Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Reexamination Certificate
2000-03-20
2001-08-28
Carlson, Karen Cochrane (Department: 1653)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
C435S363000, C435S325000, C435S366000, C514S021800, C514S025000, C424S184100
Reexamination Certificate
active
06281013
ABSTRACT:
FIELD OF THIS INVENTION
This invention relates to an improved method of in vitro fertilisation (hereinafter designated IVF).
BACKGROUND OF THIS INVENTION
Since the first IVF pregnancy was delivered in 1978, this procedure has resulted in thousands of pregnancies and opened a vast new frontier of research and treatment for the infertile couples. Still, there is a significant need for improved infertility treatment modalities today. It is presumed that about one out of seven couples experience problems with subfertility or infertility.
IVF of human oocytes has become commonly used for the treatment of female and male subfertility. The standard IVF treatment includes a long phase of hormone stimulation of the female patient, e.g. 30 days, which is initiated by suppressing the patient's own follicle stimulating hormone (hereinafter designated FSH) and luteinising hormone (hereinafter designated LH) by gonadotropin releasing hormone (hereinafter designated GnRH), and this is followed by injections of exogenous gonadotropins, e.g. FSH and/or LH, in order to ensure development of multiple preovulatory follicles and aspiration of multiple in vivo matured oocytes immediately before ovulation. The aspirated oocyte is subsequently fertilised in vitro and cultured, typically for three days before transferral back into the uterus at the 4-8 cell stage. Continuous efforts have been made to optimise and simplify this procedure. Nevertheless, the overall pregnancy rate cannot be increased significantly over about 20% with the current treatment modalities. In a large European survey of IVF patients, it was found that 7.2 oocytes out of 11.5 aspirated oocytes per patient had undergone resumption of meiosis immediately before fertilisation, only 4.3 oocytes were fertilised and only 2.2 oocytes reached the 8-cell embryo stage after fertilisation and in vitro culture (ESHRE, Edinburgh, 1997).
Due to the very unpredictable quality of the state of the art embryos today, more than one embryo has to be transferred just to give a reasonable chance of success. Therefore, it is common to transfer 2-3 embryos (up to 5 embryos in some countries), which carries the very large side effect of multiple pregnancies with great discomfort and risk to both patient and children. Moreover, it has been estimated that the increased health care expenses due to multiple birth (twins, triplets etc.) is exceeding the entire IVF expenses.
Hence, there are several disadvantages with the current treatment, the four most notable being:
1. the risk of ovarian hyperstimulation with injecting gonadotropins which is a potential fatal condition that requires hospitalisation,
2. multiple pregnancies (50-1.000 times the normal frequency of twins and triplets, respectively),
3. the existence of considerable patient segments that do not tolerate the current method due to, e.g. polycystic ovarian syndrome and many diabetics, and
4. a potential long-term cancer risk.
Furthermore, weight gain, bloating, nausea, vomiting, labile mood and other patient discomforts together with patient reluctance to inject themselves are reported as disadvantages.
It is known from WO96/00235 that certain sterol derivatives can be used for regulating meiosis. An example of such a sterol is 4,4-dimethyl-5&agr;-cholesta-8,14,24-triene-3&bgr;-ol(hereinafter designated FF-MAS).
Herein, the term MAS compounds designates compounds which mediate the meiosis of oocytes. More specifically, MAS compounds are compounds which in the test described in Example 1 below has a percentage germinal vesicle breakdown (hereinafter designated GVB) which is significantly higher than the control. Preferred MAS compounds are such having a percentage GVB of at least 50%, preferably at least 80%.
Examples of MAS compounds are mentioned in WO96/00235, 96/27658, 97/00884, 98/28323, 98/54965 and 98/55498, more specifically in claim
1
thereof.
In WO95/000265, some potential meiosis regulating substances were tested on immature female mice. 48 hours before the test animal were killed by cervical dislocation, they were given a single injection of human menopausal gonadotropin containing 20 IU FSH and 20 IU LH. The ovaries were removed, placed in a hypoxanthine medium and freed of extraneous tissue. Then, the oocytes were punctured out of the follicles, freed from cumulus cells and cultured in a medium containing a meiosis regulating derivative.
At present, in vitro maturation in humans has proven highly unsuccessful despite substantial interest and clinical efforts.
One object of the present invention is to treat human infertility.
Another object of the present invention is to improve the maturation of her human oocytes.
Another object of the present invention is to improve the synchrony of nuclear, cytoplasmic and/or membranous oocyte maturation.
Another object of the present invention is to improve the fertility of oocytes.
Another object of the present invention is to improve the rate of implantation of oocytes by human in vitro maturation and fertilisation.
Another object of the present invention is to diminish the incidence of human preembryos with chromosome abnormalities (aneuploidy).
Another object of the present invention is to improve the cleavage rate of human preembryos.
Another object of the present invention is to improve the quality of human preembryos.
SUMMARY OF THIS INVENTION
It has now, surprisingly, been found that the IVF treatment and the degree of side effects can be improved substantially if the woman, within a consecutive period of 30 days, avoids treatment with a hypothalamic hormone and/or a pituitary hormone or an agonist or antagonist thereof or an active derivative thereof (hereinafter this treatment is designated exogeneous stimulation) or if the exogeneous stimulation treatment of the female is only for a short period of time, e.g. less than 7 days, preferably less than 4 days. Using this improved method involving less or no exogeneous stimulation, a MAS compound is used to actively mature and synchronise human oocytes in vitro, leading to fertilisation and embryo development.
Briefly, the present invention relates to a method for human in vitro fertilisation wherein a woman, within a consecutive period of 30 days, is treated with a hypothalamic hormone and/or a pituitary hormone or an agonist or antagonist thereof or an active derivative thereof for a period which is less than about 7 days, preferably less than about 4 days, and, thereafter, using in vitro oocyte maturation wherein immature egg or eggs are retrieved from the woman and are in vitro matured in a synchronize manner using a MAS compound as defined herein. Preferred embodiments of this invention are those stated in the sub claims below.
DETAILED DESCRIPTION OF THIS INVENTION
Referring to the female cycle, one way of performing the IVF treatment of this invention is as follows:
Around days 6-9 in the cycle: Stimulation with FSH, e.g. 75-600 IU per day, preferably 150-225 IU per day, e.g. for 3 days.
Around day 9: The eggs are retrieved from the woman using ultrasound guided aspiration of small to medium size follicles with a diameter of about 6-12 mm, preferably 8-10 mm.
Around day 9-11: The eggs are maturated with a MAS compound in order to stimulate the meiosis. In this maturation step, the concentration of MAS compound may be in the range of about 0.1-100 &mgr;mol per litre, e.g. 10-20 &mgr;mol per litre. This medium may contain human serum albumin (hereinafter designated HSA), e.g. 0.8%, and it may additionally contain some ethanol, e.g., 0.4%, which has been used to dissolve MAS. The time for this maturation step may be in the range around 15-60 hours, e.g., about 22-40 hours, more specifically about 30-36 hours.
Around days 11-13: The eggs are fertilised in vitro.
Around days 12-16: The eggs are cultured in vitro in a suitable medium.
From the day before aspiration, the woman will receive an oestrogen, e.g. oestrogen valerate (2×10 mg daily). Two days later, she will also receive a progestogen, e.g., Progestane vagetoria, daily, which will render the lining of the uterus more
Carlson Karen Cochrane
Green, Esq. Reza
Gregg, Esq. Valeta A.
Novo Nordisk A S
Robinson Patricia
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