DETAILED CORRESPONDENCE
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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 13, 2026 has been entered.
This action is in response to the papers filed April 162, 2026. Currently, claims 1, 3-4, 11-12, 14-15 are pending. Claims 3, 11, 12, 15 have been withdrawn as drawn to non-elected subject matter.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow.
Any objections and rejections not reiterated below are hereby withdrawn.
The Improper Markush rejection has been withdrawn as the claims have been amended to require each of Cdkn1a, Egr1 and Arc genes.
Election/Restrictions
Applicant's election of Group I, Claims 1-2, 4-10, 13-14 in the paper filed October 14, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Claims 3, 11, 12, 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application is a 371 of PCT/KR2021/013992, filed October 12, 2021 and claims priority to foreign filed KOREA 10-2020-0132403, filed October 14, 2020.
It is noted that a translation of the foreign document has not been received.
Drawings
The drawings are acceptable.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 4, 14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Question 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Question 2A Prong I
The claims are taken to be directed to an abstract idea, a law of nature and a natural phenomenon.
Claim 1 and each of the claims dependent thereon are directed to “a method for predicting prognosis of autism caused by polyethylene microspheres” by obtaining a prefrontal cortex brain tissue exposed to polyethylene microspheres, performing quantitative CPR on cDNA to measure expression of each of Arc, Cdkn1a and Egr1, “comparing an expression of the biomarker with a control not exposed to polyethylene microspheres” and “determining the subject has a prognosis of autism by polyethylene microsphere exposure if the biomarker of each of Arc, Cdkn1a and Egr1 is higher than the control”.
Claim 1 and each of the claims dependent thereon are directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “comparing an expression of the biomarker with a control” and “prognosing the subject as having autism caused by microplastic exposure if the expression l”) and a law of nature/natural phenomenon (i.e. the natural correlation between the expression of the biomarker and autism caused by microplastic exposure).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Herein, claim 1 involves the patent-ineligible concept of an abstract process. Claim 1 recites the method for providing biomarker expression information usable for “predicting prognosis of autism cause by polyethylene microsphere exposure”. Neither the specification nor the claims set forth a limiting definition for "prognosing" and the claims do not set forth how “prognosing” is accomplished. As broadly recited the prognosis limitation in the preamble may be accomplished mentally by thinking about a subject’s expression and prognosing whether the subject will have or will be responsive (see para 36) to autism.
Claim 1 further recites a comparison between the expression level and a normal control that is deemed an abstract idea (see MPEP 2106.04(a)(2)(III)(A); • claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014)).
A correlation that preexists in the human is an unpatentable phenomenon. The association between expression levels and prognosis of brain diseases is a law of nature/natural phenomenon. The "prognosis" step which tells users of the process to predict brain diseases in the sample, amounts to no more than an "instruction to apply the natural law". This step is no more than a mental step. Even if the step requires something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the law of nature to a new and useful end. The "prognosing" step does not require the process user to do anything in light of the correlation. The "prognosis" step fails to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Question 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception. While the claim recites obtaining a sample and determining expression, this is not an integration of the exception into a practical application. Instead, these elements are data gathering required to perform the method. Thus, the claim is “directed to” the exception.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non patent ineligible elements, are sufficient to “’transform the nature of the claim’ into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more from a statement of a natural principle for at least these reasons:
The claims do not include applying the judicial exception, or by use of, a particular machine. The claims do not tie the steps to a “particular machine" and therefore do not meet the machine or transformation test on these grounds. The use of machines generally does not impose a meaningful limit on claim scope.
The claims also do not add a specific limitation other than what is well-understood, routine and conventional in the field. The obtaining a sample and measuring expression is mere data gathering step that amounts to extra solution activity to the judicial exception. It merely tells the users of the method to determine the expression of biomarkers of a sample without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The determining step essentially tells users to determine the markers through whatever known processes they wish to use.
The step of determining the expression levels was well known in the art at the time the invention was made. The prior art teaches that expression analysis using commercially available biochips and arrays that comprise the claimed genes. The steps are recited at a high level of generality. The claim merely instructs a scientist to use any expression analysis assay, mutation and promoter methylation analysis to determine the expression and mutation and methylation status. The claim does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements were well known. Specifically, the specification teaches the measuring the mRNA expression level may use any one of RT-PCR, competitive RT-PCR, real-time RT PCR (para 33). All of these methods are well known methods for measuring expression.
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to Arguments
The response traverses the rejection. The argues the active method steps of the method and states the steps recite a specific diagnostic assay, not a natural correlation. This argument has been considered but is not convincing the claim recites judicial exceptions, as outlined in the rejection. The mere fact the claim recites physical steps to arrive at a natural correlation judicial exception is not evidence of a patent eligible claim. Subject Matter Eligibility Examples: Life Sciences, Example 29 “Diagnosing and Treating Julitis” recites diagnostic methods, analogous to the instant claims. The method steps highlighted by the response are well-understood routine and conventional steps for performing the data gathering. The collection of a sample and performing amplification of genes is very well-understood, routine and conventional.
The response previously argued the comparison step is a specific practical application of a scientific principle. This argument has been reviewed but is not persuasive because it is an abstract idea, i.e. a judicial exception. The response compares this step to a diagnostic assay. It is noted the courts have routinely found mere diagnostic assays, without more, are not patent eligible.
The response argues the claim applies the judicial exception to a particular, specific context. This argument has been reviewed but this is not an element of determining patent eligibility. There is no integration of the prognosis of autism. The claim does not require a treatment or prophylaxis, for example.
The physical method steps recited in the instant claim that perform PCR are mere data-gathering steps. The courts have routinely held that PCR is not sufficient to render claims patent eligible. See, for example, Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014).
The response acknowledges that the steps in addition to the judicial exception are not the inventive concept (see page 12, remarks filed April 13, 2026). The intended use of “for prognosis caused by polyethylene microsphere exposure in prefrontal cortex brain issue” is the judicial exception. The natural correlation between gene expression patterns and a phenotype. The use for diagnostic purpose is the judicial exception. Thus, the elements in addition to the judicial exception are well understood routine and conventional.
At the time of the invention performing q-PCR was well understood routine and conventional. Amplifying and sequencing nucleic acid sequences was deemed well understood, routine and conventional by University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014), for example.
Thus, for the reasons above and those already of record, the rejection is maintained.
Claim Rejections - 35 USC § 112-Scope of Enablement
The following is a quotation 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.
Claims 1-2, 4-9, 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of detecting biomarkers in prefrontal cortex brain tissue, does not reasonably provide enablement for predicting prognosis of autism by any microplastic exposure by obtaining prefrontal cortex brain tissue sample. 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of 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.”
The nature of the invention and breadth of claims
The claims are drawn to predicting prognosis of autism by any microplastic exposure by obtaining prefrontal cortex brain tissue sample by determining expression level of each of Cdkn1A, Arc and Egr1 where a higher level of expression corresponds with autism prognosis.
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The unpredictability of the art and the state of the prior art
The art teaches expression levels of Egr1 and Arc are decreased in response to administration of polystyrene microplastics (PS-MPs) in mice (abstract, Figure 4). Lee et al. (J. of Hazardous Materials, Vol. 430, No 128431, 2022) teaches exposure to polystyrene microplastics impairs hippocampus-dependent learning and memory in mice.
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Alahmadi et al. (bioRxiv preprint “Polystyrene and polyethylene terephthalate nanoplastics differentially impact mouse ovarian follicle function, July 1, 2025) teaches Cdkn1a expression was significantly decreased at 100ug/mL PS compared to the control. Alahmadi does not teaches PET is higher that a control.
Thongkorn et al (Nature Research, Vol. 11, No. 1241, 2021) teaches BPA exposure disrupts genes involved in neuronal viability, neuritogenesis and learning/memory in a sex-dependent manner and the genes play an important role in the risk and higher prevalence of ASD in males (abstract). Figure 1 illustrates expression levels of genes in males and females. The expression patterns for each of the genes is different. It can be seen that Cux1 is increased expression in males and decreased expression in females. The patterns for the different sexes are not predictable.
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Mattheisen et al. (Nature Genetics, Vol. 54, pages 1470-1478, September 26, 2022) teaches genes are differentially expressed in autism spectrum disorder, ADHD and other brain diseases. Mattheisen teaches some genes are differentially expressed between the two different brain diseases while others are shared among the diseases.
Torsvik et al. (Transl Psychiatry, Vol. 13, No. 147, May 2023) teaches patients with schizophrenia and bipolar disorder display gene expression patterns. Figure 1 illustrates genes differentially expressed between the two diseases.
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Krause et al. (Toxicology Reports, Vol. 10, pages 348-356, 2023) teaches different microplastics have different effects on gene expression. Table 2 illustrates different genes show different expression upon exposure to different microplastics.
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Guidance in the Specification.
The specification provides no evidence that the broad scope of the instant claims are enabled.
The specification teaches that a subject may be any subject including human, mice, males and females. The specification does not provide any particular analysis of humans or analysis of the different genders.
The specification teaches the term prognosis is used to include “determining whether a subject will have a disease in the future for a specific diseases or disorder or determining the responsiveness of a test subject to the treatment” (para 36).
The specification teaches microplastics may be selected from polystyrene, polyethylene, polyamide, ABS, PTFE, CA, PC, PMMA, PVC, PET and PU (para 23).
The specification teaches the brain disease may be schizophrenia, frontal lobe epilepsy, ADHD, autism, Asperger’s syndrome (para 28).
Example 3, page 18, para 52, is directed to identification of changes in gene expression in the brain due to microsphere exposure. The example is directed to PE microsphere oral administration (para 54) to mice to analyze the prefrontal cortex and hippocampus regions. Table 1 illustrates elected ARC, Cdkn1a and Egr1 are upregulated in the prefrontal region.
The guidance provided by the specification amounts to an invitation for the skilled artisan to try and follow the disclosed instructions to make and use the claimed invention.
Quantity of Experimentation
The quantity of experimentation in this area is extremely large since there is significant number of parameters which would have to be studied to enable the skilled artisan to practice the broad scope of the claims as broadly as claimed.
The claims require Arc and Egr1 are overexpressed in response to polyethalyene microsphere exposure. Lee does not teach Arc and Erg1 are upregulated after 8 weeks of PS-MPs administrations. Alahmadi does not teach Cdkn1a is upregulated in response to polyethlene microplastics. It is unpredictable when Arc, Cdkn1a and Egr1 are upregulated and when they are downregulated. The skilled artisan would be required to perform significant further unpredictable and undue experimentation to define the parameters for determine when the elected genes are upregulated and downregulated in response to exposure to polyethylene microplastics.
The claims are broadly directed to any subject, including human, mice and male and female subjects. The art teaches numerous genes are not differentially expressed in female subjects. The gene expression patterns are only differentially expressed in male subjects. Thongkorn et al (Nature Research, Vol. 11, No. 1241, 2021) teaches BPA exposure disrupts genes in a sex-dependent manner and the genes play an important role in the risk and higher prevalence of ASD in males (abstract). Figure 1 illustrates expression levels of genes in males and females. The expression patterns for each of the genes are different. It can be seen that Cux1 is increased expression in males and decreased expression in females. It is unpredictable which genes would be predictably associated with prognosis of brain diseases in females vs males absent further unpredictable and undue experimentation.
This would require significant inventive effort, with each of the many intervening steps, upon effective reduction to practice, not providing any guarantee of success in the succeeding steps.
Level of Skill in the Art
The level of skill in the art is deemed to be high.
Conclusion
Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of a working example and the negative teachings in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
Response to Arguments
The response traverses the rejection. The response asserts the claims have been amended to require Arc, Cdkn1a and Egr1 are upregulated in the prefrontal cortex of subjects exposed to PE microspheres. This argument has been considered but is not convincing. The art teaches Arc, Cdkn1a and Egr1 are not upregulated in response to PE microspheres (see Lee and Alahmadi). It is unpredictable when a subject will show overexpression of Arc, Cdkn1a and Egr1 in response to PE exposure. The specification illustrates the genes were upregulated in mice in response to oral exposure to PE. There is no correlation that this will provide a reliable association with prognosis of autism. Since it is unpredictable when the genes are overexpressed in subjects in response to PE, it is unpredictable when overexpression of the genes may prognose autism without further unpredictable and undue experimentation.
While the claims have been amended to be limited to polyethylene microspheres. Alahmadi does not teach Cdkn1a is upregulated in response to polyethlene microplastics. It is unpredictable when Arc, Cdkn1a and Egr1 are upregulated and when they are downregulated. The skilled artisan would be required to perform significant further unpredictable and undue experimentation to define the parameters for determine when the elected genes are upregulated and downregulated in response to exposure to polyethylene microplastics.
The response does not particularly address the subject aspect of the rejection. The art teaches males and females show very different expression patterns. Thus it is unpredictable that all subjects would show the same expression patterns. The specification is limited to mice and PE microsphere exposure. The response does not address the scope of the claims as it relates to these two elements.
Thus for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claims allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kim et al. (US 12,228,575, February 18, 2025) teaches biomarker compositions for predicting cancer malignant prognosis induced by microplastic exposure. Kim does not teach predicting prognosis of brain disease induced by microplastic exposure.
Zaheer et al (Environment International, Vol. 161, No. 107121, 2022) teaches gene levels of EGR1 and ARC were increased in mice exposed to microplastics. Zaheer teaches EGR1 and ARC have been linked to ASD.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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, Wu-Cheng (Winston) Shen can be reached on (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
September 13, 2026
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