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 .
Claim Status
The amended claim set filed 29 Dec 2025 is acknowledged. Claims 1, 8, 20-21, and 30-31 are currently pending. Of those, claims 1 and 8 are currently amended, no claims are new. Claims 20-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6 Feb 2024. Claims 2-7, 9-19, and 22-29 are cancelled. Claims 1, 8, and 30-31 will be examined on the merits herein.
Response to Arguments
The Applicants’ arguments filed 29 Dec 2025 are acknowledged. For clarity, in this action, said arguments will be referred to as “Remarks” and the Non-Final Office Action mailed 26 June 2025 will be referred to as “NFOA.”
The Lewis declaration under 37 CFR 1.132 filed 29 Dec 2025 is insufficient to overcome the rejection of claims 1, 8, and 30-31 based upon 35 U.S.C. 112(a) enablement as set forth in the last Office action because: reasons are discussed in the response that follows the rejection below.
Information Disclosure Statement
The information disclosure statement (IDS) submitted with a fee on 29 Dec 2025 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner. A signed copy of the statement is attached with this action.
Rejection(s) Maintained
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112(a)
Claims 1, 8, and 30-31 remain 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. The rejection is amended to reflect the claim amendments and a response to the arguments follows the amended rejection.
The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01. Although all factors were considered, the Wands factors that were most relevant for this decision are discussed in detail below.
The breadth of the claims: The claims require the step of “diagnosing the patient as having an Enterobacteriaceae-caused UTI when the concentration of agmatine detected in the urine sample is greater than 170 nM”. The patient is “a human patient suspected of having a UTI”.
The amount of direction provided by the inventor and the existence of working examples: The specification teaches that “More than 75% of urinary tract infections (UTIs) are caused by organisms from the Enterobacteriaceae family including one or more of the following microorganisms: Escherichia coli (EC); Klebsiella species such as Klebsiella pneumoniae (KP) or Klebsiella oxytoca (KO); Proteus mirabillis (PM); Enterobacter species (Esp); and Citrobacter species (Csp) (hereinafter common UTI-causing microorganisms).” [0003]. The working examples measure agmatine levels in 96 human urine samples testing negative for bacterial growth, and 96 human urine samples that tested positive for Escherichia coli infection, both tested using two-stage, isocratic continuous chromatography with a multiplexed column injection schedule [0026, Figure 8-9] followed by mass spectrometry [0011]. In Figure 9, the “dotted lines in the second block indicate a threshold at 58 nM, which was determined by isotope ratio and corresponds to UTI detection threshold associated with a sensitivity of 0.94 and specificity of 0.99” [0027]. Therefore, the specification concludes that “A threshold of 170 nM agmatine or greater in the urine is indicative of an Enterobacteriaceae infection” [0033]. “Agmatine was reliably identified in samples from patients suffering from an infection of at least one of Escherichia coli, Proteus mirabilis, Citrobacter species including Citrobacter braakii, Citrobacter freundii, Citrobacter amalonaticus, Citrobacter farmeri and Citrobacter koseri, Enterobacter species including Enterobacter aerogenes and Enterobacter cloacae cplx., Klebsiella species including Klebsiella oxytoca and Klebsiella pneumoniae” [0034, Figures 9 and 11].
The state of the prior art and the level of predictability in the art: The art at the time of filing had measured levels of agmatine present in the urine of healthy controls. Zhao et al. (2006; PTO-892) measured agmatine present in two human urine samples using a capillary electrophoresis (CE)/optical fiber light-emitting diode (LED)-induced fluorescence detection method, and found that the agmatine concentration is 2.5–4.1 × 10−7 M (Abstract, Table 1 on pg. 141). This corresponds to 250-410 nM. (Calculation was performed as: 2.5*10-7 M * 109 nM/M = 2.5 * 102 nM = 250 nM.)
Zhao et al. (2009; PTO-892) measured agmatine present in four human urine samples (Table 2 on pg. 5159) using “a highly sensitive microchip electrophoresis (MCE) method with chemiluminescence (CL) detection” (Abstract), and found that the agmatine concentration is 2.61-4.3 × 10−7 M (Abstract, Table 2). This corresponds to 261-430 nM. (Calculation performed as in the other Zhao et al. reference.)
Liu et al. (2013; PTO-892) measured agmatine present in 20 healthy human urine samples (pg. 37 col. 2 par. 4) using an “ultrahigh performance liquid chromatography–tandem mass spectrometry method” (Title) and found that the agmatine concentration in healthy urine is 9.17 × 103 ± 4.66 × 103 ng/mL (Table 6 on pg. 44). This corresponds to ~70,435 nM (with a margin of error that was not converted). (Calculation performed as: 9.17 × 103 ng/mL * 1000 mL/L / 130.19 g/mol = 70,435 nmol/L = 70,435 nM).
The art at the time of filing repeatedly demonstrated that healthy subjects have urine agmatine levels higher than the claimed threshold for diagnosing a UTI, and in the case of Liu et al., the agmatine levels reported for healthy patients are higher than those reported in the instant specification for infected samples (compare with instant Figures 9 and 11). All healthy patients tested in these references would be falsely diagnosed with a UTI by the claimed method. Therefore, the data in the art at the time of filing calls into question whether the claimed diagnostic threshold can accurately diagnose an Enterobacteriaceae-caused UTI.
The quantity of experimentation needed to make or use the invention: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success and without undue experimentation. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that multiple references teach that healthy subjects have urine agmatine levels in the ”UTI-infected” range, in order to accurately diagnose an Enterobacteriaceae-caused UTI, one of ordinary skill in the art would need to perform multiple further experiments to understand why different references observe such wildly different agmatine levels- from a low level of less than 58 nM in the instant specification to a high level of 70,435 nM in Liu et al. One of ordinary skill in the art would need to design a research program to determine whether these differences can be explained by differences within the subject population of healthy patients, differences in the measurement method, some other variable that could be controlled for so that one could perform part of the claimed scope with a reasonable expectation of success, or alternately, whether the claimed method is inoperable because healthy and Enterobacteriaceae-infected subjects do not truly differ in agmatine levels. The instant specification does not provide guidance on how to perform this research program and how to understand the different agmatine levels in the art because it does not discuss the art’s measurements of urine agmatine levels.
Therefore, the amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully diagnosing an Enterobacteriaceae-caused UTI. Therefore, claims 1, 8, and 30-31 are rejected under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, for failing to meet the enablement requirement.
Response to Arguments
Applicant arguments (Remarks pg. 4-5) cite to the Lewis declaration for evidence to overcome the rejection.
Lewis declaration argues (par. 10) that the reference Yu et al. relates to rat urine, but the invention is limited to urine from human subjects.
The examiner agrees that the claim amendment differentiates the currently-claimed invention from the Yu et al. reference. References to the Yu et al. reference have been removed from the rejection above. However, the rejection is maintained for the reasons in the amended rejection.
Lewis declaration argues (par. 11) the Zhao et al. (2006) and Zhao et al. (2009) “references do not provide reliable measurements of normal agmatine concentrations in healthy urine and, therefore, cannot be used to challenge the diagnostic threshold claimed in the above-noted patent application.” This is because:
(a) the references use capillary electrophoresis, which is a method known to be quantitatively unreliable and cites references by Schaeper and Gotz,
(b) the references did not use “matrix-matched standards, which is an essential practice for accurate quantification in biological specimens”
(c) Zhao analyzed only two “healthy” samples in each reference and did not perform microbiological testing to confirm whether the samples meet the clinical definition of bacteriuria. Asymptomatic bacteriuria is common, so the references cannot establish normal agmatine levels.
This argument has been carefully considered but is not found persuasive. The claim states “analyzing the urine sample to determine a concentration of agmatine in the urine sample”. The claim does not exclude any particular methods, such as capillary electrophoresis, or require any particular methods, such as the liquid chromatography and mass spectrometry used by the specification (Example 5). Even if the capillary electrophoresis method is known to be unreliable or imperfect, those of ordinary skill in the art at the time of filing still consider it to be a method that is able to analyze the urine sample to determine a concentration of agmatine in the urine sample because the authors of the Zhao references and the peer reviewers and journal editors of both papers all approved of the papers being published in a form that includes qualification of the concentration of agmatine in the urine sample. The claim does not require the presence of matrix-matched standards or microbiological testing. The two Zhao references measured two and four (i.e. six total) human urine samples, not two. Lewis has not provided any evidence to support an argument about the frequency of asymptomatic bacteriuria, so the examiner is not persuaded that a meaningful number of the samples tested in the Zhao references would be expected to have asymptomatic bacteriuria. It is also noted that the instant specification does not disclose performing microbiological testing on the urine samples tested in Example 7 to identify and exclude asymptomatic bacteriuria. Therefore, the argument is not persuasive because it argues that only certain types of urine analysis can be used with the claimed diagnostic threshold, but that argument lacks a nexus with the broad “analyzing” method claimed.
Lewis declaration argues (par. 11) “Although Liu et al. used recognized clinical chemistry methods, they made a clear, quantitative error in their paper. Plasma agmatine produced a signal of 4x10 corresponding to 71.65 ng/mL, while urine produced a lower signal of 3x10 Despite this, the authors report a 128-fold higher concentration in urine (9170 µM). A 25% decrease in signal cannot rationally be linked to a 128-fold increase in concentration in these sample types. Like Zhao et al., they also provide no microbiological data to verify their "healthy" measurements.”
This argument has been carefully considered but is not found persuasive. The argument about microbiological testing was addressed above for the Zhao references and is not persuasive for the Liu reference for the same reason. The examiner cannot identify where in Liu applicant is pointing to for the quantification of the plasma and urine signal. The printed exponents in the declaration are also unclear, are the exponents 5 or 6? It is noted that Tables 2-3 show that there were different calibration parameters for quantifying agmatine in urine and plasma, so this is a potential explanation for the difference in signal leading to a different concentration. Due to questions about the data being cited, this argument is not strong enough to overcome the rejection of record when Liu is considered in the context that the two Zhao references are still considered relevant art. However, applicant’s declaration that a clear, quantitative error occurred would provide enough doubt to overcome the rejection if the Zhao references were excluded by an amendment to the claim.
Lewis declaration argues (par. 9) that the “invention is clinically grounded and microbiologically validated. The invention has been proven accurate over 1000 times.”
Lewis declaration further argues (par. 12) “The 170 nM threshold in my research was selected to optimize sensitivity and specificity for identifying bacteriuria at 107 CFU/mL. While agmatine levels vary across patients and may overlap between infected and uninfected groups, this specific quantitative cutoff of 170 nM provides >90% diagnostic accuracy. Adjusting the threshold changes the sensitivity-specificity balance.”
This argument has been carefully considered but is not found persuasive. The invention has been tested with a single specific urine analysis method (liquid chromatography and mass spectrometry) many times. However, this does not provide evidence that the claimed method using any possible urine analysis method that overcomes the evidence to the contrary from the art. Therefore, the examiner remains of the opinion expressed in the rejection above: “One of ordinary skill in the art would need to design a research program to determine whether these differences can be explained by differences within the subject population of healthy patients, differences in the measurement method, some other variable that could be controlled for so that one could perform part of the claimed scope with a reasonable expectation of success, or alternately, whether the claimed method is inoperable because healthy and Enterobacteriaceae-infected subjects do not truly differ in agmatine levels.”
The rejection is maintained for the reasons of record and the reasons herein.
Proposed Claim Amendment
The examiner was not able to perform an interview to suggest an examiner’s amendment. A telephonic interview is not permitted because it appears applicant has legal representation but a valid power of attorney has not been filed in the present application. Providing representative information in an Application Data Sheet (ADS) does not constitute a power of attorney. See 37 CFR 1.76(b)(4) and MPEP § 408. For information on appointing a power of attorney, see MPEP § 402.02 et seq. In the interest of compact prosecution, the following claim amendments are proposed for applicant’s consideration. These proposed amendments would place claims 1, 8, 20, and 30-31 in condition for allowance.
Applicant is reminded that claims 20 and 21 are not eligible for rejoinder in their current form. The procedure for rejoinder is as follows: “Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.” (emphasis added).
Claim 1 (Proposed Amendment): A method of diagnosing and treating an Enterobacteriaceae-caused urinary tract infection (UTI) in a human patient suspected of having a UTI, the method comprising:
receiving a urine sample from the patient;
analyzing the urine sample using at least one of liquid chromatography and mass spectrometry to determine a concentration of agmatine in the urine sample;
diagnosing the patient as having an Enterobacteriaceae-caused UTI when the a concentration of agmatine detected in the urine sample is greater than 170 nM; and
treating the Enterobacteriaceae-caused UTI with an effective amount of an antibiotic that is active against an Enterobacteriaceae species.
Claim 20 (Proposed Amendment): The method of claim [[21]]1 wherein after diagnosing, the method further includes:
incubating the patient’s
after incubation, analyzing the incubated growth medium by chemical analysis to determine a level of each of one or more metabolites in the incubated growth medium;
identifying a type of Enterobacteriaceae bacteria causing the UTI by comparison of the level of each of the one or more metabolites with reference metabolite profiles and matching the level of each of the one or more metabolites with a reference metabolite profile indicative of the type of Enterobacteriaceae bacteria;
and an antibiotic to be active against the type of Enterobacteriaceae bacteria.
Claim 21 (Proposed Cancelled)
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMELIA NICOLE DICKENS whose telephone number is (571)272-0381. The examiner can normally be reached M-R 8:30-4:30, and every other F 8:30-4:30 (EDT/EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Dan Kolker can be reached at (571) 272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMELIA NICOLE DICKENS/Examiner, Art Unit 1645
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645