Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2000-03-20
2003-07-01
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S184100, C424S185100, C424S193100
Reexamination Certificate
active
06585982
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,
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 WO 96/00235, corresponding to U.S. Pat. No. 5,716,777, that certain sterol derivatives can be used for regulating meiosis. An examples 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 WO 96/00235, corresponding to U.S. Pat. No. 5,716,777, which describes, inter alia, sterol derivatives, WO 96/27658, corresponding to U.S. Pat. No. 5,830,757, which describes, inter alia, inhibitors of enzymes involved in the biosynthesis of cholesterol, for example, lanosterol 1.4 reductase, 4-demethylase, and lanosterol 8-7-isomerase, and endogenous meiosis activating substances, for example, FF-MAS and 4&bgr;-methylzymosterol, WO 97/00884, corresponding to U.S. patent application Ser. No. 08/973,661, which describes, inter alia, sterol derivatives, WO 98/28323, corresponding to U.S. patent application Ser. No. 09/333,391, which describes, inter alia, sterol derivatives, WO 98/52965, corresponding to U.S. Pat. No. 6,177,240, which describes, inter alia, 20-aralkyl-5&agr;-pregnane derivatives, and WO 98/55498, corresponding to U.S. Pat. No. 6,262,282, which describes, inter alia, 17&bgr;-allyloxy(thio)alkyl-andostrane derivatives, more specifically in claim 1 thereof.
In WO 95/000265, 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 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 can be improved substantially when a MAS compound is added at the stage in the usual method of performing in vitro fertilisation where one would expect that the maturation had taken place in vivo.
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 where after oocytes are aspirated and actively final matured or the oocyte maturation is synchronised in vitro in contact with a MAS compound. Preferred embodiments of this invention are those stated in the sub claims below.
DETAILED DESCRIPTION OF THIS INVENTION
Referring to the female cycle, on way of performing the treatment of this invention is as follows:
Around day 21 in one cycle to around day 15 in the following cycle: The eggs are stimulated by treating the woman with GnRH, e.g. Synarel (400-600 &mgr;g per day).
Around days 6-15 in the second cycle: The eggs are stimulated by treating the woman with FSH, e.g. Gonal-F, Puregon or Humegon (150-400 IU per day).
Around days 15-16 in the second cycle: The eggs are stimulated by treating the woman with hCG, e.g. Pregnyl or Profasi (2000-5000 IU per day).
Around day 18 in the second cycle: The eggs are retrieved from the woman.
Around day 18-19 in the second cycle: The eggs are maturated with a MAS compound in order to stimulate the meiosis. In this additional maturation step, the concentration of MAS compound may be in the range about 0.1-100 &mgr;mol per liter, e.g. 10-20 &mgr;mol per liter. The time for this maturation step may be in the range around 1-60 hours. If the preovulatory follicles are induced to luthenise with a lu
Grøndahl Christian
Hansen Thomas Høst
Hegele-Hartung Christa
Rübig Alexander
Began, Esq. Mark A.
Bork, Esq. Richard W.
Fubara Blessing
Green, Esq. Reza
NNA/S
LandOfFree
Treatment of infertility does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Treatment of infertility, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Treatment of infertility will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3014012