elaborate on why it's a good idea to avoid these types of comments at https://www.hackerschool.com/manual.

Isn't this reply sort of a meta-well-actually comment in itself?

What you linked to wasn't the HN 'manual'?

In the actual guidelines found here: http://ycombinator.com/newsguidelines.html it doesn't say anything about well actually comments. It says be smart in your discussions and don't just get opinionated, it says to present facts and actually address the thing that you're arguing over. I believe having proper arguments and discussions is one of the core things HN is about. It lets people learn and see other points of view. If you don't like a comment just downvote it.

Furthermore, the character of 'well-actually' comments are that the orignal comment was close to, or intended to be close to, a certain fact, and the well-actualer is pedantically correcting the original without adding any substantial value to the conversation.

This is not what happened here. rvkennedy did not make a statement of fact, he made an off-the-cuff remark. eldude challenged the substance and tone of that remark in order to prevent further misrepresentation of the point. He corrected and clarified the remark in a clear and substal way, thus falling well outside of the 'well-actually' category.

Oh dear. I've spent way too much time reading SCOTUS rulings/blogs today.

This is also such a terrific "well-actually" I'm glad he broke this non-existant rule. It is absolutely maddening to hear people misinterpret the 3/5ths rule, and I'm convinced basically no one in this country understands it.

HN comment pages would be pretty darn empty without well-actually comments.

This isn't hacker school.

Well, actually this is Hacker News, so "hacker school"'s rules don't apply.

IMHO a much better rule is "avoid acting as thought/discourse police."

Ok, what's your point?

I don't think "well-actually" comments are bad. Wikipedia says to avoid weasel words and "expressions that lack precision" [1], and I think well-actually statements often help clear up such ambiguity.

If someone follows up their "well, actually..." with a legitimate correction of the facts, then I don't see a problem with it.

[1] http://en.wikipedia.org/wiki/Wikipedia:Avoid_weasel_words

I think that in verbal parley well-actually comments are a lesser degree of the same offense as shooting down someone else's idea in a brainstorming session. Not only does it tend to silence the first speaker by shaming, it tends to derail the larger conversation. In this written context, it's less of an issue, though nested comments do create a similar potential context.

Granted, sometimes you gotta break some eggs. But don't be surprised when the hen who laid that egg isn't to be happy about it.

For whatever it's worth, the 3/5ths number originally came from negotiations over modifying the original government documents of the united states: the articles of confederation where the question was whether or not slaves would count for the purposes of taxation. When the constitutional convention came around and the same debate showed up again, except now instead of taxation the question was representation, the proponents flipped positions but the 3/5ths number ended up getting picked up once again. Plus a ban on slave importation was set for 20 years in the future, which is a portion of the compromise often ignored in retrospect. (Mostly because it turned out not to be as effective as people hoped.)

The main thrust of your argument is absolutely correct though, in that the northern folks generally argued that slaves were treated as property (and so should be taxed as such) and the southern folks generally argued that they should count as people. (And should be represented as such.)

No one seemed to get to the idea that if you were going to count someone for the purposes of representation, maybe you also had to let them vote. That would have also brought up interesting questions around the disenfranchisement of various other classes of people, namely women, some white men without property and freed slaves right from the start. Instead we had to wait a long time to start solving those problems.

Politics can be weird.

> ... the anti-slavery republican north to prevent the southern democratic slavers ...

The party system did not form until George Washington's first term. There were certainly factions, but nothing like the "Republican" or "Democratic" parties of today.

When the party system began during George Washington's first term, the two parties were called the "Federalist" and the "Democratic-Republican" parties. New England was primarily Federalist. The Mid-Atlantic and Southern states were primarily Democratic-Republican.

The Democratic-Republican Party is, in some sense, the ancestor of both major political parties today. The Democratic-Republican Party split into the Democratic Party and the National Republican Party after the 1824 election. This division forms the basis of the two major political parties we have today. (With several messy breakups, reunions, splinterings, and Third Parties.)

I take this ruling as protection from infringement if a synthetic sequence happens to emerge naturally.

In combination with the recent Monsanto case, it'd be consistent that the individual would owe licensing fees for each additional reproduction.

That's an interesting scenario given the recent ruling in Bowman v. Monsanto. If planting the offspring of synthetic Monsanto seeds infringes Monsanto's patents, then by extension, conceiving the offspring of a person with synthetic DNA could infringe patents as well.

In practice, this would be limited by the 14th Amendment. The prohibition against slavery trumps patent law, period. But I'm curious how far biotech companies would go before they got shut down.

EDIT: As pointed out below, 13th not 14th. My bad. Although due process in 14th would probably kick in as well.

> In practice, this would be limited by the 14th Amendment. The prohibition against slavery trumps patent law, period.

The prohibition against slavery and involuntary servitude (except as punishment for a crime) is the 13th Amendment, not the 14th Amendment.

It's possible that conceiving in those circumstances could be copyright infringement, but that's just a civil tort. So the parents might get sued for lots of money, but there wouldn't be any claims against the child. I don't see how slavery enters into it.

I'd hope that a court would hold differently with human reproduction than Bowman v. Monsanto, but even if they don't it wouldn't be anything to do with the 13th Amendment.

I always thought a good compromise would be that you can sell genetically modified seeds (or eggs or whatever) but you shouldnt be able to own anything that is produced by those seeds. ie children, saplings etc

in other words, you own the process of genetically modifying an organism, not the genes.

I dont know how realistic or unrealistic this is, since ianal.

edit: someone else mentioned the monsanto ruling, which makes this idea sound unrealistic

IANAL (and for this hypothetical I don't think it matters) but with this SCOTUS ruling, you could argue that even though the original DNA strand was synthetic and patented, once it was injected into the embryo, nature takes over and copies and makes it its own. The very dynamic nature of mutations and sexual reproduction should (rationally) invalidate the "infringement" of reproduction. You could also argue that penalizing a child for what is unarguably random chance on the part of their parents is cruel and unusual, not to mention this would mean that the debt (licensing agreement) is essentially inherited by the child, which is illegal if not outright unconstitutional to my knowledge (i.e., unless the debt is under a joint card with the deceased, you cannot inherit their credit card debt, although the creditors get rights to part of the estate covering the debt).

Edit: Apparently Myriad patented more than just strands for the BRCA genes, including some methods and tests, which is one of the reasons their case is important to SCOTUS. With our current patent system, I think you'd have to patent a lot more than just the gene to be able to sue people over having it, especially children of genetically engineered parents.

http://www.bloomberg.com/news/2013-06-13/the-supreme-court-s...

it is not the scientists who removed the introns from the officially unpatentable original DNA sequence to make the new, patentable cDNA sequence. It is nature itself, through the magic by which pre-RNA, which includes the introns, becomes messenger RNA, which does not. The Supreme Court described this process by saying, “the pre-RNA is then naturally ‘spliced’ by the physical removal of the introns” -- that is, the introns are removed as part of the ordinary process by which messenger RNA is created. The role scientists then subsequently play is to take the messenger RNA and use it to synthesize the intron-free cDNA.

To put it much more simply, there is nothing that a 6-year-old would consider “invented” about the patentable cDNA. It is nothing more than the messenger RNA flipped into a DNA sequence that omits unnecessary elements that nature already excluded. The sequence that codes the proteins is just as naturally occurring as the original DNA itself, which the court held couldn’t be patented because it was naturally occurring. The distinction is, to put it bluntly, a lawyer’s distinction, not a scientist’s.

(by Noah Feldman, a professor of constitutional and international law at Harvard)

From what I understand, Myriad's test involved synthesis of cDNA (which we scientists refer to as "complementary DNA", not "composite DNA" as SCOTUS does). This is still covered by the patent. However, any test based on sequencing the genomic DNA, for example, would not violate Myriad's patent. Genomic sequencing of these genes was previously a violation of the patent. This is definitely a step forward.

In the long run, Myriad is hosed because they no longer own the sequence, including analysis. Any diagnostic not using reverse transcription of the mRNA does not violate Myriad's patent. This includes synthesis of any non-cDNA polymer, such as XNA.

The issue is that a hypothetical diagnostic attempting to sequence this region would likely be pre-processed with a PCR to facilitate sequencing of only the region of interest... this necessarily involves a cDNA step.

You could sequence the whole genome at higher depth, but this would be more expensive.

Edit: My mistake, the patent covers the reverse transcription step exclusively, not the act of transcription in general - which means PCR from genomic DNA is fine, but rtPCR or cDNA library construction is not... no scientific consistency there, but looks like cheaper BCRA tests in the near future.

PCR is not covered by the patent, only reverse transcription of the processed RNA molecule to cDNA. There are many flavors of genomic PCR that are fine under this interpretation, including a rapid SNP-detecting digital qPCR.

> To put it much more simply, there is nothing that a 6-year-old would consider “invented” about the patentable cDNA.

That's the point. Patent law is very suitable for processes that cost millions to develop, but in pharmaceutics the big cost factor isn't process development, it is the discovery. What Myriad did is identify the gene, that is where the cost was sunk that they somehow have to recover.

But since you can patent only things, and not intellectual property, the Supreme Court had to resort to all kinds of legal hacks of the sort that judges hate to see applied in their courtroom.

Saying that Myriad was the first to discover BRCA1 is somewhat disingenuous; other labs did it independently at roughly the same time. Moreover, deciding when a gene was "discovered" is a minefield. What constitues discovery? Identification of a mutant? Cloning the gene? Sequencing it? There are many steps to this process.

You'd say that correlating certain mutations in the gene to increased risk of breast cancer constitutes discovery, it certainly does in the context of a clinical test for breast cancer, which is what Myriad is selling.

Unanimous judgment, though Scalia concurred in part and filed a separate opinion.

Myriad kind of still wins as their cDNA synthesis technique is affirmed patentable, which would presumably be used in conjunction with a patient's own BRCA genes to determine their cancer risk. So the precise test itself appears patented still, but now other companies can make use of the BRCA genes themselves, perhaps to develop other treatments that don't use the cDNA synthesis technique.

Justice Scalia's concurrence, reproduced here in full:

"I join the judgment of the Court, and all of its opinion except Part I–A and some portions of the rest of the opinion going into fine details of molecular biology. I am unable to affirm those details on my own knowledge or even my own belief. It suffices for me to affirm, having studied the opinions below and the expert briefs presented here, that the portion of DNA isolated from its natural state sought to be patented is identical to that portion of the DNA in its natural state; and that complementary DNA (cDNA) is a synthetic creation not normally present in nature."

You have to appreciate his dedication to rigor.

He's consistent, which is about the only nice thing I'd want to say about him.

Your ignorance is staggering.

He voted that the police should not be permitted to take your DNA just because you were arrested.

He voted that government should not be permitted to take your property and give it to another private entity because it will generate higher taxes.

He voted that the police should not be permitted to enter your property with drug sniffing dogs without a warrant.

He voted that authorities scanning a home with an infrared camera without a warrant constituted an unreasonable search.

If you conclude that those four votes mean that nobody can think that he's vile, you're the ignorant one.

"Vile" is a pretty strong term, especially to use in a political context.

It's interesting that you just assume the OP would take your side on those issues. If literally everyone agreed, they would not be an issue. :)

Completely orthogonally, sometimes people judge someone based on the intention behind their actions.

"Seldom has an opinion of this Court rested so obviously upon nothing but the personal views of its members", said Scalia when the court found it unconstitutional to execute the profoundly mentally disabled.

"If it were impossible for individual human beings (or groups of human beings) to act autonomously in effective pursuit of a common goal, the game of soccer would not exist", he said, when the court found it unconstitutional for the VMI to refuse admission to women.

"This ruling will almost certainly cause more Americans to be killed [...] The nation will live to regret what the court has done today" he said when the court held that Guantanamo detainees have the right to appeal their captivity to federal courts.

"Is it really so easy to determine that smacking someone in the face to determine where he has hidden the bomb that is about to blow up Los Angeles is prohibited in the Constitution?" he said, under obvious circumstances.

"Today's opinion is the product of a Court, which is the product of a law-profession culture, that has largely signed on to the so-called homosexual agenda" he said, in attempting to retain a law that criminalized same-sex relationships in Texas.

I thought about saying something very rude to you about me being entitled to my opinion, but I won't.

cDNA occurs in nature (reverse transcriptase).

In fact DNA intermediates with introns spliced can be reintegrated into the genome.

Further, faulty viruses can acquire oncogenes (intron-splicted, mtuated versions of growth factors, like EGF and HER2/neu) and transfer them to other cells via cDNA intermediates. It's not hard to believe that nature has in fact passed BRCA cDNAs around via retroviral intermediates.

RT doesn't work that way, it requires a specific site near its target gene in order to make the DNA strand. There is off-target activity, but it is almost certainly vanishingly rare.

"almost certainly vanishingly rare event" * "incredibly high rate of reproduction of viruses" = almost certainty.

See the first 4 chapters of "Biology of Cancer" by Weinberg.

molecular biology can deal with probabilities that are lower than 1/the number of particles in the universe.

again, have you read "The Biology of Cancer", by Weinberg? There is strong evidence for what I'm saying.

Further, I'm not sure what the relationship of probabilities to the number of particles in the universe is. The probability of any given sequence emitted by hmmer as the "highest probability" is tiny (often 10e-50 or better, and for very good matches, 10e-138). So what's your point?

uhm, no? But do you understand the thermodynamics of base pair mismatching in DNA/RNA duplexes and how to convert the kcal/mol into probabilities?

Sure, please see my papers on that subject.

the work is mostly on okazaki fragments, but a major conclusion from my phd thesis was that B-RNA is stuck because of a very low probability event (the breaking of a large number of hbonds simultaneously).

http://scholar.google.com/citations?view_op=view_citation&hl...

Fine, then, a DNA-RNA base pair mismatch incurs approximately 1.5 kcal/mol penalty, which is a 1:10 less likelihood of matching. 3' UTRs of genes are what you need to reverse transcribe (by accident) the mRNA of interest to generate the cDNA you describe. On average they are around 700 bp, the odds of finding an exact match are about 700/4^18 - then a one bp mismatch is 700/4^17 times a 1:10 hit in terms of competitive binding. Two bp mismatch is 700/4^16 times 1:100. Then you have to consider that it's evolutionarily unlikely to have segments that exactly or inexactly match tRNAs because the resulting dsRNA is likely to engage in silencing via the DROSHA mechanism - probably because our bodies like to guess what - get rid of ssRNA viruses. So these numbers are probably at least on the order of 1:10 or even 1:100 or more in the wrong direction.

and yet, existence proofs demonstrate you are wrong. Again, re-read the section on virus tumor oncogenes in The Biology of Cancer; pretty much everythign we know about oncogenes came from this physical mechanism.

what? Most oncogene duplication comes from chromosomal abnormalities, or occasionally retrotransposon capture. Completely different mechanism from reverse transcriptase amplification. Occasionally retroviruses will incorporate themselves near or inside an oncogene and activate (and sometimes copy them) but again, that is not the same mechanism as nonspecific gene duplication, and will almost certainly not produce the same molecular product as a cDNA.

Remember, the patent is a MOLECULE patent, not a PROCESS patent.

Yes, and what I'm demonstrating is there is likely prior art in the form of cDNA molecules identical to the Myriad molecule that have existed in cells at some point in the past. That fact, which SCOTUS convenient ignored, is sufficient to override the idea that cDNA molecules can be patented.

Anyway, your comment about oncogenes again shows you haven't read Biology of Cancer. if you read the first four chapters, it works out the history through which we worked out the understand of oncogenes. And the history is different from what we know now to be the prevalent mechanisms. The use of tumor viruses, which is nicely explained, demonstrates that scientists had already described the phenomenon I'm cited in the mid-1970's. That phenomenon wasn't really followed up on after the mid-80s, when people got better mechanisms and a larger understanding of cancer. But if you go back to the tumor virus literature and really understand it at a fundamental level, you have to acknowledge that BRCA cDNAs identical to the Myriad patent have almost certainly existed in both free (nucleoplasm) and integrated forms in at least one cell in the past. Whether that cell survived, is irrelevant.

yeah, I said I hadn't read it, about 6 comments up. Also, BRCA isn't an oncogene, it's a tumor suppresor gene.

Finally, if you think an existence proof is going to break a patent, I wish you luck in your future pursuits in life.

anyway, if you're really so hung up on this, let's drop the viral intermediate and focus just on pseudogenes (instead of viral retropseudogenes), which are exactly the thing I described in my first comment.

http://en.wikipedia.org/wiki/Pseudogene#Processed

so, if you want to demonstrate your claim, you would need to write a script that showed that there was no pseudogene that ever inserted at a nonspecific site. You can't show that. ergo, my proposal is more likely than yours. Further, it's support by evidence- for example, the genome is studded with p53 pseudogenes that reintegrated from cDNA nonspecifically.

I am unable to affirm those details on my own knowledge or even my own belief.

I wish more public officials would show this kind of honesty, esp. those voting on new laws and regulations. I am waiting for the first politician to come foward with a "I have no idea of this stuff, can anyone of my constituents explain to me how and why to vote on that" message.

> I am waiting for the first politician to come foward with a "I have no idea of this stuff, can anyone of my constituents explain to me how and why to vote on that" message.

I suspect all too many of their constituents would be very happy to explain how they should vote on all sorts of matters. Getting peoples' opinions is the easy bit, working out which ones are worth listening to is the challenge.

Maybe we should just go with the most prevalent opinion on any issue. But, besides the practical issues, we can all probably think of at least one issue where we think the majority of people have got it wrong. We'd like our reasons to be considered, not just our numbers.

> "I have no idea of this stuff, can anyone of my constituents explain to me how and why to vote on that"

That is precisely the primary function of lobbyists, as distasteful as it sounds when that word is used.

Many lobbyists also buy access, which is a separate problem.

Can you imagine the disastrous mess Congress would create if they knew even _less_ than they already know about the areas they're legislating? This is why regulating lobbying is hard; at root it's just citizens speaking to elected leaders (again, until money gets involved).

But they surely don't have a patent on all cDNA synthesis techniques, especially given that that is a highly generic technique (it should fall under the "obvious from previous art" criteria). So other companies should be able to utilize a cDNA as well so long as they don't simply follow the Myriad protocol?

I believe they just have a patent on these particular cDNA types, namely cDNA created from BRCA1 or BRCA2, and not on the well-known lab techniques for creating them.

I believe you are correct here.

I don't know the details, I only browsed through the front matter/syllabus, and I've certainly not read the patent in question.

Their patent isn't on technique ("method" in the ruling), but on the actual cDNA sequence itself. As such, it's specific to the two BRCA genes.

Of course, that just makes it even more ridiculous.

I guess my question is, do they still have a patent on any BRCA1/2 cDNA or only that specifically created according to their method?

According to the ruling, their patent specifies a sequence of nucleotides of cDNA independent of any method used to create them. I read that to mean that any BRCA1 or BRCA2 cDNA that matches that exact sequence would be infringing on Myriad's patent, regardless of how it was created.

Yes, that's correct. Also, keep in mind:

"First, the case is only about whether genes are patentable subject matter; that is, are they the kinds of things that are eligible for patent protection under section 101 of the Patent Act, assuming that all other requirements for patentability are met. Even if the Supreme Court rules in favor of gene patents here, every gene patent would still have to pass the tests of novelty (section 102) and nonobviousness (section 103), and to be the subject of an adequately explicit written description (section 112)."

That's taken from this legal genomics blog: http://www.genomicslawreport.com/index.php/2013/05/01/some-t...

Highly recommend all of their articles if you are interested in this kind of thing.

But there are ways of detecting BRCA mutations without cDNA right? What does 23andme use? Isn't that a chip based method? And straight genome sequencing which should be cheap enough in a few years is another way around it, no?

yeah, but no one uses cDNA synthesis to do genotyping anymore. They use genechips or direct sequencincg. Direct sequencing is NOT covered by the myriad patent; and genechips use such short DNA sequences that the 'intron' exception doesn't hold.

While its not a complete win I think this is an ok compromise. Clearly Myriad is going to be impacted as other people come up with ways to test for the BRCA1 and BRCA2 genes without infringing on their process, and it will make screening for these genes much less expensive.

But it leaves open the question of "infringement" on cDNA when you aren't party to the creation. Specifically the guys who have GMO Wheat growing in their field in Oregon, if they didn't put it there, they didn't know it had become GMO, and it was only discovered when Japan tested it, then what is their liability? And what is Monsanto's? (GMO Wheat isn't approved) I suspect these "escapes" of cDNA will become more common and the "factories" producing them, things like e.coli and algae, won't really respect the owner's rights here. :-)

This should give Myriad a new incentive to develop less expensive tests for this gene. They should already have a head start.

cDNA synthesis is very cheap, a few cents per base. They do like everyone else: charge whatever the market will bear, and, quite frankly, in healthcare this isn't something anyone should be comfortable with.

Relevant: Idaho farmers sue Monsanto over GMO wheat

http://www.idahostatesman.com/2013/06/12/2613756/idaho-farme...

I do not see how there is any cDNA involved in a plant that has modified genes.

Are you assuming that the plant is infected with a retrovirus?

A genome with a modified gene is not cDNA, and I'm not sure how to parse your comment so I'm basically trying to see if there was an error in your comment or an error in my reading of it.

If you read the opinion that this thread links, you will see that Supreme court defines 'cDNA' as 'not naturally occurring'. In Monsanto's case, they inserted genes into crops to make them resistant to one of their own herbicides. That crosses the threshold of 'not naturally occurring' and then becomes cDNA in the context of this ruling.

An mRNA strand that is about to be translated into a protein has the introns removed, so how is the cDNA different enough from the naturally occurring mRNA other than it is a mirror image?

Also, when did cDNA come to mean composite DNA instead of complementary DNA? This seems made up to imply some kind of invention instead of it just being the mirror image of the DNA molecule.

It doesn't matter that cDNA is similar to something found in nature. The fact is that DNA complementary to the mature spliced mRNA sequences of the BRCA1/2 genes does not exist in nature.

wrong. this happens in retroviral transmission all the time.

To my knowledge, the BRCA1 mature mRNA sequence has not been shown to be reverse-transcribed during any part of the life cycle of any retrovirus.

given that retroviruses are sloppy, basically any any all genes have at some time been reverse transcribed.

True, but that's a tenuous argument. You can't prove that a particular gene has been reverse transcribed and that its cDNA is therefore a naturally-occurring product, unless that cDNA is essential to the virus' life cycle. To invalidate the patent, you would probably have to actually observe the natural reverse transcription of the complete sequence.

In any case, the original point I was trying to make was that the natural occurrence of the mRNA does not make the cDNA a naturally occurring product.

This really sounds like hair splitting to me. Along the lines of saying "well, your software patent is for a program that is stored on a GMR disk platter. Mine's stored in NAND flash, and that's never been done before!"

If the sequence is logically equivalent but stored on a different medium, how is that novel? The invention of the new medium or new techniques for transcribing between media may be, but the sequence itself isn't.

Not exactly. DNA and RNA are structurally only slightly different, but functionally, in the context of a biological system, they are very different. A technical analogy might be RAM vs disk.

It is probably more accurate to say that cDNA represents a snapshot in time of a particular mRNA "species". Any particular mRNA could lead different lives, depending on what kind of post-translational modifications are made to it (e.g. different proteins editing the mRNA differently before it is eventually transcribed).

So any particular mRNA might actually have several different products, or may just get chopped up into shRNA or microRNA.

I am a biologist (who regularly sequences cDNA), and it is properly understood to mean complementary DNA. In fact, the syllabus' description of the process is far enough from what the process of actually making cDNA is like that it seems to me there could be grounds for a challenge, even though as others have noted, cDNA is no longer widely used for these kinds of diagnostics.

The syllabus is not part of the decision and has no legal effect (it says this at the top of every syllabus), so wouldn't be grounds for a challenge.

http://en.wikipedia.org/wiki/United_States_v._Detroit_Timber...

I'm generally opposed to patents, but I think this decision is crazy. For starters, the patentability of a gene now depends on whether or not there's an intron in that gene? The isolated sequence doesn't exist as a molecule in nature, and the patent was a patent on that molecule. Should have been a straightforward "gene patents (the way they were done by myriad) are allowed". Keeping in mind, there are a ton of very facile ways of breaking such a gene patent.

EDIT: Actually I'm completely opposed to patents.

EDIT2: Here is a more detailed analysis - I didn't post it earlier since dreamhost was down. http://www.indysci.org/mission/onpatenting.html

This decision affirms a previous decision that synthetic modifications to DNA sequences are patented - regardless of whether they have introns. You see, the ruling suggests that the act of creating a new synthetic, modified DNA molecule (in this case without introns) is patent-able. (Not a comment on your opinion about patents, only the part about patentability relying on introns.)

can you link to this previous decision?

"In Chakrabarty, scientists added four plasmids to a bacte- rium, which enabled it to break down various components of crude oil. 447 U. S., at 305, and n. 1. The Court held that the modified bacterium was patentable." Diamond v. Chakrabarty, 447 U. S. 303, 309 (1980), If I am reading this correctly.

EDIT: Sorry I re-read my original comment - I meant "synthetic modifications", not necessarily only to DNA, but to natural products in general.

I think I was confused because you meant "patentable", not "patented".

But is not isolation by PCR a synthetic modification? If I made a useful machine out of a single piece of wood using a six-axis subtractive tooling device, would you argue that the machine is unpatentable because "it was already there"?

PCR actually goes even further - conceptually it's subtractive procedure but it actually does so by creating copies within the specific boundaries. These boundaries don't exist in nature, the act of specifying the boundaries is creative, and without the prior research, non-obvious.

Yes, sorry I meant patentable. This ruling specifically says that merely identifying the location of a gene and isolating it is not a patentable transformation. PCR is not transformative because the dsDNA molecule exists in nature. I think in this context isolation is similar in nature to discovery, which is not a patentable activity.

well, no, the supreme court has decided that effectively breaking four covalent bonds is not transformative (your words). I think it's a wrong decision. Even so, if you actually understand it, the act of PCR is an act of creation, not transformation. That dsDNA molecule doesn't exist in nature.

For example, there is a molecule thiostrepton which is an antibiotic compound, that's really quite poor. They have recently discovered that only the core of the molecule is necessary for antibiosis, and removal of the rest of the molecule improves its pharmacological properties. It's a distinct molecule, created by the scission of 3 covalent bonds. Should it be unpatentable? Almost certainly, somewhere in nature, there has a thiostrepton molecule that by accident happened to have been cleaved at exactly the right places to render the molecule. does that change your opinion?

I am not trying to defend the practice - I abhor patents - but a lot of people are letting their emotional reaction to "patenting genes" get in the way of a dispassionate and informed analysis of what actually is going on here.

Your perspective is confusing. You say that a modified form of thiostrepton should not be patentable, even though the patent protects the molecule as well as the process of chemical synthesis or purification, which often requires significant innovation, and in this case the natural molecule is also significantly modified. On the other hand, when you PCR something you are generating a dsDNA molecule that is identical to the original molecule. I understand PCR quite well, and doing PCR is not innovative or transformative. You are creating something, sure, but it's an exact copy of something that exists in nature. The Supreme Court clearly states here that merely finding out where a genetic sequence is and isolating it is not patentable. The process of PCR itself is an invention, and is patented (Cetus, Mullis).

It seems preposterous to say that you are strongly against patents, and then say you think the patent should be much more restrictive. I have no emotional reaction to patenting genes. I think patenting a significant modification of a naturally occurring substance is completely reasonable as it protects the investments involved in inventing and applying the modifications, while at the same time allowing others to use and understand the development. Without patents biotech would become full of trade secrets, holding back progress in the field.

Yeah, i'm against patents, but i think if we have them they should be applied fairly and according to a clear set of rules instead. It's like saying, I'm opposed to government being involved in marriage, but if we are going to have it then homosexuals should be allowed to be married.

The only reason why the perspective seems confusing is because you're conflating process with molecules. In general any given claim of a patent can protect the molecule or the process. Myriad did not choose to claim the process, because the process is obvious. But having a process that is obvious does not necessarily make the molecule obvious.

Doing PCR is not innovative. But the process DOES transform one molecule into another, unless your primers are exactly flush with the end of the dsDNA - in which case it is merely a straight copying operation. OK? The molecule that comes out at the end has a different covalent structure than the molecule that you start with. Is that not true? if you don't believe that, then you would make the claim that octane 'is the same as' dodecane, because it's just a truncated version.

Also, it is not an exact copy of something in nature, unless that 'thing' is a data fragment. It is an original molecule, that copies the data, but the molecule is distinct. That is an important point. Molecule patents don't care about the abstract qualities of something (beyond proving that it's useful). Molecule patents only care about the structure of the molecule.

addendum:

I am happy with the SCOTUS decision though from a pragmatic point of view, because there is a prokaryotic gene I'd like to "steal", that's under patent application right now of course prokaryotic genes have no introns, so I just got a field day on it.

While the second part is a bit disappointing. Does that mean if you manage to successfully isolate a natural version of a patented cDNA, then that patent becomes effectively invalid?

In practice this might not be the hardest thing to do. Do you like someone's engineered version of a gene? Then transform some randomized libraries into cell cultures (or add mutagens) and keep fishing until you extract a "natural" copy that is the same as the patented cDNA.

There's a new TV series that touches upon this - Orphan Black.

---- Spoilers, obviously ----

So they're clones, and they have a "special repeating marker" of some sorts. One of the clones is a biochemist, and she manages to decode it. Turns out, it is a copyright message covering those organisms and their biological offspring as property of X corporation. -------- Spooky, but wouldn't the message get diluted after reproduction?

From what I understand, the likelihood of any cistron in the genetic code getting diluted is dependent on the sequence length compared to the overall length of the chromosome on which it can be found.

However, since this is sci-fi, it may be possible that some of the genetic sequence is setup to actually alter the meiosis process and not perform any "crossing over" events in egg cell construction.

Can anyone with experience clarify this ruling? Is the SCOTUS saying that just because the specific cDNA strand doesn't exist in nature (as far as I know), then it is patentable?

Correct me if I misunderstood the ruling, but it seems to be absolutely ridiculous. You could just automate the process of isolating genes, sequencing them and statistically identifying their mRNA strands, isolating them, and creating cDNA strands. I know this isn't technically "nonobvious" but if you can automate the process to the point where you have robots spitting out gene patents, then it's a pretty low bar.

The process of making cDNA libraries (with and without robots) has long been solved. Usually in order to get a patent you need to prove "usefulness" which is not really automatable.

And if you want to read my writeup (which is slightly geared toward explaining the biology from simple first principles, http://www.indysci.org/mission/onpatenting.html)

Darn, well there goes my plan to patent myself and require that my wife buy a license before she can bear my children.

I imagine next generations paying the Monsanto(s) of synthetic DNA...

I think you would find a lot of competition that would be willing to provide the required service at zero cost.

Copyright would be more appropriate there. Children could be considered derivative works, but I don't see how they could be patent infringement.

You are a transformative work based on your dna anyway.

You're only licensing the patent from your parents anyway.

Does this mean we'll soon see 1000s more SNPs available from 23andme? What are the biggest new SNP's they can test for?

It absolutely should mean this. Maybe 23andme can be something more than a toy.

What are some examples of exciting new SNPs they could test for? Besides BRCA.

A quick Google search for "patented disease alleles" suggests Crohn's disease, some forms of kidney disease, diabetes, and many more!

At one point I heard that some farmers, who were unaware that their crops contained patented genetic modifications as a result of uncontrolled natural reproduction with other GM crops, were being sued by patent holders. Does this ruling weigh in on this scenario?

It seems that inventions which copy themselves and masquerade in difficult/expensive to detect ways (see plant reproduction, airborne pollen) wasn't something foreseen by those who wrote our patent laws.

This seems to be a myth: http://www.npr.org/blogs/thesalt/2012/10/18/163034053/top-fi...

I think the patents there relate to the combination and use of genes, not the genes themselves, so it's not.

The famous case about that didn't actually hinge on whether GM crops had turned up on a farm unexpectedly, but on whether the farmer had then deliberately selected seed from the GM plants to replant the next year's crop.

A co-worker in my lab pointed out that Myriad's stock is actually rising[1] after the decision.The best guess is that Myriad's competitive advantage is shifting to the enormous amounts of BRCA sequences they have obtained -- this would increase the cancer-vs-normal mutation prediction power considerably.

[1] - http://www.google.com/finance?cid=658315

Also, they now have legal certainty whereas before the decision there was a chance the whole kit and kaboodle would have been tossed out.

Not anymore.

Michael Crichton's novel "Next"[1] was a fantastic exploration of the implications of such issues being brought up here like: liability when the infringing patents are in you, in animals, in human-animal hybrids capable of human-level intelligence, and how the world deals with life when Man plays god.

Another excellent book on the ethics of bio-engineering and patentability is the true story, "The Immortal Life of Henrietta Lacks."[2]

[1] http://en.wikipedia.org/wiki/Next_(novel) [2] http://www.amazon.com/The-Immortal-Life-Henrietta-Lacks/dp/1...

This sets the stage for a simple way to overturn any cDNA patent. Somewhere in the body of any person infected with a retrovirus such as HIV exists a completely natural molecule of BRCA1 cDNA.

I'm pretty sure prior art doesn't work that way.

Isn't the standard here whether or not these molecules exist in nature? Honest question.

You can't just assert that it exists. You'd have to show that it exists.

That should be trivial, if you had a large sample and money for sequencing. The consensus in the listservs I'm on is that cDNA patentability will fall next because of these and other inconsistencies (cDNA existing in nature, being a non-natural transformation).

That hinges on the definition of non-natural. Is a nuclear reactor non-natural? Are you sure? http://en.wikipedia.org/wiki/Natural_nuclear_fission_reactor

Just because you're using components that exist in nature that may come together and occasionally produce the result you want - when a human hand enters the picture to do it deliberately and get a controlled result, to gain a certain end, that's qualifies it as non-natural.

cDNAs do not "exist in nature" the way you think they do. Viral RTs typically hijack a tRNA for use as a primer, and there is a specific tRNA footprint site that is necessary to initiate RT specifically at the position of interest to the virus. these footprint sites typically don't exist near the gene you care about.

This is the right result. Great news.

What if your life is saved from the debilitating effects of an enzyme deficiency by a virally-delivered sequence which also infects your spermatocytes (1)? And that sequence is passed to your child?

(1) http://en.wikipedia.org/wiki/Testicular_immunology#The_effec...

> The nucleotides that code for amino acids are “exons,” and those that do not are “introns.”

Should read "the nucleotide sequences". If they can't get the definitions right, why is the rest of the opinion valid?

Is it time for a "Court of Science" at the district or appellate level?

Do they allow patenting a DNA sequence specified by a regular expression or a grammar? Also, what happens if the synthetic DNA is later found to exist naturally?

Kind of wondering, did Clarence Thomas actually write this, or did it fall to some young law clerk that had to take a crash course on molecular genetics?

Isn't all synthetic DNA based on natural DNA?

No. Natural DNA occurs in nature, much like a the alignment of magnetic fields may occur in some metals. Synthetic DNA has been designed by someone who sat down and said "Okay, today we're going to write DNA, it's sequence will be ACGTTTGACGTACGTTCAGTG....." and we're going to mix our newly designed gene into a larger natural DNA strand and this synthetic gene inside of the DNA will make this tree glow a very slight yellow-tinge, then we're going to sell that on kickstarter. http://www.kickstarter.com/projects/antonyevans/glowing-plan... (the only reason they're using a larger DNA strand is a full strand might cost in the range of $100b-$1t presently)

This is not the same as what's been done more frequently for the last long while which was dissecting existing genes from other DNA strands (lets say gene XYZ from a starfish) and introducing it into a bacteria.

Also, this doesn't mean I agree with the new law. I think this motion is even more nonsensical than software patents we face today, and has already handed off all the wonderful innovations that the synthetic biology revolution has to offer to a nation who's pumping loads of cash into this sector: China.

Idiotic decision. DNA should not be patentable.

What if you engineer a completely novel protein, with novel regulatory sequences, for a novel function? Should you be unable to patent such an invention?

No, I principally think than biosubstances should not be patentable. The fact that DNA was generated artificially doesn't make it somehow magically different from the natural one.

What I'm referring to is not only synthesis (artificially generating), but design and engineering. This is substantively different than natural products, in that they are truly invented.

The problem I have with it is that, in all cases, any synthetic DNA could exist in nature. We can't even verify with 100% certainty that any given sequence doesn't already exist in nature. If it doesn't exist already, it could in the future, naturally, through evolution.

As I pointed out to shmerl above, sequence space is very large, and in general sparsely populated. A functional gene product and regulatory sequence is often thousands of base pairs. 4^1000 = 10^600. There are only 10^80 molecules in the universe. So if you have done truly de novo design, you can be pretty sure it doesn't exist somewhere else by random chance.

That being said, I think that even if you take a natural gene and modify it meaningfully - that should be patent-able. For instance, if you take an enzyme and engineer a version that doesn't degrade as readily, or has much better activity, that should be patent-able, don't you think?

EDIT: There's a good deal of prior art regarding numbers. As for patenting molecules, we allow that all the time... drugs, compounds, etc. Because they are discovered as I describe above.

Again, getting into arguments of making molecules patentable because there are so many combinations available is bizarre. Why not make numbers patentable as well - there is an infinite amount of them.

Honestly, no, it should not be patentable. This is entirely equivalent to a software patent.

Really? Say goodbye to the promise of synthetic biology then!

You can say goodbye to it if that will be patentable. Someone will patent all combinations - and goodbye.

I suspect you are a troll, but I will respond anyway...

Sequence space is very large. There are only a total of 8 million US patents. There are 16 million 12-base-pair nucleotide sequences. To patent the sequence space of a functional product and regulatory region would require more patents than there are molecules in the universe.

Also to patent something you have to show use.

I was showing sarcasm. Patenting a molecule is a ridiculous idea, but you insist that it's about the process of making it. I'm pointing out that the result is not about the process, but about the molecule.

I genuinely don't understand your point.

If a group of people synthesize and test many synthetic DNA sequences and then patent the useful ones, that seems fine to me. You might even call them "synthetic biologists". They have invented new things, which are not found in nature, by the process of their own skills, knowledge, and labor, and which are useful to other people. It seems perfectly reasonable that those inventions should be protected by the patent system.

I find the concept of patenting new biological entities rather scary and dangerous. They should not be patentable. Patent system is easily abused for many things unrelated to encouraging innovation. Therefore there is nothing reasonable in allowing these patents just because it takes time and effort to come up with synthesis method.

Unjustified fear is not a rational basis for policy.

It's not the synthesis method that is at stake here, it is the engineered biological system itself (system referring to a gene, regulatory sequence, genetic pathway, or organism). The kind of innovation involved in this kind of engineering is precisely what the patent system is designed to protect, so that it can be monetized while also disseminated. Without patents these innovations will remain trade secrets and hold back the progress of synthetic biology. Without patents private companies may not be able to justify investment required for innovation. Without patents inability to monetize inventions reduces the overall economic impact (return on investment) for public financing of life sciences, which in turn removes a powerful incentive for government financing of research.

For instance, a company finds a compound that fights cancer. The company invents a way to synthesize or purify this compound and sell it. The patent protects the inventor and allows them to recoup the investment. This is widely accepted. Now consider that company engineers an organism that can produce the compound in large bio-reactors. The modified organism - and in particular the engineered DNA sequences - are completely analogous to the chemical manufacturing process, and should be similarly protected.

Moreover, consider that the second process may remove a need to use the organic carbon precursors necessary for chemical synthesis (fossil fuels), or eliminates a toxic by-product of chemical synthesis, or is much cheaper and therefore reduces the cost of the compound, benefiting the public. These are real world consequences of synthetic biology protected by the patent system. They don't seem so scary to me.

In general I find the patentability of medicines a very abused practice. Pharma industry is one of the most corrupted, and especially when it comes to patents. So your example serves do disprove your point.

At least I have provided clear arguments. You have continued to make assertions (such as pharma being corrupted with respect to patents) without any kind of proof or even a clear argument as to why this is the case. I suggest you consider not taking any drug developed under or protected by US patent law in protest.

Well, many don't just consider - but simply can't take them. Because of the price, controlled by those who acquired the patent. When life saving medicine becomes a business for the sake of money - that's already bad.

Except that we're back in the physical world again. It's basically a very small machine at that point, one with the purpose of producing a certain protein.

I can live with this: As a general rule of thumb nature isolated is not patentable, Synthetic is.

You can make synthetic DNA?!?

Yes. This has been around for several decades. Furthermore, you can request companies on the internet to synthesize sequences for you and mail you the results.

(First result from google)

http://www.invitrogen.com/

Wikipedia Article

http://en.wikipedia.org/wiki/Artificial_gene_synthesis

Yes. It's basically a really cool version of an ink jet printer powered by sugar. A few labs will print out your sequence, pack it into a dead cell, freeze it and ship it to you.

Obviously there's more to it than this really simplified statement but that's what goes on at a high-level. There's a number of people writing software for projects to help anyone author synthetic DNA (see http://synbiota.ca/ ) and start playing with this stuff, just as we do with makerbots or the PC revolution of yesteryear.

interesting side effect - prokaryotic genes are basically unpatentable!!

Yes! Finally some forward progress. Still needs work though.

sweeeet... sanity prevails!

Patents are silly !

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