11 MMS Merged Markush Service The QuestelOrbit Alternative for Chemical Information Elliott Linder, QuestelOrbit Joe Terlizzi, QuestelOrbit 227 th ACS National Meeting Anaheim, CA 28 March 2004

22 Scenario Hypothetical Pharm X has developed a compound with the structure below, which they are finding to be a useful contraceptive in animal tests. Should they try to patent or commercialize this compound and/or its use?

33 Scenario What does Pharm X need to know? Has the compound been documented or patented, i.e., is the compound really new? Is its intended use new? If the compound and/or its use have been patented, what is the status of the patent or patents?

44 Search Pharm X searchers will want to check the standard chemical structure databases on key vendor systems: CAS Registry for exact structure MARPAT for open substitution on benzene rings or amino group Beilstein

55 Search With patentability and potential infringement at stake, Pharm X also decides to extend their structure search to MMS, the Merged Markush Service from Questel·Orbit. But what is MMS?

66 MMS Coverage and Structure Four segments Front File (FRONTF) –from Derwent week 9816 WPIM – MPHARM – Backfile (BACKF) – (FR back to 1961) The user can choose which segment(s) to search MPHARM WPIM BACKF FRONTF

77 MMS Coverage and Structure Updating MMS Front File (Derwent) updated weekly Back File now goes back to 1978 No additional updates of MPHARM from year 2000 MPHARM WPIM BACKF FRONTF

88 Link to bibliographic files MMS structure file PHARM biblio file WPIL biblio file CN 1 CN 2 AN 1 CN PN AN 1 CN PN Markush query CN link Patent retrieval CN 3 CN 4 CN = Compound Number

99 Link to bibliographic files FRONTF WPIM MPHARM BACKF WPIL PHARM MMS STRUCTURE FILE BIBLIOGRAPHIC FILES CN YYWW-CCCSS CN YYMMXXXX-NN 2 CN formats

10 MMS Search Structure Searching Steps: 1. Open Imagination or STN Express. 2. Draw query using Query Text (QT) or import structure from Derwent’s Markush Topfrag. 3. Verify and exit query input. 4. REtrieve candidates. Candidates contain fragments of the queried structure. 5. Run an Atom-by-Atom search on RE candidates. 6. Cross to Questel·Orbit bibliographic system.

11 Verifying MMS Structure using Imagination Steps 2 & 3

12 MMS Search RE search is conducted first. There are over 35,000 candidates containing structural fragments of the original query. Step 4

13 MMS Search When AA search is conducted, one answer is found. Step 5

14 Search Compound number is transferred to the PHARM database. PHARM record is as follows: AN CN - *** K***; *** T***; *** U*** PN - US [US ] AP - US [1982US ] PA - UNIVERSITY OF ILLINOIS FOUNDATION /Urbana/IL (US) IN - JOYCE CATHY L (US) - ZANEVELD LOURENS J (US) IC1 - A61K-031/53 IC2 - A61K-031/415 ET - Contraceptive method. Step 6 Indicates known structure; further investigation required

15 EAB - Use of pyrazolone derivatives of formula (I) wherein A is H, halo, trihalomethyl, lower C1-8 alkyl, -X-OH, -X-CO-R, -X-CO-OR, -X-SO-D, -X-S-D or -NR1R2; X is a lower (C1-C8) alkylene group; R, R1, and R2 are hydrogen, or the same or different lower alkyl groups, and B, C, and D, which can be the same or different, are phenyl, hydroxyphenyl or lower alkylphenyl, further provided that B and C together can form a chain of formula (II), as contraceptive agents. - The contraceptive method comprises maintaining in the genital tract of a female mammal a pyrazolone derivative in a concentration effective to inhibit the fertilization of ova. In addition to effectively, inhibiting the enzymes or other sperm components necessary for conception, the compounds used in the method of the invention are advantageous in having low toxic, caustic or irritating properties, so that the contraceptive compositions are suitable for long-term use without adverse side-effects. Search Pharm record –cont’d

16 Analysis The compound number , reveals that the answer is a Markush structure indexed by INPI in The BACKF, produced by INPI, dates back to 1978 for US patents. This structure will not be found in Marpat since it only goes back to The generic structure cannot be searched in Registry. MMS contains both specific and generic structures.

17 The PHARM record reveals that the retrieved patent contains many possible structures, and contains a variation of our structure, with a methyl group substituted on the fused benzene ring. The patent assignee is the University of Illinois Foundation, and the patent was published in The compound was also used as a contraceptive. Therefore, an infringement is possible. Analysis

18 Some things we will need to check are: Are there any family members, meaning has the patent been applied for and/or granted in any other countries? What is the status of these patents, i.e., are they still valid or have they expired or lapsed? Are there cited references that reveal any additional prior art about this compound? Are there patents citing this patent that give us more information about this compound? Analysis

19 Analysis These points are easy to check using the PlusPat database on QuestelOrbit. Using the MEM and *MEM commands, the Standardized Patent Number [XPN] is extracted and searched in PlusPat. (Standardization of the all publication, application, and priority numbers on QuestelOrbit simplifies cross-file searching.) The FAM command is executed on the publication number, and the FAMSTAT command is used to display the family members and their LEGAL STATUS.

20 Analysis 1/1 PlusPat - (C) QUESTEL-ORBIT- image CPIM PN - US A [US ]. 1/1 LGST - (C) EPO PN - US A [US ] AP - US [1982US ] ACT US/AS02-A ASSIGNMENT OF ASSIGNOR'S INTEREST OWNER: UNIVERSITY OF ILLINOIS FOUNDATION, A CORP. OF ILL.; EFFECTIVE DATE: US/AS02-A ASSIGNMENT OF ASSIGNOR'S INTEREST OWNER: JOYCE, CATHY L.; EFFECTIVE DATE: US/AS02-A ASSIGNMENT OF ASSIGNOR'S INTEREST OWNER: ZANEVELD, LOURENS J. D.; EFFECTIVE DATE: US/FP-A [-] EXPIRED DUE TO FAILURE TO PAY MAINTENANCE FEE EFFECTIVE DATE: UP FAMSTAT format. (PlusPat record edited for brevity.)

21 Analysis The PlusPat record reveals that there are no other family members, and the LGST record that the patent expired in 1991 due to a failure to pay the maintenance fee. A citation analysis can be conducted on QuestelOrbit using the FAM command and FAMCITE display, that contains: All patent families citing the source patent family All patents families cited in the source patent family The citation analysis can be helpful in finding additional prior art.

22 Conclusions In this hypothetical scenario, Pharm X has a potential opportunity due to the expiration of the patent retrieved. In general, no single resource is sufficiently comprehensive on its own. As many resources as possible should be searched for prior art and infringement.