DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. In response to the first election of species requirement, Applicant’s elected without traverse of the combination ZNF354A; EPPK1; RNASE1; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96; ARL4A; ZAP70; ERAP2; HGF; KLRF1; NEAT1; and MME in the reply filed on September 11, 2025.
In response to the second election of species requirement, Applicant’s elected without traverse none of the species in the reply filed on September 11, 2025. They requested rejoinder upon a finding of allowability of claim 1 or claim 9.
Claims 1-18 are currently pending.
Claims 3-5 and 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter (non-elected transcripts), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 11, 2025.
The claims have been examined to the extent that the claims read on the elected combination of transcripts (ZNF354A; EPPK1; RNASE1; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96; ARL4A; ZAP70; ERAP2; HGF; KLRF1; NEAT1; and MME). Prior to allowance of the claim, any non-elected subject matter (i.e., non-elected transcripts and combinations thereof) that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 101
3. 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, 6-8, and 13-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a judicial exception that is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim analysis is set forth below.
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 transcript levels and risk of developing multiple independent infection episodes following blunt trauma. 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 “comparing” the level of the transcript to a reference level. Neither the specification nor the claims set forth a limiting definition for “comparing”. The “comparing” step broadly encompasses an activity that can be performed in the human mind. While some types of comparisons require sophisticated software, the claims do not require this. The “comparing” could be performed by reading a laboratory report and thinking about whether the transcript level is increased or decreased relative to reference levels.
The claims recite a step of “calculating” a score based on the transcript levels and “comparing” the score to a threshold or reference score. Mathematical calculations are considered to be mathematical concepts which are another type of abstract idea. As explained above, “comparing” could be performed in the human mind and is an abstract idea.
Claims 14-15 state that the score is calculated using an algorithm. Mathematical algorithms are also mathematical concepts. Mathematical concepts are 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 exceptions 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 technical field;
An additional element that applies or uses 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; and
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.
Claim 7 recites a step of “treating” the subject. It is noted that a claim limitation can integrate a judicial exception by applying or using the judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. However the treatment or prophylaxis limitation must be “particular”, i.e., specifically identified so that it does not encompass all applications of the judicial exceptions. Here the administration step is not particular, and is instead merely instructions to “apply” the exception in a generic way. Claim 7 further recites the following “optional” treatment (i) administering a broad-spectrum antibiotic, (ii) increasing the frequency or length of monitoring of the subject for infection; (iii) implementing prophylactic measures; and/or (iv) enhancing patient nutrition Option (i) would be considered a particular treatment for a subject at risk of MIIE. However options (ii)-(iv) are general and non-specific and do not integrate the judicial exceptions into a practical application.
In addition to the judicial exceptions the claims require steps of providing a sample and determining transcript levels in the sample. These steps do NOT integrate the judicial exception into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions the claims require steps of providing a sample and determining transcript levels in the sample. 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.
The steps are recited at a high level of generality. Obtaining a sample in order to perform tests is well understood, routine, and conventional activity for those in the field of diagnostics. Determining the level of transcripts in a sample merely instructs a scientist to use any method of measuring gene or protein expression. 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 applicants 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 are well known or commercially available. For example the specification teaches the following:
[0051] The presence and/or level of a nucleic acid can be evaluated using methods known in the art, e.g., using polymerase chain reaction (PCR), reverse transcriptase polymerase chain reaction (RT-PCR), quantitative or semi-quantitative real-time RT-PCR, digital PCR i.e. BEAMing ((Beads, Emulsion, Amplification, Magnetics) Diehl (2006) Nat Methods 3:551-559); RNAse protection assay; RNA sequencing (RNA-Seq); Northern blot; various types of nucleic acid sequencing (Sanger, pyrosequencing, Next Generation Sequencing (NGS)); fluorescent in-situ hybridization (FISH); or hybridization-based approaches such as microarrays/chips, e.g., performed by commercially available equipment following manufacturer's protocols, e.g., using the Affymetrix GeneChip technology (Affymetrix, Santa 20 Clara, Calif.), Agilent (Agilent Technologies, Inc., Santa Clara, Calif.), or Illumina (Illumina, Inc., San Diego, Calif.) microarray technology) or Digital multiplexed gene expression analysis using the NanoString nCounter system (Kulkarni et al., Curr Protoc Mol Biol. 2011 April; Chapter 25:Unit25B.10), or barcoding methods (e.g., Serial Analysis of Gene Expression (SAGE)) (see also Lehninger Biochemistry (Worth Publishers, Inc., current addition; Sambrook, et al, Molecular Cloning: A Laboratory Manual (3. Sup.rd Edition, 2001); Bernard (2002) Clin Chem 48(8): 1178-1185; Miranda (2010) Kidney International 78:191-199; Bianchi (2011) EMBO Mol Med 3:495-503; Taylor (2013) Front. Genet. 4:142; Yang (2014) PLOS One 9(11):e110641); Nordstrom (2000) Biotechnol. Appl. Biochem. 31(2):107-112; Ahmadian (2000) Anal Biochem 280:103-110. In some embodiments, high throughput methods, e.g., gene chips or microarrays as are known in the art (see, e.g., Ch. 12, Genomics, in Griffiths et al., Eds. Modern genetic Analysis, 1999, W. H. Freeman and Company; Ekins and Chu, Trends in Biotechnology, 1999, 17:217-218; MacBeath and Schreiber, Science 2000, 289(5485):1760-1763; Hardiman, Microarrays Methods and Applications: Nuts & Bolts, DNA Press, 2003), can be used to detect the presence and/or level of the biomarkers.
The prior art also demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available.
For example Thompson (Critical Care Medicine June 2014 Vol 42 No 6) teaches that total leukocyte gene expression was compared between subjects in whom Gram-negative bacteremia developed and those in whom it did not develop (abstract). Thompson teaches that the subjects had blunt injuries (page 1398, col 2).
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.
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 § 112(b)
4. 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, 2, 6-8, 13-18 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.
Regarding Claims 1, 2, 6-8, 13-18 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 detecting or predicting risk of developing MIIE in a subject who has experiences blunt trauma, yet the method only requires active process steps of providing a sample; determining a level of transcripts in the sample; and comparing the level to a reference OR calculating a score and comparing to score to a threshold. There are no active process steps of detecting or predicting risk of developing MIIE in a subject who has experiences blunt trauma. Thus it is not clear if applicant intends to cover only a method of providing a sample; determining a level of transcripts in the sample; and comparing the level to a reference OR calculating a score and comparing to score to a threshold OR if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims.
Claim Rejections - 35 USC § 112(a)
5. 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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
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, 2, 6-8, 13-18, 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
A method of identifying a human patient with increased risk of developing multiple independent infection episodes (MIIE) following blunt trauma, the method comprising:
obtaining a blood, plasma, or serum sample from the human patient following blunt trauma;
measuring in the sample the levels of 15 transcripts, wherein the 15 transcripts are ZNF354A; EPPK1; RNASE1; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96; ARL4A; ZAP70; ERAP2; HGF; KLRF1; NEAT 1; and MME;
determining that the transcript levels of the 15 biomarkers in the sample are statistically similar to the transcript levels of the 15 biomarkers in reference samples obtained from a population of human patients that developed MIIE following blunt trauma;
identifying the human patient as having an increased risk of developing MIIE based on the determining step.
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 are drawn to a method of detecting or predicting risk of developing multiple independent infection episodes (MIIE) in a subject who has experienced blunt trauma. In view of the recitation of “subject”, the claims broadly encompass both human and non-human subjects.
The claims recite a first step of providing a sample comprising blood, serum, or plasma from a subject who has experienced blunt trauma.
The claims recite a second step of determining the transcript level of ZNF354A; EPPK1; RNASE1; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96; ARL4A; ZAP70; ERAP2; HGF; KLRF1; NEAT 1; and MME.
The third step is recited in the alternative. In the first embodiment of the third step the claims recite (i) comparing the level of the transcript to a reference level. The claim recites that the presence of: an increase in one or more of: HGF; KBTBD7; ADORA3; ARL4A; EPPK1; ZNF354A; SH3PXD2B; RNASE1, or BTBD19, or a decrease in one or more of: ZAP70; ERAP2; CD96; MME; KLRF 1; NEAT1, indicates that the subject has, or has an increased risk of developing, MIIE. The claims require measuring a combination of 15 biomarkers, yet only ONE of those 15 biomarkers has to be increased or decreased in comparison to the reference level for the subject to have or be at increased risk of developing MIIE. Further the claims do not define the reference levels. This could be the level of any transcript, in any sample type, obtained from any subject.
An alternative to the third step is (ii) calculating a score based on the transcript levels, and comparing the score to a threshold or reference score, wherein a score about the threshold or reference score indicates that the subject has or has an increased risk of developing MIIE. Here the claims broadly encompass any method of calculating a score.
The nature of the invention requires a reliable correlation between the level of ZNF354A; EPPK1; RNASE1; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96; ARL4A; ZAP70; ERAP2; HGF; KLRF1; NEAT 1; and MME and developing MIIE after a blunt trauma injury.
Teachings in the Specification and Examples
The specification (para 0098) teaches that 128 blunt trauma patients were included in the study.
The specification (para 0102) teaches that among the 128 patients in the study, there were 85 non-cases—42 with no infection and 43 with one infection episode—and 42 were MIIE-cases (i.e., ≥2 infection episodes).
The specification (para 0109) teaches that the inventors identified 137 probe sets showing at least 1.5-fold up- or down-regulated difference in expression levels between non-cases and MIIE-cases.
The specification (para 0110) teaches that to identify a multi-biomarker panel that collectively predicts the outcome of MIIE, we analyzed the 137 differentially-regulated probe sets by employing a machine learning pipeline that we previously developed and successfully used in our previous study among burn patients (Yan et al., 2015). In the current study, we further added to our analyses pipeline by utilizing a combination of LASSO and Elastic Net regression methods. The LASSO regression that reduces redundancy in predictor selection would allow for a narrow selection of a minimal biomarker panel, which is expected to be more practical. Elastic Net regression that includes correlated predictors allowed for a more comprehensive discovery of additional probe sets that are potentially biologically relevant. With LASSO, 15 probe sets were selected, mostly relevant to immune functions and signaling cascades for cellular proliferation and differentiation (see Table 3).
The specification (para 0113) teaches that the AUROC [95% CI] of the logistic regression model for predicting MIIE outcome with the 15 probe set biomarker panel developed with LASSO was 0.90 [0.84-0.96].
The specification also discloses the odds ratios (OR) [95% CI] and p-values for each of the 15 biomarkers in Table 5, partially reproduced below.
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State of the Art and the Unpredictability of the Art
While methods of determining transcript levels of biomarkers are known in the art, methods of correlating those biomarkers with a phenotype (such as risk of developing MIIE) are highly unpredictable. The unpredictability will be discussed below.
The claims recite that an increase in one or more of: HGF; KBTBD7; ADORA3; ARL4A; EPPK1; ZNF354A; SH3PXD2B; RNASE1, or BTBD19, or a decrease in one or more of: ZAP70; ERAP2; CD96; MME; KLRF 1; NEAT1, indicates that the subject has, or has an increased risk of developing, MIIE. However it is highly unpredictable if one could determine that a subject has or has an increased risk of MIIE based on increased or decreased levels of a SINGLE biomarker or even small combinations of two, three, four, etc. of the biomarkers. The specification provides data (p-values) showing that several of the individual genes were not considered to be statistically significant because they have p-values that are greater than 0.05. For example RNASE1, BTBD19, ADORA3, KBTBD7, SH3PXD2B, CD96, ARI4A, ZAP70, ERAP2, HGF, KLRF1 all had p-values that would not be considered strong enough for the basis of a conclusion. The specification does not provide support for determining that a subject has or has an increased risk of MIEE based on increased/decreased expression of one or more biomarker. The specification only provides support for a method for determining that a subject has or has an increased risk of MIEE based on the combination of each of the 15 genes.
Additionally it is highly unpredictable if the claimed method can be practiced using ANY reference levels. The claims broadly encompass a method wherein the references levels are the level of any transcript, in any sample type, obtained from any subject. However the teachings in the specification are limited to the analysis of the 15 biomarkers in samples obtained from subjects who experienced blunt trauma with ≤ 1 infection versus samples obtained from subjects who experienced blunt trauma with ≥2 infections. It is highly unpredictable if the 15 biomarkers will be differentially expressed when compared to ANY reference level encompassed by the claims.
The claims require calculating a score based on the transcript levels and comparing the score to a threshold/reference score, wherein a score about the threshold or reference score indicates that the subject has or has an increased risk of developing MIIE. Here the claims broadly encompass any method of calculating a score. The claims do not set forth any specific formulas for the score calculation. There are many different formulas known in the art for determining the required calculations. However it is highly unpredictable if one were to use other formulas for the calculations if they would be able to detect a subject who has or is at risk of having MIIE.
Finally it is highly unpredictable if the findings with human subjects could be extrapolated to non human subjects encompassed by the claims. Coleman (Drug Discovery Today. 2003. 8: 233-235) found that gene expression patterns between mice and humans 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 (page 234). Coleman concluded 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 transcript levels predictive of MIIE in humans will also work in the diverse genus of non-human subjects encompassed by the claims.
Quantity of Experimentation:
It is noted that the claimed methods encompass being able detect or predict the risk of developing MIIE in a subject who has experienced blunt trauma based on the transcript level of one or more of ZNF354A; EPPK1; RNASE1; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96; ARL4A; ZAP70; ERAP2; HGF; KLRF1; NEAT 1; and MME.
In order to practice the full scope of the invention, one would have to obtain a large number of subjects who experienced blunt trauma with and without MIIE. Then one of skill in the art would have to measure the level of each of ZNF354A; EPPK1; RNASE1; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96; ARL4A; ZAP70; ERAP2; HGF; KLRF1; NEAT 1; and MME in a blood, plasma, or serum sample obtained from the subjects. Then all the data would have to be analyzed to determine which single biomarker and which combinations of biomarkers can reliably be used to separate patients that had MIIE from patients that did not have MIIE. 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.
Claim Rejections - 35 USC § 102
6. 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.
Claims 1-2, 6-8, 8-10, and 16-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Thompson (Critical Care Medicine June 2014 Vol 42 No 6).
As noted in MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” In the present situation, the process steps are able to stand alone and the preamble limitation is not accorded patentable weight. Accordingly, the claim language of “A method of detecting or predicting risk of developing MIEE in a subject who has experienced blunt trauma” merely sets forth the purpose of the process, but does not limit the scope of the claims.
Regarding Claims 1 and 2 Thompson teaches that total leukocyte gene expression was compared between the subjects in whom Gram-negative bacteremia developed and those in whom it did not develop. We observed that Gram-negative bacteremia was an independent risk factor for death (odds ratio, 1.86; p = 0.015). We then compared gene expression at 12 and 96 hours after injury in 10 subjects in whom subsequently Gram-negative bacteremia developed matched to 26 subjects in whom it did not develop. At 12 hours, expression of 64 probes differed more than or equal to 1.5-fold; none represented genes related to innate or adaptive immunity. By 96 hours, 102 probes were differentially expressed with 20 representing 15 innate or adaptive immunity genes, including down-regulation of IL1B and up-regulation of IL1R2, reflecting suppression of innate immunity in Gram-negative bacteremia subjects. We also observed down-regulation of adaptive immune genes in the Gram-negative bacteremia subjects (abstract). Thompson further teaches that patient samples were collected and applied to the Affymetrix U133 plus 2.0 Gene Chip platform (page 1398). It is a property of this microarray that it comprises probes which detect each of ZNF354A; EPPK1; RNASEl; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96;ARL4A; ZAP70; ERAP2, HGF; KLRF I; NEAT 1; and MME. Thus Thompsan teaches a method comprising providing a sample comprising leukocytes (which are derived from blood samples) from a subject who has experienced blunt trauma; detecting a level of each of ZNF354A; EPPK1; RNASEl; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96;ARL4A; ZAP70; ERAP2, HGF; KLRF I; NEAT 1; and MME and comparing the detected levels to reference levels (the transcript levels in subjects that did not develop MIEE).
While Thomposn teaches all of the active process steps, Thompson does not teach a correlation between ZNF354A; EPPK1; RNASEl; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96;ARL4A; ZAP70; ERAP2, HGF; KLRF I; NEAT 1; and MME and risk of developing MIIE. However this art rejection is set forth because it teaches a broad interpretation of the claims which does not require such a correlation. In the instant case the preamble is considered to be an intended use of the claimed method. Further the “wherein” clause that recites that the presence of: an increase in one or more of: HGF; KBTBD7; ADORA3; ARL4A; EPPK1; ZNF354A; SH3PXD2B; RNASE1, or BTBD19, or a decrease in one or more of: ZAP70; ERAP2; CD96; MME; KLRF 1; NEAT1, indicates that the subject has, or has an increased risk of developing, MIIE is not limiting because claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed. This rejection could be overcome by amending the claim to recite an active process step of requiring the correlation e.g., detecting or predicting risk of developing MIIE based on the transcript levels of the recited genes.
Regarding Claim 6 Thompson teaches a mehtod wherein the infection is with Gram negative bacteria (abstract).
Regarding Claim 7 Thompson teaches that the subjects were treated with nutrional support (page 1398, col 1).
Regarding Claim 8 Thompson teaches that the subjects are human (page 1398).
Regarding Claims 9 and 10 Thompson teaches that total leukocyte gene expression was compared between the subjects in whom Gram-negative bacteremia developed and those in whom it did not develop. We observed that Gram-negative bacteremia was an independent risk factor for death (odds ratio, 1.86; p = 0.015). We then compared gene expression at 12 and 96 hours after injury in 10 subjects in whom subsequently Gram-negative bacteremia developed matched to 26 subjects in whom it did not develop. At 12 hours, expression of 64 probes differed more than or equal to 1.5-fold; none represented genes related to innate or adaptive immunity. By 96 hours, 102 probes were differentially expressed with 20 representing 15 innate or adaptive immunity genes, including down-regulation of IL1B and up-regulation of IL1R2, reflecting suppression of innate immunity in Gram-negative bacteremia subjects. We also observed down-regulation of adaptive immune genes in the Gram-negative bacteremia subjects (abstract). Thompson further teaches that patient samples were collected and applied to the Affymetrix U133 plus 2.0 Gene Chip platform (page 1398). It is a property of this microarray that it comprises probes which detect each of ZNF354A; EPPK1; RNASEl; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96;ARL4A; ZAP70; ERAP2, HGF; KLRF I; NEAT 1; and MME. Thus Thompsan teaches a method comprising providing a sample comprising leukocytes (which are derived from blood samples) from a subject who has experienced blunt trauma; detecting a level of each of ZNF354A; EPPK1; RNASEl; BTBD19; ADORA3; KBTBD7; SH3PXD2B; CD96;ARL4A; ZAP70; ERAP2, HGF; KLRF I; NEAT 1; and MME.
Regarding Claim 16 Thompson teaches a method wherein gene expression levels were determined using the Affymetrix U133 plus 2.0 Gene Chip (page 1398). Thus Thompson teaches a method wherein determining a level comprises microarray analysis (page 1398).
Regarding Claim 17 Thompson teaches that they compared gene expression at 12 and 96 hours after injury in 10 subjects whom subsequently Gram-negative bacteremia developled matched to 26 subjects in whom it did not develop (abstract). Thus Thompson teaches a methdo wherein the sample is obtained from the subject within 48 hours of the blunt trauma.
Regarding Claim 18 Thompson teaches that they compared gene expression at 12 and 96 hours after injury in 10 subjects whom subsequently Gram-negative bacteremia developled matched to 26 subjects in whom it did not develop (abstract). In the instant case the word subsequently has been interpreted to mean afterwards. Thus the 10 subjects are being interpreted as not having clinical signs of an infection when the sample was obtained since the bactermia did not develop until afterwards.
Claim Rejections - 35 USC § 103
7. 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.
Claims 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson (Critical Care Medicine June 2014 Vol 42 No 6) in view of Lancaster (PG PUB US 2015/0140124 Pub 5/21/2015).
The teachings of Thompson are presented above.
Thompson does not teach a method further comprising calculating a score based on the levels (clm 13). Thompson does not teach a method wherein the score is calculated using an algorithm comprising summation or weighted summation of normalized levels of the biomarkers (clm 14). Thompson does not teach a method wherein the score is calculated using principal components analysis (PCA), linear regression, support vector machine (SVM), decision trees, K-nearest neighbors (KNN), K-means, gradient boosting, or random forest methods (clm 15).
However Lancaster teaches a method of a method of diagnosing cancer comprising: obtaining an expression level of at least one Bcl-2 antagonist of cell death (BAD) pathway gene in a sample suspected of being cancerous or pre-cancerous; using the expression level of the at least one Bcl-2 antagonist of cell death (BAD) pathway gene to obtain a BAD Pathway Gene Expression Signature (BPGES) score of the sample using Principal Component Analysis (PCA); obtaining an expression level of a control; using the expression level of the control to obtain a BAD Pathway Gene Expression Signature (BPGES) score of the control; and comparing the BPGES score of the sample suspected of being cancerous or pre-cancerous to the BPGES score of the control sample. A lower BAD Pathway Gene Expression Signature (BPGES) score for the sample suspected of being cancerous or pre-cancerous as compared to the control sample is indicative of cancer (para 0009). Lancaster further teaches that the term "BAD Pathway Gene Expression Signature Score" (BPGES) as used herein refers to a number generated using the first principal component of principal component analysis to reflect the overall expression profile for the BAD pathway. This number is a summation of the BAD pathway genes and is based on the assigned weights of each gene. Lancaster further teaches using software and an algorithm to calculate the PCA model (para 0053).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Thompson by using an algorithm comprising a weighted summation to calculate a score using PCA as suggested by Lancaster. Using PCA to generate scores for diagnostic purposes was routine in the art before the effective filing date of the claimed invention demonstrated by Lancaster. One of skill in the art would have been motivated to perfrom PCA analysis to achieve the well known benefits of such analysis like simplifying the data by removing redundance and noise.
Improper Markush Grouping Rejection
8. Claims 1, 2, 6-10, and 13-18 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 claims recite the following Markush groups:
determining a level of one, two, or more transcripts in a 15 probe set biomarker panel comprising or consisting of hepatocyte growth factor (HGF); kelch repeat and BTB domain containing 7 (KBTBD7); adenosine A3 receptor (ADORA3); ADP-ribosylation factor-like GTPase 4A (ARL4A); epiplakin 1 (EPPK1); zinc finger protein 354A (ZNF354A); SH3 and PX domains 2B (SH3PXD2B); RNase A family 1 (RNASE1), BTB domain containing 19 (BTBD19), zeta chain of T cell receptor associated protein kinase 70kDa (ZAP70); endoplasmic reticulum aminopeptidase 2 (ERAP2); CD96 molecule (CD96); membrane metallo-endipeptidase (MME); killer cell lectin-like receptor subfamily F, member 1 (KLRF 1); and/or non-coding transcript, nuclear paraspeckle assembly transcript 1 (NEAT1) (claim 1)
detecting a level of transcripts consisting of two, three, or more of hepatocyte growth factor (HGF); kelch repeat and BTB domain containing 7 (KBTBD7); adenosine A3 receptor (ADORA3); ADP-ribosylation factor-like GTPase 4A (ARL4A); epiplakin 1 (EPPK1); zinc finger protein 354A (ZNF354A); SH3 and PX domains 2B (SH3PXD2B); RNase A family 1 (RNASE1), BTB domain containing 19 (BTBD19), zeta chain of T cell receptor associated protein kinase 70kDa (ZAP70); endoplasmic reticulum aminopeptidase 2 (ERAP2); CD96 molecule (CD96); membrane metallo-endipeptidase (MME); killer cell lectin-like receptor subfamily F, member 1 (KLRF 1); and non- coding transcript, nuclear paraspeckle assembly transcript 1 (NEAT1) (claim 2)
These Markush groupings are 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:
MPEP 2117(II) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)).
MPEP 2117(II) further state that alternatives (1) share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class and (2) share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent in the context of the claimed invention.
MPEP § 2117(II)(A) states that “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”. Herein the members of the Markush grouping are all RNA transcripts. These do not belong to the same recognized physical or chemical class or to the same art-recognized class because there is no expectation from the art that each of the recited RNA transcripts 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.
MPEP § 2117(II)(B) states that “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 explained in subsection IIA above, the members of the Markush grouping may still be considered to be proper where the alternatives share a substantial structure feature that is essential to a common use. Again the members of the Markush grouping are all RNA transcripts. While they are all made up of nucleic acids, the structure of comprising nucleic acids is not essential to any asserted common use.
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.
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/AMANDA HANEY/ Primary Examiner, Art Unit 1682