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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/03/26 has been entered. Claims 1, 10, 14-15, 17 and 24-28 have been amended. Claim 7 has been canceled. Claims 2-3, 6, 8-9, 11-12 and 19-22 were previously canceled. Claims 25-28 remain withdrawn as being directed to non-elected inventions. Accordingly, claims 1, 4-5, 10, 13-18 and 23-24 are under examination.
Election/Restrictions
Applicant argues that the specification presents a unified invention and that claims 25-28 represent a subcombination of the methods recited in claims 1 and 17 and that Under MPEP 806.05(c), restriction between a combination and subcombination is improper where the combination requires the particulars of the subcombination. This argument is not found persuasive because the current application was submitted under 35. U.S.C 371 and is thus analyzed under unity of invention and not analyzed under 35. U.S.C. 111(a). Thus, the Applicants arguments directed to combination/subcombination are not germane. Further, as stated in the previous office action the original claimed methods require steps of comparing a reference and aiding in the risk assessment and initiation of treatment and claims 25-28 did not require these limitations. New claims 25-28 required steps of contacting a sample with binding agents and the originally filed claims did not require these limitations. Thus, there are different method steps with different purposes and different outcomes. Under Rule 13 Applicant is entitled to one product, one method of making and one method of using. Therefore, the restriction requirement has been maintained.
Withdrawn Rejections
All rejections of claims not reiterated herein, have been withdrawn.
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 10 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Ali et al (Clinica Chimica Acta, 460, 2016, pages 93-101) (submitted in the IDS filed 08/02/22) in view of Spanuth et al., (Clin Care 2017, 21 (Suppl 1): 58) and further in view of Yu et al (Medicine, June 2019, 98;23, pages 1-7).
Ali et al discloses a method for predicting sepsis wherein the method comprises detecting the amount of presepsin and PCT in a plasma sample obtained from a patient suspected of sepsis (e.g. abstract, pgs 93-94). Ali et al discloses that the levels of presepsin and PCT were significantly higher in subjects with SIRS and sepsis than that of healthy patients (reference) (e.g. pgs 95-96, 100). Ali et al discloses that both presepsin and PCT are valuable biomarkers for early sepsis diagnosis (e.g. pg 100). Ali et al discloses that the presepsin and PCT concentrations are significantly correlated with 28-day in-hospital mortality (e.g. pg 100). Ali et al discloses that the patient can be an ICU patient (e.g. pg. 94). Ali et al also discloses that the higher on admission presepsin/PCT level, the more adverse the outcome in septic patients and that this indicates that presepsin/PCT concentration on admission are significantly correlated with mortality in patients with sepsis (e.g. page 100).
Ali et al differs from the instant invention in failing to specifically teach the patient has a known qSOFA score of 0, 1, 2 or 3 (see claims 1, 10, 17, 24).
Spanuth et al teaches the determination of qSOFA in patients with sepsis and also determining the biomarker presepsin (e.g. page 15; P384). Spanuth et al teaches that qSOFA is not a stand alone criterion for risk assessment in sepsis and that by combining; qSOFA and presepsin improved the validity significantly (e.g. page 15; P384).
Yu et al teaches that there are 4 qSOFA classes which are 0, 1, 2 or 3 (p. 3; section 3.2 and page 4, Fig. 1). Yu et al teaches that it is known and conventional to combine biomarkers with qSOFA for improving sensitivity (e.g. abstract). Yu et al teaches calculating a Quick SOFA score for each patient (e.g. abstract) and then combining with that of a biomarker for aiding in assessment of the patient (e.g. abstract). Yu et al teaches determining a qSOFA score of 0, 1, 2, 3 in the patient (e.g. Figs 1-2).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate the determination of a qSOFA score of 0, 1, 2 or 3 for the patients and to include patients with a score of 0, 1, 2 or 3 with the presepsin and procalcitonin of Ali et al because Spanuth et al specifically teaches that qSOFA is not a stand alone criterion for risk assessment in sepsis and Spanuth et al teaches that combining qSOFA and presepsin improved the validity significantly and Yu et al shows that combining qSOFA with procalcitonin improves sensitivity in the assessment of sepsis and mortality. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating patients with 0, 1, 2 or 3 qSOFA scores in the method of Ali et al.
With respect to claim 18 as currently recited. As evidenced by Tian et al (Journal of Thoracic Disease, May 2019; 11(5), pages 2034-2040) a qSOFA score consists of only three criteria: Glasgow Coma Scale (GCS) <15, systolic blood pressure 100 mmHg and respiratory rate >22). Also, Spanuth et al (methods P384) shows this criteria. Thus, it is deemed the qSOFA score in the modified method of Ali et al is based on this criteria.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Ali et al in view of Spanuth et al., and Yu et al as applied to claims 1, 4, 10 and 17-18 above, and further in view of Jansen et al (US 2012/0179006).
See above for the teachings of Ali et al., Spanuth et al., and Yu et al.
Ali et al., Spanuth et al and Yu et al differ from the instant invention in failing to teach the administration of intravenous fluids.
Jansen et al teaches that patients diagnosed with or suspected of having sepsis are often admitted to the ICU (same as patient in Ali et al) for treatment such as the administration of intravenous fluids (e.g. para 0006).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate the administration of intravenous fluids such as taught by Jansen et al to the patient of Ali et al because Jansen et al shows that it is known and conventional to administer IV fluids to patients that have or are suspected of having sepsis and that are in the ICU. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating the administration of intravenous fluids such as taught by Jansen et al to the patient of Ali et al.
Claims 13-15 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Ali et al in view of Spanuth et al and Yu et al as applied to claims 1, 4, 10 and 17-18 above, and further in view of Iami et al (US 2013/0280252).
See above for the teachings of Ali et al., Spanuth et al and Yu et al.
Ali et al., Spanuth et al and Yu et al differ from the instant invention in failing to teach treatment for infection.
Iami et al teaches that it is known and conventional in the art to use biomarker measurements to provide for the decision of a treatment for a patient with sepsis and to administer this treatment to the patient (e.g. para’s 0005, 0017, 0021, 0027-0037). Iami et also teaches selecting the patient for treatment and thus teaches initiating a therapeutic measure (e.g. para’s 0026, 0035, 0040). Iami et al also discloses that a treatment such as an antibiotic (antimicrobial) or vasopressor can be given to the patient as the treatment (e.g. para 0068).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate steps of initiating and treatment such as taught by Iami et al for the patient in the modified method of Ali et al because Iami et al shows that it is known and conventional and teaches that this allows for a timely sepsis specific treatment (e.g. para 005). Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating steps of initiating and treatment such as taught by Iami et al for the patient in the modified method of Ali et al.
Claims 16 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Ali et al in view of Spanuth et al and Yu et al as applied to claims 1, 4, 10 and 17-18 above, and further in view of Blankenberg (US 2006/0105419).
See above for the teachings of Ali et al., Spanuth et al and Yu et al.
Ali et al., Spanuth et al and Yu et al differ from the instant invention in failing to explicitly teach the reference threshold amounts as recited.
However, it was recognized in the prior art that the sensitivity and specificity is a measure of the accuracy of a test, reflecting the number (if any) of false positives and false negatives. Furthermore, sensitivity and specificity may be adjusted by adjusting the value of a threshold or cutoff value, above which (or below which, depending on how a marker changes with the disease/condition) the test is considered to be indicative of one state or condition (e.g., diseased/condition) and below which the test is considered to be indicative of another state or condition (e.g., non-diseased). See Blankenberg et al at [0007], [0028], [0084]. Accuracy need not be 100%; however Blankenberg et al indicates that particularly preferred would be where both the sensitivity and specificity are at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, still more preferably at least about 90%, and most preferably at least about 95% [0028].
The teachings of Blankenberg et al indicate that the sensitivity and selectivity of a diagnostic test was known to be a result-effective variable, impacting the number of individuals who are correctly diagnosed with disease/condition. Furthermore, the teachings of Blankenberg et al indicate that it was known in the prior art to optimize tests for desired levels of sensitivity and specificity, by selecting appropriate threshold or cutoff values. Finally, Blankenberg et al clearly expresses that tests where both the sensitivity and specificity are at least about 80% would be viewed as particularly preferred.
Therefore, it would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate comparison to a control and to arrive at the claimed invention by optimizing cutoff levels in order to achieve a desired sensitivity and specificity, given that such percentages were recognized in the art to be particularly preferred for diagnostic tests. One skilled in the art would have been motivated to select such threshold levels for sensitivity and specificity out of the course of routine optimization, given that these measures of test accuracy were recognized in the prior art to be result-effective variables that impact the number of false negatives and false positives for the test. Finally, one skilled in the art would have had a reasonable expectation of success in arriving at the claimed threshold for sensitivity and specificity since means of achieving desired sensitivity and specificity were known, namely by selecting an appropriate threshold or cutoff level (as taught by Blankenberg et al). It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation.” Application of Aller, 220 F.2d 454,456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation .” Id. At 458,105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” Application of Boesch, 617 F.2d 272,276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
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, 4-5, 10, 13-18 and 23-24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and/or to laws of nature/natural phenomena without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims are directed to a naturally occurring correlation between the amounts of the recited biomarkers and a qSOFA score in a subject suspected of sepsis compared to a reference amount.
Step 2A, Prong 2
The additional elements of detecting an amount of Presepsin and Procalcitonin in a sample from a subject having a qSOFA score of 0, 1, 2 or 3 and comparing the amounts to reference amounts does not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Also, with respect to the recitation “aiding in the risk assessment of a patient with suspected sepsis”. The “aiding” statement at best articulates the judicial exception, amounting only to a general instruction to apply or use the judicial exception. This could read on mental activity being performed solely in a practitioner’ head, e.g. A mental appreciation of the detected biomarkers being correlated with a subject with suspected sepsis. No active method steps are invoked or clearly required; the “aiding” statements do not include any activity that would constitute a practical application, i.e. steps that apply, rely on or use the natural principle in a manner such that the claims amount to significantly more that the natural principal itself.
Also, with respect to the recitations “initiating suitable therapeutic measure….”. As recited in new claim 24 the “initiating” statement at best articulates the judicial exception, amounting only to a general instruction to apply or use the judicial exception. The “initiating a suitable therapeutic measure” could read on the thought that the therapy needs to be given or recommend therapy as the first step, thus to set going and begin a treatment without actually giving the treatment. No active method steps are invoked or clearly required; the “initiating” statement does not include any activity that would constitute a practical application, i.e. steps that apply, rely on or use the natural principle in a manner such that the claims amount to significantly more that the natural principal itself. As in Mayo, there is no requirement that a doctor act on the results of the method. Thus, the steps in addition to the judicial exception(s) do not do more than describe the judicial exception(s) with general instructions.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
Further, the additional elements of the claims are recited with a high level of generality and do not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. (the active method steps/limitations recited in addition to the judicial exceptions themselves) and do not add significantly more to the judicial exception(s).
As shown the art supra it is well known routine and conventional in the art determine an amount of Presepsin and Procalcitonin in a sample from a subject having a qSOFA score of 0, 1, 2 or 3 and comparing the amounts to reference amounts.
It does not appear to be the case that the active steps recited, which are performed in order to gather the data or perform the assay, are steps recited or performed in an unconventional or non-routine way, such to provide an inventive concept under step 2B.
The claimed limitations as currently presented fail to recite limitations that add a feature that is more than well understood, conventional or routine in the field of diagnostics and biochemical assay methodologies.
For all of these reasons, the claims fail to include additional elements that are sufficient to either integrate the judicial exception(s) into practical application(s) thereof, or amount to significantly more than the judicial exception(s).
Response to Arguments
Applicant's arguments filed 03/03/26 have been fully considered but they are not persuasive.
101 rejections:
Applicant argues that claim 24 recites “treating the patient” in the preamble and “initiating a suitable therapeutic measure” with specific enumerated treatments including administration of antimicrobial agents, fluid resuscitation, vasopressors, corticosteroids, renal replacement therapy, and mechanical ventilation. Applicant states that claims 14 and 15 similarly recite specific therapeutic measures. The applicant then argues that the “initiating” statement interpretation by the Office is inconsistent with the plan claim language and controlling Federal Circuit precedent. The Applicant then directs the Examiner to Vanda Phamaceutical Inc. v. West-Ward Pharmaceuticals 887 F. 3d 1117 (Fed Cir. 2018) and states that claim 24 follows the Vanda pattern.
This argument is not found persuasive because Claim 24 does not follow the Vanda pattern because in Vanda a low dose drug was specifically administered. In the instant claims the broadest reasonable interpretation of “initiating a suitable therapeutic measure” could read on telling or recommending the administration of a therapy (see also claim 13). Thus, the claim as currently recited does not provide an actual intervention such as administering the drug which was the case in Vanda. If the Applicant intends the administration of the therapy to the patient then perhaps the Applicant should recite it as such.
Applicant argues that Under Step 2B, whether a claim element or combination of elements is well-understood, routine and conventional to a skilled artisan in the relevant field is a question of fact and makes reference to Berkeimer v. HP Inc. 881 F.3d 1360, 1368 (Fed Cir. 2018). Applicant further argues that under Berkheimer mere disclosure in these references is legally insufficient and that the Office has not provided adequate evidentiary support for this factual determination.
This argument is not found persuasive because Berkeimer was not directed to a natural correlation or additional elements of the claim. In the instant 101 the steps of establishing a qSOFA score, detecting an amount of presepsin and procalcitonin in a subject are considered to be additional elements for gathering information. The prior art of record shows that these steps are well known, routine and conventional and have been shown by others in the field. In the instant case these additional elements do not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception and do not add significantly more to the judicial exception. Thus, Applicants arguments are not found persuasive.
Applicant argues that the Specification's Improvements Create a Factual Dispute.
In Berkheimer, the Federal Circuit held that "[t]he improvements in the specification, to the extent they are captured in the claims, create a factual dispute regarding whether the invention describes well-understood, routine, and conventional activities." 881 F.3d at 1369.
The specification discloses that the claimed combination achieves:
AUC improvement from 0.801 (qSOFA alone) to 0.852 (qSOFA + Presepsin + PCT)
Sensitivity improvement from 68.42% to 89.47%
NPV improvement from 92.2% to 96.7%
Bidirectional refinement: identifying missed at-risk patients in low qSOFA scores (37.5% of qSOFA = 0; 65.9% of qSOFA = 1) and ruling out over-treatment in high qSOFA scores (26% of qSOFA = 2; 12.5% of qSOFA = 3)
Specification, Example 2. These improvements are captured in the claims through the specific combination of Presepsin and PCT detection in patients with known qSOFA scores and the "and/or" interpretive algorithm. Moreover, the specific threshold values derived from Applicant's clinical study (Presepsin approximately 1,000 pg/mL, PCT approximately 2 ng/mL) and the bidirectional rule-in/rule-out algorithm are not disclosed in the prior art. The Office has not provided evidence that this specific implementation is conventional, and these improvements create a factual dispute that remains unresolved. See also Illumina, Inc. V. Ariosa Diagnostics, Inc., 952 F.3d 1367, 1378 (Fed. Cir. 2020) ("conventional separation technologies can be used in unconventional ways").
These arguments are not found persuasive because the additional elements recited in the claims do not apply, rely on or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception and just add insignificant extra-solution activity to the judicial exception. The limitations do not provide improvements to the technical field, do not apply or use the judicial exception to effect a particular treatment, do not apply the judicial exception with or by use of, a particular machine, do not effect a transformation or reduction of a particular article to different state or thing and do not apply or use 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. Thus, the currently recited claims are not indicative of integration into a practical application.
Applicant’s arguments with respect 103 rejections have been considered but are moot in view of the new grounds of rejection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY W COUNTS whose telephone number is (571)272-0817. The examiner can normally be reached M-F 7:00-4:00.
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/GARY COUNTS/ Primary Examiner, Art Unit 1678