On advice of Counsel, I am to post my last today.

I am very sorry it comes to this, but then I am not the one making the market in the stock, or calling the shots. I wish I had that authority and responsibility. I would have had an FBI (DOJ) agent at my side and would cleaned up the act, long ago.

I will miss my friends on line, but this is how it worked out for me.

Good luck.

Sincerely,

Larry Glaser

From the moment of collapse in April, 80 to 30 in just days, I have been defending a greatly reduced position. As PURIST suspected, I indeed stayed in and held out as long as I could before harming another soul. I had to as a matter of duty to all. And I do not regret it, even for a second. In the final analysis, the money only served to represent a hollow victory, had I taken it off the table.

The primary Institution I trade with took over and did what they wanted to do at a very late moment in the Pathology of the collapse. Since that time, things did not work out (look at a chart and picture me staying in and believing) and my position was reduced to where I am not a factor in the stock, per se. I have not sold out willingly, but have been reduced gradually to where, essentially liquidated at the lowest prices throughout the range, I am not a factor at all. In essence, I now face bankruptcy as in "Chapter 11" at the personal level. But most importantly, please do note that I did not leave willingly. Please also note that my holdings are no longer large enough to matter at all. 10 minutes trading at best, given what is left. I believe at all times and in all manners and matters germane, I posted from the heart, not from the pocket.

I have watched an inconcionable personal net worth reduced to rubble. I cannot convey in words what this means to me. I am going to have to start over, at age 41. And I will. I have my family, and they are happy and healthy. That is what matters.

As to the new faction out here on these boards and the changes the SEC put in place, I see strain forming. I hope everyone realizes the point the SEC was trying to make. I could not more strongly disagree with GDV on that note. I gave you my opinion and kept it simple. I wish she would do the same. I think this is again bottom, as it was tested in April. Everyone imaginable goes under water from here and it harms me not. Still, despite my individual pain and suffering, I believe the science works perfectly. I cannot explain the delays. I do not work there. Maybe GDV can, in at least 10,000 words, directly from Management, as she lets on.

My children are vested in the stock, in cash and they will enjoy the upside. I still believe the stock can make a huge run, quite comparable to the run witnessed after a long, drawn out period at 10 on the AMEX.

I hope everyone will understand that I must focus an ever increasing amount of attention to my future and to working the next 20 years, as I did in the last.

   Cornell was a triumph of modern genetic therapeutics. So few realize what happened at Cornell. Let me
   put it this way, and leave the reader with a challenge. ENZO completely erradicated HIV from living
   human cells, inside the cells and outside the cells. The elimination was not 99.99999% it was 100.00%
   The logic and reasoning behind the methodology is as follows:

   In order to completely defeat a virus and develop a class of therapeutics which are indeed more effective
   than the current antivirals, you must demonstrate 100% erradication of the virus. If not, the remainders
   may (and probably do) represent adapted virus, which is a mutation. The mutation is now better equipped
   for the antivirals available and so there is no available barrier to the virus, and the mutation quickly claims
   its prize. ENZO needed to develop an entirely new approach. And they did just that. At the genetic level,
   ENZO created sequences of genetic material that are presumed to be completely foreign and benign to
   the human body. Although completely benign to the human body, this three sequences are deadly to the
   Human Immuno-Virus(HIV). Here is the part that people do not understand so easily. The single
   combination that ENZO developed is deadly to HIV in any and all of its forms. No matter how the virus
   tries to mutate, the three sequences (called Antisense Genes or [U1] in ENZO's experiments) are able to
   stop the virus as it goes into its replication cycle. The virus is perhaps comparable to a span bridge with
   three pylons. The bridge is remarkably well adapted and is able to make copies of itself. It you take out
   one support, it survives. If you take out two, it does not survive, but since there appear to be three, why
   not take out all three? This is what ENZO did. They took out the common support elements that appear
   in all mutations of HIV and guess what? The virus cannot overcome this approach.

How does one prove this? Well, it just so happens that there are some facts about HIV which cannot be argued. The human CD-4 T-Cell is a beautiful model for HIV experimentation. Why? Because this cell represents the most fertile ground for HIV. When HIV first gets hold of the immune system, these are the first cells to go. So let's build a model. Lets say we are going to develop a shield for these cells. Remember, in the field of genetics, these are not chemicals or proteins. These "genetics" will attach to the cell and become a permanent part of the cell. In fact, these genetics will bond to the nucleus of the cell. They will stay forever. If the cell makes a copy, the added genetics are copied, too. But there is a problem. The U1 we spoke of earlier, the three sequences which are properly called Antisense Genes. Well, it seems you can't fool mother nature. Mother nature will not permit these genes into the cell without causing a surface alteration to the cells outer membrane. This "scent" the insertion process leaves, it is troubling indeed. At the NIH (NIH.GOV) there are 1400 human trials going on. They all have one thing in common. None are able to alter human cells without leaving this "scent" on the surface of the cell. As such, even when the cells go forth and do good, the immune system eventually (and quickly) do bad. The immune system simply will not accept these seemingly "new" cells and completely destroys the entire colony. However, there is something different about ENZO and its approach to delivering this
U-1 package to a living cell. ENZO has a unique talent base of people and of prior development. They developed the worlds finest genetic probes, test kits and assays. They have an "unfair" advantage, for want of a better term. As such, through this prior development and their extremely talented group of Dr.'s, ENZO looked hard at the problem of genetic delivery. Through grueling efforts carefully described by Dr. Elazar Rabbani at the annual shareholders meeting in January, 1999, ENZO made an enormous discovery in genetic delivery vehicles. The vehicles are called "vectors". ENZO used the supercomputers at Cornell to apply a logical scheme of reduction of an Adenor class virus, to see if it could be stripped down. This of this like taking a fully equipped custom van and taking everything off, until it simply moves, and that is it. No body, no seats, no radio, etc... Logical and methodical reduction ontil all you have is a vehicle, plain and simple. The question then remained. Will this vehicle enter a human cell and not leave a scent? Without getting into the details at this point, lets say the answer is YES. A triumph and a great breakthrough was made. However, this is not the ENZO way. Dr. Engelhardt went back and piece by piece, determined which portions of the virus provoke a scent and which portions do not. As such, he gained valuable information about the reduction of living virals for conversion to suitable vectors. After all, he is now a designer of these vehicles and he needs to know all the parameters, to be a good designer. This is more important than the discovery itself. Why? Because now ENZO can Patent the reductions. They can tell the USPTO "this thing does this and that thing does that...leave this thing in and you get this effect, take it out and you get that effect". So what, you say? Well, if the USPTO grants a Patent for the reduction techniques expressed by ENZO in developing HGTV (Human Gene Transfer Vector), the vector we have been discussing, ENZO may have essentially cornered the market for "silent" vectors. Thus they coined the phrase, "Stealth Vector". Now, knowing all this, you can see that ENZO wanted to do the same thing the other 1400 human trials were doing. Jump into a human cell and change something. Cause some beneficial effect. However, ENZO was wise to the ways of mother nature and they invested years, to arrive at the proper way of doing this.

So, now lets talk turkey. We take a culture of human cells, CD4+ cells. We transduce with HGTV-43, the "immunologically silent vector" and we insert U-1 into these cells.

We can, if we wish, seperate transduced cells from those not transduced and grow the colony but it is immaterial in this experiment. WHy? Cause the next thing we do is add live HIV.

Yes, we put HIV into the dish. We want to kill these cells. Destroy them, utterly. And guess what happened? They lived. Every single, solitary cell lived. Not only that, at day 19, there is no detectible HIV in the dish or in the cells. Not one.

Then, we do it again! And again! And so forth. But there is more. We also introduce HIV-2, the Hatian Strain. The HIV mutations are classed a), b), c), d), e) and f). They are North American, Hatian, two from Sub Saharan Africa, and I believe two from South Central Asia. And what do we find? Total erradication, to the last. SUCCESS! So we announced and the world yawned. But the Journal of Virology did take note and publish us!

Here are our conclusions!

Although the U1 antisense was designed to act in the nucleus, the inability to detect provirus sequences in postchallenge cells suggests the possibility that the U1/HIV antisense is capable of acting in the cytoplasm prior to HIV-1 integration. The presence of active antisense in the cytoplasm could result from the natural kinetics of U1 processing (23) wherein the U1/HIV antisense chimeric molecules are present in the cytoplasm prior to reimportation to the nucleus.

We have successfully achieved stable resistance to HIV in human immune cells in culture. Independent multitargeting was used to combat the variability and mutability of the virus. This approach also provided independent expression of each of the target sequences from an independent and specific promoter, taking advantage of high rates of synthesis. The choice of U1 as an antisense carrier provided structural stability and nuclear localization. This successful approach in cell culture is being developed as means of achieving a high level of stable resistance in patient cells for the purpose of developing an ex vivo therapy for treating HIV infections.

>>>END<<<

Here is your challenge. Dispute these facts. Call the company. Make sure I am right. I believe that I am. And of greatest importance, read again, the October 6, 1999 press release.

Understanding 9801-230 the Human Trials 10/12/99

What is 9801-230? We have our synopsis. I published just a few excerpts from the Protocols, but can't I boil it down? Yes, I can.

Cornell is a great success. A breakthrough. Stunning and remarkable. No one else on Earth has ever done this with living human cells, not even with antivirals (protease inhibitors). So what next?

Well, we write this nice paper and we give it to the nice people at the NIH. Specifically, the ORDA. Office Of Recombinant DNA. And what do they do? Well, go back and read the synopsis. They pass it back to the FDA for their opinion. And collectively, on July 13, 1998, they conclude: ENZO, is free to commence.

What is ENZO going to do? Select some volunteers. They will be HIV+, BUT NOT AIDs patients. Remember this. It is profoundly important.

Well now, we take all their vitals and do all the standard lab tests. You name it, we do it. We chart it. Then, it is time. We connect a system to the patient called a "leukophoresis" system. We extract stem cells. These are called HSC's or Hematopoietic Stem Cells. There is much, much more to know. This is but a minor, yet paramount phase. You see, Dr. Morton Cowan jumps into the picture. Dr. Cowan exhausted 9 years of his career perfecting a system for SCID. The system is now a viable, FDA approved therapeutic. The system produces HSC's that are selected, Darwinean style. In this way, the cells we transduce are "street fighters" and more likely to engraft successfully. So what next? We poison the stem cells, of course! We poison them to see which ones survive. We want stronglings, not weaklings, because we are going to grow this colony, but wait! First we transduce. Then we purify, then we grow. We use a stromal culture (a culture made of cells extracted from human bone marrow) and we grow this transduced colony. Every cell which arises from a transduced cell, carries the HGTV-43 consctuct.

Out of breath and lost? Lets do it this way>

>attach patient to leukophoresis> collect HSC's> send patient home> poison HSC's> clean> transduce> purify> grow> add medium (liquify)> divide into three parts> cryo-freeze two> give patient tylenol and anti-biotics> infuse the saved dose of HGTV-43 transduced cells. Two weeks later, unfreeze dose 2 and administer in like fashion. Two weeks later, same with dose 3. What next?

We gather data for month 1, 2, 3, 4, 5, 6. We tabulate and chart all data. We present to the FDA.

Hopefully, they tell us it is wonderful, go forth and sell thy product. This could come as a Phase II/III but I know what the real story will be, behind the scenes. You will too, if you obtain a copy of the Protocols and read them.

On or about Jan, 1999, ENZO made a decision to switch from non-AIDs to AIDs patients. The lowest T-Cell count was 40. This patient is, I must presume, still with us. This is profoundly important. A T-Cell count of 40 is not reached because Protease Inhibitors are working. This low of a count tells us the Protease inhibitors are failing. This patient seemingly, had no place to turn to. If this is accurate, something has to be working correctly. HGTV-43 seems to be working. Where are we?

Dr. Engelhardt says "HGTV-43 is very promising". I have to imagine that is is indeed promising, and then some.

The Patents Issues, to PAT or not to PAT - 10/12/99

What a topic of discussion. Patents can mean everything and nothing, all at the same time. If we have one, and it succeeds in getting us a huge agreement and revenues, then it works. If we get in to a dispute and lose, well then it is not that important after all.

Lets explore this issue and the issue of Trade Secret information.

A Patent grants the Inventor or the Assignee, rights to the invention. However, Patents are examined claim by claim. Some claims are dependent. Lets say I have a Patent for a chair. The chair has a back. The chair has legs. The chair folds. The legs are specified as "4" legs.

Could someone create and Patent a folding chair with three legs? If so, would they owe me royalties, or not? Which parts of mine are obvious to one skilled in the art? How would the new Patent infringe on my old one? Is the new Patent even valid? Should the Patent Office have issued the Patent at all?

These issues are taken, claim by claim, disclosure by disclosure. The "rights" always resides in the Inventor with the provable prior art and the clear intent of the claim made as it relates to the art. The U.S. Patent Office does make mistakes. They are human. But with the invention of search engines, the quest for identifying parallel developments is vastly improving. The USPTO can corner off the issuance of a Patent, to be certain there is no conflict. Then there is the "provocation of interference" or just plain "interference" proceeding. The USPTO may want to hear testimony under oath, to decide who gets what claim, for what issue and in what depth or breadth. Interference is when the USPTO spontaneously sees the problems and calls for the hearings. Provocation means one or more parties compells a hearing.

Why discuss all of this? Because ENZO's development of HGTV is very, very important. Far more important than any of us realize. VIRASENSE could be equally important, as well. If ENZO receives a Patent for HGTV, I believe it will not read like a Patent for HGTV. ENZO will seek protection for the novel set of circumstances and steps necessary to reduce an Adeno class virus, to an immunologically silent form. They will probably also seek even broader protection for the generalities of reducing "any" virus to an immunologically silent form. The "STEALTH" vector need not be any particular ilk. This is perhaps comparable to explaining to the USPTO, for the very first time, the design of an arrowhead. There are perhaps thousands of designs that will work, each with different characteristics. But they all operate from a single principle. The strength of the material and the general "shape" of an arrowhead, affixed to a propelling shaft, with or without air foil (feathers), where the surface area of the "arrowhead" is fashioned in such a manner as to impart the maximum amount of force on the minimum amount of sorface area upon impact. Said "shape" taking the form of a cone, or triangle, (give illustrations) or other suitable form, including freeform, where the goal is maintained. The inventor would try to cover a vast array of materials, metals, stone, even wood hardened by fire. The configurations would be discussed. The the claims fashioned. The broader the initial claims, the better. Leading to claims that are extremely fine. Finally, preferred embodiments are given and a clear, logical reasoning as to why the preferred embodiments are the preferred embodiments.

ENZO is faced with the same task. How do we explain so novel a concept to the USPTO? We did something no one else did before. It does not occur in nature. So how do we describe the accomplishment? I know what I would do. I would try for several Patents directed at the art of designing and testing a "stealth" vector. I would Patent each individual development, tied to the first Patents, but also make claims that each Patent stands alone. In this manner, you try to cover any and all basis for such a novel idea. We then have broad protection for the overall concept. We have independent protection for each "stealth vector". We allow the broad concept and the many examples to complement one, another. But they each stand alone. This is ideal, I believe. Lets watch and wait, to see what ENZO does here.

Next comes a discussion of the Trade Secrets Act.

Trade Secrets Act - 10/12/99

Here is a link:

http://www.khlaw.com/protsec.htm
 

Protecting Trade Secrets

--------------------------------------------------------------------------------

Overview. A trade secret is any non-public information that is used in the operation of a business or other enterprise that the business takes "reasonable measures" to protect and is sufficiently valuable to afford an actual or potential economic advantage over competitors.

Companies should do everything they can to ensure that their trade secrets are protected and are not divulged to the general public. This can be achieved by implementing internal trade secret protection programs, as well as through federal and state trade secret laws designed to protect intellectual property assets. Of particular interest, a new law passed in 1996 that criminalizes the theft of trade secrets.

Identifying Trade Secrets. The starting point for the development of a comprehensive trade secrets protection program often is an intellectual property audit designed to identify the company’s trade secrets and other valuable intellectual property. Important factors a company should consider in determining whether its information is a trade secret include:

(1) the extent to which the information is known outside the company;

(2) the extent to which it is known by those within the company;

(3) the measures taken to guard the secrecy of the information;

(4) the value of the information to the company or to its competitors;

(5) the amount of effort or money expended by the company in developing the information; and

(6) the ease with which the information could be legally acquired or duplicated by others.

Typical trade secrets can include formulas, recipes, experimental data, diagrams, supplier information, process/manufacturing technology, quality control procedures and sales and marketing information, including customer lists.

Protecting Trade Secrets. Precautions must be taken to protect a trade secret against loss; it is protectable as property of the owner only as long as it remains a secret. Measures that may be taken as part of a trade secret protection program to maintain security are:

• limit disclosure of the information;

• track access to the trade secret information through sign in/sign out procedures;

• copy a limited number of documents and destroy all copies after use;

• require employees and others with whom the company does business and who have access to trade secret information to enter non-compete covenants and non-disclosure agreements;

• advise the recipients of trade secrets that the information is not to be disclosed or used by them without the express written consent of the company;

• and label and stamp documents according to the level of secrecy.

>>>END<<<

As you can see, everything ENZO does is trade secret until such time as they publically disclose the information.

This is generally a State statute, aka "The New York Trade Secrets Act". This act may entitle ENZO to treble damages plus attorney fees if there is a willful and malicious theft of corporate intellectual property. I am sure the employment contracts contain such binding language, but guess what? If the act exists in the State, it is probably binding on all employees, anyway. This also includes outside contractors.

How do you distinguish between thise things you wish to keep trade secret and those things worthy of a Patent? Well, this sometimes takes a bit of planning. Generally, those things you wish to own and control, but let others take part in, e.g. Licensing, you Patent. Obviously, there is more to the decision that that. The idea must be Patentable. The Patent, if granted, must have a certain feel or flavor of enforcability. HGTV is a perfect example. If we get the Patent, it should be very, very enforcable. Genetic Antisense occurs in nature. The means to deliver it without provoking an immune reaction in a higher organism, does not occur in nature.

ENZO's Patents in this field will be worth 100 X more than any prior patent, in my opinion. The Holy Grail of genetic medicinal delivery systems could be up for grabs, by way of ENZO's discovery in the Cornell and SF trials. DO NOT UNDERESTIMATE THE VALUE OF HAVING THESE NOVEL AND UNIQUE MEANS EXCLUSIVELY CORNERED!!!!

ENZO has labeled this technology "immune modulation". Through their discussions, it is critical to grasp several things about this technique:

1) It is completely unique to ENZO. No one else is doing it.

2) It is based upon the broad concept of detuning the immune system. In essence, turning off a targeting mechanism, so the immune system and a certain specific target will live together in harmony.

3) ENZO's teaching does not preclude the opposite or even a hybrid system. This means the immune system can be "tuned" or detuned" to numerous targets, with a single Tolerization regimen.

SUMMARY: Tolerization is able to take your existing immune system and, as an example, tell it not to attack the antigen expressed by the HEP-B virus. Tolerization could also be used to tell your immune system to attack, for example, the antigen expressed by certain papillo virals that cause warts. Therein, the warts would be rejected, without surgery!

Tolerization is independent of the use og Genetic Antisense. There is no relationship between the two. However, the two are compatible for simultaneous use. This is very critical to note.

Broadly speaking, ENZO's genetic approach to therapeutic medicine is the only one known, intending to deliver the therapeutic effect with no significant side effects. Further, nothing ENZO does harms the immune system, as it stands. Most any other therapeutic "puts down" the immune system, only adding to the Patient's discomfort and recovery time.

TOLERIZATION AS A VACCINE MODEL

ENZO has noted that Tolerization will form the broad basis for development of genetic vaccines. The Tolerization effect, is used to tune the immune system or detune the immune system. Certain viruses are too mutagenic to approach in this manner. The human immune system has limitations and when faced with a highly mutatious virus, vaccination through immune modulation may not be feasible. However, there is another approach using Genetic Antisense.

SUMMARY: Tolerization provides a unique avenue through which ENZO can develop two forms of vaccination. One form would be passive. If you were vaccinated against HEP-B you would still contract it if you came in close contact with the virus (STD or blood). However, you would not develop symptoms. The other vaccination modality is active. Your immune system would be "primed" for the virus in question, and would mroe effectively attack upon first contact.

ENZO has had its ups and downs in court, arguing about its "065" Patent. I see this as necessary, but long term, meaningless in comparison to the enviable lead they have in the "use of" Genetic Antisense and the successful applicability of the same. I think the Courts will eventually overturn all Patents for things that occur in nature. This threatens some of ENZO's Patents. But not much. In the scheme of things, if the Courts do this, ENZO's remaining Patents will become more valuable and important. Why? Because many companies attempt to defeat ENZO by convincing the U.S. Patent office to issue Patents for specific applications of ENZO's broad teachings. I think such a decision will protect the broad Patent, for novel and unique concepts that do not occur in nature, while dispelling the thousands of Patents for specific and obvious applications of a broad teaching. More and more, the Courts seem to be leaning toward rejecting the obvious. Here is an example: ENZO has a broad Patent for the very basic fundamental operation of a genetic probe. This is a concept that is not observed in nature. AFFX has some Patents that take the probes and build a simple matrix or array form them. I personally think the use of an array, to see many different DATA in one glance, is not so unique as the Patent for the singular probe. I do not think AFFX is in any danger of having their Patent erased, but I see ENZO's as the stronger Patent. If someone attempts to further drill down and obtain a Patent for a unique gene chip, at this level, the Courts may someday reject the notion as obvious.

ENZO has taken something from nature. It is a tool. It can be used to regulate specific genes that already exist within the human cell. It can also be used to target and regulate genes in foreign material that can enter into a human cell. The key has been to find the proper way to introduce Genetic Antisense to the nucleus if a cell in a higher organism, without provoking an undesirable immune reaction. This provocation is quite comparable to the scene in a movie, depicting the Piranha or Shark. Once provoked, they call their friends and attack every marked cell, with 100% destructive force. ENZO has unlocked this mystery, having discovered a very sacred key. I cannot find a way to tell you how important this series of Patents will be to ENZO.

The Patents ENZO receives in this field will place ENZO is a very enviable position for future developments of Genetic Antisense. The Courts admitted some things in their recent decision (ENZO v CALGENE) "The use of genetic antisense was inconsistent and hard to master" and "ENZO definately had the prior art, the oldest proven experiments with Genetic Antisense". It was the inconsistencies in experimental outcomes that caught the Judge's eye. What happens when ENZO demonstrates a perfect systematic use of Genetic Antisense. Well, lets use Calgene's own words>>>"Anyone who makes Genetic Antisense work on a consistent basis will have made a great scientific discovery". All I can say is that ENZO's press release on October 6, 1999, states very plainly, that they have made a very stunning breakthrough in the use of Genetic Antisense in human cells. Our worst enemy made our best case! Thanks Calgene!

Now, do you understand ENZO's announcement better? The Courts set their opinion in stone and ENZO simply followed the Court's advice. W ehave done what the Court told us to do, just weeks after their decision was handed down. Guess what? Our Patents just become more valuable! We are the undisputed kings of Genetic Antisense.

GENETIC ANTISENSE AS A VACCINE

Here rests a very important issue. Can Genetic Antisense be used as a means of imparting immunity to a particular threat? The answer is yes. Without hesitation, it is obvious to "one skilled in the art", that the moment someone perfects the use of Genetic Antisense in higher organisms, more particularly, within the immune system, they have indeed unlocked a host of opportunities to empower the living cell with weapons it formerly did not possess.

ENZO's announcement of October 6, 1999 was a very important announcement. If HGTV-43 could be altered to an injectible, single step product, say VIRASENSE-43, what happens if we innoculate everyone? HIV is history.

What issue holds us back? The issue of whole body systemmic therapeutics, whole body transfection, and thus a mass transduction. ENZO will have to prove the safety of introducing Gentic Antisense to the human germ line, or, alternatively, find a means of imparting the Genetic Antisense to all the cells we wish to target and avoid the Ovaries and Testes. Could this be done? I think, yes. If ENZO does this, is it important? I think extremely so.

SUMMARY: Depending upon certain developments with ENZO's various vectors (delivery vehicles for Genetic Antisense), genetic vaccinations and whole body therapeutics will open up as an enormous opportunity. For now, we have HGTV, a product introduced to human cells outside of the body. This is suitable for immune system transductions. Thus, we can render immunity to the immune system cells or alternatively, equip these cells with "engines" producing products which target foreign bodies. Foreign bodies can include viruses, bacterium or even a cancer. HGTV is ready for commercialization. This speaks volumes to us about ENZO's immediate plans. The undisputed kings of Genetic Antisense will deploy an army of product while the world is still stuck in neutral.

In time, Genetic Antisense will make a perfect vaccine. Only Genetic Antisense can stop viral mutability issues completely. Remember to review Cornell. Think about it carefully. A weapon against a virus can become completely ineffective if the virus mutates. A properly formed genetic weapon, fashioned from Genetic Antisense, uses a perfectly reverse, highly complementary molecular tool to target and fuse with the viruses specific gene segments. Thus, no matter how the virus mutates, its critical functions are turned off, forever. As with all viruses, they too have a life span. If they cannot reproduce, they die. ENZO has tried to tell us what they have here. Are we listening? Think it through.

What is claimed is:
1. A composition useful for inducing tolerance to one or more epitopes in a vertebrate animal, comprising:
(a) a tolerogenic amount of a fusion immunoglobulin produced from a vector DNA sequence encoding a fusion immunoglobulin heavy chain, light chain, or both heavy and light chains, said DNA sequence operably linked to functional transcriptional and translational control regions,
which fusion immunoglobulin comprises one or more heterologous tolerogenic epitopes, to which the animal is being tolerized, fused to the variable region of said immunoglobulin heavy or light chain; and
(b) a pharmaceutically acceptable excipient.
2. A composition according to claim 1, wherein the immunoglobulin is an isologous IgG.
3. A method for inducing and maintaining tolerance to one or more epitopes in a vertebrate animal, comprising:
(a) providing a vector that is stably maintained in cells which produce immunoglobulin,
which vector comprises a DNA sequence encoding a fusion immunoglobulin heavy chain, light chain, or both heavy and light chains, operably linked to transcriptional and translational control regions functional in said cells, and
which fusion immunoglobulin comprises one or more heterologous tolerogenic epitopes, to which said animal is being tolerized, fused to the variable region of said immunoglobulin heavy or light chain;
(b) stably transforming said cells, which are autologous to, or histocompatible with, said animal, with said vector to form transformed cells expressing said fusion immunoglobulin including said one or more epitopes; and
(c) administering said transformed cells to said animal, wherein said transformed cells express said fusion immunoglobulin for the lifespan of said cells in said animal and thereby provide a persistent source of said one or more epitopes to maintain tolerance in said animals for at least the lifespan of said cells,
thereby inducing and maintaining tolerance to said one or more epitopes.
4. A method according to claim 3, wherein said fusion immunoglobulin is a heavy chain dimer comprising two fusion immunoglobulin heavy chains.
5. A method according to claim 3, wherein said fusion immunoglobulin is a tetramer comprising two fusion immunoglobulin heavy chains and two light chains.
6. A method according to claim 1, wherein said one or more epitopes is fused to said immunoglobulin variable region at the N terminus of a framework region of said variable region.
7. A method according to claim 1, wherein said cells are hemopoietic cells or lymphoid cells.
8. A method according to claim 1, wherein
(i) one or more of said tolerogenic epitopes is a peptide having the sequence SEQ ID NO:2; and
(ii) said peptide is fused to the N terminus of the first framework region of said immunoglobulin variable region.
9. A method according to claim 1, wherein the vector is a retroviral vector.
10. A method according to claim 1, further comprising treating the animal to reduce the number of endogenous hemopoietic cells before administering said transformed cells.
11. A method for inducing tolerance to one or more epitopes in a vertebrate animal, comprising administering to said animal an effective tolerogenic amount of a fusion immunoglobulin which comprises an immunoglobulin heavy chain, light chain or both heavy and light chains to which is fused, at the N-terminus of a framework region of said chain, one or more heterologous tolerogenic epitopes to which tolerance is being induced, thereby inducing said tolerance.
12. A method according to claim 11, wherein said epitope is fused to the N-terminus of the first framework region of the immunoglobulin heavy chain.
13. A method for inducing and maintaining tolerance to one or more selected epitopes in a vertebrate animal, comprising:
(a) for inducing tolerance, administering to said animal a pharmaceutical composition which comprises
(i) a tolerogenic amount of a fusion immunoglobulin having said one or more epitopes fused to the immunoglobulin heavy chain variable region, light chain variable region or both the heavy chain and the light chain variable regions; and
(ii) a pharmaceutically acceptable excipient, and
(b) administering to said animal transformed autologous or histocompatible cells producing said fusion immunoglobulin in numbers sufficient to maintain tolerance to said one or more epitopes,
which cells stably express DNA encoding said fusion immunoglobulin chain operably linked to transcriptional and translational control sequences functional in said cells, wherein the DNA is expressed in said animals for the lifespan of said administered transformed cells, thereby providing a persistent source of said one or more epitopes to maintain tolerance in said animals for at least the lifespan of said cells,
thereby inducing and maintaining said tolerance.
14. A method according to claim 13, wherein said one or more epitope is fused to said immunoglobulin variable region at the N terminus of a framework region of said variable region.
15. A method according to claim 13, wherein said one or more epitope is fused to the immunoglobulin heavy chain.
16. A method according to claim 13, wherein said one or more epitope is fused to the immunoglobulin light chain.
17. A method according to claim 13, wherein said cells are hemopoietic or lymphoid cells.
18. A method according to claim 6 or 14 wherein said epitope is fused to the first framework region of said immunoglobulin variable region.
19. A method according to claim 18, wherein said epitope is fused to the immunoglobulin heavy chain.
20. A method according to claim 17, wherein said cells are hemopoietic or lymphoid cells.
21. A method for inducing and maintaining tolerance to one or more selected epitopes in a vertebrate animal, comprising administering to said animal transformed autologous or histocompatible cells which stably produce fusion immunoglobulin molecules having said one or more epitopes fused to an immunoglobulin heavy chain, light chain or both,
wherein said administered cells produce said fusion immunoglobulin for the lifespan of
said cells in said animal and thereby provide a persistent source of said one or more
epitopes to maintain tolerance for at least the lifespan of said cells in said animal, thereby inducing and maintaining said tolerance.
22. A method according to claim 3, wherein said animal is a mammal.
23. A method according to claim 11, wherein said animal is a mammal.
24. A method according to claim 13, wherein said animal is a mammal.
25. A method according to claim 21, wherein said animal is a mammal.
26. A composition according to claim 1, wherein said one or more epitopes is fused to said immunoglobulin variable region at the N-terminus of a framework region of said variable region.
27. A composition according to claim 26, wherein said framework region is the first framework region of said variable region.
28. A composition according to claim 27, wherein said framework region is the first framework region of said variable region of the immunoglobulin heavy chain.

TOLERIZATION, bullets

Note: This may or may not be the Patent that ENZO is licensing. There is no reference to ENZO, but I believe the Dr.'s listed on this one are listed on ENZO's other Patents. Regardless, this is a good example.

* Create a vector that transduces stem cells, T-Cells and White Blood Cells

* Select a means of administering the product. Oral dosage requires a means of protecting the package from the stomach acids.

* Develop a suitable retroviral vector (an ENZO plus) Remember the target is the capillaries in the bowel.

* The package to be delivered is an immunoglobulin with an attached epitophe

* Human immune cells will be transduced through the walls of the capillaries within the bowel.

* Protection of the final product is provided via a bovine protein extract. A protein pill with a viral center. mmmm mmmm good!

* Your blood is deliberately infected with a virus, through the walls of the bowel, depositing the aforementioned package.

* The infection of the blood deposits epitophes which are permanent markers that transcribe from the core of the cell. The normal replication of the cells copies the epitophes.

* Certain targets, representeed by the epitophes, are thus tolerated, as the entire blood system is transduced.

Now you see why it is a pill per day, 6 days in a row. Latent viral vectors dissolving and coating the bowel, transduce the blood system, over and over. 30% transduction means nothing if you transduce over and over. Eventually, you achieve 90% or more.

I believe this amounts to a trick played on the immune system. Certain virus' trick the immune system in nature, to leave them alone. This trick has been harnessed to trick the immune system into leaving certain targets alone. The rest is covered earlier on this board!

Sincerely,

Larry Glaser

Genetic Vaccine versus Classic - 12/16/99

We are going to learn much about the difference between a Genetic Vaccination and a classic Vaccination. In classic form, the immune system is "trained" to "know" the presence of HIV and to mount its attack more swiftly and consicely. In the case of HIV I believe this can never work. It can never work because this virus has a certain feature most others do not tout. Based upon world populations, it is logical to expect and to actually observe virus' emerge which are better equipped to cause harm. This is a Darwinean factor that is observed in all mammals, and all animals, as populations rise.

HIV has the unique property of causing immune cells to attack each other, once the surface of an immune cell is altered with the presence of HIV antigen. This is a fact, associated with the disease. It seems that a small % of the population in the world, about 2%,are naturally immune. The rest seemingly demonstrate that once HIV is in, it will never come out. It also seems that statistics bear, if no therapy is applied, AIDs will come in time. It varies per individual.

Genetic Vaccination provides key Antisense Genes which produce specific by-products that in turn, cause the virus to be incapable of replicating. In this manner, the virus cannot get a foothold and the bodies natural resistence would logically be thousands of times more effective. The key, I believe, is to understand two factors. First, no one dies from HIV in days, weeks or months. The body fights as is seen in Africa and Asia, where there are no therapeutics available to the poor. Second, the fact that there is a small % of the population that apparently has enough natural resistance to rid the body of HIV. If the virus replication cycle can be significantly interrupted, then the net result is of enormous benefit the the remaining virtues of the immune system. The CTL effect or "ability to detect HIV and spread specific Cytokines", would presumably take care of the virus ling before it could proliferate.

To sum it up, if Genetic Antisense works as a cure or a strong therapeutic, a vaccination would logically follow AND THAT VACCINATION WOULD BE KNOWN TO WORK, prior to testing. Reversal of HIV+ or AIDs to a cured condition makes the logic bear out. A non-infected individual who has their immune system transduced to include the three Antisense genes (deliberately) would then be completely immune to HIV. If it clears the virus in an infected individual, there is no doubt whatsoever, that a non-infected individual, once treated, could not contract the virus.

As to others working on a vaccination, we will see. I can take a look, but if they had a preclinical as profound as ENZO's "Stable resistance to HIV...", you would have already pointed me to that pre-clinical data or a mention of the pre-clinical trial.

Classic vaccinations will not work with HIV or with HEP-C. Mark these words for I am not alone in this thinking.

Genetic Vaccination will offer a new vista of opportunity for mankind to whipe out all virus' in the next decade.

This is my conclusion. All ENZO needs to do is announce their results and you will see what I mean.

Sincerely,

Larry Glaser
 

Re: Genetic Vaccine versus Classic  VANGO888
 12/20/99 9:30 pm

In many of my older posts, I have laid out precisely what I believe will happen. Indeed, I did not predict a "cure" claim. Rather, careful announcements citing the decisions made and the compelling reasons for the decisions, as they are made.

I believe the RAC is willing to release products very early for a chronic disease like HIV. Even under such a release, many disclaimers would follow. Call it a Phase IV, a controlled release.

If you have taken the time to order a set of the Trial Protocols from ORDA, look at the Cornell data. (If not, list these posts and find it. It is free.) HIV 1 and HIV 2 were tested. I have also heard Barry state that all forms of HIV have been tested at Cornell. This means 3, 4, 5 (and I believe there is now a 6) have been tested.

All HIV seems to retain the TAT, REV and TAT/REV site (region), much like the three pylons holding up a suspension bridge. These regions do not seem to mutate. Take out only one, the bridge may still function. Take out all three, the bridge cannot stand. As to the HIV's ability to replicate, I will say this very loudly>

THE CORNELL DATA (FOR ENZO) SHOWS THAT AFTER 25 DAYS, EVERY SINGLE SOLITARY COPY OF HIV INSIDE AND OUTSIDE THE LIVING HUMAN CD4 CELL WAS ELIMINATED. IT FURTHER SHOWS THAT AFTER REPEATED TESTS, THE SAME RESULTS PERSIST. THEY PERSISTED FOR HIV 1 and HIV 2.

Some have asked me, why did they not test 3, 4 and 5 at that time? I believe the Cornell Trials were concluded in 97 and the protocols written by Dr. Hillis (SP?) were submitted to the FDA. I believe it was January of 1998 that the protocols were preliminarily approved and July of 98' the FDA approved commencement of the 9801-230 trials. The reason could be as simple as the unique strains were not yet recognized.

These results are a true phenomena worthy of a proper valuation. Coverage will come. When it does, I will be interested in seeing the analyst point to the profound nature of this discovery as it applies universally to all virus, particularly those which are highly mutagenic.

Many lives will be spared and immeasurable agony avoided, should this platform play out. It is certainly worthy of our best efforts to believe in and to support.

ENZO is defined on their home page, in their own words. However, their message at the recent annual shareholder's meeting is clear and unambiguous. ENZO intends to do what INCY, HYSQ, CRA, AFFX, GLGC and so many others DO NOT! ENZO intends to change the living genome, human and animal, to alter a cell's instructions and either resist or eliminate the possibility of disease.

Today, during one of my discussions, I found a good way to express this. CRA and their ilk, seek to utilize diagnostics products to identify promising human genetic targets, in order to suggest a course of action to prevent or eliminate disease. ENZO seeks to use its Therapeutics products to act on the targets discovered by others. ENZO also manufactures the diagnostics components, more specifically the probes and reagents, used to identify the targets. ENZO can, in-house, identify promising targets, as well. In many ways, ENZO's Patent Estate covers the entire spectrum of modern genetics and modern genetic's diagnostics. So ENZO can actually play on both sides of the fence. Others cannot, nor do they purport the ability.

But ENZO's future vests more in Therapeutics than Diagnostics, even though Diagnostics offers immediate revenues and profits. Therapeutics simply has more near term upside. Revenues and profits which dwarf anything Diagnostics seems able to muster, near term. I could be wrong on this point and Diagnostics could provide a huge upside surprise. No matter, it is a win win.

ENZO seems to be quite alone, in the Genetic Therapeutics field. Although there is scant competition, ENZO is apparently far, far ahead. Case in point, ENZO is going to present results from its 9801-230 HIV Human Trials, hosted at UCSF, and ironically to be synopsized at the 7th annual Retrovirus conference, held in (you guessed it!) San Francisco on January 29, through Feb 1, 2000. I do not believe anyone else will present human HIV trial genetic therapeutic's based results at this meeting.

I believe the conference will end on a high note which it has not seen since its inception. Apart from this, the crowd is likely to miss the single most important element.

ENZO stands alone. This is what matters.

ENZO stands alone in its developments, in its model, in its Patents and in the data I am sure they will present. Consider, HIV is a virus and a highly mutagenic virus at that. ENZO has, in studies conducted external to the human body, proven that it can elminate HIV from the interior of a living human immune cell. The change is permanent. The change withstands infinite encounters with live HIV. The specific change replicates reliably, with time. In living HIV + humans, the altered cells grow and survive, the untreated cells die, as was expected. This is already divulged in ENZO's press release of October 6, 1999 and further clarified by the statements made at the ASM, on January 12, 2000. All that remains to be seen is the ultimate restoration of immune competance and HIV level control. HIV elimination is a future aspiration and was not promised. However, I believe the protocols do contemplate a possibility of total elimination of HIV, perhaps with molecular drugs applied at the point where the immune system is restored and is competant against HIV.

The real story here is the persistence of the solution. A highly mutagenic virus cannot mutate, cannot replicate and is potentially eliminated from the BODY and from the interior of the living cell. This is profoundly important to future research with other virus' and would be presumed to be exclusive to ENZO Therapeutics.

Next comes TOLERIZATION. In simian models, ENZO eliminated the effects of HEP-B infection. This pre-clinical breakthrough was taken to the next logical step. Human studies are under way at Hadassah University, in Tel Aviv, Isreal. ENZO received funding from a joint source which included an NIH review of the data. ENZO received 1.4 Million in additional funding to enhance the project in a multi-national effort. Dr. Engelhardt took time to explain at the ASM, the results seen in humans followed the (Topia, SIC?) simian model. Further, he explained that HEP-B viral load had actually stabilized and dropped in the human patients. He also explained that the TOLERIZATION regimen did not promote mutation. Here again, ENZO has an exclusive product.

TOLERIZATION is a broad concept, allowing ENZO to presumably address any and all human autoimmune system responses. The human immune system is responsible for much damage, including fatal damage, in a number of chronic diseases. ENZO believes it can regulate only one targeted molecular process, or a select few, to manage a disease by elimination of the symptoms. Many studies strongly suggest elimination of damage caused by the immune system, could lead to the immune system's successful purge of the target virus or pathogen. Regulating only one or a select few molecular processes in the human immune system, could lead to very profound performance against a host of chronic or persistent diseases.

In both of the aforementioned models, ENZO applies the use of novel and unique viral vectors. The HIV trials rely upon a viral vector and genetic antisense genes. ENZO can target critical processes in the HIV, to shut down mutation and replication, completely. The HEP-B trials currently underway, utilize Immune System Modulation, or "TOLERIZATION", which is another viral vector applique. A different viral vector from the antisense gene carrier, is used to carry EPITOPHES in to the mass of the human immune system. Although similar to the HIV trials, in that a vector is used and the human immune system is effected, the process of TOLERIZATION is more comparable to the natural processes the human immune system uses to determine "self". It is molecular, but it is not gene related at all.

In a sense, ENZO Therapeutics is actually working in three areas. Gene Regulation, Vectoral Genetic Delivery Systems and Immune System Modulation. If I may quote Dr. Engelhardt once more, from the ASM, "It works....They both work".

He did not necessarily mean the human trials, as much as the human PROCESSES or SYSTEMS which ENZO adequately describes at its home page. It means 20+ years of hard labor and genuine Pioneering, has yielded a basket of fruit. The three golden children of ENZO are walking and the world is soon to take note.

In closing, at this time, I believe about 1/10th of 1% of all individual investors in the United States have heard of ENZO. I could be wrong, but not all that far off. In contrast to the other genomics companies, I have hung my hat here, at ENZO. I believe ENZO was making its key discoveries as some of these other genomics organizations were formed. The final proving ground is at the USPTO and within the confines of each organization's trade secrets. I believe in each case, ENZO is far, far ahead.

It has transcended far beyond enviable. It is stunning and unparalleled!

Now I await the professional Analyst who will hang his or her hat along side mine, and begin to explore ENZO's garden of delight. And the rest will be history, for I know what I say is true.

Not only will these inventors and scientists win the Nobel Prize for Medicine, they will surely win the Nobel Prize for Peace. Nothing breeds discontent against government, destruction of an economy or of a society, than chronic disease and certainly of the magnitude we face today.

On the day that I can stand up and say "ENZO has truly done it", I will mean more than one thing. Cured disease? Yes. Changed the future of mankind? Most definately.

Sincerely,

Larry Glaser