X-Message-Number: 12464
Date: Tue, 28 Sep 1999 01:19:37 -0400
From: Mike Darwin <>
Subject: 21CM Patent: Some answers and questions
There have been a number of comments and speculations on the recently
published 21st Century Medicine (21CM) assigned patent on novel
cryoprotectants. In particular, Robert Ettinger and Thomas Donaldson have
expressed puzzlement about the lack of supporting data for the high rates
of cooling claimed, and also as to the "legitimacy" of the core patent
claims themselves. For instance, Ettinger writes (as quoted in the full
text of his message below): "The inventors acknowledge that glycol ethers
have been used before to preserve embryos and cell suspensions, but believe
they have priority in application to tissues, organs, and animals.
Obviously, there are potentially interesting questions in patent law--both
as to the relation between these inventors and prior users of glycol
ethers, and between these inventors and later users of new variations and
applications." Donaldson also states: "There is also some question in my
own mind about whether or not some of the perfusion methods described will
prove to be patentable ..."
Ettinger also notes that he is "legally untutorted" (sic) in patent law.
This last observation is a critical one. *Claims* that at first blush seem
broad and overweening may on careful scrutiny be narrower than someone
inexperienced in reading (and circumventing!) patents may percieve. The
patent issused to 21CM and created by Wowk, Darwin, Russell and Harris
acknowledges prior art in the use of alkyoxylated organic molecules as
cryoprotectants as they both morally and legally should and must (willful
failure to acnowledge prior art is grounds for voiding of a patent). The
seeming "iota" here upon which the claims rest is to *vitrification* as
opposed to freezing. And that is no iota at all.
The cryonics community as a whole has long been confused about the
difference between these two approaches to cryopreservation, and I do not
intend to spend time in further, and probably futile, attempts at their
education. Suffice it to say that ice forms crystals which greatly and
perhaps irreversibly damage (destroy information) in tissue, Merkle and
Tipler notwithstanding ;-). Alkyoxylated cryoprotectants still confer
advantages in freezing where ice is formed over conventional
cryoprotectants in many situations.
However, that is *not* the application that is being claimed in the 21CM
patent. Rather, it is the use of these compounds in clever ways to achieve
*vitrification*: cryopreservation in the absence of damaging amounts of
ice, wherein the organ system or tissueis maintained in a largely or
completely glassy or otherwise non-crystalline state. Freezing is a
workable method for cryopreservation of of many cells, small organisms, and
tissues, but fails miserably when applied to complex, interconnected masses
of cells ans tissues (such as mammals and most of their their major solid
organs).
Additional confusion results from the mechanics of patent law and the
patent process which requires *multiple* experiences with in order to even
begin to understand how it operates. In other words, you need to have dealt
with *good* patent attornies and prosecuted *multiple* patents before you
get a feel for the quirks of the system. FYI, as an aside, this is a
process that will cost you many, many thousands of dollars. It is often
said that a physician who has himself for a patient is a fool. The same can
be said for those who step into the byzantine world of *serious* patent
prosecution without the best counsel available.
One thing that is commonly done is to (seemingly rationally enough) link
integerally related novel technologies together in a single patent. The
U.S. Patent Office often has other ideas and will break a single patent
into several parts, or into several discrete patents, each of which will
issue (and finally post to the Federal website) at different times. (There
are reasons for this: each patent generates Federal revenue and must be
maintained by regular payments over its life). Thus, a large section of the
21CM patent currently under discussion on Cryonet has not yet posted to the
web. This section describes technology developed largely by Darwin and Wowk
to achieve very high rates of cooling in whole mammals via intravascular
perfusion with a variety of "inert liquids." Brian Wowk deserves
particular credit for discovering some unique and truly unexpected
properties of perflurochemicals which allow continued non-toxic perfusion
(rapid intravasclar circulation) of these agents at temperatures as low as
-150 C. This is important, because it allows not only for very fast rates
of cooling, but is below the glass transition point (Tg) of most
water-cryoprotectant mixtures. This, in effect, eliminates the danger of
ice formation during cooling and rewarming due to "devitrification." We
expect this patent to post later this year.
I will comment specifically on the full-text of Ettinger's post, and on a
relevant sentence in Dolaldson's post:
>Message #12443
>From:
>Date: Mon, 20 Sep 1999 14:08:22 EDT
>Subject: 21CM patent
>Go to www.uspto.gov to access the full text of the patent (Sep.14)
assigned
>to 21st Century Medicine Inc. Oddly enough, the inventors listed do not
>include Greg Fahy; they are Brian G. Wowk, Michael G. Federowicz
["Darwin"],
>Sandra R. Russell, and Steven B. Harris. It runs about 18 printed pages.
There is nothing odd about the omission of Greg Fahy from this patent. The
work which this patent was based upon occurred as a result of a truly
bizzare chain of circumstances which began with a request I posted to
Cryonet well over two years ago. I explained in that post that
BioPresevation (my company, which at that time was active in postmortem
human cryopreservvaion) had a client who's brain had been fixed in formlain
and been refrigerated, but not frozen, following her legal death. There was
no possibility of achieving vascular access and introducing
cryoprotectants.
I asked for advice from all quarters on what might done in such a
situation, and in particular if anyone had data on more highly permeable
cryoprotectants than those in conventional use (primarily glycerol and
DMSO). Only one person responded to my request for help and that was Doug
Skrecky. Doug played a critical role in all that was to come by providing
me with a list a of a few highly permeable likely candidates for
cryoprotection, *and* a reference paper which listed the red cell
permeabilities of well over a hundred organic compounds. This list was
daunting, but exploration was begun, initially using a mixture of physical
chemistry assays (concentration needed to vitrify, or CNV) and a simple and
inexpensive toxcological assay I developed while in high school.
Meanwhile, I had forwarded this paper to Brian Wowk who at that time was
still working on his dssertation in Medical Physics in Winnipeg, Canada.
Brian selected a number of high permeability compounds to test which he
felt, based on their stucture (and his insigtful understading of
water-cryoprotectant physical chemistry) might be good candidates. One of
these candidates, 2-methoxyethanol, behaved in a fashion unlike any
cryoprotectant I had observed before. It vitrified at anamolously low
concentrations, it penetrated the entire brain rapidly and uniformly,
including the myleinated axons which have been a major barrier to
successful brain cryoprservation, and it passed my bioassay tests,
including human RBC freezig and vitrification studies which Sandra Russell
and I ardously carried out over a period of several months. This molecule,
and related ones, also exhibited gross physical behavior unlike anything I
had observed in any class of chemicals which had been tested as putative
cryoprotectants. Space prevents me from describing these phenomena, but
they electrified both me and Steve Harris.
Brian then took up the torch in Winnipeg in the midst of his dissertation
and began systematically evaluating mathoxylated compounds in the basement
of his home using equipment I had sent him and a test tube from his
childhood chemistry set. Brian was later to elegantly discover using a $50K
differential scanning calorimeter, instread of a single test tube from an
ancient chmeistry set, that each methoxyl group added to most suitable
cryoprotectant molecules decreases the CNV by a few per cent. This is no
small matter, since a difference in concentration of 1% cryoprotectant can
mean the difference between near complete loss of viability (and serious
ultrastructural disruption) and virtually 100% survival for organs such as
the mammalian kidney. The rapid penetration (equilibration) of these agents
and their greater depression of the freezing point offered additional
opprtunities to capitalize on the decreased CNV requirement: shorter
loading and unloading times at lower temperatures were in theory possible,
with resultant further reduction in toxicity, or CNV, or both.
During this time Greg Fahy was working for a competing company and IMHO
thought little of our ability or efforts to make significant progress at
21CM. In fact, he was working with a company with whom 21CM had anything
but cordial relations. BOTH sides dealt with each at *more* than arms
length, and the nandwidth of communication was zero.
Greg was not appraised of the new approaches being developed by 21CM for
nearly two years -- and considerably after the first disclosure document
for the patent had been filed. Greg can, of course, speak for himself, but
I think he was quite astounded at the progress that had been made
completely independent of his efforts or inputs (aside from those, such as
the basic principles of vitrification, which had been openly published by
Greg in the literature).
I want to pause here in this narrative and thank Doug Skrecky publically
for his generosity and his intellectual insight in suggesting that we
consult the critical reference that lead on to much of what has happened
since. I also want to make very clear that the intellecual property in this
patent was the work of three people: Wowk, Darwin and Russell. Each made
pivotal contributions and spent countless back-breaking hours in the
laboratory.
Ettinger continues:
>Naturally, we will investigate the procedures and substances mentioned.
>There are many interesting features in the patent, not least the structure
of
>claims. The claims start broadly, including any alkoxylated organic
compound
>in a concentration sufficient to permit vitrification and cooling until
>vitrified; and the application of this to any organ, tissue, or animal.
More
>specific claims relate to use of 2-methoxyethanol and
>3-methoxy-1,2-propanediol.
>The inventors acknowledge that glycol ethers have been used before to
>preserve embryos and cell suspensions, but believe they have priority in
>application to tissues, organs, and animals. Obviously, there are
potentially
>interesting questions in patent law--both as to the relation between these
>inventors and prior users of glycol ethers, and between these inventors
and
>later users of new variations and applications.
"Summary" of the invention mentions perfusing an inert fluid through the
vascular system and controlling the temperature of the fluid; and a class
of
new glycol ether CPAs. Oddly enough, the Claims do not (to my legally
untutored mind) appear to make any direct or specific reference to cooling
methods, even though in the "Summary" that seems important.
>"Glycol ethers" are understood to include compounds containing alkoxy--and
>particularly methoxy--functional groups. Included are alkoxylated alkanes
and
> alkoxylated alcohols and polyols, with several sub-groups given.
>For some organs, cooling and rewarming rates can exceed 100 degC per
minute.
>[This seems to suggest possible use with other CPAs, such as amides.]
>"Large animals can be perfused wit high concentrations of glycol ethers
near
>0 C with rapid equilibration, no dehydration, no edema or other visible
>evidence of toxic effects. Histologic preservation is excellent at
>microscopic and ultrasturctural levels."
>References include Skrecky's proposal in Cryonet #5174, 1995; CRYONICS:
>REACHING FOR TOMORROW (Wowk & Darwin, 1991; and THE PROSPECT OF
IMMORTALITY,
>1964; and a Darwin/Hixon piece in CRYONICS July 1984, as well as various
>patents and publications in recognized journals.
>I have not found any patent entries under "ice blockers," although the
>instant patent says that suppression of ice formation is an important
>feature. I believe 21CM has a different class of substances it calls ice
>blockers, acting through a different mechanism.
>The "Conclusion" mentions unprecedentedly high rates of cooling and
>rewarming,;and the advantages of the new CPAs, including penetration and
low
>viscosity, rapid equilibration, ice inhibition, minimization of toxicity,
and
>glass forming properties.
>Congratulations to all the inventors involved. Lots of work ahead.
>Robert Ettinger
>Cryonics Institute
>Immortalist Society
>http://www.cryonics.org
What also needs to be mentioned is that during tail-end of this same period
of time a South African (SA) woman named Olga Visser appeared on the
international scene making exatrodinary claims for a novel highly
penetrating and nontoxic cryoprotectant which reputedly allowed for
successful liquid nitrogen temperature (-196 C) cryopreservation of rat
hearts. Unbeknownst to most American cryonicists, Ms. Visser was also
claiming that a similar (and it turns out identical compound) was a cure
for AIDS (HIV infection). This actually is what brough Ms. Visser to my
focused attention. I count as friends and colleagues a number of critical
care physicians ("Intensivists") in South Africa. Several of them were
distressed beyond words at the actions of Ms. Visser and her husband Ziggy
Visser in facilitating the replacement of the respected (and highly
flexible and decent) chair of the South African Medicines Council (the
approximate equivalent of our U.S. FDA) with a woman with less medical
understanding than a village Medicine Man. Using political entre and the
Medicines Council's new chief, the Visser's managed to route "Virodene"
around all normal channels of peer review, clinical trials, and informed
consent. Virodene was, my SA colleagues alleged, being given to human HIV
patiets in violation of both the Nuremberg and Helsinki codes.
I was asked for information on the matter because her connection to the
American cryonics community and her claims regarding rat heart preservation
were being bandied about in the SA media at the time. The Intensivists who
knew me and of my involvement in cryonics and cryobiology asked for my
opinion as to her credibility. They also, without my asking, provided me
with the name of the compound Ms. Visser was using as her cryoprtectant and
AIDS cure: dimethylformamide (DMF). This information was obtained, as I
understand it, from a purchasing agent at the hospital in the perfusion
department where Ms. Visser was employed.
DMF was one of the many molecules on the list Doug Skrecky had lead us
onto. We had examined it and found it be both toxic in cryoprotective
concentrations, but far more to the point, very poorly effective as a
cryoprotectant in freezing, and a complete write-off for vitrification. In
fact, DMF caused the formation of some of the largest ice crystals and the
most severe organ damage on freezing of *any* of the conventional
cryoprotectants we had evaluated it in comparison to. We had, in short,
discarded DMF as a viable highly permeating mono-agent for organ or tissue
cryopreservation. We had also investigated many related compounds
(peralkylamides)and also found them to be of no utility in our models. I
communicated this to my SA colleagues and to the Reuters and other
reporters who subsequently called. Similarly Charles Platt was instrumental
in informing key members of the international press of Visser's likely
credibility and, most importantly, of the identity of the industrial
solvent, immunosuppresive, and carcinogen (DMF) she was promoting as an
AIDS cure
Ms. Visser was ultimately discreited and left SA. However, her legacy
remains: human clinical trials, even of the most ethical and tightly
controlled nature, have become all but impossible due to the "Virodene
Scandal" or the "Visser Affair." My colleague and friend Dick Burrows,
Diector of Intensive Care Medicine at Addington Hospital in SA, to this day
remains bitter and inflamed about the "enormous harm" the Virodene fiasco
did to clinical and experimental medicine in SA. He has repeatedly stated
that his practice of medicine has suffered direct harm as a result of this
incident. (Dr R Burrows, Director Intensive Care Unit, Addington Hospital
PO Box 977 PO Box 977, Email ).
I might also note that money and support from cryonics organizations in the
US such as Alcor and CI ( I've been told in the vicinity of $50,000 to
$75,000) helped to allow Visser to continue her fraud in a country where
the level of desperation for ANY relief from AIDS simply cannot be
understood by us in the US. FYI: roughly half of all the babies born in Dr.
Burrows' hospital are HIV infected.
In fact, 21CM recently abandoned efforts at clinical trials for promising
drugs to treat shock and multisystem organ failure from trauma and sepis
which were ideally suited to a "Third World " environment and economy
*directly* as a result of the Visser affair.
Ettinger also notes:
">I believe 21CM has a different class of substances it calls ice
>blockers, acting through a different mechanism.
This is correct. This work, begun by Brian Wowk, has continued to progress
at an astounding pace. In no small part this been due to truly hurculean
efforts by Eugene Leitl, who I have seen putting in day after, day after
day of 14, 16 and even 20 hours at a stretch working to synthesize novel
ice blocking molecules: a task in which he has succeeded remarkably!
Thus, the patents which are "posting" now (i.e., becoming web accessible)
are but the tip of the iceberg, or should I more appropriately say, "the
first vitreous prearl of a mountain of precious, ice free glass which is
yet to emerge."
Thomas Donaldson comments:
>I too look forward to wider application of the cryoprotectants and
>perfusion technology created by 21st Century Medicine. Yes, it may not be
>immediate; the first thing to do is to try these methods on brains.
>(There was a time lapse between the first Wright brothers flight and
>the use of 747's, after all).
This has been done, and with stellar results and has already been reported
on. In fact, ACS has pictures on their website.
As to cooling, Thomas was apprised of the fact we had achieve cooling rates
of 10 C/min to -70 C with intact 20+ kilo dogs at the A4M meeting in a
private brefing held *at least* three years ago, if not longer.
Furthermore, the financial and technological barriers to the application of
this technology to an estimated 1/3rd of human cryonics patients NOW, are
trivial compared, say, to the effort that has gone into the construction of
CI's latest and largest cryostat or Alcor's ambitious program of training
and "suspension services" revamping.
And the ultimate irony is, the storage costs will probably be lower and the
up-front technology not more than 20% to 30% more costly than that employed
by Alcor now (the only high technology player left in the human
cryopreservation field).
As a result of all this, I have become convinced that the only thing that
will get the impact of the progress *already made* through the thick skulls
of cryonicists is when they hear about the revival and cure of the first
*human* cancer patient placed into suspended animation at -120 C or below.
I predict the response will be: "Don't waste your money on it, get *frozen*
on the cheap and wait till you can get reanimated for free and be
fantastically rich and sexually irresistiable using Nanotechnology."
Mike Darwin, Director of Research
Critical Care Research, Inc.
10743 Civic Center Drive
Rancho Cucamonga, CA 91730
Phone: (909) 987-3883
Fax: (909) 987-7253
email:
PS: My thanks to John Grigg for his warm remarks:
>I looked over the patent for 21st Century Medicine's research developments
>and must say I am VERY IMPRESSED!!! I congratulate those who made it
>possible!!
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