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 .
Election/Restrictions
Applicant’s election of the particular gene that is SH3BGRL3 in the reply filed on 08/11/2025 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 § 818.01(a)).
Claim 2 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (i.e.: the claim does not recite or require the elected SH3BGRL3 gene), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/11/2025.
Applicant’s election of the particular analyte that is mRNA in the reply filed on 12/16/2025 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 § 818.01(a)).
In light of the Examiners search and examination of the elected subject matter, the species election as it was applied to the different analytes that are mRNAs or proteins (relevant to Election I. in the Requirement of 06/11/2025) is withdrawn.
Priority
Applicant cannot rely upon the certified copy of the foreign priority application (JP2020-077036) to overcome any rejection set forth in this Office Action because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 and 6 are 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 6 are unclear over the stated purpose of the claims methods as being for “detecting severity of premenstrual syndrome of a subject”, as recited in the preamble of claim 1. There is no step in the claims in which any severity is in fact detected. The claims require only a step of “measuring expression” of a gene or translation products of the gene. But measuring an expression level is not itself any detection of severity. It is thus unclear how the purpose of the methods is accomplished by the required process step.
Claim Rejection - Improper Markush Grouping
Claims 1 and 3-6 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.
The Markush grouping of claims, which recites in the alternative a list of independent and distinct genes is improper because the alternatives (i.e.: the different gene transcripts and translation products) defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
In the instant case each different element is considered to be a method comprising analysis of a different gene transcript or translation product thereof, or a different combination of the genes or translation products. In the instant case Applicants have elected the particular gene that is SH3BGRL3.
The recited alternative species do not share a single structural similarity, as each method relies on detection of a different polynucleotide sequence (i.e.: a transcript form a particular gene) or polypeptide sequence (i.e.: a translation product arising from a particular transcript). Each polynucleotide has a different chemical structure in that it consists of a different nucleotide sequence. Each translation product has a different chemical structure in that it consists of a different amino acid sequence. Each polynucleotide has a different biological activity in that it has a different specificity of hybridization and may alter expression of a different gene to have a different biological activity and effect. Each translation product may play a different role in the physiology of a cell. Thus, the different elements (e.g.: each different recited gene) do not share a single structural similarity or biological activity. The only structural similarity present is that all of the gene expression products are composed of nucleic acids, and the translation products are composed of amino acids. The fact that the gene expression products are composed of nucleic acids, and the translation products are composed of amino acids, in each case does not per se support a conclusion that they have a common single structural similarity because the structure of comprising a nucleic acid, or comprising an amino acid, alone is not essential to the asserted common activity of being related to premenstrual syndrome severity, as asserted by the instant application. Accordingly, while the different elements are asserted to have the property of having expression that is related to premenstrual syndrome severity, they do not share a single structural similarity essential to this activity. Here it is clear that any asserted common use does not flow from any broadly ascribed common structure (see MPEP 2117). The asserted common use of being a biomarker for premenstrual syndrome severity is particular to each different biomarker (i.e.: each particular transcript or translation product) based on the specific content of the biomarker and not based on some particular common structural feature shared among the different biomarkers.
Note that when the Markush grouping is for alternatives of chemical compounds, the alternatives are regarded as being of a similar nature where the following criteria are fulfilled:
(A) all alternatives have a common property or activity; AND
(B)(1) a common structure is present, that is, a significant structural element is shared by all of the alternatives; OR
(B)(2) in cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
The phrase “recognized class of chemical compounds” means that 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, i.e. each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In the present situation, there is no evidence of record to establish that it is clear from their very nature that the different particular genes (i.e.: their transcripts or translation products) recited in the claims are associated with premenstrual syndrome severity. Additionally, the different biomarkers themselves behave differently, with each having different levels of expression in premenstrual syndrome that is severe or mild (see for example Table 3 which shows upregulated genes, and Table 4 which shows down regulated genes).
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 and 3-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas without significantly more.
The claim(s) are directed to methods of detecting severity of premenstrual syndrome in a subject where the prediction is based on a measured level of expression of genes or translation products (the association is implicit in claims 1 and 6 in light of the specification, and is explicitly recited in claims 3, 4 and 5). The claims are thus directed to an abstract idea which is a mental process in which premenstrual syndrome is deduced from a measure of gene expression (see MPEP 21106.04(a)(2)). Where claims include using measure expression to detect severity, such a concept may be performed in the human mind (e.g.: observations, evaluations, judgments, and opinions; see MPEP 21106.04(a)(2) III). Additionally, claims 5 recites a limitation related to analyzing data using a prediction model with principal component analysis, where this step of data manipulation is directed to mathematical calculations that also are interpreted as being abstract ideas (e.g.: see MPEP 21106.04(a)(2) I). Furthermore, it is noted that where the subject matter of the claims is directed to the use of gene expression values associated with premenstrual syndrome severity, such an association is a natural aspect of the biological organism function (i.e.: a gene expression:phenotype relationship), and as such the claims are directed to a judicial exception that is a law of nature and/or a natural phenomenon (e.g.: MPEP 2106.04(b). With regard to claim 5, it is noted that claims can be directed to a mental process even if they are claimed as being performed on a computer (e.g.: MPEP 2106.04(a)(2)(III)(C)).
This judicial exception(s), as identified above, are not integrated into a practical application because the claims do not require any active process step that is performed based on a particular result of the abstract ideas of the claims. The claims are directed to the analysis of biomarker (e.g.: nucleic acid or protein) levels, but the methods end with the abstract idea of using the levels detect severity of premenstrual syndrome.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the data collection of the claims uses well understood, routine and conventional methods that are properly considered insignificant extra-solution activity (e.g.: see MPEP 2106.05(g)). The data gathering steps themselves (e.g.: measuring an expression level of SH3BGRL3, as consonant with the election) were known in the art. The instant application teaches that the data collection of the instantly claimed methods may be performed using well known technologies (e.g.: p.2). And the prior art demonstrates that collection of the required data was routinely practiced in the art; Singla et al (2016) provides examples of using Affymetrix GeneChip Human Exon 1.0 ST arrays (e.g.: p.466 - RNA isolation and microarray hybridization; Microarray data preprocessing) to provide quantitative measures of gene expression levels including the level of SH3BGRL3 (e.g.: Table 2).
Claim Rejections - 35 USC § 112 – Scope of Enablement
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, 3-6 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 (as consonant with the Election):
A method for detecting severe premenstrual syndrome in a human female subject, the method comprising:
(a) providing a sample from the subject, the sample comprising skin surface lipids (SSL);
(b) detecting the level of SH3BGRL3 mRNA in the sample;
(c) comparing the level of SH3BGRL3 mRNA in the sample to a reference level, where the reference level is the level of SH3BGRL3 mRNA in SSL samples from a population of human females with mild premenstrual syndrome;
wherein a higher level of SH3BGRL3 mRNA in the sample from the subject as compared to the reference level is detected, and the subject is determined to have severe premenstrual syndrome.
does not reasonably provide enablement for the claims as broadly written. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Scope of the Claims/Nature of the Invention
The claims encompass the detection of SH3BGRL3 expression levels of any analyte (e.g.: mRNA or protein) from any sample type (e.g.: tissue; body fluid; cells) from any subject organism for determining any severity of premenstrual syndrome by comparison of the expression level to any reference.
The claimed methods thus require knowledge of a robust and reliable relationship between a variety of measured expression values in different sample types from different subject organisms and a premenstrual syndrome severity.
Teachings in the Specification and Examples
The specification (p.32) teaches an example of the analysis of RNA levels in skin surface lipids (SSL) from human female subjects that are classified as having mild or severe premenstrual syndrome (PMS) (p.54 – Example 2). The specification teaches (relevant to the Election), that SH3BGRL3 is found at higher levels in samples from subjects with sever PMS as compared to subjects with mild PMS (e.g.: Tables 3 and 6).
The specification does not teach the analysis of any non-human samples, or samples other than SSL samples.
The specification does not teach any comparison of SH3BGRL3 translation products, or an gene expression comparisons other than mRNA in SSL samples in subjects with mild PMS and severe PMS.
State of the Art and the Unpredictability of the Art
While methods of measuring gene expression are known in the art, methods of correlating the level of gene expression with a particular phenotype (e.g.: severity of PMS) are highly unpredictable.
Because the specification asserts that the methods are applicable to any subject organism (e.g.: specification at page 12), but teaches only the analysis of human samples, it is relevant to point out that it is highly unpredictable as to whether the results obtained in human subjects could be extrapolated to non-human subjects. Hoshikawa et al (2003) teaches unpredictability with regard to applying gene expression results among different organisms. The reference teaches the analysis of gene expression in lung tissue in response to hypoxic conditions which lead to pulmonary hypertension (Fig. 1). The reference teaches that the gene expression profile in mouse is different from that observed in rat (Tables 1-4; p.209 -Abstract). Thus, it is unpredictable as to whether or any genes that are associated with severe PMS in humans are in fact applicable to diagnosing severe PMS in any other non-human organism.
Because the claims encompass examining any sample types (e.g.: any tissue, any body fluid, or a secretion, such as blood, as recited on p.2 of the specification), while the specification teaches only an analysis of RNA from SSL, it is relevant to point out the unpredictability with regard to the analysis of gene expression profiles obtained from different sample types. Inoue et al (2022) teaches the analysis of RNA levels detected in sebaceous glands, epidermis, sweat glands, hair follicles, and dermis isolated using LMD, whole skin from three healthy male subjects, and SSL-RNAs obtained from 29 healthy male subjects (e.g.: Fig. 4).
The specification teaches only a diagnostically relevant comparison of SH3BGRL3 (relevant to the Election) is subjects with severe versus subjects with mild PMS, and in particular the detection of increased levels of SH3BGRL3 in samples from severe PMS subjects versus the level in samples from a population of mild PMS subjects. Because the claims broadly and generically encompass measuring any level of the biomarker in a sample, and the use of ant level in detecting severity of PMS, it is relevant to point out that the prior art of Cheung et al (2003) teaches that there is natural variation in gene expression; so it is unpredictable if any measurement, or any use such as comparison to any reference, as generically encompassed by the claims are indicative of PMS severity. Additionally in this regard it is noted that when considering the use of expression levels in prediction models (e.g.: instant claim 5), where the Election is to a single marker that is SH3BGRL3, the specification teaches only models with at least 5 gene transcripts (e.g.: Table 8 of the Specification), and does not teach any models with less that 5 genes.
Because the claims encompass the analysis of any gene expression biomarker analytes (e.g.: protein or mRNA), whereas the specification provides only the example of the diagnostic association between PMS severity and SH3BGRL3 mRNA, it is relevant to point out that Chen (2002) teaches that it is common for protein expression to be discordant with mRNA expression levels even in matched samples (e.g.: Figure 3). Thus, it is unpredictable as to how to extrapolate the mRNA-based teachings of the instant specification to the analysis of any other different analyte.
Quantity of Experimentation
The quantity of experimentation necessary to make and use the invention in the full scope as claimed is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. The experimentation would require case:control analysis of any levels of SH3BGRL3 mRNA or protein in any samples from any subjects as compared to any reference to determine PMS severity. Even if such extensive experimentation were to be performed, there is no indication that any associations, beyond those particular associations disclosed in the specification, would be found.
Conclusion
Although the level of skill in the art is high, given the particular teachings of the instant disclosure in the specification, the teachings in the related art and the unpredictability of the art, it is the conclusion that it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al (2021).
Relevant to the rejection of claim 1, Chen et al teaches measuring the expression level of SH3BGRL3 (as consonant with the election) (e.g.: p.697 - Cell culture and quantitative real-time polymerase chain reaction (qRT-PCR); Table 1; Fig. 9).
Claim(s) 1 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Singla et al (2016).
Relevant to the rejection of claim 1, Single et al teaches measuring the expression level of SH3BGRL3 (as consonant with the election) (e.g.: p.466 - RNA isolation and microarray hybridization; Table 2; p.467 - Identifying a gene signature for PH in sarcoidosis).
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.
Claim(s) 1 and 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Inouye et al (US PG Pu 2018/0371524-A1) (cited on the IDS of 10/21/2022) in view of Singla et al (2016).
Relevant to the steps of the instantly rejected methods, Inouye et al teaches quantitative measurement of RNA in a skin surface lipid (SSL) samples (e.g.: para 0037; para 0071; para 0081). Iouyne et al does not exemplify the detection of SH3BGRL3 (as recited in claim 1, and as consonant with the Election), but the reference does teach that “analysis of nucleic acid expression can be performed according to known means such as RNA expression analysis using … a microarray” (para 0037).
Singla et al teaches measuring the expression level of SH3BGRL3 (as consonant with the election) using Affymetrix GeneChip Human Exon 1.0 ST arrays (e.g.: p.466 - RNA isolation and microarray hybridization; Table 2; p.467 - Identifying a gene signature for PH in sarcoidosis).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have performed the analysis of RNA in SSL sample using a microarray, as taught by Iouyne et al, using the Affymetrix GeneChip Human Exon 1.0 ST arrays as taught by Singla et al. As evidenced by the teachings of Singla et al, using the prior art Affymetrix GeneChip Human Exon 1.0 ST array would have provided a quantitative measure of SH3BGRL3. The skilled artisan would have been motivated to use the array of Singla et al based on the expressed teachings of Iounye et al that RNA in SSL samples may be analyzed by microarrays, and the expressed teachings of Signla et al that the Affymetrix GeneChip Human Exon 1.0 ST array contains ∼1.4 million probe sets and can provide a quantitative measure of transcripts of the entire human transcriptome.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683