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 .
Detailed Action
Summary
This is the Final Office Action for application 16/646799 response filed 01/30/2026.
Claims 1, 3-6, 13-15, 23 & 27 have been examined and fully considered.
Claim 27 was newly added.
Claims 2, 7-12, 16-26 are cancelled.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-6, 13-15, 23 & 27 are rejected under 35 U.S.C. 103 as being obvious over ANGELETTI "Diagnostic and prognostic role of procalcitonin
(PCT) and MR-pro-Adrenomedullin (MR-proADM) in bacterial infections"(as cited on IDS dated 03/12/2020) in view of MAZIER in Homogeneous time-resolved fluoro-immunoassay for the measurement of midregional proadrenomedullin in plasma on the fully automated system B.R.A.H.M.S KRYPTOR (cited in prior action) and even further in view of BOUADMA in Use of procalcitonin to reduce patient’s exposure to antibiotics in intensive care units (PRORATA) trial: a multi-centre randomized controlled trial.
With respect to Claim 1 ANGELETTI teaches of a method for antibiotic therapy guidance, stratification and/or control in a patient suffering from a bacterial infection, which can include sepsis or septic shock and receiving treatment with one or more antibiotic agents (abstract, Page 740, column 2, 2nd paragraph & Page 741, column 1, paragraph 1-3), the method comprising:
- Isolating a first sample from said patient on admission and at T=1 at 12-24 hours after admission (p. 741, col. 2, para. 4). The T =0 and/ or T=1 can be interpreted as the “first sample,” through broadest reasonable interpretation in the claim. T=1 is the first sample after antibiotic treatment, which is what applicant is claiming for “isolating a first sample,” and this also reads on the instantly claimed of the “the first sample is isolated upon determining symptoms od sepsis…and initiating treatment,”
- Isolating a second sample from said patient at a time point after isolating the
first sample and initiating antibiotic treatment, “within 36 hours after isolating the first sample” (p. 741, col. 2, para. 4). The T=3-5 days reads on the second sample with T=1 as the “fist sample,” through broadest reasonable interpretation (BRI) since one of these measurements would be “within 36 hours,” after isolating the first sample and beginning antibiotic therapy upon admission to the hospital,
- Determining/measuring levels of procalcitonin (PCT) or fragment(s) thereof in the first
and the second sample, and
- Determining/measuring a level of ADM or fragment(s) thereof in at least the second sample. The determinations are made by an analyzer and using binding assays (Specifically, Angeletti teaches that “procalcitonin and MR-proADM were measured in all patients at admission (time T=0), and at 12-24 h (time T=1) and in the third and fifth day of antibiotic therapy (time T=3-5)” (p. 741, column 2, paragraph 4).
ANGELETTI also teaches of the cut-off levels for PCT and Pro ADM being > .5ng/ml, and > 1.06 mmol/L respectively for sepsis and septic shock/severe sepsis (a critically ill state) and that anything higher than this is considered significant and indicates that the patient is affected with septic shock or severe sepsis (Table 3).
ANGELETTI teaches that anything greater than 1.06mmol/L for proADM being a significant indicator of sepsis. Greater than 1.06 mmol/L also encompasses the claimed range of “above 2.25 nmol/L,” and therefore measuring a level of proADM at 2.25 nmol/l being indicative that the patient still has sepsis and that further antibiotic treatment or a change in treatment is needed as claimed.
With respect to PCT, as claimed what is required in the claims is that the measured level in the second sample is greater than the measured level in the first sample. ANGELETTI teaches that procalcitonin/PCT is “significantly higher in sepsis than in localized infection,” (Page 743, column 1, paragraph 1)—however does not teach of what is claimed in that the second sample which is after antibiotic treatment having the PCT levels being higher than in the first sample.
ANGELETTI also teaches that the combination of PCT and ProADM can be used to “guide,” antibiotic therapy utilization (meaning adjustments/changes of therapy and any unnecessary antibiotic usage) and that PCT and ProADM together allow a physician to optimize clinical management of the infections (management includes treatment of with antibiotics) (Page 747, column 1, paragraph 4 & column 2, paragraph 3). ANGELETTI also teaches that using the two biomarkers ProADM and PCT together, adds information of the antibiotic therapy effectiveness and timing and also on the prognosis of the infections, which allow the clinician to optimize/change the clinical management (which includes treatment) of both localized and systemic bacterial infections (Page 747, column 2, paragraph 3).
ANGELETTI further teaches of performing the PCT and proADM measurements using “assays,” and specifically the assays for proADM and PCT in a reference they cite (23) which uses fluoroimmunoassays, that is the examiner’s second reference (the title refers to immunoassays). Therefore, ANGELETTI calls out commercially available assays, but do not specifically call out measuring by “immunoassay,” as claimed.
MAZIER et al. (or citation 23 in ANGELETTI and the examiner’s secondary reference) is used to remedy this and teaches of using fluoroimmunoassays to measure proadrenomedullin (abstract & title). Specifically, MAZIER teaches of binding the antibody/binder anti-MR-pro-ADM sheep polyclonal antibody is used to help detect (and would complex with proADM) (Introduction, paragraph 1 & Page 726, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use the immunoassay methods of MAZIER to detect the compounds in ANGELETTI due to the advantages of the immunoassay system of MAZIER has in that it is fully automated (MAZIER, Page 725, second column, second to last paragraph).
ANGELETTI and MAZIER teach of the above, but do not specifically call out if a PCT/ procalcitonin level measured is higher after antibiotic treatment, to optimize or change the treatment.
BOUADMA in used to remedy this and more specifically teaches of use of procalcitonin (PCT) and an algorithm based on procalcitonin to reduce antibiotic exposure in intensive care settings to help with the problem multidrug resistant bacteria (Page 463, title and background).
More specifically BOUADMA teaches that if levels above a certain level of procalcitonin are measured that antibiotics are encouraged (Page 465, Figure 1, top right box) and then if there is an increase in the concentration of procalcitonin compared with a peak concentration of it and with the threshold level then changing of antibiotics(dose or of adding antibiotic) is recommended (Page 465, Figure 1, bottom, right box). BOUADMA also teaches on Figure 1 other scenarios where stopping of antibiotics, or continuing/maintenance of antibiotics is recommended. BOUADMA also teaches of using kits in the analysis (Page 473, column 1, last paragraph).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use procalcitonin increasing levels as a way to recommend changes in or optimization of antibiotic treatments as is done in BOUADMA in the methods of ANGELETTI and MAZIER due to the advantage this offers in treating bacterial infections(of which sepsis is one of) and potentially reducing antibiotic exposure with no apparent adverse outcomes (BOUADMA, Page 463, interpretation section).
With respect to Claim 2, ANGELETTI teaches of isolating a first sample from said patient (p. 741, col. 2, para. 4, here: T0 and T=1),
- isolating a second sample from said patient at a time point after isolating the
first sample and initiating antibiotic treatment (p. 741, col. 2, para. 4, here: T=
3-5). As ANGELETTI also teaches of measuring at admission, from 12-14 hours after, and a few days after and also after antibiotic therapy(abstract), this makes measuring at any time obvious to one of ordinary skill in the art.
With respect to Claims 3-4, ANGELETTI teaches of measuring at admission, from 12-14 hours after, and a few days after and also after antibiotic therapy which reads on the instantly claimed second sample being isolated 12-36 hours after the first(abstract). As ANGELETTI also teaches of measuring at admission, from 12-14 hours after, and a few days after and also after antibiotic therapy(abstract), this makes measuring at any time obvious to one of ordinary skill in the art.
With respect to Claims 5 & 23 ANGELETTI teaches of the patient having septic shock/sepsis (abstract).
With respect to Claim 6, ANGELETTI teaches of measuring the levels of MT-proADM(abstract).
With respect to Claim 13, ANGELETTI teaches of using blood samples (Page 741, column 1, paragraph 2).
With respect to Claim 14, ANGELETTI and MAZIER teach of the above, but do not teach of the claimed measurement of lactate or C-reactive protein.
BOUADMA is used to remedy this and teaches of measurement of serum lactate and c-reactive protein (Table 1, left column, half of the way down). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to measure serum lactate as is done in BOUADMA in the methods of ANGELETTI and MAZIER due to the advantage measuring additional biomarkers has in the formation of a score for indication of diseases and since the used biomarkers are known to be associated with infection (Page 466, column 1, paragraph, Page 467, column 1, paragraphs 1-2 & Table 1).
With respect to Claim 15, ANGELETTI et al. teaches of using APACHE II (Page 741, column 2, paragraph 3). BOUADMA also teaches of using SOFA (Page 465, column 1, last paragraph).
With respect to Claim 27, ANGELETTI teaches of a method for antibiotic therapy guidance, stratification and/or control in a patient suffering from a bacterial infection, which can include sepsis or septic shock and receiving treatment with one or more antibiotic agents (abstract, Page 740, column 2, 2nd paragraph & Page 741, column 1, paragraph 1-3), the method comprising:
- Isolating a first sample from said patient on admission and at T=1 at 12-24 hours after admission (p. 741, col. 2, para. 4). The T =0 and/ or T=1 can be interpreted as the “first sample,” through broadest reasonable interpretation in the claim. T=1 is the first sample after antibiotic treatment, which is what applicant is claiming for “isolating a first sample,” and this also reads on the instantly claimed of the “the first sample is isolated upon determining symptoms od sepsis…and initiating treatment,”
- Isolating a second sample from said patient at a time point after isolating the
first sample and initiating antibiotic treatment, “within 36 hours after isolating the first sample” (p. 741, col. 2, para. 4). The T=3-5 days reads on the second sample with T=1 as the “fist sample,” through broadest reasonable interpretation (BRI) since one of these measurements would be “within 36 hours,” after isolating the first sample and beginning antibiotic therapy upon admission to the hospital,
- Determining/measuring levels of procalcitonin (PCT) or fragment(s) thereof in the first
and the second sample, and
- Determining/measuring a level of ADM or fragment(s) thereof in at least the second sample. The determinations are made by an analyzer and using binding assays (Specifically, Angeletti teaches that “procalcitonin and MR-proADM were measured in all patients at admission (time T=0), and at 12-24 h (time T=1) and in the third and fifth day of antibiotic therapy (time T=3-5)” (p. 741, column 2, paragraph 4).
ANGELETTI also teaches of the cut-off levels for PCT and Pro ADM being > .5ng/ml, and > 1.06 mmol/L respectively for sepsis and septic shock/severe sepsis (a critically ill state) and that anything higher than this is considered significant and indicates that the patient is affected with septic shock or severe sepsis (Table 3).
ANGELETTI teaches that anything greater than 1.06mmol/L for proADM being a significant indicator of sepsis. Greater than 1.06 mmol/L also encompasses the claimed range of “above 2.25 nmol/L,” and therefore measuring a level of proADM at 2.25 nmol/l being indicative that the patient still has sepsis and that further antibiotic treatment or a change in treatment is needed as claimed.
With respect to PCT, as claimed what is required in the claims is that the measured level in the second sample is greater than the measured level in the first sample. ANGELETTI teaches that procalcitonin/PCT is “significantly higher in sepsis than in localized infection,” (Page 743, column 1, paragraph 1)—however does not teach of what is claimed in that the second sample which is after antibiotic treatment having the PCT levels being higher than in the first sample.
ANGELETTI also teaches that the combination of PCT and ProADM can be used to “guide,” antibiotic therapy utilization (meaning adjustments/changes of therapy and any unnecessary antibiotic usage) and that PCT and ProADM together allow a physician to optimize clinical management of the infections (management includes treatment of with antibiotics) (Page 747, column 1, paragraph 4 & column 2, paragraph 3). ANGELETTI also teaches that using the two biomarkers ProADM and PCT together, adds information of the antibiotic therapy effectiveness and timing and also on the prognosis of the infections, which allow the clinician to optimize the clinical management of both localized and systemic bacterial infections (Page 747, column 2, paragraph 3).
ANGELETTI further teaches of performing the PCT and proADM measurements using “assays,” and specifically the assays for proADM and PCT in a reference they cite (23) which uses fluoroimmunoassays, that is the examiner’s second reference (the title refers to immunoassays). Therefore, ANGELETTI calls out commercially available assays, but do not specifically call out measuring by “immunoassay,” as claimed.
MAZIER et al. (or citation 23 in ANGELETTI and the examiner’s secondary reference) is used to remedy this and teaches of using fluoroimmunoassays to measure proadrenomedullin (abstract & title). Specifically, MAZIER teaches of binding the antibody/binder anti-MR-pro-ADM sheep polyclonal antibody is used to help detect (and would complex with proADM) (Introduction, paragraph 1 & Page 726, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use the immunoassay methods of MAZIER to detect the compounds in ANGELETTI due to the advantages of the immunoassay system of MAZIER has in that it is fully automated (MAZIER, Page 725, second column, second to last paragraph).
ANGELETTI and MAZIER teach of the above, but in case it is not clear that treatment is changed based on the above measurements of PCT, BOUADMA is used to remedy this.
BOUADMA teaches of use of procalcitonin (PCT) and an algorithm based on procalcitonin to reduce antibiotic exposure in intensive care settings to help with the problem multidrug resistant bacteria (Page 463, title and background).
More specifically BOUADMA teaches that if levels above a certain level of procalcitonin are measured that antibiotics are encouraged (Page 465, Figure 1, top right box) and then if there is an increase in the concentration of procalcitonin compared with a peak concentration of it and with the threshold level then changing of antibiotics (dose or type for treatment) is recommended (Page 465, Figure 1, bottom, right box). BOUADMA also teaches on Figure 1 other scenarios where stopping of antibiotics, or continuing/maintenance of antibiotics is recommended.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use procalcitonin as a way to recommend changes in or optimization of antibiotic treatments as is done in BOUADMA in the methods of ANGELETTI and MAZIER due to the advantage this offers in treating bacterial infections (of which sepsis is one of) and potentially reducing antibiotic exposure with no apparent adverse outcomes (BOUADMA, Page 463, interpretation section).
Response to Arguments
Appellant's arguments filed 01/30/2026 have been fully considered are persuasive for some matters.
Applicant has cancelled all claims which a 101 rejection was priorly made for and newly added Claim 27 has a similar framework to instant Claim 1, which a 101 rejection was not made for in the last office action. Therefore, the instant claims and amendments dated 01/30/2206 have overcome the prior 101 rejections due to the amendments.
The prior objections are also overcome due to amendments made 01/30/2026.
The prior 112 b rejections are also overcome due to amendments made 01/30/2026.
All claims remain rejected under 103.
Prior art/103 rejection
With respect to the ANGELETTI reference applicant argues that ANGELETTI fails to teach measuring elevated PCT. With respect to this—the examiner notes that though ANGELETTI does in fact teach of measurement of PCT in addition to proADM, that a 103 rejection was made and this in fact was why the BOUDMA reference was used.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that ANGELETTI the primary reference does not teach of using PCT and proADM together to guide antibiotic therapy as claimed. The examiner again disagrees.
Specifically, ANGELETTI teaches that the combination of PCT and ProADM can be used to “guide,” antibiotic therapy utilization (meaning adjustments/changes of therapy and any unnecessary antibiotic usage) and that PCT and ProADM together allow a physician to optimize clinical management of the infections (management includes treatment of with antibiotics) (Page 747, column 1, paragraph 4 & column 2, paragraph 3). ANGELETTI also teaches that using the two biomarkers ProADM and PCT together, adds information of the antibiotic therapy effectiveness and timing and also on the prognosis of the infections, which allow the clinician to optimize/change the clinical management (which includes treatment) of both localized and systemic bacterial infections (Page 747, column 2, paragraph 3).
Applicant argues that the claims have been amended to additionally recite the features of previous dependent Claim 22 in that proADM is determined in both a first and second sample and that it is increased to 2.25 nmol/l, but applicant does not argue what if so that they think the prior art does not teach with respect to this. The examiner maintains that the rejections above shows how the prior art reads on this.
Applicant argues that MAZIER in view of BOUADMA does not cure the purported deficiencies of ANGELETTI. The examiner disagrees.
Applicant argues that the BOUADMA references refers only to PCT level and changing antibiotics based on this, and not with respect to proADM. The examiner maintains that antibiotic monitoring and optimization with respect to prodADM increase and PCT was already taught by Angeletti as shown above. BOUADMA is used to show that an increase in PCT is also used to guide antibiotic therapy.
ANGELETTI specifically teaches that the combination of PCT and ProADM can be used to “guide,” antibiotic therapy utilization (meaning adjustments/changes of therapy and any unnecessary antibiotic usage) and that PCT and ProADM together allow a physician to optimize clinical management of the infections (management includes treatment of with antibiotics) (Page 747, column 1, paragraph 4 & column 2, paragraph 3).
Applicant argues about MAZIER, with respect to the treatments too, but the examiner notes that MAZIER was used to teach of immunoassays and not treatments. Again--- a 103 rejection was made and this is permitted.
Appellant further argues with respect to the instant claims that they have “unexpected results,” and that these results are “accurately stratifying patients who will require a future change or modification in antibiotic therapy.”
One of these unexpected results that applicant argues is “that is PCT levels are increasing over the course of the antibiotic treatment, a change in antibiotic treatment is needed.” The examiner notes first of all with respect to this, that this is not required for instant Claim 27. Is the result really unexpected if the thing which is unexpected is not even in the claim? Further BOUDMA teaches of this, so this does not seem like an unexpected thing at all.
Applicant references many tables in their instantly claimed specification with respect to how the claimed measurements can guide treatment and days these determinations can be decided at. However, as claimed nothing specific is claimed with respect to guiding treatment or particular days treatment can be guided at to what specific changes. Changing antibiotics if one is not working to another unspecified known antibiotic as claimed, is known in the art, as shown above.
Applicant even further argues that the instant claims “enable a treating physician, based on the combined measurement of PCT and proADM at two time points to advantageously adjust the antibiotic treatment of such a patient that would based on PCT level along not have been identified as a high-risk patient in need to change of antibiotic therapy.” Again—the examiner maintains, that this is made obvious as shown in the above rejection as it shows that both evelvated proADM and PCT levels indicate a patient is sick with sepsis or bacterial infection and needs treatment (with antibiotics). If treatment doesn’t work—it is known to change/ “changing,” it to something that might be effective as broadly claimed or add a further antibiotic agent.
All claims remain rejected.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758