Cerovive Stroke AstraZeneca Renovis...

Centaur Pharmaceutical Statement re Cerovive Patent dispute

( from 1998 annual report )

" The Company has received correspondence from the lawyers for an individual who has obtained certain patents related to the use of phenyl butyl nitrone ("PBN") and related compounds and which include claims related to specified reactions of these compounds with certain free radicals. PBN is a commercially available material that is known to react with free radicals in certain environments. The Company's founders used PBN in their early research. The correspondence alleges that certain of the Company's compositions and methodologies may fall within the scope of such individual's patents, and that the practice of such by the Company would constitute infringement. Subsequent discussions between the Company and this individual have not resulted in a resolution of this matter. The Company does not believe that these patents materially adversely affect its ability to develop and commercialize its products....."

Compare this to the clear wording of my '502 patent. E.g., Centaur fails to inform investors that:

1) Their lead compound "Cerovive" is the disulfonic acid derivative of PBN. As they acknowledge, I do have patent claims to PBN "and related compounds". Further, my patents include all elements of Cerovive--e.g., PBN plus exemplar disulfonic acid and sulfonic acid derivatives of spin traps. Thus, it is a "slam-dunk" under doctrine of equivalents. Further, my '502 patent specifically covers "stroke" and "parenteral" (doctor-talk for "systemic") use.

2) Centaur's statements are difficult to interpret. In fact, they make no scientific sense. Apparently, they assert my patent claims cover only non-specific radical-mediated direct damage to tissues. I.e., that, since the actions of PBN, etc. are probably mostly messenger-mediated or at least involve processes that I do not specifically mention, this somehow obviates my patent claims. This is grossly misleading.

Contrary to Centaur's assertions, my patent claims are for use of such compounds to "ameliorate cellular injury to tissues" without any reference to mythical "specific reactions", found nowhere in the patent.

In case there should be any question about this or any other issue, "State of mind" when a patent was written is probative. For example, the 1984 review article incorporated "by reference " to the '502 patent clearly lays out the messenger function of radicals, etc. that mediates much "cellular damage to tissues". Go here for a specific quote.

Significantly, the concept that free radicals are messengers seems to at least partially originate with me-- E.g., as early as another review article in 1972 I noted that the role of redox processes in certain neurological diseases might involve messenger-mediated mechanisms.

This review article on free radicals and neurological diseases was over two decades before the priority date of the Cerovive patent. I presented a full-blown version of what was later known as "redox signaling" at the same scientific meeting in 1979 where Dr. Demopoulos reported the vascular action of antioxidant neuroprotectants(2). As I note below, the latter was alleged to give "novelty" to Cerovive over a decade later. T'aint so folks.

Citation Amnesia and Cerovive

Infringement does not start until a drug goes for regulatory approval. So, for now, Renovis can ignore my patent claims, figuring the worst that can happen is some back royalties, likely years away. Similarly, a judge is unlikely to grant a TRO against a life-saving drug and their putative opinion of counsel might protect them against triple damages for willful infringement.

However, their real problem is the validity of the Cerovive patents. Possibly, Renovis' management missed this in their rush to buy Centaur's IP. They are justly famous in neuronal development in fruit flies and round worms, but have no background in free radical research or its early history, much of which was produced by myself or my coworkers. We know what the prior art is, because we produced much of it.

This was rather incompletely cited in the Centaur patents, with potentially fatal effects. One example: A chief "patentable novelty" asserted for Cerovive is that this lipid-insoluble agent "unexpectedly" has a higher specific activity than the parent PBN, while not crossing the Blood-Brain barrier. That is, the action of this drug is arguably largely extracellular, most likely at the blood vessel level.

In fact, several such agents were well known to those "skilled in the art". E.g., at a meeting in 1979, my coworker Harry B. Demopoulos, MD, reported (2):

"..Large doses of methohexital protect the microcirculation in regional cerebral ischaemia models".... Superoxide dismutase gave approximately 50% of the protection afforded by barbiturates..." (Page 147)

I was there when he reported this. The same book also has a chapter with both Harry and I as coauthors (3). This paper uses SOD/catalase as probes for the extracellular toxicity of oxidant anticancer drugs, another utility claimed for Cerovive.

Nita et al give Harry proper credit: "The concept of generation of free radicals during ischemia was first presented by Demopoulos,Flamm and coworkers.....". This was the same year (1978) I published my first paper (4) with Dr Demopoulos. Again, draw your own conclusions about whether my patents cover stroke or not.

Similarly, we showed that CNS hyperbaric oxygen toxicity (1) and the toxicity of 5-hydroxy dopamine or "6-HDA" to neuronal-cell analogs is probably largely extracellular. This is because they are also ameliorated by the extra-cellularly-acting neuroprotectants SOD and/or catalase.

This was with specific reference to the well-known inability of these agents to cross the blood-brain barrier. Neuroscientists generally consider 6-HDA-toxicity the classic model for oxidative damage to cells of the nervous system.

This is just like hair loss is a model for general radical-mediated "cellular-damage to tissues", more spin-trap-related prior art uncited in the Cerovive patent. Thus, more than a year before the earliest priority date of the Cerovive patent, I note " For example, many current models for postischemic myocardial and stroke-induced tissue damage involve a combination of calcium ions and free radicals. Since calcium channel blockers also induce hair growth, perhaps balding is ultimately related to similar processes." This paper is complete with pictures of spintraps and spin labels.

Go Here for another example of neuroprotection by SOD in stroke. All this was well-known "to those skilled in the art" more than a year before the earliest priority date of the Cerovive patent. So was the extra-brain action of the antioxidant neuroprotectants Tirilazad and uric acid. In fact, action outside the Blood-Brain Barrier was well known to be the general rule with antioxidant neuroprotective agents.

The extracellular nature of these processes, as well as in (e.g.) radical-mediated damage in burn-wounds, ischaemic injury, anticancer agent toxicity, etc., was one reason both PBN and exemplar sulfonyl and disulfonyl spin traps were specifically- included in the '502 patent. I make specific reference to them in the 1984 review article incorporated by reference into my patent, almost a decade before the earliest priority date of the Cerovive patent

Parenthetically, I published my first paper on free radicals and neurological disease in 1970. Over twenty years before the earliest priority date of the Cerovive patent, I was also the first to suggest that a compound strongly-associated with stroke, homocysteine, works by inducing oxidative stress. Stated simply, I was there when large chunks of uncited prior art material to the Cerovive patent were produced.

Interestingly, the first Centaur patent for PBN and its derivatives (US#5,025,023) notes:

" Although no drugs are currently approved for clinical use in treating tissue damage due to ischemia, several compounds have been proposed as potentially being effective..... Superoxide dismutase (SOD) has been suggested as a means for limiting in vivo oxidative damage....." (emphasis-added). So the author knew about SOD. However, while claiming a similar action as "novel" in the Cerovive patent he did not tell the patent examiner about SOD or its well-known extracellular action. Run this by your local patent attorney.

Similarly, the '502 patent asserts: " These results were unexpected (emphasis-added) because in the general literature on structure/activity relationships within specific defined families of compounds therapeutic potency typically covaries with toxicity. Thus, most related compounds maintain their ratio of therapeutic potency to toxicity. In contrast, the compound of this invention deviates from this expected relationship when its potency increased and its toxicity decreased relative to closely related analogs."

This sounds plausible. But, the "general literature" cited does not seem to exist. Parenthentically, I am a twice board-certified medical toxicologist.

Peter H. Proctor, PhD, MD

1) Hilton JG, Brown GL, Proctor PH, "Effects of superoxide dismutase and catalase on central nervous system toxicity of hyperbaric oxygen" Toxicol Appl Pharmacol. 1980 Mar 30;53(1):50-3.

2) Demopoulos, H. B., Flamm, E., Seligman, M,, and Pietronigro, D. D., "Oxygen free radicals in central nervous system ischaemia and trauma", in: Pathology of Oxygen, Autor, A. P., Ed., Academic Press, New York, 1982, 127.

3) McGinness, J.E., Proctor, P.H., Demopoulos, H.B., Hokansen, J.A. and Van, N.T. "In vivo evidence for superoxide and peroxide production by adriamycin and cis-platinum" In: Pathology of Oxygen. A. Autor, (Ed.). Academic Press, New York, 1982, pp. 191-202.

4) McGinness, J.E., Proctor, P.H., Demopoulos, H.B., Hokansen, J.A. and Kirkpatrick, D. S. Amelioration of cis-platinum nephrotoxicity by orgotein (superoxide dismutase). Physiol. Chem. and Phys. 10: 267-277, 1978.

CEROVIVE (NXY-059) is a registered trademark of the AstraZeneca group of companies.

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