Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-04-21
2001-01-30
Eisenschenk, Frank C. (Department: 1643)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023720, C536S024300, C435S005000, C435S007100, C435S069300, C435S252300, C435S320100, C530S300000, C530S350000
Reexamination Certificate
active
06180768
ABSTRACT:
The invention relates to new sequences of hepatitis C virus (HCV) genotypes and their use as prophylactic, therapeutic and diagnostic agents.
The present invention relates to new genomic nucleotide sequences and amino acid sequences corresponding to the coding region of these genomes. The invention relates to new HCV types and subtypes sequences which are different from the known HCV types and subtypes sequences. More particularly, the present invention relates to new HCV type 7 sequences, new HCV type 9 sequences, new HCV types 10 and new HCV type 11 sequences. Also the present invention relates to new HCV type 1 sequences of subtypes 1d, 1e, 1f and 1g; new HCV type 2 sequences of subtypes 2e, 2f, 2g, 2h, 2i, 2k and 2l; new HCV type 3 sequences of subtype 3g, new HCV type 4 sequences of subtypes 4k, 4l and 4m; a process for preparing them, and their use for diagnosis, prophylaxis and therapy.
The technical problem underlying the present invention is to provide new HCV sequences from until now unknown HCV types and/or subtypes. More particularly, the present invention provides new type-specific sequences of the Core, the E1 and the NS5 regions of new HCV types 7, 9, 10 and 11, as well as of new variants (subtypes) of HCV types 1, 2, 3 and 4. These new HCV sequences are useful to diagnose the presence of HCV type 1, and/or type 2, and/or type 3, and/or type 4, and/or type 7, and/or type 9, and/or type 10, and/or type 11 genotypes or serotypes in a biological sample. Moreover, the availability of these new type-specific sequences can increase the overall sensitivity of HCV detection and should also prove to be useful for prophylactic and therapeutic purposes.
Hepatitis C viruses (HCV) have been found to be the major cause of non-A, non-B hepatitis. The sequences of cDNA clones covering the complete genome of several prototype isolates have been determined (Kato et al., 1990; Choo et al., 1991; Okamoto et al., 1991; Okamoto et al., 1992). Comparison of these isolates shows that the variability in nucleotide sequences can be used to distinguish at least 2 different genotypes, type 1 (HCV-1 and HCV-J) and type 2 (HC-J6 and HC-J8), with an average homology of about 68%. Within each type, at least two subtypes exist (e.g. represented by HCV-1 and HCV-J), having an average homology of about 79%. HCV genomes belonging to the same subtype show average homologies of more than 90% (Okamoto et al., 1992). However, the partial nucleotide sequence of the NS5 region of the HCV-T isolates showed at most 67% homology with the previously published sequences, indicating the existence of yet another HCV type (Mori et al., 1992). Parts of the 5′ untranslated region (UR), core, NS3, and NS5 regions of this type 3 have been published, further establishing the similar evolutionary distances between the 3 major genotypes and their subtypes (Chan et al., 1992). Type 4 was subsequently discovered (Stuyver et al., 1993b; Simmonds et al., 1993a; Bukh et al., 1993; Stuyver et al., 1994a). As well as type 5 (Stuyver et al., 1993b; Simmonds et al., 1993c; Bukh et al., 1993; Stuyver et al., 1994b), and type 6 HCV groups (Bukh et al., 1993; Simmonds et al., 1993c). An overview of the present state of the art regarding HCV genotypes is given in Table 3. The nomenclature system proposed by the inventors of the present application has now been accepted by scientists worldwide (Simmonds et al., 1994).
The aim of the present invention is to provide new HCV nucleotide and amino acid sequences enabling the detection of HCV infection.
Another aim of the present infection is to provide new nucleotide and amino acid HCV sequences enabling the classification of infected biological fluids into different serological groups.
Another aim of the present invention is to provide new nucleotide and amino acid HCV sequences ameliorating the overall HCV detection rate.
Another aim of the present invention is to provide new HCV sequences, useful for the design of HCV prophylactic or therapeutic vaccine compositions.
Another aim of the present invention is to provide a pharmaceutical composition consisting of antibodies raised against the polypeptides encoded by these new HCV sequences, for therapy or diagnosis.
All the aims of the present invention are met by the following embodiments of the present invention.
The present invention relates more particularly to an HCV polynucleic acid, having a nucleotide sequence which is unique to a heretofore unidentified HCV type or subtype which is different from HCV subtypes 1a, 1b, 1c, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 3e, 3f, 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 5a or
6
a
, with said HCV subtypes being classified as in Table 3 by comparison of a part of the NS5 gene nucleotide sequence spanning positions 7932 to 8271, with said amino acid numbering being shown in Table 1, and with said polynucleic acid containing at least one nucleotide differing from said known HCV nucleotide sequences, or the complement thereof. The sequence of known HCV isolates may be found in any nucleotide sequence database known in the art (such as for instance the EMBL database).
The present invention thus also relates to a polynucleic acid having a nucleotide sequence which is unique to at least one of HCV subtypes 1d, 1e, 1f, 1g, 2e, 2f, 2g, 2h, 2i, 2k, 2l, 3g, 4k, 4l, 4m, 7a, 7c or 7d, with said HCV being classified as defined above.
The present invention thus also relates to a polynucleic acid having a nucleotide sequence which is unique to at least one of HCV types 9, 10 or 11, with said HCV types being classified as defined above.
It is to be noted that the nucleotide(s) difference in the polynucleic acids of the invention may involve an amino acid difference in the corresponding amino acid sequences encoded by said polynucleic acids. A composition according to the present invention may contain only polynucleic acid sequences or polynucleic acid sequences mixed with any excipient known in the art of diagnosis, prophylaxis or therapy.
According to a preferred embodiment, the present invention relates to a polynucleic acid encoding an HCV polyprotein comprising in its amino acid sequence at least one of the following amino acid residues:
I15, C38, V44, A49, Q43, P49, Q55, A58, S60 or D60, E68 or V68, H70, A71 or Q71 or N71, D72, H81, H101, D106, S110, L130, I134, E135, L140, S148, T150 or E150, Q153, F155, D157, G160, E165, I169, F181, L186, T190, T192 or I192 or H192, I193, A195, S196, R197 or N197 or K197, Q199 or D199 or H199 or N199, F200 or T200, A208, I213, M216 or S216, N217 or S217 or G217 or K217, T218, I219, A222, Y223, I230, W231 or L231, S232 or H232 or A232, Q233, E235 or L235, F236 or T236, F237, L240 or M240, A242, N244, N249, I250 or K250 or R250, A252 or C252, A254, I255 or V255, D256 or M256, E257, E260 or K260, R261, V268, S272 or R272, I285, G290 or F290, A291, A293 or L293 or W293, T294 or A294, S295 or H295, K296 or E296, Y297 or M297, I299 or Y299, I300, S301, P316, S2646, A2648, G2649, A2650, V2652, Q2653, H2656 or L2656, D2657, F2659, K2663 or Q2663, A2667 or V1667, D2677, L2681, M2686 or Q2686 or E2686, A2692 or K2692, H2697, I2707, L2708 or Y2708, A2709, A2719 or M2719, F2727, T2728 or D2728, E2729, F2730 or Y2730, I2741, I2745, V2746 or E2746 or L2746 or K2746, A2748, S2749 or P2749, R2750, E2751, D2752 or N2752 or S2752 or T2752 or V2752 or I2752 or Q2752, S2753 or D2753 or G2753, D2754, A2755, L2756 or Q2756, R2757,
with said notation being composed of a letter representing the amino acid residue by its one-letter code, and a number representing the amino acid numbering according to Kato et al. (1980), as shown in Table 1, or a part of said polynucleic acid which is unique to at least one of the HCV subtypes or types as defined in Table 5, and which contains at least one nucleotide differing from known HCV nucleotide sequences, or the complement thereof.
Each of the above-mentioned residues can be found in
FIGS. 2
,
4
or
6
showing the new amino acid sequences of the present invention aligned with known sequences of other types or subtypes of HCV for the Core/E1 region.
A
Maertens Geert
Stuyver Lieven
Arnold White & Durkee
Eisenschenk Frank C.
Innogenetics N.V.
Zeman Mary K
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