Patent Medicine · 2006-04-05 18:30

Related Articles

On February 19, I published an essay, Autism & Lupron: Playing With Fire, about the worrisome promotion of the drug Lupron™ for use on autistic children. Shortly thereafter, the subject was taken up in more technical detail by blogger Orac, and discussion of the subject also began on a number of other weblogs. (A page of resources on the subject can be found here.)

On March 16, the U.S. Patent and Trademark Office published two patent applications by the proponents of that therapy, Dr. Mark Geier and David Geier. The first, 20060058271: Methods for screening, studying, and treating disorders with a component of mercurial toxicity (full text, image or 725 K .pdf) was originally filed on September 16, 2004, and outlines the theoretical basis and proposals for the use of hormonal suppressants in combination with chelation, to treat a range of disorders that supposedly include “a component of mercury toxicity,” including autism. The second, 20060058241: Methods of treating disorders having a component of mercury toxicity (full text, image or 1810 K .pdf) was filed on September 15, 2005, and is a recapitulation and continuation of the original application, offering as examples case studies of two autistic children subjected to the “Lupron Protocol.”

Published patent application images are viewable at the U.S. Patent and Trademark Office website with several TIFF image Viewers for Patent Images. AlternatTIFF is available from Medical Informatics Engineering at no charge.

I offer here a condensation of these two lengthy and often-repetitive legal documents, beginning with the claims made in the original application, then summarizing the invention background and description from the lengthier second application. Following that, I address a few questions raised by the applications, including the broad question of the desirability and potential impact of medical process patents, and the proper allocation and use of the body of knowledge derived from publicly and philanthropically-funded autism research.

Claims

The Claims section of the original September 2004 application opens with reference to a technique of diagnosing, treating and monitoring developmental disorders, including:

autism, autism spectrum disorders, ADD, ADHD, mental retardation, Asperger’s syndrome, childhood psychoses, stammering, stuttering, tics, repetitive movements, eating disorders, sleep disorders, enuresis, disturbances of emotion, developmental language disorders, developmental speech disorders, developmental delay, and other related disorders.

Specifics of the diagnostic and treatment process include:

Claim 1(I): Screening of the molecules in the steroidgenesis pathway — in other words, testosterone and estrogen testing to determine the extent to which testosterone might increase the ability of mercury compounds to damage cells, and estrogen might protect cells from damage. (Paragraph 1[I])
Claim 1(II): Screening of the analogs, antagonist, metabolites, breakdown products, and other effector molecules in and related to the steriodogenesis pathway — in other words, determining and selecting a means to reduce testosterone levels, for the purpose of decreasing the toxicity of mercury.
Claim 1(III): The use of the aforementioned molecules — that is, the use of pharmaceutical preparations such as Lupron™ — both alone and in various combinations with themselves and in combination with… chelating agents.
Claim 1(IV): The use of treatments… designed to increase the level of glutathione, Fe2+, Co2+, Mn2+, or other cofactors for enzymes in the steroidgenesis and breakdown pathways related to various molecules in the steriodogenesis pathway, either alone or in combination with the use of the therapies, both individually and in various combinations… — This claim appears to pertain to glutathione supplementation per se, whether it is recommended alone or in combination with any other therapy.
Claim 1(V): The use of various molecules… to inhibit or effect the regulation of the hypothalamus-pituitary-adrenal axis [including] secretin, and growth hormone which inhibit gonadotropin-releasing hormone, triptorelin, cyproterone, and flutamide, Lupron acetate, Nafarelin acetate, and Goserelin… their use for investigation and treatment, alone or in combination with each other or in combination with the treatments.
Claim 1(VI): Testosterone, and perhaps the binding sites for various other molecules… have the potential to bind mercurials. Therefore the use for investigation and treatment of molecules, agonists, antagonists, hormones, and drugs that inhibit, modify or otherwise influence the binding of mercurials to these sites are claimed.

Claims #2-4 detail the aforementioned related disorders, which encompass a wide range of human ills:

Alzheimer’s disease, diabetes, heart disease, obesity, ALS, nephritic syndrome, renal failure, asthma; autoimmune disorders/hyper-immune disorders such as systemic lupus, autoimmune thyroiditis, rheumatoid arthritis, arthritis, vasculitis, myelitis, glomerulonephritis, and optic neuritis; neurologic conditions such as infantile cerebral palsy, epilepsy, migraine, toxic encephalopathy, polyneuropathy, cerebral degenerations, anterior horn cell disease, spinocerebellar disease, extrapyramidal disease, and myopathy.

Claim #5 asserts that the patent is also applicable to treatment of other mammals.

Claims #6-9 expand the range of diagnoses to which the claims apply to several common conditions, and one uncommon one:

gastrointestinal problems which occur alone or as are often are found in autism
asthma, asthma-like problems or other respiratory problems which occur alone or as are often are found in autism
stroke and cardiovascular disease which involve testosterone and or mercury
precocious puberty in males and females and other disorders resulting from high or early expressed testosterones, estrogens, FSH, LH, and other associated molecules

Claims #10-11 specifically describe the use of Lupron™.

Claim #12 asserts that the patent shall apply to methods of diagnosis and monitoring as well as to treatment.

Claims #13-30 expand the range of metals to be encompassed by the patent:

cadmium, arsenic, lead, antimony, silver, thallium, tin, aluminum, magnesium, manganese, molybdenum, copper, nickel, platinum, thorium, tungsten, and uranium; all other heavy metals

Claims #31-37 outline a number of other substances and conditions to which the claims apply:

hypoxia; acidosis; burns; inducers of oxidative stress; inducers of inflammation; inducers of trauma; inducers of hemmorhage.

The September 2005 application reiterates these original claims, summarized as:

A method of lowering the level of mercury in a subject suffering from mercury toxicity, the method comprising the steps of: a) administering to said subject a pharmaceutically effective amount of at least one luteinizing hormone releasing hormone composition; b) administering to said subject a pharmaceutically effective amount of at least one chelating agent; and c) repeating step a), step b) or steps a) and b) as necessary to lower the level of mercury in said subject. (Claim I)

The 2005 application also includes some new information. At Claims 9, 15, 25, and Paragraphs 32, 39, 46, 96, the inventors disclose that their treatment is intended to be employed on children between the ages of two and seventeen. Claim 13 broadens the definition of chelation to include any combination of oral, intravenous and transdermal chelation. Claims 14-33 ensure that the patent would cover treatment of children diagnosed with autism, mercury toxicity, or any combination of diagnoses, rendered in any sequence, in combination with a diagnosis of precocious puberty or without.

Claims 34-37 describe a technique of assessing the risk of whether a child is susceptible of developing autism by measuring serum testosterone level. Children with readings at the high end of the reference range are regarded as at risk of developing autism, those at the low end are regarded as not at risk.

Background

The Background section of the September 2004 application includes much text identical to that of an article, Potential importance of steroids in the treatment of autistic spectrum disorders and other disorders involving mercury toxicity, which was submitted for publication in Medical Hypotheses on November 9, 2004.

The Field of the Invention subsection of the original application casts a wide net, targeting all conceiveable forms of mercury toxicity, whereas the same section in the second application is more focused on autism:

Paragraph 0002 (2004): The present invention involves the fields of immunology and medicine, and more particularly relates to new investigative and treatment methods that relate to diseases in humans and other mammals that are caused by, worsened by, or otherwise affected by exposure to various mercurials.
Paragraph 0002 (2005): The present invention relates to methods of 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 and methods of assessing the risk of whether a child is susceptible of developing autism.

The Background section of the 2005 application incorporated significant portions of text from the original application, updated with references to work published in 2005. I shall therefore continue by focusing on the 2005 application.

Paragraphs 0003-0004 (2005): The applicants briefly discuss the history of mercury toxicity, and environmental sources of mercury, including vaccines. Forms of mercury are described, and the claim is made that mercuric chloride binds and forms a complex with testosterone in subjects. The reference provided to substantiate this claim is Cooper et al., The Crystal Structure and Absolute Configuration of the 2:1 Complex between Tesosterone and Mercuric Chloride (Acta Crystallogr B., 1968 (15:24(7):935-41)).

Paragraphs 0005-0010: Symptoms of mercury poisoning are described, including gum problems; mood and mental changes; tremors; allergies; burns and dermatitis; and birth defects. A number of diseases believed by the applicants to have a mercury toxicity component are listed, including autism, Alzheimer’s disease, diabetes, heart disease, obesity, amyotrophic lateral sclerosis (ALS), asthma, and other immune disorders.

Paragraph 0011: Autism is briefly described, and references are provided to several works on autism prevalence and diagnostic trends (Brick Township study [2001]; Metropolitan Atlanta [2003]; Gerlai [2004] and 2003; California DDS study [2003]; Blaxill, Baskin, and Spitzer on Croen et al [2003]; Mark Blaxill’s What’s going on? The question of time trends in autism [2004]; and National autism prevalence trends from United States special education data [2005]). Reference is made to the phenomenon of regression, and to the fact that regression often occurs subsequent to administration of vaccines; the recent University of Washington study of home videotapes is cited.

Paragraph 0012-14: The applicants allege that mercury exposure can precipitate symptoms similar to autism, citing Bernard, Redwood et al., Autism: a novel form of mercury poisoning, and two other articles by the same authors. The applicants assert that children in the United States, within their first two years, may have received a quantity of mercury that exceeded Federal Safety Guidelines, citing another restatement of the Bernard, Redwood et al hypothesis, and the article, An Assessment of Thimerosal Use in Childhood Vaccines. More estimates by Redwood et al. are cited, as are the applicants’ own articles alleging a link between thimerosal and neurodevelopmental disorders. The applicants estimate that mercury in thimerosal containing vaccines represented almost 50% of the total mercury dose infants received.

Paragraph 0015-0017: In support of their contention that mercury builds up in the human brain subsequent to administration of thimerosal-containing vaccines, the applicants cite Burbacher’s 2005 monkey study. In support of their contention that thimerosal-containing vaccines are capable of causing autistic symptoms, the applicants cite Hornig’s 2004 study of the effects of thimerosal on mice, characterizing the behavior of the mice in that study as autistic. In support of their contention that thimerosal is capable of causing birth defects in humans, the applicants cite a 1987 study of chickens published in the Journal of Anatomical Society of India; and in vitro studies by Parry (1993) and Wallin (1993) (plants); Brunner (1991) (cultured pig neurons); and Baskin (2003), James (2005) and Humphrey (2005) (cultured human neurons). In support of their contention that thimerosal-containing vaccines are capable of inhibiting neuronal development in vivo, the applicants cite in vitro studies published by Parran (2005), Waly (2004), and Mutkus (2005).

Paragraph 0018-0021: The applicants cite six of their own articles (2003, 2003, 2003, 2004, 2004, 2005) to support their assertion that children receiving thimerosal-containing childhood vaccines are at significantly higher risk of developing autism and other neurodevelopmental disorders than those not receiving such vaccines. They also cite a study they conducted with Dr. Jeffrey Bradstreet employing chelation-provoked urinalysis, and Amy Holmes’ first baby haircut study in support of their assertion that autistic children have relatively high levels of heavy metals. Jill James’ 2004 study of oxidative stress in autistic children, and Boris’ 2004 study are cited in support of the argument that autistic children are metabolically impaired in their ability to eliminate mercury.

Paragraph 0022: The applicants assert that the understanding of the cause of the epidemic — that is, that autism is a consequence of mercury toxicity — has enabled the development of effective treatments for autism, including chelation. Reference is made to a 2001 article hypothesizing a role for prenatal zinc deficiency in the development of autism.

Paragraph 0023-0024: The applicants discuss sex differences in susceptibility to mercury toxicity and in the potential for autistic development, citing Clarkson’s 1985 study of the effects of mercury on male and female mice, and Muraoka and Itoh’s 1980 study of mercury exposure in male and female rats. With respect to the second study, the applicants note that, Necrosis was inhibited by castration of male rats and promoted by testosterone pretreatment. Reference is also made to Grandjean’s 1998 study of the effects of prenatal mercury exposure on cognitive function. The applicants cite two studies out of Cambridge University indicating a direct correlation between levels of prenatal testosterone and severity of autistic symptoms.

Paragraph 0025: The applicants end their discussion of the theoretical background of their invention, and segue to presenting their new way to screen and treat disorders that have a mercury component by utilizing the interaction of mercurials with the steroidgenesis pathway and its control by the hypothalamus-pituitary-adrenal axis.

Summary and Detailed Description of “The Invention”

Paragraphs 0026-32, 0033-39, and 0040-0046 are nearly-identical passages describing the applicants’ proposed method of lowering the level of mercury in a subject diagnosed or suffering from mercury toxicity, who may also be diagnosed with autism, by means of the alternating administration of:

a luteinizing hormone releasing hormone;
one or more chelating agents administered orally, transdermally and intravenously;
antiandrogenic hormones as needed.

The target population for the proposed treatment are children between the ages of two and seventeen years, who may have any of the many developmental disorders or “related disorders” originally described in the Claims section.

Paragraphs 0047-50: The applicants describe a means of evaluating a child’s risk of developing autism by serum testosterone testing. Simply put, a child is regarded at risk for developing autism if their serum testosterone level tests at the high end of the reference range for same-age children; lower serum testosterone levels mean lower risk.

Figures

Both patent applications include references to figures that can be viewed in TIFF format, and correspond to figures published in Potential importance of steroids in the treatment of autistic spectrum disorders and other disorders involving mercury toxicity.

Description of the precursors to testosterone and estrogen in the steroidgenic pathway
Role of mercury and glutathione in the testosterone pathway
Breakdown pathway for testosterone
Regulation of the hypothalamus-pituitary-adrenal axis
Anatomy of the hypothalamus-pituitary-adrenal axis
Seemingly unrelated clinical treatments that… all in one way or another lower testosterone

As previously mentioned, published patent application images are viewable with several TIFF image viewers designed for use with patent images, some available at no cost.

Definitions

Paragraphs 0054-80: This section is devoted to definitions of terms, including administer (54), antiandrogenic hormone (55), chelating agent (56), effective amount (57), gonadotropin (58), luteinizing hormone releasing hormone (59), luteinizing hormone releasing hormone composition (60-76), precocious puberty (77), subject (78), test sample (79), and treatment (80). The sections discussing pharmaceutical preparations provide technical information about the preparations’ chemical structure. (These are best viewed in TIFF format).)

Paragraph 0077: Here the applicants define precocious puberty as the appearance of physical and hormonal signs of puberty at an earlier age in a subject, preferably a human, than is considered normal. In girls, the cut-off age is eight; in boys, nine. Here the applicants indicate that testosterone and estradiol levels can be used to determine and diagnose whether a child is suffering from precocious puberty.

Description of the Process

Paragraphs 0082-85: The applicants describe blood testing (83); urine testing (84); or a combination of both (85) that can be used to determine the existence of mercury toxicity. The applicants state that, these tests can also be used to gauge the efficacy of chelation therapy in a subject.

Paragraph 0086-89: For those diagnosed with “mercury toxicity,” the applicants describe administration of Lupron™ or a similar substance, simultaneously or alternately with one or more chelating agents, administered orally, transdermally or intravenously; and the “optional” use of antiandrogenic hormones in conjunction with the above-described treatment, until the level of mercury in the subject has been lowered.

Paragraph 0090-92: The applicants assert that many subjects who have been determined to have a high level of mercury also have low levels of plasma reduced glutathione, and that subjects having a high level of mercury, frequently are determined to have high levels of total serum testosterone. They reassert their thesis that testosterone binds with mercury, and state that These testosterone-mercury chloride complexes are difficult to remove from the subject with a chelating agent. They assert that 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, more mercury can be removed by administering to the subject at least one chelating agent.

Paragraph 0093-94: The applicants indicate the goal for patients is an undetectable level of mercury, and total serum testosterone at a level within the normal range for the patient’s age and sex, maintained for a minimum of three months. They describe the optional use of antiandrogenic hormones for certain patients, in order to minimize the potential for testosterone-mercury toxicity.

Paragraph 0095: The applicants reiterate the range of diseases and disorders that have a mercury component originally set forth in the Claims section.

Paragraph 0096: The applicants propose use of their method as a treatment for children who are autistic and mercury poisoned, especially those with precocious puberty. They state that, Autistic children, male or female, between the ages of two and seventeen, particularly benefit from the methods of the present invention.

Paragraph 0097-101: The applicants describe the ATEC (Autism, Treatment, Evaluation, Checklist) Form developed by the Autism Research Institute, which tests the domains of speech, language and communication; sociability; sensory and cognitive awareness; health and physical behavior.

Paragraph 0102-0103: The applicants reiterate their autism-risk assessment technique, based on interpretation of serum testosterone readings. They note that, Reference levels tend to vary depending on the laboratory performing the test.

Paragraph 0104: The applicants segue to their presentation of case histories.

Example 1: Autistic Child X

Paragraph 0105-9: The applicants describe an eight year old boy born in 1996 who received vaccines according to the recommended vaccine schedule, declined into a fully autistic state in his second year of life, and suffered from gastrointestinal problems. In October 2000, he began chelation with DMSA; he continued the treatment for a year and a half, until February 2002. Behavioral improvements coincided with the treatment.

In November 2000 — two weeks after beginning chelation — a urine sample was collected, tested and found to be high in mercury (15µg/g creatinine; reference range <3); therefore, a diagnosis of mercury toxicity was made. Eleven months later, in September 2001, another urine cample was collected, tested and found to be high in mercury (5.4µg/g creatinine; reference range <3); the applicants determined that a state of heavy metal toxicity continued to exist.

Paragraph 0110-0111: The applicants describe the boy’s persistent difficulties with communication and at school, and occasional aggressive behavior. They describe conducting a genetic screening and various metabolic tests, indicating no abnormalities. An absence of autism or any other neurological disorders in the family is noted; the applicants point out that in fact, both of his parents have advanced degrees.

Paragraph 0112: The applicants move forward three years; the boy is now eight. In October 2004, a blood sample was taken, and his total serum testosterone was determined to be 25 ng/dL, compared to a reference range of 0-25 ng/dL. On this basis, and on the basis of increased body hair and inappropriate sexual behavior, a diagnosis of precocious puberty was made. The applicants indicate that they performed CBC, liver, and kidney function testing.

Paragraph 0113-0115: In November 2004, the boy was assessed using the ATEC form, and was found to have severe autistic symptoms placing him in the 90-99 percentile of severity. The next day, he was administered a single shot of Lupron Depot™. The applicants state that, No observable side effects were noted. He began transdermal DMPS chelation a week later, on December 1, 2004. Over the next eight months, he was given four more shots of Lupron Depot™. He also commenced oral DMSA chelation treatment in addition to the ongoing transdermal DMPS. His fluctuating testosterone levels were tested frequently, and an anti-androgen was prescribed when those levels rose. In August 2005, his homocysteine levels and plasma reduced glutathione levels were tested. Over the nine months of therapy, the boy received a total of five shots, and his blood was drawn and tested approximately twelve times.

Paragraph 0116-0117: The applicants state that the boy’s report card for the school year prior to initiation of therapy demonstrated that Child X had not mastered any skills. They describe report cards issued during the year in which Lupron Depot™ was administered to the child, which document numerous physicial and cognitive improvements. These include improvement in gastrointestinal symptoms, behavior, and attention. Another ATEC evalution was conducted in July 2005; the boy moved from the 90-99 percentile of autistic severity in November 2004 to the 20-29 percentile of autistic severity on July 2005.

Example 2: Autistic Child Y

Paragraph 0118-122: The applicants describe a six year old boy born in 1999 who received vaccines according to the recommended vaccine schedule, declined into a fully autistic state in his second year of life, and suffered from gastrointestinal problems. In June 2002, the boy began DMSA chelation, a treatment that continued for a year, to May 2003.

Three days after the first chelation treatment, the child’s urine was tested for toxic metals. Based on his urinary mercury reading (29µg/g creatinine; reference range <3), he was determined to be suffering from mercury toxicity. Six months later, in December 2002, his urine was retested. His urinary mercury reading was above the reference range being used for the test (11µg/g creatinine; reference range <3); the applicants determined that a state of heavy metal toxicity continued to exist.

Paragraph 0124: The applicants describe conducting a genetic screening and various metabolic tests. In January 2003, plasma cysteine and plasma reduced glutathione were tested, with results below the normal reference range used by the laboratory. A November 2003 genomic survey demonstrated that indicated the child had single nucleotide polymorphisms in the MTHFR gene.

Paragraph 0125: Fourteen months later, in January 2005, a blood sample was taken, and the boy’s total serum testosterone was determined to be 20 ng/dL, compared to a reference range of 0-20 ng/dL. On this basis, and on the basis of increased body hair and premature physical development, a diagnosis of precocious puberty was made. The applicants indicate that they performed CBC, liver, and kidney function testing.

Paragraph 0126-0127: In April 2005, the boy was assessed using the ATEC form, and was found to have severe autistic symptoms placing him in the 70-79 percentile of severity, with sensory/cognitive awareness placing him in the 90-99 percentile of severity. The next day he was administered a single shot of Lupron Depot™. According to the applicants, No observable side effects were noted. Improvement in gastrointestinal symptoms was noted within a few days, and in communication skills. The boy began transdermal DMPS chelation three days after the Lupron™ shot. Over the next three months, he was given two more shots of Lupron Depot™. In May, he also commenced oral DMSA chelation treatment in addition to the ongoing transdermal DMPS. His fluctuating testosterone levels were tested frequently, and an anti-androgen was prescribed. Over the six months of therapy, the boy received three shots, and his blood was drawn and tested approximately eight times.

Paragraph 0128-0131: The applicants note numerous physicial and cognitive improvements during the period during which Lupron Depot™ was administered to the child; these include improvement in gastrointestinal symptoms, behavior, and communication, and expression of emotion. Another ATEC evalution was conducted in May 2005; the boy’s performance in speech, language and communication moved from the 80-89th percentile of autistic severity on April 1, to the 60-69th percentile two months later. The applicants provide a report in which a teaching assistant documented the boy’s acquisition of skills over a six-week period following the treatment (July-August 2005).

At Long Last

Paragraphs 0133-136: The patent application draws to a close with a few paragraphs of legalese, broadening the range of pharmaceutical product substitutions permissible under the patent. The applicants assert that their proposed technique is well adapted to carry out the objects and obtain the ends and advantages mentioned.

A Broad Request

Taken together, the two applications constitute a request to monopolize techniques intended not only for the medical treatment of autistic children, but also for individuals of all ages experiencing any condition that the applicants suspect might have a “component” of mercury or other metal “toxicity,” or toxicity resulting from other substances. The applicants speculate a vast range of conditions to which the technique might apply, and agents that might give birth to those conditions. The techniques described in the application are basic elements of diagnosis and treatment, including visual observation, blood and urine tests, nutritional supplementation (including glutathione supplementation), and the administration of pharmaceutical agents.

Tenuous Evidence

Cited work often offers only tenuous support for the applicants’ assertions. The entire process outlined in the applications is predicated on the assumption that mercuric chloride binds and forms a complex with testosterone in subjects (Paragraph 0004). Blogger Prometheus recently obtained a copy of the only study cited in connection with this assertion — The Crystal Structure and Absolute Configuration of the 2:1 Complex between Tesosterone and Mercuric Chloride — and learned that the crystal under discussion was created by dissolving testosterone-mercury in hot benzene — not as a result of normal physiological processes in human research subjects.

Although the applicants cite a 2005 University of Washington study to support their statement that there are significant numbers of children with regressive autistic disorders that manifest between the ages of 12 and 24 months of age, a temporal period directly post-administration of mercury from thimerosal-containing childhood vaccines in the United States, the University of Washington article refers only to regression; its authors do not tie that phenomenon to vaccination schedules (Paragraph 0011).

The article, An Assessment of Thimerosal Use in Childhood Vaccines was cited to support the contention that children commonly received dangerous levels of mercury via vaccinations (Paragraph 0013). However, the authors of that article recommended reduction in the use of thimerosal in vaccines (since enacted), at the same time that they found no evidence of harm caused by doses of thimerosal found in vaccines, except for local hypersensitivity reactions.

The article, Thiomersal in vaccines: balancing the risk of adverse effects with the risk of vaccine-preventable disease, was cited to support the statement that, it has been estimated the mercury in thimerosal-containing vaccines represented almost 50% of the total mercury dose infants received (Paragraph 0014). However, the author of the cited article concluded that the health benefit of eliminating thiomersal from a vaccine, if any, is likely to be very small… Because of the contribution to overall mercury exposure from breast milk and diet in later life, the removal of thiomersal from vaccines would produce no more than a 50% reduction of mercury exposure in infancy and <1% reduction over a lifetime.

The applicants state that, Recent studies have reported that exposure to mercury can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with autism, and the similarities extend to neuroanatomy, neurotransmitters, and biochemistry, referring to three articles produced by the founders of SafeMinds, a political action organization supporting litigation against pharmaceutical companies and the government. However, they make no attempt to address well-documented rebuttals, such as Karin Nelson and Margaret Baumann’s substantial 2003 article in Pediatrics. In support of their assertion that there is a positive relationship between administration of thimerosal-containing vaccines and the development of autism, the applicants cite six of their own articles and no other epidemiological studies.

In support of their assertion that high testosterone levels indicate an individual’s risk for developing autism, the applicants cite two Cambridge University studies indicating a correlation between levels of prenatal testosterone and severity of autistic symptoms. However, these articles addressed only the issue of prenatal testosterone levels, and are insufficient to establish postnatal testosterone levels as an indicator of susceptibility to postnatal onset of autism.

Insufficient Original Data

Although the applicants state that they have found that the level of mercury in a subject can be lowered by treating a subject with a combination of a pharmaceutically effective amount of at least one luteinizing hormone releasing hormone composition and a pharmaceutically effective amount of at least one chelating agent and then by repeating this treatment until the level of mercury in said subjects has been lowered (Paragraph 0092), they provide no data demonstrating that administration of Lupron™ actually succeeded in creating that effect.

The two case studies provided indicate that close attention was paid to monitoring the children’s testosterone levels; however, each case study contain only two sets of urinalysis results, and assessments of mercury levels after administration of Lupron™.

In the first case study, the first, provoked urinalysis was conducted in November 2000, the second in September 2001. There is no indication that any unprovoked baseline urinalysis was ever conducted prior to the deliberate disruption of the child’s metal metabolism by the chelation agents. Neither is there any record of any new urinalysis prior to the initial administration of Lupron™ a full three years later, in November 2004. Post-treatment test results were not reported.

In the second case study, the first urinalysis was conducted in June 2002, the second in December 2002. There is no indication that any unprovoked baseline urinalysis was ever conducted. Treatment with Lupron™ began two and a half years later, in April 2005; however, there is no record that any new urinalysis was conducted prior to the initial administration of the drug, or after it.

The sole evidence provided to support the applicants’ claim that Lupron™ lowers the level of mercury in a subject are behavioral reports from parents and teachers. While such reports are significant, they are insufficient to establish the procedure’s pharmaceutical efficacy for the stated purpose.

Paragraph 0023 of the original application states:

It is clear that many that a significant number of persons suffering from mercury intoxication do not respond to the present treatment therapies that are designed to help eliminate mercury from the body. What is needed is another modality of clinical treatment to complement the work on eliminating mercury from these mercury toxic individuals.

Here the applicants acknowledge that chelation is not always effective in relieving the conditions it is intended to relieve. However, there is no consideration of the possibility that persons presumed suffering from mercury intoxication who do not respond to chelation, might not be responding as hoped because mercury intoxication might not actually be the source of their problems, and chelation might not be the appropriate treatment.

Human Subjects Research

Lupron™ is a hormonal suppressant whose only FDA-approved pediatric use, and the only pediatric use for which its manufacturer promotes it, is the treatment of precocious puberty. In adults, its most common uses are the treatment of prostate cancer, endometriosis, and infertility. Paragraph 0032 of the 2005 patent application indicates that the subject of the proposed treatment:

…can be a human male or female, adult or child. If the subject being treated is a child, said child can have an age between two (2) years old and seventeen (17) years old. In addition, the human male or human female subject may also be suffering from a disorder selected from the group consisting of:</blockquote

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, migraine, toxic encephalopathy, cerebral degenerations, anterior horn cell disease, spinocerebellar disease, extrapyramidal disease or myopathy.

No extent of subsequent references to conditions for which the marketing of Lupron™ is currently authorized can obscure the fact that the applicants seek to extend the use of the drug to the treatment of the many other conditions, which they regard as consequences of mercury toxicity; and that they are advocating the administration of Lupron™ to adolescents, who are by definition pubescent and ineligible for a diagnosis of precocious puberty.

Online reports indicate that the applicants are currently conducting and seeking participants for “trials” on thirteen and fourteen year olds. An attendee offered this report of a presentation given by Dr. Mark Geier in Kansas City in early March 2006:

Oral chelating therapy has been used in the past[…] but Dr. Mark Geier recommends an additional treatment to this protocol. He has treated eleven children (ages 4-9) from November 2004 through February 2005 using Lupron Depot (there is an eligibility assessment for enrollment in the test program). Lupron decreases the body’s production of testosterone. Testosterone suppression might increase the efficacy of chelation to remove mercury. MARKED RESULTS HAVE COME ABOUT in the test subjects.[…].
Administering Lupron does not come without its problems. The question arises “What happens to a child receiving Lupron when he/she is supposed to naturally be going through puberty?” Because this study has only gone on for a short time, that question cannot be answered yet in how to handle that. They are currently doing trials on 13 and 14 year olds. Also, the question arises, “When do we stop administering the Lupron, or can we/should we?” It is also costly, about $1500/month but HMO’s currently pick up on the cost.

The potential impact of powerful drugs on developing children, the proper time to discontinue their use, program duration, and other such matters are appropriately considered before the commencement of research, not afterwards.

The original 2004 application acknowledges the investigational nature of the proposed use of Lupron™ in conjunction with chelation:

The present invention involves the fields of immunology and medicine, and more particularly relates to new investigative and treatment methods that relate to diseases in humans and other mammals that are caused by, worsened by, or otherwise affected by exposure to various mercurials.

However, there is no indication in either application that the applicants have sought FDA approval for the clinical investigation of the experimental use of this drug on children. There is also no indication that any safety studies of the use of Lupron™ in conjunction with chelation agents — that is, substances that deliberately alter mineral metabolism — have ever been conducted. The applicants refer to the absence of observable short-term side effects, but do not discuss the possibility of long-term side-effects of Lupron™ on developing children.

Searches of http://www.clinicaltrials.gov give no indication that this “test program” is being supervised by an Institutional Review Board. There is no indication in the application that the applicants’ research was conducted in collaboration with or with the knowledge of TAP Pharmaceuticals, manufacturer of Lupron™.

The applicants indicate that diagnoses of precocious puberty were rendered based on high testosterone readings and observation of premature development, with no other tests conducted on either child prior to administration of pharmaceuticals. The physicians’ instructions provided by TAP Pharmaceuticals for the administration of Lupron™ pursuant to a diagnosis of precocious puberty also call for:

determination of adrenal steroid level to exclude congenital adrenal hyperplasia;
beta human chorionic gonadotropin level to rule out a chorionic gonadotropin secreting tumor;
pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor;
computerized tomography of the head to rule out intracranial tumor.

The true source of a child’s hormonal anomalies — which could include operable tumors — could go completely unrecognized if they were diagnosed in the manner described in the application.

The applicants offer no evidence of prior expertise in the field of endocrinology prior to the development of this theory; for example, they have published no previous work on the subject. The case studies give no indication that any clinically experienced pediatric endocrinologists were consulted in the process of diagnosing the rare disorder of precocious puberty in two children. Discussion of hormonal function in developing children is limited to its intersection with the applicants’ unsubstantiated theory that testosterone increases the toxicity of mercury.

Medical Process Patents

I will regard his sons as my brothers and teach them the science, if they desire to learn it, without fee or contract. — Hippocratic Oath

Setting aside the questions of whether or not the claims in the patent applications are legitimate, whether or not the procedures are safe and effective for their intended use, and whether or not proper safeguards have been taken to protect patients, other questions persist. Should individual doctors (and their non-physician business associates) be allowed to claim private ownership of diagnostic and treatment techniques that utilize existing products and devices, and common methods of testing, treatment and evaluation? Should monopolies be granted for ways of thinking and looking at health, disease and disability, and ways of thinking about and interpreting biological processes?

Medical process patents are outlawed worldwide, as against the public interest and at fundamental odds with good medical practice. The World Medical Association Statement on Medical Process Patents distinguishes between the invention of material goods, and the development of medical techniques by medical professionals:

Unlike device development, which requires investment in engineers, production processes, and factories, development of medical processes consists of physicians attaining and perfecting manual and intellectual skills. …[P]hysicians already have both obligations to engage in these professional activities as well as rewards for doing so… Devices are manufactured and disseminated by companies, whereas medical processes are “produced and disseminated” by physicians. Physicians have ethical or legal obligations to patients and professional obligations towards each other, which companies do not have. Having particular ethical obligations is part of what defines medicine as a profession.

Medical process patents impede the free flow of information about new treatments, undermining the ideal of disclosure and peer review that is integral to scientific progress, and that enhances the quality of patient care. The patenting of medical procedures contributes to their increased cost, and to unnecessary restrictions on doctors’ autonomy and intellectual freedom. Patient access to procedures is limited by patents, since patients seeking a provider for a patented procedure would be required to seek care from the patentholder or a licensee, who might refuse Medicaid reimbursement or require prepayment. Doctors’ judgment in determining therapies might be strongly influenced by reluctance to obtain a license to perform a procedure; or reluctance to refer patients to licensed doctors; or an economic interest in promoting the procedure. A patented procedure for which no alternative exists could be kept out of reach of patients most in need of it.

Patenting medical procedures also restricts access within the research community, and limits opportunities for peer review, replication, or further development of promising new techniques. The safety and efficacy of new medical procedures should be widely studied, and criticisms and recommendations made publicly in order to establish their worth; this is subverted by medical process patents.

The stifling effects of disease gene patents on research were comprehensively discussed by Jon Merz in Disease Gene Patents: Overcoming Unethical Constraints on Clinical Laboratory Medicine:

Monopolization of medical testing services threatens to restrict research activities; creates unacceptable conflicts of interest; may reduce patient access to testing; may lead to inequitable extensions of patent terms on tests and related discoveries; and grants to patent holders the ability to dictate the standard of care for testing, and to otherwise interfere with the practice of medicine.
Potential restrictions on research may arise from: the monopolization of research resources (i.e., blood and other clinical tissue samples); the inhibition of widespread clinical use and observation so typical and necessary for medical advances; the inhibition of external study and validation of the patentee’s research and clinical services; the imposition of stifling reach-through conditions on licensees, if any (e.g., rights of first refusal or compulsory cross-licensing of related discoveries); and the imposition of unethical constraints on the performance of research by others (e.g., limits on clinical uses of research results inconsistent with local Institutional Review Board requirements and accepted medical research practices).
Patents clearly raise concerns about conflicts of interest. Laboratories may engage in unwarranted promotion, including direct patient marketing. Individual clinician/researchers may inappropriately (over)use tests in which they have financial or research interests and may be overly aggressive in solicitation of research subjects. In addition, patents clearly raise serious concerns in performing research and publishing findings. Indeed, it is not a patent per se that raises these concerns, but the very filing of a patent application that should raise a warning flag regarding scientific objectivity.

Even in the absence of aggressive enforcement, medical procedure patents create legal risk for anyone who might even inadvertently violate them in their practice of medicine or search for medical care. A patent holder may seek enforcement of a patent at any time, and defense of even meritless cases can be costly. Enforcement procedures could also compromise patient privacy, since details about the use of the procedure would be sought by the patent holder.

The process of patent review does not entail determining whether an “invention” is effective, only whether it is novel, non-obvious, useful, and adequately described in the patent application. The award of a patent is not a guarantee of scientific merit, efficacy, safety, or ethical conduct of research. Unfortunately, this is not widely known. Since patents are awarded by the government, a patent can provide unearned credibility and a misleading marketing tool for unsound and even unsafe theories, and contribute to patients’ decisions to undergo unnecessary or unwarranted procedures, or parents’ decisions to subject their children to them. This risk could be created by the grant of a patent for the regimen described in these applications.

Australia and the United States are the only countries in the world that issue medical process patents, and the United States has established limits to their enforcement. The subject of medical process patents gained prominence with a highly publicized lawsuit filed in 1993 by Dr. Samuel Pallin against fellow ophthalmologist Dr. Jack Singer. Dr. Singer had refused to pay a licensing fee in order to perform a particular sutureless incision in cataract surgery for which Dr. Pallin had succeeded in obtaining a patent; Dr. Pallin subsequently sued for patent infringement. If Dr. Pallin’s suit had succeeded, he could have sought royalties from 2,000 other physicians who had also reported using a similar incision. Dr. Singer’s defense was eventually taken up by his employer and several professional associations whose membership recognized the threat to the practice of medicine posed by the use of such tactics. Ultimately, a federal district court judge ruled in favor of Dr. Singer, declared the patent invalid, and forbade Dr. Pallin from any future attempts to enforce it.

During and after Pallin v. Singer, several physicians organizations issued official condemnations of medical process patents, including the American Medical Association:

A physician has the ethical responsibility not only to learn from but also to contribute to the total store of scientific knowledge when possible Physicians should strive to advance medical science and make their advances known to patients, colleagues, and the public. This obligation provides not merely incentive but imperative to innovate and share the ensuing advances. The patenting of medical procedures poses substantial risks to the effective practice of medicine by limiting the availability of new procedures to patients and should be condemned on this basis. Accordingly, it is unethical for physicians to seek, secure, or enforce patents on medical procedures.

In September 1996, President Clinton signed Public Law 104-208, which exempts medical practitioners from liability for infringement of patents for medical and surgical procedures issued after enactment of the law. However, procedures incorporating patentable drugs, reagents and methods are still subject to patent remedies.

In her article, Patent Policy and Medical Procedure Patents, Wendy Yang argued:

When the cost of inventing and developing a procedure is low, and the demand for the procedure high, the case against patenting the medical procedure is strong.

The applicants appear to have incurred little expense in developing or conducting preliminary “trials” of their idea to use Lupron™ in conjunction with chelation, since the children were private patients, the medications covered by insurance. The applicants have benefited from the efforts of their patients’ mothers to publicize the treatment at a 2005 autism conference; one has edited three journal articles for them.

The case against patenting medical procedures intended to support the health of autistic individuals is strong. The numbers of children and adults diagnosed with autistic spectrum conditions are increasing. Demand for appropriate, well-informed health care for autistic children and adults is high, and prices for specialized medical services are already exorbitant, placing significant strain on many families. Inevitably, increased health care costs are borne by consumers; patent licensing fees for autism-related health care will be paid out of parents’ pockets, and not just parents of children who are receiving medical services subject to royalties. Given the growing demand, it seems particularly appropriate to consider the desirability of granting private ownership rights to procedures that might ultimately prove to be of value to alleviating anyone’s suffering, and could otherwise be learned, evaluated and applied as needed by qualified doctors, using their professional skills and readily available tools of the trade.

It is also appropriate to consider the ramifications of granting patents for speculative and potentially dangerous therapies for children and disabled individuals, who have long been considered suitable subjects for experimentation.

Autism research — including most of the studies cited by the applicants — is funded by taxpayer-funded government grants and tax-exempt private philanthropy, the latter often solicited from many individuals in the context of large non-profit fundraising campaigns and community events. Those who donate to autism research do so not with the intention of enriching well-placed entrepreneurial doctors, but of improving public welfare.

Appendix 1: Resources

A “submission” is a legal filing that can be made with respect to a patent application within two months from the date of publication. Since these applications were published on March 16, the deadline for mailing a submission to the US Patent and Trademark Office would be May 16, 2006. There is a $180 filing fee. “Submissions” generally entail the submission of evidence of “prior art” by those opposed to the grant of a patent. Any submission made regarding the safety, efficacy or ethics of the invention is considered irrelevant to the Patent Office’s examination of the application. Submissions made for such purposes are unlikely to be effective in preventing the grant of a patent.

U.S. Patent & Trademark Office Contact Center
(800) 786-9199

Those concerned about the proposed use of Lupron™ on autistic children can express their concerns to appropriate federal officer:

Paul Seligman, Director
FDA Office of Pharmacoepidemiology and Statistical Science
Paul.Seligman@fda.hhs.gov

Appendix 2: Bibliography

American Medical Association. Ethical Issues in the Patenting of Medical Procedures. American Medical Association, June 1995.

Margo A. Bagley. Patent First, Ask Questions Later: Morality and Biotechnology in Patent Law. William and Mary Law Review, February 2004.

Kathleen Fasanella, Patently arrogant (A brief and witty essay on garment-industry methods patents.)

Robert M. Hunter. Glossary of Patent Terms.

Chris J Katopis, Patients v. patents? Policy implications of recent patent legislation (St. John’s Law Review, Spring 1997).

Robert Patrick Merges, John Fitzgerald Duffy. Patent Law and Policy: 2005-06 Supplement.

Jon F. Merz. Disease Gene Patents: Overcoming Unethical Constraints on Clinical Laboratory Medicine. Clinical Chemistry 45: 324-330, 1999.

New York State Office of Industrial Liaison/Technology Transfer. Inventor’s Handbook

Patients, Not Patents. “The major activity of Patients not Patents is challenging the validity of medical patents before the United States Patent and Trademark Office.”

Seth Shulman. Cashing In On Medical Knowledge. MIT Technology Review, March 7, 2002.

United States Patent and Trademark Office: 1901 Protest Under 37 CFR 1.291 [R-3] – 1900 Protest

University of Tennessee Research Center. An Overview of the United States Patent System. January 1, 2003.

World Medical Association Statement on Medical Process Patents

Wendy W. Yang. Patent Policy and Medical Procedure Patents: The. Case for Statutory Exclusion From Patentability, Boston University Journal of Science and Technology Law, Volume 1, May 1995.

Appendix 3: Other Autism-Related Medical Patents and Patent Applications

Barstow, Leon E.; (Tucson, AZ); Weisbart, Richard; (Los Angeles, CA); Ostrem, James A.; (Tucson, AZ); Enriquez, F. Javier; (Tucson, AZ)

Use of oral gammaglobulin for the treatment of immune-mediated diseases (Filed October 4, 2002; published May 29, 2003)

Beck, Victoria; (Bedford, NH) ; Rimland, Bernard; (San Diego, CA); Repligen Corporation, Assignee

Method of using secretin and compositions made therefrom for the treatment of autism and other neurological, behavioral and immunological disorders (Filed March 5, 2001; published December 6, 2001)
Method of using secretin and compositions made therefrom for the treatment of autism and other neurological, behavioral and immunological disorders (Filed August 8, 2003; published November 10, 2005)

Beck, Victoria; (Bedford, NH) ; Horvath, Karoly; (Baltimore, MD); Repligen Corporation, Assignee

Method for assisting in differential diagnosis and treatment of autistic syndromes (Filed December 20, 2002; published July 29, 2004)

Brewitt, Barbara A.; (Seattle, WA)

Treatment methods using homeopathic preparations of growth factors (Filed November 26, 2002; published October 9, 2003)

Finegold, Sydney M.; (Marina Del Rey, CA)

Method of testing gastrointestinal diseases associated with species of genus clostridium (Filed June 5, 2001; published April 1, 2004)
Method of treating diseases associated with abnormal gastrointestinal flora (Filed December 9, 2003; published September 2, 2004)

Fallon, Joan M.; (New Rochelle, NY)

Method for diagnosing and treating dysautonomia and other dysautonomic conditions (Filed August 14, 2001; published March 28, 2002)
Methods for diagnosing pervasive development disorders, dysautonomia and other neurological conditions (Filed November 16, 2001; published June 27, 2002)
Methods of treating pervasive development disorders (Filed December 31, 2001; published July 11, 2002)
Methods for treating pervasive development disorders (Filed October 8, 2003; published April 15, 2004)
Methods for diagnosing and treating dysautonomia and other dysautonomic conditions (Filed December 8, 2003; published June 17, 2004)

Houston, Devin B.; (Forsyth, MO)

Compositions and methods relating to reduction of symptoms of autism (Filed December 6, 2002; published September 11, 2003)
Compositions and methods relating to reduction of symptoms of autism (Filed December 6, 2002; published September 11, 2003)
Compositions and methods relating to reduction of symptoms of autism (Filed September 6, 2002; published July 17, 2003)

Neumann, Liisa; (Valrico, FL)

Use of retinoic acid for treatment of autism (Filed June 21, 2002; published May 13, 2004)
Use of synthetic retinoic acid in form of 13-cis vitamin A for treatment of autism (Filed September 8, 2004; published February 10, 2005)

Skurkovich, Boris; (Pawtucket, RI) ; Skurkovich, Simon; (Rockville, MD)

Treatment of autism (Filed June 15, 2004; published December 15, 2005)

Vojdani, Aristo; (Los Angeles, CA)

Identification of etiology of autism (Filed February 3, 2004; published August 4, 2005)

Walsh, William John; (Naperville, IL) ; Usman, Anjum Iona; (Lisle, IL)

Nutrient supplements and methods for treating autism and for preventing the onset of autism (Filed November 30, 2001; published October 4, 2002)

Welch, Martha G.; (New York, NY) ; Ruggiero, David A.; (New York, NY) ; Anwar, Muhammad; (New York, NY)

Novel multipeptide regimen for the treatment of autistic spectrum, behavioral, emotional and visceral inflammation/autoimmune disorders (Filed March 11, 2004; published September 15, 2005)

Comments


  1. Wow, Kathleen. You are absolutely tireless. Who knew it was possible to write so gracefully about this nonsense?! I hope you have shared this piece with the FDA.

    — Lisa Randall    2006-04-05 22:41    #

  2. “Forms of mercury are described, and the claim is made that mercuric chloride binds and forms a complex with testosterone in subjects. The reference provided to substantiate this claim is Cooper et al., The Crystal Structure and Absolute Configuration of the 2:1 Complex between Tesosterone and Mercuric Chloride (Acta Crystallogr B., 1968 (15:24(7):935-41)).”

    Nice! Too bad prometheus took the time to track down the full article where they describe equimolar concentrations in boiling benzene. Not exactly conditions that apply in humans.

    Great work documenting all of this Kathleen. As always, I stand in awe.

    — notmercury    2006-04-06 07:23    #

  3. I hope the patent examiner is familiar with the science. I imagine there’s no way this can pass if it contains knowingly false claims.

    — Joseph    2006-04-06 11:53    #

  4. Great Stuff, Kathleen!

    I was going to write to Simon Baron-Cohen asking if he was happy with the work of the Autism Research Centre being used to support the Geiers’ dubious theories. But you only link to one of them in your blog. Can you email me the references so I don’t have to plough through the Geiers verbiage, please :-)

    — Mike Stanton    2006-04-06 13:32    #

  5. Everybody, thanks for the compliments, and for ploughing through that whole post. It’s a long slog.

    Mike, thanks for letting me know about the broken link, which I just fixed. Here are the citations:

    Manning J T, Baron-Cohen S, Wheelwright S, Sanders G.
    The 2nd to 4th digit ratio and autism
    Dev Med Child Neurol 2001;43:160-4

    Complete article in .pdf

    Lutchmaya S, Baron-Cohen S, Raggatt P, Knickmeyer R, Manning J T.
    2nd to 4th digit ratios, fetal testosterone and estradiol
    Early Hum Dev 2004;77:23-8

    Complete article in .pdf

    — Kathleen Seidel    2006-04-06 13:52    #

  6. Joseph,

    Patents don’t have to prove efficancy, just originallity. When I worked at a drug company, the patent abstracts contained all sorts of weird stuff. How about freeze-dried earthworms and lemon peel in oil for earaches? Yep, it was patented. The people who should see this are at the office for protection of human subjects.

    Kathleen, I love reading your blog. The ND folks are much kinder, gentler and wiser than the screamers at GR. : )

    — Ruth    2006-04-07 09:10    #

  7. I found your article on patents to have a refreshing perspective, and I appreciate the research and effort you’ve given to make this available online. Along these lines, what are your thoughts on this patent application that appears to be pending?

    — Paul Levy    2006-06-05 03:29    #