YAMANOUCHI PHARM. CO. V. DANBURY PHAR. Yamamouchi’S Patent
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Obviousness Obviousness • Definition of one of ‘ordinary skill in the art’ • Combining two or more prior art references • Motivation to combine • Some teaching, suggestion, or motivation to modify or combine found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art Graham factors (US) Graham et al. v. John Deere Co. of Kansas City et al., 383 U.S. 1 (1966) 1. the scope and content of the prior art; 2. the level of ordinary skill in the art; 3. the differences between the claimed invention and the prior art; and 4. objective evidence of nonobviousness. In addition, the Court mentioned “secondary considerations” which could serve as evidence of nonobviousness. They include: 1. commercial success; 2. long felt but unsolved needs; and 3. failure of others. Problem-solution approach (EPO) 1. identifying the closest prior art, the most relevant prior art; 2. determining the objective technical problem, that is, determining, in the view of the closest prior art, the technical problem which the claimed invention addresses and successfully solves; and 3. examining whether or not the claimed solution to the objective technical problem is obvious for the skilled person in view of the state of the art in general. Obviousness • Genus-species claims • Species always anticipates genus, not vice-versa • Rule against double patenting • Only claims can be compared • Terminal disclaimer overcomes double patenting • Cannot cure same invention type double patenting • The ‘two-way’ test and the ‘one-way’ test YAMANOUCHI PHARM. CO. v. DANBURY PHAR. Yamamouchi’s Patent • U.S. Patent No. 4,283,408- inhibitors of gastric acid secretion • Claims famotidine for treating heartburn and ulcers • Class- histamine2 antagonists • Inhibit production of stomach acid • Substituted heterocycle" group, "alkyl containing" chain (called a "bridge"), and a "polar tail Famotidine History of related compounds • 1960s and 70s - search for H2 antagonists with improved pharmacological properties, including low toxicity, high activity, and lack of side effects • Hundreds of thousands of potential compounds • More than 11,000 H2 antagonist compounds synthesized Failure in finding acceptable compounds • Most not pharmacologically suitable • Notable failures: tiotidine, which caused cancer in rats. burimamide- ineffective for oral dosing. metiamide- white blood cell loss. lupitidine- which caused pre-cancerous lesions in rats. oxmetidine, which caused hepatitis • Fewer than fifty showed enough promise Patents granted • Cimetidine- SmithKline Beecham sells it as TAGAMET • Ranitidine-Glaxo-sells it as ZANTAC • Famotidine-Merck sells it as PEPCID • Nizatidine- Eli Lilly sells it as AXID Prior art compounds Cimetidine Ranitidine Nizatidine Litigation and issue • Danbury filed ANDA for generic compound • Claims that Patent is invalid as obvious • Yamanouchi filed suit • Is there motivation to combine pieces from different prior art • Example 44 from Yamanouchi's U.S. Patent No. 4,252,819 (N-carbamoyl-3-(4-methyl- 5-imidazolylmethylthio)propionamidine Combining • Combine the polar tail from example 44 with the substituted heterocycle from tiotidine, thus creating the intermediate compound • Bioisosteric substitution of the carbamoyl (CONH2) group in the intermediate compound with a sulfamoyl group Motivation to combine • Danbury's assertion of motivation rests on the fact that example 44 is three times more active than cimetidine • Activity alone not sufficient motivation • Other prior art references disclosed compounds with H2 antagonist activity up to ten times higher than cimetidine Motivation • Motivation to use the process- Danbury asserts that one skilled in the art could except the resultant compound to show baseline activity • Baseline level is1/165th of cimetidine • This level of motivation does not show a "reasonable expectation of success” Expectation of success • Success of discovering famotidine was not discovering one of the tens of thousands of compounds that exhibit baseline H2 antagonist activity. Rather, the success was finding a compound that had high activity, few side effects, and lacked toxicity Motivation to manipulate • very specific series of steps • Any deviation in the order of combination would have taught away from famotidine • Substituting sulfamoyl group for the carbamoyl group on example 44 without attaching the substituted heterocycle from tiotidine- the resulting compound would have 1/100th the activity of cimetidine Prima facie case for structural obviousness • Famotidine, has 40 times the activity of cimetidine • Danbury fails to show prima facie case for structural obviousness • “This case has all the earmarks of somebody looking at this from hindsight." OLANZAPINE LITIGAITON Background •DRL was the first to challenge Lilly’s compound patent 5229382 (‘382 patent) •DRL (along with Ivax the first filer for the strength) challenged the patent on the following grounds. •Anticipation over Chakrabarti 1980a and Schauzu •Obviousness over US patent ‘574, Chakrabarti articles and Sullivan and Franklin article •Public use - Phase I studies were conducted more than one year before the priority date of ‘382 patent •Inequitable conduct - dog study was flawed and confounding ‘574 patent ‘574 patent specifically claims Ethyl Flumezapine, which expired in 1997 R6 N N N C R1 Halogen Ethyl, C2H5 -fluoro N S H R2 Compound 222 Flumezapine – compound pursued by Lilly in clinical studies, but had to be discontinued due to raised CKP, liver enzymes. R6 N N N C R1 Halogen -fluoro N S H R2 382 patent • ‘382 patent claims Olanzapine which in under challenge • Olanzapine needs methyl at 2nd position and hydrogen at th 7 position. R6 N N N C R1 7 2 Methyl, CH3 N S H R2 Chakrabarti 1980a • Preference for halogen constituent at the 7th position of phenyl ring • It also reports short alkyl substitution (methyl, ethyl, isopropyl) at 2nd position of a thiophene ring seems to increase in activity • Chakrabarti 1982 and 1989 further confirmed fluorine R6 substitution for good antipsychotic activity N N R N N N C N C R R1 2 Halogen R1 Ethyl, C2H5 -fluoro N S N S H H R2 • Chakrabarti 1980a discloses various compounds of general formula given below •Author examined 1-45 specific compounds for the testing • Significantly olanzapine was not one of the compound the author examined • Five compounds 9, 12, 17, 29, 34 found to be more potent • Four of five compounds have a fluorine at 7th position Anticipation Generics argued that - Argument centered on 1-45 compounds with various substitutions for R, R1 and R2 Chakrabarti 1980a discloses olanzapine The Court ruled in favor of Lilly on following grounds- Disclosure of a genus does not anticipate a claim to species The court ruled that the article did not disclose genus Even though the article showed the preferred substituents – there was no preference for hydrogen at 7th position, as the case in olanzapine. Anticipation by Schauzu • DRL argues that the olanzapine is described as compound 11 in a scientific article by Schauzu • Biological data in Schauzu comes from Chakrabarti 1982 • The compounds disclosed in Chakrabarti 1982 were flourinated piperazine • The structure drawn in Schauzu is not flourinated piperazine compound because it is missing both the fluorine atom at the 7th position and one of the nitrogen atom in piperazine ring Anticipation by Schauzu • The biological data from Chakrabarti 1982 does not include olanzapine since it is unflourinated • In order to find that olanzapine is described as compound 11 in Schauzu, one with ordinary skill in the art would have to mentally insert a nitrogen atom into the structure in Schauzu. • Moreover Schauzu article from Chakrabarti 1982 for fluorinated compounds. Obviousness The Generics argued that – • Chakrabarti 1980a teaches that a short alkyl substitution (Me, Et, i-Pr) at 2nd position of the thiophene ring seemsR6 to increase the activity R6 N • Substituting ethyl with methyl wouldN be obvious over Chakrabarti 1980a N N N C N C R1 R1 Halogen Ethyl, C2H5 -fluoro Methyl, CH3 NH S N S H R2 R2 Ethyl Olanzapine Flumezapine The Court ruled in favor of Lilly Following are the grounds- • The Generics did not even meet the initial burden of showing prima face obviousness • The article actually teaches away form using hydrogen at 7th position • Failed to convince that one ordinary skill would work on compound (corresponding to ethyl olanzapine) as a starting point to carry out the substitutions • Could not prove any motivation to start with fulmezapine (fluorine at 7th position) and put hydrogen at the 7th and methyl at 2nd position Unexpected properties for Olanzapine over compound 222 •Compound 222 raised cholesterol whereas olanzapine did not and shown unexpected property over prior art compounds •Generics alleged that the dog study was flawed as it is not inappropriate model, total cholesterol is not the proper parameter, dogs were not properly randomized, overweighed, double-fed, too high dosages and no clarity in statistical data. •Court ruled out all the allegation mentioned above Additional Topics Discussed in the UK Litigation of Olanzapine Obviousness - SAR Optimization •Chakrabarti publication discusses 45 compounds •Is there motivation work more with these? Selection Patents •If prior art discloses a class, and patentee selects 1+ of them to patent for himself, he must show how those selected are advantageous over all of the others •claim “an advantage for a compound within a previously disclosed class of compounds which has not been disclosed in the prior patent”, as described by the court. •Unlike originating or genus patents, which cover an originating invention involving a new reaction or a new compound, selection patents build on previously disclosed classes of compounds but identify a new use or benefit of the compound undisclosed in the originating patent. IN RE MERCK & CO., INC., 800 F.2d 1091 (Fed. Cir. 1986) Background • Appeal from a final decision of the Board of Patent Appeals and Interferences • Sustaining the rejection of claims 1 through 3 in the reexamination application of U.S. Patent No. 3,428,735 • Ground of rejection: 103 Claims • 1.