Claim Rejections - 35 USC § 102
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. The claims filed Jan 25, 2024 have been entered. Claims 1-15 are under consideration.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on Nov 20, 2024 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
4. Claims 1-2 and 8-15 are rejected under 35 U.S.C. 102(a)(1) and/or 102(a)(2) as being anticipated by Degonda et al., (US20140363410 published 2014-12-11; priority to 2012-11-30). At the outset, it is noted that Limosilactobacillus reuteri is also known as Lactobacillus reuteri and is often abbreviated as L. reuteri.
The claims are drawn to method of treating one or more neurodevelopmental deficits in a subject, the method comprising providing one or more probiotics to the subject via indirect maternal administration.
Degonda et al., Lactobacillus reuteri DSM 17938 for promoting the establishment of healthy and normal cognitive function in young mammals. In particular, the invention relates to the use of Lactobacillus reuteri DSM 17938 for promoting development of the brain structures responsible for cognitive functions (e.g. cortex and hippocampus) and its associated neural pathways and/or to reverse retardation and/or to prevent retardation of the establishment of cognitive functions. Humans in particular, a foetus, pre-term or term born infant, may benefit [abstract]. Thus teaching claim 15. The Lactobacillus reuteri DSM 17938 may be administered to the foetus in utero, via the expectant mother [para 39]. Thus teaching claims 1-2 and 9. The administration of the probiotic may be to a foetus via the mother. It may also be to a pre-term or term-born infant either directly or via mothers' milk [para 52]. Thus teaching claims 10-11.
By administering the L. reuteri, the brain, including, in particular, the cerebral cortex and its associated neural pathways, of the treated subject develops healthily. More specifically, the expression of a number of proteins associated with axon myelination, neuronal growth and plasticity (all of which essential for learning and memory are upregulated. Thus, the administration has a positive impact on learning and memory, and thus mental performance. The risk of the infant, or toddler, child or young adult, thus treated, suffering from pathologies associated cognitive function impairment after birth is reduced. This impairment includes delayed and/or impaired learning ability, loss of higher reasoning, learning disabilities, concentration difficulties, decreased intelligence, and thus, poor mental performance. Other disorders linked to the inability to communicate and socialize normally (for example, autism), may also result [para 58]. Thus teaching claim 8.
The probiotic may be administered as a daily dose and in the form of a composition. The daily dose of L. reuteri administered to the expectant or breast feeding mother is from 1×106 to 1×1012 cfu [para 60], Thus teaching claim 12. The scientific literature reports on the use of probiotics to impact positively on the health of neonates, and infants, in particular, with respect to reducing inflammation, protecting against infection, and positively impacting on bowel habits and gastrointestinal motility [para 24]. Colonization and immunomodulation by Lactobacillus reuteri in the human gastrointestinal tract is well known [para 25]. Thus, administration of L. reuteri and/or L. reuteri containing compositions also has benefits for mammals experiencing abnormal cognitive function (cognitive function impairment). Cognitive function impairment may follow, for example, any stress situations, such as those affecting the foetus (in utero) such as IUGR, mentioned above, or the newborns (hypoxia-ischemia at birth, oxygen therapy and hyperoxia, inflammation, need for parenteral support, etc), or any cause leading to oxidative stress [para 55]. It is noted that claim 13-14 inherently occur upon administration.
Therefore the rejected claims are anticipated by the reference.
Claim Rejections - 35 USC § 102
5. Claims 1-6 and 8-15 are rejected under 35 U.S.C. 102(a)(1) and/or 102(a)(2) as being anticipated by Costa-Mattioli et al., (US 20190070226 published 2019-03-07; priority to 2016-04-15). At the outset, it is noted that Limosilactobacillus reuteri is also known as Lactobacillus reuteri and is often abbreviated as L. reuteri.
The claims are drawn to method of treating one or more neurodevelopmental deficits in a subject, the method comprising providing one or more probiotics to the subject via indirect maternal administration.
Costa-Mattioli et al., teach a method of treating or preventing in an individual with one or more social behavioral deficiencies, neurodevelopmental, and/or psychiatric disorders, comprising the steps of providing to the mother during gestation of the individual a therapeutically effective amount of a formulation comprising Lactobacillus, and an example of Lactobacillus is Lactobacillus reuteri [para 12]. Thus teaching claims 1-2 and 9. In specific embodiments, the social behavioral deficiency comprises impaired sociability, preference for social novelty, difficulty in social use of verbal and nonverbal communication, or a combination thereof. The individual may have a neurodevelopment disorder. The individual may have autism spectrum disorder [para 12]. Tus teaching claim 8. The individual whose mother or father is obese, overweight, and/or that was on a high-fat diet or individual carrying mutations associated with neurodevelopmental disroders, may be provided with an effective amount of L. reuteri before and/or after being born. In some cases, a pregnant female may be provided with an effective amount of L. reuteri, and in such cases her offspring may be provided with an effective amount of L. reuteri before and/or after being born. A fetus may have improvement of the gut microbiome upon receipt of one or more bacteria by the mother, for example through the placenta and/or blood circulation [para 10]. Thus teaching claims 10-11. An individual having a social behavior deficiency is provided an effective amount of a formulation comprising at least an effective amount of L. reuteri. In a particular form of the disclosure, an initial treatment regimen may comprise of at least about 105 -1010 cells per dose [para 57]. Thus teaching claim 12. In certain embodiments, at least one symptom of at least one neurodevelopmental disorder is treated with an effective amount of L. reuteri. An individual may be treated for social deficits and changes in gut microbiome by providing the pregnant mother or the offspring an effective amount of a L. reuteri formulation. Embodiments of the disclosure impact the consequences of maternal diet, gut microbiota dysbiosis, ventral tegmental area (VTA) plasticity and abnormal social behavior by providing an effective L. reuteri probiotic therapy for an individual [para 76]. Thus teaching claims 13-14.
The individual may have impaired social behavior of any kind. In some cases, the neurodevelopmental disorder is autism spectrum disorder (ASD) either caused by environmental (diet, pathogen infection, exposure to toxin, pesticides, etc.) or genetic factors (mutations in genes associated with ASD and other neurological disorders), paternal/maternal age and prematurity, or any combination of these factors [para 8]. Other medical conditions that may be treated and/or prevented at the same time with other probiotics include at least anxiety, cognition, schizophrenia, bipolar disorder, mood disorder, seasonal affective disorder, irritable bowel syndrome, inflammatory bowel disease (IBD), infectious diarrhea (caused by viruses, bacteria, or parasites), antibiotic-related diarrhea, skin conditions (such as eczema), urinary and vaginal health, preventing allergies and colds, and oral health [para 53]. Thus teaching claim 6. The individual was born from a mother that is obese, overweight, and/or is on a high-fat diet, undergoes immune activation during pregnancy, although in some cases the individual was born from a mother that was not obese, not overweight, and/or not on a high-fat diet [para 8].
Embodiments of the disclosure provide that specific microbiome reconstitution reverses maternal diet-induced synaptic deficits in addition to or alternative to social behavioral deficits in the offspring [para 11]. However, maternal obesity has been shown to alter the gut microbiome of offspring [para 88]. Costa-Mattioli et al., investigated how maternal diet-induced obesity affects offspring neurodevelopment in Example 1, given that maternal obesity is associated with autism spectrum disorder (ASD) [para 86-88]. Thus teaching claims 3-5. Precise Microbiome Reconstitution Holds Therapeutic Potential for Individuals with ASD and other neurodevelopmental disorders [para 102].
Therefore the rejected claims are anticipated by this rejection.
Claim Rejections - 35 USC § 102
6. Claims 1, 3-7,10-11 and 13-15 are rejected under 35 U.S.C. 102(a)(1) and/or 102(a)(2) as being anticipated by Norkild (WO 2019092201 published 2019-05-16; priority to 2018-11-09).
The claims are drawn to method of treating one or more neurodevelopmental deficits in a subject, the method comprising providing one or more probiotics to the subject via indirect maternal administration.
Recent studies suggest the presence of a microbiome within the placenta as well as fetal meconium, suggesting that the colonization process begins well before delivery [para 20]. Preterm infants, especially ELBW infants, are at a disadvantage when it comes to development of a healthy microbiome. Factors contributing to this are not limited to their gut immaturity, but also include preterm ruptured membranes, maternal infection, increased incidence of Caesarian delivery, perinatal and postnatal broad spectrum antibiotic exposure as well as exposure to other gut-modifying medications [para 22].
The methods can be used for treatment, prevention or normalization of a dysbiotic microbiota/metabolome in the gut and/or lung of a preterm infant and/or an infant who's mother during pregnancy has undertaken an antibiotic treatment or immunosuppressive therapy, or another treatment that has negative effects on the lung or gut microbiota [para 235]. Normalizing the gut and/or lung microbiota may also involve changing the metabolome to one that produces relatively more butyrate and relatively less acetate [para 236]. The methods of treatment described herein can be performed by administration of a composition comprising at least one mammalian α- and/or β-defensin in combination with either a probiotics or a combination of other components [para 235]. Infections can be congenital or acquired. The congenital infections consist of pneumonia and chorioamnionitis attributable to maternal enteric organisms. The acquired infections are mainly caused by candida and nosocomial bacteria. Infection of the amniotic fluid leading to pneumonia [para 8]. Several studies in preterm infants show an association between late-onset sepsis and adverse neurodevelopmental outcomes in childhood, with repeated infections and Gram-negative pathogens conferring the highest risk [para 15].
A "woman about to give birth to a premature infant", as used herein, refers to a pregnant woman who is in labor and about to give birth to an infant who has a gestational age of 37 or less, such a gestational age of 35 week or less, for example 30 weeks or less, such as 25 weeks or less. The woman about to give birth to a premature infant may also be a pregnant woman who has been diagnosed with a particular disorder such as an inflammatory disorder of the lungs or the intestines, suffers from particular symptoms indicative of a disorder, such as an inflammatory disorder of the lungs or the intestines. Such a pregnant woman is considered to be at risk of giving premature birth [para 182]. The methods can treat or prevent lung and/or gut inflammation by changing bacterial phenotypes through a change at the transcriptional level as well as structure and composition of the lung and/or gut bacterial flora or the lung and/or gut metabolome of a subject affected by one of the said conditions as described herein [para 230]. While the epithelial barrier ensures that microorganisms are largely confined to the gut, microbial metabolites can penetrate the epithelial barrier, allowing them to enter and accumulate in the host circulatory system where they are sensed by immune cells [para 232].
Therefore the rejected claims are anticipated by the reference.
Pertinent Art
7. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Limosilactobacillus reuteri is also known as Lactobacillus reuteri and is often abbreviated as L. reuteri. This bacterium is a common probiotic found in the human gut and other mammals, and it has been studied for its benefits in gut health and immunity.
Maternal inflammation can activate maternal immune activation (MIA) in utero, leading to inflammatory and epigenetic changes that affect fetal neurodevelopment. This can occur through the release of inflammatory cytokines and other molecules, which can cross the placenta or alter the placental environment to impact the developing fetal brain.
McConnell et al., (WO 2021105964 published 2021-05-29; priority to 2020-11-30) teach supplementing the diet of a pregnant woman with a synthetic composition comprising an HMO for use in supplementing the diet of a pregnant woman, and a method for improving health outcomes in an infant by supplementing the diet of a pregnant woman [abstract]. The nutritional composition can also contain various other conventional ingredients such as prebiotics (e.g. fructooligosaccharides, galactooligosaccharides), and probiotics (e.g. B. animalis subsp. lactis BB-12, B. lactis HNO19, B. lactis Bi07, B. infantis ATCC 15697, L. rhamnosus GG, L. rhamnosus HNOOI, L. acidophilus LA-5, L. acidophilus NCFM, L. fermentum CECT5716, B. longum BB536, B. longum AH1205, B. longum AH1206, B. breve M-16V, L. reuteri ATCC 55730, L. reuteri ATCC PTA-6485, L. reuteri DSM 17938) [para 83]. Supplementation of a pregnant woman is for: promoting the development of a balanced immune system in an unborn infant; promoting the normal development of the brain in an unborn infant; promoting the development of a healthy gastrointestinal system in an infant later born to the woman; reducing the severity and/or occurrence of immune related disorders in an infant later born to the woman; reducing the severity and/or occurrence of neurodevelopmental disorders in an infant later born to the woman, and/or reducing the severity and/or occurrence of functional gastrointestinal disorders in an infant later born to the woman [para 6].
WO2020247536 published 2020-12-10; priority to 2019-06-13) teach the pharmaceutical composition, comprising PGLA or dextranomer biocompatible microsphere, one or more biofilm generating probiotic bacterium of at least Lactobacillus reuteri (“L. reuteri”), and a nutritional supplementation is administered to a fetus of a subject in need of treatment before the fetus is born (i.e., prenatal). In some embodiments, the pharmaceutical composition is administered to a mother pregnant with the subject in need of the treatment for treating or preventing a neurodevelopmental deficiency in a subject in need thereof.
WO2012092155 published 2012-07-05; priority to 2010-12-31) teach nutritional compositions including human milk oligosaccharides and probiotics that can be administered to individuals including pregnant women for improving gastrointestinal function and tolerance, as well as the growth of beneficial microbiota. Suitable additional methods of using the nutritional compositions including the human milk oligosaccharides are also disclosed.
WO2010130643 Lactoferrin and probiotics such as L. reuteri for brain health and development in infant where the composition may be consumed for pregnant and/or lactating mothers.
WO2022218336 application of Lactobacillus reuteri in preparing a product for preventing or treating a developmental disorder.
8445429 a composition that can be used for the treatment or prevention of a delayed development of the enteric nervous system. Neuronal cells in the gut can be protected. Disorders linked to a delayed development of the enteric nervous system and/or to an impaired enteric nervous system can be treated or prevented by the administration of lactofererrin and probiotics containing compositions during pregnancy.
Kong (WO 2022133198 published 2022-06-23; priority to 2020-12-18). Kong describes methods and compositions useful for the treatment of subjects suffering from Prader-Willi Syndrome (PWS). The methods include administering compositions comprising probiotics, such as Lactobacillus reuteri (L. reuteri) and Bifidobacterium animalis subsp. lactis (B. Lactis) to subjects in need thereof [abstract].
The efficacy of the prenatal administration of Lactobacillus reuteri LR92 DSM 26866 on the prevention of infantile colic: a randomized control trial Journal. See 2020, European Journal of Pediatrics, № 10, p. 1619-1626
Lactobacillus reuteri in its biofilm state promotes neurodevelopment after experimental necrotizing enterocolitis in rats. Thus, administration of Lr in its biofilm state protects the brain, as well as the intestines, from the detrimental consequences of NEC. See Brain Behav Immun Health. 2021 Apr 6;14:100256.
Cerdo et al., Probiotic, Prebiotic, and Brain Development. Nutrients 2017, 9(11), 1247. Here, we explore and summarize the potential beneficial effects of probiotics and prebiotics in the neurodevelopmental process and in the prevention and treatment of certain neurological human diseases, highlighting current and future perspectives in this topic.
Maternal administration of probiotics promotes brain development and protects of spring’s brain from postnatal inflammatory insults in C57/BL6J mice Jing Lu et al., Scientific Reports volume 10, Article number: 8178 (2020). 18 May 2020. Maternal LB supplementation, carried out by giving Lactobacillus acidophilus and Bifidobacterium infantis (LB) to pregnant C57/BL6J mice daily from E16 to weaning, significantly suppressed postnatal peripheral proinflammatory insult-induced systemic inflammation and normalized compromised blood-brain barrier permeability and tight junction protein expression in the offspring at pre-weaned age. The suppressed neuroinflammation by maternal LB supplementation was associated with reduced astrocyte/microglia activation and downregulation of the transcriptional regulators CEBPD and IκBα. Furthermore, maternal LB supplementation promoted neuronal and oligodendrocyte progenitor cell development.
Conclusion
8. No claims allowed.
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/JANA A HINES/Primary Examiner, Art Unit 1645