When induced pluripotent stem (iPS) cells burst onto the scene in 2007, they brought along with them a new approach to stem cell research, which had previously been restricted to human embryonic stem (hES) cells1,2. Unlike hES cells, which were made from two-day old human embryos and would require cloning technologies to generate genetically matched lines for future therapeutic use, iPS cells were quickly deployed to do better, using somatic cells rather than embryos as the source material. The power of the technique lay in its ability to take any differentiated cell—diseased or otherwise—and reprogram it to an embryonic state, producing an immortal line with an exact genetic match to the donor cell3.

The field has moved along at a blistering pace, and this is reflected in the international patent landscape. As of this writing, dozens of applications have been filed internationally, and in the past two years, the first three patents including claims to this technology have issued in Japan, the United Kingdom and the United States. (Tables 1 and 2) We briefly discuss the scope of the three issued patents by examining the extent of the protection as described by their claims.

Table 1 Characteristics of issued iPS cell patents
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Table 2 Selected pending iPS cell patent applications
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Granted patent landscape

The first issued patent, granted in Japan to Shinya Yamanaka on September 12, 2008, was filed on December 12, 2006, with a priority date of December 13, 2005. The fast-tracked patent covers a method for preparing an iPS cell from a somatic cell by introducing the embryonic transcription factors Oct 3/4, Klf4, c-Myc and Sox2. Claims directed to cells produced by this method were previously filed in Japan and several other countries4.

The second patent was granted in the United Kingdom to Kazuhiro Sakurada on January 12, 2010. It was filed on June 13, 2008, with a priority date of June 15, 2007. The Sakurada patent covers a method of inducing human iPS cells from human postnatal tissue by forcing expression of some combination of Oct3/4, Sox2 and Klf4, providing that c-Myc is not included, and culturing in the presence of FGF-2 (ref. 5). According to Sakurada, these cells self-renew and differentiate into ectoderm, mesoderm and endoderm. The elimination of c-Myc in preparing iPS cells is a significant advancement for therapeutic application, as it is a potentially cancer-causing gene.

The broadest claims of the Yamanaka and Sakurada methods have three genes in common: Oct 3/4, Klf4 and Sox2. Despite this overlap, the patents cover different methods. Most notably, the Sakurada patent claims expressly require the elimination of c-Myc in preparing iPS cells, whereas to infringe the Yamanaka issued claims, all four genes must be used. The Sakurada is part of the portfolio held by iPierian, a company recently formed by the merger of iZumi Bio, a San Francisco Bay Area biotech and Boston-based Pierian (see p. 544). The Yamanaka patent is owned by Kyoto University.

The iPS cell intellectual property landscape was radically realigned recently with the news of a granted patent that considerably predates the Sakurada and Yamanaka patents. Filed by Rudolf Jaenisch, the patent issued on March 23, 2010 (ref. 6). Jaenisch's patent, also known as the '828 patent, was filed on November 24, 2004, with an earliest possible priority claim to November 26, 2003. The patent's broadest independent claim—that claim with the largest scope which is not ancillary to another claim—covers a somatic cell with an endogenous pluripotency gene linked to DNA encoding a selectable marker such that expression of the marker substantially matches expression of the endogenous gene, and an exogenously introduced nucleic acid encoding a pluripotency protein linked to a regulatory sequence. The endogenous gene is expressed in a pluripotent ES cell, is required for pluripotency of the ES cell and is downregulated as the ES cell differentiates. The pluripotency protein is expressed in a pluripotent ES cell and is downregulated as the ES cell differentiates.

Another independent claim from the '828 patent covers a somatic cell similar to the broadest claim, but requires that the first endogenous pluripotency gene encode Oct4 or Nanog. It furthermore requires that the exogenously introduced nucleic acid encode Oct4, Nanog or Sox2 and be linked to a regulatory sequence. The patent also includes an independent composition of matter claim directed to the line itself, which includes a somatic cell as described in the second claim above, as well as a candidate agent of interest in its potential to reprogram a somatic cell, where the endogenous pluripotency gene encodes Oct4 or Nanog.

Below we explore some of the underlying assumptions and limitations of this first patent related to IPS cells to issue in the United States.

Is there adequate support for Jaenisch's claims?

The scope of the '828 patent might be limited by the disclosure requirements of the Patent Statute7. Those requirements state that to rely on the benefit of its earliest priority date, the Jaenisch patent application would have to adequately describe and enable the claimed invention as of 2003.

To determine what invention the application covers, the written description and enablement requirements must first be met. To satisfy the written description requirement, we need to assess whether the application shows Jaenisch possessed the claimed invention. To determine enablement, we must consider to what extent the patent application, as filed in 2003, would enable one of ordinary skill in the art of stem cell research to make and use the claimed invention without undue experimentation.

The US Court of Appeals for the Federal Circuit recently revisited an important 2009 decision on the issue of written description in Ariad v. Lilly8. In this decision, the Federal Circuit invalidated broad patent claims to methods of reducing activity of a transcription regulator. In particular, the court held that the patent failed to provide an adequate description of the molecules that could carry out this inhibition.

The Federal Circuit has also provided guidance to determine whether a patent enables one of ordinary skill to make and use an invention without undue experimentation. In In re Wands, the Federal Circuit set forth the factors to be considered in determining whether a patent meets the enablement requirements: (i) the quantity of experimentation necessary, (ii) the amount of direction or guidance presented, (iii) the presence or absence of working examples, (iv) the nature of the invention, (v) the state of the prior art, (vi) the relative skill of those in the art, (vii) the predictability or unpredictability of the art and (viii) the breadth of the claims9.

Courts apply these factors in assessing whether an applicant has provided sufficient disclosure to support the claims of the patent. In the discussion below, we draw broadly on these factors in determining the likely scope and impact of Jaenisch's claims.

Which types of somatic cells?

The broadest claim of the '828 patent covers somatic cells with pluripotency genes, including mammalian cells. To support this claim, the application needs to show that in 2003, Jaenisch possessed the ability to create induced pluripotent stem cells, including in mammals, and enabled others to make and use the invention without undue experimentation.

Jaenisch claims a murine-based product that might be extended to any somatic cell line, including mammalian cells. This is reminiscent of a pre-Ariad decision, UC Regents v. Lilly, where the Federal Circuit determined that a patent describing only rat insulin cDNA would not support a claim directed to vertebrate and mammalian insulin cDNA10. The rationale for this limitation was based on the degeneracy of the genetic code. To determine if the '828 patent adequately describes mammalian cells, a court would need to determine if one with ordinary skill could visualize the members of the genus based on the description provided. More disclosure must be provided for more unpredictable members of a genus11.

A notable feature of the '828 patent is its priority date of November 26, 2003. It was not until four years later in 2007 that two independent reports announced successful creation of iPS cells without the use of embryos or using human fibroblasts1,2. The '828 patent was also filed considerably earlier than the December 13, 2005 priority date of the Yamanaka patent and the June 15, 2007 priority date of the Sakurada patent. The large gap in filing raises the question of what the state of the art was at the time of the filings, particularly in assessing whether the Jaenisch claims extend to mammalian cells. The fact that his examples are limited to murine reprogramming suggests that the claims to mammalian cells may not be supported by a disclosure that shows possession or teaches others how to make and use the claimed invention.

The relatively quick development from reprogramming murine to human cells, however, suggests that perhaps translation between murine and human may not have been unpredictable. Yamanaka's murine iPS cell lines appeared in the literature in 2006, followed quickly by his successful reprogramming of human fibroblasts in 2007. Contrast this rapid development to the species-barrier jump for hES cell lines: James Thomson's 1995 priority date for hES cells was over 13 years after mouse embryonic stem cells were first reported in Nature12. The Thomson patents survived a 2008 reexamination, in which they were found to be nonobvious, because the technique to isolate mouse ES cells was unpredictable and not universally applicable to the isolation of ES cells from other species, particularly human13. In other words, Thomson's invention could not have been informed by knowledge of the mouse literature at the time. Whereas the lack of iPS cell literature in 2003 similarly suggests that Jaenisch's invention was nonobvious, it is unclear whether the '828 patent will support the claims to human cells with pluripotency genes. Recently, the Board of Patent Appeals and Interferences reversed the reexamination decision for one of the Thomson patents, finding that it would have been obvious to try the known mouse protocols to isolate hES cells14.

Which pluripotent genes?

Because the '828 patent is limited to a somatic cell that requires the introduction of genes, the claims should not cover the introduction of proteins without alteration of the cell's genome. However, Jaenisch filed at least two continuations to cover different aspects of the invention described in his granted patent that also claim the priority date of November 2003 (ref. 15, 16). The specification of the granted patent, which is the same as that of the continuations, mentions various categories of reprogramming agents, including chromatin remodeling agents, pluripotency proteins (protein products of the genes Nanog, Oct4, Stella), and genes important for maintaining pluripotency (Sox2, FoxD3, LIF, Stat3, BMP, PD098059). Although the continuation applications are not yet publicly available, Jaenisch may attempt to claim these categories in these applications, as he was required to elect a subset of his claims during prosecution of the '828 patent17.

In the recently issued patent, Jaenisch's broadest independent claim, and many of the claims dependent on it, may face challenges because they do not specify which “pluripotency genes” are necessary for reprogramming. In the absence of demonstrating reprogramming, the mere mention of several types of pluripotency genes that might be effective may not have adequately described or enabled the invention. And, as Yamanaka demonstrated, uncovering the right combination of transcription factors was not trivial: his experiments used 24 genes in varying combinations. On the other hand, Jaenisch specifies in two other independent claims three potentially useful genes: Oct4, Sox2 and Nanog, which in the end were shown to reprogram cells, albeit inefficiently. Significantly, it now appears that the essential factors are Oct4 and Sox2—two of the genes that Jaenisch listed18.

Therefore, if applications corresponding to the Yamanaka and Sakurada patents are examined in the United States, the '828 patent might render them obvious. Courts might find it obvious for one of ordinary skill to attempt to use such genes, provided there is a reasonable expectation of success in choosing them from a finite number of predictable solutions19. Given Jaenisch's early filing date, his patent would then have an advantage in a priority race.

Reprogramming with proteins

Does the disclosure of the '828 patent foreclose later claims to reprogramming with proteins? Although not present in the granted claims, the specification of the patent mentions chromatin remodeling agents and pluripotency proteins (products of the genes Nanog, Oct4 and Stella). The question is whether using proteins to reprogram would be obvious in light of this disclosure. Would one of ordinary skill have a reasonable expectation of success, and are there a finite number of predictable solutions? This seems doubtful, given the difficulty in constructing and purifying proteins at the time of filing and the inefficiencies encountered six years later20. In light of this need for considerable experimentation as well as the lack of examples, it is unlikely the '828 patent provided sufficient information about reprogramming using such protein products in 2003, despite the mention of “candidate agents of interest” in the claims. Finally, the Jaenisch patent relies on selectable, vector-mediated delivery of genes and nucleic acids whereas the field is moving away from gene delivery as a necessary caution for eventual use of iPS cells for human therapeutics.

Conclusions

If newer methods of reprogramming are not covered by a continuation patent, the reach of the '828 patent may be quite narrow, especially given the movement toward reprogramming with proteins rather than genes. Protein reprogramming has taken years since the '828 patent's disclosure, suggesting that it was not entirely predictable.

In sum, the '828 patent: (i) may render obvious reprogramming using pluripotency genes Oct4 and Sox2; (ii) is unlikely to support claims to all somatic cells, including mammalian cells, with pluripotency genes; and (iii) is unlikely to foreclose reprogramming with pluripotency proteins or chromatin remodeling agents.

Although these determinations will ultimately be made at the discretion of a court or during a reexamination by the US Patent and Trademark Office, and are thus uncertain, our analysis suggests the '828 patent is not as far-reaching as some have feared and as Fate Therapeutics, a company founded by Jaenisch, triumphantly pronounced21. However, even if the impact of the '828 patent is dulled somewhat, it may still have a lengthy reach. Just as H1 and H9 became standard lines in hES cell research, arguably so too might lines reprogrammed using the '828 patent factors. These lines could become the next set of experimental controls, and if they remain in widespread use, the patent could prove to have considerable value.