In re Droge (Fed. Cir. 2012)

By Kevin E. Noonan --

It is an occupational hazard for patent attorneys to be tempted to over-interpret Supreme Court and Federal Circuit opinions relating to certain areas of patent law or their applications to certain technologies.  This is particularly true with regard to the question of obviousness for biotechnology inventions, in the aftermath of the Court's implementation of the Supreme Court's KSR v. Teleflex opinion in its In re Kubin opinion.  This temptation arises again when considering the Federal Circuit's In re Droge opinion, where the Court affirmed a determination by the U.S. Patent and Trademark Office that claims for recombination methods were obvious.

The technology involved recombination of exogenous DNA introduced into eukaryotic cells.  As explained in the opinion, the exogenous DNA comprises a bacteriophage λ vector wherein the vector sequences are important for specific recombination of the exogenous DNA into the cellular chromosomal (genomic) DNA.  Bacteriophage λ has a storied history in molecular biology.  It is a temperate phage, meaning that in bacteria it has two life cycles.  The first, the lytic phase, displays conventional viral behavior, wherein the virus infects the bacterial cell, replicates exponentially and eventually lyses the cell with release of the multiplied viral particles.  In the other phase (termed the lysogenic phase), the bacteriophage inserts itself into the bacterial chromosome where it resides until a stimulus (for example, irradiation with ultraviolet light) causes the virus to enter the lytic phase.  Elucidation of the molecular basis for these alternative behaviors was one of the first tours de force of molecular biology; it is elegantly described (befitting its biological elegance) in A Genetic Switch by its elucidator, Mark Ptashne.

But phage λ played an even more important role in biotechnology, a role directly related to the lytic/lysogenic alternative life cycles.  Because the genes encoding the proteins that mediated the lysogenic life cycle are unnecessary for the lytic phase, the virus was an ideal candidate for use as a cloning vector.  Deleting these genes, and substituting this DNA with fragments of human cellular DNA, for example, enabled scientists to create libraries of genomic DNA that were used to isolate and identify genes during the golden age of biotechnology in the 1970's and 80's.  While such inserted human cellular DNA fragments were limited to a size (~20 kilobases) that would fit inside the proteinaceous phage head, >95% coverage of human genomic DNA could be achieved in a library of about 1 million recombinant phage.

Here, the purported invention (by inventors Droge, Christ and Lorbach, collectively "Droge") was dependent on the enzymes involved in lysogeny.  The molecular species involved were DNA sequences (attB, attP, attR, and attL) that are recognized by phage enzymes (specifically enzymes termed integrases, Int) that catalyze integration of phage DNA into bacterial chromosomal DNA.  The Patent Office finally rejected the pending claims for obviousness and the Board affirmed.  Claim 29 was cited by the Federal Circuit as representative:

A method of sequence specific recombination of DNA in a eukaryotic cell, comprising:
    (a) providing said eukaryotic cell, said cell comprising a first DNA segment integrated into the genome of said cell, said first DNA segment comprising an [attB, attP, attL, or attR sequence or derivative thereof] . . . ;
    (b) introducing a second DNA segment into said cell . . . ;
    (c) further comprising providing to said cell a modified bacteriophage lambda integrase Int, wherein said modified Int is Int-h or Int-h/218, which induces sequence specific recombination through said attB and attP or attR and attL sequences.

(emphasis in opinion).  As set forth in the opinion, the integrase recited in the claims was a mutant integrase, termed Int-h or Int-h/218.  The prior art cited against the Droge claims were two references,  the primary reference being the Crouzet reference that disclosed "methods of making therapeutic DNA molecules using sequence-specific recombination either in a host cell or in vitro" and that specifically disclosed embodiments using λ phage and wildtype Int for integration of exogenous ("foreign") DNA into a mammalian host cell "using the attB and attP recognition sites."  Relevant to the Board's decision and the Federal Circuit's assessment of it, the Crouzet reference also disclosed that these methods "'may be carried out in any type of cell host,' such as 'bacteria or eukaryotic cells (yeasts, animal cells, plant cells).'"  Droge, the Board, and the Federal Circuit agreed that the Crouzet reference did not disclose the mutant integrases recited in the Droge claims.

These elements of the claims were disclosed in a second reference to Christ and Droge, which also disclosed that the mutant integrases were active (could "mediate sequence-specific recombination") in prokaryotic cells.  In addition, the Christ and Droge reference disclosed that these mutants were capable of mediating recombination even in the absence of accessory proteins produced in bacteria but not in eukaryotic cells.  As set forth in the Federal Circuit's opinion, the Droge applicants conceded that the combination of the references disclosed all the elements of their claims, but contended that the skilled worker would not have had a reasonable expectation of success that the mutant enzymes that worked in prokaryotic cells would also work in eukaryotic cells and thus their claims were non-obvious.  This assertion was supported by a Rule 132 declaration by inventor Droge, but while the Office considered the opinions and evidence in the declaration, the Examiner and Board determined that the allegations in the Droge declaration was rebutted by the disclosure of another reference, the Lange-Gustafson and Nash reference.

The Federal Circuit affirmed the Office's obviousness rejection, in an opinion by Judge Moore joined by Judges Newman and O'Malley.  The opinion recognized that the crux of the matter was whether a person skilled in the art would have had a reasonable expectation of success in substituting the wildtype integrase disclosed in the Crouzet reference with the mutant integrases disclosed in the Christ and Droge reference for sequence-specific integration of exogenous DNA into eukaryotic chromosomal DNA.  The Federal Circuit, pursuant to In re Gartside, 203 F.3d 1305, 1316 (Fed. Cir. 2000) (a decision that implemented the Supreme Court's direction in Dickinson v. Zurko, 527 U.S. 150 (1999)), deferred to factual determinations made by the Office (while exercising plenary review over the ultimate legal question of obviousness).  In this case, the panel found "substantial evidence" that "supports the Board's determination that a person of ordinary skill in the art would have had a reasonable expectation of success when combining" the references.  Importantly, the opinion found that the Lange-Gustafson and Nash reference "directly contradicts the assertion in the Droge Declaration that a skilled artisan would not expect the modified integrases Int-h and Int-h/218 to work in eukaryotic cells" based on arguments relating to the topography of the DNA molecules involved in integration.

Having determined that substantial evidence supported the factual determinations by the Office, the panel concluded that the claims were obvious.  Regarding Droge's allegations that the skilled worker would not have a reasonable expectation of success in using the mutant integrases in eukaryotic cells, the panel opined that "absolute predictability" was not the standard:  "all that is required is a reasonable expectation of success." In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (citing In re O'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988))."

It is an unconsidered reading of this citation that leads to mischief and over-interpretation of Federal Circuit precedent (particularly as that precedent is viewed as an accommodation of Supreme Court decisions).  What is significant about the legal basis for the panel opinion is the citation to In re O'Farrell (a decision by Judge G.S. Rich that was cited by the Supreme Court regarding its KSR v. Teleflex opinion).  This citation points to the fact that these rubrics of obviousness do not represent a sea change (and not even a change in how obviousness is applied to biotechnology, when it is recalled that O'Farrell was a biotechnology case).  The almost per se non-obviousness of claims to nucleic acid was impacted by the Federal Circuit's implementation of KSR v. Teleflex in its In re Kubin opinion.  But in truth, the time for per se non-obviousness had passed for nucleic acids after the disclosures of the Human Genome Project and advances in DNA cloning technology.  The test will be when this precedent is applied to the cucumber genome, which is likely to have much less prior art to be applied.  But obviousness will always be plagued by the siren song of hindsight balanced by evidence of unexpected results; provided that this balance is properly maintained it is unlikely that per se rules (of obviousness or non-obviousness) will imbalance the extent of patent protection available for biotechnology inventions.

In re Droge (Fed. Cir. 2012)
Panel: Circuit Judges Newman, Moore, and O'Malley
Opinion by Circuit Judge Moore

Comments

[Anne Barschall]

It is an ongoing problem that neither the CAFC nor patent attorneys in general seem well versed in distinguishing dicta from holding.

[Keep It Real]

" the Droge applicants conceded that the combination of the references disclosed all the elements of their claims, but contended that the skilled worker would not have had a reasonable expectation of success that the mutant enzymes that worked in prokaryotic cells would also work in eukaryotic cells and thus their claims were non-obvious. This assertion was supported by a Rule 132 declaration by inventor Droge,"

Always good for a laugh when the inventor chimes in.

Having spent a good portion of my pre-law career studying this field, it's pretty clear that the USPTO and the Federal Circuit got it right. Well done. This case is well-reasoned and doesn't break any new ground, in my opinion.

[Kevin E. Noonan]

Dear Keep:

Agreed. This is line drawing by the Office, and under the facts presented the level of predictability seems high enough to pass muster for an obviousness determination. And my point is that this would have been the case pre- or post-KSR.

Thanks for the comment.