Last month, the Federal Circuit dismissed an appeal by Institut Pasteur of a determination by the Board of Patent Appeals and Interferences affirming the rejection of claim 14 of U.S. Patent No. 7,309,605 in an inter partes reexamination requested by Precision BioSciences. The Federal Circuit also reversed the Board's affirmance of the rejection of claims 10 and 12 of U.S. Patent No. 6,610,545, and vacated and remanded the Board's affirmance of the rejection of U.S. Patent No. 6,833,252. Both the '545 and '252 patents were also the subject of inter partes reexaminations requested by Precision BioSciences.
The '605, '545, and '252 patents, which are owned by Institut Pasteur, claim methods and tools for the site-directed insertion of genes into eukaryotic chromosomes. The claimed methods and tools take advantage of the discovery by the Institut Pasteur in the early 1990's of a class of enzymes called group I intron-encoded (GIIE) endonucleases. Institut Pasteur demonstrated that GIIE endonucleases, which have recognition sites of over eighteen nucleotides (and therefore provide superior specificity over other endonucleases), could cleave chromosomal DNA in eukaryotic cells, and that eukaryotic cells were able to successfully repair such cleavages via homologous recombination. All three of the patents at issue expired on May 6, 2012.
Claim 1 of the '605 patent, which was not at issue on appeal (and which includes amendments, indicated by underlining, that were proposed by Institut Pasteur during reexamination) recites:
1. A method for inducing at least one site directed double-stranded break in the chromosomal DNA of an organism comprising:
(a) providing an isolated, viable cell of said organism containing at least one Group I intron encoded endonuclease recognition site at a location in the chromosomal DNA of the cell,
(b) providing said Group I intron encoded endonuclease to said cell by genetically modifying the cell with a nucleic acid comprising said Group I intron encoded endonuclease or by introducing said Group I intron encoded endonuclease protein into the cell such that the Group I intron encoded endonuclease cleaves said Group I intron encoded endonuclease site at the location in the DNA of the cell.
Claim 14 of the '605 patent, which was at issue, recites:
14. The method of claim 1, wherein said method further comprises providing to said cell
a plasmid comprising a DNA sequence homologous to the sequence of the chromosome, which allows homologous recombination, and
a modified sequence,
wherein said Group I intron encoded endonuclease cleaves the Group I intron encoded endonuclease recognition site,
whereby said cleavage promotes the insertion of said modified sequence into said chromosomal DNA of said cell at a specific site by homologous recombination.
Claim 7 of the '545 patent, which was not at issue on appeal (and which includes amendments proposed by Institut Pasteur during reexamination) recites:
7. A method for in vivo site directed genetic recombination in an organism comprising:
(a) providing a transgenic eukaryotic cell having at least one Group I intron encoded endonuclease recognition site inserted at a unique location in a chromosome;
(b) providing an expression vector that expresses said endonuclease in said transgenic cell;
(c) providing a plasmid comprising a gene of interest and a DNA sequence homologous to the sequence of the chromosome, allowing homologous recombination;
(d) transfecting said transgenic cell with said plasmid of step (c);
(e) expressing said endonuclease from said expression vector in said cell; and
(f) cleaving said at least one Group I intron encoded endonuclease recognition site with said endonuclease, whereby said cleavage promotes the insertion of said gene of interest into said chromosome of said organism at a specific site by homologous recombination.
Claims 10 and 12, which were at issue, depend from claim 7 and limit the method to yeast and mammalian cells, respectively.
Finally, claim 1 of the '252 patent (the patent's only independent claim) recites:
1. A recombinant mammalian chromosome comprising an exogenous Group I intron encoded endonuclease site,
wherein the endonuclease site is within an integrated nucleic acid sequence from a vector,
wherein the site is selected from the group consisting of an I-SceIV site, an I-CsmI site, I-PanI site, I-SceII site, an I-CeuI site, an I-PpoI site, an I-SceIII site, an I-CreI site, an I-TevI site, an ITevII site, an I-TevIII site, and an I-SceI site.
In 2009, Precision BioSciences filed inter partes reexamination requests for the '605, '545, and '252 patents (as well as a fourth patent not involved in the appeal). The Office granted all four requests, and the Examiner rejected most claims as anticipated or obvious.
On appeal, the Board affirmed the Examiner's rejections as to obviousness, basing its decision on two references (Quirk and Bell-Pedersen) that disclosed using a GIIE endonuclease to transfer DNA from a plasmid to non-chromosomal DNA in bacterial cells. In particular, the Board determined that there was reason to substitute the nonchromosomal prokaryotic DNA of Quirk and Bell-Pedersen with chromosomal DNA of a eukaryotic cell, and that one of skill in the art would have a reasonable expectation of success based on two other references (Frey and Dujon), which the Board characterized as disclosing cleavage of chromosomal DNA in yeast cells. The Board considered evidence that the claimed inventions were praised, copied, and licensed by the industry, but determined that the evidence did not outweigh the strong case of obviousness. Institut Pasteur appealed the Board's affirmance of the Examiner's rejections to the Federal Circuit.
In dismissing the appeal as to claim 14 of the '605 patent, the Federal Circuit noted that the patent had expired since the Board's decision, and that Institut Pasteur did not dispute that the Office could not issue amended claims for an expired patent if the amendments change the claim’s scope. The Court concluded that the amendments Institut Pasteur proposed during reexamination did narrow the scope of claim 1 and dependent claim 14. In countering Institut Pasteur's argument that the amendments to claim 1 did not change the scope of claim 14 because the unamended claim was implicitly limited to chromosomal DNA, the Court explained:
That homologous recombination occurs between the targeted DNA and an introduced plasmid that is homologous to a chromosome does not require that the targeted DNA actually be chromosomal DNA. It requires only that the targeted DNA be homologous to chromosomal DNA. Non-chromosomal DNA, such as mitochondrial DNA or DNA in an additional plasmid, can be homologous to chromosomal DNA. Thus, the original claim covered situations where nonchromosomal DNA is the targeted DNA. The amendment substantively narrowed the claim in requiring chromosomal DNA as the target.
The Court therefore determined that the amendments narrowed the scope of claim 14 (claim 1 not being at issue on appeal), and concluded that the Office could not issue the amended claim now that the '605 patent had expired.
In reversing the Board's decision with respect to claims 10 and 12 of the '545 patent, the Federal Circuit noted that the "key issue" in determining whether claims 10 and 12 of the '545 patent are invalid for obviousness was:
[W]hether the relevant skilled artisan -- after reading Quirk's and Bell-Pedersen's disclosure that a GIIE endonuclease can promote targeted gene transfer into non-chromosomal DNA in prokaryotic cells -- would have expected that a GIIE endonuclease would successfully promote targeted gene transfer into the chromosomal DNA of eukaryotic cells, and thus had good reason to pursue that possibility.
(emphasis in opinion).
The Court also noted that the Board, in ascertaining the scope and content of the prior art, made factual determinations that were not supported by substantial evidence, and that the Board also failed to give proper consideration to teachings in the prior art that targeting a cell's chromosomal DNA could be toxic to the cell, and to the evidence of industry praise and the licensing of Pasteur's invention. The Court first concluded that the Board had erred in finding that the Frey and Dujon references showed that a GIIE endonuclease cleaved yeast chromosomal DNA when expressed in yeast cells. The Court explained that Frey discloses cleaving yeast chromosomes that had been extracted from yeast cells and purified, not chromosomes still "in yeast cells," and that Dujon was silent about what type of DNA is cleaved. For Dujon, the Court noted that "the PTO bears the burden of demonstrating a prima facie case of obviousness," and that "Dujon's language is insufficient to establish that the GIIE endonuclease targeted chromosomal DNA."
The Court added that "[t]he Board compounded its erroneous findings by ignoring teachings that targeting a GIIE endonuclease to chromosomal DNA in a living cell could be highly toxic to the cell." The Court also pointed out that "the Board identified no reason at all that a skilled artisan would have pursued a method toxic to cells."
Finally, the Court indicated that Institut Pasteur had "presented compelling evidence that the industry has licensed, praised, and copied its inventions," and that the Board did not properly weigh this evidence. That evidence consisted of a declaration from the CEO of the exclusive licensee of the '545 patent that the exclusive licensee had entered into more than a dozen sublicenses. The Board had discounted this evidence because the declaration failed to establish that the sublicensees licensed the '545 patent to gain access to the claimed subject matter as opposed to other technology described, but not claimed, in the patent. As for the evidence of industry praise, the Board acknowledged the connection between industry praise and the claimed step of homologous recombination, but found that step to be possessed by the prior art.
In vacating the Board's decision with respect to the '252 patent, the Court indicated that it was remanding for consideration of "whether one of ordinary skill would have been motivated simply to create a recombinant chromosome with a GIIE endonuclease recognition site -- without having the reasonable expectation . . . that the GIIE endonuclease could successfully cleave the recognition site and that homologous recombination could successfully repair the break." The Court explained that because the Board "mistakenly thought that there was sufficient motivation for the '545 patent," the Board did not consider whether motivations other than those for the '545 patent would have made the subject matter of the '252 patent, which essentially claims the first step of the methods of claim 10 and 12 of the '545 patent, obvious.
Institut Pasteur v. Focarino (Fed. Cir. 2013)
Panel: Circuit Judges Newman, Clevenger, and Taranto
Opinion by Circuit Judge Taranto