Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-03-15
2004-12-14
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C530S350000, C424S009100, C424S239100, C424S195110, C435S069700, C435S320100
Reexamination Certificate
active
06831059
ABSTRACT:
BACKGROUND OF THE INVENTION
In 1971, after years of intense research, Andrew Schally finally was able to identify the structure of the releasing hormone responsible for stimulating the secretion of luteinizing hormones (LH) and follicle-stimulating hormones (FSH) from the pituitary gland. This releasing hormone is produced by the hypothalamus and reaches the pituitary gland by a neurohumoral pathway.
Today, the importance of this releasing hormone is widely recognized for its regulatory role in human development and growth. Furthermore, this releasing hormone may be the basis of various crippling illnesses. Commonly, this particular releasing hormone is referred to as the gonadotrophin-releasing hormone (GnRH).
A normal production of GnRH beneficially regulates the body's level of LH and FSH (also known as gonadotrophins). LH together with FSH stimulates the release of estrogens from the maturing follicles in the ovary and induces the process of ovulation in the female. In the male, LH stimulates the interstitial cells and is, for that reason, also called interstitial cell stimulating hormone (ICSH). FSH induces maturation of the follicles in the ovary and together with LH, plays an important role in the cyclic phenomena in the female. FSH promotes the development of germinal cells in the testes of the male.
However, an abnormally high production of GnRH by the hypothalamus may cause an increased gonadotrophin secretion, which may deleteriously harm the body. A high level of circulating gonadotrophin is known to cause, for example, precocious puberty, endometriosis, breast cancer, prostate cancer, pancreatic cancer and endometrial cancer. These illnesses may be treated by reducing the level of gonadotrophin secretion.
GnRH agonists and antagonists are existing drugs that act to decrease gonadotrophin secretion. GnRH agonists act by initially increasing the quantity of gonadotrophin secreted by the pituitary. However, with treatment of the agonist over a period of time, gonadotrophin secretion will decrease. (Presently, the mechanism behind how the agonist reduces gonadotrophin secretion is not fully understood.)
GnRH antagonists act by binding competitively to the GnRH receptors on the pituitary thereby preventing GnRH from exerting its stimulatory effect on pituitary cells.
GnRH antagonists and agonists have proven effective in the treatment of certain conditions which require a reduction of gonadotrophin release. For example, they have proven effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and several gonadal steroid-dependent neoplasia, most notably cancers of the prostate, breast and ovary.
GnRH agonists and antagonists have also been investigated as a potential contraceptive in both men and women. They have also shown possible utility in the treatment of pituitary gonadotroph adenomas, sleep disorders such as sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, hirsutism, as an adjunct to growth hormone therapy in growth hormone deficient children, and in murine models of lupus.
Although GnRH agonist and antagonist have been useful, their continual administration may be problematic. For example, treatment using GnRH agonists is normally limited to a six-month duration because of the negative effects that GnRH agonist therapy can have on bone mineral density (BMD). Women of reproductive age who undergo GnRH agonist therapy often show as much as 2.3% loss in BMD, comparable to the loss typically experienced by women in the first several years of menopause. This loss in women of reproductive age is particularly noteworthy, because bone density in women of this age group is still often increasing. Use of GnRH antagonists in the clinical setting is a relatively new event.
Nett et al. in U.S. Pat. No. 5,631,229 further discloses a potential method of reducing GnRH secretion by administering to a patient a cytotoxin conjugate, for example a diphtheria toxin-GnRH. (The disclosure of Nett et al. is incorporated in its entirety herein by reference). Although such conjugate may reduce GnRH secretion, its long-term administration may amount to a continual destruction of cells in the brain, which may be detrimental.
Botulinum
Toxin
The bacterial genus Clostridium includes more than one hundred and twenty seven species, grouped according to morphology and function. The anaerobic, gram-positive bacterium
Clostridium botulinum
produces a potent polypeptide neurotoxin,
botulinum
toxin, which causes the neuroparalytic illness in humans and animals referred to as botulism. The spores of
Clostridium botulinum
are found in soil and can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating food infected with a
Clostridium botulinum
culture or spores. The
botulinum
toxin can apparently pass unattenuated through the lining of the gut and attack peripheral motor nerves. Symptoms of
botulinum
toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.
Botulinum
toxin type A is the most lethal natural biological agent known to man. About 50 picograms of a commercially available
botulinum
toxin type A (purified neurotoxin complex)
1
is a LD
50
in mice (i.e. 1 unit). One unit of BOTOX® contains about 50 picograms (about 56 attomoles) of
botulinum
toxin type A complex. Interestingly, on a molar basis,
botulinum
toxin type A is about 1.8 billion times more lethal than diphtheria, about 600 million times more lethal than sodium cyanide, about 30 million times more lethal than cobra toxin and about 12 million times more lethal than cholera. Singh,
Critical Aspects of Bacterial Protein Toxins,
pages 63-84 (chapter 4) of Natural Toxins II, edited by B. R. Singh et al., Plenum Press, New York (1976) (where the stated LD
50
of
botulinum
toxin type A of 0.3 ng equals 1 U is corrected for the fact that about 0.05 ng of BOTOX® equals 1 unit). One unit (U) of
botulinum
toxin is defined as the LD
50
upon intraperitoneal injection into female Swiss Webster mice weighing 18 to 20 grams each.
Seven generally immunologically distinct
botulinum
neurotoxins have been characterized, these being respectively
botulinum
neurotoxin serotypes A, B, C
1
, D, E, F and G, each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of
botulinum
toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that
botulinum
toxin type A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is
botulinum
toxin type B. Additionally,
botulinum
toxin type B has been determined to be non-toxic in primates at a dose of 480 U/kg which is about 12 times the primate LD
50
for
botulinum
toxin type A. Moyer E et al.,
Botulinum Toxin Type B: Experimental and Clinical Experience,
being chapter 6, pages 71-85 of “Therapy With
Botulinum
Toxin”, edited by Jankovic, J. et al. (1994), Marcel Dekker, Inc.
Botulinum
toxin apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine.
Regardless of serotype, the molecular mechanism of toxin intoxication appears to be similar and to involve at least three steps or stages. In the first step of the process, the toxin binds to the presynaptic membrane of a motor neuron through a specific interaction between the heavy (or H) chain of the
botulinum
toxin and a neuronal cell surface receptor. The receptor is believed to be different for each type of
botulinum
toxin and for tetanus toxin. The carboxyl end segment of the H chain, H
C
, appears to be important for targeting of the toxin to the surface of the motor neuron.
In the second step, the toxin crosses the plasma membrane of the motor neuron.
Allergan Inc.
Baran Robert J.
Donovan Stephen
Kam Chih-Min
Low Christopher S. F.
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