Blog readers investigate BioGatekeeper, the Yamanaka patent challenger

The readers of this blog never cease to amaze me. What an informed, energetic, bright group.

Within just days they may have collectively shed some light on an intriguing mystery in the stem cell field surrounding this question:

Who is trying, via the name BioGatekeeper, Inc., to nullify Yamanaka’s patent on cellular reprogramming to produce induced pluripotent stem (iPS) cells?

This past week the mysterious organization BioGatekeeper, Inc. filed a challenge to the Yamanaka Patent. The basis of the challenge is the assertion that cellular reprogramming was supposedly obvious based on pre-existing art, in this case meaning previous work and intellectual property (IP) on cellular reprogramming by others.

More specifically, BioGatekeeper focused on one other patent as the leverage for its argument to cancel the Yamanaka Patent: the Whitehead Institute Patent on reprogramming (aka The Whitehead Patent). The Whitehead Patent pre-dated Yamanaka’s. Like Yamanaka’s, the Whitehead Patent also focused on reprogramming of cells to pluripotency.

The Whitehead Institute has indicated that it has no involvement in BioGatekeeper.

A logical question then is why the people behind BioGatekeeper, whoever they might be, chose to focus on the Whitehead Patent as the driving force in their argument? That remains unclear at this time.

Who might be behind BioGatekeeper? The most logic candidates would be those who have been involved in cellular reprogramming over the years, particularly in the early days even before iPS cells. Read on on Page 2!

26 thoughts on “Blog readers investigate BioGatekeeper, the Yamanaka patent challenger


  1. This is more exciting than any movie or series aired this year. Forget “Game of Thrones” here we have ‘Game of iPSC patents’


  2. I am surprised that one of the “related posts” to this post is “Stem Cell Community Tribute to Yoshiki Sasai (笹井芳樹)”. Was there a connection there? I couldn’t believe it!


    • Yeah, that’s puzzling. The WordPress App, Related Posts, has an algorithm for choosing the “related” posts. Not sure how they do it.


  3. While trying to pay a tribute to Yoshiki Sasai by reading his famous STAP cell paper very recently published in Nature (3 0 J A N U A R Y 2 0 1 4 | V O L 5 0 5 | N A T U R E | 6 4 1), I found the following amazing statement contained there:
    “Over the past decade, the presence of pluripotent cells (or closely relevant cell types) in adult tissues has been a matter of debate, for which conflicting conclusions have been reported by various groups5–11.However, no study so far has proven that such pluripotent cells can arise from differentiated somatic cells.”.
    The firm statement, which apparently was agreed by all the authors of that paper and most likely all the peer reviewers selected by Nature, that “no study so far has proven that such pluripotent cells can arise from differentiated somatic cells” seems to be a direct slap on the faces of those, certainly including Yamanaka, who have claimed induction of pluripotent stem cells from differentiated somatic cells.
    Thus, it even makes me thinking of a reality drama of “STAP cells” slapping on “iPS cells”.


    • My reading of that was different than yours. I thought that they meant spontaneous formation of pluripotent stem cells from differentiated cells in vivo.


      • What is your interpretation of the last paragraph of the Nature paper: “The question of why and how this self-driven reprogramming is directed towards the pluripotent state is fundamentally important, given that STAP reprogramming takes a remarkably short period, only a few days for substantial expression of pluripotency marker genes, unlike transgene- or chemical-induced iPS cell conversion38. Thus, our results cast new light on the biological meaning of diverse cellular states in multicellular organisms”. Does this “self-driven” reprogramming means “spontaneous arising” while the “iPS cell conversion” means “artificial induction”?


    • You appear to have misinterpreted the text you have cited. “Arise” does not mean “induce” (active vs. passive), and “SUCH pluripotent cells” specifically refers back to “presence of pluripotent cells in adult tissues,” i.e., pluripotent cells already present in adult tissues. They are not talking about iPS cells. They are talking about the lack of support for spontaneous development of pluripotency, in situ, without outside manipulation. They are clearly not challenging the concept or existence of induced pluripotency. You also appear to not be familiar with Dr. Sasai or aware that he himself also worked with iPS cells. He was collaborating with Kyoto University for the first clinical trial for iPS cells, which is being run out of his insitute, RIKEN CDB. If he did not believe in induced pluripotency, he would not be involved in its groundbreaking first clinical trial. STAP was the low point, not the high point, of his very distinguished career. If you really wish to pay tribute to him, you should read some of his pioneering works on stem cell differentiation, for which he was considered for the Nobel Prize.


      • “Spontaneous development of pluripotency, in situ”? Is that not the reason why some “poorly differentiated” malignant tumors form in situ? As an “outsider” of cell division-based stem cell research I am certainly not familiar with Dr. Sasai’s groundbreaking work. How could you know that his pioneering works on stem cell differentiation “was considered for the Nobel Prize”? I thought the Nobel Prize selection is an extremely secret process which would not be known to public until 50 years after the awarding of the Prize.


        • So you are saying that STAP stem cells, if they exist, and Rongxiang Xu’s in situ formed stem cells are actually malignant tumor cells? That is an interesting idea.


          • No! I didn’t say that. What I was trying to say is: Yamanaka’s iPS reprogramming transformed normal stem cells into cancer stem cells. Xu’s in situ activation of tissue stem cells actually achieved tissue regeneration without forming malignant tumor. As to STAP cells, it is so far a joke in Nature.


            • Totally agree with you about STAP. Regarding the rest, I mentioned the as-yet unsubstantiated concept of in situ pluripotency (which is what was referred to by the text you cited and is what has been described by Xu). You said that this concept actually represents the development of malignant cells. Therefore, indeed, you did say that in situ pluripotency such as that claimed by Xu represents the development of malignant tumor cells. My comments were only based on what you said. Thank you for clarifying. Is there any peer-reviewed evidence to support Xu’s claims? As for iPS cells, you mentioned yourself that you are not a stem cell biologist; can you provide evidence that iPS cells are cancer stem cells? By stating that iPS cells are identical/equivalent to cancer stem cells, you imply that cancer stem cells isolated from excised tumor masses could also be used as a stem cell source and be differentiated to useful cells and tissues for regenerative medicine (like iPS cells). Can you provide references where cancer stem cells have been differentiated to, e.g., non-cancerous neurons, oligodendrocytes, retinal epithelial cells, etc? This is an interesting idea but seems rather unlikely to me.


              • Where did I say (in situ pluripotency) “actually represents the development of malignant cells” and “in situ pluripotency such as that claimed by Xu represents the development of malignant tumor cells”? Xu’s burn patient treatment-based proof of in situ activation of tissue stem cells remains rejected by peer-reviewed western journals even though one book in English has been published. However, that doesn’t mean his discovery is invalid. On the other hand, we have seen thousands peer-reviewed publication on iPS reprogramming within a short time of just seven years but I cannot find a single publication which proves beyond doubt that a “de-differentiation” “clock-reversing” reprogramming has turned (terminally) differentiated (non-pluripotent non-stem) cells into (less-differentiated) pluripotent stem cells. Yes! I am an “outsider” of the stem cell research. But that does not mean I should know (much) less about stem cells than (most) “stem cell biologists”. To support this, Jaenisch once (privately) “totally agreed with me” on my criticisms against a big shot in stem cell research and Yamanaka even (publicly) “thanked” me in Science for my criticisms on his flawed iPS research. As to the “equivalency” in malignancy between iPS cells and cancer stem cells, it was very hard to convince even cancer experts to accept my discovery on this. But it is now even unavoidable to read publications on the cancer risk of iPS cells. I guess, understanding oncogenic nature of iPS reprogramming may even become a hot topic of the next phase of iPS research. Once we understand the mechanisms of cancer cell-formation by iPS reprogramming then we will find ways to guide the differentiation of iPS cells back to normal ways and even find some root-killing anti-cancer drugs.


  4. As for why BioGatekeeper focused on the Whitehead patent, I think it is the logical choice because its teachings are relatively close to what Yamanaka did. Of course, this does not necessarily establish obviousness, but if one were to try, the Whitehead patent would be an obvious place to start. The selection of the Whitehead patent has no bearing on the Whitehead patent itself, i.e., it won’t add to or affect the value of the Whitehead patent. Rather, the Whitehead patent is being used as a tool to attack the Yamanaka patent in the same way that the other two references are being used.


  5. Admirable detective work, and yet, what really matters is the merit of the case against the Yamanaka (Y-) patent, not who brings it. If the Yamanaka application cited the Whitehead (W-) patent as a reference, then the examiner would most likely have considered the obviousness of the Y-patent claims with respect to it already, and concluded that the Y-patent claims are not obvious. That makes the suit an even tougher row to hoe.


    • Shinsakan,

      I agree with you that the W patent plus the papers are being used to argue for obviousness of the Y patent.

      I’m not a lawyer, but I’ve gotten a big dose of patent law through my involvement in the WARF patent challenge. In that context, making human ES cells using the same methods used for making mouse ES cells is, to me, far more obvious than determining what transcription factors will make cells pluripotent.

      But the logic of science is not the same as the logic of law.

      The “standing” issue is what’s standing in our way right now with the WARF challenge. So, down the line, the identity of the challenger is important, since he or she or it will have to be clearly harmed by the existence of the patent.

      Jeanne


      • Great point, Jeanne. I also think the stem cell world needs to know who is behind BioGatekeeper because more generally it is important to understand the different players, priorities, etc. in the field.


      • Jeanne, it’s possible that I’m wrong but under my understanding, standing would not be a threshold issue here (inter partes review) nor in your WARF case (inter partes reexamination).

        That changes however, if and when it comes to the right to appeal (which is the case with WARF, obviously).


      • Dr. Loring,

        Thanks for your comment! I am an ex-regenerative medicine researcher who now works in the patent field. I totally agree with you about the considerations for obviousness and the difference between science and the law (which is one of the most difficult things to get used to for those of us who make a career transition over to the legal side).

        In this case, I can think of at least 5 factual and legal arguments that counter Biogatekeeper’s allegation of obviousness for Yamanaka over Jaenisch. Additionally, it would be interesting to know when Yamanaka first actually generated iPS cells. If it were before November or December of 2003 (unlikely, I admit), then Yamanaka would predate Jaenisch and Jaenisch would no longer be available as prior art.

        Regarding the “standing” issue, I get what you are saying, but I believe that the situations are different. My understanding is that the standing issues for the WARF challenge were specifically related to the Federal Circuit appeal and not to the original patent challenge before the PTAB. I was under the impression that any third party could initiate an inter partes review before the PTAB; “standing” is only required when you want to appeal the decision of the PTAB to a higher court. In that context, it seems that the standing and identity of BioGatekeeper would not be relevant until the PTAB affirms the patent and BioGatekeeper then tries to appeal the decision, at which point, lack of standing may shut down the appeal (please correct me if I am wrong, though!).

        I still believe that BioGatekeeper’s challenge is more likely related to ego and hurt feelings than to any particular business consideration or strategy. If BioGatekeeper were really someone working in the field with “skin in the game,” then I would have expected them to hire a law firm with more patent expertise and experience (especially in the life sciences), and more firepower. Put it this way: if your life depended on a heart transplant, would you ask the local dermatologist to do the surgery?


        • Shinsakan,

          You are correct – anyone can challenge a patent.

          It’s only now, in the appeals court, that the issue of standing has arisen…and federal laws have changed (a couple of times) since we challenged the WARF patents in 2006.


          • Dr. Loring,

            Thanks for your comment! This is really interesting. I am not a litigator, so this aspect is outside of my experience/expertise. Speaking from a purely personal perspective, I wonder then what the threshold is to determine “standing.” Does this then mean that NPOs and consumer/patient advocacy groups can never appeal PTAB decisions? Would it be possible to recruit a for-profit company with a conceivable financial stake in the outcome to be part of a consortium aiming at invalidation of a patent? What are your thoughts?


    • Li You Hu, I totally agree with you regarding the merit of the case itself vs. who is filing it. Regarding the citation of the Whitehead patent, though, in the original prosecution history it appears to have been only cited by the applicant as part of an information disclosure statement (along with a whole bunch of other references) and not actually used as a basis for rejection by the examiner. It seems that the only art-based rejection that was applied was over Tada et al. (Current Biology 2001, Vol 11, pages 1553- 1558). So the grounds for rejection being brought by Biogatekeeper have not been considered before. I personally think that the arguments presented by Biogatekeeper are weak; however, I think that the outcome will depend on how strong of a counter-argument Kyoto University’s attorneys can make and what the judges at the Patent Trial and Appeal Board eventually think about it.

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