NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

Other questions before I re-read your post: You said...

"They may have not told us outright in 2014, but I believe they changed the lymphocyte count “inclusion” criteria after six weeks of chemoradition. Those blood cell counts can make a difference of 6 months in OS even before immunotherapy is introduced. And that kind of "inclusion" change will affect both arms before and after crossover. After crossover is where it will be seen most in immunotherapy. The less comprised and immunotherapy patient is going into an immunotherapy treatment, the better off they will do." -- RK

I thought they changed that WBC criterion also, but I can't remember why I thought that. Why do you think they changed it? I worry too that it might not benefit the experimental group more than the control group, even if they did not have crossover. An intact immune system is always a good thing, just a question of how much of a good thing. But I was very much in favor of having such a criterion because it seems unfair to test an immunotherapy on patients that no longer have a healthy immune system... -- Dok

Honestly, I’m not 100% if they did, but I read Reefrad tell Flip he had seen the new protocol. They haven’t updated the NCT inclusion/exclusion criteria. But, the idea came to me last month when Flip asked an lymphocyte inclusion question about the info arm, it made me think about it.

http://investorshub.advfn.com/boards/replies.aspx?msg=122271346

I’m not sure if you were around at the time but back in January a Ladygray showed up on the board.

http://investorshub.advfn.com/boards/read_msg.aspx?message_id=120105440

During that post conversation speaking about a HE patient, I became convinced that NW Bio had made a manufacturing change back in 2013 in the U.S. and then pursued that patent in Europe, and the August 2014 change to the trial was related to that.

http://www.nwbio.com/nw-bio-obtains-approvals-for-enhancements-of-phase-iii-trial-of-dcvax-l-for-gbm-brain-cancer/

“The patient finally was able to enter the compassionate use/self-pay program at the end of 2014 beginning of 2015, when the program in the UK was reopened, at which time he under went a leuk and 3 doses were made. After those were administered he was informed that there was sufficient tumor lysate available to make more vaccine if he would do another blood draw, which he did.

That time they were able to manufacture 17 doses of the vaccine. “ — Ladygray

Once she wrote that, I immediately thought the only way to produce that many vaccines is if the TFF manufacturing patent was in use.

“In late 2013 the Company began a pursuit to change the trial, to "enhance it". The process took well into the next year. Shareholders were unaware that the trial was on any clinical halt. In August 2014, they issued a press release (below) that the changes were made to the statistical analysis to account for a "low white blood cell" count that patients experienced after chemotherapy. But, they were still working on European approvals. THIS patent has very much to do with being able to produce a higher potency leukapheresis draw. The VACCINE they use in the trial is the same vaccine they used in the compassionate use arm program. The only way to go from being able to MANUFACTURE a significant supply from 3 to 17 is if this US patent is in use. It has an equivalent patent counterpart in Europe, which as I remember was issued sometime in 2014. And what your unique experience is telling me is that this PATENT IS NOW in use for DCVax-L. Thank you for sharing it.

This tangential flow patent is the difference in the number of injections. Review the patent for yourself.

And getting this patent approved to be used in the Phase III trial, in the DCVax-L product, was likely the low WBC count they referenced in their 2014 press release. It is a patent for the "next generation process for manufacturing higher quality and higher reliability dendritic cells". “ — RK

http://www.nwbio.com/nw-bios-patent-portfolio-further-expanded-with-manufacturing-automation-patent/

And then I found this on the SEC reports, and they did disclose manufacturing changed:

www.nasdaq.com/markets/spos/filing.ashx?filingid=9193123

Recent Developments

On September 10, 2013, we announced that we had been issued another U.S. patent (#8,518,636) covering a next-generation process for manufacturing lower cost human dendritic cells of both a higher quality and higher reliability. This next generation system has already been cleared by the FDA for use in the manufacturing of dendritic cells for our clinical trials. These systems are now in use producing the vaccines which have already been injected into the tumors of DCVax-Direct patients.


Changes in manufacturing methods for DCVax-L could require us to conduct equivalency studies and/or additional clinical trials.

With biologics products, “the process is the product”: i.e., the manufacturing process is considered to be as integral to the product as is the composition of the product itself. If any changes are made in the manufacturing process, and such changes are considered material by the regulatory authorities, the company sponsor may be required to conduct equivalency studies to show that the product is equivalent under the changed manufacturing processes as under the original manufacturing processes, and/or the company sponsor may be required to conduct additional clinical trials. Our manufacturing processes have undergone some changes during the early clinical trials. Accordingly, we may be required to conduct equivalency studies, and/or additional clinical trials, before we can obtain product approval, unless the regulatory authorities are satisfied that the changes in processes do not affect the quality, efficacy or safety of the product.

And the European Patent as it turns out was issued in August 6, 2014:

https://www.google.com/patents/EP2298436B1?cl=en

And of course I was excited about it back then, as the issue of insufficient vaccines would go down. If patients crossed over, even on vaccine they would have enough vaccine to get more than 10 injections. Linda Liau's comments about the study make more sense too.

As it turns out, I believe my assumption was correct, and in 2013, the US started using that patent. Great Britain followed suit in August 2014. But, here is where it gets interesting, in July 17, 2015, German had issue with some of the claims within the TTF patent, and denied it.

“T 1554/14 (Tangential flow filtration device/NW BIOTHERAPEUTICS) of 17.7.2015”

www.epo.org/law-practice/case-law-appeals/pdf/t141554eu1.pdf

Of course, the Company attempts an appeal. Then the study stopped screening new patients. If the patent would have been denied, then that probably would have meant that the trial would be in jeopardy. I would think they hold off recruiting until the end as they want some of German patients to be under this patent. Manufacturing consistencies across the board.

It's a good thing I only stumbled on this today as the shorts would of had a field day. The excellent news is the process is now complete, and within a couple of days we should hear news that all is fine, assuming that is what the screening halt was about. All claims have been satisfied and updated as of Wednesday, May 25, 2016.

Grant of patent is intended as of 22.05.2016
Database last updated on 25.05.2016

https://register.epo.org/application?number=EP03761157&tab=main