The Non-obviousness of DNA

    By Kevin E. Noonan --

The recent discussion of the Federal Circuit's decision in the In re Kubin case suggests there may be some misunderstanding of the science behind the legal question of obviousness.  Because obviousness is a question of law based heavily on underlying issues of fact, it is important for commentators as well as judges to have some understanding of the underlying science.  The Federal Circuit's decision in the Kubin case illustrates the possible consequences of misunderstanding, or of Judge Rich's recitation of the "rudiments" of biotechnology from In re O'Farrell as somehow conferring on appellate judges the illusion that their understanding is per se sufficient.

We must start, generally and classically, with a protein.  (The complications involved with the massive amount of sequence information generated by the Human Genome Project will be discussed separately below.)  Proteins, and the extent of knowledge in the prior art about proteins, varies enormously, from simple knowledge of its existence (as in Kubin) to a complete determination of the amino acid sequence of the protein, as in In re Bell.  Knowledge commensurate with Bell limits the scope of any claim for a gene encoding the protein to the specific nucleotide sequence of the isolated cDNA.  This is because of the degeneracy of the genetic code:  there are multiple codons for all but two of the 20 naturally-occurring amino acids, so the number of possible nucleotide sequences for any amino acid sequence is typically astronomical -- the number of possible nucleotide sequences that could encode the insulin-like growth factor in the Bell case was 10³⁶ (for a protein encoded by 70 amino acids).  Non-obviousness on these grounds is Federal Circuit precedent from the Bell case, and neither Kubin nor KSR International Co. v. Teleflex Inc. overrules it (unless 10³⁶ can be considered a "small" number of predicable solutions).

More typically, only partial amino acid sequence information from a protein is known in the art, of variable reliability (albeit the reliability has improved over the past 25 years).  This knowledge is used to produce probes for screening libraries prepared according to the Sambrook reference, but the predictability of being able to isolate a cDNA encoding the desired protein depends on whether the amino acid sequence known in the art can produce a degenerate probe that reliably detects a cDNA clone in the library.  Alternatively, longer probes can be developed depending on conserved functional motifs in the encoded protein (such as ATP-binding cassettes or G-protein coupled receptors).  However, the efficiency of using such probes depends on how closely conserved the particular motif is in the protein of interest, which is frequently not known in the prior art.  (As in Kubin, there are also ways of screening that rely on expression of antigenic epitopes of the protein of interest that are detected by antibodies, but the principles are the same.)

This screening step depends upon more that the quality of the probe, however.  Most importantly, the art needs to provide a source for messenger RNA that can be used to make the cDNA library.  In addition, the cell or tissue source must make enough of the specific mRNA to be cloned so that its representation in the library (i.e., the number of cDNAs produced from the specific mRNA) is high enough to be detected.  This is because cells and tissues express mRNAs in generally broad classes of abundance:  structural proteins like actin and tubulin are expressed at high abundance, while cell- or tissue-specific genes are frequently expressed at low abundance.  While there may be some clues in the art about cell or tissue sources of an mRNA and the expression abundance thereof, these are generally gene-specific factual matters that cannot be presumed when making an obviousness determination.  This is why Judge Rader (at left) was incorrect when he said "No, [Sambrook] tells one of skill in the art how to produce those libraries, and when you [have] the probe it's not so hard to do" during the Kubin oral argument, since Sambrook did not provide any teaching on what cells to use or how to treat them to stimulate production of NAIL-encoding mRNA to detectable levels.

Now we come to the Human Genome Project (HGP), which has put lots of sequences into public databases and impacts both anticipation and obviousness.  For anticipation, there will frequently be In re Hall issues raised:  was the sequence sufficiently annotated so that the skilled worker would recognize it in the database?  This is not a trivial question, due to one of the vagaries of genome structure (at least in most eukaryotic organisms like mammals and vertebrates).  This feature is that genes are not set forth "in one piece" in the genomic DNA (which is the DNA sequenced in the Human Genome Project).  Instead, the gene sequences encoding a protein are broken up by non-coding sequences (variably termed "intervening sequences," "introns" or "junk DNA").  This gives the typical gene the structure (see link):  beginning of protein code -- intron -- continuing protein code -- intron -- end of protein code.

When the gene sequence is transcribed into RNA, at first the whole sequence, coding and introns alike are transcribed.  Then, cellular enzymes splice out the introns, leaving the mRNA with the coding sequence arranged in one contiguous piece.  cDNA is prepared from mRNA because it has the coding sequence in this linear fashion and has the least amount of "extra" RNA, usually at each end.  This makes cDNA cloning much more efficient that genomic cloning.

But these aspects of cellular biology have consequences for what we can tell from the HGP data.  First, is the data is present in the database in such a way that the skilled worker would be able to identify the "open reading frames" (i.e., portions of genomic DNA that could potentially be translated into protein via an mRNA intermediate) that encode the complete gene.  This is not always the case, because a gene made up of 1,000 nucleotides may have introns that are 35,000 nucleotides in length.  Certainly, as the data has been analyzed more and more vigorously these sequences have become more and more accessible and algorithms are available having the capacity to detect open reading frames separated by large intron sequences and to identify properly positioned splice sites that would predict how these open reading frames could be assembled into an mRNA encoding the desired protein.  Thus, it has become more and more likely that the Hall conditions will be satisfied.  But this will be a fact-specific question to be answered anew for each gene under consideration.  For example, transcripts can be alternatively spliced in some instances and if the art did not disclose this the cDNA ultimately obtained would not be anticipated by the "predicted" sequence in the HGP data.

Returning to obviousness, one of the hallmark discoveries of the HGP is the detection of genes (and hence proteins) otherwise never before identified or suspected; this is particularly true of members of multigene families, especially those more distantly related by evolution.  It seems that these genes should fall outside the Kubin standard of DNA obviousness because they lack the fundamental predicate of the decision:  knowledge in the art that the protein existed in the first place.  Indeed, the issue over the patentability of these genes has not been (and should not be after Kubin) whether they were obvious; the issue is whether applicants claiming these genes know (and disclose in their applications) the function of the encoded protein, its activity, in order to satisfy the utility requirements of 35 U.S.C. § 101.  So it isn't as easy as looking up open reading frames in a database and filing a patent application for these "unknown" genes identified through the HGP.

It is fair to ask, if these are all the reasons why the Kubin sequence is non-obvious, under what circumstances could it be obvious?  I think these factors would support an obviousness determination:  the protein was known to exist in the prior art; the art identifies a cell or tissue type that expresses the gene of interest in amounts that permit cDNA from that gene to be represented in the library at levels (>1 clone in 100,000, for example) where the clones would be readily detectable (whether natively or as the result of some experimental treatment or manipulation); the art provides a probe (whether stemming from a reliable amino acid sequence encoded by a sufficiently non-degenerate collection of oligonucleotides or with a monoclonal antibody such as Valiante's C1.7 mAb) that efficiently detects the desired cDNA sequence; and the cDNA contained no features (hairpin structures, alternative splice sites, other anomalies) that would preclude or prevent cloning using conventional methods.

Dwight Eisenhower said "[f]arming looks mighty easy when your plow is a pencil and you're a thousand miles from the corn field."  (Hat tip to zimmer at Patently-O for the quote.)  It appears that isolating cDNA clones looks equally easy to Examiners, APJs, and Federal Circuit judges when they fail to consider the underlying facts.  Neither is a good idea, nor good for the country.

Comments

[Bill Piscuitowicz]

Hold on now. I thought we were still in the "unpredictable arts such as chemistry and biology" world. Thank God now Kubin will save me from ever getting another one of those bogus enablement rejections based on case law that's now 15 years old.

Oh wait. The PTO will have its cake and eat it, too. I forgot. Never mind.

[SK]

Why isn't Valiante's mention of NK cell library not enough for obviousness? Skilled artisans working with immune cells necessarily know that to get a decent amount of mRNA, one needs to activate them. Matthew, even though with mouse, fills that gap. I agree with your overall analysis, but there cannot be a bright-line rule that designates all cDNAs as obvious or non-obvious if a partial amino acid sequence and a possible method of isolation is known. I am not convinced of the 10e36 argument. If there is a specific DNA probe, let's say 21 bp, it is sufficient to pick out the full-length target of 1000 bp even though there may be 10e36 combinations. I don't think KSR prevents someone from doing a one-step experiment to reduce the possibilities to being finite.

[Kevin E. Noonan]

Dear SK:

As far as I know, there was no teaching in Valiante or Matthew about activating the NK cells; I think (I could be wrong) that mouse cells may be different from human cells in that regard. And keep in mind that the art did not recognize that Matthew's 2B4 cDNA was NAIL, so the Board at least limited it use of Matthew to showing that following Valiante + Sambrook would predictably produce NAIL cDNA. If mouse cells and human cells have different activation requirements, then the human cDNA should be non-obvious because obtaining it, while maybe obvious to try would have met with unexpected results (i.e., not being able to obtain it following the prior art).

As for the Bell analysis, that was different from Deuel. There, the argument was that what was claimed was 1 out of 10^36 sequences, and the skilled worker would not have been able to predictably identify that specific sequence. Still seems like a proper distinction (and the claim scope is so narrow that it shouldn't pose problems for the "promote the progress" crowd - indeed, since the claim doesn't cover anything but the sequence, it enables the skilled worker to produce any other sequence without (literal) infringement).

I also agree that there should be a bright line rule - indeed, Deuel was a reaction against another PTO per se obviousness determination (protein known in the prior art + Sambrook = obvious). I think there may be situations where the result is so predictable (something which has become more likely in the time since Deuel due to technology improvements) that it may be obvious because 1) it is obvious to try and 2) the level of predictability makes what is obvious to try also obvious. I think what Judge Lourie was saying in Deuel was that JUST because something is obvious to try doesn't mean it is necessarily obvious. Of course, O'Farrell stands for the reasonable proposition that sometimes something that is obvious to try is also obvious, and KSR sets forth the Supreme Court's delineation of when that "sometimes" applies - a small number of known alternative solutions to a recognized problem that perform as expected by the skilled artisan.

The PTO's problem is that they consistently applied these rubrics to the method rather than the composition - the cDNA - claimed. Which is what Deuel stands for, not as a bright line rule but as the antidote to a PTO bright line rule.

Thanks for the comment.

[Kevin E. Noonan]

Dear Bill:

The PTO always eats its cake and has it too, but sometimes the chickens come home to roost (see posts about 10% reduction in applications and massive shortfalls in funding due to lower allowance rates, higher abandonment rates and fewer maintenance fee payments).

The pendulum will swing back, and soon I suspect.

Thanks for the comment.

[Grimace]

You say: Knowledge commensurate with Bell limits the scope of any claim for a gene encoding the protein to the specific nucleotide sequence of the isolated cDNA. Non-obviousness on these grounds is Federal Circuit precedent from the Bell case, and neither Kubin nor KSR International Co. v. Teleflex Inc. overrules it...

I find that odd, a genus of nucleotides is obvious, but no particular one is? What exactly is within the possession of the public then? So Kubin could have just claimed each species separately?

I disagree, and I think that what is obvious under Kubin is the sequence found in Rader's cells, or maybe the sequences in available cultured cells, and that sequences other than that might be obvious.

[Kevin E. Noonan]

Dear Grimace:

It is frequently the case that a species is non-obvious over a genus, provided that it embodies an unexpected result. Here, it would be that out of the 10^36 possible sequences, the one Bell claimed was the "human" sequence.

From a chemical context, a species anticipates a genus, and since anticipation is the epitome of obviousness it is consistent that a different species would not be obvious, absent any reason the skilled artisan would have had to choose that species.

Certainly one of the problems in Kubin was the breadth of the claims (although written description provided a better ground for findng the claims invalid).

Thanks for the comment.

[Grimace]

Kevin

I understand that a given species might be patentable over a genus. What I don't understand is when EVERY species is patentable over a genus.

Is the fed cir telling patentees to crank out the permutations and pop in a ridiculous markush? The reasoning articulated above leads one there.

[Kevin E. Noonan]

Dear Grimace:

That was the objection in the Gleave case (for different reasons).

I think the link is the "surprising and unexpected" result that Bell's 1 nucleotide sequence (out of the 10^36 possible sequences) was "the" human sequence. So that a further listing of alternative sequences, without more, would not get the non-obvious determination.

Thanks for the comment.

[Keep It Real]

Kevin: "This is because of the degeneracy of the genetic code: there are multiple codons for all but two of the 20 naturally-occurring amino acids, so the number of possible nucleotide sequences for any amino acid sequence is typically astronomical -- the number of possible nucleotide sequences that could encode the insulin-like growth factor in the Bell case was 1036 (for a protein encoded by 70 amino acids). Non-obviousness on these grounds is Federal Circuit precedent from the Bell case, and neither Kubin nor KSR International Co. v. Teleflex Inc. overrules it (unless 1036 can be considered a "small" number of predicable solutions)."

Did Kubin's counsel raise this obvious issue during prosecution?

[Kevin E. Noonan]

Dear Keep:

Kubin's counsel was limited because their claim was the exact opposite: not only was it broader than Deuel (which was limited to a nucleotide sequence encoding a specific amino acid sequence) but it also included nucleotide sequences that were only 80% identical to the disclosed sequence (so 20 aas out of every hundred could be "non-identical").

A massive number of species. The only thing that saved them from Matthew is that the mouse NAIL cDNA was only 69% identical. So they couldn't argue that their claim was a Bell-like claim (and for some reason both the Board and the CAFC didn't discuss any of the narrower claims).

Short answer, no because it wouldn't have helped them.

Thanks for the comment.

[Bill Piscuitowicz]

Kevin:

Thanks for the reply. I think that many have given the method/composition distinction short shrift. The reliance on Sambrook is borderline laughable, in my honest opinion. So are we to assume that there will never be a patentable small organic molecule unless someone somehow comes up with a new synthesis scheme that is itself per se novel and non-obvious? That doesn't even pass the laugh test.

And taking it a step further, if the product is obvious, you can use the techniques described in Sambrook to express it in various cell types, so all the in vitro testing one might do is also obvious. And when you find a biological activity for the peptide/nucleic acid/whatever, whatever it might be is also merely obvious. Therefore, your method of use claims are also obvious.

The U.S. has been the world leader in the biotechnology game since its inception. Taking this opinion and its "logic" to its absurd extreme, which I argue the CAFC has already come very close to doing, runs the great risk of killing the industry off. You think it was hard to raise capital for a fledgling biotech recently? You ain't seen nothing yet.

[6]

"The pendulum will swing back, and soon I suspect."

You are right about that.

I haven't been able to go over all this quite yet since I just saw it. But, at a glance, I have to say this:

Kev, you realize that if the underlying facts are that complicated (and you are right, rather than wrong about the mouse reference, which from the above poster it seems like you're wrong) then Kubin should have made his case like you're doing rather than the weak attempts at high level reasoning that in no way support a finding of non-obviousness. The PTO only has to establish a prima facie case rather than a rock solid case. Kubin can always go to the DC and sue for allowance of his application, or he can file an RCE, explain all this, and get his claim allowed, and he can be more specific than you were in his explanation. Why do attorneys and applicants make conclusory statements/arguments just as often as examiners do? YOU HAVE TO SHOW THE FACTS IN THEIR ENTIRETY. Sure, the examiner may, or may not have understood all of this from the beginning, but maybe he wanted it all on the record before he just up and allowed the case. A prima facie case existed based upon the case before him n he wrote it down. The appeals court affirmed. According to your explanation, they all did their jobs 100% properly, and Kubin, or his attorney, did a miserable job. But, that's just what you say leads to. I'm not quite sure if the case could have been saved yet or not. It seems to me like, upon a glance, there are great many huge gaping holes in the factual case on either side, but Kubin doesn't highlight the holes on the PTO's side sufficiently or adequately in language. That's the applicant's job you know. 35 USC 132 iirc. Furthermore, the holes on the PTO's side might be filled by just general knowledge, but nobody talks about it if it is, so I can only presume that perhaps it is, and perhaps it isn't. But since nobody talks about it in the case specifically and adequately, the applicant's arguments would be unavailing it seems to me.

You'd be surprised the amount of times where the applicant does actually have a point or argument to make with regards to obviousness etc. but they choose to spout some incomplete nonsense or total nonsense in leiu of telling me all about it. Estoppel concerns maybe idk. Of course they get a final, and then they want to AF and get an allowance. Well, by then you're a bit late for any easy mercy, your facts/argument is going to have to be GREAT.

Now, I'll get to the merits of your argument later on.

[Kevin E. Noonan]

Dear 6:

One of the things that people who don't do this for a living (i.e., people other than patent attorneys and examiners) don't realize is that frequently it gets pretty complicated. Examiners are limited by the time they get to perform the examination, and attorneys (believe it or not) are limited by budgets, and so it isn't surprising that the outcome, or even the process, isn't always perfect.

But as long as each side is trying to do their best (and avoids the temptation to turn the other side into "the enemy") what more can we do?

Thanks for the comment.