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Reflections on Chirality
There are several aspects that I would like to bring out in the title. I would like to include a series of historical vignettes about why Louis Pasteur and some of his counterparts in the mid 1800’s opened a way to how we view medical treatments today.
Pasteur in his early work on crystallography set the tone for many of his subsequent observations in the life sciences which went on to revolutionize medicine as we know it today. The concept of mirror images–chirality were first described by Louis Pasteur in the 1850’s and gave vivid contrast between the symmetry of minerals and the subsequent importance of asymmetry in the life sciences. This approach should give us an additional appreciation in the role that historical personages played in the foundations of subsequent life sciences and medicine.
It will give me an opportunity, also, to bring you up-to-date on the latest in basic biochemistry involved with proton pump inhibitors as well as the impact they have had on medical management of acid peptic diseases in the last 20 years. The forces that have led to a world-wide push to change the most popular drug in the world, Prilosec, to an alternate drug, Nexium, will also be discussed. The role of the FDA in setting up this transformation is of particular interest. The basic economics of medicine, as we know it, will be impacted dramatically by many of the advances that are to be presented with Nexium as the sentinel example of such changes.
The first slide is a summary from the French School in about 1830 describing a patient who was found to have epigastric pain. As one might note, the patient went on to have hematemesis followed by gross anemia. The up-to-date treatments of the time included mustard plasters to the feet, and when he was showing some improvement but small amounts of hematemesis still present 20 leeches were applied to the epigastrium. Additional mustard plasters as well as rice extract and a syrup of quinces led the physicians at the time to feel that he was better. Additional leeches to the anus were applied as well as mustard plaster, but to the surprise of the treating physicians, the patient had sudden hematemesis and died. His autopsy did reveal a lesser curvature gastric ulcer. Treatments have definitely changed in the past 170 years. Many of the initial treatments for peptic ulcer disease today can be looked at with almost humor if not sadness given the level of understanding available to physicians at the time.
Two months ago a patient from Brewton brought me a copy of her instructions that were given to her in Birmingham in the early 1940’s. These handwritten instructions were for the Sippy diet which included hourly feedings of milk, eggs, and purees. Modifications of the diet included subsequent inhospital stays with a nasogastric tube and dripping of milk. Broad-spectrum anticholinergics of the atropine family had such serious side effects that there was little doubt that the evolution of stomach and duodenal surgery were really in their heydays of the 1940’s through 1960’s. Certainly, in the late 60’s to early 1970’s there was not as much push-pull between the surgeons and the medicine physicians–medicine had very little to offer the patient who was really quite sick.
The first series of H2 receptor antagonists were developed in the early 1970’s and subsequently taken to clinical trials including in Dallas where I trained. This important work eventually led to a Nobel Prize for Dr. Black and a multi-billion dollar product for Smith, Kline, and French. The advent of cimetidine in the early 1970’s was the first therapeutic choice with limited therapeutic toxicity and the ability for broad application. Many of those studies were done in Dallas, and I can remember the folklore that our teachers had all invested in an unknown company named SKF thus ensuring their ability to stay in academic medicine later since they didn’t make any money working in that field itself. I have included a sliding showing some of the early antagonists as well as the histamine structure itself.
Certainly, in the late 1970’s H2 blockers were very hot and competition only increased when Zantac came on the market by a competing company. I probably would not be giving this lecture today if I had followed through on my lecture of 1984. I do remember plotting the stock prices for SKF and showing where the drug trials occurred in Dallas in 1975 and where the doctors bought the stock in 1976 leading up to the release in 1977. In 1984, the first potentially clinical application of a new type of drug named the hydrogen potassium ATPase inhibitors became available to me for review. Omeprazole itself had been synthesized in 1979, and the very first clinical uses of the drug had occurred in 1982 with release of the information in 1983. I strongly remember that as part of my lecture I went to the library in Dallas and pulled up the London Financial Times and plotted the stock of a then unheard of company Astra–and I had to plot it in kroners. In the preceding six months before my lecture the stock had already increased seven fold, and I jokingly described the application of the hydrogen potassium ATPase inhibitors as already having proven their worth to somebody. I remember when Dr. Fortran asked exactly how he can buy some of that stock, but it was not available in the United States, and one would have had to go to Sweden.
The hydrogen potassium ATPase inhibitor story is really quite remarkable. One must remember that the parietal cell itself is a unique cell within the body with an ability to concentrate acid more than a thousand fold and develop a remarkable pH gradient between the lumen of the cell and the cell itself. Earlier considerations in the 1930’s said some form of acid precursor was developed in the stomach and subsequently released acid was essentially debunked with the advent of ATPase pump information. Of course, the first ATPase pumps were described as the sodium ATPase pumps and had broad application in multiple cells as well as clinical application with cardiac blocking agents such as digoxin resulting in increasing cardiac function.
The unique character of the hydrogen potassium ATPase pump did not become apparent until the mid 1970’s when in many ways they were discovered in the same time frame that histamine-blocking agents were described. The chemical development of omeprazole is described in the accompanying slide. The anti-viral drug pyridine 2–acetamide had been initially purchased by a company in Sweden thinking that it was an anti-viral agent which could be with some application. Though they were looking for anti-viral activity, an interesting spin-off was that it had some anti-secretory activity for gastric acid. Thus, as can be seen in the slide, a sulfur group was added giving no increase in anti-viral activity but an ongoing gastric acid inhibition activity was noted.
SKF had developed cimetidine in 1973 which of course had an H2 receptor antagonist activity. Scientists at Hassle and subsequently Astra thought they would pursue the acid blocking thinking they had an additional H2 blocker on their hands. They added a benzimidazole to the purported anti-viral agent thinking that they were going to emulate the structure of cimetidine. If you will recall in the cimetidine structure a similar ring structure is present and gives H2 blocker activity. The initial compound was a bit unstable, and the sulfide group was modified to sulfoxide and thus was born timoprazole. This compound was described in 1975, and within 3-4 years omeprazole was described. Billions of dollars later we are discussing this. The substitution of a benzimidazole occurred for the wrong reason since subsequently it was not found to have anti-secretory activity on the basis of H2 blocking. The new pump system was in fact present and the blocking activity was completely independent of H2 blocker action.
As was subsequently shown, the parietal cell is acted on by numerous agents. There is the neurocrine component which represents muscarinic receptor stimulation involving acetylcholine and vagal activity. There is an additional paracrine component which involves modulation by the enterochromaffin cells. The latter are involved with the histamine 2 receptor blocking agents. There is another set of modulators from endocrine cells for gastrin which arises in the antral G cell.
All of these components modulate parietal cell acid production. The latter acid production is a recruitable event that can happen in a matter of minutes using microtubules and rapid mobilization of smooth endoplasmic reticulum. When the latter occurs a remarkable matrix of membranes occur involving multiple indentations, and an enormous increase in lumen surface area occurs. The hydrogen potassium ATPase that was being blocked with the new drugs represented the final common pathway for the various modifying events described above.
Recognition of this led Astra to aggressively pursue clinical trials since therapeutic index was likely to be very good if blocking occurred in an enzyme quite unique to the gastric cells and low toxicity being very likely. The acid space of the canaliculus with a pH of 1-4 is quite unique in the body. It became apparent that a weak base would be needed since a drug with a pK of 4 or less would tend to accumulate in the canaliculus itself. By 1977 it was apparent that omeprazole as well as its precursor timoprazole and some other derivatives such as picoprazole were quite effective at blocking acid. The drugs that had been developed in fact filled several of the requirements that were necessary for blocking the recently described hydrogen potassium ATPase pump–not by design but by serendipity.
The pKA was excellent tending to give accumulation of greater than a thousand fold if the drug could be gotten into the canalicular space. Once it was in the space it turns out that it was activated by the acid itself since the omeprazole and all of its family of proton pump inhibitors are actually pro drugs.
The concept of a pro drug here is really quite remarkable. The tricyclic formation of omeprazole and all of its subsequent following drugs are converted in the acid lumen of the canaliculus to a re-arranged planar tetracyclic compound with a remarkably reactive sulfonamide group. The sulfonamide group turns out to be the active moiety necessary for the drugs action. The sulfa group once formed can interact with the most reactive species available amongst amino acids of the gastric hydrogen potassium ATPase. When one is designing a drug harsh conditions are necessary for covalent linkage to such moieties as carboxylic acid, histidine, lysine, arginine, and tyrosine. The exposed sulfhydryl group present in cysteine offers just the ideal amino acid to neutralize a functioning protein. The substituted benzimidazole family, when activated in an acid environment, becomes remarkably thiol reactive (thiophilic).
Subsequent studies on the hydrogen potassium ATPase have shown that there are two main sub-units. The catalynic unit has 1033 amino acids and is mainly cytoplasmic in location. There are 10 membrane-spanning domains which have a total of 28 cystines available. Only 5 of these cystines are accessible on the luminal side to bulky cationic molecules. These cystines are at amino acid 321, 813, 822, 892, and 981. Several of these become the main target of the activated pro drug. Of note is that there is a second beta sub-unit which has 291 amino acids as well as specific glycosolation changes. There is a transmembrane component to this beta sub-unit, and there are 9 cystines available. However, these are not actually available since they are almost all in disulfide linkages making cystine and are too stable for reaction. In fact, if they do react they often revert to their original form.
The basic differences between the current proton pump inhibitors essentially all involve changes at three specific locations in the ring structures. These changes affect stability at neutral pH as well as nucleophilic attacks by the nitrogen in the ring structure. These actions are summarized in the accompanying slides. Major manipulations in the drug have occurred at these three sites, primarily for purposes of stabilization at neutral pH when the drug is ingested as well as potentially changing the pK which improves the concentration coefficient in the canaliculus lumen. I am unaware of any of the changes affecting the membrane permeability. Membrane permeability would potentially affect invasion of the hydrophobic domain of the membrane and possibly change which cystine moiety is attacked. Changes in the pK in a drug such as Rabeprazole contributed to some pH instability but an actual increase in parietal cell concentration in the lumen. I am unclear that these balancing acts in fact have enough of a difference in clinical net effect.
The changes that I will discuss in regards to chirality have a potential broader application and actually have more economic impact on the drug industry as a whole then specific drug chemical substitutions. I will discuss the latter further later.
In summary, the drugs in the family substituted benzimidazoles have the characteristics of very short action with significant lability to degradation in the stomach. A number of the actual patent issues with the current owners of Prilosec deal with mechanisms of delivering the drug to a neutral pH location where uptake can occur. Though the patent will be off in October of this year for the compound itself, I suspect that additional legal wrangling will be attempted since Prilosec is the most financially successful drug in the world. They would sure like to keep their hands on it as long as they could.
Once the drug is taken up it has a very short time in the blood stream of 30 to 90 minutes, and it is important to realize that it is taken up through the basolateral membrane in the parietal cell–and is no longer measurable in the blood at that point. The most important activity occurs with the movement across the parietal cell and subsequent concentration in the lumen of the canaliculus. This concentration of course is also associated with the activation of the process in an acid environment since omeprazole and its family of competitors are all simply pro drugs.
Once the tetracyclic compound is available in the lumen it can react with specific cystine moieties and give a covalent linkage. The latter is really quite important since this is not a reversible reaction. We will almost certainly see reversible reaction hydrogen potassium ATPase inhibitors evolving in the next 5-7 years. Actually, Astra-Zeneca is working on two of them that I know of. They offer more flexibility in drug dosing.
I also mentioned at the beginning of the talk that the canaliculus itself has great variability in concentration within the parietal cell. The presence of the pro drug can only have activity against a functioning parietal cell. About 25% of parietal cells are active at any one time, and it takes about 3 days for the body to make additional new parietal cells. This is why there is a wash-out phase and a wash-in phase of 3-5 days to get the full net effect of the drug as well as why it is important to take the drug temporally with a meal. The latter stimulates the presence of acid production thus making the parietal cell susceptible to covalent linkage and deactivation.
It strikes me that a major modification of the drug delivery system would be to make some form of combination drug which would include a substituted benzimidazole with a concurrent drug that can activate the microtubular system to actually generate acid production and lead to a much broader blockage in a shorter term fashion. I don’t know of a chemical at this point or signal that could specifically bring on the microtubules. Though it has not been reported, I suspect that microtubial blocking agents such as colchicine might inhibit the actual activation of a drug such as omeprazole since active microtubules are necessary for full drug effect. I also find it really quite remarkable that this entire family of drugs evolved while looking for an anti-viral agent and juxtaposing the notion that they were dealing with an H2 blocker thus affecting the type of moiety that was added to the original agent.
Now, why have we included Louis Pasteur in a talk about a 21st century drug? One need look back at the 19th century and early science which had very few tools. One of the tools involved with the study of crystallography involved devices designed for goniometry. These were devices that could measure in minerals the axes, angles, and forms of crystals. Another early tool was that of a polarimeter. This was able to measure rotational properties of light. Using these simple tools, Louis Pasteur deduced some of the basic axioms that defined life itself.
His predecessors certainly laid the groundwork for the opportunity to apply these tools. In the 17th century Robert Boyle postulated invisible constituents of matter having important relations that determined a structures organization into crystal form. An important step included Mendeleyev who postulated the connection between atomic composition and a crystalline structure. He, of course, is best known for his work in developing the periodic table. The organization of the periodic table allowed chemists of the time to make predictions with accuracy that had tremendous relevance to defining structures in the time before electron microscopy, etc.
In the early 1800’s Abbe Hauy moved from botany to the physical sciences after being excited by a visiting lecturer on crystallography. He spent the rest of his life in this field and went on to describe the observation that compounds with the same chemical composition can have a completely different crystalline form. Though he was still just working with minerals, he made an effort at molecular identity in a process inferred from the form of the crystals. His background in botany helped him to remember that like plants, which flower each year with the same form, a mineral can regenerate the same crystal. He made the observation that one has to know a question in order to answer it. At one point, a sudden observation on a broken piece of calcareous spar giving a rhomboid shape allowed him to realize that with further breaking and re-breaking the same rhomboid shape was recurrent. He was able to postulate the relationship of symmetry and structure and extrapolated it down to the smallest molecular levels which turns out to be the basis for crystalline structure.
An interesting fellow was Etienne Malus who established a relationship of polarization of light which occur in light reflected by an opaque body or refracted by a crystal. He had his early background when he was traveling as a soldier in Napoleon’s army and became very interested in light and its effect–especially the glaring sun of the Egyptian desert. When he returned in 1809 to Paris he went on to study light and its physical effects.
His major insight occurred concurrent with development of love, or at least his desire for a particular woman. He was skilled in optics and had crafted a telescope which allowed him to watch his love from afar. With the reflector telescope he made he found that the image of his desire kept disappearing depending on the angulation of the telescope. What he was discovering was that light will polarize through specific compounds, in this case a quartz window. He went on to describe his finding of polarization of light. One of the immediate precursors to Louis Pasteur was his teacher Jean Biot. This teacher taught lessons in polarization and then went on to invent the polarimeter. He described polarity in many inorganic as well as organic products, and it was within 10-15 years of this development that young Louis Pasteur finished his thesis in chemistry and physics.
It was left to Pasteur to define that the polarity of an object is in fact the essence of life. He made the observation that all living organisms need asymmetry. He was able to identify that an organism that is alive can differentiate molecules with identical atomic properties but with different physical characteristics. Polarity was a characteristic he studied, and he basically defined the science of spatial chemistry–stereo chemistry.
The study of chirality in fact was defined by him using the Greek word kheir which means ‘the hand.’ Of course, the hand is a familiar nonsuperimposable structure and an excellent derivative indeed. Pasteur made the leap that minerals often don’t seem to need any specific rotation but organic compounds do need and have the ability to deliver asymmetry in rotation often described as R or L.
His legendary work with synthetic tartaric acid was chosen again on the same line that the rest of his career was chosen, often with potential commercial application. In this case, tartaric acid was an important constituent in wine, and as was often the case he chose simple problems from a commercial standpoint and made much larger generalizations once the information for the simple problem had been solved. A synthetic solution of tartaric acid is in fact racemic having both the R and L forms present. He had the insight to place a mold into the solution and noted that as the solution was metabolized the residual tartaric acid became optically active. The mold was only utilizing one of the two crystals available.
With this observation he opened the door to modern biology. One of his famous quotes was that “In the realm of scientific observation, luck is granted only to those who are prepared.” Another famous quote is “The universe is asymmetric, and I am persuaded that life, as it is known to us, is a direct result of the asymmetry of the universe or of its indirect consequences.”
I found reference to an important event of Louis Pasteur’s early life–he was only 4 years old. Once he stood on his toes on a crate in the courtyard of his house, peeping through the little grill at the door. He was watching his neighbors pass by. His father was standing behind him and asked “What are you watching, son?” Little Louis answered, “I’ve been watching the people passing by. I have seen Monsieur Piroz and he looked very fat and red, and I have seen Sister Marie going to her convent. She was so late that she was nearly running. And I have seen Monsieur Dubois. He is very solemn, he is talking to himself. I think he is worried.” His father told him, “Louis, you are very observant.” It is quite prescient in that his reply at 4 years of age reportedly was “You notice little things, and you always think about what you see. It is good to be observant; if you notice details you will learn to understand important things.”
I really could spend the better part of the next two hours on the subject of Louis Pasteur. In fact, I may do a full lecture on the remarkable contents found in a new book by Patrice Debre on the history of Louis Pasteur. His work on fermentation and spontaneous generation alone would place him at the list of those with great insight in revealing that science has a mechanism and that life does not just happen. Though he had industrial applications for his studies on yeast and bacteria, his subsequent work with anaerobes and aerobes in defining the germ theory revolutionized the way physicians handle their patients.
Some of you will remember his interesting work in saving the silkworm industry of France, and others will remember that he was important in wine making and beer making and the process of pasteurization. Such basic concepts of hand washing and his constant use of the microscope helped him define contagion and disease with such significant problems of anthrax and puerperal fever. He developed the autoclave and the process of antisepsis, and he inspired others such as Lister to change the way physicians handled wounds. He, of course, founded the field of immunology with his initial work on cow pox and subsequent development of immunizations for rabies. I could go on but would just challenge anyone in this room to read the book I referenced and become excited.
The actual content of my talk distills down to changes that were incurred by the FDA in 1992 and by the European Union in 1993 encouraging the development of stereo isomeric drugs. Basically, the FDA has come out in favor of single enantiomer drugs but has been allowing ongoing racemic production of chiral drugs. It is felt that there are advantages of a single chiral drug derivative as opposed to the racemic mix that has been so common in the past. In theory, the total dose would be reduced and there is a simpler dose response relationship. Variability having been removed, one can focus on other aspects of genomics and genetic variations in metabolism. Also, whatever toxicity of an inactive isomer would be removed.
Certainly the drug market is well more than a trillion dollars a year overall, but single chiral drugs now account for somewhere in the neighborhood of 90 billion dollars a year. There has been much written in the last five years about denovo development of pure chiral drugs. This has been a very significant challenge to the drug industry since intellectual property law at this level involved billions of dollars.
With this recent change of FDA emphasis, it is also noted that few drugs have separate enantiomers which are protected and in fact omeprazole in the form of Prilosec is a racemic mix, but an enantiomer that is more active is not protected, thus leading to an interesting opportunity to save the most productive financial product in history by application of chirality to Prilosec leading us to Nexium.
A patent right is a government grant. It grants a monopoly for a period of time. This is a United States constitutional right, and currently it is a 20-year right. Think back to the history I alluded to earlier and we are at that 20-year right. One will see increasingly applications of a chiral switch and this falls under a 1952 patent act which allows selective invention if the selection includes a group of individually novel members now present from a previously known class. The advantage must be proven substantial, and it is basic that the whole group of the selected members must possess this advantage. The new characteristic must be unique to the selected group.
Though I think the process involving Nexium is undoubtedly going to be the biggest economic impact in the history of pharmaceuticals, it turns out that this process has been building for some time. In 1960 the United States Court of Customs and Patent Appeals ruled for single enantiomers and anti-spasmodic agents. They applied the 1952 patent act to allow them to do this ruling. This patent board, which none of us are likely to think much of, in fact controls the intellectual property known as drug patents.
A similar process occurred in England in 1980 when amoxicillin was coming off patent, and it was felt that selection of a single enantiomer from the nine semisynthetic penicillins would be more beneficial. This resulted in a flurry of patents which were upheld and essentially extended the life of the amoxicillin derivative.
An interesting twist in the drug business was in 1993 when Isoflurane, an anesthetic, came to fruition from the drug research process. At that time the drug company patented both the L and R forms of the drug in hopes of heading off future defense of the intellectual material. Current fights are underway involving ibuprofen which has only the S form being particularly active, a large patent fight in Europe is undergoing a similar process, and of course it was in the newspapers last week that Prozac came off patent. Of note is that the S form has significantly fewer side effects, and one can anticipate a selective enantiomer to be marketed soon as Eli Lilly struggles against its seemingly smaller but ever sharper opponent Sepracor. The latter company has been involved in a number of drugs and finding opportunities to reach out for drugs that are off patent but only in the racemic form. I will note that propoxyphene has of course two forms. The dextral form is an analgesic known has Darvon. The levo form is an antitussive known as Novrad.
A far more infamous story is that of Thalidamide. The sedative was noted to have remarkable teratogenic effects in the early 1960’s in Europe. Only one of the isomers is the teratogen. One will see the use of Thalidamide in this country in the next 10 years potentially in application of various inflammatory diseases including Crohn’s, though the psychological barrier of the 1960’s may prevent that option. Knowing the active isomer teratogenicity may allow the public to accept the potentially beneficial uses of this drug.
So, we come back to Louis Pasteur and his tartaric acid. Subsequently, all life on earth has certain characteristics. Many of you can refer to the my lecture on the human genome project which talked about the unique characteristics of DNA which travel through every single species. DNA in fact is a highly specific compound in which rotation makes a very big difference. But, other applications in homochirality can be seen throughout organic evolution. All amino acids that are used by life forms are of the L form, all sugars used by life forms are of the D form. Astra-Zeneca, of course, would like to make all omeprazole of the S form–Nexium.
Now, why should be consider Nexium as an optical isomer beneficial to the racemic form known as Prilosec of omeprazole. I guess sometimes it is better to be just lucky as those who originally designed omeprazole. Certainly, the FDA rulings of 1992 through 1994 have played right into the process that we see today in which Astra-Zeneca is pushing the acceptance of Nexium. After extensive reading I will have to say that they certainly have a good point. Omeprazole is metabolized by the cytochrome P-450 system. This is a complex system in the liver responsible for drug detoxification.
Two of the more important components for the P-450 system in regard to omeprazole have different biologic activity regarding the R and S isomer. Specifically, the greater clinical efficacy of Esomeprazole in comparison with omeprazole is probably related to the lower first pass hepatic metabolism and slower plasma clearance which results in increased systemic bioavailability. With the same dosing one gets more bang for the buck. I can just see the scientists at Astra-Zeneca being prodded by the patent lawyers as they looked at the world’s most successful drug and saw the patent clock ticking.
One does get a two to four fold effect of bioavailability without any increase in biotoxicity. I have used the drug with a number of patients, and I don’t find it 100%, but I certainly find an increased acceptability with a number of patients compared to Prilosec. There are limited studies to date, and all of them have been done with the 40 mg size–the size of Prilosec acceptable for FDA purposes regarding GERD. It is difficult to sort through this process, but a head-on-head 20 mg isomer study was not performed and seems to cause some confusion in prescribing physician understanding.
I think there are several reasons for the 40 mg dosing, only one of which is FDA requirements. I also think that they are well aware that the bulk of patients take the 20 mg dose rather than the 40 mg dose of Prilosec. The apple to apple comparison of course should not be 20 versus 40, but equal milligram amount comparisons. As patients try out the Nexium they will often be jumping a dose from 20 to 40. I think it is somewhat sly but very overt that the pricing structure for Nexium 40 is essentially equal to the price of Nexium 20 mg size. This is no slight of hand–it was done on purpose, but one cannot be too critical for a drug class that has had such remarkable acceptance and even better therapeutic index.
I perceive the use of Nexium as a bridge until Astra-Zeneca can get some of its other reversible binding agents off the ground. As long as they are pricing Nexium cheaper than Prilosec I don’t have any reservation in recommending the drug since it is more beneficial. I do see, however, future acid mechanisms still waiting to be tried. The Laboratory Of Life has already developed a remarkable antacid mechanism in pernicious anemia. This disease is well known for the relationship of intrinsic factor deficit and Vitamin B12 absorption impairment and resulting clinical illness. Intrinsic factor is fairly unique in that it accompanies the parietal cell canaliculi responsible for acid production. The antibodies that cause pernicious anemia also cause complete achlorhydria.
I can foresee monoclonal antibody therapy similar to that with Remicade against anti-tumor necrosis factor someday being applied to the parietal cell. In the meantime, I would favor clinical results. Drug costs will be an issue, and bioavailability in the soon-to-be-produced generics will be the subject of future lectures.
Overall, I would congratulate Astra-Zeneca in trying to preserve the intellectual property no matter how they came to this product.