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30 April 2013AmericasJames Monroe and Lawrence Ilag

Obviousness of DNA fragments in the post-Kubin era

Four years ago, the Federal Circuit held in In re Kubin, 561 F.3d 1351 (Fed. Cir. 2009) that the claimed polynucleotide (DNA) sequences in that case were obvious, although the prior art did not disclose or suggest what the claimed sequences would look like. In effect, the Federal Circuit found the sequences obvious because the prior art disclosed sufficient information to make isolating and characterising the claimed DNA sequences a rather straightforward project.

We explore in this report how the Kubin decision has informed the United States Patent and Trademark Office’s (USPTO) standard in determining obviousness of DNA fragments. In particular, we describe and analyse here the USPTO’s Patent Trial and Appeal Board’s (PTAB) recent adjudications in appeals arising from obviousness rejections of polynucleotide claims. We then reflect on how DNA patent applications may be made more robust given this legal landscape.

In Ex parte Levinson, 2013 Pat. App. LEXIS 923 (PTAB Mar. 1, 2013), the invention related to compositions generating an immune response that did not target IgE sitting on mast cells and therefore avoided potentially deleterious mast cell release reactions.

“The Federal Circuit found the sequences obvious because the prior art disclosed sufficient information to make isolating and characterising the claimed DNA sequences straightforward.”

Specifically, the claims related to nucleic acid molecules encoding a hybrid protein free of serum IgE epitopes that included at least one membrane IgE epitope and at least one nonIgE helper T cell epitope, fused by a proteolytic cleavage sequence. Additional claims were directed to nucleic acid molecules encoding a protein that included an IgE leader sequence and at least one membrane IgE epitope, and that was free of serum IgE epitopes.

The examiner found these claims obvious over various reference combinations. In response, with respect to the claims reciting a proteolytic cleavage sequence, the patent applicants/appellants argued that the prior art taught away from using a proteolytic cleavage sequence as a linker, because cleavage by a protease would result in an unrelated, unconjugated composition that the prior art taught would undesirably result in no inhibition of IgE responses.

According to the examiner, however, the prior art contemplated using a cleavage sequence recognised by a protease not expressed in IgE-producing animals, so that the sequence would not be subject to cleavage under physiologic conditions. The board agreed with the examiner.

The board then addressed the appellants’ argument that the specification required the claims to be interpreted to mean that the proteolytic cleavage sequence served to allow for the separation of the membrane IgE epitope from the non IgE helper T cell epitope in vivo, instead of providing two separate genes or proteins. The board was not persuaded, observing that the specification taught that the epitopes in the composition may be provided as separate entities or as a fusion protein.

As to the claims reciting an IgE leader sequence, the board noted that the appellants did not contend that a skilled artisan would not have been motivated to combine the teachings of the prior art. The appellants instead asserted that the prior art did not suggest a nucleic acid sequence with an IgE leader sequence. In support of this assertion, the appellants submitted a declaration from a co-inventor, which contained an alignment of the IgE leader sequence with the leader sequences from the different isotypes.

The board however did not assign the declaration persuasive weight, and finding that the appellants did not respond to the examiner’s position regarding the equivalence of isotype leader sequences, the board affirmed the obviousness rejections of the IgE-leader-sequence claims. We again see the importance of meaningfully responding to the examiner’s position in Ex parte Arnold, 2013 Pat. App. LEXIS 756 (PTAB February 19, 2013). In this case, the invention related to oligonucleotides containing a “molecular switch” region for use as a hybridisation probe or primer.

“The appellants contended that there were numerous possibilities known in the art for choosing different linkages, different conjugates, and different ways to attach the conjugate to the dsRNA.”

Based on whether it was in an “open” (non-hybridised) or “closed” (hybridised) position, the molecular switch region was able to detect the presence of a mismatch or a match with a target sequence. Claims directed to these oligonucleotides were found anticipated. Two other claims containing additional limitations were found obvious, which we further describe here.

One of these claims was drawn to an oligonucleotide with a structural 5’ modification resistant to digestion by enzymes possessing 5’ nuclease activity. The appellants argued that the examiner failed to point to any reference or other evidence, and instead relied on an unsupported personal opinion, in alleging motivation to add a 5’-modification group to an oligonucleotide to prevent enzymatic degradation. The board was not persuaded and affirmed the rejection.

The board found that the prior art reference provided by the examiner taught that oligonucleotide modifications can include 3’ and 5’ modifications such as capping. The board then extended this finding by noting that the dictionary definition of capping in molecular biology was a modification which protected against nucleases.

The board also found that in the absence of evidence presented by the appellants, incorporating the 5’ modification taught by one prior art reference into the oligonucleotide taught by another prior art reference would inherently result in an oligonucleotide resistant to 5’ nuclease activity.

The other claim rejected for obviousness required the oligonucleotide to be attached to an electron conducting solid surface where the amount of hybridisation to the target nucleic acid controls the amount of current flow.

The appellants contended that the examiner did not explain why the prior art reference teachings would be combined to yield the claimed oligonucleotide. Finding that the examiner did not respond as to this claim and did not provide a reason to place the prior art oligonucleotide onto a solid support, the board reversed the rejection.

Reason to combine prior art teachings was likewise a central issue in In Ex parte Hadwiger, 2012 Pat. App. LEXIS 7059 (PTAB Dec. 17, 2012). In this case, the invention related to polynucleotides that suppressed gene expression. Specifically, the claims were directed to double-stranded ribonucleic acid (dsRNA) RNA interference agents with a lipophilic group covalently linked to the 5’-end of the complementary (antisense) strand, where the linkage comprised a phosphodiester group.

The appellants contended that there were numerous possibilities known in the art for choosing different linkages, different conjugates, and different ways to attach the conjugate to the dsRNA. They further contended that the art did not provide a reason for conjugating a lipophilic group to the 5’-end of the antisense strand of a dsRNA through a phosphodiester linkage.

“Evidence of unpredictability in the relevant art will be helpful in countering any obviousness rejections.”

The board was not persuaded, citing to the contrary various prior art teachings about conjugates and linkages, and found no error in the examiner’s prima facie case of obviousness.

The appellants also argued that one would not have expected that the claimed polynucleotides would be effective as RNA interference agents, given the disclosures in the specification and various references in the art at the time of the invention that 5’-end lipophilic group-phosphodiester modification of an antisense strand of a dsRNA completely abolished, or at least reduced, the RNA’s genesuppression activity.

The examiner refuted such statements, relying on an art reference teaching, undisputed by the appellants, that a complementary strand modified at the 5’-end with 6-amino-hexyl phosphoester retained the ability to suppress target mRNA expression.

The cases above indicate that the USPTO’s analysis of the obviousness of claimed polynucleotides is predicated on the availability in the art of the components comprising the polynucleotide (e.g., protease cleavage sequence in Levinson), and motivation to combine these components to arrive at the claimed polynucleotide.

The USPTO’s inquiry is based on the specific facts of the case. Indeed, where no reason is of record to support a motivation to combine the prior art teachings, an obviousness rejection may be reversed, as in Arnold above with respect to the claim with the solid-surface limitation. If, however, the record needs only to be supplemented with a citation to support an examiner’s assertion of common knowledge, the USPTO may proceed to provide that citation to affirm the obviousness rejection, as in Arnold, with respect to the claim requiring a 5’ modification.

Given this fact-specific obviousness analysis, the USPTO thus appears to cabin application of Kubin to cases that have similar fact patterns. This is a welcome development, given that Kubin appears to blur the distinction between the obviousness of a process claim and the obviousness of a claim directed to the product of that process. In Kubin, because the method of isolating the DNA of interest using an antibody in the prior art was obvious, the isolated DNA of interest was found obvious as well.

With these cases in mind, a patent application may be strengthened by a specification that clearly supports the non-obviousness of the claims. Statements that are vague are unhelpful, as in Levinson, where the statement in the specification indicating that the epitopes may be provided as separate entities or as a fusion protein was used to undermine the appellants’ argument regarding the function of the proteolytic cleavage sequence.

In cases where there is art that tends to undermine the non-obviousness of the invention, as in Hadwiger, this art must be addressed headon, for example, by credibly discussing how it does not relate to the invention, or amending the claims accordingly. In addition, evidence of unpredictability in the relevant art will be helpful in countering any obviousness rejections.

For example, evidence of unpredictability of the effect of capping on protecting an oligonucleotide from 5’ nuclease activity, if available in Arnold, might have had an impact on the ultimate disposition of that case. And a patent applicant must address all issues raised by the USPTO to succeed in getting the patent issued, and avoid the outcome for example in Levinson, where failure to respond to the examiner’s position regarding the IgE leader sequence resulted in the affirmance of the obviousness rejection.

James Monroe is a partner at Finnegan, Henderson, Farrow, Garrett & Dunner LLP. He can be contacted at: james.monroe@finnegan.com

Lawrence Ilag is an associate at Finnegan, Henderson, Farrow, Garrett & Dunner LLP. He can be contacted at larry.ilag@finnegan.com