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: (I) the particular gene combination that is IFITM1, IFITM3, JUNB, IFI27, LGALS1, MAFB, NFKBIA, and CEBPD; and (II) the particular cell type that is a CD14 monocyte, in the reply filed on 11/25/2025 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 Examiner’s search of the elected gene combination of the eight particular genes as set forth in (I) above, the requirement between the elected combination and the subcombination that is IFI27 and IFITM1 is withdrawn, and the subcombination that is IFI27 and IFITM1 is rejoined with the elected invention.
Claims 6, 7, 17 and 17 are withdrawn from further consideration, as noted in Applicants’ reply of 11/25/2025, pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/252/2025.
Claim Rejections – Improper Markush Group
Claims 1-5, 8-15, and 18-20 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 the genes, the expression of which is measured, recited in the alternative in claims 1 and 11 (i.e.: measuring an expression level of at least two genes selected from) directing the claims to any combinations or subcombinations of those different recited genes is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Here each species is considered to be a different method requiring the analysis and detection of a distinct gene product (transcript), and combinations thereof.
The recited alternative elements do not share a single structural similarity, as each method relies on the detection of a different biomolecule (i.e.: a unique polynucleotide sequence that is distinct form other sequences and allows the identification of the specific transcript). Each transcript arising from a particular gene has a different chemical structure in that it consists of a different polynucleotide sequence context. And each transcript has a different biological activity in that it codes for the translation of a different protein having a different biological function in a cell. Thus, these different species do not share a single structural similarity or biological activity.
The only structural similarity present is that all elements may be present as nucleic acid transcripts in a biological sample obtained from a subject (as relevant to the claimed methods). The fact that the transcripts comprise nucleotides does not per se support a conclusion that they have a common single structural similarity because this property (i.e.: being a nucleic acid) is not mainly responsible for the asserted common activity of being a biomarker for mortality risk related to critical COVID-19 infection (e.g.: there are thousands of RNAs in samples from COVID patients that are not in fact associated with mortality risk). Accordingly, while the different gene transcripts are asserted be associated with COVID-related mortality, they do not share a single structural similarity essential to this activity.
Here it is clear that the asserted common use does not flow from any broadly ascribed common structure (see MPEP 2117 II B). The common use of having a detectable expression that is related to COVID mortality is particular to each different transcript because of the role of the gene in biological response to COVID infection, not based on some particular common structural feature shared among the different transcripts themselves.
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 1-5, 8-15, and 18-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas without significantly more.
The claim(s) recite(s) several abstract ideas that encompass mental process (see MPEP 21106.04(a)(2)). Steps in the claims such as “comparing” and “determining” (e.g.: as recited in claim 1) and steps requiring that a “a change in gene expression … indicates a change in the subject’s risk of mortality” (e.g.: as recite in claim 11) are concepts that may be performed in the human mind (e.g.: observations, evaluations, judgments, and opinions; see MPEP 21106.04(a)(2) III). Additionally, the steps of data manipulation such as “computing a … score”, and a comparison “computed as a difference”, are 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 COVID-19 pathology, such an association is a natural aspect of the biological response to infection (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).
This judicial exception is 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 gene expression values, but the methods end with the abstract idea of “determining” a risk (claim 1), or an indication of a change in risk (claim 11), which are themselves judicial exceptions (as detailed above). It is noted that claims 8 and 18 recite that “the subject is hospitalized”, but such a limitation does not integrated the judicial exception into a practical application because it is unclear if the limitation is intended to set forth a quality of the subject prior to the analysis of gene expression, of if the hospitalization is intended to be a result of the analysis of gene expression. Additionally, such a limitation does not set forth any particular required treatment. Similarly, where claims 10, 19 and 20 recite limitations related to the administration of a treatment, the treatments are recited at the highest level of generality, and require no particularly therapeutic regimens or treatment modalities (see MPEP 2106.04(d).
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 gene expression levels in a sample obtained from a subject) were known in the art. The instant application teaches that the data collection of the instantly claimed methods was relevant to the prior art study of COVID samples in the WU350 study (e.g.: specification at page 38), and sample analysis of Liu et al provides data consonant with the claimed methods (e.g.: p.37-38 of the specification). Xu et al (2020) and Schulte-Schrepping al (2020) are prior art references teaching collection of gene expression values in COVD-related PMBC samples using single-cell RNA-sequencing (scRNA-seq), which provides an evaluation of expression of the entire transcriptome.
Claim Rejections - 35 USC § 112 – Written Description
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 1-5, 8-15, and 18-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The rejection of claims for lack of an adequate written depiction of the claimed subject matter in the application as originally filed is relevant to several features of the claimed methods. As a first aspect, the claims are directed to computing a score from gene expression values, but there is no teaching in the application as originally filed of how any gene expression values from a plurality of genes are combined to arrive at a value. This characteristic is particularly relevant where the scores of the claims have a required functionality of being associated with risk of mortality in a critical COVID-19 subject. For example, while the specification teaches that survival prediction may be related to “ranked feature importance scores” (e.g.: p.34) and that some genes “were identified as key in predicting survival”, there is no teaching of how a score is made with the expression values (e.g.: what weight or coefficient is assigned to any expression value). This is relevant where the related art teaches that using any different particular measure of gene expression may provide different results (e.g.: Millenaar et al (2006)), and gene expression values can be combined in many different ways such as: weighted sum/linear combination methods; rank-based and non-parametric methods using the relative rank of gene expression rather than absolute values; methods using normalization and statistical scaling where data is transformed before score calculation to ensure comparability across samples; and machine learning methods (such as principal component analysis (PCA) and random forest classification).
The functionality (i.e.: association with COVID-19 mortality) of the generically encompassed scores of methods is further relevant when considering that the claims are directed to comparing a score from a sample from a subject to a reference score from a reference sample (i.e.: singular sample, singular reference). But the specification teaches classification of sample based on comparisons of particular populations (p.30 - those who survived infection (n = 6) and those who succumbed to infection (n = 6)). Given the accepted variation of gene expression levels among individuals (e.g.: Cheung et al (2003) teaches that there is natural variation in gene expression), the specification does not provide what sort of score from any single particular reference, might be suitable to determine a difference related to COVID mortality.
Furthermore, where the claims are directed to a comparison to any reference sample to establish a risk of COVOD-19 mortality, it is noted that the teachings of the specification as originally filed provide only for the classification of subjects with critical COVID-19 who then survive infection and subjects with critical COVID-19 who then succumb to infection. There is no description in the application as filed of genes that have measurable expression in a subject related to COVID mortality where the subject is a healthy subject, or even as compared to a critical COVID subject that is not known to have survived critical COVID.
Given the broadly encompassed gene expression scores of the claimed methods, and the required functionality of the scores and the teachings of the prior art with regard to the complicated nature of establishing scores and establishing a relationship between gene expression and a phenotype prediction, it is the conclusion that the claimed subject matter is not supported by an adequate written description in the application as originally filed. In this regard it is notes that although there is often significant overlap between the enablement and written description requirements, they are independent of each other. An invention may be enabled even though it has not been described. A showing of how to potentially identify score computations that might be used in the claimed methods is not sufficient to establish that Applicants were in possession of the invention as broadly claimed.
Claim Rejections - 35 USC § 102/103
In the rejection of claims in view of the cited prior art, it is noted that the claims are previously rejected in this Office Action under 35 USC 112(a) as lacking and adequate written description in the application as originally filed. In this case the cited prior art provides the same information and teachings as the instant application, and so if Applicants can show that the claims are described by the application, then the claims are properly addressed by the prior art. Where the cited prior art includes additional authors who are not inventors of the application, and the reference is published prior to the effective filing date of the application, the reference qualifies as prior art.
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.
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) 1-5, 8-15 and 18-20 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Amrute et al (2002) including the Supplementary information.
Relevant to independent claims 1 and 11, Amrute et al teaches the analysis of gene expression levels using single-cell RNA sequencing of PBMCs (relevant to claims 2 and 12) from critical COVID-19 subjects admitted to an intensive care unit (relevant to claims 8 and 18) (e.g.: p. 9 - Subject selection criteria and specimen collection; PBMC isolation and single-cell RNA sequencing), and teaches scores that include IFITM1 and IFI27 (e.g.: Fig. 3 j). Further relevant to the genes of the elected invention, the reference teaches CEBPD, MAFB, LGALS1, and IFITM3 (Fig 4j; p.6) as well as JUNB and NFKBIA (Fig 4 c) as genes which have expression associated with COVID mortality.
The reference teaches the analysis of samples taken form subjects at day 0 and day 7 (e.g.: Fig 1b), and teaches comparisons in gene expression among healthy controls, samples taken at day 0 and day 7 from subjects surviving critical COVID, and samples taken at day 0 and day 7 form subjects that succumb to critical COVID (relevant to claim 9).
The reference teaches a comparison of scores to identify differences in scores related to subjects that are control subjects, alive at day 7, or deceased at day 7 (e.g.: Fig 3), thus teaching making a determination of risk based on a comparison to a reference score (relevant to claim 1), or indicating a change in mortality risk in a subject based on a change in an expression score (relevant to claim 11). Alternatively, it would have been obvious to the skilled artisan to have use expression values of samples from a test subject as compared to reference values from subjects known to have survived COVID, reference values from subjects known to not have survived COVID, to determine a risk of mortality in the test subject. The skilled artisan would have been motivated to determine risk of mortality (relevant to claim 1), or a change in mortality risk (relevant to claim 11) based on the expressed teachings of Amrute et al that gene expression values can predict COVID mortality with 90% accuracy, and that prognostic indicators among critical COVID-19 can be a tool in risk stratification and clinical management used to develop strategies to treat the sickest COVID-19 patients (relevant to claims 10, 19 and 20).
Relevant to claims 3, 4, 13 and 14, the reference teaches the analysis of cells that include CD14+ monocytes (e.g.: p.4 - Early cell-specific gene expression predicts COVID-19 survival).
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/ Primary Examiner, Art Unit 1683