Brain-Tools

Excerpt 2 – Finding MSF – 1984

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

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

[ Setting and Summary:  Due to gross inattention to crucial time deadlines by an attorney at the patent law firm engaged by the University, Moss' disclosure of technical details at a scientific meeting resulted in loss of the right to file for a broad patent on the use of high-specificity sulfonyl fluorides for the treatment of Alzheimer's and other conditions characterized by serious memory decline.  This debacle motivated Moss to search for new molecular structures in this same family of sulfonyl fluorides which might still be discovered and patented.  That search led him to the discovery that MSF (methane sulfonyl fluoride) provided unprecedented activity for selectively blocking the key enzyme in the brain that must be blocked in order to renew the concentration of acetylcholine in the brains of Alzheimer's patients, and thereby revive their memories.]

******************************

I spent a few months licking my wounds from losing everything in the patent fiasco. Without a patent, and no prospect of getting one, there was no information that had to be kept secret anymore. I published everything I knew, making all I’d found public. I hoped that a drug company, or somebody else, would see the superiority of my strategy of combining a long-acting AChE inhibitor with a quality of the brain itself, the slow new synthesis of AChE, to develop an advanced drug that would really help people. I tried to convince myself that the scientific implications of what I had discovered were enough.

Everyone else working on Alzheimer’s was stuck on using short-acting AChE inhibitors that produce no clear memory improvement in individual patients. The enhancing effects could only be proven by looking at average scores in large groups. Maybe only ten or twenty percent of the patients had noticeable improvement. Short-acting drugs also had the down side of causing nausea, vomiting, and diarrhea, making the patients’ lives miserable. The patients had to make a choice of remembering enough to know that the side effects of the drugs were making them sick, or skipping the drugs and forgetting. Surely someone would come forward and continue what I had started.

Trying to rationalize away my failure to get a patent didn’t work. No one showed any interest in the sulfonyl fluorides, and no one began any innovative research. All the big drug companies and everyone I knew continued to work on the short-acting inhibitors even with all their warts and shortcomings. I went to national and international conferences and told everyone that would listen about the sulfonyl fluorides. After a year of being miserable, I couldn’t let it go. I obsessed that there had to be another way to move forward. The potential good outweighed the problems that I faced. PMSF was only one of a whole class of bizarre chemicals that few people had explored. None of them had ever been used for any therapeutic purpose, human or veterinary, and there would be a lot to learn about them. There might even be other clinical applications that couldn’t be anticipated.

I started over.
* * *

Lisa stayed with me even through the setback. I’m not sure she ever knew how bummed out I was over the patent debacle, but I took her to lunch one day to Casa Jurado, a Mexican food place within walking distance of campus, to see if she wanted to keep going.

“Why are we having lunch?” Lisa asked after we’d both ordered the enchiladas. “This must be important.”

She was right. I didn’t generally take my research assistants out to lunch. I took a sip of my iced tea and thought a moment before I answered. “I’m not sure. But I have some ideas that I want to kick around, see what you think. I want to try an end run around the patent problem.”

“So we can get the patent after all?” she asked. “What can we do?”

“No. We can’t get the patent on PMSF or sulfonyl fluorides in general. Once you miss a patent opportunity, it’s permanent – gone, done, dead, no recovery. Believe me, I’ve looked into it.”

“What if we had a drug that would absolutely cure Alzheimer’s disease? What if you had a drug that would cure AIDS and save a million lives? What would happen then?” Her eyes were locked on mine. “There must be a way.”

“If I were dumb enough to take a bottle of some wonder drug to a conference, hold it up, tell people what it was and how it worked – before I did the patent application – it would forever prevent the drug from being used in patients. It would be like it never existed. There’s no way around it. Period.”

“I wonder how many drugs there are in the world that can’t be developed because they can’t be patented, because they aren’t profitable?” Her lips were tight and her eyes flashed. “Is this all about money? Nothing else?”

Our waiter brought our plates and refilled our iced teas as we sat in silence. After he’d left, Lisa picked at the edge of a steaming enchilada.

“I don’t know the answer to your question,” I said. “Nobody will work on drugs that can’t be patented. They would spend hundreds of millions to develop a drug and get FDA approval only to have some generic company step in and knock it off for cheap. The original company wouldn’t be able to charge enough to make back all the money they’d spent. How dumb would that be? Stockholders wouldn’t like that.”

“Soo Y What are we going to do?” she asked.

I took a bite of food, swallowed it, and had a sip of tea before I answered. “I want to keep working on the sulfonyl fluorides.”

Lisa’s eyebrows shot up and she stopped with a bite halfway to her mouth. “Why? I thought you said we couldn’t get a patent on them.”

“I can’t give it up.”

“What are you thinking?” she asked as she put down her fork, incredulous. I could tell that she thought I’d lost my mind. She was too polite to put it in those words.

“I’m probably not being rational, I admit. But I can’t give up.”

“What can we do?”

I noticed that she used “we” in her question. Maybe she would still go down the path to nowhere with me.

“Well, it’s a long shot – probably hopeless but worth a try. What I’ve done is screw up one patent.” I paused for a moment. “Well, that’s not true. The attorneys went along with a workman-like efficiency and helped me screw up one patent. We can’t do anything about it. That’s water under the bridge. But we might be able to start a new strategy, get a different patent.”

“How can we do that?” she asked. She was eating again and I took that as a sign that she would hear me out.

“What I’ve lost is that ability to get what is called a use patent. I wanted a patent to use sulfonyl fluorides to treat dementia. What we might be able to do is make a new molecule that does not exist yet, our own sulfonyl fluoride. We’ll have to find one that inhibits AChE that has never been made before.
This will be a composition of matter patent, a new compound that we are the first to ever make. If we do that, we can get a patent on the compound itself. If we can pull that off, we’ll have drug companies knocking the doors down to use it for treating Alzheimer’s.”

“They didn’t knock any doors down to get to PMSF.” She wrinkled her forehead and leaned forward, bringing her face closer to me and tipped her head. “Why do you think this would be different?”

“It was my fault. I didn’t explain to the scientific community and the drug companies why it was so much better than anything else.  I need to get better at self-promotion. We’ll have to make a new one and start over.”

“Will that work?”

“Theoretically, yes, if we can pull it off, and that’s a big if. Remember it’s a quality of the brain that makes these things valuable, not the specific drug. They work because the brain makes new AChE very slowly. All we have to do is find something that doesn’t exist, something that inhibits AChE, and make it. I know what we need to do but beyond that things are a little fuzzy right now. I don’t know what to make – or how to make it. And I don’t know that it will inhibit AChE when we’re done. I know it sounds crazy, probably a hopeless stab in the dark. But will you try it with me?”

Our meals were finished and the waiter cleared the table. Lisa pushed back in her chair. “Let’s do it,” she said.

“But if we find the magic bullet,” I said, “this time let’s keep it to ourselves until we get the patent application filed.” I smiled.

I had a hunch that something might work out. A new but as yet unfounded feeling of excitement filled me, the first time since losing the patent that I felt like I could get back into the race and do something worthwhile about Alzheimer’s.

* * *

The new direction, making a drug, would cost some money. That was my main problem. I found myself in a “Catch 22″. No government grants were available for drug discovery because that’s what drug companies are supposed to do. They’re the ones that will make all the money – let them pay the costs. But drug companies weren’t interested in the sulfonyl fluorides because I didn’t have a patent. I was stuck in a revolving door where I could see the exit go by each time I went around but there was no way to get out.

What I had to do was get a drug company interested. It took me weeks of letter writing to finally get an appointment with a vice-president of a big pharmaceutical firm in New York. I think he finally gave me an appointment because he was too kind to tell me it was hopeless. Jo Anne helped me buy a new suit, and I had to take money out of our meager savings to make the trip.

I flew to New York the day before my appointment and checked into a nineteenth-century flea-bag hotel a few blocks from the steel and glass skyscraper that had the company name emblazoned in big letters above the oversize doors. The next morning I walked over, checked in at the security desk and got escorted to one of the top floor executive levels. We walked down long walnut-paneled hallways covered in thick carpet and through big reception areas that opened into the sky over New York through twenty-foot high windows.

The guard finally stopped and ushered me into a cavernous conference room that had a dark polished wood table the size of a flatbed truck. The room and table dwarfed the group of five scientists and an executive waiting for me.

After the introductions, we all signed confidentiality agreements, checked IDs and signed a roster that would be a permanent record of the conference.

“Everything said in this room,” the chairman paused for emphasis, “is secret – it is not a public disclosure that will threaten any potential patent for anyone.”

All the confidentiality paperwork and the chairman’s extra warning was an unnecessary precaution on my part because that was my whole damn problem. I was there exactly because I had no patentable information.

After the formalities, I stood up and started my pitch. I got through the first slide about using an AChE inhibitor to treat Alzheimer before an older man, the executive, jumped to his feet.

“Stop right there,” he said holding up his hand. “What the hell are we doing here?” He looked around the table with an expression of exasperation and amazement. “We can’t talk about AChE inhibitors. It’ll compromise our physostigmine project. Any discussion of this is unacceptable.”

I sat in my chair astonished. I couldn’t believe what he said. He’d just given away a huge piece of information about what they were doing. Physostigmine was the gold-standard drug that had been tested a few years before in some pivotal studies in Alzheimer patients to prove that an AChE inhibitor could improve memory. I knew physostigmine best because of my painful memories of meeting with the U.T. El Paso patent committee. I’d tried to compare that exact same drug to PMSF in my unfortunate demonstration where I’d killed the rat in front of everyone.

The older man pushed back his chair, made his way to the door and had his hand on the door knob when the chairperson intervened.

“We’re here to discuss another molecule. This won’t threaten getting a patent on that project.” The older man looked around the table at the others in the group as though in disbelief, shrugged, and sat down as I started up again.

A few of my slides compared PMSF very favorably to physostigmine, and I made general remarks about the deficiencies of short-acting AChE inhibitors. But, having been warned that I’d be stopped if I said the P-word, I kept my remarks vague. I thought if they saw the advantage of sulfonyl fluorides over their secret project, they would instantly switch to the sulfonyl fluorides.

They listened to me politely for an hour before they asked me about my patent situation. With my answer to the patent question, the interview ended. As I was being shown out by the vice-president I had come to see, he said they would consider my proposal and let me know.

I was so broke that on the way to the door I asked the guy if they were interested enough to pay for my trip. He smiled kindly and said he would see about it. My trip costs were chump change in their multibillion dollar per year budget and I hoped they would.

On the flight home I couldn’t get the information the older man had spilled about physostigmine out of my head. Several studies had shown that it could improve memory and the results had been published, killing any patent opportunity. That was the same problem I had with PMSF. What were they doing? What kind of a secret project could they have that might get a patent? If they had some trick to make a well-worn drug into a patented product, why couldn’t they do the same with PMSF?

I’d come to the right company.

* * *
A few days after my trip, I got the call. The company in New York would pay for my trip but they didn’t have any interest in helping me find a better drug.

After the trip to New York, I went to every Alzheimer’s conference Jo Anne and I could afford. I went to Sydney, Australia, Eilat, Israel, and Paris, France. I also made presentations at annual Society for Neuroscience meetings in Toronto, New Orleans, Dallas, and Anaheim. I was an invited colloquium speaker at a University of Pittsburgh retreat in Oglebay Park, West Virgina, University of Cincinnati, at an Alzheimer’s conference in Austin, Texas, and at the University of New Mexico, Albuquerque.

For each trip, the University administrators said they didn’t have any money for my travel – good luck. But I scrambled around for money and everywhere I went, I talked to every drug company representative, colleague, graduate student, or dog who would listen to me about the sulfonyl fluorides. Except for the dogs, the conversations always ended with the question: “What is your patent position?” When I said that I didn’t have one, they would laugh politely and explain what I already knew. Without a patent, there was no future.

* * *

When Lisa and I started the new phase of the project, trying to make an original compound, I had also started a research project on how marijuana might be used to successfully treat movement disorders like Tourette syndrome. It was working out great, but I didn’t have any money for it either.

I guess St. Jude, the patron saint of lost causes and fools might have been looking over my shoulder. I had a talent for picking hopeless undertakings. My marijuana research, even though it was successful, was dead at the start because it was politically incorrect to propose using cannabinoids for therapeutic purposes. Interest in funding something like that ranked right up with pouring money down a rat hole leading to a dead-end drug like PMSF. But after several applications for marijuana money, I got a small grant, something that would keep my lab going. I could use some of the money for making new sulfonyl fluorides.

The next problem I had was to figure out how to get into a lab and carry out the complicated steps that would make new molecules. I thought that I had wasted three years of undergraduate work as a double major in math and chemistry before I had changed my course of study to psychology. Now I needed that background and the skills I’d learned in hundreds of hours of chemistry labs. Even with that, I didn’t know enough to take on what highly trained medicinal chemists do at drug companies – actually make something, purify it, and put it in a bottle.

To find out how to make new sulfonyl fluorides, I went to the literature and looked up how others had made the ones that were already available. Because the molecules are so simple, the procedures looked fairly straightforward.

Encouraged that I might be able to make what I wanted, I went to see Dr. William Herndon, Chairman of the Chemistry Department, and exposed my ignorance of medicinal chemistry to him. I hoped Bill, an internationally recognized irascible colleague, wouldn’t laugh me out of his office. Somewhat older than me, he had slightly graying hair and a long moustache, an energetic man with piercing blue eyes. I knew that he wouldn’t mince words with me if he thought I was totally wrong or crazy.

Bill’s office looked like an explosion had gone off in a library. Papers and books were stacked on every flat surface, including the window sill. He cleaned off a place for me to sit by moving everything from a chair to the top of another stack.

After I’d outlined my ideas and the procedures that had been used by others, Bill tipped back his chair and looked at the ceiling for a minute before he turned to his computer and typed rapidly. At the end of his search, he looked around me. “I can help you do this, but I don’t have time to actually do the work. I’ll set you up with my postdoc who can help you get started, and I can give you a corner of my lab. And I’ll help if we have problems.”

A feeling of real appreciation filled me. Bill had taken my project seriously and was giving me a break of the first order. Bill’s collegiality counted heavily in the positive column of why taking a job at U.T. El Paso years before was a good move.

* * *
It took me a few weeks to order the chemicals we needed and get organized. Bill kicked in the general lab supplies, glassware, and the other equipment we needed. Finally the time came for Lisa and me to make an appointment with Bill to start making new compounds. We met at the lab and were introduced to Bill’s postdoc.

After familiarizing us with the lab and where everything was, Bill took my arm and looked directly into my eyes. I guessed he wanted to tell me something important and he had to be sure that I was paying attention.

“If you mix some things together, and it starts getting hot, be sure to put it into the hood and pull down the sash.” He paused, still holding my sleeve, and then added, “And you should do that as fast as you can.”

A hood is a sturdy box about the size of big oven that has a sliding door that can be pulled down to seal off whatever is in the box from the rest of the lab. Hoods are vented directly out the roof of the building in case the material in the hood is poisonous. They can also vent an explosion safely up and out.

Bill’s advice about putting anything that got hot in the hood is some of the best advice I’ve ever received. It was his way of saying that he didn’t want me to blow up his lab.

* * *
A year later, Lisa, a few other willing students, and I had spent hundreds of hours in Bill’s lab and had created dozens of new sulfonyl fluorides. We tested our new compounds, along with some others that we’d bought, for their ability to inhibit AChE. At the end of the year, we had stacks of notebooks with information about each compound, whether or not it was ours or we had purchased it, a drawing of its chemical structure, and what the results of the AChE tests showed.

“What do we have here?” I asked as Lisa and I spread out the papers on a long table in an empty classroom that I’d commandeered for a few hours between classes. Sorting the results was easy. Lots of them didn’t inhibit AChE at all – total failures. And most of the others only had weak activity. The results were quirky.

“But look at this one, MSF,” I said. “It’s a hundred times better than any of the others, including PMSF.” I handed her the summary sheet.

“What makes it special? Lisa asked. “Why is this particular one so powerful?”

“It’s the smallest molecule in the bunch. Its size, its ability to fit into AChE, makes it perfect. AChE is like a grinder that normally rips up acetylcholine. Acetylcholine has to fit into the throat of the grinder and get to the blades to be cut up. These results show us that to stop the grinder with a sulfonyl fluoride, like throwing a rock into the blades, it must be small to fit through the throat. If it’s too big or it’s not the right shape to squeeze in, it’ll bounce off without getting to the guts of the machine. Look at the others, the bigger they are, the worse they are.”

“So this is the one we have been looking for all year?” she asked as she studied the page.

“Yes, we know the best compound now, exactly what we need. But overall, it doesn’t solve our problem.” I sat back in the chair and let out a long sigh.

“What’s wrong?” She looked at me with furrowed brows. “We’ve worked on this, and now we know the answer.”

“If you’ll notice, MSF is one of the ones that is commercially available. It’s not one we made. It’s only patentable if it’s a new one, something we created. Even though it’s much better than PMSF and most others, it’s not patentable. We’ve discovered an astounding drug but we haven’t solved our problem. Without a patent, it’s useless to anyone who has to make a profit.”

“Why can’t we start again? Now that we know MSF is an ideal model, we can tweak it to get something new, something patentable.”

“It won’t work,” I said taking the MSF page from her hands and pointing to the drawing of the molecular formula. “MSF is the smallest molecule in this whole family of compounds. If we take anything off it to make it smaller it’ll no longer be a sulfonyl fluoride. It won’t work. If we add anything to it, making it any bigger, it’ll lose a lot of its activity, like all the others. This is it or nothing.”

“So this year has been a waste?” she asked.

“No, absolutely not.” I held up the MSF summary and shook it. “We’ve found a gang-buster drug. Whether or not we can ever do anything with it, get it to patients, is another issue. But we’ve made progress. We’ve found something a hundred times better than what we had before.”

I’d tried to fake my enthusiasm about finding MSF for Lisa. Some of it was fake anyway. Finding that MSF worked so well meant we had a good outcome. We had a drug that could be extremely effective. But I couldn’t admit to myself or Lisa that we’d spent a year finding another dead end for a patent. Unless I could figure out something else, MSF would never make it into patients.

I had a sinking feeling in my stomach. I felt like Don Quixote tilting at windmills. I knew in my gut what he meant when he said: “That’s exactly it, that’s just how beautifully I’ve worked it all out – because for a knight errant to go crazy for good reason, how much is that worth? My idea is to become a lunatic for no good reason at all.”

I couldn’t do anything about MSF. I couldn’t get anyone else to do anything about it. And I couldn’t let it go. I was going crazy for no good reason.