- Email: [email protected]
Temozolomide
C H A P T E R
6 Temozolomide: Patents and the Perils of Invention Malcolm F.G. Stevens Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK
INTRODUCTION A fortunate inventor involved in the discovery and development of a drug that actually makes it to market usually moves on in their career and loses interest in the drama of what happened often decades earlier. The welcome receipt of a slice, a small percentage, from a royalty stream, shared with former colleagues, reminds him of the successful journey accomplished against all odds. But it doesn't prepare him for an interrogative ordeal where his very integrity as a dedicated and responsible scientist is challenged. This saga can be considered to start in November 1976, with a draft agreement between Aston University, Birmingham, United Kingdom, and the research director (Dr Kenneth Wooldridge) of May & Baker Ltd, a pharmaceutical company based in Dagenham, Essex, United Kingdom, to fund a postgraduate student under the CASE Scheme (Collaborative Award in Science and Technology) operated by the then UK Science Research Council. The project was originally designed to investigate cyclic compounds with multiple nitrogen atoms that might have antiallergic activity: this disease area was a therapeutic target of May & Baker at that time, but abandoned soon after. A tenet of this scheme was that the postgraduate student would be based primarily in the Pharmacy Department of the university but spend a 3-month secondment in the company working with industrial colleagues: importantly, under the scheme, the company would be responsible for all intellectual property (IP) issues and the prosecution of patents. Accordingly, Robert Stone was appointed to the May & Baker Studentship and started work in the autumn of 1978. By early 1980, the first syntheses of examples of the new ring system imidazo[5,1-d]-1,2,3,5-tetrazine, with intriguing chemical properties, had been achieved by what has become known as the “Stone synthesis” [1]. An entry in a May & Baker laboratory book records that Stone, when working in Dagenham under the supervision of Dr Eddy Lunt, first synthesized the 3-methyl analog (temozolomide) on 29 April 1980. The first paper Cancer Drug Design and Discovery, Second Edition http://dx.doi.org/10.1016/B978-0-12-396521-9.00006-1
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revealing the synthesis and properties of imidazotetrazines was published in 1984 [1]. The US Food and Drug Administration (FDA) granted a first approval for the treatment of refractory anaplastic astrocytoma in the United States in 1999, and the drug was subsequently marketed by Schering-Plough as a treatment for glioblastoma multiforme in Europe (Temodal™) and in the United States (as Temodar™) (see Chapter 5 for a fuller account of the discovery and development of the drug and photographs of some of the Aston team). Temozolomide has occupied a niche market in cancer chemotherapy, being the only approved drug at the time for this condition, and by 2008 sales of the drug broached the “blockbuster” barrier, exceeding US$1000 million per annum. It was an unlikely, and quite unexpected, outcome; but this success inevitably attracted the interest of predators anxious for their cut of the cash flow, and a challenge to the US patent protecting the temozolomide invention was duly launched in 2007 by Barr Laboratories, Inc., which filed an Abbreviated New Drug Application (ANDA) to launch a generic version of temozolomide on the US market. Cancer Research Technology (CRT, formerly CRCT; the technology transfer arm of the UK charity Cancer Research UK, formerly Cancer Research Campaign), which was the patent assignee, and Schering-Plough, which was the licensee, sued. So, just when pleasant memories of a rewarding roller-coaster ride had started to fade, this coinventor was wrenched from a state of agreeable and genteel post-Hayflick decline to face an ordeal before a judge in a foreign court, to account for every word and action even three decades earlier, where a wrongly chosen word could jeopardize a successful commercial operation and blight a personal reputation established over half a century. To add insult to injury, a comprehensive archive of laboratory books, references, reports, legal documents, notes, and correspondence, assiduously preserved intact despite many office moves and career changes, were to be used as ammunition by the opposition.
HISTORY OF US PATENT 5,260,291 (1993) The priority date claiming rights to the temozolomide invention was established by the f iling of a UK application on 24 August 1981. The US patent, titled “Tetrazine Derivatives” (Fig. 6.1) and composed by Mr Terry Miller, the patent manager at May & Baker, was filed in 1982. The patent, at only nine pages, was a masterpiece of economical writing. It exemplified the synthesis of just 13 novel structures (Fig. 6.2) and described their antitumor properties against some of the mouse tumor models of the day—TLX5 lymphoma, leukemia L1210, and B16 melanoma, for example. In wordings that proved to be controversial in court, these compounds were described as “important” and possessing “valuable antineoplastic activity”. The compound identified by formula 8-carbamoyl-3-methyl-[3H]-imidazo[5,1-d]-1,2,3, 5-tetrazin-4-one (temozolomide) was highlighted as being “of particular importance,” and the 3-(2-chloroethyl) analog (mitozolomide) especially so. After 1981, patents were granted expeditiously in major national jurisdictions where the patent life was triggered on initial filing. However, in a fact overlooked by the court, patent approval was also completed in Canada (1985), which had a similar policy to that in the United States at the time, in that the patent clock commenced ticking on grant. The progress to granting of the US patent had many elements of a soap opera: the initial application was rejected by the US examiner in 1983 on the grounds of “lack of utility”, asserting that
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History of US Patent 5,260,291 (1993)
FIGURE 6.1 US Patent 5,260,291.
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FIGURE 6.2 Novel structures described in US Patent 5,260,291.
the invention should include clinical data in humans and that no such data were included. Mitozolomide entered phase I trials only in 1983. In a perfectly legal tactic, May & Baker abandoned the parent case and filed a continuation; the same examiner reiterated his original rejection. Again, no response was forthcoming, but instead May & Baker abandoned the parent case and filed another continuation. In a corporate complication, May & Baker (through their parent company, Rhône-Poulenc) abandoned the tetrazine project in the mid-1980s, when trials on mitozolomide indicated that only sporadic antitumor activities could be discerned, and then only at unacceptable toxicity levels. This notwithstanding, Miller, concerned that the invention had, in the main, been engendered by ideas from the University of Aston, on his own initiative continued the “ping-pong” duel with the US examiner: in total, over a 10-year period, 10 continuations were filed in response to the lack-of-utility rejoinder. After the demise of mitozolomide in 1985, clinical attention switched to temozolomide, which entered clinical trial in 1987 under the auspices of the Cancer Research Campaign Phase I Committee. When clear evidence of safety and modest clinical activity, especially against brain tumors and melanoma, emerged, in 1991 May & Baker transferred the tetrazine IP estate to CRCT, which, as assignee, took over responsibility for bringing the vexed and unresolved matter of the US application to a conclusion. As was testified in court by Dr Sue Foden, then CEO of CRCT, to make temozolomide available for cancer patients, it was considered essential to have the manufacturing and marketing clout of a global pharmaceutical company on board, and that a granted US patent would be an essential requirement to secure a deal. In a considerable coup for CRCT and its 2.5 employees at the time, a license agreement was negotiated with Schering-Plough in 1992 following a “road show” to several companies in the United States. A successful substantive response to a new examiner claimed that applicants did not need to provide data on clinical efficacy and that animal test data alone were sufficient. Such thorough animal data were noted by the examiner in a 1987 paper by the Aston/May & Baker team [2]. On this basis, the examiner mailed a “notice of allowability”, and the US patent was duly issued on 9 November 1993, 11 years after the first application. The name of an extra inventor, Dr Edward Newlands, was added to reflect his pivotal role in
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the preclinical and clinical development of both mitozolomide and temozolomide. In 1999, Schering-Plough filed successfully for a patent term extension, which added 1006 days to the patent's term; the patent was also granted a pediatric exclusivity period and is due to expire in February 2014, some 34 years after the initial synthesis of the drug.
CANCER RESEARCH TECHNOLOGY LTD ET AL. (PLAINTIFFS) VS BARR LABORATORIES INC. ET AL. (DEFENDANTS) In advance of the trial, fact witnesses may be required to undergo a deposition, which involves answering questions from counsel for the defendants that they deem necessary to establish any facts they consider relevant to the upcoming trial. For inventor Stevens, this event took place in New York in June 2008 and lasted a full day. It was pointed out by plaintiff's counsel that a case “cannot be won on deposition, but can be lost.” The core of the questioning by Barr's counsel concerned the provenance of the new compounds, their screening, and, significantly, their structural relationships to dimethyltriazenes (see Chapter 5 for structures), which are well-known in the chemical and biological literature, especially their propensity to undergo metabolic activation to cytotoxic and mutagenic species [3]. A particular focus on the antimelanoma drug dacarbazine (DTIC) carried the implication that Barr was building a case to challenge the patent on the grounds of “obviousness”, and that an expert medicinal chemist, given access to all published work in the field, pen, and paper, could have independently designed the same compounds. If only it were that easy! However, nothing in the published work of the Aston team in the 1970s indicated that the imidazotetrazines were in any way conceived as stable variants of MTIC, the ring-opened form of DTIC. Chemical inquisitiveness was the sole motivating factor, and it was only after the postdiscovery phase of the project that the ring-opening relationship with imidazotriazenes was revealed. In another tack, counsel for Barr posited the belief that hydrolytic ring opening of tetrazinones would be “expected”. Unfortunately for his argument, the only example he highlighted was that of a monocyclic 1,2,4,5-tetrazinone, not a bicyclic 1,2,3,5-tetrazinone. Chemists will know they are like chalk and cheese. After this initial skirmish, and to prepare for the real trial and counter the expected attack on “obviousness”, this inventor spent many days familiarizing himself with the voluminous literature on dimethyltriazenes from the first publication of their antitumor properties in 1955 [4]. Box files full of reprints on triazenes, some hoarded lovingly for nearly 50 years, provided nostalgic reading; it was like being reunified with faded and dusty old friends. A telling quotation in a paper by Hansch [5] was held in reserve: “Unless one had new biochemical or molecular biological information suggesting that a new triazene might be more effective in some specific way, we would not recommend the synthesis and testing of new congeners.” Even more helpful was a comment in a 1986 paper by a competitor group [6] that mitozolomide was “ingeniously designed and synthesized”, words that would support the originality claims in US Patent 5,260,291. In any event, Barr dropped the “obviousness” slur and, in the run up to the trial in 2009, charged that the patent was unenforceable due to “prosecution laches”—the deliberate implementation of delaying tactics to extend the life of the patent— and the more personally menacing “inequitable conduct” by inventors and those responsible for prosecuting the patent.
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FIGURE 6.3 The courthouse in Wilmington, Delaware. (For color version of this figure, the reader is referred to the online version of this book.)
Other changes had taken place in advance of the trial: May & Baker's parent company Rhône-Poulenc had been reincarnated firstly as Rhône-Poulenc Rorer, then Aventis, and finally Sanofi Aventis; Barr Laboratories had been acquired by Teva Pharmaceuticals; and Schering-Plough had been acquired by Merck and Co. Inc. On the personal front, coinventors Wooldridge and Lunt and patent manager Miller had retired from May & Baker; and, sadly, Newlands was deceased. Stone, who had had no contact with the project since 1981 on completion of his PhD, was originally charged with “inequitable conduct”, but this was subsequently dropped. Stevens, whose academic positions had given him the privilege of continuous tenure during the history of the temozolomide story, was confident he had a compelling story to convey to the court as the protagonists assembled in the US District Court for the District of Delaware (Fig. 6.3) on 20 July 2009. For Barr to succeed in its challenge, only one individual had to be successfully charged with “inequitable conduct”, but they had to prove that there was an “intent to deceive” the US Patent and Trademark Office (PTO). As mentioned in this chapter, according to the terms of the CASE Award, May & Baker were to be responsible for all IP issues, including patents. Thus, apart from signing the US application in 1982 and ensuring that the compounds were correctly described and characterized (in some cases, by X-ray structures), Stevens had no further role in its prosecution; he was unaware until patent issuance in 1993 that there had been problems with US examiners. By the mid-1980s, mitozolomide had been abandoned by May & Baker, and there was every expectation that the orphaned temozolomide would suffer the same fate. His career had moved on to other research projects and the responsibility of headship of a large academic department in Aston University at a time of swingeing cuts—known locally as the “decade of the python”. He had no role in planning clinical trials or selecting clinicians to run them, on principle never visited wards where patients were treated, and to this day has only ever spoken to one patient treated with temozolomide. At meetings of the CRC Phase I Committee in the 1980s and early 1990s, he had to sign a declaration that on no account could any clinical information be communicated to third parties. Clinical “data”—that is, diagnostic tests, laboratory biochemical investigations, measurements taken at bedside, brain scans, and so on—were deemed to be utterly confidential to patients, clinicians, and the hospital concerned. He had no financial interest whatsoever in the success or otherwise of the project until after
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a deal was signed with Schering-Plough in 1992, and then only indirectly through an agreement between CRCT and Aston University. Of course, none of this cut any ice with Barr's counsel and, ominously, as the trial proceeded, inventor Stevens, the only one of those listed still on active service, found himself in the crosshairs. Barr's main line of attack was to invoke an applicant's continuing “duty of candor” in its dealings with the PTO and a “duty to disclose” to the PTO any information that may be “material” to the examination of the patent application. (Although this policy may be familiar to non-US laboratory scientists now, it was not in the 1980s.) But ignorance of the scope of these duties, and the severance of the conduit of information from Stevens→Lunt→Miller that had occurred when May & Baker relinquished all further interest in the commercialization of mitozolomide and temozolomide, did not, according to Barr, cancel the obligation on an inventor. In the patent, all 13 compounds were identified as being “important”. Barr asserted that this meant all the compounds had potentially valuable anticancer activity. Not so, claimed Miller: the word indicated that, as the first characterized examples of a novel structural type, they merited being so described. The use of this word was not to be confused with identification of the compounds temozolomide and mitozolomide as having “particular importance”, which did teach someone skilled in the art of drug discovery that this was where the seam of useful biological activity lay. Pursuing this line, counsel for Barr then produced several abstracts and publications that described antitumor evaluations of compounds against mouse tumors. Some compounds identified in the patent had T/C values ≤125%; these, by convention, were not considered as showing antitumor outcomes in the test. Several publications used the word “inactive” in such cases, but always in the context of a particular tumor, and not to imply inactivity against all tumors. (This point was reinforced by witness Dr Ed Sausville, formerly of the US National Cancer Institute, who explained that it was a normal outcome in drug discovery programs that compounds ineffective against one tumor may well have potent activity against a tumor of different lineage.) A lot of the court's time was spent arguing semantic points around the meaning of a compound being “active” or “inactive” in animal tests and how this information might be of value to the examiner. In exasperation, Miller did make the cutting comment that May & Baker had no intention of developing a drug to treat mouse cancer! Barr's case was that information from these animal tests—especially negative tests—was “material” and should have been conveyed to the examiner, who might then have made an earlier decision on grant or rejection, thus possibly allowing earlier launch of a generic product in the US market. Barr also contended that publications on the phase I studies on mitozolomide [7] and temozolomide [8] were “material” in that they revealed clinical information that would have been valuable to the examiner. In court, Stevens explained that he had no inputs into these trials but was listed as a “courtesy author” on the basis that it was reasonable that first clinical publications on a new drug should acknowledge the role of the originator of the product. His injudicious use of the word “disastrous” in deposition to describe the outcome of the phase I study on mitozolomide was claimed by Barr's counsel to indicate that he considered the trial a failure and that such a conclusion was “material” and should have been available to the examiner. However, the word “disastrous” was intended to refer to the extinguishing
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of the expectation of the inventors and their colleagues that the elusive “magic bullet” lay in their grasp and that immortalization in a Hollywood movie would surely follow. There was even a suggestion that Steve McQueen should be approached for a starring role! This hubristic fantasy had been sustained by the extraordinary, often curative efficacy of mitozolomide against transplanted mouse tumors [9]. (Actually, the mitozolomide phase I trial could have been considered a success as it did just what such trials are designed to accomplish: it defined a maximum tolerated dose and identified the dose-limiting toxicities; and clinicians keenly sought to be involved in phase II trials.) Also, it was explained to the court that this trial was not seeking to identify tumor responses and that the results were preliminary. Although evidence of tumor responses was reported, especially in the temozolomide phase I trial, it is a common experience in oncology trials that seemingly dramatic outcomes at phase I are unlikely to be repeated in formal efficacy trials against specific tumor types. When questioned in court about his role in the delay of issuance of the US patent, Miller claimed that his being “obdurate” was in response to the similar attitude of the examiner. (In a rare moment of humor appreciated by the court, Miller explained that the unfolding confrontation was an example of “Old Bird's Law” in action. This law, named after a senior colleague at May & Baker, posited thus: “By the time a US patent is granted, the company will have abandoned the project.”) How true in this case! Miller also robustly defended his actions on the grounds that he anticipated that the patent would be a significant contribution to cancer research. As subsequent history showed, his dogged persistence was of crucial significance in protecting the commercial standing of temozolomide and securing its availability for many thousands of patients with brain tumors. Toward the end of the trial, coinventor Stone took the stand and was able to describe his experiences as a postgraduate student at Aston University and working at May & Baker. He especially contrasted the rudimentary equipment and grim laboratories of the Pharmacy Department at Aston in the late 1970s with those of the modern institution in 2008. Much of the investment to finance the transformation was through royalties received by the university from sales of temozolomide. To Stone's disappointment, counsel for Barr declined to crossexamine him: at the very least, a congratulatory comment on his remarkable contribution to a rare event in drug discovery history—a marketed drug, and a blockbuster to boot—would not have gone amiss.
THE VERDICT Ignoring the fact that CRT (through CRCT) became involved with temozolomide in only 1991 (as discussed in this chapter), the court concluded that it didn't seek to develop the technology prior to the signing of the Schering-Plough license in 1992 (how could it?) and engaged with the PTO only when it had a “profit motive” for doing so. The court also concluded that Stevens withheld information on inactivity data in animal studies, and clinical results in humans that it considered were “highly material”. The fact that he and his colleagues had authored some 40 publications on antitumor imidazotetrazines, many in American journals, to the wider scientific community over the period in question was, perversely, taken as evidence from which to infer an “intent to deceive”. In pronouncing its verdict in January 2010, the court found CRT's conduct sufficiently egregious to warrant rendering US
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The Appeal(s)
FIGURE 6.4 Bridge over the Garonne in Toulouse, France. (For color version of this figure, the reader is referred to the online version of this book.)
Patent 5,260,291 unenforceable due to “prosecution laches”, and found that Stevens committed “inequitable conduct” for disclosure failures with intent to deceive. The bad news was conveyed to Stevens when he was attending the winter meeting of the European Organisation for the Research and Treatment of Cancer (EORTC) Pharmacology and Molecular Mechanisms (PAMM) group's meeting in Toulouse, France. It was a bitter and humiliating blow, and his blood ran cooler than the icy waters of the river Garonne. But for the steadying support of Secretary Nicola Thomas back in the office, the bridge over the river (Fig. 6.4) might have witnessed a dramatic end to his ordeal. Had the CRT vs Barr tussle been a soccer match, then the score at this point would have been Barr-2: CRT-0. But, in a surprise decision in February 2010, the judge granted a temporary restraining order (TRO) preventing Barr (Teva) from launching generic temozolomide on the US market until an appeal before the Federal Circuit Court of Appeals in Washington, DC, had been heard. For the appeal to be successful, it would be necessary for lawyers for CRT to convince two of the three judges to overturn both “prosecution laches” and “inequitable conduct” decisions. Only legal issues could be argued, and no new evidence presented.
THE APPEAL(S) The US Appeals Court, in its judgment on 9 November 2010, took the view that CRT could not possibly develop and market temozolomide in the United States until ScheringPlough became its licensee, but on securing that liaison speedily moved to secure issuance of its patent. The public interest was secured by the fact that CRT did make the product available for treating cancer patients, and it should not lose that protection because patent issuance was delayed. In the view of the appeals court, Barr had not “invested in temozolomide or any other claimed tetrazine compound between 1982 and 1991, the period of the delay”. By a 2:1 majority, they concluded that the district court committed legal error in holding the patent unenforceable for “prosecution laches” and overturned the original decision.
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The appeals court also determined that nothing in Stevens's widespread publication of data in the world literature “evidences wrongful intent, but rather the opposite, extreme candor”. They also agreed with CRT that the district court erred in finding that Stevens intended to deceive the PTO by not disclosing data on the claimed compounds and thereby relied solely on its finding of materiality to infer intent. Again, by a 2:1 majority they reversed the district court's decision, holding the patent unenforceable for “inequitable conduct”. So the final score was Barr-2: CRT-2, but as the Federal Circuit Appeals Court decision trumped that of the district court, CRT prevailed on what would be, in soccer parlance, the “away-goals-count-double” rule. There was one final twist: because the decision of the appeals court was not unanimous, Barr sought leave to appeal to the US Supreme Court. This was rejected.
CONCLUSIONS It could be argued that many drug discoverers would positively welcome the opportunity to sit in the hot seat in a foreign court to defend their actions in respect of a generic challenge to their patented invention. This scenario would happen only if their drug had achieved notable sales. But the charge of “inequitable conduct” does carry an unsavory taste, especially for researchers whose sole motivation is to do their best for patients. Fortunately in the present case, the taint was removed and the threat to a professional reputation nullified, but in other cases mud can stick. The circumstances surrounding the battle for the US patent protecting temozolomide are unlikely to be repeated since patent terms in the United States are now triggered from filing date. However, there are some lessons that could be learned by researchers lucky (or unlucky?) enough to follow a similar track: 1. Never use the words “active” or “inactive” in any publications or notes reporting biological tests on compounds. Perhaps the terms “prioritized” or “de-prioritized” would be less of a hostage to fortune, but even then a smart counsel might claim some hidden nuance in their meanings. 2. Always keep open the information trail between the laboratory bench and those prosecuting your patent: if in any doubt, disclose the most trivial of data, even if you drive the patent examiner mad. 3. Be wary of agreeing to be a “courtesy author” on a publication where you have not contributed meaningfully to the work. In the 1980s this practice was widespread, but it leaves one open to a challenge in court that, as a listed author, one must somehow have complete knowledge of the totality of the contents of the publication. This is potentially hazardous for laboratory scientists appearing as coauthors on papers reporting clinical results. Some esteemed journals now require every author to make a declaration describing their contribution to the work, and this principle should become standard. “When it comes to apportioning credit, science could learn from the movies” [10]. 4. And, finally, be candid and publish because your own career and the careers of your colleagues depend on it. But prepare yourself to be damned.
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Acknowledgments Although this chapter is a personal account of a traumatic milestone in a career, it is also a heartwarming story of how a charity in the United Kingdom prevailed against the odds. The successful outcome of the trans-Atlantic battle for US Patent 5,260,291 could not have been achieved without the testimony of colleagues, some of whose contributions have been highlighted herein. The author would also like to express his thanks and admiration for the legal team of Ropes & Gray LLP led by Jesse Jenner, who spent 2 years mastering a complex brief spanning a third of a century, constructing a compelling case from naïve witnesses, and tutoring them in the do's and don’ts of court etiquette. They were such fun people to be with. But this witness found their instruction “No jokes, please” on the stand somewhat restrictive. Thanks are also due to legal representatives of CRT, Schering-Plough, and Merck & Co. who attended the trial in a supportive role. And—yes—Barr's counsel and interrogator-in-chief George Lombardi was polite and considerate at all times in his questioning. No hard feelings, George: we both know it was business.
References [1] Stevens MFG, Hickman JA, Stone R, Gibson NW, Baig GU, Lunt E, et al. Antitumour imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one, a novel broadspectrum antitumour agent. J Med Chem 1984;27:196–201. [2] Lunt E, Newton CJ, Smith C, Stevens GP, Stevens MFG, Straw CG, et al. Antitumor imidazotetrazines. 14. Synthesis and antitumor activity of 6- and 8-substituted imidazo[5,1-d]-1,2,3,5-tetrazinones. J Med Chem 1987;30:357–66. [3] Audette RCS, Connors TA, Mandel HG, Merai K, Ross WC. Studies on the mechanism of action of tumor inhibitory triazenes. Biochem Pharmacol 1973;22:1855–64. [4] Clark DA, Barclay RK, Stock CC, Rondestvedt CS. Triazenes as inhibitors of mouse sarcoma 180. Proc Soc Exp Biol Med 1955;90:484–9. [5] Hansch C, Hatheway CJ, Quinn FR, Greenberg N. Antitumour 1-(X-aryl)-3,3-dimethyltriazenes. 2. On the role of correlation analysis in decision making in drug modification. Toxicity quantitative structure-activity relationships of 1-(X-phenyl)-3,3-dialkyltriazenes in mice. J Med Chem 1978;21:574–7. [6] Cheng CC, Elslager EF, Werbel LM, Leopold III WR. Pyrazole derivatives 5. Synthesis and antineoplastic activity of 3-(2-chloroethyl)-3,4-dihydro-4-oxopyrazolo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide and related compounds. J Med Chem 1986;29:1544–7. [7] Newlands ES, Blackledge G, Slack JA, Goddard C, Brindley CJ, Holden L, et al. Phase 1 clinical trial of mitozolomide. Cancer Treat Rep 1985;69:801–5. [8] Newlands ES, Blackledge GRP, Slack JA, Rustin GJ, Smith DB, Stuart NS, et al. Phase 1 clinical trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 1992;65:287–91. [9] Hickman JA, Stevens MFG, Gibson NW, Langdon SP, Fizames C, Lavelle F, et al. Experimental anti-tumor activity against murine tumor model systems of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin4(3H)-one (mitozolomide), a novel broad-spectrum agent. Cancer Res 1985;45:3008–13. [10] Frische S. It is time for full disclosure of author contributions. Nature 2012;489:475.
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6 Temozolomide: Patents and the Perils of Invention Malcolm F.G. Stevens Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK
INTRODUCTION A fortunate inventor involved in the discovery and development of a drug that actually makes it to market usually moves on in their career and loses interest in the drama of what happened often decades earlier. The welcome receipt of a slice, a small percentage, from a royalty stream, shared with former colleagues, reminds him of the successful journey accomplished against all odds. But it doesn't prepare him for an interrogative ordeal where his very integrity as a dedicated and responsible scientist is challenged. This saga can be considered to start in November 1976, with a draft agreement between Aston University, Birmingham, United Kingdom, and the research director (Dr Kenneth Wooldridge) of May & Baker Ltd, a pharmaceutical company based in Dagenham, Essex, United Kingdom, to fund a postgraduate student under the CASE Scheme (Collaborative Award in Science and Technology) operated by the then UK Science Research Council. The project was originally designed to investigate cyclic compounds with multiple nitrogen atoms that might have antiallergic activity: this disease area was a therapeutic target of May & Baker at that time, but abandoned soon after. A tenet of this scheme was that the postgraduate student would be based primarily in the Pharmacy Department of the university but spend a 3-month secondment in the company working with industrial colleagues: importantly, under the scheme, the company would be responsible for all intellectual property (IP) issues and the prosecution of patents. Accordingly, Robert Stone was appointed to the May & Baker Studentship and started work in the autumn of 1978. By early 1980, the first syntheses of examples of the new ring system imidazo[5,1-d]-1,2,3,5-tetrazine, with intriguing chemical properties, had been achieved by what has become known as the “Stone synthesis” [1]. An entry in a May & Baker laboratory book records that Stone, when working in Dagenham under the supervision of Dr Eddy Lunt, first synthesized the 3-methyl analog (temozolomide) on 29 April 1980. The first paper Cancer Drug Design and Discovery, Second Edition http://dx.doi.org/10.1016/B978-0-12-396521-9.00006-1
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revealing the synthesis and properties of imidazotetrazines was published in 1984 [1]. The US Food and Drug Administration (FDA) granted a first approval for the treatment of refractory anaplastic astrocytoma in the United States in 1999, and the drug was subsequently marketed by Schering-Plough as a treatment for glioblastoma multiforme in Europe (Temodal™) and in the United States (as Temodar™) (see Chapter 5 for a fuller account of the discovery and development of the drug and photographs of some of the Aston team). Temozolomide has occupied a niche market in cancer chemotherapy, being the only approved drug at the time for this condition, and by 2008 sales of the drug broached the “blockbuster” barrier, exceeding US$1000 million per annum. It was an unlikely, and quite unexpected, outcome; but this success inevitably attracted the interest of predators anxious for their cut of the cash flow, and a challenge to the US patent protecting the temozolomide invention was duly launched in 2007 by Barr Laboratories, Inc., which filed an Abbreviated New Drug Application (ANDA) to launch a generic version of temozolomide on the US market. Cancer Research Technology (CRT, formerly CRCT; the technology transfer arm of the UK charity Cancer Research UK, formerly Cancer Research Campaign), which was the patent assignee, and Schering-Plough, which was the licensee, sued. So, just when pleasant memories of a rewarding roller-coaster ride had started to fade, this coinventor was wrenched from a state of agreeable and genteel post-Hayflick decline to face an ordeal before a judge in a foreign court, to account for every word and action even three decades earlier, where a wrongly chosen word could jeopardize a successful commercial operation and blight a personal reputation established over half a century. To add insult to injury, a comprehensive archive of laboratory books, references, reports, legal documents, notes, and correspondence, assiduously preserved intact despite many office moves and career changes, were to be used as ammunition by the opposition.
HISTORY OF US PATENT 5,260,291 (1993) The priority date claiming rights to the temozolomide invention was established by the f iling of a UK application on 24 August 1981. The US patent, titled “Tetrazine Derivatives” (Fig. 6.1) and composed by Mr Terry Miller, the patent manager at May & Baker, was filed in 1982. The patent, at only nine pages, was a masterpiece of economical writing. It exemplified the synthesis of just 13 novel structures (Fig. 6.2) and described their antitumor properties against some of the mouse tumor models of the day—TLX5 lymphoma, leukemia L1210, and B16 melanoma, for example. In wordings that proved to be controversial in court, these compounds were described as “important” and possessing “valuable antineoplastic activity”. The compound identified by formula 8-carbamoyl-3-methyl-[3H]-imidazo[5,1-d]-1,2,3, 5-tetrazin-4-one (temozolomide) was highlighted as being “of particular importance,” and the 3-(2-chloroethyl) analog (mitozolomide) especially so. After 1981, patents were granted expeditiously in major national jurisdictions where the patent life was triggered on initial filing. However, in a fact overlooked by the court, patent approval was also completed in Canada (1985), which had a similar policy to that in the United States at the time, in that the patent clock commenced ticking on grant. The progress to granting of the US patent had many elements of a soap opera: the initial application was rejected by the US examiner in 1983 on the grounds of “lack of utility”, asserting that
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History of US Patent 5,260,291 (1993)
FIGURE 6.1 US Patent 5,260,291.
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FIGURE 6.2 Novel structures described in US Patent 5,260,291.
the invention should include clinical data in humans and that no such data were included. Mitozolomide entered phase I trials only in 1983. In a perfectly legal tactic, May & Baker abandoned the parent case and filed a continuation; the same examiner reiterated his original rejection. Again, no response was forthcoming, but instead May & Baker abandoned the parent case and filed another continuation. In a corporate complication, May & Baker (through their parent company, Rhône-Poulenc) abandoned the tetrazine project in the mid-1980s, when trials on mitozolomide indicated that only sporadic antitumor activities could be discerned, and then only at unacceptable toxicity levels. This notwithstanding, Miller, concerned that the invention had, in the main, been engendered by ideas from the University of Aston, on his own initiative continued the “ping-pong” duel with the US examiner: in total, over a 10-year period, 10 continuations were filed in response to the lack-of-utility rejoinder. After the demise of mitozolomide in 1985, clinical attention switched to temozolomide, which entered clinical trial in 1987 under the auspices of the Cancer Research Campaign Phase I Committee. When clear evidence of safety and modest clinical activity, especially against brain tumors and melanoma, emerged, in 1991 May & Baker transferred the tetrazine IP estate to CRCT, which, as assignee, took over responsibility for bringing the vexed and unresolved matter of the US application to a conclusion. As was testified in court by Dr Sue Foden, then CEO of CRCT, to make temozolomide available for cancer patients, it was considered essential to have the manufacturing and marketing clout of a global pharmaceutical company on board, and that a granted US patent would be an essential requirement to secure a deal. In a considerable coup for CRCT and its 2.5 employees at the time, a license agreement was negotiated with Schering-Plough in 1992 following a “road show” to several companies in the United States. A successful substantive response to a new examiner claimed that applicants did not need to provide data on clinical efficacy and that animal test data alone were sufficient. Such thorough animal data were noted by the examiner in a 1987 paper by the Aston/May & Baker team [2]. On this basis, the examiner mailed a “notice of allowability”, and the US patent was duly issued on 9 November 1993, 11 years after the first application. The name of an extra inventor, Dr Edward Newlands, was added to reflect his pivotal role in
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the preclinical and clinical development of both mitozolomide and temozolomide. In 1999, Schering-Plough filed successfully for a patent term extension, which added 1006 days to the patent's term; the patent was also granted a pediatric exclusivity period and is due to expire in February 2014, some 34 years after the initial synthesis of the drug.
CANCER RESEARCH TECHNOLOGY LTD ET AL. (PLAINTIFFS) VS BARR LABORATORIES INC. ET AL. (DEFENDANTS) In advance of the trial, fact witnesses may be required to undergo a deposition, which involves answering questions from counsel for the defendants that they deem necessary to establish any facts they consider relevant to the upcoming trial. For inventor Stevens, this event took place in New York in June 2008 and lasted a full day. It was pointed out by plaintiff's counsel that a case “cannot be won on deposition, but can be lost.” The core of the questioning by Barr's counsel concerned the provenance of the new compounds, their screening, and, significantly, their structural relationships to dimethyltriazenes (see Chapter 5 for structures), which are well-known in the chemical and biological literature, especially their propensity to undergo metabolic activation to cytotoxic and mutagenic species [3]. A particular focus on the antimelanoma drug dacarbazine (DTIC) carried the implication that Barr was building a case to challenge the patent on the grounds of “obviousness”, and that an expert medicinal chemist, given access to all published work in the field, pen, and paper, could have independently designed the same compounds. If only it were that easy! However, nothing in the published work of the Aston team in the 1970s indicated that the imidazotetrazines were in any way conceived as stable variants of MTIC, the ring-opened form of DTIC. Chemical inquisitiveness was the sole motivating factor, and it was only after the postdiscovery phase of the project that the ring-opening relationship with imidazotriazenes was revealed. In another tack, counsel for Barr posited the belief that hydrolytic ring opening of tetrazinones would be “expected”. Unfortunately for his argument, the only example he highlighted was that of a monocyclic 1,2,4,5-tetrazinone, not a bicyclic 1,2,3,5-tetrazinone. Chemists will know they are like chalk and cheese. After this initial skirmish, and to prepare for the real trial and counter the expected attack on “obviousness”, this inventor spent many days familiarizing himself with the voluminous literature on dimethyltriazenes from the first publication of their antitumor properties in 1955 [4]. Box files full of reprints on triazenes, some hoarded lovingly for nearly 50 years, provided nostalgic reading; it was like being reunified with faded and dusty old friends. A telling quotation in a paper by Hansch [5] was held in reserve: “Unless one had new biochemical or molecular biological information suggesting that a new triazene might be more effective in some specific way, we would not recommend the synthesis and testing of new congeners.” Even more helpful was a comment in a 1986 paper by a competitor group [6] that mitozolomide was “ingeniously designed and synthesized”, words that would support the originality claims in US Patent 5,260,291. In any event, Barr dropped the “obviousness” slur and, in the run up to the trial in 2009, charged that the patent was unenforceable due to “prosecution laches”—the deliberate implementation of delaying tactics to extend the life of the patent— and the more personally menacing “inequitable conduct” by inventors and those responsible for prosecuting the patent.
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FIGURE 6.3 The courthouse in Wilmington, Delaware. (For color version of this figure, the reader is referred to the online version of this book.)
Other changes had taken place in advance of the trial: May & Baker's parent company Rhône-Poulenc had been reincarnated firstly as Rhône-Poulenc Rorer, then Aventis, and finally Sanofi Aventis; Barr Laboratories had been acquired by Teva Pharmaceuticals; and Schering-Plough had been acquired by Merck and Co. Inc. On the personal front, coinventors Wooldridge and Lunt and patent manager Miller had retired from May & Baker; and, sadly, Newlands was deceased. Stone, who had had no contact with the project since 1981 on completion of his PhD, was originally charged with “inequitable conduct”, but this was subsequently dropped. Stevens, whose academic positions had given him the privilege of continuous tenure during the history of the temozolomide story, was confident he had a compelling story to convey to the court as the protagonists assembled in the US District Court for the District of Delaware (Fig. 6.3) on 20 July 2009. For Barr to succeed in its challenge, only one individual had to be successfully charged with “inequitable conduct”, but they had to prove that there was an “intent to deceive” the US Patent and Trademark Office (PTO). As mentioned in this chapter, according to the terms of the CASE Award, May & Baker were to be responsible for all IP issues, including patents. Thus, apart from signing the US application in 1982 and ensuring that the compounds were correctly described and characterized (in some cases, by X-ray structures), Stevens had no further role in its prosecution; he was unaware until patent issuance in 1993 that there had been problems with US examiners. By the mid-1980s, mitozolomide had been abandoned by May & Baker, and there was every expectation that the orphaned temozolomide would suffer the same fate. His career had moved on to other research projects and the responsibility of headship of a large academic department in Aston University at a time of swingeing cuts—known locally as the “decade of the python”. He had no role in planning clinical trials or selecting clinicians to run them, on principle never visited wards where patients were treated, and to this day has only ever spoken to one patient treated with temozolomide. At meetings of the CRC Phase I Committee in the 1980s and early 1990s, he had to sign a declaration that on no account could any clinical information be communicated to third parties. Clinical “data”—that is, diagnostic tests, laboratory biochemical investigations, measurements taken at bedside, brain scans, and so on—were deemed to be utterly confidential to patients, clinicians, and the hospital concerned. He had no financial interest whatsoever in the success or otherwise of the project until after
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a deal was signed with Schering-Plough in 1992, and then only indirectly through an agreement between CRCT and Aston University. Of course, none of this cut any ice with Barr's counsel and, ominously, as the trial proceeded, inventor Stevens, the only one of those listed still on active service, found himself in the crosshairs. Barr's main line of attack was to invoke an applicant's continuing “duty of candor” in its dealings with the PTO and a “duty to disclose” to the PTO any information that may be “material” to the examination of the patent application. (Although this policy may be familiar to non-US laboratory scientists now, it was not in the 1980s.) But ignorance of the scope of these duties, and the severance of the conduit of information from Stevens→Lunt→Miller that had occurred when May & Baker relinquished all further interest in the commercialization of mitozolomide and temozolomide, did not, according to Barr, cancel the obligation on an inventor. In the patent, all 13 compounds were identified as being “important”. Barr asserted that this meant all the compounds had potentially valuable anticancer activity. Not so, claimed Miller: the word indicated that, as the first characterized examples of a novel structural type, they merited being so described. The use of this word was not to be confused with identification of the compounds temozolomide and mitozolomide as having “particular importance”, which did teach someone skilled in the art of drug discovery that this was where the seam of useful biological activity lay. Pursuing this line, counsel for Barr then produced several abstracts and publications that described antitumor evaluations of compounds against mouse tumors. Some compounds identified in the patent had T/C values ≤125%; these, by convention, were not considered as showing antitumor outcomes in the test. Several publications used the word “inactive” in such cases, but always in the context of a particular tumor, and not to imply inactivity against all tumors. (This point was reinforced by witness Dr Ed Sausville, formerly of the US National Cancer Institute, who explained that it was a normal outcome in drug discovery programs that compounds ineffective against one tumor may well have potent activity against a tumor of different lineage.) A lot of the court's time was spent arguing semantic points around the meaning of a compound being “active” or “inactive” in animal tests and how this information might be of value to the examiner. In exasperation, Miller did make the cutting comment that May & Baker had no intention of developing a drug to treat mouse cancer! Barr's case was that information from these animal tests—especially negative tests—was “material” and should have been conveyed to the examiner, who might then have made an earlier decision on grant or rejection, thus possibly allowing earlier launch of a generic product in the US market. Barr also contended that publications on the phase I studies on mitozolomide [7] and temozolomide [8] were “material” in that they revealed clinical information that would have been valuable to the examiner. In court, Stevens explained that he had no inputs into these trials but was listed as a “courtesy author” on the basis that it was reasonable that first clinical publications on a new drug should acknowledge the role of the originator of the product. His injudicious use of the word “disastrous” in deposition to describe the outcome of the phase I study on mitozolomide was claimed by Barr's counsel to indicate that he considered the trial a failure and that such a conclusion was “material” and should have been available to the examiner. However, the word “disastrous” was intended to refer to the extinguishing
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of the expectation of the inventors and their colleagues that the elusive “magic bullet” lay in their grasp and that immortalization in a Hollywood movie would surely follow. There was even a suggestion that Steve McQueen should be approached for a starring role! This hubristic fantasy had been sustained by the extraordinary, often curative efficacy of mitozolomide against transplanted mouse tumors [9]. (Actually, the mitozolomide phase I trial could have been considered a success as it did just what such trials are designed to accomplish: it defined a maximum tolerated dose and identified the dose-limiting toxicities; and clinicians keenly sought to be involved in phase II trials.) Also, it was explained to the court that this trial was not seeking to identify tumor responses and that the results were preliminary. Although evidence of tumor responses was reported, especially in the temozolomide phase I trial, it is a common experience in oncology trials that seemingly dramatic outcomes at phase I are unlikely to be repeated in formal efficacy trials against specific tumor types. When questioned in court about his role in the delay of issuance of the US patent, Miller claimed that his being “obdurate” was in response to the similar attitude of the examiner. (In a rare moment of humor appreciated by the court, Miller explained that the unfolding confrontation was an example of “Old Bird's Law” in action. This law, named after a senior colleague at May & Baker, posited thus: “By the time a US patent is granted, the company will have abandoned the project.”) How true in this case! Miller also robustly defended his actions on the grounds that he anticipated that the patent would be a significant contribution to cancer research. As subsequent history showed, his dogged persistence was of crucial significance in protecting the commercial standing of temozolomide and securing its availability for many thousands of patients with brain tumors. Toward the end of the trial, coinventor Stone took the stand and was able to describe his experiences as a postgraduate student at Aston University and working at May & Baker. He especially contrasted the rudimentary equipment and grim laboratories of the Pharmacy Department at Aston in the late 1970s with those of the modern institution in 2008. Much of the investment to finance the transformation was through royalties received by the university from sales of temozolomide. To Stone's disappointment, counsel for Barr declined to crossexamine him: at the very least, a congratulatory comment on his remarkable contribution to a rare event in drug discovery history—a marketed drug, and a blockbuster to boot—would not have gone amiss.
THE VERDICT Ignoring the fact that CRT (through CRCT) became involved with temozolomide in only 1991 (as discussed in this chapter), the court concluded that it didn't seek to develop the technology prior to the signing of the Schering-Plough license in 1992 (how could it?) and engaged with the PTO only when it had a “profit motive” for doing so. The court also concluded that Stevens withheld information on inactivity data in animal studies, and clinical results in humans that it considered were “highly material”. The fact that he and his colleagues had authored some 40 publications on antitumor imidazotetrazines, many in American journals, to the wider scientific community over the period in question was, perversely, taken as evidence from which to infer an “intent to deceive”. In pronouncing its verdict in January 2010, the court found CRT's conduct sufficiently egregious to warrant rendering US
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The Appeal(s)
FIGURE 6.4 Bridge over the Garonne in Toulouse, France. (For color version of this figure, the reader is referred to the online version of this book.)
Patent 5,260,291 unenforceable due to “prosecution laches”, and found that Stevens committed “inequitable conduct” for disclosure failures with intent to deceive. The bad news was conveyed to Stevens when he was attending the winter meeting of the European Organisation for the Research and Treatment of Cancer (EORTC) Pharmacology and Molecular Mechanisms (PAMM) group's meeting in Toulouse, France. It was a bitter and humiliating blow, and his blood ran cooler than the icy waters of the river Garonne. But for the steadying support of Secretary Nicola Thomas back in the office, the bridge over the river (Fig. 6.4) might have witnessed a dramatic end to his ordeal. Had the CRT vs Barr tussle been a soccer match, then the score at this point would have been Barr-2: CRT-0. But, in a surprise decision in February 2010, the judge granted a temporary restraining order (TRO) preventing Barr (Teva) from launching generic temozolomide on the US market until an appeal before the Federal Circuit Court of Appeals in Washington, DC, had been heard. For the appeal to be successful, it would be necessary for lawyers for CRT to convince two of the three judges to overturn both “prosecution laches” and “inequitable conduct” decisions. Only legal issues could be argued, and no new evidence presented.
THE APPEAL(S) The US Appeals Court, in its judgment on 9 November 2010, took the view that CRT could not possibly develop and market temozolomide in the United States until ScheringPlough became its licensee, but on securing that liaison speedily moved to secure issuance of its patent. The public interest was secured by the fact that CRT did make the product available for treating cancer patients, and it should not lose that protection because patent issuance was delayed. In the view of the appeals court, Barr had not “invested in temozolomide or any other claimed tetrazine compound between 1982 and 1991, the period of the delay”. By a 2:1 majority, they concluded that the district court committed legal error in holding the patent unenforceable for “prosecution laches” and overturned the original decision.
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The appeals court also determined that nothing in Stevens's widespread publication of data in the world literature “evidences wrongful intent, but rather the opposite, extreme candor”. They also agreed with CRT that the district court erred in finding that Stevens intended to deceive the PTO by not disclosing data on the claimed compounds and thereby relied solely on its finding of materiality to infer intent. Again, by a 2:1 majority they reversed the district court's decision, holding the patent unenforceable for “inequitable conduct”. So the final score was Barr-2: CRT-2, but as the Federal Circuit Appeals Court decision trumped that of the district court, CRT prevailed on what would be, in soccer parlance, the “away-goals-count-double” rule. There was one final twist: because the decision of the appeals court was not unanimous, Barr sought leave to appeal to the US Supreme Court. This was rejected.
CONCLUSIONS It could be argued that many drug discoverers would positively welcome the opportunity to sit in the hot seat in a foreign court to defend their actions in respect of a generic challenge to their patented invention. This scenario would happen only if their drug had achieved notable sales. But the charge of “inequitable conduct” does carry an unsavory taste, especially for researchers whose sole motivation is to do their best for patients. Fortunately in the present case, the taint was removed and the threat to a professional reputation nullified, but in other cases mud can stick. The circumstances surrounding the battle for the US patent protecting temozolomide are unlikely to be repeated since patent terms in the United States are now triggered from filing date. However, there are some lessons that could be learned by researchers lucky (or unlucky?) enough to follow a similar track: 1. Never use the words “active” or “inactive” in any publications or notes reporting biological tests on compounds. Perhaps the terms “prioritized” or “de-prioritized” would be less of a hostage to fortune, but even then a smart counsel might claim some hidden nuance in their meanings. 2. Always keep open the information trail between the laboratory bench and those prosecuting your patent: if in any doubt, disclose the most trivial of data, even if you drive the patent examiner mad. 3. Be wary of agreeing to be a “courtesy author” on a publication where you have not contributed meaningfully to the work. In the 1980s this practice was widespread, but it leaves one open to a challenge in court that, as a listed author, one must somehow have complete knowledge of the totality of the contents of the publication. This is potentially hazardous for laboratory scientists appearing as coauthors on papers reporting clinical results. Some esteemed journals now require every author to make a declaration describing their contribution to the work, and this principle should become standard. “When it comes to apportioning credit, science could learn from the movies” [10]. 4. And, finally, be candid and publish because your own career and the careers of your colleagues depend on it. But prepare yourself to be damned.
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Acknowledgments Although this chapter is a personal account of a traumatic milestone in a career, it is also a heartwarming story of how a charity in the United Kingdom prevailed against the odds. The successful outcome of the trans-Atlantic battle for US Patent 5,260,291 could not have been achieved without the testimony of colleagues, some of whose contributions have been highlighted herein. The author would also like to express his thanks and admiration for the legal team of Ropes & Gray LLP led by Jesse Jenner, who spent 2 years mastering a complex brief spanning a third of a century, constructing a compelling case from naïve witnesses, and tutoring them in the do's and don’ts of court etiquette. They were such fun people to be with. But this witness found their instruction “No jokes, please” on the stand somewhat restrictive. Thanks are also due to legal representatives of CRT, Schering-Plough, and Merck & Co. who attended the trial in a supportive role. And—yes—Barr's counsel and interrogator-in-chief George Lombardi was polite and considerate at all times in his questioning. No hard feelings, George: we both know it was business.
References [1] Stevens MFG, Hickman JA, Stone R, Gibson NW, Baig GU, Lunt E, et al. Antitumour imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one, a novel broadspectrum antitumour agent. J Med Chem 1984;27:196–201. [2] Lunt E, Newton CJ, Smith C, Stevens GP, Stevens MFG, Straw CG, et al. Antitumor imidazotetrazines. 14. Synthesis and antitumor activity of 6- and 8-substituted imidazo[5,1-d]-1,2,3,5-tetrazinones. J Med Chem 1987;30:357–66. [3] Audette RCS, Connors TA, Mandel HG, Merai K, Ross WC. Studies on the mechanism of action of tumor inhibitory triazenes. Biochem Pharmacol 1973;22:1855–64. [4] Clark DA, Barclay RK, Stock CC, Rondestvedt CS. Triazenes as inhibitors of mouse sarcoma 180. Proc Soc Exp Biol Med 1955;90:484–9. [5] Hansch C, Hatheway CJ, Quinn FR, Greenberg N. Antitumour 1-(X-aryl)-3,3-dimethyltriazenes. 2. On the role of correlation analysis in decision making in drug modification. Toxicity quantitative structure-activity relationships of 1-(X-phenyl)-3,3-dialkyltriazenes in mice. J Med Chem 1978;21:574–7. [6] Cheng CC, Elslager EF, Werbel LM, Leopold III WR. Pyrazole derivatives 5. Synthesis and antineoplastic activity of 3-(2-chloroethyl)-3,4-dihydro-4-oxopyrazolo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide and related compounds. J Med Chem 1986;29:1544–7. [7] Newlands ES, Blackledge G, Slack JA, Goddard C, Brindley CJ, Holden L, et al. Phase 1 clinical trial of mitozolomide. Cancer Treat Rep 1985;69:801–5. [8] Newlands ES, Blackledge GRP, Slack JA, Rustin GJ, Smith DB, Stuart NS, et al. Phase 1 clinical trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 1992;65:287–91. [9] Hickman JA, Stevens MFG, Gibson NW, Langdon SP, Fizames C, Lavelle F, et al. Experimental anti-tumor activity against murine tumor model systems of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin4(3H)-one (mitozolomide), a novel broad-spectrum agent. Cancer Res 1985;45:3008–13. [10] Frische S. It is time for full disclosure of author contributions. Nature 2012;489:475.
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