Brain-Tools

Excerpt 9 – Clinical Trial Results and Patent – 1996 – 1998

from:
ALZHEIMER’S:
My Journey to a
Next Generation Treatment
By
Donald E. Moss, Ph.D.

[Setting and Summary by Jim Summerton, Ph.D.]

was continued after the end of the clinical trial, this precious renewal continued for several years.

And complementing these thrilling clinical trial results, several months later Dr. Joseph Rogers, a long-time friend and colleague of Moss, suggested a strategy for finally getting the long-sought patent on the use of sulfonyl fluorides (including MSF) for treating Alzheimer’s disease.

Implementing this suggested strategy led two years later to the issue of US Patent 5,798,392 in August 1998.

With both dramatic clinical trial results and a new patent in hand, by 1998 it appeared MSF was now poised to revolutionize the treatment of Alzheimer’s. ]
********************************
Mary and I finished loading the car the next morning, closed the door to the apartment for the last time, and headed over to the clinic so Mary could say good-bye to Pati. I had a lump in my throat as Mary and I cleared the edge of the city and started our journey north across the desert. Although the final tests on the last few patients had not been done, leaving Chihuahua that morning signaled the end of the study for me.

I returned to Chihuahua by myself a few times over the following weeks, until I had made all the capsules, run the final red cell AChE assays, and Hugo, Ceci, and Pati had conducted the last cognitive tests. Finally, once Pati and I had all the data collected, including the follow-up clinical blood work that she had to do, the study was over. I loaded the spectrophotometer and the other lab equipment I’d brought to Chihuahua in my old Mercury and prepared to head north.

It was hard to say good-bye to Pati after all that we had been through, the good times and the bad. I was going to miss Pati and Chihuahua. We hugged each other and I drove off with a hot cup of strong Combate Mexican coffee for the road. I knew the study was over but our friendship was not. I am in regular contact with Pati today.

* * *

Before I left Chihuahua, we carried out the most thrilling and satisfying part of the entire project, finding out the final results. To accomplish this, Pati, Hugo, Ceci and I went through the files and compiled each patient’s scores at the beginning, at the cross-over point, and again at the end. Then for the first time, I showed Pati, Hugo, and Ceci my spread sheet, the key to knowing when the patients were on MSF or placebo (identical capsules, but lacking MSF).

Using the spread sheet as a guide, we separated the people into two groups. One group received MSF first and then placebo. The other group received placebo first and then MSF. I then graphed the results, which are shown in the below.

figure1

“These results are great.” I showed Pati, Hugo, and Ceci the dotted lines. “Look how the patients’ memory goes down on placebo. That’s the normal course of the disease.  Because we have the placebo for comparison, we can be confident that the improvement, the upward going solid lines, with MSF treatment is real. Without having the placebo as an anchor for what is normal, we wouldn’t know what MSF was doing.”

Over the next few days, I computed the statistical analyses. As is shown in the graph, MSF was highly effective. Though not all patients improved as much as Concha and Don Manuel (and Fred whose data are not included), nevertheless, most of the patients showed clear recovery of cognitive functions and did better in activities of daily living.

What surprised and pleased me was that the patients who started on MSF didn’t crash down to baseline even after receiving nothing but placebo for the following eight weeks.

I had initially anticipated that their cognitive function would relapse, even going lower than their beginning scores at entry into the protocol (week zero). I expected this because throughout the sixteen weeks of the study, Alzheimer’s disease should have continued to kill the brain. Once the MSF was discontinued at the crossover, I expected that the underlying deterioration of the brain would show itself as a decline to below the scores at entry. Contrary to this, I was delighted to see that, like Concha, the patients who started out on MSF maintained most of their improvement over the subsequent eight weeks with nothing but the placebo.

It is particularly notable that MSF was substantially more effective than the two FDA-approved drugs, donepezil (Aricept®) and rivastigmine (Exelon®) which are currently used for treating Alzheimer’s patients. The comparison of MSF with these FDA-approved drugs is shown in the figure below.

figure2

From this comparison, it is clear that MSF can provide much greater improvement than these two currently used FDA-approved drugs. Not only was the superiority of MSF shown in the graph and with statistics, I had also seen Fred and Concha improve dramatically, along with the other patients who showed less striking results but clear improvement nonetheless.

Don Manuel provided another interesting and impressive case study. He also weathered the second eight weeks in the placebo phase without much loss of cognitive function, and at the end of the study he wanted to go back on MSF. With that extended treatment he continued to improve. I knew he was a success, but what I didn’t know at the time was that he would go on to be declared competent to return to the control of his affairs. However, a couple of years later, he finally succumbed to the disease and
reached a point where MSF ceased to be useful. In the end, he had to be cared for continually, and soon thereafter he died in his home.

* * *

These clinical results were an exciting vindication of all the years of effort my colleagues and I had committed to the sulfonyl fluorides, and the repeated disappointments we had endured during the course of this odyssey. These results clearly promise a substantial improvement in the lives of Alzheimer’s patients and, furthermore, to ease the burden of care for their family members.

In the weeks that followed the end of my Chihuahua study, the success of the experiment was harder to endure than if the whole thing had collapsed and ended in complete failure. If MSF had bombed, it would have been over. I could have suffered through the defeat and let it go.

But now, in spite of the outstanding results I obtained in Mexico, a cloud of frustration and despair hung over me. I had no patent on the use of MSF to treat memory decline, and it appeared that I would never be able to get one simply because fourteen years earlier I had made the colossal mistake of disclosing the effectiveness of the sulfonyl fluorides for treating memory at that fateful meeting in Louisville. That tragic mistake had plagued me ever since, and was the cause of my current conundrum.

Without a patent it appeared that there would never be a way to attract the hundred million dollars or more likely to be needed to carry out the large-scale clinical trials which would be required to obtain FDA approval in the US.

With the dramatic success of my clinical trial in Mexico, I was damned. I couldn’t see how I could live the rest of my life with a key that could improve the quality of life for so many people all over the world without finding some way to use it. Without a patent, that key could never be used.

* * *

By April, 1996, I’d endured two months of wondering what I could do to move MSF forward. As usual, when frustrated and feeling like I was lost in the woods, I went out to Phoenix to visit Joe Rogers.

At that time, he was working on how a slow inflammatory process was contributing to the destruction of brain tissue in Alzheimer’s disease. He was fighting his own battles because most people at that time thought that the brain was walled off from inflammatory processes by the blood-brain barrier.

People talked about Joe and his crazy ideas in hushed tones at the Neuroscience meetings.

Joe and some of his colleagues had an article coming out in Neurobiology of Aging in September that gave some hard evidence that would quell the chuckling about his inflammation hypothesis. If Joe could figure out a way to block inflammation in the brain, it might stop the progression of Alzheimer’s disease. If he could stop or slow the destruction of brain tissue, I could rehabilitate cognitive function, at least to some degree, with MSF.

I drove over to Phoenix one afternoon and stayed with Joe and Mimi and enjoyed Joe’s gourmet cooking over a bottle of fine wine from the temperature-controlled vault in his home. Although we talked about a lot of things that night, we didn’t get around to my problems with MSF. I was just as happy to let it go and enjoy the evening.

The next morning, Joe gave me a tour of the new Sun Health Research Institute building that he had gotten funded and constructed. The long hallways filled with labs and teams of people working on Alzheimer’s and Parkinson’s diseases impressed me. After the tour we ensconced ourselves in his office for a serious conversation.

Talking to Joe was not a public disclosure that would interfere with a patent, if I could ever find a way to get one, so I let it out. As I paced around his spacious office, stopping from time to time to look out the tall ceiling-to-floor windows, I spilled everything about MSF and the success of the clinical trial in Mexico.

At the end of my rant, Joe thought for a few minutes. “Is there any teaching away?” “What’s teaching away?” I asked. “I don’t even know what you’re asking.”

“Teaching away is when an expert says that an idea may seem obvious, but it won’t work. Your own publications about how MSF will treat dementia are blocking your chances to file for a new patent. To overcome the problem caused by your publications, you’ll have to find someone who says the sulfonyl fluorides won’t work, that your published ideas are wrong. That’s teaching away, saying that your strategy is wrong. Find teaching away and you will get a patent.”

I stood there, mouth agape, as I struggled to understand that Joe was telling me that there was hope of a patent after all. And he was telling me how to do it.

“See if you can find a published report that says MSF won’t work,” Joe said. “That’ll be the key.”

* * *

Back in El Paso, I scoured the literature on AChE inhibitors for the treatment of dementia, looking for experts to conclude that they are useless. I found one that had been published only the month before by Dr. Robert Becker. He stated emphatically that metrifonate, the AChE inhibitor he used in a clinical study, was not useful and he went on to conclude: “… acetylcholinesterase inhibition cannot significantly improve cognitive performance in AD [Alzheimer's disease] … The changes in our and others’ studies of
acetylcholinesterase inhibitors are not adequate to suggest clinical significance ….. Our data do not support the hypothesis that correction of deficient cholinergic function [acetylcholine] will result in clinically significant improved cognition in AD.”

Becker and his colleagues were teaching away from the idea that MSF or any other AChE inhibitor could ever work. They were burying this whole strategy of treating dementia. The fresh publication of a decisive new study concluding that AChE inhibition cannot improve cognitive performance in Alzheimer’s was another outstanding stroke of good luck. This article was exactly what I needed to get a patent.

Armed with Becker’s article, I disclosed the results of my clinical study and my strategy for getting a new patent to the University. I explained how teaching away opened the door to the patent and that the University should fight for it. The stakes were too high to let this opportunity slip away. The University finally agreed to file the patent and try again.

I also asked that the University not contract with ABC law firm, the one used in 1982 that helped me drive a wooden stake through the heart of my first patent attempt. My new patent application was submitted to the U.S. Patent and Trademark Office August 28, 1996, by an attorney from a different law firm.

We had a year from the time we filed the patent application in the U.S. to file for patent rights in the rest of the world. Eleven months went by and we still had not obtained the U.S. patent. We had a choice to make. We could lose all patent rights worldwide, except for the U.S. and Canada, or we could spend $1500 to file for an extension on the worldwide rights under the patent cooperation treaty.

The University was neglecting my patent application and we were within days of the deadline and forfeiting decades of my work over a $1,500 fee. I finally had to write a letter to the president demanding that they either file for the extension or give me back the rights in time for me to file. I could not stand by and be a victim of bad patent
management again. The University finally paid the fee and we reserved the worldwide rights.

After a two year battle with the patent examiner, I received a big envelope from the attorney. Patent #5,798,392, Sulfonyl Fluorides for the Treatment of Alzheimer’s Disease was issued to me August 25, 1998. That was one of the best days of my life. Finally, I had some basis for hope.

Now all the University and I had to do was convince a drug company to spend a hundred million dollars or more to get MSF approved by the FDA and get it out into a world market. The patent was good for 17 years.

With the patent issued, I could shout about MSF from the tops of mountains and tell everyone who would listen what a wonderful drug it was. Now that the patent had issued, Pati and I, along with our research team as co-authors, published the results of the Chihuahua study in the 1999 volume of Alzheimer Disease and Associated Disorders  where everyone could read about it.