1. ACS Symposium – Challenges In Structure Searching
April 8, 2007
Comparing Merged Markush Service (MMS) and Marpat Search Results: Two Case Studies
Joe Terlizzi
Questel, Inc.

2. Background
In October 2007, the JFA pharmaceutical group, a group of professional searchers from the pharmaceutical industry in Japan, asked me to compare two chemical structures searched in both MMS and Marpat. They had received inconclusive results when they ran the searches.
The following two case studies conducted at that time illustrate many of the similarities and differences in the two systems. They show my search procedure, results, and conclusions.

3. Background
The Merged Markush Service (MMS), jointly produced by Thomson and the French Patent Office (INPI) is a database containing both Markush structures and specific compounds from patents. It is based on the Markush Darc system and the service is exclusively hosted on Questel.
Marpat, produced by Chemical Abstracts Service and available only on STN, contains Markush structures from patents. It can be searched with the REGISTRY file (for specific structures) using the CASLINK cluster on STN.

4. Background
Both MMS and Marpat are usually recommended for a basic chemical structure search strategy covering Markush structures in patents.
Derwent’s Chemical Fragmentation Code system (only available to Derwent Subscribers) can also yield unique answers, but since it is not a graphical system and was not requested by the JFA, it was not used for this study.

5. Comparing MMS and Marpat
CASE 1:
The following chemical structure is from an EP patent document published in In a JFA study, this document was retrieved from MMS. It was not retrieved in Marpat. Why not?
X: N or CR2
Y: N or CR2
R: C1-5 alkyl, C3-6 cycloalkyl
R1: halogen, amino, -N=CH-R2
R2: independently H, halogen, hydroxyl,
C1-5 straight or branched alkyl, or an optionally
substituted aromatic or heteroaromatic residue

6. Case 1:The query was created in MMS in the following way:
X: N or CR2
Y: N or CR2
R: C1-5 alkyl, C3-6 cycloalkyl
R1: halogen, amino, -N=CH-R2
R2: independently H, halogen, hydroxyl,
C1-5 straight or branched alkyl, or an optionally
substituted aromatic or heteroaromatic residue
X = G1 G0
Y =G2

7. R =G3 R1 =G4 X: N or CR2 Y: N or CR2 R: C1-5 alkyl, C3-6 cycloalkyl
R1: halogen, amino, -N=CH-R2
R2: independently H, halogen, hydroxyl,
C1-5 straight or branched alkyl, or an optionally
substituted aromatic or heteroaromatic residue
R1 =G4

8. A free site was put on the carbon in G1, G2 and G4 to cover R2
X: N or CR2
Y: N or CR2
R: C1-5 alkyl, C3-6 cycloalkyl
R1: halogen, amino, -N=CH-R2
R2: independently H, halogen, hydroxyl,
C1-5 straight or branched alkyl, or an optionally
substituted aromatic or heteroaromatic residue

9. Comparing MMS and Marpat
In MMS, the AA search resulted in 19 answers and no RX candidates:
1 CN =
2 CN =
3 CN =
4 CN =
5 CN =
6 CN =
7 CN =
8 CN =
9 CN =
CN =
CN =
CN = RAITC9
CN = RAITCA
CN = RAITCM
CN = RAITCN
CN = RAITCP
CN = RAITD3
CN = RAITD8
CN = RAJLWV
The first CN listed corresponds
to the EP document AN
CN N; T
PN - EP [EP ]
AP - EP [1986EP ]
PR - IT [1985IT ]
- IT [1985IT ]
RL - US [US ]
PA - RORER ITALIANA S.p.A. / Via Valosa di Sopra, 9 / I S.Fruttuoso
di Monza (Milan) (IT)
- ROTTAPHARM S.p.A. / Via Dandolo, 4 / I Varese (IT) (Updated
8825)
IC1 - C07D-215/56
IC2 - C07D-471/04; A61K-031/47; A61K-031/53; A61K-031/495
ET amino-piperazinyl - or 7- 4-chloro-piperazinyl quinolinone and
azaquinolinone derivatives, a process for the preparation thereof and
pharmaceutical compositions containing them.
EAB - 4-oxo-7-piperazino-(quinoline or azaquinoline)-3-carboxylic acid
derivatives. Process of preparation thereof. These compounds are
antibacterial agents
PHCN- 11 : INFECTION
- 08 : NEPHROLOGY, UROLOGY

10. Comparing MMS and Marpat
CASE 1 results in MMS:
There were 12 unique patent records retrieved – 3 from PHARM and 10 from DWPI, with 1 overlap.
The most recent record was US from August 2007.
The EP record from the JFA study was only in PHARM, since it was indexed in the BACKF segment (Backfile)

11. Comparing MMS and Marpat
The query was created for Marpat:
G1=
G2=
G3=

12. Comparing MMS and Marpat
There were not many differences in creating this query in MMS and Marpat. Some differences were:
G1 could be repeated in Marpat; you cannot repeat a G group in MMS
Rings default to possible non-hydrogen substitution (see next slide) whereas in MMS, no free sites were substituted on ring

13. Non-Hydrogen Attachments
Default is for
Non-Hydrogen Attachments
Searchers can choose to override defaults in Marpat.

14. Some other differences in this query in MMS and Marpat were:
Atom/Class in Marpat (translation in MMS) was set with CLASS (equivalent to BT in MMS) on G group substituents. The MMS structure defaults to equal translation.
Atom/Class Match Level

15. Comparing MMS and Marpat
Case 1 Results using CASLINK (Marpat/Registry/MarpatPrev):
CASLINK search had 25 results.
There were unique patent results in both MMS and Marpat for this structure.
Most recent US patent was only in MMS.
The EP patent missing from JFA study was found in Marpat!

16. Comparing MMS and Marpat
Why didn’t the JFA study retrieve this result in Marpat?
The JFA query used for Marpat was not as broad as my query; therefore the EP patent was not retrieved.
What were the possible differences in my query and the JFA’s?
Not sure, but it could have been that my query allowed for substitution on the rings.
Why the difference in Marpat results and MMS?
Since the Marpat query was broader than the MMS query because of the open substitution, there were a greater number of results in Marpat.

17. Comparing MMS and Marpat
CASE 1 Conclusions:
Default levels in both systems must always be taken into account. Atom/Class in Marpat corresponds to Translation Level in MMS. Defaults are very different in both systems, with Marpat having more broader search defaults.
Non- Hydrogen attachment defaults (Marpat) and free sites (MMS) must also be taken into account.
Unique results are often achieved in both systems.

18. Comparing MMS and Marpat
CASE 2:
The following structure is from an US patent document published in Is there unique retrieval in MMS or Marpat in a freedom-to-operate search? (Do not take into account specific structures in MMS or differences in patent coverage.)
X: N or CH
Y: O, S, or NH
Z: O, S, or NH
R1: an unsubstituted carbocyclic or heterocyclic aromatic group, or a carbocyclic or heterocyclic aromatic group substituted with at least one lower alkyl, lower alkoxy, halogen, lower alkylthio or nitro group
R2: C1-3 alkyl
R3: C1-3 alkyl
or R2 together with R3 may form a heterocyclic ring, which includes at least one heteroatom selected from O, N, or S.

19. Case 2 Using MMS X = G1 X: N or CH Y: O, S, or NH Original query
Z: O, S, or NH
R1: an unsubstituted carbocyclic or heterocyclic aromatic group, or a carbocyclic or heterocyclic aromatic group substituted with at least one lower alkyl, lower alkoxy, halogen, lower alkylthio or nitro group
R2: C1-3 alkyl
R3: C1-3 alkyl
or R2 together with R3 may form a heterocyclic ring, which includes at least one heteroatom selected from O, N, or S.
Original query
X = G1

20. Case 2 Using MMS Y = G2 Z = G3 G2 and G3 are identical X: N or CH
Y: O, S, or NH
Z: O, S, or NH
R1: an unsubstituted carbocyclic or heterocyclic aromatic group, or a carbocyclic or heterocyclic aromatic group substituted with at least one lower alkyl, lower alkoxy, halogen, lower alkylthio or nitro group
R2: C1-3 alkyl
R3: C1-3 alkyl
or R2 together with R3 may form a heterocyclic ring, which includes at least one heteroatom selected from O, N, or S.
Y = G2
Z = G3
G2 and G3 are identical

21. Case 2 Using MMS R1 = G4 5 free sites have been
X: N or CH
Y: O, S, or NH
Z: O, S, or NH
R1: an unsubstituted carbocyclic or heterocyclic aromatic group, or a carbocyclic or heterocyclic aromatic group substituted with at least one lower alkyl, lower alkoxy, halogen, lower alkylthio or nitro group
R2: C1-3 alkyl
R3: C1-3 alkyl
or R2 together with R3 may form a heterocyclic ring, which includes at least one heteroatom selected from O, N, or S.
R1 = G4
5 free sites have been
applied to the superatoms

22. Case 2 Using MMS R2 and R3 are substituted with free sites
X: N or CH
Y: O, S, or NH
Z: O, S, or NH
R1: an unsubstituted carbocyclic or heterocyclic aromatic group, or a carbocyclic or heterocyclic aromatic group substituted with at least one lower alkyl, lower alkoxy, halogen, lower alkylthio or nitro group
R2: C1-3 alkyl
R3: C1-3 alkyl
or R2 together with R3 may form a heterocyclic ring, which includes at least one heteroatom selected from O, N, or S.
Because of MMS tautomer rules,
unspecified bonds are applied

23. Case 2 Using MMS CASE 2 RESULTS
There was 1 answer in MMS; it was the 1990 US patent.
AN [50]
TI - New penta:cyclic furo:benzoxazine derivs. having antimicrobial and antitumour activity and useful as intermediates to known tetra:cyclic antitumour cpds.
PN - US A DW Eng *
AP: 1989US
- JP A DW Jpn
AP: 1990JP
AP US ; 1990JP
PR US
PA - (FUJI) FUJISAWA PHARM CO LTD
- (RIPT) RI PATENTS INC
- (RICV) UNIV RICE
CN N N

24. Case 2 Using Marpat
The query was drawn similarly in Marpat, but there was one problem. G groups in Marpat cannot be attached to more than 2 nodes and the system would not prepare the query. MMS allows attachments to more than two nodes.
Since X has three attachments in the original query, a different solution had to be sought.
Original query

25. Case 2 Using Marpat The following query was searched using CASLINK.
Original query
Case 2 Using Marpat
The following query was searched using CASLINK.
The A atom (any atom except H) was substituted for the G group. This allowed for a three node attachment.
Cy variable was used for cyclic substitution at R1
All nodes were open for substitution

26. Original query
Case 2 Using Marpat
Another problem – This query had too many iterations in Marpat and would not run. The system limit was exceeded.
S L2 SSS SAM FILE=MARPAT SAMPLE SEARCH INITIATED 16:22:46 FILE 'MARPAT' SAMPLE SCREEN SEARCH COMPLETED TO ITERATE 23.3% PROCESSED 2000 ITERATIONS 0 ANSWERS INCOMPLETE SEARCH (SYSTEM LIMIT EXCEEDED) SEARCH TIME: FULL FILE PROJECTIONS: ONLINE **INCOMPLETE** BATCH **INCOMPLETE** PROJECTED ITERATIONS: TO PROJECTED ANSWERS: 0 TO 0

27. Original query
Case 2 Using Marpat
Replacing A with C and N with the intention of running two queries also exceeded the system limits!
Another tactic was approached. R2 and R3 were substituted with Ak (alkyl). I received the following message:
STRUCTURE TOO LARGE - SEARCH ENDED
A structure in your query is too large. You may delete
attributes or atoms to reduce the size of the structure
and try again.

28. Case 2 Using Marpat The query shown was entered:
Original query
Case 2 Using Marpat
The query shown was entered:
The bonds coming off the fused ring were denoted as ring bonds.
Match level was ATOM for all nodes except the CY variable, which was CLASS.
This query ran!

29. Case 2 Using Marpat
=> sss l1 full
FULL SEARCH INITIATED 17:13:38 FILE 'MARPAT'
FULL SCREEN SEARCH COMPLETED TO ITERATE
100.0% PROCESSED ITERATIONS ANSWERS
SEARCH TIME:
L SEA SSS FUL L1
=> dis bib
L3 ANSWER 1 OF 1 MARPAT COPYRIGHT 2007 ACS on STN
AN 114: MARPAT Full-text
TI Preparation of novel pentacyclic compounds as antimicrobial and antitumor
agents
IN Goto, Shunsuke; Fukuyama, Tohru
PA Japan
SO U.S., 11 pp.
CODEN: USXXAM
DT Patent
LA English
FAN.CNT 1
PATENT NO KIND DATE APPLICATION NO. DATE
PI US A US
JP A JP
PRAI US
The full search had 1 answer: the US patent from 1990!
No other answers were obtained in Marpat.

30. Comparing MMS and Marpat
Conclusions:
Is there unique retrieval for this case in Marpat or MMS? No
Complex queries may not always run in MMS or Marpat but can usually be adjusted to run.
Features such as bond attributes, unspecified bonds, unspecified atoms, can often help in allowing a structure to process.
Speed and number of iterations will be different in each system.

31. Comparing MMS and Marpat
Summary:
Know the defaults in both MMS and Marpat, especially translation and free sites (MMS) and class level and non-hydrogen attachment (Marpat) defaults
Familiarize yourself with bond normalization rules in both systems – they are different!
Learn the unique features of both systems (ring isolation, subset searching, JOIN command, etc.)
Use both systems for a comprehensive search!

32. HELP MMS Documentation and Information www.questel.com/mms
MarPat Documentation and Information:
Questel Help Desk:
STN Help Desk:

33. Finally, much thanks to:
Sandy Burcham (Service Is Our Business)
Judy Philipsen (Philipsen Search Services)
Kyoko Kaji (Pfizer) for allowing me to use these JFA examples
Thank You!