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Chemical Crystallography and patents

Chemical Crystallography and patents. “Symmetry E70 (Butterflies)” by M.C. Escher - 1948. “Symmetry E72 (Fish and Boats)” by M.C. Escher - 1949. Introduction. A patent is a social contract , known since the middle ages. According to the Oxford English dictionary definition, it is

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Chemical Crystallography and patents

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  1. Chemical Crystallographyand patents “Symmetry E70 (Butterflies)” by M.C. Escher - 1948 “Symmetry E72 (Fish and Boats)” by M.C. Escher - 1949

  2. Introduction A patent is a social contract, known since the middle ages. According to the Oxford English dictionary definition, it is “a licence to manufacture, sell, or deal in an article or commodity, to the exclusion of other persons; in modern times, a grant from the government to a person or persons conferring for a certain definite time the exclusive privilege of making, using, or selling a new invention.” Originally patents granted the right to sell something, specifically commodities. -First known English patent in 1449 to John of Utyman for a method for making stained glass. Today’s patents only give the right to exclude. Adapted from Bernstein – Polymorphism in Molecular Crystals – Chapter 10

  3. Introduction contd. The aim of a “patent system is to reward the competitive, create drive with a temporary, limited, exclusive right, in return for the cooperation of an inventor in teaching the rest of society how to use his or her findings for all time thereafter.” – Maynard and Peters. • Patent laws differ from country to country although there is some degree of standardization • Science and law are dynamic and as a consequence the interpretation of any given patent may change over time – no guarantees

  4. Criteria for obtaining a patent • Must be a product of human ingenuity • Must have novelty - not part of the “state of the art” • Must not be obvious - obviousness is construed by hypothetical person “one skilled in the art” - competent but without imagination • Must have utility - must serve some worthwhile practical use. In some places this includes drugs, but not methods of medical diagnosis or treatment • Must contain an enabling description - sufficient detail to allow one skilled in the art to make and use invention • Inventor gains exclusive rights, but is responsible for policing these New crystalline materials such as co-crystals and polymorphs can be patented!

  5. Co-crystals - as patentable materials • A multiple component crystal in which at least one component is molecular and a solid at room temperature (the co-crystal former) and forms a complex with a molecular or ionic active pharmaceutical ingredient (API) • A new form of an API exhibits different physical properties • A new form of an API = new intellectual property • Co-crystals can be designed Chem. Commun., 2004, 1889-1896.

  6. Polymorphism and patents The discovery or creation of a new polymorph can confer advantages to the manufacturer of a drug or a competitor. These could be: • Chemical – perhaps it is more stable with a longer shelf life. • Physical – the polymorph might have a crystal habit that makes it easier to handle, filter or create tablets. • Biological – the new polymorph might be more bio-available and hence be more affective than the original polymorph All of these mean a lot of money to a manufacturer For legal and financial reasons therefore, the creator of a drug has to ensure that any solid-state form of a drug be precisely characterized, and also that any other polymorphs of the drug be search for, identified, characterized and possibly patented.

  7. Polymorphism and patents contd. What is important to note is that each drug is usually protected by many patents. Such patents might include: • APIpatents; • Synthesispatents; • Processing patents; • Formulation patents; • Formulation patents for particular diseases; • Tabletting patents; • Polymorph or equivalent patents.

  8. Polymorphism and patents contd. All of these act as a “picket fence” protecting an inventors right to exclusively market a drug, i.e. being able to circumvent the patent protection becomes a lot more difficult. Also, the inventor has “1st mover” advantage and as a consequence will probably have patented the best manufacturing methods for a particular drug. It may even add more patents even after the 1st patent for a drug has expired. Lastly, even if a new drug’s patent protection is weak, the ability to delay the approval of a generic can mean millions of dollars gained per day

  9. The effect of structure on physical properties - Chocolate • 6 polymorphs known • 3 polymorphs used commercially • Polymorph VI most stable • Polymorph V is the most useful because it is the best tasting and also makes the chocolate look glossy and melt in the mouth, i.e. its melting point is almost 37 ºC

  10. The effect of structure on physical properties - Chocolate

  11. Two triacylglyceride structures

  12. Ritonavir/Norvir • HIV protease inhibitor invented by researchers at Abbott laboratories • Approved by FDA (American Food and Drug Administration) in 72 days – a record • Original drug available as capsule in 1996 – form I • Form II produced in batch #260 in 1998 with the result that it was no longer possible to grow form I again

  13. Tempering to prepare Form V • TemperingIn order to make the chocolate crystallize exclusively in form V, the crystallization process has to be controlled by a sophisticated temperature regime (tempering). • First, the chocolate is melted at 50 °C. For the optimum formation of type V nucleation sites, it is then cooled at 1°C/min to 22 °C, where it is held for several minutes so that a sufficient number of nucleation sites can form. • Subsequently, it is heated again at 4 °C/min to 31 °C so that the thermodynamically unstable nucleation sites, particularly those of form IV, are melted. • Here, an exact temperature control is of the utmost importance; one degree too high or too low will decide on the product quality. Another cooling process follows, with the cooling rate depending on the chocolate variety and the recipe. http://www.chemistryviews.org/details/ezine/808827/Chocolate__The_Noblest_Polymorphism_II.html

  14. The problem with Ritonavir • Form II is not as soluble as Form I • No longer possible to provide drug as powder capsule • Drug provided as liquid containing 42% alcohol which is a problem for recovering drug addicts and alcoholics. Also tastes awful. • Drug then provided soft-gel capsule. Only stable between 20 and 25 ºC due to crystallization and stability problems Imagine then if Form II had been the original polymorph and a competitor had subsequently discovered a stable Form I. For the competitor this would mean lots of profits with very little money invested in research. For the creator of the drug it would mean millions of $$$ and many years of effort lost in research and development costs.

  15. Ranitidine hydrochloride (RHCl) - Zantac • Developed in the 1970’s by accident by Glaxo • Used for the treatment of peptic (stomach) ulcers • In 1977, David Collin, a Glaxo chemist, first prepared RHCl • This was patented in 1978 as U.S. Patent No. 4,128,658 (the ‘658 patent) Cl S

  16. The ‘658 – Form I - patent Included here is Example 32 which gives the procedure for preparation of From I of RHCl

  17. Ranitidine hydrochloride (RHCl) - Zantac • Developed in the 1970’s by accident by Glaxo • Used for the treatment of peptic (stomach) ulcers • In 1977, David Collin, a Glaxo chemist, first prepared RHCl • This was patented in 1978 as U.S. Patent No. 4,128,658 (the ‘658 patent) • In 1980, during a scale up process, Glaxo discovered the existence of a second polymorph – Form II. The ‘658 Form was subsequently designated Form I. • This new Form lead to another two patents for Glaxo – Patent No. 4,521,431 and 4,672,133 • The abstract of the ‘431 patent states simply, ‘A novel form of ranitidine….hydrochloride, designated Form 2, and having favourable filtration and drying characteristics…’

  18. [Ranitidine]+ FORM 1 FORM 2

  19. By 1992, Zantac sales (at this stage Form II) had reached $3.5 billion, nearly twice the next best selling drug

  20. Patent History of RHCl (Zantac) 1977 - First preparation of RHCl 1978 - Registration of U.S. ‘658 patent 1980 - Discovery of Form 2 of RHCl 1984 - Zantac first marketed in U.S as Form 2 (under patent pending protection. 1985 - Registration of U.S. ‘431 patent on Form 2  1992 - Sales of Zantac reach $3.44 billion  1995 - U.S. ‘658 patent expires   2002 - U.S. ‘431 patent on Form 2 expires

  21. As a consequence generic companies were interested in marketing Form I of the drug themselves as soon the patent expired (1995) • One of these, Novopharm Ltd., started working on Form I in the early 1990’s by following the procedure given in the original ‘658 patent but was unable to create Form I • In 1991 Novopharm filed an abbreviated new drug application (ANDA) at the FDA to market Form II in 1995 saying that the method given in the ‘658 patent produces Form II and not Form I • At the same time Novopharm notified Glaxo of its contention that the ‘431 (Form II) patent was invalid • Glaxo sues Novopharm for infringement of the ‘431 patent

  22. Novopharm admitted infringement but insisted that patent ‘431(the Form II patent) was invalid because the formation of Form II was inherent in the ‘658 patent. • In other words Novopharm theorized that if Glaxo had strictly followed the ‘658 patent recipe then it would have obtained Form II • In 1993, Glaxo by getting hold of the original scientist’s (David Collin) note books (dating back to 1977), and comparing these in detail with the example given in the patent, as well as having the experiment reproduced at Oxford was able to prove that patent ‘658 lead exclusively to Form I. • As a consequence the Court was convinced that the ‘431 patent was valid and lead to Form I.

  23. Subsequent events • Novopharm loses appeal • World Trade Agreement extends ‘658 patent from December 8, 1995 to July 25, 1997

  24. At this point Novopharm examined the possibility of marketing Form I and tried to get permission to market it upon expiration of the ‘658 patent • Glaxo sued Novopharm for infridging the ‘431 patent saying that their drug was a mixture of Form I and Form II, and not pure Form I. • The initial Novopharm application (ANDA) for marketing Form I indicated that the marketed product would be 99 % pure but later was amended to 90 % pure. At Court, however, Novopharm submitted X-ray evidence that the actual samples of RHCl did not contain any detectable Form II. • The court therefore found that Novopharm had established that its product would not contain Form II and if it did would contain it as an impurity • The court had therefore allowed Novopharm to market mixtures of Form I and II

  25. Final analysis of the Zantac court case • This decision was maintained by the appeals court • The mistake that Glaxo made was not to prove that Novopharm’s product was likely to contain Form II by testing the samples themselves • In particular the appeals court noted it had explicitly declined to address the question of whether small amount of Form II in a mixture containing primarily Form I would infringe the ‘431 patent This case has a lot in common with the more recent Paxil (an antidepressant) case – GSK (the inventor) vs Apotex An important factor in both cases is whether very low levels of patented impurities would cause financial losses to GSK or whether GSK was just using these as excuse to keep out the competition. Also, how low is low – is one crystal enough?

  26. Finally The above examples illustrate many aspects and concepts important in the study and analysis of materials – especially polymorphs in this case. Some of these are: • the role of solvent, heating, stirring and other experimental techniques used to control the polymorph obtained; • analysis techniques for characterizing materials; • the relative stability of polymorphic forms; • the role of serendipitous polymorph discovery; • and the distinction between polymorphic identity and polymorphic purity.

  27. ‘Courts of law are not the optimal fora for trying questions of scientific truth… (Zenith Laboratories v. Bristol-Myers Squibb, 1994) As a consequence of the above if you ever intend to patent anything make sure that you do the following things: • Keep a very good log book • Be observant and take note of details • Make sure that you belong to some professional bodies such as the RSC or SACRs or the IUCr or the Freemasons or the Illuminati or ….

  28. The Economist on Patent Litigation08.03.03 (Citing Judge Posner’s decision in Paxil case) “Forget horse-racing, says one patent lawyer: ‘Patent litigation is the true sport of kings.’”

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