Six weeks ago I posted on the apparent high quality of the research combined with an avowedly entrepenurial bent at the Stanford Pain Center http://paincenter.stanford.edu/ overseen by by Sean Mackey, MD, PhD, Chief, Pain Management Division. (Post # 10 (10.01.09) to the thread "I feel lost and alone after the specialist appointment" at http://neurotalk.psychcentral.com/thread104385.html)

So imagine my surprise when running Dr. Mackey's nmae through PubMed earlier today, and comming across one for the ages, which I either overlooked or had not been indexed at the time of my previous post:

Sympathetic block with botulinum toxin to treat complex regional pain syndrome, Carroll I, Clark JD, Mackey S, Ann Neurol. 2009 Mar;65(3):348-51, free full text at http://www.ncbi.nlm.nih.gov/pmc/arti...ihms140157.pdf

Department of Anesthesiology, Stanford University School of Medicine, Stanford, CA 94304-1573, USA. irc39@pain.stanford.edu

Abstract
Complex regional pain syndrome is a refractory pain condition with few tested therapies. We hypothesized that botulinum toxin A (BTA) would prolong analgesia after sympathetic blocks in patients with complex regional pain syndrome. We compared the duration of standard lumbar sympathetic block (LSB) with bupivacaine to LSB with bupivacaine and BTA in nine patients with refractory complex regional pain syndrome. Median time to analgesic failure was 71 (95% confidence interval, 12-253) days after LSB with BTA compared with fewer than 10 days (95% confidence interval, 0-12) after standard LSB (log-rank, p < 0.02). BTA profoundly prolonged the analgesia from sympathetic block in this preliminary study.

PMID: 19334078 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/1...m&ordinalpos=6

In the article, the authors explain how this unfunded pilot study took just under three years to recruit 9 subjects who met the author's rigidi includion criteria (essenetially people who had had lower extreimty CRPS-1 for at least six months, failed other therapies, and yet still had at least a 50% reduction im pain, lasting 4 or more hores to conventional sympathetic blocks) and while they hade been hoping for ten subjects, they finally cut it off at 9. And of those 9, only 7 of the subjects could be used in the end. Yet out of the 7, statistically significant results were obtained:

Primary End Point—The rate of pain return was significantly lower after LSB with BTAcompared with local anesthetic alone (Fig 1). Median time to analgesic failure was 71 (95% confidence interval, 12–253) days after LSB with BTA compared with fewer than 10 days (95% confidence interval, 0–12) among those receiving local anesthetic alone (log-rank, p < 0.02).

Secondary End Point—Botulinum toxin–enhanced sympathetic blockade was significantly more effective at reducing VAS pain scores over time than bupivacaine alone. Assignment to the BTA-enhanced LSB was associated with a mean decrease in VAS of 1.6 points (95% confidence interval, 1.2–2.0; p < 0.0001). However, among the more robust responders, the effect size was much larger (Fig 2).

Adverse Events—One patient experienced significant nausea and emesis that started 5 hours after her BTA injection and lasted 2 days; it resolved spontaneously.

http://www.ncbi.nlm.nih.gov/pmc/arti...ihms140157.pdf manuscript page 3.

The authors then go on to note, in part, that:

This study presents preliminary evidence that BTA-supplemented sympathetic blocks may represent a significant novel therapeutic modality for the treatment of sympathetically maintained pain in patients with highly refractory CRPS. Within the context of the otherwise limited options for patients with refractory CRPS, these findings are striking. The small number of patients in this study should be noted. A larger study is now warranted to further test the safety and efficacy of this procedure.

Botulinum toxin is generally understood to be primarily, if not exclusively, a potent inhibitor of release of acetylcholine from cholinergic nerves. This inhibition is long lasting but not permanent, and it does not result in cytotoxicity or neural loss. Inhibition of sympathetic nerve transmission at cholinergic sympathetic ganglia in the lumbar sympathetic chain may be
the mechanism of analgesia. [Citation omitted.]

Id.

So what's the Stanford UGLY? Something that appreared in the htlm copy of the article, but inexplicably didn't make it to the pdf file I've shared with you. Immediately after the Conclusion and before the References, the html copy has the following:

Footnotes

Potential conflict of interest: The authors report filing a patent for the use of botulinum toxins in sympathetic block.

Additional Supporting Information may be found in the online version of this article. [Empahsis added.]

http://www.ncbi.nlm.nih.gov/pmc/arti...ool=pubmed#FN3

Here the good doctors come up with this potentially useful technique and then they patent it, so that anyone elese who uses it has to pay them an agreed royalty. Fortunately, the whole question of the ability to patent "processes" is currently before the Supreme Court. See, The Supreme Court, Process Patents, and Medical Innovation, Aaron S. Kesselheim, M.D., J.D., M.P.H, New England Journal of Medicine http://content.nejm.org/cgi/content/...9658?query=TOC November 18, 2009 (10.1056/NEJMp0909658):

On November 9, the U.S. Supreme Court heard oral arguments in Bilski v. Kappos, one of the most closely watched cases in the Court's current term. The central question involves the legitimacy of a patent on a method for hedging risk in commodities trading, but the outcome will have important implications for health care delivery and research. Although patents covering medicines, devices, and research targets such as DNA sequences have become commonplace, in recent years there has been a surge in new patents on medical processes. Patents have been awarded for processes such as making diagnoses, performing surgery, making prescribing decisions, and other methods for treating patients and engaging in research. The Bilski case represents the first time in nearly three decades that the Supreme Court has considered the standard for issuing process patents. . . . [Footnote omitted.]

You can read the transcript of the Court's November 9, 2009 oral argument here:http://www.supremecourtus.gov/oral_a...pts/08-964.pdf What struck me in reading the transcript was that the government, which had won earlier when the lower appellate court had thrown out the patent, was (through its counsel) pretty well battered about by the Supreme Court, even though they didn't have any sympathy for the position of the would-be patent holder, suggesting that it would be unlikely for it to state a rule that would have broad ramifications, e.g., in the biomed world. For an extensive commentary to that effect, see, http://acslaw.org/node/14771 On the other hand, it could order the case re-argued, specifying the proposed (new) test it wished the parties to address, much as it did in the campaign financing case that was just reargued in September. We shall see.

Mike

And the plot thickens, huh ?

Small wonder that the patent bar thinks this full employment act is the greatest thing since sliced bread, which someone would have no doubt patented (using just a knife) had the law allowed it at the time.

Before touching on the perceptive comment of finz, it should be pointed out that the ethical issues raised in medical patents are perhaps best dealt with in a single page of the BRIEF OF AMICI CURIAE [Friends of the Court] AMERICAN MEDICAL ASSOCIATION, THE AMERICAN COLLEGE OF MEDICAL GENETICS, THE AMERICAN SOCIETY OF HUMAN GENETICS, THE ASSOCIATION OF PROFESSORS OF HUMAN AND MEDICAL GENETICS, AND MAYO CLINIC IN SUPPORT OF RESPONDENTS [essentially the U.S. Patent and Trademark Office, which began the saga at issue in Bilski v. Kappos by denying the requested patent]. Because the filed brief is a public record, and as such not susceptible to copywrite, that (small) page is cited in full, as follows:

1. Patents on Scientific Principles Raise Ethical Concerns for Physicians

Physicians have longstanding ethical obligations to advance and share useful medical knowledge with patients and physicians. Principle V of the AMA’s Principles of Medical Ethics states that a “physician shall continue to study, apply and advance scientific knowledge,” and “make relevant information available to patients, colleagues, and the public.”3 Opinion 9.08 of the Code of Medical Ethics of the AMA elaborates upon this basic principle:

Physicians have an obligation to share their knowledge and skills and to report the results of clinical and laboratory research. . . . The intentional withholding of new medical knowledge, skills and techniques from colleagues for reasons of personal gain is detrimental to the medical profession and to society and is to be condemned.4

Discovery of a basic scientific principle that could be useful to others in devising medical applications or to physicians in diagnosing and treating patients is a quintessential example of the kind of medical knowledge that physicians are obliged to share freely. To interpret the patent laws to make scientific principles eligible for patent protection threatens to undermine, rather than promote, the ethical practice of medicine. [p. 14; emphasis added.]
____________
3 Available at http://www.ama-assn.org/ama/pub/cate...2.<br /> html (last visited April 5, 2009).
4 Available at http://www.ama-assn.org/ama1/pub/upl.../ceja_3i07.pdf (last visited April 5, 2009).

http://www.abanet.org/publiced/previ...edicalGrps.pdf [URLs to footnotes in Amici brief as maintained on ABA site do not appear to be working.]

Moreover, it was only after reviewing this brief that I understood why some of the justices had been giving the government's lawyer such a rough going over when he was merely calling on the Court to affirm the Federal Circuit's “machine or transformation” test that had been employed against a patent that all members of the Court (except the unspeaking Justice Thomas) clearly found objectionable. It was because in an earlier case, Laboratory Corp. of Am. Holdings v. Metabolite Labs., Inc., 548 U.S. 124 (2006) the Federal Circuit had held patent on a blood test extended to all use of general knowledge derived from test, and specifically to an observed correlation between a blood test report and a patients health, under the same “machine or transformation” test, and subsequently after the Supreme Court agreed to review the case, it changed it's mind over the strong dissent of Justices Stevens, Breyer and Souter and dismissed the appeal.

Now, finz speaks of the plot thickening, and does it ever. For in the first pages of the Amici brief, the Supreme Court is informed that a Mayo Clinic entity just lost an indistiguishable case before the Federal Circuit, in September of this year, where the appellate court also relied on its interpretation of the "machine or transformation” test. So what these folks are telling the Supreme Court is, in effect, "don't think you can get away with a simple rejection of the would-be patent holders' claims through an application of the 'machine or transformation' test, because if you do, we have another case teed up for next year's docket."

Mike

This brings to mind the two Canadian doctor's who discovered that botox had significant applications for cosmetic purposes, Dr. Jean Carruthers & Dr. Alastair Carruthers. I don't know what the ethical obligations of Canadian doctors are but I assume it is much the same as the AMA. I read an interview with this dynamic duo where they discussed this very issue. Early on in their discovery they made a conscious decision to share the information with the medical world without applying for a patent. Ultimately they decided that it was the right thing to do despite the fact that they knew they would not make money off it once the information was released.

Is it the simply smell of money behind this or is it the laws that allow the arguments to be put forth? Perhaps it's both?

It certainly brings up some important questions. Would doctors & researchers be more inclined to look for more treatments such as this if there is more financial incentive in it for them personally?

If two doctors can give up their financial rights for the sake of a wrinkle free world surely a few doctors can share this information for the sake of patients experiencing refractory pain like CRPS.

This is very interesting information Mike, thanks for posting.

MsL

So the two Canadian doctors who had discovered the cosmetic use of what became to be known as Botox had intentionally foresworn a patent (which would now be highly valued) in the belief that their discovery should be freely available to all. And now we have pain management physicians at Stanford placing a patent on the use of the same drug in a purely palliative procedure.

That is quite the coda! Thank you.

Mike

PS Any further answer to your question as to this phenomena arising out of the nature of the law, where the patent statute in the U.S. hasn't changed in any material fashion since 1952, would require an examination of the composition of the Federal Circuit Court of Appeals, which oversees it. I suspect - but do not know - that such an examination would show a greater swing towards "free market oriented judges" on that court over the last decade or so.

Hi Mike,

Below is the quote from the article written about these two doctors last June.

It was quite a few months back that I had read this so I didn't recall all the the details about the patent. It appears that the loss of the patent rights ultimately boiled down to incorrect legal advice.

Here is a link to the full article if you are interested. http://www.vanmag.com/News_and_Featu...eep?page=0%2C0

Thanks very much for bringing this small but highly interesting study to our attention.

MsL