United States: Yamanaka iPSC Patent Challenged

Dr. Shinya Yamanaka of Kyoto University shared the 2012 Nobel Prize in Physiology or Medicine with Dr. John B. Gurdon for their respective discoveries that mature, specialized cells can be reprogrammed to become immature cells capable of developing into all tissues of the body. In the 2012 Nobel announcement, the Nobel Assembly at Karolinka Institutet stated that the findings of Drs. Yamanaka and Gurdon "have revolutionized our understanding of how cells and organisms develop."

Dr. Gurdon was recognized for his 1962 discovery that the specialization of cells is reversible when he replaced the immature cell nucleus in an egg cell of a frog with the nucleus from a mature intestinal cell. The modified egg developed into a normal tadpole. Dr. Yamanaka was recognized for his later discovery that intact mature cells in mice could be reprogrammed to become immature stem cells, now known as induced pluripotent stem cells (iPSCs).

Patents and iPSCs

In 2006, Dr. Yamanaka along with Kazutoshi Takahashi filed a U.S. patent claiming the technique to make iPSCs. The application entitled "Oct3/4, Klf4, c-Myc and Sox2 produce induced pluripotent stem cells" issued as U.S. Patent No. 8,058,065 ('065 Patent) on November 15, 2011. The sole issued claim recites:

  1. A method for preparing an induced pluripotent stem cell by nuclear reprogramming of a somatic cell from a mammalian species, comprising:

    1. introducing into the somatic cell one or more retroviral vectors comprising a gene encoding Oct3/4, a gene encoding Klf4, a gene encoding c-Myc and a gene encoding Sox2 operably linked to a promoter; and
    2. culturing the transduced somatic cell on a fibroblast feeder layer or extracellular matrix in a cell media that supports growth of ES cells of the mammalian species, wherein one or more pluripotent cells are obtained.

On August 12, 2014, BioGatekeeper, Inc. ("BioGatekeeper") petitioned for Inter Partes Review ("Petition") of the '065 Patent on the ground that the sole issued claim is obvious in view of U.S. Patent No. 7,682,828 (the '828 Patent), entitled "Methods for Reprogramming Somatic Cells" that issued on March 23rd, 2010 when combined with additional prior art. The '828 Patent is assigned to the Whitehead Institute for Biomedical Research and lists Rudolf Jaenisch and Konrad Hochedlinger as the inventors. Twelve claims issued in the '828 Patent. The validity of the claims of the '828 Patent were challenged in a reexamination proceeding but were reaffirmed by the USPTO.

Independent claim 1 of the '828 Patent recites:

  1. A primary somatic cell comprising in its genome a first endogenous pluripotency gene operably linked to DNA encoding a first selectable marker in such a manner that expression of the first selectable marker substantially matches expression of the first endogenous pluripotency gene, wherein the cell additionally comprises an exogenously introduced nucleic acid encoding a pluripotency protein and operably linked to at least one regulatory sequence, wherein the endogenous pluripotency gene is a gene that is expressed in a pluripotent embryonic stem cell, is required for the pluripotency of the embryonic stem cell, and is downregulated as the embryonic stem cell differentiates, and wherein the pluripotency protein is a protein expressed in a pluripotent embryonic stem cell, is required for the pluripotency of the embryonic stem cell, and is downregulated as the embryonic stem cell differentiates.

According to BioGatekeeper, the invention of the '065 Patent is obvious in view of the teachings of the '828 Patent when combined with Benvenisty (Genes Dev. (1992) Dec;6(12B):2513-23) and in view of Li (Blood (2005) Jan 15:105(2):635-7, epub. Sept. 9, 2004).

Petitioner BioGatekeeper alleges that the iPSC cells of the '065 Patent are the same as the embryonic-like stem cells (ES) claimed in the '828 Patent and that prior to the '065 invention, it was known that the genes that convey pluripotencey were known as well as methods to make iPSCs. The argument is that the invention of the '065 Patent was the result of the simple and obvious substitution of one known element for another to obtain predictable results over what was taught in the prior art or the result of "choosing from a finite number of identified, predictable solutions" with a reasonable expectation of success and/or "obvious modification of prior art teachings, with a reasonable expectation of success." Petition at page 3.

The method of the '065 Patent requires the introduction of 4 genes into the cell to convey pluripotency: Oct3/4, a gene encoding Klf4, a gene encoding c-Myc and a gene encoding Sox2. BioGatekeeper finds that the '828 Patent discloses the use of Oct 4 and Sox2 genes (and the Nanog gene) to convey pluripotency. Benvenistry is alleged to teach the use of c-Myc as a pluripotency gene and the Li article is alleged to teach Klf4 as a pluripotency gene. However, because the '828 Patent also teaches the use of the Nanog gene in combination with the Oct 4 and Sox2 genes to reprogram cells, one of skill in the art would need to know to substitute the c-Myc and Klf4 genes for the absent Nanog gene and combine them with Oct 4 and Sox2 to arrive at the '065 Patent claim.

Déjà vu?

The validity U.S. Patent No. 7,029,913 entitled "Primate Embryonic Stem Cells" awarded to Dr. James A. Thomson for the in vitro culturing of embryonic stem cells also was challenged before the USPTO. See prior posts of June 15, 2014; February 3, 2014; December 1, 2013; September 15, 2013; and July 8, 2013. The USPTO upheld the validity of the patent and the challenger failed to have the decision reviewed by the U.S. Court of Appeals for the Federal Circuit because the challenging party lacked standing to pursue the case in federal court.

Interestingly Petitioner BioGatekeeper, Inc. does not appear to have a business related to iPSCs and therefore its interest in the '065 Patent is still a mystery. No doubt the identity and interest of BioGatekeeperwill become known given the high profile and commercial success of the Yamanaka technology.

BioKeeper Petition for IPR of '065 Patent.

Special thanks to the Knoepfler Lab Stem Cell Blog for first reporting on the BioGatekeeper challenge.

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