DNA Non-obviousness under Ex parte Kubin (It Gets Worse)

    By Kevin E. Noonan --

Last week, the U.S. Patent and Trademark Office promulgated its long-awaited guidelines for Examiners in making obviousness determinations in view of the U.S. Supreme Court's decision in KSR Int'l Co. v. Teleflex Inc. (see "Patent Office Issues Examination Guidelines Regarding Obviousness after KSR").

As part of these guidelines, the Office provided various rationales available to Examiners to fulfill KSR's requirement that the factfinder provide a reasoned basis for an obviousness determination.  One such rationale dealt with the "obvious to try" issue, as discussed by the Supreme Court in KSR:

When there is motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.  If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.  In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.

The guidelines with regard to the "obvious to try" standard are set forth in Rationale E:

(E) ''Obvious to try'' - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;

(1) a finding that at the time of the invention, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem;

(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;

(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success; and

(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.

Citing KSR, the Notice requires for this rationale that an Examiner articulate facts supporting the conclusion that ''a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.  If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.  In that instance the fact that a combination was obvious to try might show that it was obvious under § 103."

The issue for biotechnology arises in Example 3 illustrating how an Examiner should apply this rationale; that Examiner relates to the Board's decision in Ex parte Kubin (see Patent Docs post on this case):

Example 3:  The claimed invention in Ex parte Kubin, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007), was an isolated nucleic acid molecule.  The claim stated that the nucleic acid encoded a particular polypeptide.  The encoded polypeptide was identified in the claim by its partially specified sequence, and by its ability to bind to a specified protein.

A prior art patent to Valiante taught the polypeptide encoded by the claimed nucleic acid, but did not disclose either the sequence of the polypeptide, or the claimed isolated nucleic acid molecule.  However, Valiante did disclose that by employing conventional methods, such as those disclosed by a prior art laboratory manual by Sambrook, the sequence of the polypeptide could be determined, and the nucleic acid molecule could be isolated.  In view of Valiante's  disclosure of the polypeptide, and of routine prior art methods for sequencing the polypeptide and isolating the nucleic acid molecule, the Board found that a person of ordinary skill in the art would have had a reasonable expectation that a nucleic acid molecule within the claimed scope could have been successfully obtained.

Relying on In re Deuel, Appellant argued that it was improper for the Office to use the polypeptide of the Valiante patent together with the methods described in Sambrook to reject a claim drawn to a specific nucleic acid molecule without providing a reference showing or suggesting a structurally similar nucleic acid molecule.  Citing KSR, the Board stated that ''when there is motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.  If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.''  The Board noted that the problem facing those in the art was to isolate a specific nucleic acid, and there were a limited number of methods available to do so.  The Board concluded that the skilled artisan would have had reason to try these methods with the reasonable expectation that at least one would be successful.  Thus, isolating the specific nucleic acid molecule claimed was ''the product not of innovation but of ordinary skill and common sense.''

This is nothing more, and nothing less, than a per se obviousness standard.  According to the guidelines, the existence of an isolated polypeptide in the prior art, without more, renders obvious a claim to a nucleic acid encoding the polypeptide.  Note that the guidelines do not require that even a partial amino acid sequence of the prior art polypeptide be known, nor does it require that a cell or tissue source of the protein be known, to raise a prima facie obviousness determination against a nucleic acid claim.  To put this in context, human blood clotting Factor VIII, which causes Hemophilia A, was "isolated" from fractionated blood components many years before the gene encoding the protein was isolated.  During that time, the cells producing the protein were not known; it has since been found to be produced by vascular endothelial cells.  Despite this inherent uncertainty, according to the Patent Office (no doubt having been "constantly advised by the patent examiners, who are highly skilled in this art, that cloning procedures are routine in the art"), the nucleic acid encoding Factor VIII would be prima facie obvious in view of the mere existence of a purified preparation of the protein in the art.  This rationale goes even further than the Board in Deuel, since there, the Board's obviousness decision was based on "the examiners urg[ing] that when the sequence of a protein is placed into the public domain, the gene is also placed into the public domain because of the routine nature of cloning techniques."  Here, even this requirement has been dropped.

This result is not required by KSR, and is in fact contrary to it.  The Court did not abrogate In re Deuel in the KSR decision, and the portion of KSR dealing with the "obvious to try" standard is consistent with Federal Circuit precedent, including Deuel:

It is true that this court and its predecessors have repeatedly emphasized that "obvious to try" is not the standard under §103.  However, the meaning of this maxim is sometimes lost.  Any invention that would in fact have been obvious under §103 would also have been, in a sense, obvious to try.  The question is: when is an invention that was obvious to try nevertheless nonobvious?

The admonition that "obvious to try" is not the standard under § 103 has been directed mainly at two kinds of error.  In some cases, what would have been "obvious to try" would have been to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful.  In others, what was "obvious to try" was to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it.

Obviousness does not require absolute predictability of success.  Indeed, for many inventions that seem quite obvious, there is no absolute predictability of success until the invention is reduced to practice.  There is always at least a possibility of unexpected results, that would then provide an objective basis for showing that the invention, although apparently obvious, was in law nonobvious.  For obviousness under § 103, all that is required is a reasonable expectation of success.

In re O'Farrell (Fed. Cir. 1988) (citations omitted).  Neither of these situations apply per se to isolating a nucleic acid that encodes a known protein.

The guidelines are not even consistent with the Board's decision in Kubin.  There, the Board cited several factual distinctions between the obviousness issue presented by Kubin and the facts in Deuel, including:

1.  In Kubin, a cell "unambiguously" (see below) expressing the gene was known; in Deuel, a protein that the prior art taught was expressed in brain was cloned from placenta.

2.  In Kubin, the nucleotide and amino acid sequence of the mouse ortholog of human NAIL was known; in Deuel, the prior art disclosed three different brain-specific proteins and a partial amino-terminal amino acid sequence thereof.

3.  In Kubin, the art provided an isolated preparation of the cognate protein and a monoclonal antibody that binds to the protein; in Deuel, the art disclosed isolated preparations of three different brain-specific proteins but no antibodies.

4.  In Kubin, the art provided a monoclonal antibody specific for the gene product of the desired cDNA and thus providing a specific probe; in Deuel, the probes were a plurality of degenerate oligonucleotides prepared from the partial amino-terminal amino acid sequences.

5.  In Kubin, the art has developed expression cloning technology and provided an antibody probe specific for the gene product of the desired clone; in Deuel, the absence of a specific antibody precluded use of expression cloning technology.

None of these factual issues are mentioned or required to be considered under the guidelines.

On the law, the Board conflated (and the guidelines set in stone) the issues of the obviousness of a composition of matter and the obviousness of producing it.  This is the same mistake that the Board made in Deuel:

The PTO's focus on known methods for potentially isolating the claimed DNA molecules is also misplaced because the claims at issue define compounds, not methods.  See In re Bell, 991 F.2d 781, 785, 26 USPQ2d 1529, 1532 (Fed. Cir. 1993).  In Bell, the PTO asserted a rejection based upon the combination of a primary reference disclosing a protein (and its complete amino acid sequence) with a secondary reference describing a general method of gene cloning.  We reversed the rejection, holding in part that "the PTO's focus on Bell's method is misplaced.  Bell does not claim a method.  Bell claims compositions, and the issue is the obviousness of the claimed compositions, not of the method by which they are made."  Id.

We today reaffirm the principle, stated in Bell, that the existence of a general method of isolating cDNA or DNA molecules is essentially irrelevant to the question whether the specific molecules themselves would have been obvious, in the absence of other prior art that suggests the claimed DNAs.  . . .  There must, however, still be prior art that suggests the claimed compound in order for a prima facie case of obviousness to be made out; as we have already indicated, that prior art was lacking here with respect to claims 5 and 7.  Thus, even if, as the examiner stated, the existence of general cloning techniques, coupled with knowledge of a protein's structure, might have provided motivation to prepare a cDNA or made it obvious to prepare a cDNA, that does not necessarily make obvious a particular claimed cDNA. "Obvious to try" has long been held not to constitute obviousness.  In re O'Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1680-81 (Fed. Cir. 1988).  A general incentive does not make obvious a particular result, nor does the existence of techniques by which those efforts can be carried out.  Thus, Maniatis's teachings, even in combination with Bohlen, fail to suggest the claimed invention.

The differences in the underlying technological sophistication in the art noted by the Board in Kubin could, under the appropriate circumstances,  render obvious a nucleic acid encoding, for example, a highly-conserved sequence where the art disclosed closely-related species orthologs, the cell or tissue of  origin was reliably known, and specific reagents, such as monoclonal antibodies to the protein, were readily available.  None of these factors are required under the Office's KSR rationale to permit an Examiner to assert a prima facie case of obviousness against a nucleic acid claim.  Perhaps the Office is merely reflecting the current trend to pass as much of the examination burden as possible onto applicants, and expects that in instances where there are facts contrary to Kubin or the guidelines, applicants will provide sufficient rebuttal evidence to overcome the prima facie case.  This procedural avenue, however, does not address the analytical mistake of equating obviousness of the method of making with the obviousness of the thing made.  And by promulgating a per se rule of obviousness it is the Office, not the Federal Circuit, that runs directly afoul of Supreme Court precedent.

Unless Kubin has filed an appeal with a district court or the Federal Circuit, the only way that this guideline will be overturned will be after it has been improperly applied, appealed, affirmed by the Board, and then sent to the Federal Circuit for review.  Even then, the facts of that case will need to be sufficient for the CAFC to properly consider the issue.  It would be easier, and better for American innovation (in biotechnology, where the U.S. remains a leader) if the Office would be more preoccupied with allowing than rejecting patents.  On recent evidence, at least with regard to nucleic acid claiming, the Patent Office appears more interested in settling scores with the Federal Circuit.

Comments

[Patent Attorney]

Kevin: I enjoy your work but on this issue I respectfully disagree. In re Deuel has always been a poorly reasoned and nonsensical decision, at least to me.
It is In re Deuel that set a per se standard, whereby obviousness of cloning the gene was irrelevant to gene patentability. It flies in the face of common sense: if cloning techniques are in fact well known, why should it be irrelevant to determining whether it was obvious to clone a particular gene?
To me, parsing the difference between obviousness of the methods and obviousness of the composition is semantics--if the methods were well known and relatively routine, why is the successful use of these methods non-obvious? The Board is correct: the problem faced by the inventors was to clone a gene. Absent unexpected results, it seems that the gene sequence obtained by the use of well known methods should be obvious.
The Board's (and European) approach makes much more sense.

[Patent Attorney]

In other words, what is inventive in using well-known methods to arrive at a specific gene? I realize that in re Deuel seems to support the artificial distinction, but it's rationale appears to conflict with the Supreme Court's obviousness jurisprudence that rejects per se standards.

[Kevin E. Noonan]

Dear Patent Attorney:

The distinction is the complexity of the gene itself. The "well-known methods" argument is a canard - the methods are not of they type that "you mix A with B to get C." They are rather that you take a very big haystack and try to isolate one particular piece of hay from it, with only a limited knowledge of whether the probe you are using to select that piece of hay is specific enough to do the job. The problem is the difference between the "relative" predictability of a chemical reaction and the (relatively) high unpredictablity of molecular biology.

Which is where the factual discussion of Kubin gets it partially right. Under the right circumstances it could be obvious to clolne a particular gene, when what you get is consistent with what you expected from what was known from the orthologs, and the probe is sufficiently specific that the predictability of obtaining the gene you expect to get is high. This is not usually the case, however.

Finally, for anyone who has every tried to clone a gene, it is frankly an insult for a patent examiner to say that something that is so fraught with uncertainty is obvious.

And that doesn't even get to the policy argument that being able to protect the claims that result from cloning genes is the basis for the biotechnology industry. We would be foolish indeed if, trying to produce some kind of theoretical consistency (that ignores the factual distinctions between different scientific disciplines) we precluded from patetnability the very things for which patent protection is needed. I think patent protection is a very practical matter, and a policy or practice that results in something as complex and unpredictable as a gene being routinely determined to be obvious is the wrong result.

Thanks for the comment.

[me]

Kevin-

I find this blog the best for making points, and in depth analysis, and I absolutely love it. That said, I think the Kubin discussion in the rules is a bit less problematic as in most cases the nucleic acid encoding the protein is known first with genomes sequencing and the like, thus the facts of Kubin separate it a bit from the regular case and are somewhat in line with Ex Parte Bandman.

My real concrn of the day is the wrong-headed approach the Office is currently taking in my office actions as it relates to 101.

[Kevin E. Noonan]

Dear Me:

Yes, 101 has been the battleground in the genomics patenting wars in the PTO. I think there are good reasons to think Kubin won't affect the same claims as much, since the difficulty under 101 is where someone is claiming an unknown gene, usually that's related by sequence homology to another, known gene. But in that case, the art does not contain the required known protein that Kubin and the KSR guidelines seem to require.

The big problem with 101 is that the Office's rules were promulgated (January, 2001) after a large number of genomics patents were filed, and so applicants didn't appreciate what was required to satisfy this new interpretation of the statute at the time their applications were filed. Another PTO Catch 22.

Thanks for the comment.

[me]

The ability to argue 101 rejections seems to be getting harder - or maybe I am just losing my touch.

[Patent Attorney]

Dear Kevin:

Thanks for the response. You make some good points but ultimately I am not convinced. I worked in the lab for several years and I know that isolating a gene is not as predictable as "mixing A and B to get C". Respectfully, you can't have it both ways: on the one hand, you cite approvingly the Fed. Cir's comment that a gene is nothing but a chemical, albeit a complex one (something with which I also disagree; to me, gene is more than a chemical) and on another hand, you make an argument that because it is less predictable to isolate a gene than it is to synthesize a chemical, we should afford patentable protection to an isolated gene when the polypeptide expressed by the gene is known.

Yes, it is less predictable to isolate a gene. However, the methods that scientists use are known and are relatively straightforward (not to disparage the scientists but following Maniatis "Bible", one would be able to clone a gene given sufficient time). Moreover, as the Supreme Court said in KSR, a person of ordinary skill is not an automoton; accordingly, he should be expected to be able to clone a gene following known techniques, it is relatively predictable that he would succeed.

While the gene is complex, the methods leading to its cloning are not as complex. Since the scientists do not "make" the gene but rather "find" it (using your needle in a haystack analogy), the complexity of the "needle" itself is irrelevant--the inventive step is the process of finding the needle using the thread (the expressed protein). And when has the thread, the thread would eventually lead one to the needle.

Thank you for replying. I enjoy this exchange.

[Kevin E. Noonan]

Dear Patent Attorney:

I think your reply gets to the heart of the matter. If, as in Kubin, we know the protein, and have a predictable source and have sufficiently accurate amino acid sequence information OR ortholog nucleotide/amino acid sequence information, AND a specific probe, then I think the gene may be predictable enough to be obvious. Lots of "ifs" there. What I object to is the per se aspect of "if a protein is known the gene is obvious" that seems to underlie the PTO's KSR guidelines with regard to gene patent claims.

So I think we (generally) agree.

Thanks for the comment. I enjoy the back-and-forth on this as well.