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 .
Election/Restrictions
2. In the response filed on November 17, 2025, Applicant elected Group I (claims 1-6). This election was made without traverse. In this response, Applicant also elected species A5 (development of infection and sepsis) as well as the following combination of markers: PAFAH2, SLC39A8, and TDRD9.
Applicant’s response of November 17, 2025 prompted an additional election of species requirement. This additional election of species requirement was mailed on December 17, 2025.
In the response of March 17, 2026, Applicant elected, with traverse, the following additional combination of markers: DHRS3, HLA-DMB, NABP1, PKIA, and TEX2.
The traversal is on the ground that the combination of markers recited in claims 1 and 6 constitutes a special technical feature linking the claims together (Remarks, page 4).
This is not found persuasive because the different species encompassed by the claims are not, in fact, linked to form a single general inventive concept. The different species must all share the three markers recited in claims 1 and 6, but the marker combinations encompassed by the claims that include these three markers contain 1-43 additional markers (see claims 2 and 9). The different combinations of markers necessarily have different functional properties (i.e., the ability to predict development of sepsis versus organ dysfunction versus infection versus some other condition). Therefore, the three markers recited in claims 1 and 6 do not constitute a general inventive concept that links the claims. Accordingly, the election of species requirement is still considered to be proper and is therefore made FINAL.
Claims 1, 3, 6, 10, 12, and 13 read on the elected invention and species. 1
Claims 2, 4, 9, and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on March 17, 2026.
Priority
3. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
4. The Information Disclosure Statement filed on March 16, 2023 has been considered.
Duplicate Claims
5. Applicant is advised that should claim 12 be found allowable, claim 13 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
In this case, claims 12 and 13 are identical. It appears that one of the claims was intended to depend from claim 1 rather than from claim 6.
Claim Interpretation
6. The specification states that “Sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, wherein organ dysfunction can be identified as an increase in the total sequential organ failure assessment (SOFA) score of >2 or more points from one day to the next following infection” (page 2, lines 10-13).
The specification states that this definition of “sepsis” is in contrast to the traditional definition, which is “a systemic inflammatory response syndrome (SIRS) in response to infection which, when associated with acute organ dysfunction, may ultimately cause severe life-threatening complications” (page 2, lines 8-10).
Claim Rejections - 35 USC § 101
7. 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, 6, 10, 12, and 13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Claims 1 and 6
Claim 1 is drawn to a method for predicting development of infection and/or organ dysfunction and/or sepsis in a subject that comprises measuring the levels of nucleic acid markers in a sample obtained from the subject. The markers comprise PAFAH2, SLC39A8, and TDRD9. Applicant has also elected “development of infection and sepsis” as the species of medical condition to be examined.
Claim 6 drawn to a method for monitoring a subject at risk of developing infection and/or organ dysfunction and/or sepsis in a subject that comprises measuring the levels of nucleic acid markers in samples obtained from the subject at multiple time points. The markers comprise PAFAH2, SLC39A8, and TDRD9. Applicant has also elected “development of infection and sepsis” as the species of medical condition to be examined.
Each of claims 1 and 6 recites a judicial exception—namely, the correlation between the measured levels of the aforementioned nucleic acid markers and the likelihood of developing infection and sepsis. The judicial exception recited in the claims is a natural law. Thus, the claims are directed to a judicial exception.
The judicial exception in claims 1 and 6 is not integrated into a practical application because the claim does not require using them in any sort of practical application (e.g., to treat a subject). Instead, the claims only recite the natural law and a step of measuring levels of the different nucleic acid markers in a biological sample(s) obtained from a subject.
Claims 1 and 6 also do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they only recite routine and conventional elements in combination with the natural law. More specifically, the claims only recite the additional elements of obtaining a biological sample(s) from a subject and measuring the level of various known nucleic acids. The teachings in the specification of the instant application indicate that these steps are routine and conventional (see, e.g., page 16, last para. – page 17, line 20; page 22, line 12 – page 23, line 11; and page 24, lines 10-23). See also the teachings of Spencer et al. (WO 2015/121605 A1; IDS reference) on pages 16-17 as well as the teachings of Brandon et al. (WO 2017/106918 A1) in paras. 80, 98, 133-156, and 225.
It is also noted that the additional elements recited in claims 1 and 6 do not integrate the judicial exception into a practical application because they merely indicate a field of use or technological environment in which to apply the judicial exception and also constitute only insignificant extra-solution activity. As discussed in MPEP 2106.04(d) I, such limitations do not integrate a judicial exception into a practical application. MPEP 2106.05(g) and 2106.05(h) discuss insignificant extra-solution activity and limitations that merely limit a judicial exception to a particular field or technological environment, respectively, and each section lists several examples of activities that have been found by the courts to constitute insignificant extra-solution activity or merely indicate a particular field of use or technological environment. Examples of insignificant extra-solution activity in MPEP 2106.05(g) include (1) performing clinical tests on individuals to obtain input for an equation, and (2) determining the level of a biomarker in blood. As well, MPEP 2106.05(h) notes that the question of whether a limitation merely limits a claim to a particular field of use or technological environment “overlaps significantly” with the question of whether a limitation is merely insignificant extra-solution activity. In this case, the additional elements in the instant claims correspond to activities (1) and (2) above. As such, they fail to integrate the judicial exception into a practical application.
Thus, claims 1 and 6 are rejected under 35 U.S.C. 101 as being directed to ineligible subject matter.
Claims 3 and 10
Claims 3 and 10 respectively depend from claims 1 and 6 and require the nucleic acid markers to further include DHRS3, HLA-DMB, NABP1, PKIA, and TEX2.
These claims recite a judicial exception for the same reason as claims 1 and 6. More specifically, the correlation between the measured levels of the nucleic acid markers and the likelihood of developing infection and sepsis is a natural law.
Claims 3 and 10 are not integrated into a practical application for the same reasons set forth above with respect to claims 1 and 6. As well, these claims do not contain any elements that would cause them to amount to significantly more than the judicial exception since they only further define the natural law by requiring analysis of additional nucleic acid markers.
Thus, claims 3 and 10 are also rejected under 35 U.S.C. 101 as being directed to ineligible subject matter.
Claims 12 and 13
Claims 12 and 13 are identical. Each claim depends from claim 6 and requires the measured levels of the nucleic acid markers to be predictive of the development of infection and sepsis in the subject.
These claims recite a judicial exception for the same reason as claims 6. More specifically, the correlation between the measured levels of the nucleic acid markers and the likelihood of developing infection and sepsis is a natural law.
Claims 12 and 13 are not integrated into a practical application for the same reasons set forth above with respect to claim 6. As well, these claims do not contain any elements that would cause them to amount to significantly more than the judicial exception since they only further define the natural law by requiring the measured levels of the nucleic acid markers to be predictive of the development of infection and sepsis in the subject.
Thus, claims 12 and 13 are also rejected under 35 U.S.C. 101 as being directed to ineligible subject matter.
Claim Rejections - 35 USC § 112
8. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 6, 10, 12, and 13 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 claims contain 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). These factors include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative
skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. Each of these factors is discussed below.
Nature of the Invention
Claims 1 and 3 are drawn to a method for predicting the development of infection and/or organ dysfunction and/or sepsis in a subject that comprises measuring the levels of nucleic acid markers in a sample obtained from the subject. The markers comprise PAFAH2, SLC39A8, and TDRD9 (claim 1) or PAFAH2, SLC39A8, TDRD9, DHRS3, HLA-DMB, NABP1, PKIA, and TEX2 (claim 3). Applicant has also elected “development of infection and sepsis” as the species of medical condition to be examined.
Claims 6, 10, 12, and 13 are drawn to a method for monitoring a subject at risk of developing infection and/or organ dysfunction and/or sepsis in a subject that comprises measuring the levels of nucleic acid markers in samples obtained from the subject at multiple time points. The markers comprise PAFAH2, SLC39A8, and TDRD9 (claims 6, 12, and 13) or PAFAH2, SLC39A8, TDRD9, DHRS3, HLA-DMB, NABP1, PKIA, and TEX2 (claim 10). Applicant has also elected “development of infection and sepsis” as the species of medical condition to be examined.
The claimed invention is classified in the unpredictable arts of molecular biology and biochemistry.
Relative Skill of the Ordinary Artisan
The ordinary artisan typically holds a graduate degree and has at least several years of post-graduate laboratory and/or clinical experience.
Breadth of the Claims
Several aspects of the claims are very broad. In particular, the subject is not limited and encompasses human and animal subjects. The sample is also not limited and encompasses any type of sample (e.g., blood, urine, saliva, other bodily fluids, and tissue samples). Still further, the sample, or samples in the case of claims 6, 10, 12, and 13, may be obtained at any time point prior to sepsis diagnosis. The number of nucleic acid markers used to predict the risk of developing infection and sepsis is also very small, ranging from just three markers in claims 1, 6, 12, and 13 to eight markers in claims 3 and 10.
State of the Prior Art
The prior art describes methods for measuring nucleic acid levels in samples obtained from a subject, including in the context of detecting sepsis. See, e.g., Hall et al. (WO 2018/060739 A2; IDS reference) (see, e.g., the abstract and pages 175-188). See also Zipfel et al. (US 2004/0259090 A1) (see, e.g., the abstract and Example 1 on page 4).
The prior art does not teach using the three markers recited in claims 1 and 6 or the additional markers recited in claims 3 and 10 to predict the development of infection and sepsis.
Guidance Presented in the Application & Working Examples
The specification contains guidance relevant to the claimed methods. In particular, the specification discloses methods for obtaining biological samples from subjects and measuring nucleic acid levels (see, e.g., pages 22-24).
The working example, which begin on page 21 and extends to the end of the specification, is also relevant to the claimed methods. Here, Applicant obtained blood samples from patients before elective surgery and at multiple time points after surgery and measured nucleic acid levels in said samples using microarrays (pages 22-24). The patients were divided into the following groups: (i) infection group, (ii) non-infective systemic inflammation (SIRS) group, and (iii) an uncomplicated post-operative recovery group. See page 24, first para. The infection group was further divided into those with and without organ dysfunction as defined by an increase of the patients SOFA score by 2 or more from one day to the next (i.e., infection or infection and sepsis) (page 24, first para.).
Applicant then identified (i) nucleic acids differentially expressed in patients who developed an infection compared to healthy post-operative controls, (ii) nucleic acids differentially expressed in patients with organ dysfunction (i.e., sepsis) compared to patients with a noncomplicated infection, and (iii) nucleic acids differentially expressed in patients with organ dysfunction (i.e., sepsis) and all other patients (page 25, last two paras.).2
Applicant then used the differentially expressed genes identified using microarray analysis to obtain various classifiers, including classifiers capable of predicting organ dysfunction (pages 26-32). The 16-gene classifier disclosed in the first paragraph of page 32 contains the three markers recited in claims 1 and 6, but it does not include all of the additional markers recited in claims 3 and 10. Table 1 on pages 32-35 shows the results obtained for classifiers containing subsets of the markers in the aforementioned 16-gene classifier, but none of these classifiers with fewer markers contains all three of the markers recited in claims 1 and 6.
On page 37, the specification identifies markers (i.e., “recurring genes”) that should be especially useful in classifiers for predicting organ dysfunction and goes on to identify 47 genes as the best candidates for differentiating patients with organ dysfunction from all other patients irrespective of the day of sample collection (pages 37-38). The recurring genes on page 37 and the 47 genes on page 38 include the three markers recited in claims 1 and 6 as well as the additional five markers recited in claims 3 and 10. On page 38, the example also teaches that 3-nucleic acid signature of PAFAH2, SLC39A8, and TDRD9 (i.e., the combination of markers in claims 1 and 6) for predicting organ dysfunction had an AUC of 0.864 (PPV 0.720), whereas the 8-nucleic acid signature of PAFAH2, SLC39A8, TDRD9, DHRS3, HLA-DMB, NABP1, PKIA, and TEX2 (i.e., the combination of markers in claims 3 and 10) had an AUC of 0.904 (PPV 0.800).
This teaching on page 38 of the specification provides evidence that the 3-nucleic acid signature recited in claims 1 and 6 and the 8-nucleic acid signature recited in claims 3 and 10 can predict organ dysfunction (i.e., the development of infection and sepsis) in blood samples obtained from a human subject, but it is not clear that this result will extend over the full scope of the claims (e.g., to nonhuman subjects and sample types other than blood samples), especially since the claims encompass a wide variety of nonhuman subjects and samples. It is also not clear from the discussion on pages 37-38 as to when the samples from which the data used to obtain the above 3-nucleic acid and 8-nucleic acid classifiers were obtained. The paragraph bridging pages 37 and 38 states that classifiers were obtained using data from samples obtained before the onset of symptoms of sepsis, with all days combined in one analysis, but it is not clear as to how many days before the onset of sepsis symptoms the samples were collected. That is, it is not clear whether data used to obtain the classifiers on page 38 was from samples collected (i) 1-3 days before clinical presentation of post-operative infection (i.e., as described on page 25); (ii) 1-3 days after infection diagnosis but before sepsis diagnosis (i.e., as described on page 26); or (iii) as in (i) and (ii) (i.e., as described on page 30).
Thus, although the specification provides some guidance as to the claimed methods, the claimed methods are much broader, and it is not clear that the results presented on page 38 will extend over the full scope of the claims. It is also not clear as to when the sample(s) must be collected from the subject for the 3-nucleic acid and 8-nucleic acid classifiers to successfully function to predict organ dysfunction as described on page 38.
Quantity of Experimentation & Unpredictability
In view of the limitations in the specification and prior art, the ordinary artisan would have to conduct a very large quantity of highly unpredictable experimentation to enable practice of the claimed methods. In particular, the ordinary artisan would have to determine that the claimed 3-nucleic acid and 8-nucleic acid classifiers function to predict the development of infection and sepsis in each of the many different nonhuman subjects and sample types encompassed by the claims. This experimentation would be highly unpredictable, especially with nonhuman subjects, given the differences in physiology between species. As well, different samples may not contain the required nucleic acids, which would preclude use of the claimed classifiers for those samples. And, results obtained for one sample or type of nonhuman subject may not extend to any other sample or nonhuman subject. The ordinary artisan would have to conduct this experimentation with minimal guidance from the specification and would have no guarantee of success. In addition, the ordinary artisan would have to determine which days preceding sepsis diagnosis are suitable for sample collection. As discussed above, it is not entirely clear as to when the samples from which the data used to obtain the 3-nucleic acid and 8-nucleic acid classifiers disclosed on page 38 were obtained. Therefore, the ordinary artisan would have to perform the complex and unpredictable experimentation described throughout the working example to determine when the sample(s) should be collected. Thus, a very large amount of complex and highly unpredictable experimentation would be required to practice the claimed methods.
In view of the foregoing, the instant claims 1, 3, 6, 10, 12, and 13 are not enabled.
Claim Rejections - 35 USC § 112
9. 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, 6, 10, 12, and 13 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.
In view of the species election, claims 1, 3, 6, and 10 require the levels of particular nucleic acid levels in a sample(s) obtained from a subject to be predictive of the development of infection and sepsis in the subject.
Claims 12 and 13 each depend from claim 6 and recite “wherein the measured levels of nucleic acid markers are predictive of development of infection and sepsis in the subject.”
The language “development of infection and sepsis in the subject” causes claims 1, 3, 6, 10, 12, and 13 to be indefinite because the reason for including “infection” is unclear. A subject with sepsis necessarily also has an infection as evidenced by, e.g., page 2 of the specification. Therefore, it is unclear why the claims require predicting development of “infection and sepsis” and not simply “predicting development of sepsis.” In other words, it is not clear whether the word “infection” in the phrase “development of infection and sepsis in a subject” is simply redundant or if some other meaning for the claim language is intended.
In view of the foregoing, claims 1, 3, 6, 10, 12, and 13 are indefinite.
Conclusion
10. No claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Angela Bertagna whose telephone number is (571)272-8291. The examiner can normally be reached 8-5, M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
1 Applicant’s response of March 17, 2026 states that claims 3, 4, 10, and 11 read on the elected species (Remarks, page 4). This is not correct because claims 4 and 11 require analysis of a non-elected combination of markers (i.e., the elected markers plus additional markers).
2 It is noted that the working example apparently uses the term “organ dysfunction” to refer to “sepsis,” where “sepsis” includes infection and organ dysfunction, based on the disclosure on page 24, where the “infection group” of patients is subdivided into patients with and without organ dysfunction, and there is not an “organ dysfunction without infection” group. See also the heading at the top of page 27. Applicant is invited to clarify if this is incorrect. The Office action uses “organ dysfunction” to refer to the elected species (sepsis and infection) since sepsis does not occur without an infection.
Prosecution Insights