Patenting cord blood therapy – a game changer?

It has come to our attention that Duke University has filed a half dozen patent applications^1-6 that cover the use of allogeneic cord blood stem cells to treat hypoxic-ischemic encephalopathy or cerebral palsy, the use of autologous cord blood stem cells to treat autism, as well as the use of allogeneic mesenchymal stromal cells from cord tissue (UC-MSC) to treat autism. The initial filings date back to 2017, but several of these patent applications were only made public within the past few months.

What stem cell therapies can and can’t be patented

At the annual meeting  of the Perinatal Stem Cell Society held during the first week of March 2020, the attendees were fortunate to hear a timely talk by attorney John Wetherell, PhD JD, of Pillsbury Law. The talk was titled "Patent Protection of Stem Cell Innovations", and gave a primer on what types of stem cell inventions are patentable. Patent law is a very complex field, but based on the briefing to the Perinatal Society meeting, we summarize a few key facts that may apply to the Duke patent applications.

The subject matter of a patent cannot be something that is naturally occurring, like minimally manipulated stem cells. However, the treatment protocol for therapy with minimally manipulated stem cells can be patented, with regards to factors like patient selection, cell preparation, dosing, and method of delivery. This is often called a “method of use” patent.

In the arena of patents, the concepts of “prior art” and “novelty” are very important.  Prior art refers to technology and information already known to the public anywhere in the world. Prior art includes published literature, abstracts, poster presentations, talks, public databases, sales, previous patent applications, or any other information that is available to the public. In order to be eligible for a patent, the inventor must file the patent application before making any public disclosures about the invention. The novelty requirement means that the invention must not be obvious to persons who are skilled in the art.

Legal experts emphasize that a patent only grants exclusionary rights. It does not guarantee that the inventor will have a monopoly on sales in the field of their invention, in fact it does not even guarantee they will have any sales. It merely prevents copycats from reverse engineering their invention and trying to sell the same thing.

Patenting cord blood therapy for cerebral palsy

The cerebral palsy community was shocked when the Duke application to patent the use of cord blood from donors to treat cerebral palsy became public in January 2020⁶. Since the patent application does not employ a manipulated cell type, no one anticipated the patent filing. The bigger reason for shock is that there is a body of prior art from other research groups that published papers on this approach before the first Duke filing, starting with a randomized controlled trial in South Korea that was published on-line in Dec. 2012^7-10 (this list of papers may not be comprehensive).

A careful reading of patent application US20200016213A1 reveals that it is based on the Duke “ACCeNT-CP” trial NCT03473301. This trial is active but no longer recruiting; the estimated completion date is May 2020.

Does the existence of substantial prior art invalidate this patent application? The experts say “NO”. Each research group that is treating cerebral palsy with stem cells has somewhat different criteria for selecting patients, setting stem cell doses, delivering stem cells, giving concomitant therapy, and measuring outcomes. In 2018, Parent’s Guide to Cord Blood published a comparison of several cerebral palsy clinical trials that had control groups, and the downloadable spreadsheet required 23 columns of information in order to properly compare the multiple variables between studies.

It is reasonable to conclude that, since the Duke protocol for treating cerebral palsy with high doses of allogeneic cord blood is unique and not previously presented, they can get a “method of use” patent on that protocol. In this patent application, “high dose” cord blood therapy is defined as a single infusion of 100 million TNC/kg, plus or minus 25%. This is five times higher than the cord blood transplant dose of 25 million TNC/kg. The 2015 paper by Romanov et al.¹⁰ may have given doses this high, but this is unclear because their results are not shown in units of TNC/kg. Several researchers prefer to treat cerebral palsy with multiple doses of cord blood stem cells that cumulatively are comparable to Duke’s high dose^9-11.

Presuming this patent is granted, how will it impact the cerebral palsy patient community? Opinions on that topic have been mixed. One thought is that the existence of a patent will increase the prestige of cord blood therapy. At present in the United States, the Duke Expanded Access Program under clinical trial NCT03327467 is the only well established and legal program of cord blood therapy for cerebral palsy, and that is unlikely to change with or without a patent. Some are concerned that awarding a patent could increase costs and decrease access for patients, because only caregivers that are licensed by Duke will be able to provide the cord blood treatment protocols that are covered by the patent. It is even conceivable that a patent on the use of donor cord blood will drive more parents of cerebral palsy patients to use cord tissue UC-MSC therapies instead.

The impact that this patent might have on cord blood banks should also be considered. The high dose of donor cord blood that is employed in the Duke patent application can only be achieved by giving large cord blood units to small children, and these large units are almost exclusively found in public cord blood banks. Hence, this patent application throws out a lifeline to the Carolinas Cord Blood Bank at Duke, as well as any other public banks that partner with them. The patent will not impact autologous cord blood therapy from family banks.

Patenting stem cell therapy for autism

To treat the diagnosis of autism, Duke has filed patent application WO2018169952A1 for cord blood and WO2019195506A1 for UC-MSC.

Of note, the Duke patent application to treat autism with cord blood is filed both worldwide and specifically in Korea as KR20190124300A. This patent application is based on clinical trial NCT02176317, a phase 1 trial of autologous cord blood that was subsequently published in 2017¹². The paper was submitted 2016-11-28, the patent was filed 2017-03-13, and the paper was first published 2017-04-05. In this study the median dose of autologous cord blood was 26 million TNC/kg. A phase 2 trial of both autologous and allogeneic cord blood for autism, called the “ACT” trial NCT02847182, has completed and results have been presented in conferences.

Regarding prior art, we believe that the Duke group was the first to publish the use of autologous cord blood for autism¹². A competing trial in the United States, NCT01638819, started at Sutter Health in California two years before the Duke trial but published one year later¹³.  The mean dose in the California trial was 16 million TNC/kg and the results were not statistically significant. If this patent is granted, it will impact autologous cord blood therapy from family banks. Worldwide, the first trial NCT01343511 to use cord blood for autism took place in China in 2011 and was published in 2013, employing allogeneic cord blood¹⁴.

The Duke patent application to treat autism with UC-MSC WO2019195506A1 describes the phase 1 trial NCT03099239, as well as a phase 2 trial NCT04089579 that is called the “IMPACT” trial. The phase 1 trial is completed but not published, and the phase 2 IMPACT trial is recruiting.

The existence of prior art or competing patent applications is almost irrelevant when it comes to therapy with the UC-MSC cell type. The reason for this outlook is that almost everyone cultures their UC-MSC in order to grow enough cells for therapy, and no two laboratories isolate and culture UC-MSC exactly the same way. Effectively, no two UC-MSC products are the same, so there will never be a conflict between rival labs unless one tries to copy the procedures of another. For example, the biggest center for treatment of autism with UC-MSC is the Panama Stem Cell Institute, and their founder Dr. Neil Riordan holds patent applications on this therapy, US20160263162A1 and WO2009046377A2, which both date back to 2007. But there is no conflict between the patent applications from Panama and from Duke because their UC-MSC preparation methods differ, and hence they are treating patients with different cellular products.

Perspective

Many people who work in the field of cord blood therapy were unaware that Duke University has been systematically filing patent applications on all of the therapies in the clinical trials of Dr. Kurtzberg’s group. The patent applications have never been announced. However, if you consider that the FDA now regulates cord blood therapy as a drug, then the appropriate analogy is to the pharmaceutical industry, where filing for patents is business as usual. A good example would be the history of Dr. Carl June’s work to develop CAR-T therapy for cancer, which evolved over many years in academia, but culminated in an FDA-approved drug Kymriah that is now provided by Novartis. The Duke patent applications confirm that regenerative medicine therapies with cord blood stem cells are serious business.

References

1. Methods of Treating Brain Injury Using Cord Blood or a Component Thereof. US20190350985A1 2017-01-12 first filed; 2019-11-21 publication
2. Methods for the treatment of autism spectrum disorders. WO2018169952A1 2017-03-13 first filing; 2018-09-20 publication (Note: specifically submitted for Korea as KR20190124300A )
3. Methods for the treatment of autism spectrum disorders. US20200069741A1 2017-03-13 first filing; 2020-03-05 publication
4. Methods of treating cerebral palsy and hypoxic-ischemic encephalopathy using human umbilical cord tissue-derived mesenchymal stromal cells. WO2019195554A1 2018-04-04 first filing; 2019-10-10 publication
5. Methods of treating autism spectrum disorders using human umbilical cord tissue-derived mesenchymal stromal cells. WO2019195506A1 2018-04-04 first filed; 2019-10-10 publication
6. Methods of Treating Cerebral Palsy Using High Dose Allogeneic Umbilical Cord Blood. US20200016213A1 2018-07-12 first filing; 2020-01-16 publication
7. Min KH, Song JY, Kang JY, Ko J, Ryu JS, Kang MS, Jang SJ, Kim SH, Oh D, Kim MK, Kim SS, Kim MY. Umbilical Cord Blood Therapy Potentiated with Erythropoietin for Children with Cerebral Palsy: A Double‐blind, Randomized, Placebo‐Controlled Trial.  Stem Cells 2013; 31(3):581-591.
8. Kang M, Min KH, Jang JY, Kim SC, Kang MS, Jang SJ, Lee JY, Kim SH, Kim MK, An SSA, Kim MY. Involvement of Immune Responses in the Efficacy of Cord Blood Cell Therapy for Cerebral Palsy. Stem Cells and Development 2015; 24(19):2259-2268
9. Feng M, Lu A, Gao H, Qian C, Zhang J, Lin TX, Zhao Y. Safety of Allogeneic Umbilical Cord Blood Stem Cells Therapy in Patients with Severe Cerebral Palsy: A Retrospective Study. Stem Cells International 2015; 2015:325652
10. Romanov YA, Tarakanov OP, Radaev SM, Dugina TN, Ryaskina SS, Darevskaya AN, Morozova YV, Khachatryan WA, Lebedev KE, Zotova NS, Burkova AS, Sukhikh GT, Smirnov VN. Human allogeneic AB0/Rh-identical umbilical cord blood cells in the treatment of juvenile patients with cerebral palsy. Cytotherapy. 2015; 17(7):969-78.
11. McDonald C. Multiple Doses of Cord Blood are Better for Cerebral Palsy in Animal Model newsletter June 2019; Parent's Guide to Cord Blood Foundation.
12. Dawson G, Sun JM, Davlantis KS, Murias M, Franz L, Troy J, Simmons R, Sabatos‐DeVito M, Durham R, Kurtzberg J. Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single‐Center Phase I Open‐Label Trial. Stem Cells Translational Medicine 2017; 6(5):1332-1339
13. Chez M, Lepage C, Parise C, Dang‐Chu A, Hankins A, Carroll M. Safety and Observations from a Placebo‐Controlled, Crossover Study to Assess Use of Autologous Umbilical Cord Blood Stem Cells to Improve Symptoms in Children with Autism. Stem Cells Translational Medicine 2018; 7(4):333-341
14. Lv YT, Zhang Y, Liu M, Qiuwaxi JNT, Ashwood P, Cho SHC, Huan Y, Ge RC, Chen XW, Wang ZJ, Kim BJ, Hu  X. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. Journal of Translational Medicine 2013; 11:196