Thursday, March 20, 2008

Two Remaining Challenged WARF Embryonic Stem Cell Patents Upheld in Ex Parte Reexamination

In a March 13 post I reported that the Wisconsin Alumni Research Foundation (WARF) had prevailed in an inter partes reexamination of its patent that claims cultured pluripotent human embryonic stem (ES) cells (7,029,913). That decision will likely be appealed by the third-party challenger Public Patent Foundation (PPF).

On March 5, the two other WARF embryonic stem cell patents (5,843,780 and 6,200,806) that were challenged by PPF were also found valid in final PTO actions (Notice of Intent to Issue Ex Parte Reexamination Certificate). These two reexamination were both ex parte (as opposed to the inter partes examination of the ‘913 patent), and thus PPF will not have an opportunity to appeal these decisions. Both decisions were based on essentially the same logic as the Action Closing Prosecution in the inter partes reexamination: the fact that multiple parties had tried for years without success to derive cultured, immortal ES cells for non-rodent mammals animals, that the prior art reported success only for certain rodents (most notably mice), and thus prior art teaching directed to the derivation of mouse ES cells was not enabling for primate ES cells, nor was there a reasonable expectation that the techniques could be successfully applied to primates.

The ‘806 patent claims are directed stable cultures of human ES cells – the claims are very similar to those in the ‘913 patent, the primary difference being that the ‘913 patent includes the limitation that the cells will proliferate in an undifferentiated state in the absence of leukemia inhibitory fact (LIF). The reexamination resulted in the amendment of the claims to specifically recite that the claimed human ES cells are “derived from a pre-implantation embryo,” and that the cell culture will proliferate in culture “in an undifferentiated state.” These limitations, which were also incorporated into the claims of the ‘913 patent, were probably inherently present in the original claims, but the explicit recitation of the limitations is one positive outcome of the reexamination. For example, the Action Closing Prosecution notes that prior art disclosing human embryonic germ (EG) cells derived from post-implantation embryos are different from ES cells, and thus the prior art EG cells did not anticipate or render obvious Thomson’s human ES cells.

The ‘780 patent claims are directed to stable cultures of primate ES cells – the claims are very similar to those in the ‘806 patent, the primary difference being that the ‘806 patent is limited to human ES cells. This reexamination also resulted in the amendment of the claims to specifically recite that the primate ES cells are “derived from a pre-implantation embryo,” and that the cell culture will proliferate in culture “in an undifferentiated state.”

Thursday, March 13, 2008

WARF Human Embryonic Stem Cell Patent Upheld in Inter Partes Reexamination

On February 25, 2008, the PTO issued an action closing prosecution in the inter partes re-examination of patent number 7,029,913. The patent, which claims cultured pluripotent human embryonic stem (ES) cells capable of proliferating for over one year in an undifferentiated state without the application of exogenous leukemia inhibitory factor (LIF), is based on the pioneering work of the University of Wisconsin’s James Thomson. Thomson is credited as the first to successfully derive stable cultured human/primate ES cell. The patent is assigned to the Wisconsin Alumni Research Foundation (WARF), and has been the source of much controversy based on what many consider to be restrictive licensing practices on the part of WARF. Pluripotent human stem are capable of differentiating into any fetal or adult cell type, and are widely viewed as critical reagents in a variety of research and (potentially) therapeutic contexts. The patent is one of several WARF patents relating to human ES cells that have been challenged by the third-party requester Public Patent Foundation (PPF).

Prior to Thomson's success in deriving primate embryonic stem cells, the technology for deriving embryonic stem cells in mice, and possibly other rodents, had been well established, but attempts in primates and other mammals had proven unsuccessful. However, PPF argues that the claimed human ES cells were derived using essentially the same methodology that had been used for years to derive mouse ES cells, and pointed to a number of prior art references which it argues render the ‘913 patent anticipated and/or obvious. Two of the references from the scientific literature, "Robertson 1983" and "Robertson 1987," describe the process for deriving pluripotent mouse ES cells, which PPF asserts is the same process used to derive human ES cells. Another non-patent reference, Piedrahita, describes the isolation of mouse, pig, and sheep ES cells. Importantly however, Piedrahita does not report success in creating stable, pluripotent ES cell cultures from pig and sheep. A patent reference is also cited (5,166,065) which prophetically discloses pluripotent ES cells derived from humans and other mammals, but only provides working examples of mouse ES cells. The other cited patent reference (5,690,926) describes human embryonic germ (EG) cells derived from post-implantation embryos (the human ES cells claimed in the ‘913 patent are derived from pre-implantation embryos).

PPF was unable to persuade the examiner with any of its arguments. The examiner found that while the ‘065 patent provided prophetic disclosure of the claimed human embryonic stem cells, subsequent publications by the inventor of the ‘065 patent acknowledged that he had been unable to use the methodology to derive sustainable cultures of human or other mammalian ES cells. The examiner pointed to numerous other examples where researchers attempted but failed to derive stable culture to pluripotent embryonic stem cells from animals other than mice (or perhaps other rodents). Based on this, the examiner found that the ‘065 patent did not anticipate under 102(b) for failure to enable primate ES cells, and failed to provide the basis for a finding of obviousness because there was no reasonable expectation that the disclosed technology could be used successfully to derive non-rodent ES cells.
Likewise, while the non-patent references reported success in deriving mouse ES cells, none reported success in deriving human or other non-mouse ES cells. In view of the general lack of success by others in using the methods to derive non-rodent cells, the examiner determined there was no reasonable expectation that the teaching of these references could be successfully modified to arrive at the claimed human ES cells.

Finally, the examiner found that the human EG cells disclosed in the ‘926 patent were different from the human ES cells claimed by Thomson, and thus did not anticipate or render obvious the claimed human ES cells. In particular, the human EG cells contain the cell surface marker SSEA-1 (a protein), which is absent from human ES cells.

PPF will have an opportunity to appeal the decision to the Board of Patent Appeals and Interferences, and eventually perhaps to the Federal Circuit.

I think this case raises an interesting enablement issue. The examiner found that the prior art patent prophetically disclosing human ES cells was not enabled as of the date of Thomson's invention because one of skill in the art could not have implemented the disclosed methodology (for deriving mouse ES cells) to derive human ES cells without engaging in undue experimentation. But PPF argues, and the examiner seems to agree, that the method for deriving human ES cells disclosed in the Thomson patent is essentially the same as the prior art methods used to derive mouse cells. So if the prior art patent was not enabling for human ES cells as of the date of Thomson's invention, then logic seems to suggest that Thomson's patent is likewise not enabled. In other words, how can one patent be enabling, while a second disclosing essentially the same methodology is not? Of course, the distinction is the Thomson reported success, but is that relevant to the enablement of one of ordinary skill in the art?

As described in a declaration by Jeanne Loring, an expert in this area technology, Thomson’s success was not due to any tangible scientific breakthrough disclosed in his patent. Perhaps Thomson succeeded because he and his laboratory had a higher level of skill than one of ordinary skill in the art, or engaged experimentation exceeding “due experimentation,” or had some other advantage that allowed him to produce human embryonic stem cells by use of methodology that was not enabling for those of ordinary skill in the art. Or perhaps his success reflected the improved quality of reagents or a general increase in the level of skill of those working in this field, and Thomson just happen to be the first to succeed. Of course, enablement cannot be challenged directly in re-examination proceedings, but this could be an issue if the validity of the patent were ever challenged in infringement litigation.

Thursday, March 6, 2008

The Federal Circuit Considers Equivalence of Nucleic Acids and Peptide Nucleic Acids (PNAs)

Nucleic acids, such as DNA and RNA, are polymers of purine and pyrimidine bases linked together by a sugar-phosphate backbone. Peptide nucleic acids (PNAs), on the other hand, are synthetic polymers of purine and pyrimidine bases linked together by peptide bonds, the same bonds present in polypeptides, i.e. proteins. Like nucleic acids, PNAs are capable of hybridizing to a complementary nucleic acid strand, and thus can be used as functional analogs for nucleic acids in a host of research and diagnostic applications that employ nucleic acids as hybridization probes, as well as in antisense therapies.

However, there are important functional differences between nucleic acids and PNAs. Because the backbone of a PNA contains no charged phosphate groups, the binding between PNA/DNA strands is stronger than between DNA/DNA strands (due to a lack of electrostatic repulsion). PNAs also show greater specificity in binding to complementary DNAs, with a PNA/DNA base mismatch being more destabilizing than a similar mismatch in a DNA/DNA duplex. This binding strength and specificity also applies to PNA/RNA duplexes. PNAs are not easily recognized by either nucleases or proteases, making them resistant to enzyme degradation. PNAs are also stable over a wide pH range.

In Regents of the University of California v. Dakocytomation (Doc. No. 2006-1334), decided by the Federal Circuit on February 28, 2008, defendant Dako argues that its diagnostic test kits do not infringe the University of California's patent because the claims recite "blocking nucleic acids” (which the parties stipulate to be limited to RNA and DNA), and the accused kits employ PNAs. The kits are used to identify the presence of excess HER2 genes in cancerous cells, in order to decide if treatment with Herceptin is appropriate.

Although the stipulation precludes a finding of literal infringement, UC argues that the use of PNAs infringes under the doctrine of equivalents. The district court ruled on motion for summary judgment that UC was precluded under Festo from establishing infringement under the doctrine of equivalents by prosecution history estoppel, since the "blocking nucleic acid" limitation was added by narrowing amendment to overcome prior art. However, on appeal the Federal Circuit reversed, finding that the motivation for UC’s narrowing amendment "centered on the method of blocking-not on the particular type of nucleic acid that can be used for blocking.” The case was remanded to the trial court to determine the question of infringement under the doctrine of equivalents.

In dissent, Judge Prost argued that the majority had misapplied Festo, finding that prosecution history estoppel should apply to the nucleic acid itself, not just the blocking method.

Applying the traditional function-way-result test, Dako might be able to successfully argue non-equivalence. Dako submitted expert testimony to the trial court that “PNA probes accomplish blocking in a substantially different way from DNA probes and are not ‘interchangeable’ with DNA. For example, PNA probes can bind to DNA that is not been denatured. PNA is also less susceptible to changes in hybridization conditions, such as temperature.” UC presumably submitted testimony that would minimize the significance of these functional distinctions. It should be interesting to see how the trial court, and perhaps eventually the Federal Circuit, decides on the issue of equivalents.