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To understand better the stage at which this lethality arises, we examined siliques 29 h after pollination and found that a significant proportion of developing endCYCD7;1 embryos had aborted (Figure 4d), although this was a lower frequency of abortion than is observed in mature siliques. These siliques showed no aborted embryos (n = 128) that had progressed beyond globular phase, suggesting that the early stages of embryo development are particularly susceptible to the effects of endCYCD7;1.
"1. Use of a composition comprising a combination of growth hormone and gonadotrophins for the production of a medicament for treatment of infertility in mature human beings or mature higher female mammals, said growth hormone being specific to the species in question."
"2. Use of a composition comprising a combination of growth hormone and gonadotrophins for the production of a medicament for treatment of infertility in mature human beings or mature higher female mammals, by administration of individually adapted amounts effective to enhance ovarian follicle and oocyte maturation in said mammal or human being, said growth hormone being specific to the species in question."
- The claimed medical use was not novel over document (1) disclosing the use in vivo of growth hormone together with gonadotrophins to induce ovulation in immature (prepubertal) female rats, which went from an infertile state to a fertile one.
Document (1) taught that pregnant mare serum gonadotrophin (PMSG) induced ovulation in prepubertal rats weighing less than 60 g only if these had previously been treated with GH. The administration of PMSG was associated with hypersecretion of luteinizing hormone (LH). Therefore, the skilled person would expect that the combination of gonadotrophins with growth hormone (GH) would achieve the same effect in mature female with hypothalamic amenorrhea, having regard to the fact that the physiological status of an immature (prepubertal) female rat and that of a mature female with hypothalamic amenorrhea were identical (in both cases there was a lack of gonadotrophin releasing hormone (GnRH) signal from the brain being delivered to the anterior pituitary (see Ref. (1) to (3) and (10)).
- While the (prepubertal) female rat was a widely accepted animal model for studying the mechanisms involved in the onset of puberty, it was not used for studying infertility in mammals. Facts relating to inducing puberty in immature rats had no relevance to the treatment of infertile mature sexually active rats. The adult infertile state was not equivalent to the prepubertal state. Growth hormone (GH) did not play the same role in both states. In the prepubertal state, the plasma concentration of GH first raised then dropped when maturation was reached. All the cited documents dealt with investigations on factors (including GH) involved in pubertal development, not with unwanted pathological infertility.
2. The wording "mammal" in claims 1, 2 and 7 finds a basis on page 1, line 2 of the application as filed. Although not stated expressis verbis, the term "mature" in these claims is implicit from the whole context of the application as filed (page 5, lines 23 to 24) referring to infertility of couples ("Infertility among couples is estimated to have an annual incidence of 1.2 couples for every 1,000..."): infertility of necessity occurs in spite of sexual maturity and unprotected sexual activity. It is also implicit that the patients subjected to the claimed infertility treatment (see the Examples in the application as filed) are "mature" since they are aged 35, 39, 39 and 38. The wording "specific to the species in question" in claims 1, 2 and 7 finds a basis on page 5, lines 18 to 19 of the application as filed.
3. The term "mature" is clear and means "sexually mature", as can be deduced from the application as filed relating to females who fail to become pregnant in spite of sexual maturity and unprotected sexual activity (see page 5, lines 23 to 24: infertility of couples; see also the Examples in the application as filed, wherein the patients are aged 35, 39, 39 and 38).
5. Document (1) discloses the use in vivo of bovine growth hormone (see page 180, l-h column, under the heading "Treatments"), together with gonadotrophins to induce ovulation in immature (prepubertal) female rats. The wording in claims 1, 2 and 7, however, requires inter alia that the growth hormone should be specific to the species in question. The subject-matter of claims 1, 2 and 7 is therefore novel over document (1), wherein bovine growth hormone is administered to rats. This conclusion also applies to claims 3 to 6 by virtue of their dependency on claim 1.
9. The appellant argues that it was obvious to combine gonadotrophins with GH for the treatment of infertility in the light of document (1) and of the fact that the immature (prepubertal) female rat was a widely accepted animal model for studying infertility in mammals. The board observes that Table (1) of document (1) relates to the ovulatory effect of various hormones on rats weighing less than 60 g previously treated with PMSG (equivalent to gonadotrophins). This Table shows that LH, FSH, ACTH (1-39) (porcine corticotropin), its fragment ACTH (1-24) and corticosterone all perform better than GH in potentiating PMSG. Administration of GH with PMSG thus achieves one of the worst results (only 12 out of 22 rats ovulate). Therefore, in the board's view, even if one accepts the appellant's "rat model for studying infertility", the conclusion cannot be drawn that document (1) encourages the skilled person to combine gonadotrophins with GH. Further, in another experiment aiming at studying the effect of PSMG, GH and corticosterone on the ovarian function (see Table (2) of document (1)), the number of hCG binding sites in ovarian tissue is measured. It turns out that the addition of GH to PSMG has no effect in increasing the number of hCG binding sites in ovarian tissue (PMSG alone = 29.59 cpm x 10-2; PSMG + GH = 29.36 cpm x 10-2). In the board's opinion, this experimental result further dissuades the skilled person from combining gonadotrophins with GH. 59ce067264