Staking New Claims on the Autism Treatment Frontier · Nov 10, 05:30 PM


Significant Misrepresentations
Mark Geier, David Geier & the Evolution of the Lupron Protocol
(Part Sixteen) • Related articles

On November 1, 2007, the U.S. Patent and Trademark Office (USPTO) published Methods of treating autism and autism spectrum disorders (Patent Application No. 20070254314), by Dr. Mark Geier and David Geier. The application contains Dr. and Mr. Geier’s most recent articulation of the “Lupron Protocol,” a pharmaceutical regimen developed for the treatment of autistic children, adolescents and young adults, which has been discussed in depth on this weblog since February 2006.

Methods of treating autism and autism spectrum disorders supercedes Dr. and Mr. Geier’s two previous patent applications (20060058271 and 20060058241), which were published simultaneously in 2006, and are described in the new application as “now abandoned.” (These are discussed in my April 2006 article, Patent Medicine.) The law firm of Wood, Phillips, Katz, Clark & Mortimer is named as the Geiers’ legal representative; the firm also represents TAP Pharmaceuticals, manufacturer of Lupron. Although TAP is not named as a co-inventor on Methods of treating autism and autism spectrum disorders, the company is listed as such on World Intellectual Property Organization (WIPO) application 2006033907. The WIPO application is otherwise identical to USPTO application 20060058241; it is likely that it, too, will soon be superceded by a new application identical to the one just published by the USPTO.

The new patent application differs in significant respects from its predecessors. A change of title brings the primary target market for the “Lupron Protocol” into greater focus.

2006: Methods of treating disorders having a component of mercury toxicity
2007: Methods of treating autism and autism spectrum disorders

The Abstract summarizing the invention has been expanded:

2006: The present invention relates to methods of lowering the level of mercury in a subject, methods of lowering the level of mercury in a child diagnosed with autism and methods of assessing the risk of whether a child is susceptible of developing autism.
2007: The present invention relates to methods of treating a subject diagnosed with autism or an autism spectrum disorder, lowering the level of mercury in a subject determined to contain a high level of mercury, methods of lowering the level of mercury in a child diagnosed with autism, lowering the level of at least one androgen in a subject diagnosed with autism, lowering the level of mercury and the level of at least one androgen in a subject diagnosed with autism and methods of assessing the risk of whether a child is susceptible of developing autism.

In both the original and revised applications, proposed subjects include individuals presumed to be “mercury toxic,” and autistic males and females between the ages of 2 to 17 years, most preferably autistic boys also diagnosed with precocious puberty. A technique for assessing a child’s likelihood of developing autism characterizes a serum testosterone reading “at the reference level or greater than the reference level for… a child of approximately the same age” as an indicator of risk.

In their 2006 application, Dr. and Mr. Geier outlined a treatment in which the luteinizing hormone releasing hormone (LHRH) agonist Lupron was always administered in combination with chelating agents, and in which chelation agents were always administered three times per day.

…[T]he methods of the present invention involve administering to said subject a pharmaceutically effective amount of at least one luteinizing hormone releasing hormone composition. In addition to the pharmaceutically effective amount of at least one luteinizing hormone releasing hormone composition, the subject is also administered a pharmaceutically effective amount of at least one chelating agent. [Paragraphs 0086-0087]

In their new, revised application, Dr. and Mr. Geier outline a treatment in which Lupron is always administered, and chelation is optional.

Optionally, and if necessary, the subject can also be administered a pharmaceutically effective amount of at least one chelating agent. [Paragraph 0119]

The original patent application asserted 37 claims, each one representing a distinct activity and circumstance that might occur in the course of assessing and pharmaceutically treating patients. The revised application asserts 109 claims. This threefold increase results from the dissection of the “protocol” into its component parts, the inclusion of new medications in the “protocol,” and the expansion of the target market for the treatment. (The “autism risk assessment” technique remains largely unchanged.)

The new patent application indicates that the “level of mercury in a subject” can be lowered by:

administration of leutinizing hormone release hormone (LHRH) compounds such as leuprolide acetate (Lupron), gonadrelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, or meterelin;
[Paragraphs 0029, 0041, 0057, 0118, 0163, 0184]
administration of LHRH compounds in combination with chelating agents such as ethylenediaminetetraacetic acid (EDTA), dimercaptosuccinic acid (DMSA), or sodium dimercaptopropanesulfonate (DMPS);
[Paragraphs 0031, 0043, 0059, 0119-0120, 0164-0165, 0185-0186]
administration of Lupron in combination with antiandrogenic compounds such as cyproterone acetate (Androcur), finasteride, flutamide, progesterone, spironolactone, or fluconazole;
[Paragraphs 0035, 0047, 0063, 0121, 0166, 0187]
administration of Lupron in combination with both chelating agents and antiandrogenic compounds;
[Paragraphs 0035, 0047, 0063, 0121, 0166, 0187]
administration of androgen compounds (i.e., testosterone supplementation) in addition to any of the above regimens;
[Paragraphs 0036, 0048, 0064, 0122, 0167, 0188]
administration of estrogen, progesterone or progestin compounds, such as conjugated estrogens (Premarin) and birth control pills, in addition to any of the above regimens, to females at the age of puberty;
[Paragraphs 0037, 0049, 0065, 0124, 0168, 0190]
administration of vitamin and mineral supplements in addition to any of the above regimens.
[Paragraphs 0123, 0168, 0189]

Whereas the original application described administration of the “Lupron Protocol” to individuals who are “mercury toxic,” or to individuals who are both “mercury toxic” and autistic, the new version adds a new eligibility criterion:

In still yet another embodiment, the present invention relates to a method of treating a subject suffering from autism or an autism spectrum disorder, wherein said subject has an elevated level of at least one androgen (such as, but not limited to, an increase in serum testosterone or an elevated level of free serum testosterone) when compared to a reference level for said at least one androgen in a subject of approximately the same age. [Paragraph 0056]

That is, according to the revised application, a subject need not demonstrate “mercury toxicity” in order to be considered a candidate for the “Lupron Protocol,” only an “elevated level of at least one androgen.”

The original application described a regimen primarily intended for autistic boys diagnosed with precocious puberty.

Preferably, the subject is a male child, who has autism and who has also been diagnosed with precocious puberty. [Paragraph 0032]

The new application reiterates this ultimate “preference,” but leaves more room for consideration of female subjects.

Preferably, the subject is suffering from autism, more preferably, the subject is a male child who has autism. Even more preferably, the subject is a male child, who has autism and who has also been diagnosed with precocious puberty. [Paragraph 0039]

In the new application, the definition of “precocious puberty” has been modified.

2006: As used herein, the term “precocious puberty” refers to the appearance of physical and hormonal signs of puberty at an earlier age in a subject, preferably a human, than is considered normal. [Paragraph 0077]
2007: As used herein, the term “precocious puberty” refers to the appearance of physical signs of puberty, the hormonal signs of puberty and a combination of the physical signs of puberty and hormonal signs of puberty at an earlier age in a subject, preferably a human, than is considered normal. [Paragraph 0107]

Whereas the original definition implies that both physical and hormonal signs of puberty must be present in order to diagnose precocious puberty, the revised definition implies that a clinician can diagnose the condition in the absence of signs of accelerated physical development, based on the results of hormone testing alone.

The range of conditions Dr. and Mr. Geier envision might be treated by the “Lupron Protocol” has been broadened by the addition of schizophrenia to the list.

autism, autism spectrum disorders, attention deficit disorder, attention deficit hyperactivity disorder, mental retardation, Asperger’s syndrome, childhood psychoses, stammering, stuttering, tics, repetitive movements, eating disorders, sleep disorders, enuresis, developmental language disorders, developmental speech disorders, developmental delay, Alzheimer’s disease, diabetes, heart disease, obesity, amyotrophic lateral sclerosis, nephritic syndrome, renal failure, asthma, systemic lupus, autoimmune thyroiditis, rheumatoid arthritis, arthritis, vasculities, myelitis, glomerulonephritis, optic neuritis, infantile cerebral palsy, epilepsy, schizophrenia, migraine, toxic encephalopathy, cerebral degenerations, anterior horn cell disease, spinocerebellar disease, extrapyramidal disease or myopathy. [Claim 15]

A number of changes and additions have been made to the section, “Background of the Invention,” which describes the scientific rationale for Dr. and Mr. Geier’s treatment recommendations. The list of possible sources of environmental mercury has been expanded.

2006: Today, humans are exposed to mercury from a variety of different sources, including dental amalgams, certain industries such as battery, thermometer and barometer manufacturing, ingestion of certain foods such as fish and shellfish, environmental pollution resulting from the use of fossil foods [sic], and from vaccinations containing thimerosal, a mercury-containing preservative. [Paragraph 0003]
2007: Today, humans are exposed to mercury from a variety of different sources, including dental amalgams, certain industries such as battery, thermometer and barometer manufacturing, ingestion of certain foods such as fish and shellfish, environmental pollution resulting from the use of fossil foods [sic], prescription medicines, and from vaccinations and other biologicals, such as Rh.sub.o immune globulin, containing thimerosal, a mercury-containing preservative. [emphasis added] [Paragraph 0004]

A passage describing chemical bonding between mercury and testosterone has been reduced from a statement of scientific certainty to conjecture.

2006: It is known in the art that mercuric chloride binds and forms a complex with testosterone in subjects (See, Cooper et al., The Crystal Structure and Absolute Configuration of the 2:1 Complex between Tesosterone [sic] and Mercuric Chloride, Acta Crystallogr B., 1968, 15:24(7):935-41). [Paragraph 0004]
2007 It is known in the art that mercuric chloride binds and forms a complex with testosterone in vitro and possibly in subjects (See, Cooper et al., The Crystal Structure and Absolute Configuration of the 2:1 Complex between Tesosterone [sic] and Mercuric Chloride, Acta Crystallogr B., 1968, 15:24(7):935-41). [emphasis added] [Paragraph 0005]

Dr. and Mr. Geier hereby acknowledge the inaccuracy of their original interpretation of Cooper et al., offered as sole authority for their hypothesis that mercury and testosterone bond to form chelation-resistant sheets. Nonetheless, further in the application, they reiterate that original hypothesis, unaltered but for a new speculation about the potential for Lupron to initiate metabolic changes that supposedly increase the body’s ability to eliminate stored mercury.

[S]ubjects having a high level of mercury frequently, but not always, also exhibit high levels of one or more androgens, particularly, total serum testosterone. In these instances, as the level of one or more androgens (such as the level of total serum testosterone) in the subject increases, the higher the amount of one or more of said androgens (such as testosterone) is available to bind with mercury. When the one or more androgens bind with mercury, a complex is formed. These androgen-mercury chloride complexes (particularly testosterone-mercury chloride complexes) are difficult to remove from the subject with a chelating agent.
…By reducing the amount of testosterone being produced in a subject determined to have high levels of mercury, less testosterone is available to bind to mercury. Because few testosterone-mercury complexes are formed, if necessary, more mercury can be removed by administering to the subject at least one chelating agent. Additionally, the pharmaceutically effective amount of at least one luteinizing hormone releasing hormone will lower androgen levels and may raise glutathione levels. The higher glutathione levels may allow for a more effective removal of the mercury and thus indirectly, the use of a pharmaceutically effective amount of at least one luteinizing hormone release hormone may, by itself, also help to lower the body burden of mercury.
[A]t least one antiandrogenic hormone can be optionally administered to a subject. This treatment is administered to a subject because as the testosterone-mercury complexes begin to break apart, there is the potential to release biologically active testosterone into the body. The result is that the released biologically active testosterone may interact at the cellular level with deposit of mercury within cells, and thus produce testosterone-mercury toxicity to such cells. The at least one antiandrogenic hormone administered to a subject can help minimize the functioning of released biologically active testosterone, and hence minimize the potential for testosterone-mercury toxicity to cells within the subject. [Paragraphs 0139-0140, 0142]

References have been added to a review article by Prof. Boyd Haley and to two animal studies purporting to demonstrate potential benefits of estrogen supplementation.

Haley (See, Haley B E. Mercury toxicity: genetic susceptibility and synergistic effects. Med Ver 2005; 2:535-42) has shown in tissue culture that mercury induced neuronal damage is exacerbated by concurrent exposure with testosterone, whereas mercury induced neuronal damage was ameliorated by concurrent exposure with estrogen.
Additionally, estrogens have been shown to themselves raise glutathione levels and thus may be of help to the patients being treated. (See, Oliveira F R, Ferreira J R, dos Santos C M, Macedo L E, de Oliveira R B, Rodrigues J A, do Nascimento J L, Faro L R, Diniz D L. Estradiol reduced cumulative mercury and associated disturbances in the hypothalamus-pituitary axis of ovariectomized rats. Exotoxicol Environ Saf 2006; 63:488-93. Olivieri G, Novakovic M, Savaskan E, Meier F, Baysang G, Brockhaus M, Muller-Spahn F. The effects of beta-estradiol on SHSY5Y neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and beta-amyloid secretion. Neuroscience 2002; 113:849-55). [Paragraphs 0023-0024]

Although the original application indicated that autistic boys and girls between the ages of 2 and 17 might be treated with the “Lupron Protocol,” no further mention was made of the treatment of adolescents. Dr. and Mr. Geier’s addition of androgen and estrogen/progesterone/progestin compounds to the their preferred range of pharmaceuticals reflects the expansion of their experimentation to include this group. Lupron is not FDA-approved for the treatment of adolescents; elevated hormone levels are normal and necessary for development at this time of life. Nonetheless, the revised application describes specific procedures for the administration of supplemental hormones to adolescents who have been prescribed Lupron for the treatment of autism and presumed “mercury toxicity.”

The methods described above can also further optionally comprise the step of administering a pharmaceutically effective amount of at least one androgen compound… Administration of the at least one androgen can be repeated as necessary to lower the level of mercury in the subject.
The method described above can also further optionally comprise the step of administering to the subject (if the subject is a female who is of pubertal age) a pharmaceutically effective amount of at least one estrogen compound… The administration of the at least one progesterone compound or at least one progestin compound is repeated as necessary to lower the level of mercury in the subject. [Paragraphs 0036-0037]

In their 2007 patent application, Dr. and Mr. Geier add porphyrin testing to the list of assays used to determine an individual’s mercury levels, and cite their own recent paper on the subject.

An additional medical test that can be used to measure the level of body-burden of mercury in a subject is a porphyrin test (potential test sample sources include in the urine, blood and feces of a subject). For example, it has been shown researchers (See Nataf R, Skorupka C, Amet L, Lam A, Springbett A, Lathe R. Porphyrinuria in childhood autistic disorder: implication for environmental toxicity. Toxicol Appl Pharmacol 2006; 214:99-108. Geier D A, Geier M R. A prospective assessment of porphyrins in autistic disorders: a potential marker for heavy metal exposure. Neurotox Res 2006; 10:57-64) that specific porphyrins… known to be elevated by an increased body-burden of mercury were significantly elevated in the urine of children with autistic disorders.
In the present invention, for example, a whole blood test, a urine test, a porphyrin test or a combination of a whole blood test and a urine test, a whole blood test and a porphyrin test, or a urine test and a porphyrin test, or a whole blood test, urine test or porphyrin test a can be used to determine the level of mercury in a subject. Based on the results of the medical test, a determination is made by one skilled in the art whether the level of mercury in said subject is high and whether said subject is suffering from mercury toxicity. [Paragraphs 0115-0116]

The revised application includes a complicated description of a regimen of daily subcutaneous injections and monthly or semi-monthly intramuscular depot injections, which can be increased in dosage and frequency in order to control autistic children’s androgen levels and their behavior.

LUPRON® can be administered in daily doses of about 5 ug/kg per day to about 1.0 mg/kg per day for children (ages 18 years or younger) or about 0.3 to about 5 mg per day to adults. LUPRON DEPOT® can be administered to the subject once at least every 28 days in doses of about 2.5 mg to about 100 mg for adults or about 5 mg to about 100 mg for children. Preferably, LUPRON® is administered in either daily doses of about 20 ug/kg per day to about 150 ug/kg per day for children (ages 18 years or younger). LUPRON® can also be administered at about 0.5 mg to about 10 mg per day to adults. LUPRON DEPOT® is preferably administered to the subject at least once every 28 days in doses of about 5.0 mg to about 75 mg for adults or about 10 mg to about 75 mg for children. Moreover, to achieve the treatment described herein, a subject can be treated with both LUPRON® and LUPRON DEPOT® during the course of the subject’s treatment regimen. The LUPRON® and LUPRON DEPOT® can be administered to a subject sequentially, one right after another on the same day, or on different days… Preferably, the LUPRON® is given every day during the course of treatment. Additionally, if necessary, the amount of LUPRON® administered to a subject can be increased in 1.0 mg increments as needed to control the androgen levels and clinical symptoms of the subject. Additionally, the LUPRON DEPOT® can be administered at an additional frequency of more than once every 28 days as needed to control the androgen levels and clinical symptoms of the subject. [Paragraph 0118]

In the original application, the success of treatment was determined by an “undetectable” level of mercury, as measured by blood or urine tests, sustained at that level for at least three months; and a simultaneous reduction in serum testosterone [Paragraph 0093]. The new application offers a more open-ended scenario and a wider range of diagnostic variables.

The above-described methods (i.e., treatment regimens) are repeated as long as necessary until the level of mercury in the subject is reduced and the patient makes/maintains a significant overall improvement in their symptoms… Preferably, the level of mercury in the subject is lowered or reduced to a level that is undetectable… Moreover, if appropriate, the level of one or more androgens (such as, but not limited to, the level of total serum testosterone) is lowered or reduced to a level that is well within the normal range for the patient’s age and sex and that these reduced levels of mercury and levels of androgens remain lowered or reduced for a period of at least three months. [Paragraph 0141]

Five new case studies, two girls and three boys, join those of “Autistic Child X” and “Autistic Child Y” in the revised application. Four were described as “significantly impaired” prior to treatment. A six-year old autistic boy and a seven-year old autistic girl both experienced gastrointestinal problems and were diagnosed with precocious puberty; an eighteen-year old autistic boy “presented with extreme aggressive behaviors”; an eleven-year old autistic boy displayed “undetectable” levels of mercury and androgen levels within normal range; and an eleven-year old girl diagnosed with ADHD experienced difficulty concentrating and painful menstrual periods. Each of these young people was administered daily subcutaneous injections and monthly intramuscular depot injections of Lupron; the eleven-year old girl was also administered low-dose birth control pills. None were given chelating agents. In each case, parents reported improvements in their children’s physical problems and behavior. However, the case study for “Autistic Child B” illustrates the short-term, drug-dependent nature of these effects.

Child B’s LUPRON® therapy was interrupted for several weeks due to a lack of drug supply. During this period, Child B was observed to regress to a condition approaching her former level of impairment. When the LUPRON¯ therapy was re-initiated the observed improvements on the LUPRON¯ therapy returned and have been to seen to remain stable or even to exhibit further improvements in attention, cognitive awareness and receptive language skills. [Paragraph 0238]

In summary, Dr. and Mr. Geier assert that:

One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned… [Paragraph 0260]

Those “skilled in the art” of medicine would do well to ask whether daily injections of short-acting castration drugs are, in fact, “well adapted” for treating the behavioral problems of autistic children and adolescents — a group at special risk of medical abuse and mistreatment.

Comments


  1. Skilled in the art? More like the dark arts! So Lupron is the new chelator and the Geiers want it all. That will make them popular with the rest of the quacks.

    — mike stanton    Nov 10, 05:59 PM    #

  2. Poor kids. Birth control pills and Lupron injections for an 11 year old girl! Barbarians.

    — Ms. Clark    Nov 11, 12:17 AM    #

  3. Boy, they’re real humanitarians, aren’t they? Better hurry up and get that quackery patented so no one else can use it without paying you a royalty!

    I suppose we ought to be glad, actually, that they’re trying to corner the market on Lupronizing kids, if it means fewer will actually have to undergo it.

    I am thoroughly baffled at how anyone can take these clowns seriously. Too bad the promise of a cure is as strong as Svengali’s gaze.

    — isles    Nov 11, 02:23 AM    #

  4. Usually, quacks claim their quackery is a panacea. I see the Geiers finally woke up to the idea that they could expand their scam to all sorts of maladies.

    — Tom    Nov 11, 12:12 PM    #

  5. Excellent work as usual, Kathleen. Thank you for the wonderful work you do for our community.

    — Ari    Nov 14, 04:24 AM    #

  6. i have cpp,with pinealoma, and was researched at nih ,high test.and bench pressed 355 lb. at 12 yeards old and use a keto diet !

    — gene    May 27, 08:12 PM    #