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 Invention I (claims 1-15) and species (i) Staphylococcus and (ii) nucleic acid tumor biomarkers in the reply filed on March 12, 2026 is acknowledged. Applicant’s cancellation of claim 7 is acknowledged. Applicant’s amendments of claims 1, 3-6, 8-10, and 13 are acknowledged.
Claims 1-6 and 8-20 are currently pending.
Claims 14-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 12, 2026.
Priority
Claim to benefit of provisional applications 63/433,391 and 63/587,266 is acknowledged and the effective filing date of the instant application is considered to be December 16, 2022.
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.
Claim(s) 1-6 and 8-13 is/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 claims are drawn to methods of predicting onset of sepsis using microbial biomarkers. Claim 1 recites the steps of: obtaining lymphatic fluid; measuring an amount of a microbial biomarker in the lymphatic fluid; and predicting sepsis onset on the basis of the measured amount.
Claim 2 recites that the measuring step comprises sequencing microbial ribosomal nucleic acid and identifying a bacterial class, order, family, genus, or species.
Claims 3 and 4 recite that the method comprises further steps of measuring the biomarker at two different times and detecting a change in the amount of the microbe.
Claim 9 recites a further step of culturing the microbe
Claim 10 recites a further step of selecting an antibiotic against the microbe.
Claims 11-13 recite further steps of measuring a tumor biomarker.
The claimed microbial biomarker is required to possess certain characteristics in order to perform the method as recited. It must be capable of being measured in lymphatic fluid and the amount of it must be correlated with the onset of sepsis. It must be associated with a microbe which is culturable, and present in a sample which also contains tumor biomarkers.
In the instant case, claims 1-6 and 8-13 do not set forth microbial biomarkers in terms of sufficient relevant identifying characteristics. Claim 2 describes more specific microbial biomarkers in the form of microbial ribosomal nucleic acid, but does not specify a particular microbe.
The size of the genus is very large, encompassing microbial biomarkers which exhibit a wide variety in origin, structure, and function. The genus includes a subject’s endogenous biomarkers which indicate response to the presence of bacteremia, including nucleic acids (such as epigenetically modified DNA, mRNA, miRNA, etc.) and proteins/polypeptides (such as interleukin levels, procalcitonin, etc.). The genus also includes markers originating from a microbe, including nucleic acids (such as 16S ribosomal sequences specific to the microbe) and proteins/polypeptides (such as hyaluronic acid or toxins). Claim 2, which restricts the type of microbial biomarker to microbial ribosomal nucleic acid, still encompasses a large genus – there are many microbial species, not all of which are associated with sepsis onset.
The specification allows for any type of microbial biomarker (par. 102, 105), but examples are provided only for 16S ribosomal rRNA. The specification does not describe any structural features of the disclosed biomarkers (16S sequences) which would have been expected to be shared by members of the claimed genus (biomarkers). The specification does not describe physical and/or chemical characteristics of the disclosed 16S sequences that would be shared by members of the claimed genus. All members of the genus have the same function, i.e., they are measurable in lymphatic fluid, correlated with the onset of sepsis, associated with a culturable microbe, and present in combination with tumor biomarkers. However, no correlation between their structural features or physical/chemical characteristics is disclosed. The level of knowledge and skill in the art does not allow those skilled in the art to envisage or recognize additional members of the claimed genus. Because the structure of the species within the claimed genus is expected to vary unpredictably from the structure of the 16S sequences disclosed in the specification, the disclosed 16S sequences are not a “representative number” of species within the claimed genus.
Because the 16S sequences are not representative of the entire claimed genus, and the specification does not disclose structural features or physical/chemical characteristics shared by members of the genus, the description of the 16S sequences would not have put the applicant in possession of common structural features or physical/chemical characteristics shared by members of the genus that structurally distinguish the members of the genus from non-members of the genus at the time of filing. Thus, the description of 16S sequences is not sufficient to describe the claimed genus of microbial biomarkers. Accordingly, the specification does not provide a representative number of species or sufficient common structural features to show that the applicant would have been in possession at the claimed genus as a whole at the time of filing.
Claim(s) 1-6 and 8-13 is/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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Scope of the Claims/Nature of the Invention
The claims are drawn to a method of predicting onset of sepsis on the basis of a measured amount of a microbial biomarker in lymphatic fluid. In view of the non-limiting claim language, the claims broadly encompass ANY type of sample containing lymphatic fluid (i.e. surgical drain fluid, fine needle aspirate, biopsied lymph nodes, etc.). In view of the non-limiting claim language, the claims broadly encompass ANY human or non-human subject, with or without any disease or having any risk for the development of sepsis.
The claims recite a first step of obtaining lymphatic fluid.
The claims recite a second step of measuring an amount of a microbial biomarker in the lymphatic fluid. In view of the recitation of “an amount,” the claims broadly encompass ANY amount, including the presence of any level of the microbial biomarker or the absence of the microbial biomarker. In view of the recitation of “a microbial biomarker,” the claims broadly encompass ANY microbial biomarker. It is noted that microbial biomarker can be interpreted to include any polypeptide, any nucleic acid, and any other molecule which indicates the presence of a microbe.
The claims recite a third step of predicting sepsis onset on the basis of the measured amount of the microbial biomarker. The claims broadly encompass a method wherein any amount (including even absence of a microbial biomarker) can be used to predict onset of sepsis.
Claim 3 recites additional steps of measuring the microbial biomarker at two different times and detecting ANY change in the amount of the microbial biomarker.
Claim 9 recites the additional step of culturing the microbe.
Claim 10 recites a further step of selecting an antibiotic against the microbe.
Claims 11-13 recite additional steps of measuring a level of a tumor biomarker in the lymphatic fluid.
The nature of the invention requires reliable correlations between ANY measured amount of ANY microbial biomarker in ANY sample containing lymphatic fluid and the onset of sepsis.
Teachings in the Specification and Examples
The specification states that probing surgical drain fluid can give an early indication of the development of sepsis (par. 102-109). The specification states that the detection of “sepsis-associated or pathogenic bacteria” in surgical drain fluid correlates with development of sepsis, and that increasing levels of a biomarker specific to a pathogenic bacterium is predictive of sepsis. No evidence is provided to support these statements. The specification teaches a method which comprises sequencing 16S ribosomal rRNA (par. 102) from surgical drain fluid, and identifying one or more genera/species of bacteria (par. 103).
Microbial metagenomics of this kind were performed for eight patients with HPV-head and neck cancer: drain fluid was obtained, 16S sequences were determined, and genus-level taxonomy was identified (par. 104). Figure 14 shows the relative abundance of several genera of bacteria for 6 of the 8 patients, with labels indicating genera which are known to be potentially pathogenic as well as ‘normal, healthy flora.’ The specification states that the data suggest “that drain fluid may be used for monitoring surgical site infection.” No evidence is given to support that statement.
Although the specification states that the disclosed method of predicting onset of sepsis using surgical drain fluid is predictive of bacterial infection and sepsis earlier than other assays, no data is shown comparing the method to other assays. While the specification states that the “SSI” (or surgical site infection) outcomes for each patient were known, the SSI status of the patients in Figure 14 is not indicated in the instant application’s disclosure, and no data is shown regarding the correlation between the presence of ‘pathogenic’ genera of bacteria and the onset of sepsis.
State of the Art and the Unpredictability of the Art
While methods of measuring microbial biomarkers are known in the art, methods of correlating microbial biomarkers with a phenotype such as the onset of sepsis are highly unpredictable. The unpredictability will be discussed below.
The claims are drawn to methods of predicting onset of sepsis based on measurements from ANY type of sample containing lymphatic fluid. The claims broadly encompass being able to predict sepsis in, for example, fine needle aspirate and core needle biopsy samples as well as in surgical drain fluid. However, the specification teaches only the measurement of microbial biomarkers from surgical drain fluid. Thomas (Thomas et al. (2013). Nature of axillary drainage fluid after axillary lymph node dissection in breast cancer. Clinical Cancer Investigation Journal, 2(2), 113-117) teaches that surgical drain fluid is composed of more than just lymphatic fluid (pg. 116, col. 1) and that the nature of surgical drain fluid can change over time (Abstract). Thus, it is highly unpredictable as to whether the findings in the specification regarding the amount of microbial biomarkers from surgical drain fluid could be extrapolated to samples containing lymphatic fluid derived from other sources.
The claims broadly encompass predicting onset of sepsis using microbial biomarkers in human subjects as well as non-human subjects. However, the specification’s data regarding microbial biomarkers is based on the analysis of samples obtained from human subjects. The prior art teaches that there is a large amount of unpredictability with regard to the development of sepsis (a systemic inflammatory response to bacterial infection) in humans and non-human animals. For example, Fink (Fink MP. Animal models of sepsis. Virulence. 2014 Jan 1;5(1):143-53) teaches that LPS is used in studies to simulate the activation of the immune system in response to infection and serve as a model for sepsis (pg. 148, col. 1, 2nd full par.). In mice (even those developed to be more sensitive to LPS challenge), it takes a much higher dose of LPS to induce toxic and lethal effects: i.e. the murine immune system is more resistant to developing sepsis-like symptoms in response to challenge with a bacterial antigen (pg. 148, col. 2). This relative insensitivity to bacterial challenge is true also of non-human primates such as baboons (pg. 150). These teachings support the finding that there is no predictable means for determining whether a microbial biomarker which is predictive of sepsis onset in humans will also be predictive of sepsis onset in a representative number of non-human subjects. The specification provide support only for human subjects.
The claims broadly encompass the use of ANY kind of microbial biomarker for predicting onset of sepsis. Note that the language ‘microbial biomarker’ broadly encompasses any molecule measured in a sample which indicates the presence of a microbe (including fungi, viruses, bacteria, and parasites). However, the specification’s data regarding the type of microbial biomarker are limited to the sequencing of 16S ribosomal rRNA and the detection of sepsis-associated or pathogenic bacteria. The prior art teaches that there is a large amount of unpredictability with regard to the reliability of the use of microbial biomarkers, and also regarding the presence of any given species/genus of bacteria and the development of sepsis. First, note that not all microbial biomarkers are equally reliable for detection of microbes. For example, Franco-Duarte (Franco-Duarte et al. Advances in Chemical and Biological Methods to Identify Microorganisms-From Past to Present. Microorganisms. 2019 May 13;7(5):130) teaches that phenotypic markers (as would be used in traditional and common culturing methods) are not always useful for unambiguous identifications (pg. 3), but molecular methods such as 16S rRNA sequencing can be highly precise (identifying to species level), especially when bacteria are difficult to grow in laboratory conditions (pg. 13, 1st par.). Furthermore, Siggins (Siggins et al. Extracellular bacterial lymphatic metastasis drives Streptococcus pyogenes systemic infection. Nat Commun. 2020 Sep 17;11(1):4697) teaches that the presence or even lymphatic metastasis of bacteria such as Streptococcus pyogenes (generally considered a ‘pathogenic’ bacterial species) in a subject is very rarely associated with invasive and severe infections in humans (pg. 7 – pg. 8: Discussion). Although the instant application’s specification mentions that samples were taken from patients with known surgical site infection outcomes (par. 104), the specification does not provide any data regarding the correlation between the presence of any given microbe and the development of sepsis. Therefore, it is unpredictable as to whether 16S rRNA sequencing, as presented in claim 2 and the specification, would be concordant with microbial identification made using ANY microbial biomarker. Furthermore, it is unpredictable as to whether detecting even known pathogens such as Staphylococcus in surgical drain fluid, as determined by sequencing of 16S rRNA, would be predictive of sepsis onset.
The claims recite a correlation between ANY amount of a microbial biomarker and sepsis onset. Claims 3 and 4 require that the amount exhibits ANY change over two timepoints. Note that there is no information given regarding criteria for declaring a bacterium present in sample (i.e. there are no disclosed thresholds or cutoffs for declaring a positive result from sequencing data). The claims encompass scenarios in which decreases in expression, low expression, or even the absence of a microbial biomarker is associated with sepsis onset. The specification only teaches that the presence of a microbial biomarker is detectable in lymphatic fluid. Therefore, correlation to sepsis onset of ANY amount or ANY change of amounts of a microbial biomarker is unpredictable and must be obtained before the skilled artisan could practice the claimed invention.
Claim 9 requires the culturing of ANY microbe detected from lymphatic fluid. However, Franco-Duarte demonstrates that not all microbes which can be detected or measured from a biological sample are culturable (Table 1). The specification provides no examples of culturing microbes and no explanation of methods which could be used to culture microbes. Therefore, the culture of any microbe detected by the method would be unpredictable.
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 predict sepsis onset by measuring ANY amount of ANY microbial biomarker from ANY sample containing lymphatic fluid from ANY human or non-human subject and culturing ANY microbe present in the sample.
In order to practice the breadth of the claimed invention one of skill in the art would first have to gather a representative number of types of lymphatic fluid samples from human and non-human subjects. The amount of a representative number of microbial biomarkers would have to be measured in a plurality of subjects, at multiple time points, and subject would have to be followed to determine if they developed sepsis or not. Then, sophisticated data analysis would have to be conducted to determine which biomarkers and which amounts of each biomarker would be predictive of the onset of sepsis. 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.
Claim(s) 3-5, 9, 10, and 13 is/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 3-5, 9, 10 are rejected for the recitation of “the microbe,” as lacking antecedent basis. The claim on which they depend (claim 1) does not recite “a microbe” and there could be several microbes or no microbes present in the lymphatic fluid. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claim 4 is rejected for the recitation of “the patient,” as lacking antecedent basis. The claim on which it depends (claim 1) does not recite “a patient,” and it is unclear whether “the patient” of claim 4 is the origin of the lymphatic fluid obtained in claim 1. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claim 13 is rejected for the recitation of “the nucleic acid,” as lacking antecedent basis. The claims on which it depends (claims 12 and 1, specifically) allow for embodiments in which there are a plurality of nucleic acids present in the sample (tumor-, microbe-, and host-derived), and thus it is unclear which nucleic acid(s) is/are meant to be sequenced in this step. If what is required by claim 13 is that the tumor-derived nucleic acid is sequenced, the claim must be amended to reflect that meaning.
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 1-6 and 8-13 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 microbial biomarkers in lymphatic fluid and the onset of sepsis. 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 “predicting” sepsis onset based on an amount of a microbial biomarker. Neither the specification nor the claims set forth a limiting definition for “predicting.” The broadest reasonable interpretation of the “predicting” step is that it may be accomplished by a mental process. For example, one may “predict” sepsis onset by thinking about the amount of the microbial biomarker. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Claim 2 recites a step of “identifying” a bacterial class, order, family, genus, or species. Neither the specification nor the claims set forth a limiting definition for “identifying” and the claims do not set forth how this step is accomplished. The broadest reasonable interpretation of the “identifying” step is that it may be accomplished by a mental process. For example, one may “identify” a bacterial genus by looking at sequencing data and thinking. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Claims 3 and 4 recite a step of “detecting” a change in an amount of a microbe. Neither the specification nor the claims set forth a limiting definition for “detecting” and the claims do not set forth how this step is accomplished. The broadest reasonable interpretation of the “detecting” step is that it may be accomplished by a mental process. For example, one may “detect” a change by thinking about the amounts of microbial biomarker obtained at two different times. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Claim 10 recites a step of ”selecting” an antibiotic against a microbe. Neither the specification nor the claims set forth criteria for selection and the claims do not set forth how this step is accomplished. The broadest reasonable interpretation of the “selection” step is that it may be accomplished by a mental process. For example, one may “select” the antibiotic by looking at the amount of the microbial biomarker and deciding which antibiotic to administer. 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” lymphatic fluid. 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” an amount of a microbial or tumoral biomarker. Claims 2 and 13 recite that the measuring comprises “sequencing.” Claims 11-13 require an additional measurement of a level of a tumor biomarker. These steps are not considered to integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exceptions.
In addition to the judicial exceptions, claim 9 recites a step of “culturing” the microbe. 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” lymphatic fluid, “measuring” an amount of a biomarker, “sequencing” nucleic acid, and “culturing” a microbe. 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. Obtaining lymphatic fluid, measuring biomarkers, sequencing nucleic acids, and culturing microbes merely instruct a scientist to use any known technique for obtaining lymphatic fluid, measuring biomarkers, sequencing nucleic acids, and culturing microbes. 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 this step from well-understood, routine, and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well-understood, routine, 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.
It is noted that claims rejected in this portion of the Office Action under 35 USC 102 and 103 as anticipated by, or obvious in view of, the prior art have been previously rejected in this Office Action under 35 USC 112(a) as not fully described or enabled by the specification as originally filed. In the instant case, where the prior art does anticipate and render obvious particular embodiments of the broadly claimed methods, the prior art is not sufficient to provide an adequate written description of the breadth of the claims, nor is the prior art sufficient to enable the skilled artisan to practice the claimed method in the full scope of the claims.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of pre-AIA 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) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 1, 3-5, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Labugger et al. (published May 22, 2014; International Publication No. WO 2014/076286).
Labugger discloses methods of diagnosing or monitoring pathogen infections in bodily fluids (Abstract).
Regarding claim 1, Labugger discloses obtaining lymphatic fluid (pg. 13, ln 28-30); measuring an amount of a microbial biomarker in the lymphatic fluid (pg. 8, ln 18-26; pg. 20, ln 25-30); and predicting sepsis onset on the basis of the measured amount (pg. 15, ln 21-30). Given that Labugger specifies that monitoring of infection includes embodiments in which measurements are taken in advance of the subject exhibiting outward signs of disease (pg. 27, ln 6-11), the reference is considered to anticipate the requirement for predicting sepsis onset.
Regarding claims 3 and 4, Labugger discloses measuring the microbial biomarker at two different times and detecting a change in the amount of the biomarker (pg. 10, ln 21 – pg. 11, ln 4).
Regarding claim 5, Labugger discloses Staphylococcus (pg. 31, ln 19-23).
Regarding claim 10, Labugger discloses selecting an antibiotic against the microbe (pg. 7, ln 26 – pg. 8, ln 5).
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).
Claim 2 is rejected under 35 U.S.C. 103 as unpatentable over Labugger et al. (published May 22, 2014; International Publication No. WO 2014/076286), as applied to claim 1 above, and further in view of Janda et al. (published July 11, 2007; Janda et al. 16S rRNA gene sequencing for bacterial identification in the diagnostic laboratory: pluses, perils, and pitfalls. J Clin Microbiol. 2007 Sep;45(9):2761-4).
Labugger teaches the limitations of claim 1, as discussed above.
Regarding claim 2, Labugger does not teach that the measuring step comprises sequencing microbial ribosomal nucleic acid and identifying a bacterial class, order, family, genus, or species.
Janda teaches sequencing microbial ribosomal nucleic acid and identifying a bacterial genus or species (pg. 2761, col. 1, 1st full par.). Here, the ribosomal nucleic acid is 16S rRNA. Note that due to taxonomical hierarchy, use of sequencing to identify genus or species also inherently entails an identification of class, order, and family.
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 Labugger and Janda. One would have been motivated to do so because sequencing of 16S rRNA provides high levels of genus-level identification even in cases of organisms which are difficult to identify using other means (pg. 2761, col. 1, 1st full par.).
Claims 6 and 8 are rejected under 35 U.S.C. 103 as unpatentable over Labugger et al. (published May 22, 2014; International Publication No. WO 2014/076286), as applied to claim 1 above, and further in view of Broggi et al. (published May 6, 2019; Broggi et al. Tumor-associated factors are enriched in lymphatic exudate compared to plasma in metastatic melanoma patients. J Exp Med. 2019 May 6;216(5):1091-1107)
Labugger teaches the limitations of claim 1, as discussed above.
Labugger does not teach that the lymphatic fluid is obtained by collecting surgical drain fluid from a site of surgery, nor that it is obtained via a drain positioned to collect the drain fluid from a surgical site where a tumor or lymph node has been removed.
Broggi teaches obtaining lymphatic fluid by collecting surgical drain fluid from a site of surgery, and obtaining it via a drain positioned to collect the drain fluid from a surgical site where a tumor or lymph node has been removed (pg. 1102, col.1, last par.).
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 Labugger and Broggi. One would have been motivated to do so because surgical drains are relatively easy methods of collecting lymphatic fluid, and allow for large volumes of material to be analyzed (pg. 1102, col. 1, last par.).
Claim 9 is rejected under 35 U.S.C. 103 as unpatentable over Labugger et al. (published May 22, 2014; International Publication No. WO 2014/076286), as applied to claim 1 above, and further in view of Jorgensen et al. (published Dec 1, 2009; Jorgensen et al. Antimicrobial susceptibility testing: a review of general principles and contemporary practices. Clin Infect Dis. 2009 Dec 1;49(11):1749-55).
Labugger teaches the limitations of claim 1, as discussed above.
Regarding claim 9, Labugger does not teach culturing a microbe generally, or for all embodiments of the reference’s invention.
Regarding claim 9, Jorgensen teaches culturing microbes (pg. 1750, col. 1, 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 Labugger with Jorgensen. One would have been motivated to so do in order to perform antimicrobial susceptibility testing in bacteria (pg. 1754, col. 1). This may be desired in cases where a pathogen is detected which may have multiple drug resistance, such as Staphylococcus aureus.
Claims 11-13 are rejected under 35 U.S.C. 103 as unpatentable over Labugger et al. (published May 22, 2014; International Publication No. WO 2014/076286), as applied to claim 1 above, and further in view of Thierry et al. (published March 3, 2012; European Patent No. 2,426,217).
Labugger teaches the limitations of claim 1, as discussed above.
Regarding claims 11-13, Labugger does not teach measuring a level of any tumor biomarkers, nor sequencing tumor nucleic acids.
Regarding claims 11 and 12, Thierry teaches measuring a level of a tumor biomarker in the form of nucleic acid (par. 27) in lymphatic fluid (par. 72).
Regarding claim 13, Thierry teaches sequencing a nucleic acid (par. 152).
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 Labugger and Thierry. One would have been motivated to do so in order to monitor the progression or regression of tumors (par. 1) using methods with unambiguous results (par. 152).
Conclusion
No claims are allowed.
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/C.M.J./Examiner, Art Unit 1682
/AMANDA HANEY/Primary Examiner, Art Unit 1682
