DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/20/2026 has been entered.
Withdrawal of Rejections
The response and amendments filed on 01/20/2026 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality correction and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous claim rejections under 35 U.S.C. 103 for obviousness have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112(a), Written Description
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 7, 10, 14, 25-28, and 32-33 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 recites “A method of treating a neurodevelopmental disorder in a subject in need thereof comprising, administering to the subject a mammalian alkaline phosphatase (AP) selected from intestinal alkaline phosphatase (IAP), placental alkaline phosphatase (PLAP), germ cell alkaline phosphatase (GCAP), and tissue non-specific alkaline phosphatase (TNAP), wherein the neurodevelopmental disorder is selected from the group consisting of autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, and wherein the subject is an unborn child, and wherein the AP is administered orally to the unborn child's pregnant mother”. Therefore, the claim, as a whole, pertains to treating a neurodevelopmental disorder in an unborn child by administering an AP to the unborn child’s pregnant mother.
Claim 1 recites “…treating a neurodevelopmental disorder in a subject in need thereof…” and “…wherein the subject is an unborn child…”; therefore, treatment of an unborn child would mean that the unborn child has been diagnosed with a neurodevelopmental disorder. The instant specification does not contemplate diagnosis of an unborn child with a neurodevelopmental disorder in order to subsequently treat an unborn child with said disease/disorder a neurodevelopmental disorder, such as ASD, bipolar disorder, schizophrenia, ADHD, schizoaffective disorder, etc. The specification states “In various embodiments, the method provides administering an AP-based agent, including without limitation orally administered IAP, to a pregnant woman afflicted with a risk factor for ASD (e.g., without limitation, one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut), to reduce the likelihood of the subject's offspring from developing ASD (and/or reducing or eliminating one or more symptoms of ASD in the subject's offspring)” (see, e.g., instant specification, pg. 39, lines 24-28). Therefore, the pregnant mother is diagnosed with one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut, or even could be diagnosed with ASD herself, which would then increase the risk of the unborn child having ASD. Therefore, the mother is diagnosed with a risk factor for an unborn child developing a neurodevelopmental disorder; however, the unborn child itself has not been diagnosed.Risk factor does not equate diagnosis of a disease state.
Examples 4-5 of the instant specification teaches reduction in the risk of neurodevelopmental disorders, such as ASD, in mice born from mothers with obesity (see, e.g., instant specification, Examples 4-5, pgs. 46-50). Examples 4 and 5 teach the induction of obesity in female mice, followed by administration of AP, followed by breeding (see, e.g., instant specification, Example 4). Newborn mice were then assessed for alleviation of maternal diet-induced behavior deficits, such as autism spectrum disorder (see, e.g., instant specification, Example 5). However, diagnosis or assessment of these mice in utero to determine if they actually have ASD was not described. Therefore, nowhere in the instant specification, in general, and in the examples, does Applicant teach or provide any methods for testing or diagnosing if a fetus has a neurodevelopmental disorder or disease in utero in order to determine if the fetus actually needs to be treated. Moreover, the diagnostic methods that the instant specification does set forth are for children that have already been born, such as “the Checklist of Autism in Toddlers (CHAT), the modified Checklist for Autism in Toddlers (M-CHAT), the Screening Tool for Autism in Two-Year- Olds (STAT), the Social Communication Questionnaire (SCQ), the Autism Spectrum Screening Questionnaire (ASSQ), the Australian Scale for Asperger's Syndrome, the Childhood Asperger Syndrome Test (CAST), the Autism Diagnosis Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS-G), the Childhood Autism Rating Scale (CARS), audiologic hearing evaluation, Administered PTSD Scale, the Eysenck Personality Inventory, the Hamilton Anxiety Scale, or in various animal models such as the well-known Vogel (thirsty rat conflict) test, or the elevated plus maze test” (see, e.g., instant specification, pg. 41, lines 29-33 & pg. 42, lines 1-3). Moreover, at a bare minimum, the specification contemplates a pregnant mother being diagnosed with a risk factor (i.e., gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut) and this diagnosis in relation to ASD in an unborn child (see, e.g., instant specification, pgs. 39-42 & Examples 4-5); however, the specification primarily focuses on ASD as the neurodevelopmental disorder, and not the other claimed neurodevelopmental disorders, such as schizophrenia, ADHD, schizoaffective disorder, or bipolar disorder. Moreover, the specification does not provide guidance on how the pregnant mother diagnosed with a risk factor (i.e., gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut) increases the risk of an unborn child developing schizophrenia, ADHD, schizoaffective disorder, or bipolar disorder. Written description and guidance is primarily centered around ASD.
Therefore, the instant specification does not describe how an unborn child is diagnosed with having a neurodevelopmental disorder, such as ASD, bipolar disorder, schizoaffective disorder, schizophrenia, ADHD, etc., in utero in order for these neurodevelopmental disorders to subsequently be treated. In order to treat a subject in need thereof (i.e., unborn child) there needs to be a diagnosis, which the specification does not contemplate. Instead, the specification sets forth risk factors that the pregnant mother is diagnosed with, wherein these risk factors increase the risk of the unborn child developing ASD.
Claim Rejections - 35 USC § 112(a), Scope of Enablement
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 7, 10, 14, 25-28, and 32-33 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for treating a pregnant mother with increased risk of ASD, does not reasonably provide enablement for treatment of ASD, schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder in an unborn child diagnosed with said disease . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In re Wands (858 F2d, 721, 727, 8 USPQ 2d 1400, 1404 (Fed Cir. 1988)), the issue of
enablement in molecular biology was considered. It was held that the following factors should be
considered to determine whether the claimed invention would require the skilled artisan undue
experimentation:
1) Amount of experimentation necessary;
2) Amount of direction or guidance presented;
3) Presence or absence of working examples;
4) Nature of the invention;
5) State of the prior art;
6) Relative skill of those in the art;
7) Predictability or unpredictability of the art; and
8) Breadth of the claims.
Independent claim 1 recites:
“A method of treating a neurodevelopmental disorder in a subject in need thereof comprising, administering to the subject a mammalian alkaline phosphatase (AP) selected from intestinal alkaline phosphatase (IAP), placental alkaline phosphatase (PLAP), germ cell alkaline phosphatase (GCAP), and tissue non-specific alkaline phosphatase (TNAP), wherein the neurodevelopmental disorder is selected from the group consisting of autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, and wherein the subject is an unborn child, and wherein the AP is administered orally to the unborn child's pregnant mother”.
Nature of the invention: The invention is directed towards a method of treating autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder in an unborn child by administering AP to a pregnant mother of the unborn child
Breadth of the claims: As claimed, the method comprises treating autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder in an unborn child. Furthermore, recitation of “…treating a neurodevelopmental disorder in a subject in need thereof…” has been interpreted to mean that the subject in need thereof (i.e., unborn child) has been diagnosed with a neurodevelopmental disorder in order to be treated for a neurodevelopmental disorder.
Amount of direction or guidance presented: The instant specification recites “in various embodiments, the present AP-based agent is administered to a mother or expecting mother, where the mother is afflicted with one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut and/or the mother or expecting mother has a high fat diet. In various embodiments, the mother or expecting mother is at risk for having a child with a neurodevelopmental disorder, e.g., ASD, by being afflicted with one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut and/or having a high fat diet, and the present method reduces the likelihood or severity of the neurodevelopmental disorder, e.g., ASD, in the unborn child or newly born child of the mother or expecting mother” (see, e.g., instant specification, pg. 5, lines 4-11). Furthermore, the instant specification recites “In some aspects, the present invention provides a method of treating autism spectrum disorder (ASD), comprising administering an effective amount of an AP-based agent described herein, including without limitation, orally
administered IAP, to a patient in need thereof. In various embodiments, the method provides administering an AP-based agent, including without limitation orally administered IAP, to a pregnant woman afflicted with a risk factor for ASD (e.g., without limitation, one or more of
gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut), to reduce the likelihood of the subject's offspring from developing ASD (and/or reducing or eliminating one or more symptoms of ASD in the subject's offspring)” (see, e.g., instant specification, pg. 39, lines 21-28). Therefore, the instant specification teaches that AP can theoretically treat neurodevelopmental disorders, such as ASD, in unborn children, wherein the pregnant mother is afflicted with one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut and/or having a high fat diet. The instant specification mainly provides direction and guidance for diagnosis of a pregnant mother with risk factors for an unborn child developing ASD; however, the instant specification does not provide direction or guidance on how diagnosis of a pregnant mother with a risk factor increases the risk of the other claimed neurodevelopmental disorders, such as schizophrenia, ADHD, schizoaffective disorder, and bipolar disorder in the unborn child.
Presence or absence of working examples: The instant specification in Example 4 teaches an in vivo model comprising feeding female mice a regular chow and high fat chow diet to induce obesity, and at the same time administering either bovine intestinal AP or placebo (i.e., water) to the female mice. After 8 weeks of high fat chow feeding, the female mice were mated, and the diets and AP treatments were kept the same (see, e.g., instant specification, Example 4). Example 5 teaches assessing the efficacy of the AP treatment in alleviating maternal diet-induced behavior deficits in offspring, wherein the offspring performed social interaction tests. Example 5 states that offspring of mothers fed high fat diets and AP behaved like control mice (see, e.g., instant specification, Example 5 & Figures 7-18), however, there are no statistical analyses performed between the different treatment groups in order to determine that there are actually differences in the treatment due AP treatment and obesity in the pregnant mothers. Furthermore, nowhere in the instant specification does it teach or provide examples that the unborn mice actually have been diagnosed a neurodevelopmental disorder, such as ASD, to treat. Based on these examples, the instant specification teaches reducing the risk of offspring from developing ASD, wherein the offspring are at an increased risk of ASD due to obesity in the pregnant mothers. Moreover, the specification’s embodiments and examples primarily focus on ASD. Contemplation for treatment of other claimed neurodevelopmental disorders, such as schizophrenia, ADHD, schizoaffective disorder, and bipolar disorder, was not performed.
Moreover, in Applicant’s Declaration filed on 01/20/2026, Applicant provides evidence that AP treatment administered to healthy volunteers does not enter the bloodstream and is not absorbed into systemic circulation (see, e.g., Declaration, Table 1). Additionally, the Declaration states “oral IAP has its mode of action from within the GI tract” (see, e.g., Declaration, pg. 2). However, if AP is not absorbed into the bloodstream of the pregnant mother, then it would not reach the unborn child to treat the unborn child in need of treatment. Instead the AP would be treating the pregnant mother afflicted with a risk factor, such as gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and/or leaky gut. Therefore, the unborn child would not be treated through AP administration, which directly supports this enablement rejection. Based on Applicant’s Declaration, AP would be instead treating the pregnant mother diagnosed with a risk factor instead of treating the unborn child since the AP does not enter circulation and stays in the GI tract. Moreover, Ganapathy (Placental transporters relevant to drug distribution across the maternal-fetal interface; 2000 – previously cited) teaches distribution of drugs for therapeutic use across the placenta for the treatment of the mother and fetus (see, e.g., Ganapathy, pg. 413, col 1). Therefore, if there is no placenta transport because the AP is not being absorbed into the bloodstream, then Applicant is showing in the Declaration that the AP is not acting on the unborn child itself in order to treat a neurodevelopmental disorder.
Based on Applicant’s disclosure, the Applicant would not be enabled for treatment of autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder. There is no guidance that the unborn mice, and even unborn children, have these neurodevelopmental disorders to treat because Applicant does not provide evidence of diagnosing a neurodevelopmental disorder in utero. Therefore, Applicant has only reduced to practice reducing the risk of an unborn child from developing ASD.
State of the prior art: The prior art does not teach diagnosis of neurodevelopmental disorders, such as ASD, schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, in utero; however, the prior art does teach that there is prenatal genetic testing that can be performed to inform parents about their unborn child’s risk for ASD (see, e.g., Chen, “Autism spectrum disorders: a qualitative study of attitudes toward prenatal genetic testing and termination decisions of affected pregnancies”; 2015). The prior art teaches that “Neurodevelopmental disorders (NDDs) are multifaceted conditions characterized by impairments in cognition, communication, behavior and/or motor skills resulting from abnormal brain development. Intellectual disability, communication disorders, autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD) and schizophrenia fall under the umbrella of NDD.1, 2, 3 Currently, there are no biomarkers to diagnose NDD or to differentiate between them. Rather, these disorders are categorized into discrete disease entities, based on clinical presentation” (see, e.g., Mullin, “Neurodevelopmental disorders: mechanisms and boundary definitions from genomes, interactomes and proteomes; 2013). Therefore, the prior art teaches that diagnosis relies on clinical signs, which cannot be observed in utero. Furthermore, the art does not teach diagnosis of ASD in utero, but teaches risk factors for ASD.
Furthermore, in regards to bipolar disorder, Culpepper (The Diagnosis and Treatment of Bipolar Disorder: Decision-Making in Primary Care; 2014) teaches “Bipolar disorder is a chronic episodic illness, characterized by recurrent episodes of manic or depressive symptoms. Patients with bipolar disorder frequently present first to primary care, but the diversity of the potential symptoms and a low index of suspicion among physicians can lead to misdiagnosis in many patients. Frequently, co-occurring psychiatric and medical conditions further complicate the differential diagnosis. A thorough diagnostic evaluation at clinical interview, combined with supportive case-finding tools, is essential to reach an accurate diagnosis” (see, e.g., Culpepper, abstract). Therefore, bipolar disorder is a difficult disorder to diagnose properly due to the diversity of symptoms. Moreover, the prior art does not teach diagnosis of bipolar disorder in an unborn child and the prior art does not teach prenatal genetic testing that can be performed to determine if an unborn child has an increased risk of developing bipolar disorder once born. However, child born to mothers with bipolar disorder have an increased risk for mood disorders and other adverse psychosocial outcomes due to genetic and environmental risk (see, e.g., Peay, “Parenting with Bipolar Disorder: Coping with Risk of Mood Disorders to Children; 2015). Therefore, a child is at an increased risk for developing bipolar disorder if their mother has been diagnosed with bipolar disorder.
Furthermore, “The term “neurodevelopmental disorders” encompasses a large group of disorders that share the fact that disease onset is during periods of ongoing maturation and development. These disorders are often associated with complex neuropsychiatric features including intellectual disability, specific learning disabilities, ADHD, autism, and epilepsy, among others. Neurodevelopmental disorders are caused by a wide range of genetic mutations and environmental factors (e.g., infections, immune dysfunction, intoxication, endocrine and metabolic dysfunction, nutritional factors, trauma, etc.). Heritability estimates indicate that genetic factors play an important role in these disorders” (see, e.g., Ehninger, “Reversing Neurodevelopmental Disorders in Adults”; 2009). Therefore, there are many etiologies and types of neurodevelopmental disorders. Moreover, “Diagnosis and treatment of these disorders can be difficult; treatment often involves a combination of professional therapy, pharmaceuticals, and home- and school-based programs” (see, e.g., EPA; “Neurodevelopmental disorders”; 2015). Based on the prior art, there are many types of neurodevelopmental disorders with different etiologies; however, neurodevelopmental disorders cannot be diagnosed in utero because diagnosis is based on clinical presentation. Moreover, there are no biomarkers to diagnose neurodevelopmental disorders or to differentiate between neurodevelopmental disorders, which his why clinical presentation is used for diagnosis. Additionally, a pregnant mother is able to perform prenatal genetic screening on their unborn child to determine if they are at an increased risk of developing ASD; however, this is not a diagnosis. Moreover, a unborn child whose mother has bipolar disorder is at an increased risk of having bipolar disorder; however, again, this is not a diagnosis. Furthermore, since neurodevelopmental disorders are diagnosed by clinical presentation, treatment focuses on a combination of professional therapy, pharmaceuticals, and home- and school-based programs.
Relative skill of those in the art: Based on the state of the prior art, the relative skill of those in the art pertaining to diagnosing and treating a neurodevelopmental disorder, such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, with AP in utero is low.
Predictability or unpredictability of the art: The level of unpredictability within the art is high, as there are many types and etiologies of neurodevelopmental disorders. Furthermore, the prior art does not teach diagnosis of a neurodevelopmental disorder in utero for subsequent treatment in utero, which makes it even more unpredictable as to how AP is used to treat an unborn child who may or may not even have a neurodevelopmental disorder. Further, the specification does not contemplate how an unborn child is even diagnosed with a neurodevelopmental disorder, such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, in utero for subsequent treatment with AP. Therefore, the level of unpredictability within the art is high.
Amount of experimentation necessary: Since there are many types of neurodevelopmental disorders, all with different etiologies, one of ordinary skill in the art would have undue experimentation in order to determine if an unborn child actually has a neurodevelopmental disorder in utero in order to subsequently treat this neurodevelopmental disorder in utero. Therefore, the amount of experimentation is high.
Claim Interpretation
For compact prosecution, the claims have been interpreted to be related to an unborn child having increased risk for ASD, schizophrenia, ADHD, schizoaffective disorder, and bipolar disorder based on the pregnant mother being diagnosed with risk factors, such as gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, leaky gut, or even a neurodevelopmental disorder itself.
Claim Rejections - 35 USC § 103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 7, 10, and 32-33 are rejected under 35 U.S.C 103 as being unpatentable over Malo (US2016/0201110; Publication date July 14, 2016 – previously cited) in view of Wang (Maternal Body Mass Index and Risk of Autism Spectrum Disorders in Offspring: A Meta-analysis; 2016 – newly cited).
For compact prosecution, this rejection is made based on the pregnant mother being diagnosed with risk factor(s) resulting in an increased risk of the unborn child having a neurodevelopmental disorder.
Malo’s general disclosure relates to a method for “predicting incipient diabetes, metabolic disorders or the metabolic syndrome by developing a personal temporal Phosphatase profile” (see, e.g., Malo, abstract). Additionally, Malo discloses that the incipient diabetes is “type 2 diabetes mellitus, gestational diabetes, diabetes insipidus, or type I diabetes” (see, e.g., Malo, [0010]), and that the incipient metabolic syndrome is “a cardiovascular disease, coronary heart disease, cerebrovascular disease, stroke, peripheral vascular disease, nonalcoholic fatty liver disease, retinopathy, asthma, chronic pulmonary obstructive disease, cystic fibrosis, Alzheimer's disease, arthritis, eczema or psoriasis” (see, e.g., Malo, [0011]). Furthermore, Malo discloses “patients with type 2 diabetes mellitus (T2DM) have less amount of the brush-border enzyme intestinal alkaline phosphatase (IAP) in their stools compared to the control non-diabetic healthy subjects. Disclosed herein is a protocol for diagnosing the incipient diabetes and other metabolic disorders (e.g., cardiovascular diseases (coronary heart disease), cerebrovascular disease (stroke), peripheral vascular disease, nonalcoholic fatty liver disease, etc.) and the metabolic syndrome (e.g., obesity, hyperglycemia, insulin resistance, hyperinsulinemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein (HDL), high low-density lipoprotein (LDL), hypertension, fatty liver, etc.) by developing a temporal profile of stool TAP levels for humans and other animals, such as cattle, pig, sheep, goats, cows, horses, dogs, cats, monkeys, rabbits, rats, mice, chickens, turkeys, etc.” (see, e.g., Malo, [0004]).
Regarding claims 1, 7, and 10 pertaining to administration of AP and treatment of a neurodevelopmental disorder, Malo teaches “specific doses of IAP, as an oral supplementation, can be administered to a mammal to decrease the risk of incipient diabetes, other metabolic disorders or the metabolic syndrome” (see, e.g., Malo, [0005]), wherein metabolic disorders include “cardiovascular diseases (coronary heart disease), cerebrovascular disease (stroke), peripheral vascular disease, nonalcoholic fatty liver disease, etc.” and metabolic syndrome includes “obesity, hyperglycemia, insulin resistance, hyperinsulinemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein (HDL), high low-density lipoprotein (LDL), hypertension, fatty liver, etc.” (see, e.g., Malo, [0004]). Malo teaches “the phosphatase is intestinal alkaline phosphatase, placental alkaline phosphatase, tissue nonspecific alkaline phosphatase (liver/bone/kidney alkaline phosphatase), germ cell alkaline phosphatase, neutrophil alkaline phosphatase, mammalian alkaline phosphatase, a bacterial alkaline phosphatase, a fungal alkaline phosphatase, alkaline phosphatase, an acid phosphatase or a peptide with phosphatase activity” (see, e.g., Malo, [0008]). Malo teaches that the phosphatase is administered orally (see, e.g., Malo, [0021]). Furthermore, Malo teaches that the phosphatase can be administered to treat a chronic disease, wherein the chronic disease includes attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar mood disorder, and schizophrenia (see, e.g., Malo, [0039])
Regarding claim 32 pertaining to treatment of ASD, Malo teaches reduction in the risk of various symptoms associated with ASD, such as obsessive compulsive disorder (see, e.g., Malo, [0039]) and depression (see, e.g., Malo, [0039]).
Malo teaches administering alkaline phosphate to humans; however, Malo does not teach administration to a pregnant woman to treat an unborn child. Malo does teach administering AP to a patient that has obesity and metabolic syndrome.
Regarding claims 1 and 33, Wang’s general disclosure relates the association between maternal body mass index (MBI) and risk of autism spectrum disorder in offspring (see, e.g., Wang, abstract). Moreover, Wang discloses that “Compared with children whose mothers were at normal weight, children born to overweight and obese mothers have a 28% and 36% higher risk of developing ASD, respectively” (see, e.g., Wang, Discussion, pg. 2). Furthermore, Wang discloses “A linear dose-response relationship was found, with the risk of ASD increasing by 16% for each 5 kg/m2 increment in maternal BMI compared with that of normal weight” (see, e.g., Wang, Discussion, pg. 2). Wang discloses “Although the causal pathway remains to be elucidated, the effects of maternal BMI on ASD may be explained by several hypothesizes. Of the proposed mechanisms, inflammation is the most frequently mentioned one to explain the association of maternal BMI and ASD. It is observed that obese women had higher levels of C-reactive protein in the plasma compared with normal weight pregnant women21. In addition, increased CD68 + and CD14 + cells with elevated expression of inflammatory cytokines including tumor necrosis factor-alpha, interleukin-6, and interleukin-1 in the placentas have also been found in obese pregnant mothers22,23. As placenta inflammation is associated with neonatal brain damage and can induce a systemic fetal inflammatory response which may contribute to white matter injury in the fetal brain23, it is plausible that the risk of mental disorders increases for children born to mother with overweight/obesity” (see, e.g., Wang, Discussion, pg. 2). Additionally, Wang discloses that maternal diabetes also significantly increases the risk of ASD in offspring (see, e.g., Wang, Discussion, pg. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer AP to the patient population suffering from obesity and metabolic syndrome, as taught by Malo, because Wang teaches that obesity in pregnant mothers significantly increases the risk of a child developing a neurodevelopmental disorder. Moreover, if a pregnant woman was diagnosed to suffer from obesity and/or metabolic syndrome, one would have been motivated to treat the pregnant woman with AP since Malo teaches the diagnosis and treatment of a subject with obesity and metabolic syndrome. Furthermore, treatment of obesity in a pregnant woman would implicitly reduce the risk of an unborn child developing a neurodevelopmental disorder, such as autism, as taught by Wang, because if a pregnant woman with obesity is treated with AP, as suggested by Malo, this would treat obesity in the pregnant mother which would implicitly reduce the risk of ASD in the unborn child. Therefore, based on the teachings of Malo and Wang, it would have been obvious to treat a pregnant woman suffering from obesity with AP since AP can be administered to treat obesity, which would implicitly reduce the risk of the unborn child developing ASD. One would have expected success because Malo and Wang both teach obesity and neurodevelopmental disorders.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Malo and Wang as applied to claims 1, 7, 10, and 32-33 above, and further in view of Tang (US2007/0042392; Publication date: February 22, 2007 – previously cited).
The combined teachings of Malo and Wang herein referred to as modified-Malo-Wang, are discussed above.
However, modified-Malo-Wang does not teach the alkaline phosphatase comprising an amino acid sequence having at least 97% sequence identity with any one of SEQ ID Nos: 1-11 and 17-18 (claim 14).
Tang’s general disclosure relates to the identification of “novel polynucleotides and proteins encoded by such polynucleotides, along with uses for these polynucleotides and proteins, for example in therapeutic, diagnostic and research methods” (see e.g., Tang, [0002]). Additionally, Tang discloses that the invention encompasses methods for treating diseases or disorders, such as neurodegenerative diseases and gastrointestinal diseases (see, e.g., Tang, [0025], [0172]).
Regarding claim 14 pertaining to the amino acid sequences of the alkaline phosphatase, Tang teaches SEQ ID NO: 1024, which has 100% and 99.2% sequence identity to SEQ ID NOs: 1 and 17 in the instant application, respectively (see, e.g., Tang, [0068]).
It would have been obvious to one of ordinary skill in the art to administer Tang’s SEQ ID NO:1024 to a pregnant woman with obesity in order to reduce the risk of an unborn child developing a neurodevelopmental disorder, as taught by modified-Malo-Wang. One would have been motivated to do so because Tang teaches administration of polypeptides, such as SEQ ID NO:1024, “for preventing, treating, or ameliorating a medical condition which comprises the step of administering to a mammalian subject a therapeutically effective amount of a composition comprising a polypeptide of the present invention and a pharmaceutically acceptable carrier” (see, e.g., Tang, [0020]), which can encompass treatment of a neurodevelopmental disease. Moreover, modified-Malo-Wang teach the administration of AP for the treatment of neurodevelopmental disorders (see, e.g., Malo, [0039]), and modified-Malo-Wang teaches administration of AP to reduce a metabolic syndrome disorder, such as obesity (see, e.g., Malo, [0004]), in a subject, because this would result in reduction in the risk of the unborn child developing a neurodevelopmental disorder, such as ASD, as taught by Wang (see, e.g., Wang, Discussion, pg. 2). Therefore, based on the teachings of modified-Malo-Wang and Tang, it would have been obvious to administer an AP to a pregnant woman with a metabolic syndrome disorder, such as obesity, in order to implicitly reduce the risk of a neurodevelopmental disorder in an unborn child. Furthermore, modified-Malo-Wang teaches administration of AP to a pregnant mother, which would implicitly affect an unborn child; therefore, it would have been obvious to administer Tang’s AP to a pregnant mother to implicitly treat an unborn child because Tang teaches that the AP can be administered “for preventing, treating, or ameliorating a medical condition” (see, e.g., Tang, [0020]). One would have expected success because of modified-Malo-Wang and Tang both teach administration of AP for the treatment of diseases, which can encompass neurodevelopmental disorders.
Claims 25 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Malo and Wang as applied to claims 1, 7, 10, and 32-33 above, and further in view of Aiba (US2014/0030790; Publication date: January 30, 2014 – previously cited) and Robinson (Enzymes: principles and biotechnological applications; 2015- previously cited).
The combined teachings of Malo and Wang herein referred to as modified-Malo-Wang, are discussed above.
However, modified-Malo-Wang does not teach the alkaline phosphatase having a specific activity of at least about 100 U/mg to about 20000 U/mg (claim 25); or that the alkaline phosphatase is active at a pH of about 6.0 to about 12.0 (claim 27).
Aiba’s general disclosure relates to an alkaline phosphatase with a high specific activity and stability (see, e.g., Aiba, abstract). Additionally, Aiba discloses that the alkaline phosphatase has an optimum reaction pH, pH stability, thermal stability, and specific activity (see, e.g., Aiba, [0042]).
Regarding claim 25 pertaining to the specific activity, Aiba teaches the alkaline phosphatase having a “specific activity of 5,000 U/mg or more” (see, e.g., Aiba, [0016]).
Regarding claim 27 pertaining to the pH, Aiba teaches that the alkaline phosphatase is stable at a pH between 5.5 to 10.4 (see, e.g., Aiba, [0014]).
Robinson’s general disclosure relates to the industrial application of enzymes and how they are used to catalyze commercially important processes (see, e.g., Robinson, abstract).
Regarding claim 25 pertaining to the specific activity, Robinson teaches that the specific activity of enzymes can be increased through enzyme purification methods (see, e.g., Robinson, pg. 22), which is important for commercial uses (see, e.g., Robinson, pg. 22).
It would have been obvious to one of ordinary skill in the art to administer Aiba’s alkaline phosphatase to a pregnant woman to implicitly reduce the risk of an unborn child developing a neurodevelopmental disorder, as taught by modified-Malo-Wang. One would have been motivated to do so to because Aiba teaches that the alkaline phosphatase exhibits high specific activity at a broad pH range, which is advantageous when treating diseases, such as neurodevelopmental diseases, as these enzymes can have higher specificities when used as a treatment (see, e.g., Robinson, pg. 22). Moreover, modified-Malo-Wang teach the administration of AP to treat a pregnant woman suffering from a metabolic syndrome disorder, such as obesity, wherein treatment of obesity would decrease the risk of the unborn child developing a neurodevelopmental disorder (see, e.g., Malo, [0004] & Wang, Discussion, pg. 2). Therefore, based on the teachings of by modified-Malo-Wang, Aiba, and Robinson, it would have been obvious to administer an AP to a pregnant woman, wherein the AP has a specific activity at a broad pH range, in order to implicitly treat an neurodevelopmental disorder in an unborn child. Furthermore, modified-Malo-Wang teaches administration of AP to a pregnant mother, which would implicitly treat an unborn child; therefore, it would have been obvious to administer Aiba’s AP to a pregnant mother to implicitly treat an unborn child because Aiba teaches that the AP has an optimum reaction pH, pH stability, thermal stability, and specific activity (see, e.g., Aiba, [0042]). One would have expected success because modified-Malo-Wang, Aiba, and Robinson all teach AP-based treatments, or enzymes, in general.
Claims 26 and 28 are rejected under 35 U.S.C 103 as being unpatentable over Malo and Wang as applied to claims 1, 7, 10, and 32-33 above, and in further view of Raaben (US2017/0009216; Publication date: January 12, 2017 – previously cited).
The combined teachings of Malo and Wang herein referred to as modified-Malo-Wang, are discussed above.
However, modified-Malo-Wang does not teach the alkaline phosphatase being stable and/or active in the GI tract, in one or more of the mouth, esophagus, stomach, duodenum, small intestine, jejunum, ileum, large intestine, colon, cecum, and rectum (claim 26); or that the alkaline phosphatase is stable in chyme (claim 28).
Raaben’s general disclosure relates to an improved alkaline phosphatase that has improved specific activity, stability, and substrate specificity (see, e.g., Raaben, [0007]). Additionally, Raaben discloses that the alkaline phosphatase can be used in the treatment of “sepsis, acute kidney injury, inflammatory bowel disease, enterocolitis, ischemia reperfusion damage, or other inflammatory diseases” (see, e.g., Raaben, [0006]).
Regarding claims 26 and 28 pertaining the stability and/or activity of the alkaline phosphatase, Raaben teaches that alkaline phosphatase maintains its activity in various organs, including the stomach, colon, and small intestine (see, e.g., Raaben, [0207], Tables 10-11). Furthermore, since the alkaline phosphatase is stable in the stomach and small intestine it would also be stable in chyme.
It would have been obvious to one of ordinary skill in the art to administer Raaben’s alkaline phosphatase to a pregnant woman afflicted with metabolic syndrome, such as obesity, in order to implicitly reduce the risk of an unborn child developing a neurodevelopmental disorder, as taught by modified-Malo-Wang. One would have been motivated to do so because Raaben teaches administration of an alkaline phosphatase “with improved properties for preventing, treating, or curing diseases” (see, e.g., Raaben, [0001]), which can include neurodevelopmental diseases. Furthermore, Raaben teaches that the alkaline phosphatase has an improved in vivo half-life (see, e.g., Raaben, [0007]), which is advantageous when treating diseases, such as neurodevelopmental diseases, as this can allow for high levels of activity after oral administration, and increased stability in the stomach, colon and small intestine (see, e.g. Raaben, [207]). Moreover, modified-Malo-Wang teaches administration of AP for the treatment of neurodevelopmental disorders (see, e.g., Malo, [0039]), wherein the AP can be administered to a pregnant woman with a metabolic syndrome, such as obesity, in order to decrease the risk of the unborn child developing a neurodevelopmental disorder, such as autism (see, e.g., Malo, [0004] & Wang, Discussion, pg. 2). Therefore, based on the teachings of by modified-Malo-Wang and Raaben, it would have been obvious to administer an AP to a pregnant woman, wherein the AP is stable/active following oral administration, in order to implicitly reduce the risk of an unborn child developing a neurodevelopmental disorder. Furthermore, modified-Malo-Wang teaches administration of AP to a pregnant mother, which would implicitly affect an unborn child; therefore, it would have been obvious to administer Raaben’s AP to a pregnant mother to implicitly affect an unborn child because Raaben teaches that the AP has improved specific activity, stability, and substrate specificity (see, e.g., Raaben, [0007]), as well as maintains its activity in various organs, including the stomach, colon, and small intestine (see, e.g., Raaben, [0207], Tables 10-11). One would have expected success because modified-Malo-Wang and Raaben both teach AP treatments.
Examiner’s Response to Arguments
Applicant's arguments filed 01/20/2026 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments pertaining to the method of treatment taught by Malo are in the context of Malo’s diagnostic method (remarks, pages 5-6), this argument is not persuasive for multiple reasons:
First, the instantly claimed invention pertains to a method of treatment, not a method of diagnosis; therefore, the diagnosis methods taught by Malo are irrelevant. Malo teaches administration of intestinal alkaline phosphatase (IAP) to individuals afflicted with metabolic disorders and metabolic syndrome (see, e.g., Malo, [0004]), which can inherently include pregnant woman since pregnant woman can suffer from these afflictions. Moreover, Malo teaches “In a further illustrative embodiment, the method for decreasing the risk of or for treating a chronic disease, an acute disease, an infectious disease, a disorder or a syndrome involves administering an effective amount of phosphatase to a mammal in need thereof” (see, e.g., Malo, [0038]); therefore, Malo does teach treatment without diagnostic methods.
Secondly, Applicant argues that for Malo’s method, AP would need to be measured in the stools of infants; however, Applicant’s argument is not consistent with the instantly claimed invention. Applicant’s invention pertains to administering AP to a pregnant mother that is afflicted with one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut, wherein all of these afflictions increase the risk of an unborn child developing a neurodevelopmental disorder. Therefore, since AP is administered to the pregnant mother, AP would be measured in the stools of the pregnant mother, not the infant, when applying the art of Malo. The instantly claimed invention pertains to treating a pregnant mother in order to decrease the risk of the unborn child developing a neurodevelopmental disorder; therefore, in this context, the pregnant mother is really the subject and the unborn child is indirectly being affected.
Thirdly, Applicant provides supportive evidence in the declaration filed on 01/20/2026 that AP cannot undergo placental transport and does not enter the circulation (see, e.g., Declaration, pgs. 2-3) (remarks, pages 7-8); therefore, this is more evidence that the AP stays within the gut of the pregnant mother and treats one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut within the pregnant mother, which reduces the risk of the unborn child from developing a neurodevelopmental disorder. Furthermore, the declaration shows that IAP administered to volunteers was not quantifiable in the serum of the volunteers, but quantifiable in the feces of almost all the volunteers (see, e.g., Declaration, pg. 3), which further shows that the IAP administered stays within the gut of the pregnant mother. This further supports that, in the context of Malo’s diagnostic methods, AP should be measured within the stools of the pregnant mother, and not the infant. Moreover, since AP does not enter into the circulation, it is not able to reach the unborn child to treat or act upon the unborn child. Furthermore, Applicant does not provide evidence that this is absolutely no placental transport of the claimed AP, Applicant only provides mere statements that placental transport would not occur. Mere statements do not replace evidence of the record (see, e.g., MPEP 716.01(c)(II)).
Fourthly, Malo teaches “A low IAP level or a persistent loss of IAP from a previously high level in a healthy subject is indicative of incipient diabetes, other metabolic disorders or the metabolic syndrome” (see, e.g., Malo, [0004]). Furthermore, Malo teaches “that specific doses of IAP, as an oral supplementation, can be administered to a mammal to decrease the risk of incipient diabetes, other metabolic disorders or the metabolic syndrome. The level of IAP in stool greatly varies from one individual to another individual. An individual with less than the average IAP level in control healthy humans (approx. 65 U/gm stool using the assay conditions disclosed herein) can be immediately provided with IAP supplementation” (see, e.g., Malo, [0005]). Therefore, in the context of treating a pregnant mother, Malo’s diagnostic methods would show that IAP levels are decreased in a pregnant mother afflicted with a metabolic syndrome and would therefore be provided IAP supplementation, which would treat the metabolic syndrome and subsequently decrease the risk of the unborn child developing a neurodevelopmental disorder, as evidence by Wang in the 103 rejection above.
Fifthly, since the pregnant mother is actually being treated with AP, and AP should be measured within the pregnant mother, Malo teaches “In yet a further illustrative embodiment, in addition to measuring the concentration of phosphatase in a stool sample, a sample of saliva, urine, blood, plasma, serum, gastric fluid, intestinal fluid, ocular fluid, peritoneal fluid, vaginal fluid, or a body cavity fluid is also analyzed” (see, e.g., Malo, [0009]). Therefore, there is no inoperability because the diagnosis of the disorder (i.e., reduced AP levels) may be achieved in other methods known in the art, wherein these methods do not involve stool sampling. Furthermore, MPEP 2121 states “"Even if a reference discloses an inoperative device, it is prior art for all that it teaches." Beckman Instruments v. LKB Produkter AB, 892 F.2d 1547, 1551, 13 USPQ2d 1301, 1304 (Fed. Cir. 1989). Therefore, "a non-enabling reference may qualify as prior art for the purpose of determining obviousness under 35 U.S.C. 103." Symbol Techs. Inc. v. Opticon Inc., 935 F.2d 1569, 1578, 19 USPQ2d 1241, 1247 (Fed. Cir. 1991)”. Therefore, the prior art of Malo is operable because Malo teaches treatment of patients with AP, which reads upon the instantly claimed invention. Moreover, since the declaration proves that AP stays within the stool of the feces of the individual(s) administered the AP (see, e.g., Declaration, pg. 3), then in the context of Malo, the stool should be sampled from the pregnant mother, not the unborn child; therefore, further proving that Malo is operable.
Regarding Applicant’s arguments pertaining to the prior art of Ganapathy (remarks, page 6), Ganapathy was not relied upon in the above presented rejection; therefore, Applicant’s arguments pertaining to Ganapathy are moot.
Regarding Applicant’s argument that the unborn child has not been diagnosed with the neurodevelopmental disorder (remarks, page 7), this argument is not persuasive because the instantly claimed invention pertains to a method of treating a neurodevelopmental disorder in the unborn child. Applicant argues that the unborn child has not been diagnosed with a neurodevelopmental disorder; however, if this is the case, then it is unclear how a neurodevelopmental disorder can be treated in the claimed invention (see 112(b) rejection above regarding this). Furthermore, it appears that AP is being administered to treat a pregnant mother afflicted with one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut in order to reduce the risk of the unborn child developing a neurodevelopmental disorder (see 112(a) rejections above regarding this). Neither the pregnant mother nor the unborn child are being treated for a neurodevelopmental disorder, but the pregnant mother is being treated for one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut, which reduces the risk of the unborn child from developing a neurodevelopmental disorder. Applicant is arguing and claiming that the neurodevelopmental disease is being treated (see 112(a) rejections above regarding this); however, an unborn child cannot be diagnosed with a neurodevelopmental disorder in order to be treated, and Applicant provides evidence throughout the instant specification that the risk of a neurodevelopmental disorder in the unborn child is being reduced, not the unborn child being treated (see, e.g., instant specification, examples 4-5). Therefore, Applicant’s arguments, data, and claimed invention are not consistent.
Regarding Applicant’s arguments that Tang, Aiba, Robinson, and Raaben do not teach treatment of a disease in an unborn child by administering to the unborn child’s pregnant mother a drug that does not act by placental transport (remarks, pages 9-10), these arguments are not persuasive because Tang, Aiba, Robinson, and Raaben were not relied upon to teach these limitation. Instead Malo and Wang were used to teach these limitations. Tang was cited to teach SEQ ID NOs: 1 and 17 (claim 14). Aiba and Robinson were cited to teach the specific activity and pH activity of the alkaline phosphatase (claims 25 and 27). Raaben was cited to teach the stability of the alkaline phosphatase in the GI tract and chyme (claims 26 and 28). The combined prior art of Malo, Wang, Tang, Aiba, Robinson, and Raaben teaches the instantly claimed invention.
Conclusion
Claims 1, 7, 10, 14, 25-28, and 32-33 are rejected.
No claims are allowed.
Correspondence Information
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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