Compositions and Methods for Controlled Ovarian Stimulation

The present invention relates to methods, compositions and pharmaceutical products for the treatment of infertility.

Background

Assisted reproductive technologies (ART) such as in vitro fertilisation (IVF) and

microinsemination are well known. ART generally requires a step of controlled ovarian stimulation (COS), in which a cohort of follicles is stimulated to full maturity. Standard COS regimens include administration of gonadotrophins, such as follicle stimulating hormone (FSH), alone or in combination with luteinising hormone (LH) activity to stimulate multiple follicular development. Usually COS requires administration of a GnRH analogue, or GnRH agonist, prior to and/or during stimulation to prevent a premature LH surge which may induce ovulation before planned oocyte retrieval. The pharmaceutical compositions generally used for COS include recombinant follicle stimulating hormone (rFSH) including REKOVELLE® and GONAL-F®, urinary derived FSH, recombinant FSH + LH preparations, urinary derived menotrophin [human menopausal gonadotrophin (hMG)] and highly purified human menopausal gonadotrophin (HP-hMG).

In case of a too high ovarian response, COS can be associated with a risk of ovarian hyperstimulation syndrome (OHSS), which can become life threatening in severe cases.

The ability to predict the ovarian response potential of women to COS may allow the development of personalised or individualised COS protocols. Such individualised protocols could, for example, reduce the risk of OHSS in women predicted to have an excessive ovarian response to COS, and/or improve the chance of pregnancy in women classed as poor responders. Levels of AMH are directly correlated with the ovarian response to gonadotrophins during COS. Thus, high levels of AMH are a good predictor of excessive ovarian response, and an indicator of risk of OHSS, whereas low levels of AMH predict a poor ovarian response to COS.

Clinical research has focused the last years on the development of individualised dosing regimens for COS, initially without using AMH but based on other predictors of ovarian response. These predictors include age, body mass index (BMI), FSH, and antral follicle count (AFC).

As indicated above, standard COS protocols require daily FSH administration to induce multiple follicular growth to obtain sufficient oocytes for IVF. FSH is a natural hormone that is secreted by the anterior pituitary gland. In healthy women FSH induces monthly the growth of a single dominant follicle that ovulates during each natural cycle. FSH purified from the urine of post-menopausal women has been used for many years in infertility treatment, both to promote ovulation in natural reproduction and to induce multiple follicular growth to obtain sufficient oocytes for ART.

Until recently, the only approved rFSH products for ovarian stimulation, such as follitropin alfa (GONAL-F®, Merck Serono / EMD Serono) and follitropin beta (PUREGON® /

FOLLISTIM®, MSD / Schering-Plough), were derived from a Chinese Hamster Ovary (CHO) cell line. The present applicants have developed a human cell line-derived rFSH which is the subject of International Patent Application No. PCT/GB2009/000978, published as WO2009/127826A. On 13 December 2016, the European Commission (EC) granted marketing authorisation for REKOVELLE® (follitropin delta, also known as FE 999049), a human cell line-derived recombinant follicle stimulating hormone (human rFSH), for use in controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART), such as an in vitro fertilisation (IVF) cycle.

REKOVELLE® is the first rFSH to be derived from a human cell line. The REKOVELLE® (follitropin delta) product is produced by the methods disclosed in International Patent Application No. PCT/GB2009/000978.

The posology of REKOVELLE® is individualised for each patient and aims to obtain an ovarian response which is associated with a favourable safety/efficacy profile, i.e. aims to achieve an adequate number of oocytes retrieved and reduce the interventions to prevent OHSS. REKOVELLE® is dosed in micrograms (pg). For the first treatment cycle, the individual daily dose is determined on the basis of the woman’s serum AMH concentration and, depending on serum AMH concentration, her body weight. The dose is based on a recent determination of AMH (i.e. within the last 12 months) measured by the ELECSYS® AMH Plus immunoassay (Roche). The individual daily dose is maintained throughout the stimulation period. For women with AMH <15 pmol/L the daily dose of REKOVELLE® is 12 pg, irrespective of body weight. For women with AMH >15 pmol/L the daily dose of

REKOVELLE® is lower, and ranges from 0.19 pg /kg to 0.10 pg /kg over AMH

concentrations of 15 to ³40 pmol/L. For subsequent treatment cycles, the daily dose of REKOVELLE® is maintained or modified according to the patient’s ovarian response in the previous cycle. If the patient had adequate ovarian response in the previous cycle without developing OHSS, the same daily dose is used. In case of ovarian hypo-response in the previous cycle, the daily dose in the subsequent cycle is increased by 25% or 50%, according to the extent of response observed. In case of ovarian hyper-response in the previous cycle, the daily dose in the subsequent cycle is decreased by 20% or 33%, according to the extent of response observed. In patients who developed OHSS or were at risk of OHSS in a previous cycle, the daily dose for the subsequent cycle is 33% lower than the dose the cycle where OHSS or risk of OHSS occurred. The maximum daily dose of REKOVELLE® is 24 pg.

Still, there is a need for COS protocols which provide adequate response to stimulation and/or decreased risk of OHSS.

SUMMARY

In accordance with some aspects, there are provided compositions comprising recombinant follicle stimulating hormone (rFSH) for use in the treatment of infertility in a patient of age ³ 35 years, wherein the composition is for administration at a (e.g., starting) dose of, or a (e.g., starting) dose equivalent to, 15 pg rFSH per day. Also provided are compositions for use in the treatment of infertility in a patient of age ³ 35 years, wherein the composition comprises a (e.g., starting) dose of, or a (e.g., starting) dose equivalent to, 15 pg rFSH per day. The composition may be for administration at a (e.g., starting) dose of 15 pg rFSH per day.

In accordance with some aspects, there are provided compositions comprising rFSH for use in the treatment of infertility in a patient of age ³ 35 years, wherein the composition is for administration at a starting dose of 15 pg rFSH per day, wherein the starting dose is administered on at least day 1 of treatment (preferably on at least day 1 and day 2 of treatment, more preferably on each of days 1 to 4 of treatment), optionally wherein the dose is (i) increased by a first incremental dose increase of 3 pg recombinant FSH on any subsequent day of treatment; and/or (ii) decreased by a first incremental dose decrease of 3 pg recombinant FSH on any subsequent day of treatment. The dose may be maintained at the starting dose for the duration of the treatment. Alternatively, a first incremental dose increase of 3 pg rFSH may be (a) followed by at least one further incremental dose increase of 3 pg rFSH at least two days after the previous incremental change in dose; and/or (b) followed by at least one incremental dose decrease of 3 pg rFSH at least one day after the previous incremental change in dose. Additionally or alternatively, a first incremental dose decrease of 3 pg rFSH may be (a) followed by at least one incremental dose increase of 3 pg rFSH at least two days after the previous incremental dose change in dose; and/or (b) followed by at least one further incremental dose decrease of 3 pg rFSH at least one day after the previous change in dose. The dose may be increased to a maximum daily dose of 24 pg or decreased to a minimum daily dose of 6 pg.

In accordance with some aspects, there are provided compositions comprising rFSH for use in the treatment of infertility in a patient identified as being of age £ 34 years, wherein the composition is for administration at a (e.g., starting) dose of, or a (e.g., starting) dose equivalent to, 12 pg rFSH per day. Also provided are compositions for use in the treatment

of infertility in a patient identified as being of age £ 34 years, wherein the composition comprises a (e.g., starting) dose of, or a (e.g., starting) dose equivalent to, 12 pg rFSH per day. The composition may be for administration at a (e.g., starting) dose of 12 pg rFSH per day.

In accordance with some aspects, there are provided compositions comprising rFSH for use in the treatment of infertility in a patient of age £ 34 years, wherein the composition is for administration at a starting dose of 12 pg rFSH per day, wherein the starting dose is administered on at least day 1 of treatment (preferably on at least day 1 and day 2 of treatment, more preferably on each of days 1 to 4 of treatment), optionally wherein the dose is (i) increased by a first incremental dose increase of 3 pg rFSH on any subsequent day of treatment; and/or (ii) decreased by a first incremental dose decrease of 3 pg rFSH on any subsequent day of treatment.

The dose may be maintained at the starting dose for the duration of the treatment.

Additionally or alternatively, a first incremental dose increase of 3 pg rFSH may be (a) followed by at least one further incremental dose increase of 3 pg rFSH at least two days after the previous incremental change in dose; and/or (b) followed by at least one incremental dose decrease of 3 pg rFSH at least one day after the previous incremental change in dose. Additionally or alternatively, a first incremental dose decrease of 3 pg rFSH may be (a) followed by at least one incremental dose increase of 3 pg rFSH at least two days after the previous incremental dose change in dose; and/or (b) followed by at least one further incremental dose decrease of 3 pg rFSH at least one day after the previous change in dose. The dose may be increased to a maximum daily dose of 24 pg or decreased to a minimum daily dose of 6 pg.

In accordance with some aspects, there are provided methods of treating infertility in a female patient age ³ 35 years, comprising administering recombinant follicle stimulating hormone (rFSH) at a dose of, or a dose equivalent to, 15 pg rFSH per day starting on day 1 of treatment. The rFSH may be administered at a dose of 15 pg rFSH per day starting on day 1 of treatment.

In accordance with some aspects, the method comprises administering rFSH at a starting dose of 15 pg per day for at least 1-4 days; and, optionally, on any subsequent day,

(i) increasing the dose of rFSH by an incremental dose increase of 3 pg rFSH or (ii) decreasing the dose of rFSH by an incremental dose decrease of 3 pg rFSH. The rFSH dose may be maintained at the starting dose of 15 pg per day throughout the treatment. Additionally or alternatively, an incremental dose increase of 3 pg rFSH may be followed by (a) a further incremental dose increase of 3 pg rFSH at least two days after the previous incremental dose increase or (b) an incremental dose decrease of 3 pg rFSH at least one

day after the previous incremental dose increase. Additionally or alternatively, an incremental dose decrease of 3 pg rFSH may be followed by (a) an incremental dose increase of 3 pg rFSH at least one day, or at least two days, after the previous incremental dose decrease or (b) a further incremental dose decrease of 3 pg rFSH at least one day after the previous incremental dose decrease. In accordance with some aspects, throughout the treatment the maximum daily dose of rFSH is 24 pg and the minimum daily dose is 6 pg.

In accordance with some aspects, there are provided methods of treating infertility in a female patient identified as being of age £ 34 years, comprising administering rFSH at a dose of, or a dose equivalent to, 12 pg rFSH per day starting on day 1 of treatment. The rFSH may be administered at a dose of 12 pg rFSH per day starting on day 1 of treatment.

In accordance with some aspects, the method comprises administering rFSH at a starting dose of 12 pg per day for at least 1-4 days; and, optionally, on any subsequent day,

(i) increasing the dose of rFSH by an incremental dose increase of 3 pg rFSH or (ii) decreasing the dose of rFSH by an incremental dose decrease of 3 pg rFSH. The rFSH dose may be maintained at the starting dose of 12 pg per day throughout the treatment. Additionally or alternatively, an incremental dose increase of 3 pg rFSH is followed by (a) a further incremental dose increase of 3 pg rFSH at least two days after the previous incremental dose increase or (b) an incremental dose decrease of 3 pg rFSH at least one day after the previous incremental dose increase. Additionally or alternatively, an incremental dose decrease of 3 pg rFSH is followed by (a) an incremental dose increase of 3 pg rFSH at least one day, or at least two days, after the previous incremental dose decrease or (b) a further incremental dose decrease of 3 pg rFSH at least one day after the previous incremental dose decrease. In accordance with some aspects, throughout the treatment the maximum daily dose of rFSH is 24 pg and the minimum daily dose is 6 pg.

In accordance with some aspects, there are provided methods of treating infertility in a female patient, comprising determining the age of the patient; if the patient is age ³ 35 years, administering recombinant follicle stimulating hormone (rFSH) at a starting dose of 15 pg rFSH per day for at least 1-4 days; if the patient is age £ 34 years, administering rFSH at a starting dose of 12 pg rFSH per day for at least 1-4 days; optionally, on any subsequent day, (i) increasing the dose of rFSH by an incremental dose increase of 3 pg rFSH or (ii) decreasing the dose of rFSH by an incremental dose decrease of 3 pg rFSH, wherein, throughout the treatment, the maximum daily dose of rFSH is 24 pg and the minimum daily dose is 6 pg.

In accordance with any embodiments, the treatment of infertility may comprise a step of determining the age of the patient, and a step of administering the defined dose of rFSH to a patient having the defined age. In accordance with any embodiments, the treatment of infertility may comprise determining the age of the patient, and then administering the starting dose of rFSH described herein for the patient’s age.

In accordance with any embodiments, the treatment of infertility further comprises retrieving (e.g. harvesting) oocyte(s); fertilizing (e.g. inseminating) the oocytes (s); and allowing the fertilized oocytes to develop to the blastocyst stage. In accordance with any embodiments, the treatment of infertility further comprises assessing the quality of blastocysts obtained after fertilization of the harvested oocytes.

In accordance with any embodiments, the treatment of infertility step of monitoring the patient for over-response to treatment by identifying, during treatment, a patient with > 20 follicles with a diameter of ³ 12mm and/or a serum estradiol concentration > 3,000 pg/mL; and optionally administering a dose of GnRH agonist (e.g. 4.0 mg) to the patient identified during treatment as having > 20 follicles with a diameter of ³ 12mm and/or a serum estradiol concentration > 3,000 pg/mL.

In accordance with any embodiments, patient may be over 30 years of age and/or previously failed at least one cycle of infertility treatment.

In accordance with any embodiments, the rFSH may include a2,6-sialylation and a2,3-sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation, optionally wherein 5% to 20% of the total sialylation is a2, 6-sialyation, and 80% to 95% of the total sialylation is 2,3-sialyation, optionally wherein 50% to 80% of the total sialylation is a2, 6-sialyation, and 20% to 50% of the total sialylation is 2,3-sialyation.

In accordance with any embodiments, the treatment of infertility is for development of multiple follicles and pregnancy after fresh and/or cryopreserved embryo transfer in ovulatory women undergoing assisted reproductive technology (ART). In accordance with any embodiments, the treatment of infertility is for optimising cumulative efficiency and/or reducing ovarian hyperstimulation syndrome (OHSS) risk.

Detailed Description

The present applicants have now developed a dosing protocol with the aim of maximizing both oocyte yield and resultant cumulative pregnancy rates while maintaining safety. The applicants have devised COS protocols wherein specific doses of recombinant FSH are used to treat patients based on their age, thereby increasing the likelihood of adequate response to stimulation (e.g., in patients having a low response potential), and/or decreased risk of OHSS (e.g., in patients classed as high or excessive responders). Also provided are protocols and compositions for treatment of patients with high ovarian response through use of a GnRH agonist trigger and cryopreserved embryo transfer-only cycles for those patients.

With regard to efficacy, the outcome variable defining ART success now goes beyond the initial fresh transfer of the embryos/blastocyst. Cryopreservation of surplus embryos for potential use after the fresh cycle now is standard practice in ART treatment, and serves to improve chances of pregnancy from a single stimulation cycle. The percentage of transfer cycles involving cryopreserved embryos has steadily increased over recent years. Thus, the cumulative outcomes from both the fresh and subsequent cryopreserved cycles provide an overall measure of a clinical efficacy of a single controlled ovarian stimulation cycle in a more complete manner and reflects the evolution in clinical management of infertility.

With regard to safety, implementation of a gonadotropin-releasing hormone (GnRH) agonist trigger improves patient safety by reducing the risk of early severe ovarian hyperstimulation syndrome (OHSS), which impairs the efficacy in a fresh transfer perspective but does not compromise the overall efficacy based on a cumulative pregnancy rate perspective.

Implementation of GnRH agonist triggering in patients with excessive response to reduce the risk of OHSS, as well as implementation of mandatory single blastocyst transfer to maximize the incidence of singletons and reduce the risk of multiple gestation, address the most common safety concerns.

Therefore, provided herein are dosing regimens constructed to establish a high cumulative ongoing pregnancy rate by a safe high dose while minimizing the risk for OHSS, especially moderate and severe OHSS, such as by using GnRH agonist triggering in case of excessive response.

Definitions

Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art of assisted reproductive technology to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies known to those of ordinary skill in the art. Any suitable materials and/or methods known to those of ordinary skill in the art can be utilized in carrying out the present invention.

However, specific materials and methods are described. Materials, reagents and the like to which reference is made in the following description and examples are obtainable from commercial sources, unless otherwise noted.

It is to be understood, that any definitions and terms herein defined is meant to have the same meaning and purpose in any of the aspects and embodiments of the invention unless explicitly otherwise stated not to.

As used herein, the singular forms“a,”“an,” and“the” designate both the singular and the plural, unless expressly stated to designate the singular only.

As used herein, the term“about” means that the number or range is not limited to the exact number or range set forth, but encompass ranges around the recited number or range as will be understood by persons of ordinary skill in the art depending on the context in which the number or range is used. Unless otherwise apparent from the context or convention in the art,“about” mean up to plus or minus 10% of the particular term.

Herein the terms“patient” and“subject” are used interchangeably.

A subject may have normal serum FSH level of 1 to 16 IU/L, for example 1 to 15 IU/L, for example 1 to 12 IU/L in the early follicular phase. Thus a composition or medicament as described herein may be for (use in) the treatment of infertility (and/or for controlled ovarian stimulation) in a subject having normal serum FSH level of 1 to 16 IU/L, for example 1 to 15 IU/L, for example 1 to 12 IU/L in the early follicular phase.

A subject may have a BMI >1 and BMI < 40 kg/m2, for example a BMI >17.5 and BMI< 38 kg/m2, for example a BMI >18 and BMI < 25 kg/m2, for example a BMI >20 and BMI<25 kg/m2. Thus a product as described herein may be for (use in) the treatment of infertility (and/or for controlled ovarian stimulation) in a subject having BMI >1 and BMI < 40 kg/m2, for example a subject having BMI >17.5 and BMI < 38 kg/m2, for example a subject having BMI >18 and BMI < 25 kg/m2, for example a subject having BMI >20 and BMI < 25 kg/m2.

Herein the term“treatment of infertility” includes treatment of infertility by controlled ovarian stimulation (COS) or methods which include a step or stage of controlled ovarian stimulation (COS), for example in vitro fertilisation (IVF), or intracytoplasmic sperm injection (ICSI). The term“treatment of infertility” includes treatment of infertility in a subject having tubal or unexplained infertility, including treatment of infertility in a subject having endometriosis, for example stage I or stage II endometriosis, and/or in a subject with a partner with male factor infertility. The composition may be for (use in) the treatment of infertility (and/or for controlled ovarian stimulation) in a subject having endometriosis, for example in a subject having stage I or stage II endometriosis, as defined by The American Society for

Reproductive Medicine (ASRM) classification system for the various stages of

endometriosis, (stage IV most severe; stage I least severe) [American Society for

Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67,817 821.].

Herein the term“GnRH agonist” means gonadotropin-releasing hormone agonist. GnRH agonists are a class of medications that act as agonists of the gonadotropin-releasing

hormone receptor (GnRH receptor), the biological target of gonadotropin-releasing hormone.

Herein the term“GnRH antagonist” means gonadotropin-releasing hormone antagonist. GnRH antagonists are a class of medications that antagonize the gonadotropin-releasing hormone receptor (GnRH receptor) and thus the action of gonadotropin-releasing hormone (GnRH).

The term“follicle” herein means an ovarian follicle which is a fluid-filled sac that contains an immature egg, or oocyte.

A blastocyst forms in the early development of a human (or other mammal). In humans, blastocyst formation begins about 5 days after fertilization. The use of blastocysts in (IVF) generally involves retrieval (harvesting) from the woman a number of oocytes resulting from a controlled ovarian stimulation cycle; fertilization (insemination of) one or more oocytes and culturing the fertilized egg (oocyte) for five days to form a blastocyst (i.e. allowing the fertilized oocyte to develop to the blastocyst stage); and implanting the blastocyst into the uterus.

In accordance with all aspects described herein, it is preferred that the treatment of infertility described herein, is or includes, a step of COS. The cause of infertility could be the woman’s partner suffering from male infertility, although it will be appreciated that according to the present invention it is the woman (female) who is treated by COS.

A treatment of infertility as described herein may be for, and may be effective for, development of multiple follicles and pregnancy after fresh and/or cryopreserved embryo transfer in ovulatory women undergoing assisted reproductive technology (ART).

A treatment of infertility as described herein may be for, and may be effective for, promoting good quality blastocysts (e.g., category 3BB or higher blastocysts, e.g., treatment of infertility to increase the number of category 3BB or higher blastocysts on day 5 after oocyte retrieval) and/or to improve embryo implantation. The treatment of infertility may be treatment of infertility to increase the number of category 3BB or higher blastocysts on day 5 after oocyte retrieval (e.g., as compared to treatment with GONAL-F®). The treatment of infertility may be treatment of infertility to increase the number of fertilised (2PN) oocytes (e.g., as compared to treatment with GONAL-F®).

As used herein,“day one of treatment”, also referred to as“day one of stimulation”, refers to the first day that the dose of (e.g., recombinant) FSH is administered to the patient. Day one of treatment (stimulation) may take place on day 1 , 2 or 3, for example on day 2 or day 3, of the patient’s menstrual cycle. In other words, day one of treatment (stimulation) may

be one, two or three days, for example two or three days, after the patient commences menstrual bleeding, consistent with usage of this term in clinical practice with GnRH antagonist or GnRH agonist protocols. The term“during treatment” means on a day or on days that FSH is being administered to the patient.

In the treatments described herein, the administration of recombinant FSH starts on day one of treatment and may continue for two to twenty days, for example continue for 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 days. The dose administered on day 1 is referred to herein as the“starting dose”. The administration of recombinant FSH starts on day one of treatment and may continue for four to twenty days, for example seven to thirteen days, for example nine to thirteen days, for example 10 to 13 days, for example 10 to 1 1 days. The dose may be the same every day. However, variation of the dose depending on the patient’s ovarian response (e.g., as measured by ultrasonography) is more likely.

In accordance with all aspects described herein, the recombinant FSH may be human cell line-derived recombinant FSH as described in more detail below. In all aspects, the recombinant FSH may be that sold under the trademark REKOVELLE® (follitropin delta) (Ferring B.V.). In all aspects, the recombinant FSH may be administered by injection, e.g., subcutaneous injection.

In accordance with all aspects described herein, the recombinant FSH composition (e.g., pharmaceutical composition) or medicament may be administered after pre-treatment of the patient with a (different) pharmaceutical composition, herein termed“composition A”, which suppresses endogenous gonadotropin production prior to day one of the treatment with rFSH. In other words, the composition (e.g., pharmaceutical composition) or medicament may be administered after the subject has been (pre-) treated with composition A, wherein composition A is a steroid, a GnRH agonist, a GnRH antagonist, etc. Herein, the term“pre treated” or“pre-treatment” refers to administration of the pharmaceutical composition which suppresses endogenous gonadotropin production prior to day one of the treatment with rFSH (i.e., prior to day 1 of treatment), consistent with usage of this term in clinical practice with long GnRH agonist protocols.

Thus, the composition (e.g., pharmaceutical composition) or medicament for use described herein may be for administration 12 to 16, e.g., 13 to 15, e.g., 14 days, after administration of (e.g., after initiation of administration of, e.g., after initiation of daily administration of) a GnRH agonist (e.g., SYNAREL®, LUPRON®, DECAPEPTYL®). Additionally or alternatively, the recombinant FSH composition for use described herein may be for administration with a GnRH agonist.

Alternatively, the recombinant FSH composition (e.g., pharmaceutical composition) or medicament may be administered, or may be for administration, prior to administration of a GnRH antagonist (e.g., GANIRELIX®, CETRORELIX®), for example for administration five or six days prior to administration of a GnRH antagonist (i.e. , for administration such that day 1 of stimulation is 5 or 6 days prior to administration of a GnRH antagonist). Additionally or alternatively, the recombinant FSH composition (e.g., pharmaceutical composition) for use described herein may be for administration with a GnRH antagonist.

Typically, in accordance with all aspects described herein, the recombinant FSH

composition (e.g., pharmaceutical composition) or medicament is administered, or is for administration, prior to administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG) (for example 4,000 to 1 1 ,000 IU hCG, e.g., 5,000 IU hCG, 10,000 IU hCG, etc.; or 150 to 500 pg recombinant hCG, for example 250 pg recombinant hCG); to induce final follicular maturation. Thus, in some embodiments, the methods described herein further comprise administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG).

In accordance with all aspects described herein, the treatment of infertility described herein may further comprise: retrieving (e.g., harvesting) oocyte(s); fertilizing (e.g., inseminating) the oocytes (s); and allowing the fertilized oocytes to develop to the blastocyst stage. The fertilization (e.g., insemination) may be in vitro fertilization, optionally intra-cytoplasmic sperm injection (ICSI).

In accordance with all aspects described herein, the treatment of infertility described herein may further comprise assessing the quality of blastocysts obtained after fertilization of the harvested oocytes [e.g., to identify one or more good quality (i.e. grade 3BB or above) blastocysts]. Assessment of blastocyst quality may take place on day 5 after oocyte retrieval and may study three parameters: blastocyst expansion and hatching status (grade 1-6), blastocyst inner cell mass grading (grade A-D) and trophectoderm grading (grade A-D), as is well known in the art. Blastocysts can be given a numerical score by using the system of Gardner & Schoolcraft, as is well known in the art, with the addition of D-categories for inner cell mass and trophectoderm.

In accordance with all aspects described herein, the treatment of infertility described herein may further comprise transfer of one or more blastocyst(s) identified by assessment of quality of the blastocysts (e.g., fresh blastocyst transfer). In specific embodiments, a single blastocyst is transferred.

In accordance with all aspects described herein, the treatment of infertility described herein may further comprise freezing one or more blastocysts identified by assessment of quality of the blastocysts (for later transfer).

Thus, In accordance with all aspects described herein, the treatment of infertility described herein may further comprise— in addition to optional administration of a GnRH agonist or antagonist, administration of recombinant FSH, and administration of an ovulatory dose of hCG, retrieving (e.g., harvesting) oocyte(s); fertilizing (e.g., inseminating) the oocyte(s)— allowing the fertilized oocytes to develop to the blastocyst stage and cryopreserving one or more blastocysts (e.g., blastocysts identified by assessment of quality of the blastocysts, e.g., for later transfer).

The treatment of infertility described herein may be for, and may be effective for, optimising cumulative efficiency (i.e. , maximising the patient’s chance of successful pregnancy following fresh or subsequent cryopreserved cycle) and/or reducing OHSS risk (i.e. reducing the risk of OHSS by e.g., monitoring and/or control of over-response to treatment).

Treatments Reducing OHSS Risk

In accordance with all aspects described herein, a treatment of infertility described herein may include a step of monitoring the patient for over-response to treatment. Herein“over response to treatment” is defined as a patient reaction to treatment which results in > 20 follicles with a diameter of ³ 12mm and/or a serum estradiol concentration > 3,000 pg/mL at any point in treatment. This step of monitoring the patient for over-response to treatment may comprise identifying, during treatment, a patient with > 20 follicles with a diameter of ³ 12mm and/or a serum estradiol concentration > 3,000 pg/mL.

In accordance with all aspects described herein, a treatment of infertility described herein may further comprise administering a dose of GnRH agonist (e.g., 4.0 mg) to a patient identified during treatment as having > 20 follicles with a diameter of ³ 12mm and/or a serum estradiol concentration > 3,000 pg/mL.

In accordance with all aspects described herein, a treatment of infertility described herein wherein the patient is identified during treatment as having > 20 follicles with a diameter of ³ 12mm and/or a serum estradiol concentration > 3,000 pg/mL, may further comprise retrieving (e.g., harvesting) oocyte(s); fertilizing (e.g., inseminating) the oocyte(s); allowing the fertilized oocytes to develop to the blastocyst stage; and cryopreserving one or more blastocysts (e.g., blastocysts identified by assessment of quality of the blastocysts, e.g., for later transfer). In this way, patients identified as over-responders (by their excessive number of large follicles and/or excessive serum estradiol level) may have a cryopreserved

blastocyst thawed and transferred (frozen cycle, cryopreserved embryo transfer-only cycle) after their recovery from over-response.

The recombinant FSH doses listed herein may be for treatment of infertility in the patient’s (subject’s) first stimulation protocol (first stimulation“cycle”) by the methods and treatment protocols described herein. Thus, the composition(s) may be for use in the treatment of infertility in a patient (subject) who has not previously been treated for infertility by controlled ovarian stimulation; for use in the treatment of infertility in a patient (subject) who has not previously completed a treatment for infertility by controlled ovarian stimulation; or for use in the treatment of infertility in a patient (subject) who has not been treated for infertility by controlled ovarian stimulation in the previous six months, more preferably a patient (subject) who has not been treated for infertility by controlled ovarian stimulation in the previous twelve months. It will be appreciated that for further stimulation cycles (that is, treatments of infertility by controlled ovarian stimulation) by the methods and treatment protocols described herein, the doses may be adjusted according to actual ovarian response in the first cycle by the methods and treatment protocols described herein.

T reatments For Patients Age ³ 35 years

In some aspects, the patient is a female patient of age ³ 35 years, such as age 35-42 years. The patient may be 35 or over 35 years of age. The patient may be 36 or over 36 years of age, or 37 or over 37 years of age, or 38 or over 38 years of age, or 39 or over 39 years of age, or 40 or over 40 years of age, or 41 or over 41 years of age, or 42 years of age.

The patient may have previously failed at least one cycle of infertility treatment (i.e. , the patient may have previously completed a treatment by controlled ovarian stimulation but not become pregnant), such as a previous infertility treatment by a different protocol and/or using different therapeutic agents, such as GONAL-F® instead of rFSH.

In specific embodiments, the composition is for treatment of a patient over 35 years of age, the patient having have previously failed at least one cycle of infertility treatment (such as a previous infertility treatment by a different protocol and/or using different therapeutic agents). The patient may have previously failed up to three cycles of infertility treatment (such as by a different protocol and/or using different therapeutic agents).

The treatment of infertility may comprise a step of determining the age of the patient, and a step of administering a dose of recombinant FSH as described herein to a patient having age ³ 35 years. The step of identifying the patient (prior to treatment) based on the age of the patient may take place just before (e.g., 0 to 2 days before) a dose of rFSH is first administered to the patient (e.g., before a starting dose of rFSH is administered).

In a first aspect, there is provided a composition (e.g., a pharmaceutical composition) comprising recombinant follicle stimulating hormone (rFSH) for use in the treatment of infertility in a patient of (e.g., identified as being of) age ³ 35 years, wherein the composition is for administration at a dose of, or a dose equivalent to, 15 pg recombinant FSH per day. For example, the composition can be for administration at a dose of 15 pg recombinant FSH per day. The dose of recombinant FSH may be administered at a dose equivalent to the daily doses mentioned above. For example, the composition may be for administration at a dose of 15 pg recombinant FSH every day, or less typically at an equivalent of 45 pg recombinant FSH every three days (e.g., for administration on days 1 , 4, 7 and so on).

In a further aspect, there is provided a composition (e.g., a pharmaceutical composition) for use in the treatment of infertility in a patient of (e.g., identified as being of) age ³ 35 years, wherein the composition comprises a dose of, or a dose equivalent to, 15 pg recombinant follicle stimulating hormone (FSH) per day. For example, the composition can be for administration at a dose of 15 pg recombinant FSH per day.

Also provided are methods of treating infertility in a patient in need thereof being of (e.g., identified as being of) age ³ 35 years, comprising administering to the patient recombinant follicle stimulating hormone (rFSH) at a dose of, or a dose equivalent to, 15 pg recombinant FSH per day. As noted above, the administration of recombinant FSH starts on day one of treatment and may continue for two to twenty days. The dose may be the same every day. However, variation of the dose depending on the patient’s ovarian response (e.g., as measured by ultrasonography) is more likely.

As noted above, the recombinant FSH composition (e.g., pharmaceutical composition) or medicament may be administered after pre-treatment of the patient with a (different) pharmaceutical composition, herein termed“composition A”, which suppresses endogenous gonadotropin production prior to day one of the treatment with rFSH, such as a steroid, a GnRH agonist, a GnRH antagonist etc.

As noted above, typically, the recombinant FSH composition (e.g., pharmaceutical composition) or medicament is administered, or is for administration, prior to administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG) (for example, 4,000 to 1 1 ,000 IU hCG, e.g., 5,000 IU hCG, 10,000 IU hCG, etc.; or 150 to 500 pg recombinant hCG, for example 250 pg recombinant hCG); to induce final follicular maturation. In some embodiments, therefore, the methods described herein further comprise administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG).

As noted above, the treatment of infertility may further comprise: retrieving (e.g., harvesting) oocyte(s); fertilizing (e.g., inseminating) the oocytes (s); and allowing the fertilized oocytes to develop to the blastocyst stage. As noted above, the treatment of infertility may further comprise assessing the quality of blastocysts and fresh transfer of blastocyst(s) or freezing of blastocysts for later transfer.

As noted above, the treatment may further comprise monitoring and/or control of over response to treatment (e.g., OHSS).

According to a further aspect, there are provided methods of treating infertility in a patient of age ³ 35 years, and a composition comprising recombinant follicle stimulating hormone (FSH) for use in the treatment of infertility in a patient of age ³ 35 years, wherein the methods comprise, or composition is for, administration at a starting dose of 15 pg recombinant FSH per day, wherein the starting dose is administered on at least day 1 of treatment (for example on at least day 1 and day 2 of treatment, for example on each of days 1 to 4 of treatment), optionally wherein the dose is (i) increased by a first incremental dose increase of 2 to 4 pg rFSH (including 3 pg rFSH) on any subsequent day of treatment; and/or (ii) decreased by a first incremental dose decrease of 2 to 4 pg rFSH (including 3 pg rFSH) on any subsequent day of treatment.

The dose may be maintained at the starting dose for the duration of the treatment. The dose may be the same every day. However, variation of the dose e.g., depending on the patient’s ovarian response (e.g., depending on follicular growth, e.g., as measured by

ultrasonography) is more likely.

The method of treating infertility may include monitoring the patient’s ovarian response to administration of rFSH (e.g., monitoring follicular growth, e.g., as measured by

ultrasonography). The method of treating infertility may include monitoring the patient’s ovarian response to administration of rFSH (e.g., monitoring follicular growth, e.g., as measured by ultrasonography) and, depending on follicular growth, increasing or decreasing the dose by 2 to 4 pg rFSH (including 3 pg rFSH). The method of treating infertility may include monitoring the patient’s ovarian response to administration of rFSH (e.g., monitoring follicular growth, e.g. as measured by ultrasonography) on one or more days throughout the course of treatment, such as on one or more of day 5, day 7, day 9, day 1 1 , day 13, day 15, day 17 and day 19 of treatment. The method of treating infertility may include monitoring the patient’s ovarian response to administration of rFSH (e.g., a step of monitoring follicular growth, e.g., as measured by ultrasonography) on one or more days throughout the course of treatment, such as on one or more of day 5, day 7, day 9, day 1 1 , day 13, day 15, day 17 and day 19 of treatment, and, depending on follicular growth ,

increasing or decreasing the dose by 2 to 4 pg rFSH (including 3 pg rFSH). That is, the dose may be increased or decreased depending on follicular growth on one or more days throughout the course of treatment, such as on one or more of day 5, day 7, day 9, day 1 1 , day 13, day 15, day 17 and day 19 of treatment.

The dose may be increased in increments during treatment, decreased in increments during treatment, or be varied during treatment by both incremental dose increases and incremental dose decreases. Typically, dose increases are not implemented more frequently than once every 2 days; that is, a second incremental dose increase is not implemented until at least two days after a first incremental dose increase. This gradual increase constitutes a safe approach, and permits the treating physician to assess ovarian response to a given dose level before possibly increasing the dose. For example, the treating physician may decrease the dose for subjects with follicular growth indicating that a dose reduction would be an appropriate course of action. Dose decreases may be implemented as frequently as every day. The dose may be increased to a maximum daily dose of 24 pg rFSH or decreased to a minimum daily dose of 6 pg rFSH.

Thus, a first incremental dose increase of 2 to 4 pg rFSH (including 3 pg rFSH) may be (a) followed by a further incremental dose increases of 2 to 4 pg rFSH (including 3 pg rFSH) at least two days after the previous incremental increase in dose; and/or (b) followed by an incremental dose decrease of 2 to 4 pg rFSH (including 3 pg rFSH) at least one day after the previous incremental increase in dose. A first incremental dose decrease of 2 to 4 pg rFSH (including 3 pg rFSH) may be (a) followed by an incremental dose increase of 2 to 4 pg rFSH (including 3 pg) rFSH at least one day, or at least two days, after the previous incremental decrease in dose; and/or (b) followed by at a further incremental dose decrease of 2 to 4 pg rFSH (including 3 pg rFSH) at least one day after the previous incremental decrease in dose.

It will be appreciated that this aspect contemplates, for example, a dose of 15 pg

recombinant FSH per day from day 1 of treatment to day 4 of treatment, the dose being increased in subsequent days of treatment by at least one increment of, e.g., 3 pg rFSH to 18 pg rFSH (e.g., on day 5 or 6). The dose of 18 pg rFSH may be continued to the end of treatment, or there may be one or two further incremental dose increases of, e.g., 3 pg rFSH to 21 pg rFSH, or to 21 pg rFSH and then to the maximum dose of 24 pg rFSH, with each incremental dose increase being at least two days after the previous incremental dose increase, or the dose being varied by both incremental dose increases and incremental dose decreases, each at the appropriate interval after the previous incremental dose change, such as may be warranted in view of the patient’s ovarian response, as discussed above. Similarly, an initial dose reduction of, e.g., 3 pg rFSH to 12 pg rFSH (e.g., on day 5 or 6) may be implemented and that dose continued to the end of treatment, or there may be one or

two further incremental dose decreases of, e.g.,3 pg rFSH to 9 pg rFSH, or to 9 pg rFSH and then to the minimum dose of 6 pg rFSH, with each decrease being at least one day after the previous incremental dose decrease, or the dose being varied by both incremental dose increases and incremental dose decreases, each at the appropriate interval after the previous incremental dose change, such as may be warranted in view of the patient’s ovarian response, as discussed above. This aspect provides a means of varying the FSH dose in a safe manner based on the patient’s response.

As with the first aspect discussed above, treatment in accordance with this aspect may further comprise administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG), and, optionally, retrieving (e.g., harvesting) oocyte(s); fertilizing (e.g., inseminating) the oocytes (s); allowing the fertilized oocytes to develop to the blastocyst stage, further optionally assessing the quality of blastocysts and fresh transfer of blastocyst(s) or freezing of blastocysts for later transfer. Additionally or alternatively, the treatment may further comprise monitoring and/or control of over-response to treatment (e.g., OHSS).

T reatments For Patients Age £ 34 years

In some aspects, the patient is a female patient of age £ 34 years, such as from 18-34 years of age. The patient may be 34 or under 34 years of age, for example 33 or under 33 years of age, for example 30 or under 30 years of age, for example 28 or under 28 years of age.

The patient may have previously failed at least one cycle of infertility treatment, such as a previous infertility treatment by a different protocol and/or using different therapeutic agents, as discussed above. In a specific example, the composition is for treatment of a patient < 34 years of age, the patient having have previously failed at least one cycle of infertility treatment (such as a previous infertility treatment by a different protocol and/or using different therapeutic agents). In a specific example, the composition is for treatment of a patient 30 to 34 years of age, the patient having have previously failed at least one cycle of infertility treatment (such as a previous infertility treatment by a different protocol and/or using different therapeutic agents). The patient may have previously failed up to three cycles of infertility treatment (such as by a different protocol and/or using different therapeutic agents).

The treatment of infertility may comprise a step of determining the age of the patient, and a step of administering the dose of recombinant FSH to a patient having age £ 34 years of age. The step of identifying the patient (prior to treatment) based on the age of the patient may take place just before (e.g., 0 to 2 days before) the first dose of rFSH is administered to the patient, for example, to determine or confirm the appropriate starting dose of rFSH.

In a further aspect there is provided a composition (e.g., pharmaceutical composition) comprising recombinant follicle stimulating hormone (FSH) for use in the treatment of infertility in a patient identified as being of age £ 34 years, wherein the composition is for administration at a dose of, or a dose equivalent to, 12 pg recombinant FSH per day. For example, the composition is for administration at a dose of 12 pg recombinant FSH per day.

In a further aspect there is provided a composition (e.g., pharmaceutical composition) for use in the treatment of infertility in a patient identified as being of age £ 34 years, wherein the composition comprises a dose of, or a dose equivalent to, 12 pg recombinant follicle stimulating hormone (FSH) per day. For example, the composition may be for administration at doses of 12 pg recombinant FSH every day, or less typically at an equivalent of 36 pg recombinant FSH every three days (e.g., for administration on days 1 , 4, 7 and so on). For example, the composition is for administration at a dose of 12 pg recombinant FSH per day. Also provided are methods of treating infertility in a patient in need thereof of (e.g., identified as being of) age £ 35 years, comprising administering to the patient recombinant follicle stimulating hormone (rFSH) at a dose of, or a dose equivalent to, 12 pg recombinant FSH per day.

As noted above, the administration of recombinant FSH starts on day one of treatment and may continue for two to twenty days. As noted above, the dose may be the same every day. However, variation of the dose e.g., depending on the patient’s ovarian response (e.g., depending on follicular growth, e.g., as measured by ultrasonography) is more likely.

As noted above, the recombinant FSH composition (e.g., pharmaceutical composition) or medicament may be administered after pre-treatment of the patient with a (different) pharmaceutical composition, herein termed“composition A”, which suppresses endogenous gonadotropin production prior to day one of the treatment with FSH, such as a steroid, a GnRH agonist, a GnRH antagonist etc.

As noted above, typically the recombinant FSH composition (e.g., pharmaceutical composition) or medicament is for administration prior to administration of a high (ovulatory) dose of hCG (for example 4,000 to 1 1 ,000 IU hCG, e.g., 5,000 IU hCG, 10,000 IU hCG etc.; or 150 to 500 pg recombinant hCG, for example 250 pg recombinant hCG) to induce final follicular maturation. In some embodiments, the methods described herein further comprise administration of a high (ovulatory) dose of human chorionic gonadotropin (hCG).

As noted above, the treatment of infertility may further comprise: retrieving (e.g., harvesting) oocyte(s); fertilizing (e.g., inseminating) the oocytes (s); and allowing the fertilized oocytes to develop to the blastocyst stage. As noted above, the treatment of infertility may further

comprise assessing the quality of blastocysts and fresh transfer of blastocyst(s) or freezing of blastocysts for later transfer.

As noted above, the treatment may further comprise monitoring and/or control of over response to treatment (e.g., OHSS).

In a further aspect there are provided methods of treating infertility in a patient of age £ 34 years and a composition comprising recombinant follicle stimulating hormone (FSH) for use in the treatment of infertility in a patient of age £ 34 years, wherein the methods comprise, and composition is for, administration at a starting dose of 12 pg recombinant FSH per day, wherein the starting dose is administered on at least day 1 of treatment (including on at least day 1 and day 2 of treatment, including on each of days 1 to 4 of treatment), optionally wherein the dose is (i) increased by a first incremental dose increase of 2 to 4 pg rFSH (including 3 pg rFSH) on any subsequent day of treatment; and/or (ii) decreased by a first incremental dose decrease of 2 to 4 pg rFSH (including 3 pg rFSH) on any subsequent day of treatment.

The dose may be maintained at the starting dose for the duration of the treatment. However, variation of the dose e.g., depending on the patient’s ovarian response (e.g., depending on follicular growth e.g., as measured by ultrasonography) ) is more likely.

The method of treating infertility may include monitoring the patient’s ovarian response to administration of rFSH (e.g., monitoring follicular growth, e.g., as measured by

ultrasonography). The method of treating infertility may include monitoring the patient’s ovarian response to administration of rFSH (e.g., a step of monitoring follicular growth, e.g., as measured by ultrasonography) and, depending on follicular growth (e.g., as measured by ultrasonography), increasing or decreasing the dose by 2 to 4 pg rFSH (including 3 pg rFSH). The method of treating infertility may include monitoring the patient’s ovarian response to administration of rFSH (e.g., a step of monitoring follicular growth, e.g., as measured by ultrasonography) on one or more days throughout the course of treatment, such as on one or more of day 5, day 7, day 9, day 1 1 , day 13, day 15, day 17 and day 19 of treatment. The method of treating infertility may include monitoring the patient’s ovarian response to administration of rFSH (e.g., monitoring follicular growth, e.g., as measured by ultrasonography) on one or more days throughout the course of treatment, such as on one or more of day 5, day 7, day 9, day 1 1 , day 13, day 15, day 17 and day 19 of treatment, and, depending on follicular growth (e.g., as measured by ultrasonography), increasing or decreasing the dose by 2 to 4 pg rFSH (including 3 pg rFSH). That is, the dose may be increased or decreased depending on follicular growth on one or more days throughout the course of treatment, such as on one or more of day 5, day 7, day 9, day 1 1 , day 13, day 15, day 17 and day 19 of treatment.

The dose may be increased in increments during treatment, decreased in increments during treatment, or be varied during treatment by both incremental dose increases and

incremental dose decreases. Typically, dose increases are not implemented more frequently than once every 2 days; that is, a second incremental dose increase is not implemented until at least two days after a first incremental dose increase. This gradual increase constitutes a safe approach, and permits the treating physician to assess ovarian response to a given dose level before possibly increasing the dose. Dose decreases may be implemented as frequently as every day. For example, the treating physician may decrease the dose for subjects with follicular growth indicating that a dose reduction would be an appropriate course of action. The dose may be increased to a maximum daily dose of 24 pg rFSH or decreased to a minimum daily dose of 6 pg rFSH.

Thus, a first incremental dose increase of 2 to 4 pg FSH (including 3 pg rFSH) may be (a) followed by a further incremental dose increase of 2 to 4 pg rFSH (including 3 pg rFSH) at least two days after the previous incremental increase in dose; and/or (b) followed by at least one incremental dose decrease of 2 to 4 pg rFSH (including 3 pg FSH) at least one day after the previous incremental increase in dose. A first incremental dose decrease of 2 to 4 pg rFSH (including 3 pg rFSH) may be (a) followed by an incremental dose increase of 2 to 4 pg rFSH (including 3 pg rFSH) at least one day, or at least two days, after the previous incremental decrease in dose; and/or (b) followed by a further incremental dose decrease of 2 to 4 pg rFSH (including 3 pg rFSH) at least one day after the previous decrease in dose.

Claims

1. A composition comprising recombinant follicle stimulating hormone (FSH) for use in the treatment of infertility in a patient of age ³ 35 years, wherein the composition is for administration at a (e.g. starting) dose of, or a (e.g. starting) dose equivalent to, 15 pg recombinant FSH per day.

2. A composition for use in the treatment of infertility in a patient of age ³ 35 years, wherein the composition comprises a (e.g. starting) dose of, or a (e.g. starting)

dose equivalent to, 15 pg recombinant follicle stimulating hormone (FSH) per day.

3. A composition for use according to claim 1 or claim 2 wherein the composition is for administration at a (e.g. starting) dose of 15 pg recombinant FSH per day.

4. A composition comprising recombinant follicle stimulating hormone (FSH) for use in the treatment of infertility in a patient of age ³ 35 years, wherein the composition is for administration at a starting dose of 15 pg recombinant FSH per day, wherein the starting dose is administered on at least day 1 of treatment (preferably on at least day 1 and day 2 of treatment, more preferably on each of days 1 to 4 of treatment), optionally wherein the dose is (i) increased by a first incremental dose increase of 3 pg recombinant FSH on any subsequent day of treatment; and/or (ii) decreased by a first incremental dose decrease of 3 pg recombinant FSH on any subsequent day of treatment.

5. A composition for use according to claim 4 wherein the dose is maintained at the starting dose for the duration of the treatment.

6. A composition for use according to claim 4 wherein the first incremental dose increase of 3 pg recombinant FSH is (a) followed by at least one further incremental dose increase of 3 pg recombinant FSH at least two days after the previous incremental change in dose; and/or (b) followed by at least one incremental dose decrease of 3 pg recombinant FSH at least one day after the previous incremental change in dose.

7. A composition for use according to claim 4 wherein the first incremental dose decrease of 3 pg recombinant FSH is (a) followed by at least one incremental dose increase of 3 pg recombinant FSH at least two days after the previous incremental dose change in dose; and/or (b) followed by at least one further incremental dose decrease of 3 pg recombinant FSH at least one day after the previous change in dose.

8. A composition for use according to claim 4, 6 or 7 wherein the dose is increased to a maximum daily dose of 24 pg or decreased to a minimum daily dose of 6 pg.

9. A composition comprising recombinant follicle stimulating hormone (FSH) for use in the treatment of infertility in a patient identified as being of age £ 34 years, wherein the composition is for administration at a (e.g. starting) dose of, or a (e.g. starting) dose equivalent to, 12 pg recombinant FSH per day.

10. A composition for use in the treatment of infertility in a patient identified as being of age £ 34 years, wherein the composition comprises a (e.g. starting)dose of, or a (e.g. starting) dose equivalent to, 12 pg recombinant follicle stimulating hormone (FSH) per day.

1 1. A composition comprising recombinant follicle stimulating hormone (FSH) for use in the treatment of infertility in a patient of age £ 34 years, wherein the composition is for administration at a starting dose of 12 pg recombinant FSH per day, wherein the starting dose is administered on at least day 1 of treatment (preferably on at least day 1 and day 2 of treatment, more preferably on each of days 1 to 4 of treatment), optionally wherein the dose is

(i) increased by a first incremental dose increase of 3 pg recombinant FSH on any

subsequent day of treatment; and/or

(ii) decreased by a first incremental dose decrease of 3 pg recombinant FSH on any subsequent day of treatment.

12. A composition for use according to any of claims 1 to 1 1 wherein the treatment of infertility comprises a step of determining the age of the patient, and a step of administering the defined dose of recombinant FSH to a patient having the defined age.

13. A composition for use according to any preceding claim wherein the recombinant FSH includes a2,6-sialylation and a2,3-sialylation, optionally wherein 1 % to 50% of the total sialylation is a2, 6-sialyation, and 50% to 99% of the total sialylation is a 2,3-sialyation; and/or wherein the patient is over 30 years of age and/or has previously failed at least one cycle of infertility treatment; and/orwherein the treatment of infertility further comprises: retrieving (e.g. harvesting) oocyte(s); fertilizing (e.g. inseminating) the oocytes (s); and allowing the fertilized oocytes to develop to the blastocyst stage, optionally wherein the treatment of infertility further comprises assessing the quality of blastocysts obtained after fertilization of the harvested oocytes.

14. A composition for use according to any preceding claim wherein the treatment includes a step of monitoring the patient for over-response to treatment by identifying, during treatment, a patient with > 20 follicles with a diameter of ³ 12mm and/or a serum estradiol concentration > 3,000 pg/mL; and optionally administering a dose of GnRH agonist (e.g. 4.0 mg) to the patient identified during treatment as having > 20 follicles with a diameter of ³

12mm and/or a serum estradiol concentration > 3,000 pg/mL; and/or wherein the treatment of infertility is for development of multiple follicles and pregnancy after fresh and/or

cryopreserved embryo transfer in ovulatory women undergoing assisted reproductive technology (ART); and/or wherein the treatment of infertility is for optimising cumulative efficiency and/or reducing ovarian hyperstimulation syndrome (OHSS) risk.

15. A composition comprising recombinant follicle stimulating hormone (FSH) for use in the treatment of infertility in a female patient, wherein the treatment comprises:

determining the age of the patient;

if the patient is age ³ 35 years, administering recombinant follicle stimulating hormone (rFSH) at a starting dose of 15 pg rFSH per day for at least 1-4 days;

if the patient is age £ 34 years, administering recombinant follicle stimulating hormone (rFSH) at a starting dose of 12 pg rFSH per day for at least 1-4 days;

optionally, on any subsequent day, (i) increasing the dose of rFSH by an incremental dose increase of 3 pg rFSH or (ii) decreasing the dose of rFSH by an incremental dose decrease of 3 pg rFSH,

wherein, throughout the treatment, the maximum daily dose of rFSH is 24 pg and the minimum daily dose is 6 pg.

16. A composition for use according to any preceding claim wherein the recombinant FSH is the sole active pharmaceutical ingredient in the composition.

17. A composition for use according to any preceding claim for use in the treatment of infertility in a patient who has not previously been treated for infertility by controlled ovarian stimulation; for use in the treatment of infertility in a patient who has not previously completed a treatment for infertility by controlled ovarian stimulation; or for use in the treatment of infertility in a patient who has not been treated for infertility by controlled ovarian stimulation in the previous six months.