DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I and biomarkers ISG15 and PPP1R3D in the reply filed on July 8, 2026 is acknowledged. Applicant further elected influenza as the respiratory viral infection, with traverse.
Applicant’s traversal is on the grounds that the specification supports the use of the biomarkers from Tables 2, 3, and 4 for detection of various types of respiratory viral infections (according to par. 148 and Fig. 8C of the specification).
This argument is not found persuasive. There may be multiple interpretations of claim 17, as discussed in the rejections under 35 U.S.C. 112(b) below. If claim 17 is interpreted to mean that the viral score is capable of rendering a diagnosis of a specific viral infection (i.e. diagnosing someone with influenza), the specification does not support the use of (any) biomarkers for this purpose. Claim 17 could also be interpreted to mean that the pool of subjects is limited to those having respiratory viral infections comprised of the recited species. In that case, par. 148 and Fig. 8C still do not support the breadth of the biomarkers encompassed by claims 1 and 17, because they show only specific viral infections with different distribution of viral scores when compared to either healthy subjects/non-viral ARI. No indications of practical or statistical significance are given for these comparisons, and the score is based on an 88-gene subset, not a representative sample of all of the combinations of the biomarkers in Tables 2, 3, and 4. See a fuller discussion in the rejections under 35 U.S.C. 112(a) below. The requirement is deemed proper and is made FINAL.
Claim 1-9, 12,14-17, 19, 22-25, and 27 are currently pending.
Claims 2, 12, 19, 22-25, and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim.
Claims 1, 3-9, and 14-17 have been examined to the extent that they read the elected species. The additionally recited species have been withdrawn from consideration as being directed to non-elected subject matter.
Priority
It is acknowledged that the instant application is a 371 of international PCT Application No. PCT/US2022/028703, filed May 11, 2022, and that it claims benefit of provisional 63/187,337, filed May 11, 2021. The effective filing date is considered to be May 11, 2021.
Information Disclosure Statement
Information disclosure statements from have been received. Several IDS entries have been crossed out and not considered, as they are missing a publication year:
- IDS filed 12/12/23: NPL #1
- First IDS filed 4/03/24: NPL #s 1, 6, 7, 9, 12, 28
- Third IDS filed on 4/03/24: NPL # 15, 26, 34, 35, 37, 44, 46
- Fourth IDS filed on 4/03/24: NPL # 1
For the remaining entries in each of the filed IDS, the given references have been considered to the extent of their documentation which has been submitted or provided on the record in English.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-9, and 14-17 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 some combinations of some mRNA expression levels for some viral infections as elaborated below, does not reasonably provide enablement for determining whether any subject has any viral infection based on any viral scores generated from any other combinations of mRNA expression levels.
The embodiments which are enabled are:
The 88-gene panel, the 5-gene panel, and the 3,385 pairs having AUC > 0.78 (Table 4);
Diagnosis of general respiratory viral infection;
Human subjects; and
RNA expression
The embodiments which are not enabled are:
ANY individual biomarker or ANY combinations of biomarkers from Tables 2-4, including the pairs of the 88-gene set having AUC < 0.78;
Diagnosis of specific viral respiratory infections (e.g. diagnosis of influenza)
Non-human subjects
Protein expression
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.
Scope of the Claims/Nature of the Invention
Claims 1-9, 12, and 14-17 are drawn to a method of administering medical care to a subject presenting one or more symptoms of a respiratory viral infection. In view of the recitation of “subject,” the claims broadly encompass both human and non-human subjects.
The claims recite a step of measuring and generating a viral score based on the expression levels of one or more biomarkers from Tables 2, 3, and/or 4. In view of this recitation, the claims broadly encompass the measurement and use of any possible combination of the biomarkers listed in Tables 2-4 – this amounts to more than 5.47 x 10^98 possible unique combinations. Claims 2 and 3 limit the biomarkers to specific Tables. Claim 12 requires the biomarkers to comprise a particular subset (IFITM1, TLNRD1, CDKN1C, INPP5E and TSTD1). In view of the recitation of “biomarkers,” the claims broadly encompass the measurement of polypeptides as well as RNA expression. Claim 9 implicitly requires measurement of RNA expression. In view of the recitation of viral scores which indicate a “viral infection,” the claims broadly encompass diagnosis of ANY viral infection. Claim 17 requires the viral infection to be selected from adenovirus, coronavirus, human metapneumovirus, human rhinovirus (HRV), influenza, parainfluenza, picornavirus, or respiratory syncytial virus (RSV).
The nature of the invention requires reliable correlations between the expression level of ANY combination of biomarkers selected from Tables 2-4 and the diagnosis of ANY respiratory virus infection.
Teachings in the Specification and Examples
The specification describes a multicohort analysis of public datasets having subjects with and without viral infections (Table 1; par. 157; par. 161). 12,678 genes were commonly presented in 6 of those datasets (par. 153). The expression of these genes was assessed and statistical analysis performed to identify genes having an effect size with a magnitude greater than or equal to 0.6 and an FDR (false discovery rate) less than or equal to 0.1, which the specification asserts is a threshold that corresponds to 80% power for moderate heterogeneity (par. 149, 151). Examiner interprets ‘effect size’ to mean differential expression for a specific gene between subjects having a respiratory virus infection and subjects not having a respiratory virus infection. 328 genes (Table 2) were identified using these criteria in 5 of 6 datasets, and 308 in all 6 datasets (par. 151). The 328 mRNAs were further filtered to correspond to mRNA having appropriate expression in a 7th cohort having only nasal swab samples from viral-infected patients (analyzed as mean and standard deviation of log 2 FPKM; par. 152). The selected 88 mRNAs are listed in Table 3.
AUC values were determined for: 1) each of the total 12,678 mRNAs having measurements across 6 studies, 2) the individual mRNAs in the 88-gene set, 3) all 3,828 unique pairs of mRNAs of the 88-gene set, and 4) 10,000 randomly selected pairs of mRNAs from the 12,678 mRNAs. It is unclear if these AUC values were generated using a particular kind of viral score, or simply raw expression values. Of note, AUC values above 0.78 were observed for 88% of the pairwise combinations of the 88-gene set (par. 153; Table 4). However, the remaining 12% of pairwise combinations, as well as the individual mRNAs of the 88-gene set, had AUC as low as 0.4 (Fig. 2B-D).
Geometric means-based viral scores were generated using the 88-gene signature and found to be significantly higher for infected samples vs uninfected samples (Fig. 3A), with a corresponding AUC showing high discriminatory power (Fig. 3B: ranging from 0.818 – 1). An algorithm was used to identify a narrower 5-gene signature having a viral score AUC comparable to the full 88-gene set (par. 155; Fig. 4A-B). The genes in the 5-gene subset were: IFITM1, TLNRD1, CDKN1C, INPP5E and TSTD1.
The 88-gene set was validated in several additional datasets: GSE163151 and GSE152075 (par. 158, 161). GSE163151 included expression data from swab samples from patients having SARS-COV-2, influenza, coronavirus, and other viral infections as well as healthy subjects and patients with non-viral respiratory illness (par. 158). GSE152075 included expression data from nasopharyngeal swab samples taken from patients having COVID-19 and 54 healthy donors (par. 161). The geometric-mean-based score for these samples was determined and shown as boxplot and ROC curves (Fig. 8A, B; Fig. 9A,B). AUC of the 88-gene signature were 0.91 and 0.92 for GSE163151 and GSE152075 datasets, respectively.
For the dataset GSE163151, samples were further divided by virus type into subgroups. For each subgroup, boxplots of the (88-gene signature) viral score were generated (Fig. 8C). The specification asserts that this data “showed that our 88-mRNA-based score works for various types of viruses captured in this study including SARS-COV-2" and "healthy donors but also those with the non-viral ARI showed the clear separation from those virus-infected patients" (par. 160). However, for these individual virus subgrouping, no indication of statistical or practical significance is given (e.g. p-values, AUC values, etc.). The analysis does not appear to include examination of the 88-gene set as diagnostic of specific infections caused by specific viruses.
State of the Art and the Unpredictability of the Art
While methods of measuring gene expression and generating biomarker scores are known in the art, methods of correlating gene expression and/or biomarker scores with a phenotype such as respiratory virus infection are highly unpredictable. The unpredictability will be discussed below.
The claims broadly encompass diagnosis of respiratory virus infection of ANY type of virus. However, the analyses in the specification addressed only infections involving the following viruses: adenovirus, coronavirus, human metapneumovirus, influenza, parainfluenza, rhinovirus, RSV, and SARS-COVID-2 (Fig. 8C; Table 1). Furthermore, said analyses demonstrated only that a state of general respiratory virus infection (vs. healthy or non-viral infections) could be determined using some subsets of mRNA expression levels. There is no evidence in the specification that the 88-gene signature or any other signature is informative for anything other than potentially diagnosing general respiratory viral infection. Smith (published 2012; Smith et al. PLoS One. 2012;7(3):e33174) teaches that even among pathways shared between immune responses to diverse respiratory viruses, the proportion of specific genes which are shared between infections ranges between 9% - 36% (Table 2; pg. 5, col. 2, 1st par.). Thus, Smith supports the finding that it is highly unpredictable whether a given gene expression signature will be suitable for diagnosis of general respiratory virus infection AND diagnosis of specific respiratory virus infection involving ANY individual respiratory virus. The instant specification supports only diagnosis of general respiratory virus infection.
The claims broadly encompass diagnosis of respiratory virus infection using ANY one or more of the biomarkers of Tables 2-4. However, the specification provides support for only the following combinations of mRNAs as respiratory viral infection diagnostic markers:
The 88-gene signature as a whole (Fig. 3; par. 154)
The optimized 5-gene signature, consisting of IFITM1, TLNRD1, CDKN1C, INPP5E and TSTD1 (Fig. 4; par. 155)
The 3,385 unique pairwise combinations of the 88-gene set listed in Table 4
The discriminatory ability of the remaining pairwise combinations or individual biomarkers of the 88-gene set is potentially very poor, with some having AUC values as low as 0.4 (Fig. 2D). For the larger 328-gene set listed in Table 2, AUC values or other measures of practical/statistical significance were not given. However, 10,000 randomly selected mRNA pairs showed a wide range of discriminatory ability, with AUC values for the pairs of as little as 0 (Fig. 2E). Thus, the instant disclosure supports the highly unpredictable nature of these biomarkers, and supports only the above-listed embodiments.
The claims broadly encompass diagnosis of respiratory virus infection in human and non-human subjects. However, the specification’s analyses are based on data from human subjects. The prior art teaches that there is a large amount of unpredictability with regard to comparing results from gene expression analysis in human to even closely related animals. For example, Coleman (published March 6, 2003; Coleman et al. Drug Discovery Today. 2003. 8:233-235) found that gene expression patterns between mice and human shared some degree of similarity, but that the basic patterns of gene expression differed and that there was no general rule for predicting gene expression (pg. 234). Coleman conclusion that "[t]he validity of mouse or other animal species as a human surrogate should not be assumed." These teachings of Coleman support the finding that there is no predictable means for determining whether the gene expression profile that is predictive of respiratory virus infection in a human subject will also be predictive of respiratory virus infection in a representative number of non-human subjects. The specification provides support only for human subjects.
The claims broadly encompass diagnosis of respiratory virus infection using any marker of gene expression (e.g. mRNA, protein, etc.). Therefore, it is relevant to point out the unpredictability of whether or not a measure of RNA expression is indicative of the level of protein in a sample. Haider (published Apr. 2013; Haider & Pal. Curr Genomics. 2013 Apr;14(2):91-110) teaches that correlation between mRNA and protein expression can be low due to various factors (Abstract), including translation efficiency and differing half-lives (pg. 92-93: "Correlation Between Transcriptomic and Proteomic Data"). Therefore, it is unpredictable as to whether results pertaining to RNA expression, as presented in the instant specification, would be applicable to methods requiring or encompassing the analysis of protein expression. The specification provides support only for RNA expression.
Quantity of Experimentation:
The quantity of experimentation necessary 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. In support of this position, it is noted that the claimed methods encompass being able to determine whether human or non-human subjects are likely to have ANY specific or general respiratory viral infection using viral scores generated from RNA or protein expression levels of ANY one or more of the biomarkers from Table 2-3.
In order to practice the breadth of the claimed invention one of skill in the art would first have to gather samples from human and non-human subjects having respiratory infections caused by a representative number of viruses. The expression levels of a representative number of individual or combination biomarkers from Tables 2-4 would have to be determined and then compared to a representative number of reference threshold values. Then, sophisticated data analysis would have to be conducted to determine which combinations of biomarkers would be predictive of respiratory infections of any type of virus. The specification has merely provided an invitation for further experimentation. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even "a considerable amount of experimentation is permissible," as long as it is "merely routine" or the specification "provides a reasonable amount of guidance" regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360- 61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is "not without bounds." Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation "would be excessive, e.g., that it would involve testing for an unreasonable length of time." 707 F .3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a "diverse and relatively poorly understood group of microorganisms," with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years' work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a "predictable" factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusions:
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
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, 3-9, and 14-17 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, 3-9, and 14-17 are rejected because it is not clear if the “viral infection” recited in the last line of claim 1 is the same as the “respiratory viral infection” recited in the preamble of claim 1. Thus, it is further unclear whether the recitation of a specific “respiratory viral infection” in claim 17 requires that the method be capable of distinguishing between different respiratory viral infections, or whether it is merely limiting the subject pool (i.e. the method is only used with subjects presenting symptoms of these particular viral infections). As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
Claims 1, 3-9, and 14-17 are rejected for referring to specific figures and/or tables in the specification. MPEP 2173.05(s) states that “Where possible claims are to be complete in themselves. Incorporation by reference to a specific table or figure ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicated a drawing or table into a claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.”"
Regarding claims 1, 3, 5-9, and 17, it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites a method of administering medical care, yet the method steps in the claims only set forth steps of “obtaining,” “measuring,” “generating,” “determining,” and “detecting.” Thus, it is not clear if the applicant intends to cover only a method comprising these steps, OR if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the latter, than the claims appear incomplete, as they fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims.
Claim 15 is rejected because it is unclear if the claim is intended to require that the administered medical care is an organ-supportive therapy, or if it is merely a limitation of the possible organ-supportive therapies included in claim 14’s selections of medical care. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
Claim 16 is rejected because it is unclear if the claim is intended to require that the administered medical care is a therapeutic drug, or if it is merely a limitation of the possible therapeutic drugs included in claim 14’s selections of medical care. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
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, 3-9, and 14-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4, Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature. The claims recite a correlation between the expression level of one or more biomarkers and whether a subject has a respiratory viral infection. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas. The claims recite a step of “generating a viral score” based on the measured expression levels of biomarkers. Neither the specification nor the claims set forth a limiting definition for “generating a viral score” and the claims do not set forth how this step is accomplished. The “generating” step broadly encompasses mathematical concepts, as “generating a viral score” in the broadest sense would involve the use of mathematical comparisons and operations, constituting a mathematical process.
Claims 4 and 14-16 recite a step of “determining” that a subject has a viral infection. Claim 5 recites “determining” that a subject does not have a viral infection. Neither the specification nor the claims set forth a limiting definition for “determining” and the claims recite only that it is accomplished based on a viral score. The “determining” step broadly encompasses mental processes. For example, one may “determine” that a subject has a viral infection by looking at data and thinking about whether it indicates the subject has a viral infection. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exception(s) into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or a technological field;
An additional element that applies or used a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing;
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition to the judicial exceptions, the claims recite a step of “obtaining” a respiratory sample from the subject. This step is not considered to integrate the judicial exceptions into a practical application because it merely adds insignificant extra-solution activity (data gathering) to the judicial exceptions.
In addition to the judicial exceptions, the claims recite a step of “measuring” expression levels of one or more biomarkers. This step is not considered to integrate the judicial exceptions into a practical application because it merely adds insignificant extra-solution activity (data-gathering) to the judicial exceptions.
In addition to the judicial exceptions, the claims recite “administering the immunotherapy treatment to the subject.” Claims 1-3, 5-9, 12, and 17 broadly encompass situations where the subject is found to NOT to have a respiratory viral infection. In those situations, the immunotherapy treatment would not be administered. In claims 4 and 14-16, the administering step occurs when the subject is found to have a viral infection based on the viral score. Here, the administering step is not ‘particular,’ i.e., specifically identified so that it does not encompass all application of the judicial exceptions. The step is merely instruction to apply the exception in generic ways. As the treatment step need not occur and the treatment steps are not particular, the claims do not recite any steps or elements that integrate the judicial exception so as to practically apply the judicial exception.
In addition to the judicial exceptions, claims 7 and 8 recite a step of “detecting” the presence or absence of one or more viruses in the sample. Claim 8 requires detection using a nucleic acid amplification test. This step is not considered to integrate the judicial exceptions into a practical application because it merely adds insignificant extra-solution activity (data gathering) to the judicial exceptions.
Step 2B: Evaluate Whether the Claim Provides and Inventive Concept
In addition to the judicial exceptions, the claims recite steps of “obtaining” a sample, “measuring” expression levels, “administering” medical care, and “detecting” a virus. These steps do not amount to significantly more because they simply append well-understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
These steps are recited a high level of generality. Determining the expression levels of biomarkers, obtaining a respiratory sample, and/or administering medical care merely instruct a scientist to use any known technique for measuring expression levels, obtaining a respiratory sample, and/or administering medical care. The claims do not require the use of any particular non-conventional reagents or equipment or methodology. When recited at this high level of generality, there is no meaningful limitation that distinguishes the steps 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, and conventional nature of additional elements because it teaches that the additional elements are well-known or commercially available. For example, the specification teaches the following:
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Further, it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, and 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.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
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 the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 3-8, 14, 16, 17 are rejected under 35 U.S.C. 103 as unpatentable over Oved (published May 30, 2019; Patent Application Publication No. US 2019/0161813).
Regarding claims 1 and 3, Oved teaches a method comprising obtaining a respiratory sample from the subject (par. 103, 162). Oved teaches measuring the expression levels of one or more biomarkers in the sample selected from Oved’s Tables 3 and 15A to determine infection type (par. 16, 28). At least Tables 3 and 15A encompass the elected species ISG15 (Table 3: pg. 15; Table 15A: pg. 46), and Table 15A encompasses the elected species PPP1R3D (par. 33; Table 15A: pg. 49). Oved teaches generating classifiers or indices from biomarkers which are indicative of whether a subject has a bacterial or viral infection (par. 16, 28, 92). The instant claim’s recitation of “viral score” broadly encompasses these viral-indicating classifiers and indices, and therefore the limitation is considered to have been met.
For clarity, Oved teaches determining the level of ISG15 in a subject, wherein ISG15 exceeding a threshold level may indicate that a subject has a viral infection (par. 42; Table 3). Oved teaches that the level of PPP1R3D is also associated with viral infection (pg. 49, Table 15A) and may be used as a determinant in combination with other markers (par. 28). Thus, Oved teaches the combination of ISG15 and PPP1R3D as biomarkers for determining viral respiratory infections status.
Regarding claims 1 and 4, Oved teaches administering medical care to a subject presenting one or more symptoms of a respiratory viral infection and/or a subject presenting one or more symptoms of a respiratory viral infection or to a subject determined to have a viral infection (par. 313).
Regarding claims 1, 4, and 5, Oved teaches determining the level of biomarkers (including ISG15) in a subject, wherein the biomarker(s) exceeding a threshold level may indicate that a subject has a viral infection (par. 42; Table 3). Oved further teaches the combination of ISG15 and PPP1R3D as biomarkers for determining viral respiratory infection status, as discussed above. “Generating a viral score based on the measured expression levels of the biomarkers in the sample” broadly encompasses any manner of generating a viral score from biomarker expression levels, including an assessment of ISG15’s level compared to a reference (as set forth in Oved: par. 42, 134), and thus Oved’s teachings are considered to have met the limitations “generating a viral score…” and “determining that the subject has/does not have a viral infection based on the viral score exceeding/not exceeding the threshold” of claims 1, 4, and 5.
Regarding claim 5, Oved teaches determining that the subject does not have a viral infection (par. 85).
Regarding claim 6, Oved teaches respiratory samples including nasopharyngeal and saliva samples (par. 103, 162)
Regarding claims 7 and 8, Oved teaches detecting the presence or absence of one or more viruses in the sample using a nucleic acid amplification tests (par. 314, 385).
Regarding claims 14 and 16, Oved teaches administering medical care to a subject determined to have a viral infection comprising administering a therapeutic drug, including antiviral agents (par. 85, 313).
Regarding claim 17, Oved teaches samples obtained from patients having respiratory viral infections including those caused by adenovirus, human metapneumovirus, influenza, parainfluenza, and respiratory syncytial virus (Fig. 7-I).
Claim 9 is rejected under 35 U.S.C. 103 as unpatentable over Oved (published May 30, 2019; Patent Application Publication No. US 2019/0161813), as applied to claim 1 above, and further in view of Stahl (published Oct. 13, 2016; Patent Application Publication No. US 2016/0298085).
Oved teaches the limitations of claim 1, as discussed above.
Regarding claim 9, Oved does not explicitly teach that the expression of the biomarkers is detected using qRT-PCR or isothermal amplification, wherein the isothermal amplification method is qRT-LAMP. However, Oved teaches the use of various methods for measuring expression of RNA, including qPCR, RT-PCR, and microarray (par. 173, 180, 221)
Stahl teaches that methods of measuring RNA expression include microarrays and qRT-PCR (par. 122).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to substitute the qRT-PCR of Stahl for the methods explicitly recited in Oved because the methods are used for the same purpose (i.e. they all measure expression of RNA), and therefore they may be considered functional equivalents. One would have had reasonable expectation of success because these methodologies are well-known in the art (Stahl: par. 122; Oved: par. 169).
Claim 15 is rejected under 35 U.S.C. 103 as unpatentable over Oved (published May 30, 2019; Patent Application Publication No. US 2019/0161813), as applied to claims 1, 4, and 14 above, and further in view of Kelesidis (published Nov. 28, 2014; Kelesidis et al. BMC Infect Dis. 2014 Nov 28;14:321)
Oved teaches the limitations of claims 1, 4, and 14, as discussed above.
Regarding claim 15, Oved does not explicitly teach administering medical care to a subject determined to have a viral infection, wherein the medical care comprises organ-supportive therapy, which comprises connecting the subject to any one or more of a mechanical ventilator, a pacemaker, a defibrillator, a dialysis or a renal replacement therapy machine, or an invasive monitor selected from the group consisting of a pulmonary artery catheter, arterial blood pressure catheter, and central venous pressure catheter. However, Oved does teach determining whether a subject has a viral infection and treating said patient accordingly (par. 312).
Kelesidis teaches that supportive therapies for viral infections include mechanical ventilators and dialysis (Table 1: pg. 3; pg. 4, col. 2, par. 1).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Oved and Kelesidis. One would have been motivated to do so because Kelesidis’s treatments are known to be appropriate for viral respiratory infections (see Table 1), and because Kelesidis explicitly states that “All the reported respiratory viruses can cause severe pneumonia with acute respiratory distress syndrome (ARDS) requiring mechanical ventilation” (pg. 4, col. 2, par. 1). One would have had reasonable expectation of success because supportive therapies such as mechanical ventilation are conventional forms of treatment for severe viral respiratory infections (Table 1; pg. 4).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-9, and 14-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 163-182 of co-pending Application No. 17/736,495, in view of Oved (published May 30, 2019; Patent Application Publication No. US 2019/0161813).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods (claim 163). Both sets of claims require:
Obtaining samples from a subject which are respiratory samples (claim 163, 174)
Measuring expression levels of one or more biomarkers in a sample obtained from a subject (claim 163)
Generating a viral score based on measured expression levels of biomarkers (claim 163)
In this case, the reference requires biomarkers from a Table 8 in the reference specification. Table 8 is drawn to a set of biomarkers which overlaps in at least two biomarkers with the instant claims: ISG15 and PPP1R3D.
Although the reference does not explicitly require that the viral score must exceed a threshold value to indicate that a subject has a viral infection, it would be obvious to optimize a classification model to arrive at such an embodiment (e.g. see Oved: par. 42, 317, 324). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/C.M.J./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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