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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 .
This action is in response to the papers filed October 14, 2025. Currently, claims 1-15 are pending. Claims 3, 11, 12, 15 have been withdrawn as drawn to non-elected subject matter.
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Claims 3, 11, 12, 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
Improper Markush Rejection
Claims 1-2, 4-10, 13-14 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
A Markush claim contains an “improper Markush grouping” if:
(1) the species of the Markush group do not share a “single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent. See MPEP § 2117.
Here each species is considered to each of the biomarker genes listed in the claim and the combinations.
The recited alternative species in the groups set forth here do not share a single structural similarity, as each different gene that could be detected is itself located in a separate region of the genome and has its own structure. The genes recited in the instant claims, do not share a single structural similarity since each consists of a different nucleotide sequence with different expression patterns. The specification teaches some of the genes are upregulated while others are down regulated.
The only structural similarity present is that all detected positions are part of nucleic acid molecules. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with brain disease caused by microplastic exposure. Accordingly, while the different markers are asserted to have the property of being expressed in brain disease caused by microplastic exposure, they do not share a single structural similarity.
MPEP 2117 (II)(A) provides the following guidance as to what constitutes a physical, chemical, or art recognized class:
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”
The recited genes do not belong to a recognized chemical class because there is no expectation from the knowledge in the art that the genes will behave in the same manner and can be substituted for one another with the same intended result achieved. In other words, there is no expectation from the knowledge in the art that each of the recited genes would function in the same way in the claimed method; it is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention. Further there is no evidence of record to establish that it is clear from their very nature that each of the recited genes possess the common property of being associated with brain disease caused by microplastic exposure.
MPEP 2117 (II) further states the following:
Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the compounds do not appear to be members of a recognized physical or chemical class or members of an art-recognized class, the members are considered to share a "single structural similarity" and common use when the alternatively usable compounds share a substantial structural feature that is essential to a common use. Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The recited alternative species do not share a substantial common structure just because they all have a sugar phosphate backbone. The sugar phosphate backbone of a nucleic acid chain is not considered to be a substantial common structural feature to the group of genes being claimed because it is shared by ALL nucleic acids. Further, the fact that the genes all have a sugar phosphate backbone does not support a conclusion that they have a common single structural similarity because the structure of comprising a sugar phosphate backbone alone is not essential to the asserted common use of being associated with brain disease caused by microplastic exposure.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
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 1-2, 4-10, 13-14 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 brain diseases caused by microplastic exposure” by obtaining a brain tissue, detecting the presence of a biomarker, “comparing an expression of the biomarker with a control” and “prognosing the subject as having brain diseases caused by microplastic exposure if the expression of the biomarker 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 brain diseases caused by microplastic exposure if the expression of the biomarker is higher than the control”) and a law of nature/natural phenomenon (i.e. the natural correlation between the expression of the biomarker and a brain disease 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 requires performing the step of “prognosing the subject as having brain diseases caused by microplastic exposure if the expression of the biomarker is higher than the control”. 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 prognosing step 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 brain diseases. Thus, the determining step constitutes an abstract process idea.
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 "prognosing" 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 "assessing" 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.
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, 4-10, 13-14 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 brain tissue, does not reasonably provide enablement for predicting prognosis of any brain disease by any microplastic exposure by obtaining any 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 any brain disease by any microplastic exposure by obtaining any brain tissue sample.
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.
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 is 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 (parar 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 microplastics. Lee teaches Arc and Erg1 are downregulated after 8 weeks of PS-MPs administrations. Alahmadi teaches Cdkn1a is downregulated in response to 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 microplastics.
The claims are directed to any brain disease caused by microplastic exposure. The specification teaches this encompasses autism, schizophrenia, epilepsy, ADHD, for example. The specification does not provide any nexus between over expression of the elected genes in mice exposed to PE microplastics and any particular disease. Further, the art teaches that different brain diseases have different expression patterns. Mattheisen and Torsvik analyze different diseases including autism, autism spectrum disorder, bipolar and schizophrenia and finds different expression patterns for different genes. Therefore, it is unpredictable that any one gene is similarly associated with expression in all brain diseases. The overexpression in schizophrenia is not indicative of autism expression. Significant further experimentation and unpredictable experimentation would be required to determine which genes are differentially expressed in which brain diseases. The genus of brain diseases is heterogeneous and the over expression in one disease is not indicative of all other brain diseases.
The claims are broadly directed from any brain tissue sample. The specification analyzed the expression of the elected genes in prefrontal and hippocampal tissues and found that each of the genes were only expressed in prefrontal brain tissue. Therefore, it would be unpredictable and undue that gene expression patterns would be predictive in any brain tissue sample. Further undue and unpredictable experimentation would be required to determine which if any brain tissue samples would allow for prognosis of brain diseases caused by microplastic exposure since the specification teaches not all genes are expressed in all brain tissues in response to microplastic exposure.
The claims are directed to any microplastic exposure. The specification provides numerous microplastics including polyethylene, polystyrene, bisphonol-A (BPA), phthalate, as well as those listed in Claim 8. The specification analyze gene expression patterns caused by PE microsphere exposure (para 54, 60). The art teaches that different microplastics cause different gene expression patterns in response to exposure. Table 2 of Krause illustrates different genes are expressed differently when exposed to different microplastics. Therefore, the skilled artisan would be unable to predict prognosis of brain diseases in response to any microplastic exposure when the specification has only analyzed PE microsphere exposure. Therefore, it would require further unpredictable and undue experimentation to determine which microplastic exposure changes gene expression patterns and which microplastics do not change gene expression patterns.
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 is 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.
Claim Rejections - 35 USC § 112- Failure to Further limit
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 4 requires oral exposure, inhalation exposure, and transdermal exposure. This limitation does not appear to limit Claim 1 in any way since Claim 1 also may include any exposure means. There does not appear to be any additional ways to be exposed, therefore, Claim 4 encompasses all exposures. The claims are identical in scope. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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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
December 17, 2025