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 .
Claims 1, 2, 5, 6, 11, 12, 14, 17, 19, 22, 24, 25, 28, 34, 35, 37 and 42 are pending in this application, Claims 14, 19, 22 and 42 are acknowledged as withdrawn, Claims 1, 2, 5, 6, 11, 12, 17, 24, 25, 28, 34, 35 and 37 were examined on their merits.
Objections/Rejections Withdrawn
The objection to Claim 1 because of minor informalities has been withdrawn due
to the Applicant's amendments to the claims filed 08/05/2026.
Claim Objections
Claim 1 is objected to because of the following informalities: The words “of the autism biomarkers” should be inserted between the words “levels” and “toward” in line 18 of the claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 5, 6, 11, 12, 17, 24, 25, 28, 34, 35 and 37 are rejected under 35
U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA ), first paragraph, as necessitated by Applicant’s amendments to the claims filed 08/08/2026, because the specification,
while being enabling for a method comprising:
procuring one or a plurality of cell samples from a human, comprising one or a plurality of cell types; reprogramming the one or the plurality of cell samples to produce one or a plurality of induced pluripotent stem cell samples; treating the one or the plurality of induced pluripotent stem cell samples to obtain one or more patient specific neural organoids; collecting a biological sample from the patient specific neural organoid; detecting biomarker expression in patient-specific organoids, contacting the patient specific organoid with a candidate therapeutic agent,
then further detecting biomarker expression from the patient-specific organoids and detecting a change in the biomarker expression levels, does not reasonably provide enablement for identifying/selecting a candidate therapeutic agent for autism, when the difference in biomarker expression levels detected in the treated patient specific organoids shifts toward expression levels in a control organoid from a non-autism individual. 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.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands, 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art,
(7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
1) quantity of necessary experimentation
The claims would require not just the preparation of a neural specific brain model organoid from any cell sample obtained from a human (with autism) and without autism as an appropriate control for determining differential biomarker expression, but screening thereof to identify agents that alter differential expression of unknown biomarkers and select these agents as patient-specific therapeutic agents for autism. Thus, the ordinary artisan would have to obtain and prepare at least two distinct neural organoid brain models, one derived from cells from an autistic individual and one from cells derived from a non-autistic individual, assess each neural organoid brain model for differential expression of unspecified biomarkers, and then screen the neural organoid brain model with unspecified agents that alter this differential expression the unspecified autism biomarkers and, select an appropriate candidate therapeutic agent for autism (presumably identified by altering the differential expression of the unspecified autism biomarkers in the autism neural organoid brain model as compared to a non-autism organoid).
2) the amount of direction or guidance presented
The Specification is directed to the preparation of neural organoid brain models, and contains prophetic embodiments wherein the organoids, in conjunction with various biomarkers, could be used for early diagnosis of autism, testing the effectiveness of known therapeutics, potentially used to identify risk and/or onset of autism and provide patient specific treatments, as well as non-specific global treatments (Filed Specification, Pg. 62, Paragraph [0087]). The Specification however, does not indicate that the in vitro neural organoid brain models correlate with autism in vivo either generally or specifically. The Specification does not indicate that there is a recognized correlation between expression of the numerous potential biomarkers disclosed in the Specification with either; expression in the in vitro neural organoid brain models or any correlation with biomarker expression seen in vivo autism. Finally, the Specification does not indicate or teach that any agent or potential therapeutic whether identified by the claimed process or not has any efficacy in treating autism in a human subject.
3) the absence of working examples
The Specification provides no working examples wherein any agent or potential therapeutic whether identified by the claimed process or not has any efficacy in treating autism in a human subject. The Examples are drawn to the production of neural organoid brain models and characterizing their physical aspects and gene expression characteristics and the sole example (Published Specification, Pg. 86, Paragraph [00149]) tests the effect on gene expression of the antibiotic rapamycin and was tested on a neural organoid brain model derived from a subject with tuberous sclerosis.
However, TS is only correlated with about a 50% co-occurrence with autism and the example does not indicate the degree of any difference in gene expression, such that the embodiment treatment will effectively treat autism or that any other putative agent, identified by the claimed method or not, has utility in the treatment of autism. Since there are no working examples, then one must consider the guidance provided by the instant specification and the prior art.
4) the nature of the invention and breadth of the claims
The invention requires that a neural organoid brain model for autism prepared from cells derived from an autistic individual will accurately reflect the physical and genetic profile of the autistic individual such that it can be used to screen and identify/select therapeutics to treat the autism in the individual. The claims would require not just the preparation of a neural specific brain model organoid from; any cell sample obtained from a human (with any autism subtype or severity) and any cell sample derived from a subject without autism as an appropriate control for determining differential biomarker expression, but also the screening thereof for agents that differentially alter the expression of any number of unknown, putative biomarkers and identifying/selecting these agents for the ability to "treat" autism.
5) the state of the prior art
Won et al. (2013), of record, teaches that autism is an etiologically heterogeneous disorder in that no single genetic mutation accounts for more than 1-2% of ASD cases (Pg. 1, Column 2, Lines 28-30).
Further, recent advancements in exome sequencing and next-generation sequencing have enabled the discovery of an overwhelming number of de novo mutations that confer a risk for ASD. These mutations include rare mutations or copy number variations in synaptic proteins such as Shanks/ProSAPs and neuroligins. However, how these mutations lead to ASD phenotypes is poorly understood. In addition, many ASD-related genes are also associated with other neuropsychiatric disorders (Pg. 2, Column 1, Lines 9-20). The reference teaches that while animal models for ASD have been developed, and are useful for exploring ASD mechanisms and testing novel interventions, we should be cautious in interpreting the results from animal models of ASD because what we are observing in animals are behavioral features that look similar to some of the ASD symptoms in humans (Pg. 2, Column 2, Lines 23-27). The reference further teaches that:
"Given the diverse genetic variations underlying the development of ASD, one obvious challenge in understanding how ASD develops is the wide range of mechanisms associated with it. This diversity poses a serious additional problem in treating ASD: a single medication is likely to cover only a small fraction of individuals with ASD, or a limited spectrum of ASD symptoms."
Szatmari (2003), of record, teaches that the genetics of the disorder (ASD) must be complex, as the mode of transmission does not follow any recognizable pattern. Modelling studies have shown that multiple genes in interaction probably account for the genetic complexity underlying the disorder (Pg. 173, Column 1, Lines 44-49).
6) the relative skill of those in the art
The relative skill of those in the art is deemed to be high, at the graduate level or above
7) the unpredictability in the art
There is grave unpredictability with regard to the in-vitro autism model as an appropriate model for selecting/identifying an effective in-vivo treatment for autism. Inventions targeted for disease treatment bear a heavy responsibility to provide supporting evidence because of this unpredictability in biological responses to therapeutic treatments. The standard of enablement is higher for such inventions because as the state of the art stands, there is no known "prevention" or "cure" for autism and treatments are necessarily rare, as evidenced by the complexity of the disorder and the multiple contributing causes such as genetics and environmental factors. Thus, claims to putative treatments for autism may be unbelievable in the absence of strong supporting evidence. There is no conclusive evidence in the instant disclosure which indicates that administration of any identified/selected compound as instantly claimed, would effectively decrease occurrence of autism or ameliorated any symptom thereof in a subject with autism. Nor has Applicant provided any nexus between the claimed neural brain organoid model and autism seen in vivo in a subject, such that an identified/selected effective agent in the model is necessarily correlated with an effective treatment in an autism subject. Thus, it is deemed that the neural brain organoid model would not qualify as an acceptable model for all autism spectrum disorders. The instant claims encompasses a vast, almost limitless, number of autism spectrum disorders for which treatments could be identified/selected for, yet the instant specification provides no working examples and no guidance that would permit the skilled artisan to practice the invention commensurate with the scope of the instant claims.
Claims drawn to disease treatment generally require supporting data because of the unpredictability in biological responses to therapeutic treatments. For the efficacy of a drug intended for treatment in vivo faces unfavorable obstacles not present in in-vitro models. As such, in vivo utility necessarily involves unpredictability with respect to physiological activity of an asserted process in humans. See discussion in Ex parte Kranz, 19 USPQ 2d 1216, 1218-1219 (6/90). For example, drug delivery to the target area must survive the acidic environment of the stomach if administered orally. Additionally, the delivery of the drug across necessary cell surfaces in amounts needed to be efficacious, but not lethal to the subject, necessitates sensitive testing in order to adequately determine the proper human dosage. The high degree of unpredictability associated with the claimed method underscores the need to provide teachings in the specification that would provide the skilled artisan with specific treatment regimens that achieve a therapeutic benefit by in vivo or ex vivo therapy; however, the specification does not provide such guidance and without such guidance in the specification and the lack of correlative working examples, the claims would require an undue amount of experimentation without a predictable degree of success on the part of the skilled artisan.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 5, 6, 11, 12 and 17 are newly rejected under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claims 1 and 11 now recite, “selecting the candidate therapeutic agent as the therapeutic agent for the autism-related co-morbidity when the alteration shifts expression levels toward expression levels in a control neural organoid from an individual without the autism-related co-morbidity”. It is unclear if the control neural organoid is generated at the same time, using the same method as the patient-specific neural organoid and also comprises microglia or is generated prior to the generation of the patient-specific neural organoid, using some other process and does not comprise microglia. Claims 2, 5, 6, 12 and 17 are rejected as being dependent upon rejected Claims 1 and 11 and for failing to rectify the indefiniteness thereof.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 2, 11, 12, 17, 24, 34 and 35 are newly rejected under 35 U.S.C. § 103 as being obvious over Marchetto et al. (2017) in view of Lee et al. (2017), both of record, Stagno (2015), of record, ScienceDaily (2015), of record, Sanchack et al. (2016), of record, Di Lullo et al. (2017) and Abud et al. (2017), as necessitated by Applicant’s amendments to the claims filed 08/08/2026.
Marchetto et al. teaches obtaining a human autism patient fibroblast cell sample and control non-ASD skin fibroblasts and reprogramming the cells to produce induced pluripotent stem cells (iPSCs) (Pg. 821, Column 2, Lines 25-39);
treating the iPSC to obtain a neural progenitor cell (NPC) organoid/embryoid (Pg.
821, Lines 44-60);
and collecting and analyzing a total cellular RNA sample from organoid NPC
cells to detect changes in expression in biomarkers (including ADORA2B, found in
Table 1, VLDLR, found in Tables 2 and 5 and COL1A1, CLDN10 and COL3A1, found in co-morbidities Table 7), differentially expressed in autistic humans (Pg. 822, Column 1, 50-61 and Pg. 823, Column 1, Lines 25-50 and 51-66 and Pg. 832, Fig. 5b), and reading on Claim 1, steps a)-e), Claim 11, steps a)-e), Claim 24, Claim 34, steps a)-e) and Claim 35.
With regard to Claim 2, Marchetto et al. teaches the sample cells reprogrammed
to iPSC are human autism patient skin fibroblasts (Pg. 821, Column 2, Lines 25-39).
With regard to Claim 12, the reference teaches detecting changes in expression in biomarkers in patient specific organoids (COL1A1, CLDN10 and COL3A1, found in co-morbidities Table 7), differentially expressed in autistic humans (Pg. 822, Column 1, 50-61 and Pg. 823, Column 1, Lines 25-50 and 51-66 and Pg. 832, Fig. 5b). Thus, the method “identifies” targets for autism-related co-morbidities.
With regard to Claim 17, the reference further teaches obtaining an NPC sample
(derived from iPSC obtained from autism skin fibroblasts) and contacting the sample
with an array of antibodies specific for particular biomarkers (such as anti-Pax6, found
in Table 2) and detecting binding thereof (Pg. 821, Column 2, Lines 63-69 and Pg. 822,
Lines 1-12).
The teachings of Marchetto et al. were discussed above.
Marchetto et al. did not teach the patient neural organoid comprises microglia,
contacting the patient neural organoid with a candidate agent, after contacting, detecting an alteration in the expression of the autism-markers in the patient-specific neural organoid,
selecting the candidate therapeutic agent as the patient-specific therapeutic agent for autism when the alteration shifts expression levels of the autism biomarkers toward levels in a control neural organoid from and individual without autism, wherein the neural organoid biological sample is collected after about one hour up to about 12 weeks after treatment to obtain one or more patient specific organoids, wherein the neural organoid (biological) sample is procured from structures of the neural organoid that mimic structures developed in utero at about 5 weeks, wherein the neural organoid at about twelve weeks post-inducement comprises structures and cell types of retina, cortex, midbrain, hindbrain, brain stem, or spinal cord, wherein the human is diagnosed with before twenty-four months of age, as required by Claim 1, steps f), g) and h), Claim 11, step f), g) and h) and Claim 34, step f).
Lee et al. teaches a method wherein patient iPSC brain organoids from subjects with neurological disorders, such as autism (Pg. 1, Abstract) are analyzed by transcriptome sequencing to help identify novel diagnostic markers which may enable a more personalized treatment regime and that development of pharmacotherapies that interrupt or reverse (alter) gene expression changes would be beneficial to the treatment strategies. In genome-editing approach (Fig. 2e), patient-derived organoids
harboring genetic defects are contacted with a candidate therapeutic agent (gene editing/CRISPR) to correct the faulty gene can be employed to define the role of mutated genes that are suspected to cause the disease using genome-editing technologies, such as CRISPR-Cas9.
In addition, repaired patient derived organoids (therapeutic agent) using genome-editing techniques could be a potential option for replacing impaired brain tissue via transplantation. (Pg. 1, Abstract and Pg. 8, Column 1, Lines 22-24 and Column 2, Lines 1-14 and Fig. 2D-E).
Stagno teaches a human brain organoid that after 15 weeks (reading on about 12 weeks) of culture in vitro exhibits a level of development comparable to that of a human embryonic brain after about 5 weeks in utero (Pg. 1, Lines 7-10 and Pg. 2, Line 19 and Pg. 3, Lines 1-5).
ScienceDaily teaches these organoids have all the major regions of the brain (e.g. cortex, midbrain, hindbrain, brain stem) including the retina, all major regions of the brain, multiple cell types, signaling circuitry and the spinal cord in a single brain (Pg. 2, Lines 10-11) and expresses >98% (expresses 99%) of the genes known to be expressed in the human brain (Pg. 3, Lines 1-2). This organoid is useful as a platform to enable testing of experimental drugs before the clinical trial stage (Pg. 1, Lines 5-7) and has been used to create a brain organoid model for autism (Pg. 3, Lines 3-4).
Sanchack et al. teaches that some signs and symptoms (of ASD) may emerge
between 6 and 12 months of age and in many cases, a reliable diagnosis can be made
by 24 months of age (Pg. 973, Column 2, Lines 1-3 and Pg. 974, Column 1, Line 1.
Di Lullo et al. teaches many uniquely human cognitive and behavioral diseases such as autism spectrum dis-order (ASD) or schizophrenia present polygenic etiology, making them difficult to study with existing animal models. The advantages of in vitro models of human brain disease are numerous. They hold promise for the study of at least some features of disease in a 3D multicellular environment. Organoid models are also amenable to studies that require live, functioning tissue, such as the analysis of electrophysiological features or dynamic cell behaviors. Additionally, organoids derived from patients harboring genetic diseases afford the possibil-ity of studying disease mechanisms. In particular, the use of patient-derived iPSCs provides a unique opportunity to model complex polygenic disorders, including those with unidentified risk loci. (Pg. 580, Column 2, Lines 14-33). The reference however, further teaches that brain organoids currently lack some of the cell types present in primary cortex, such as endothelial cells (which have been shown to influence progenitor cell behav-ior) and microglia (which also have a role in early stages of cortical development).
Abud et al. teaches that iPSC can be differentiated into microglial like cells, develop in vitro similarly to microglia in vivo and when transplanted into brain organoids resemble microglia in vivo (Pg. 278, Abstract).
It would have been obvious to those of ordinary skill to modify the method of
Marchetto et al. for preparing and analyzing autism patient specific neural organoids for
differentially expressed genes (transcriptome analysis) with the use of transcriptome
analysis and correcting faulty genes associated with patient-specific diseases as taught by Lee et al. because this would provide a model basis for a patient-specific autism. It would have been further obvious to the ordinary artisan to perform the gene correction treatment in the patient-specific organoid, detect whether the gene expression is corrected as compared to a non-autistic control brain organoid and selecting the gene editing approach as a potential autism treatment because this would correct and verify correction of the potential genetic cause of the autism phenotype in the patient-specific brain organoid. This treatment could then be applied to an autism subject in vivo. Those of ordinary skill in the art would have been motivated to make this modification in order to provide a more personalized autism model based on the genetic profile of the patient as reflected in patient specific brain organoids. There would have been a reasonable expectation of success in making this modification because both references are drawn to the same field of endeavor, that is, the characterization of neurological disorder (autism) patient-derived brain organoids.
It would have been further obvious to those of ordinary skill to modify the method of Marchetto et al. and Lee et al. for preparing and analyzing autism patient specific neural organoids for differentially expressed genes with the use of transcriptome
analysis to provide a model basis for a patient-specific autism, to include iPSC differentiated into microglia-like cells in the organoid, as taught by Abud et al. because this would provide a brain organoid which more closely resembles the brain in vivo, as taught by Di Lullo et al. above. Those of ordinary skill in the art would have been motivated to make this modification in order to provide a more personalized in vitro autism model based on the genetic profile of the patient as reflected in patient specific brain organoids which more closely resemble the brain in vivo. There would have been a reasonable expectation of success in making this modification because all of the references are drawn to the same field of endeavor, that is, brain organoids as in vitro models for neurological conditions in vivo.
It would have been further obvious to those of ordinary skill to modify the method of Marchetto et al., Lee et al., Di Lullo et al. and Abud et al. of preparing and analyzing autism patient specific neural organoids for differentially expressed genes (transcriptome analysis) with transcriptome analysis as the basis for a personalized treatment regime and administration of a therapeutic agent to use the neural brain organoid of Stagno and ScienceDaily because this would provide a sample which closely corresponds to the subject brain from which it is derived.
Those of ordinary skill in the art would have been motivated to make this modification because ScienceDaily teaches the organoid is useful as a platform to enable testing of experimental drugs before the clinical trial stage and has been used to create a brain organoid model for autism. There would have been a reasonable expectation of success in making this modification because all of the references are drawn to the same field of endeavor, that is, the characterization of neurological disorder brain organoids.
It would have been further obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Marchetto et al., Lee et al., Di Lullo et al., Abud et al., Stagno and ScienceDaily of detecting differentially expressed autism biomarkers in neural organoids from ASD subjects identified and diagnosed (therefore inherently predicting a risk of developing autism) with ASD when they were toddlers, to use subjects whom have been diagnosed before 24 months of age as taught by Sanchack et al. because Sanchack et al. teaches that 24 months is the age at which a reliable diagnosis can be made.
Those of ordinary skill in the art would have been motivated to make this modification in order to obtain samples from subjects as early as reliably possible to confirm autism diagnosis/risk. There would have been a reasonable expectation of success in making this modification because at least both Marchetto et al. and Sanchack et al. are both drawn to the same field of endeavor, that is Autism Spectrum Disorder.
With regard to the limitation of Claim 1, "wherein the neural organoid sample is procured from structures of the neural organoid that mimic strictures developed in utero at about 5 weeks", this would be inherent in the method of the prior art as Stagno teaches a human brain organoid that after 15 weeks of culture in vitro exhibits a level of development comparable to that of a human embryonic brain after about 5 weeks in utero. Thus, any sample derived from such a neural organoid would be obtained from structures of the neural organoid that mimic strictures developed in utero at about 5 weeks.
While the references listed above do not specifically teach the limitation of Claim 1, that the neural organoid sample "is collected after about 1 hour up to about 12 weeks after treatment.. to obtain one or more patient specific organoids", one of ordinary skill in the art would recognize that the timing for obtaining a neural organoid sample is a result-effective optimizable variable. Marchetto et al. teaches that RNA samples obtained from organoid NPC cells can be used to detect changes in expression in biomarkers which are differentially expressed in autistic humans. This is motivation for someone of ordinary skill in the art to practice or test the sample collection times widely to find those that are functional or optimal to sufficiently detect differential gene expression which then would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by the Applicant concerning the timing of the organoid sample collection post inducement, it would be prima facie obvious that one of ordinary skill in the art would recognize this limitation as an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B).
Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain a more
physiologically relevant patient specific neural model. There would have been a
reasonable expectation of success in making these modifications because at least the
Marchetto, Lee, Stagno and ScienceDaily references are reasonably drawn to the same
field of endeavor, that is, neural organoid generation and characterization.
Claims 1, 2, 5, 11, 12, 17, 24, 34 and 35 are newly rejected under 35 U.S.C. § 103 as being obvious over Marchetto et al. (2017) in view of Lee et al. (2017), both of record, Stagno (2015), of record, ScienceDaily (2015), of record, Sanchack et al. (2016), of record, Di Lullo et al. (2017) and Abud et al. (2017), as applied to Claims 1, 2, 11, 12, 17, 24, 34 and 35 above, and further in view of DeRubeis et al. (2015), of record.
The teachings of Marchetto et al., Lee et al., Di Lullo et al., Abud et al., Stagno, ScienceDaily, and Sanchack et al. were discussed above.
None of the above references taught wherein the detected biomarker is ADNP, as required by Claim 5.
DeRubeis et al. teaches that ADNP has been identified as one of 50 high-risk genes for Autism Spectrum Disorder (ASD) (Pg. R25, Column 2, Lines 36-54 and Pg. R26, Fig. 2).
It would have been obvious to those of ordinary skill in the art to modify the method of Marchetto et al., Lee et al., Di Lullo et al., Abud et al., Stagno, ScienceDaily and Sanchack et al. for preparing and screening autism patient brain organoids, so that the skin fibroblasts used to obtain the brain organoids could be identified by the ADNP gene as DeRubeis et al. teaches the gene is a known high-risk gene for ASD. It therefore would have also been obvious to those of ordinary skill to use ADNP as the measured biomarker for ascertaining differential expression in autism as it is a known biomarker correlated with autism. Those of ordinary skill in the art would have been motivated to make this modification in order to ensure that the relevant biomarker for autism was present in the fibroblasts used to obtain the patient brain organoids and that the relevant biomarker demonstrates desired gene expression changes in response to a putative autism treatment. There would have been a reasonable expectation of success in making this modification because all of the references are reasonably drawn to the same field of endeavor, that is characterization of autism and its' genetic basis.
Claims 1, 2, 6, 11, 12, 17, 24, 34 and 35 are newly rejected under 35 U.S.C. § 103 as being obvious over Marchetto et al. (2017) in view of Lee et al. (2017), both of record, Stagno (2015), of record, ScienceDaily (2015), of record, Sanchack et al. (2016), of record, Di Lullo et al. (2017) and Abud et al. (2017), as applied to Claims 1, 2, 11, 12, 17, 24, 34 and 35 above, and further in view of Margulies et al. (CA 2773049 A1), of record.
The teachings of Marchetto et al., Lee et al., Di Lullo et al., Abud et al., Stagno, ScienceDaily, and Sanchack et al. were discussed above.
The Examiner notes that Marchetto et al. teaches detection of a combination of
biomarkers including the gene ADORA2B, found in Table 1.
None of the above references taught wherein a combination of biomarkers is
detected, the combination comprising TSC1 or TSC2 variant, as required by Claims 6
and 37.
Margulies et al. teaches that detection of variations in TSC1 and TSC2 genes are
correlated with the presence of or increased risk of developing an autism spectrum
disorder in a subject (Pg. 54, Claims 1 and 8).
It would have been obvious to those of ordinary skill in the art to modify the
method of Marchetto et al., Lee et al., Di Lullo et al., Abud et al., Stagno, ScienceDaily and Sanchack et al. for preparing and screening autism patient brain organoids for the presence of a combination of biomarkers known to be associated with autism (ADORA2B and VLDLR) to include detection of TSC1 and/or TSC2 variants as taught by Margulies et al. because this would provide an additional autism biomarker which could be monitored. Those of ordinary skill in the art would have been motivated to make this modification in order to detect and monitor multiple known autism biomarkers in autism patient brain organoids.
There would have been a reasonable expectation of success in making this modification because most all of the references are reasonably drawn to the same field of endeavor, that is characterization of autism and its' genetic basis.
Claims 1, 2, 11, 12, 17, 24, 25, 28, 34 and 35 are newly rejected under 35 U.S.C. § 103 as being obvious over Marchetto et al. (2017) in view of Lee et al. (2017), both of record, Stagno (2015), of record, ScienceDaily (2015), of record, Sanchack et al. (2016), of record, Di Lullo et al. (2017) and Abud et al. (2017), as applied to Claims 1, 2, 11, 12, 17, 24, 34 and 35 above, and further in view of Yasuda et al. (2013), of record.
The teachings of Marchetto et al., Lee et al., Di Lullo et al., Abud et al., Stagno, ScienceDaily, and Sanchack et al. were discussed above.
None of the above references taught wherein the method is used to identify environmental factors that cause or exacerbate autism and interact with the detected biomarker or identifying nutritional factors related to pathways regulated by genes identified in Tables 1, 2, 5 or 7, as required by Claims 25 and 28.
Yasuda et al. teaches that zinc and magnesium deficiency and/or high levels of toxic heavy metals, such as lead, may epigenetically play principal roles as environmental factors in autistic disorders (Pg. 1, Abstract and Pg. 5, Table 5).
It would have been obvious to those of ordinary skill in the art to modify the method of Marchetto et al., Lee et al., Di Lullo et al., Abud et al., Stagno, ScienceDaily and Sanchack et al. for preparing and screening autism patient brain organoids for the presence of a combination of biomarkers known to be associated with autism to further use the method to detect and identify levels of zinc, magnesium and/or other toxic heavy metals because Yasuda et al. teaches that these elements are potential environmental factors in the epigenetics of autistic disorders. Those of ordinary skill in the art would have been motivated to make this modification in order to assess an autism model for the presence or effect of environmental/nutritional factors known to be correlated with autism. There would have been a reasonable expectation of success in making this modification because most all of the references are reasonably drawn to the same field of endeavor, that is characterization of autism and its genetic basis.
With regard to the limitation of Claim 25, that "the accelerators are environmental factors or nutritional factors that interact with the detected biomarker", this would be inherent in the method of the prior art. The Specification as filed at Paragraphs [0087] and [0089], indicates that;
"An accelerator of autism is an environmental or nutritional factor that specifically interactions with an autism specific biomarker to affect downstream process related to these biomarkers biological function such that a subclinical or milder state of autism becomes a full blown clinical state earlier or more severe in nature".
The Specification at Paragraph [0097] additionally teaches:
"Examples in Table 1, Table 5, Table 7 include, but are not limited to lead, infectious agents or biological toxins. In still another aspect the method can be used to identify treatments that are causes or accelerators of autism and nutritional factors/supplements for treating autism. Examples in Table 1, Table 5, Table 7 include, but are not limited to nutritional factors, vitamins, minerals, and supplements such as zinc, manganese, or cholesterol".
Thus, the disclosed environmental/nutritional compounds or the prior art, which are the same as the disclosed accelerators would be expected to have the same properties and characteristics, of interacting with the detected biomarker.
Response to Arguments
Applicant’s arguments, see Remarks, filed 08/05/2026, with respect to the withdrawn objections/rejections have been fully considered and are persuasive.
The remaining arguments have been considered only insofar as they apply to the current rejections.
The Applicant argues that Marchetto does not teach or suggest the limitations of amended Claim 1 (Remarks, Pg. 11, Lines 1-11).
This is not found to be persuasive for the reasoning provided in the new rejections above.
The Applicant argues that Lee does not remedy the alleged deficiencies of Marchetto. Applicant notes that Lee does not teach microglia as claimed (Remarks, Pg. 11, Lines 13-30 and Pg. 12, Lines 12, Lines 1-13).
In response to applicant's arguments against the Lee reference individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As discussed above, it is though combination of Marchetto et al. (2017) in view of Lee et al. (2017), both of record, Stagno (2015), of record, ScienceDaily (2015), of record, Sanchack et al. (2016), of record, Di Lullo et al. (2017) and Abud et al. (2017), that the instantly claimed invention is obviated.
DiLullo et al. teaches that brain organoids currently lack some of the cell types present in primary cortex, such as endothelial cells (which have been shown to influence progenitor cell behav-ior) and microglia (which also have a role in early stages of cortical development). Abud et al. teaches that iPSC can be differentiated into microglial like cells, develop in vitro similarly to microglia in vivo and when transplanted into brain organoids resemble microglia in vivo (Pg. 278, Abstract). Thus, the ordinary artisan would have found obvious the modification of the method of Marchetto et al. and Lee et al. for preparing and analyzing autism patient specific neural organoids for differentially expressed genes with the use of transcriptome analysis to provide a model basis for a patient-specific autism,
to include iPSC differentiated into microglia-like cells in the organoid, as taught by Abud et al. because this would provide a brain organoid which more closely resembles the brain in vivo.
The Applicant argues that neither Stagno or ScienceDaily teach or suggest the limitations of amended Claim 1 (Remarks, Pg. 12, Lines 15-22).
This is not found to be persuasive for the reasoning provided in the new rejections above. The Examiner notes that Stagno was cited only for its’ teaching of a human brain organoid that after 15 weeks (reading on about 12 weeks) of culture in vitro exhibits a level of development comparable to that of a human embryonic brain after about 5 weeks in utero (Pg. 1, Lines 7-10 and Pg. 2, Line 19 and Pg. 3, Lines 1-5).
While ScienceDaily was only cited for its’ teaching that these organoids have all the major regions of the brain (e.g. cortex, midbrain, hindbrain, brain stem) including the retina, all major regions of the brain, multiple cell types, signaling circuitry and the spinal cord in a single brain (Pg. 2, Lines 10-11) and expresses >98% (expresses 99%) of the genes known to be expressed in the human brain (Pg. 3, Lines 1-2). This organoid is useful as a platform to enable testing of experimental drugs before the clinical trial stage (Pg. 1, Lines 5-7) and has been used to create a brain organoid model for autism (Pg. 3, Lines 3-4).
The Applicant argues that Sanchack does not provide the risk prediction method of Claim 34 or provide the limitations of Claim 1 (Remarks, Pg. 12, Lines 24-30 and Pg. 13, Lines 1-3).
This is not found to be persuasive for the reasoning provided in the above rejections. As discussed above, it would have been further obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Marchetto et al., Lee et al., Di Lullo et al., Abud et al., Stagno and ScienceDaily of detecting differentially expressed autism biomarkers in neural organoids from ASD subjects identified and diagnosed (therefore inherently predicting a risk of developing autism) with ASD when they were toddlers, to use subjects whom have been diagnosed before 24 months of age as taught by Sanchack et al. because Sanchack et al. teaches that 24 months is the age at which a reliable diagnosis can be made. Those of ordinary skill in the art would have been motivated to make this modification in order to obtain samples from subjects as early as reliably possible to confirm autism diagnosis/risk. There would have been a reasonable expectation of success in making this modification because at least both Marchetto et al. and Sanchack et al. are both drawn to the same field of endeavor, that is Autism Spectrum Disorder.
The Applicant argues that the Examiner has not provided articulated reasoning with rational underpinning to modify the combined prior art to arrive at the instantly claimed invention (Remarks, Pg. 13, Lines 4-18).
This is not found to be persuasive for the reasoning provided in the above rejections, which the Examiner maintains obviate the instant invention for the logical rationale and reasoning provided.
The Applicant argues that neither of DeRubeis, Margulies or Yasuda remedy the alleged deficiencies of the other cited references much less teach or suggest the claimed invention (Remarks, Pg. 14, Lines 1-10, 17-26 and Pg. 15, Lines 4-13).
This is not found to be persuasive for the reasoning provided in the new rejections above.
The Examiner notes that DeRubeis et al. was cited only for its’ teaching that ADNP has been identified as one of 50 high-risk genes for Autism Spectrum Disorder (ASD) (Pg. R25, Column 2, Lines 36-54 and Pg. R26, Fig. 2), Margulies et al. was cited only for its’ teaching that detection of variations in TSC1 and TSC2 genes are correlated with the presence of or increased risk of developing an autism spectrum disorder in a subject (Pg. 54, Claims 1 and 8) and Yasuda et al. cited only for its’ teaching that zinc and magnesium deficiency and/or high levels of toxic heavy metals, such as lead, may epigenetically play principal roles as environmental factors in autistic disorders (Pg. 1, Abstract and Pg. 5, Table 5).
The Applicant argues that the Examiner’s inherency rationale with regard to Claims 25 and 28 is unsupported as they require identifying environmental or nutritional factors in the context of the claimed patient specific brain-organoid biomarker method. Applicant asserts that the hair sample trace element association of Yasuda does not necessarily identify an accelerator that interacts with the detected biomarker as claimed (Remarks, Pg. 15, Lines 14-21).
This is not found to be persuasive for the following reasons, as discussed in the prior action and above, Yasuda et al. teaches that zinc and magnesium deficiency and/or high levels of toxic heavy metals, such as lead, may epigenetically play principal roles as environmental factors in autistic disorders (Pg. 1, Abstract and Pg. 5, Table 5).
It would have been obvious to those of ordinary skill in the art to modify the
method of Marchetto et al., Lee et al., Stagno, ScienceDaily and Sanchack et al. for
preparing and screening autism patient brain organoids for the presence of a
combination of biomarkers known to be associated with autism to further use the
method to detect and identify levels of zinc, magnesium and/or other toxic heavy metals
because Yasuda et al. teaches that these elements are potential environmental factors
in the epigenetics of autistic disorders. Those of ordinary skill in the art would have
been motivated to make this modification in order to assess an autism model for the
presence or effect of environmental/nutritional factors known to be correlated with
autism.
There would have been a reasonable expectation of success in making this
modification because all of the references are reasonably drawn to the same field of
endeavor, that is characterization of autism and its genetic basis. The instant Specification as filed at Paragraphs [0087] and [0089], indicates that;
"An accelerator of autism is an environmental or nutritional factor that specifically interactions with an autism specific biomarker to affect downstream process related to these biomarkers biological function such that a subclinical or milder state of autism becomes a full blown clinical state earlier or more severe in nature".
The Specification at Paragraph [0097] additionally teaches;
"Examples in Table 1, Table 5, Table 7 include, but are not limited to lead, infectious agents or biological toxins. In still another aspect the method can be used to identify treatments that are causes or accelerators of autism and nutritional factors/supplements for treating autism. Examples in Table 1, Table 5, Table 7 include, but are not limited to nutritional factors, vitamins, minerals, and supplements such as zinc, manganese, or cholesterol".
Thus, the disclosed environmental/nutritional compounds of the prior art, which
are the same as the disclosed accelerators would be expected to have the same
properties and characteristics, of interacting with the detected biomarker.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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