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.


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