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
Claims 1-12, 17, 22 and 24 are cancelled. Claim 23 is withdrawn.
Claims 13-16 and 18-21 are under examination herein.
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.
Maintained rejection: Claims 13-16 and 18-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (abstract ideas – mental steps) without significantly more.
The claims recite a method for guiding the treatment to a patient infected with a strain of Gram-negative bacteria of the Enterobacteriaceae family comprising measuring an amount of 2-hydroxymyristate and 3-hydroxymyristate present in lipopolysaccharide of the bacteria; comparing said amount of 2-hydroxymyristate with said amount of 3-hydroxymyristate; treating the patient with anti-infection treatments before an invasive infection, septic shock, and death of the patient if a ratio of 2-hydroxymyristate to 3-hydroxymyristate is greater than 0.01. Thus, the claims are directed to a process (Step 1: Yes).
The claims set forth judicial exceptions which are abstract ideas. In claim 13, the amount of 2-hydroxymyristate and 3-hydroxymyristate acid is measured and compared, and if the ratio of 2-hydroxymyristate to 3-hydroxymyristate is greater than 0.01, the patient is treated with anti-infection treatments (Step 2A: Yes).
This judicial exception of mental steps is not integrated into a practical application. If the ratio of 2-hydroxymyristate to 3-hydroxymyristate is less than 0.01, a treatment is not administered. The only additional elements recited are measuring the amount of 2-hydroxymyristate and 3-hydroxymyristate present in lipopolysaccharide of the bacteria in claim 13, and isolating the bacteria from a sample in claim 21. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the limitations do not impose any meaningful limits on practicing the abstract idea. While the claims recite an active method step of measuring the amount of 2-hydroxymyristate and the amount of 3-hydroxymyristate present in lipopolysaccharide of bacteria, and isolating the bacteria from a sample, these steps are a well-understood, routine and conventional activity known in the art before the filing of the current invention. While claim 13 contains an additional step of initiating anti-infection treatments before an invasive infection, septic shock and death, this step is recited at such generality that it is still considered to be well-understood, routine and conventional.
Gosiewski et al. (“Comparison of Methods for Isolation of Bacterial and Fungal DNA from Human Blood”, Current Microbiology, 2014, Vol. 68, pp.149-155; previously cited) describes the isolation of DNA from blood to detect Escherichia coli, Staphylococcus aureus, Candida albicans, and Aspergillus fumigatus (abstract). Gosiewski identifies ready-to-use kits on the market including Septifast (Roche) and Septitest (Molzym) that detect microbes in the blood (p.149 2nd column last paragraph – p. 150, 1st column top paragraph).
Gibbons et al. (“An Inner Membrane Dioxygenase that Generates the 2-Hydroxymyristate Moiety of Salmonella Lipid A”, Biochemistry, 2008, Vol. 47, No. 9, pp.2814-2825; previously cited) describes the synthesis of 2-hydroxymyristate modified lipid A in the presence of O2 by E. coli (p.2821, 2nd column top paragraph). Gibbons further identifies GC/MS analysis of 3-hydroxymyristate and 2-hydroxymyristate standards as the TMS derivatives of their methyl esters (p.2823, 2nd column 3rd paragraph).
Weil et al. (“Circulating levels of 3-hydroxymyristate, a direct quantification of endotoxaemia in noninfected cirrhotic patients”, Cirrhosis and Liver Failure, 2019, Vol.39, Issue 1, pp.106-114) describes measuring 3-hydroxymyristate (3-HM), a lipid component of lipopolysaccharide (abstract). Weil states that bacterial endotoxin lipopolysaccharide (LPS) is the culprit component of the outer surface of gram-negative bacteria and has been considered as a marker of endotoxaemia (p.107, 1st column 1st paragraph). Weil further discusses that the lipid A structure of LPS is composed of primary esterified acyl chains, most frequently represented in the different bacterial strains by 3-hydroxymyristate (3-HM) (p.107, 1st column 1st paragraph).
The isolation of bacteria from a blood sample is well-understood, routine and conventional in the field of sepsis detection in blood, as taught by Gosiewski et al. The concept of comparing a measured value to a reference value is well-understood, routine and conventional as taught by Gibbons et al. The concept of measuring 2-hydroxymyristate and 3-hydroxymyrsistate from lipid A of bacteria is well-understood, routine and conventional as taught by Gibbons et al. and Weil et al.
Thus, claims 13-16 and 18-21 are rejected under 35 U.S.C. §101.
Response to Arguments
Applicant argues that LPS from bacteria contains not only the claimed 3-hydroxymyristate, but also other species that are not encompassed by the present application, and while LPS from bacteria generally contains 3-hydroxymyristate, this is not necessarily the case for 2-hydroxy myristate (See Remarks dated 4/28/2026, p.6 2nd paragraph from bottom). Applicant argues that one of ordinary skill in the art would not have recognized the utility of measuring the amounts of 2-hydroxymyristate and 3-hydroxymyristate, much less using a ratio of 2-hydroxymyristate to 3-hydroxymyristate greater than 0.01 as a means to guide treatment of a patient infected with a pathogenic strain of Gram-negative bacteria of the Enterobacteriaceae family (See Remarks dated 4/28/2026, p.6 last paragraph). Applicant argues that claim 13 has been further amended to recite a method of treatment of a patient infected with a pathogenic strain of Gram-negative bacteria of the Enterobacteriaceae family, and replace the final two steps with a treatment step: treating the patient if the ratio of 2-hydroxymyristate and 3-hydroxymyristate is greater than 0.01 (See Remarks dated 4/28/2026, p.7 paragraph 1). Applicant argues that amended claim 13 provides a rapid and reliable technique for detecting the pathogenicity and/or virulence of clinical strains of Enterobacteriaceae, such as Enterobacter cloacae, which is further reflected in the limitations introduced in amended claim 13, which recites concrete steps of “measuring”, “comparing” and “treating” (See Remarks dated 4/28/2026, p.7, paragraph 2).
Applicant's arguments filed April 28, 2026 have been fully considered but they are not persuasive. Although applicant has amended the preamble and added a step of “treating the patient with anti-infection treatments before an invasive infection, septic shock, and death of the patient”, these actions still comprise a judicial exception as discussed in the rejection above. The step of “treating the patient with anti-infection treatments” is conditional upon the ratio of 2-hydroxymyristate and 3-hydroxymyristate being greater than 0.01; if the ratio is less, no treatment would be administered. The treatment step “treating the patient with anti-infection treatments” is recited at such generality that it does not integrate the judicial exception into a meaningful practical application. The step of “measuring the amount of 2-hydroxymyristate and 3-hydroxymyristate present in the lipopolysaccharide of the bacteria” is a routine, conventional and well-known step in the art as taught by Gibbons et al. and Weil et al. The step of “comparing said amount of 2-hydroxymyristate with said amount of 3-hydroxymyristate” is a mental step. Further, the determination of the ratio of 2-hydroxymyristate and 3-hydroxymyristate being greater than 0.01 is a mental step.
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.
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.
Modified rejection necessitated by amendment: Claims 13-16, 18 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Gibbons et al. (“Oxygen Requirement for the Biosynthesis of the S-2-Hydroxymyristate Moiety in Salmonella typhimurium Lipid A”, The Journal of Biological Chemistry, 2000, Vol. 275, No. 42, pp.32940-32949; previously cited) in view of Munford (“Sensing Gram-Negative Bacterial Lipopolysaccharides: a Human Disease Determinant?”, Infection and Immunity, 2008, Vol. 76, No. 2, pp.454-465; previously cited), Bartholomew et al. (“2-Hydroxylation of Acinetobacter baumannii Lipid A Contributes to Virulence”, Infection and Immunity, 25 March 2019, Vol. 87, No.4, article e00066-19, 17 pages; previously cited) and Weil et al (“Circulating levels of 3-hydroxymyristate, a direct quantification of endotoxaemia in noninfected cirrhotic patients”, Cirrhosis and Liver Failure, 2019, Vol.39, Issue 1, pp.106-114).
Regarding claim 13, Gibbons teaches that Lipid A molecules of certain Gram-negative bacteria, including Salmonella typhimurium and Pseudomonas aeruginosa may contain secondary S-2-hydroxyacyl chains (abstract). Gibbons teaches that Lipopolysaccharide is the principal constituent of the outer leaflet of the outer membranes of Gram-negative bacteria, and recognition of LPS by mammalian cells activates innate immune responses (p.32940, 2nd column 2nd full paragraph). Gibbons further teaches the purification of 2-hydroxymyristate-modified Lipid A from E. coli cells using chromatography and TLC plates (p.32942, 1st column – Purification of Unmodified and 2-hydroxymyristate-modirided Lipid A from E. coli Cells Expressing S. typhimurium lpxO). Gibbons teaches that two closely migrating lipid A species were resolved and could be seen transiently as distinct white zones; the more slowly migrating component containing the 2-hydroxymyristate substituent (p.32942, 1st column last paragraph). Gibbons teaches that stimulation of S-2-hydroxymyristate biosynthesis at low Mg2+ concentrations suggest a function for 2-hydroxylation in pathogenesis (p.32941, 1st column 2nd paragraph). Gibbons further teaches that mutants defective in PhoP/PhoQ do not make any of these substituents, and such strains are much less virulent than wild type and are susceptible to cationic anti-microbial peptides (p.32946, 2nd column last paragraph).
Gibbons does not disclose comparing 2-hydroxymyristate to 3-hydroxymyristate, or treating the patient with anti-infection treatments if a ratio of 2-hydroxymyristate to 3-hydroxymyristate is greater than 0.01.
However, Munford teaches that a prominent role for host-LPS interactions in the pathogenesis of gram-negative bacterial diseases is plausible because LPS is the gram-negative bacterial molecule that vertebrates seem to detect most sensitively (p.454, 1st column, 3rd paragraph). Munford further teaches that the lipid A moiety retains certain features in almost all gram-negative bacteria, and it is this semiconserved structure that animals can sense to detect the presence of many gram-negative bacteria in their tissues (p.454, 1st column, 3rd paragraph). Munford teaches that the hydroxyl groups of the hydroxymyristates at positions 2’ and 3’ are substituted by laurate and myristate respectively (p.455, FIG. 1).
Bartholomew teaches that 2-hydroxylation of Acinetobacter baumannii lipid A contributes to virulence (title). Bartholomew teaches that the lipid A structure can be modified by pathogens in response to different conditions, which may result in resistance to cationic antimicrobial peptides, reduced or increased activation of inflammatory responses (p.1, 1st paragraph). Bartholomew teaches that LpxO encodes the enzyme responsible for the 2-hydroxylation of lipid A (abstract). Bartholomew further teaches the importance of LpxO-dependent modification in immune evasion, as 2-hydroxylation of lipid A limits the activation of the mitogen-activated protein kinase Jun N-terminal protein kinase to attenuate inflammatory responses (abstract). Bartholomew teaches Acinetobacter baumannii is an opportunistic gram-negative pathogen causing a wide range of nosocomial infections, although the most common clinical manifestations comprise ventilator-associated pneumonia and central line-associated blood stream infections (p.2, 1st paragraph). Bartholomew further teaches colistin and tigecycline have become the last-line treatment for multidrug-resistant A. baumannii (p.2, 1st paragraph).
Weil teaches measuring 3-hydroxymyristate (3-HM), a lipid component of lipopolysaccharide (abstract). Weil teaches bacterial endotoxin lipopolysaccharide (LPS) is the culprit component of the outer surface of gram-negative bacteria and has been considered as a marker of endotoxaemia (p.107, 1st column 1st paragraph). Weil further teaches the lipid A structure of LPS is composed of primary esterified acyl chains, most frequently represented in the different bacterial strains by 3-hydroxymyristate (3-HM) (p.107, 1st column 1st paragraph). Weil teaches LPS concentration was determined at baseline by direct quantification of 3-hydroxymyristate (3-HM) by high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS/MS assay) (p.107, 2nd column last paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to measure the amount of 2-hydroxymyristate and measure the amount of 3-hydroxymyristate, because Gibbons teaches the purification of 2-hydroxymyristate-modified Lipid A from E. coli cells and Weil teaches the lipid A structure of LPS is most frequently represented by 3-hydroxymyristate. One of ordinary skill in the art would have been motivated to use 2-hydroxymyristate as an identifying feature of pathogenicity because Bartholomew teaches that the lipid A structure can be modified by pathogens which may result in resistance to cationic antimicrobial peptides. One of ordinary skill in the art would have found it beneficial to detect 2-hydroxymyristate as a pathogenic marker because both Gibbons and Bartholomew teach that there is a role of 2-hydroxylation as a marker of pathogenicity, and Munford teaches that the lipid A moiety retains certain features in almost all gram-negative bacteria, and animals can sense this semiconserved structure to detect the presence of many gram-negative bacteria in their tissues.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat the patient with anti-infection treatments as taught by Bartholomew following detection of 2-hydroxymyristate and 3-hydroxymyristate, because Gibbons and Weil identify 2-hydroxymyristate and 3-hydroxymyristate as markers of lipid A structure from LPS. One of ordinary skill in the art would find it beneficial to treat a patient with anti-infective treatment following detection of 2-hydroxymyristate or 3-hydroxymyristate, because Gibbons, Bartholomew, Munford and Weil all teach that the detection of either marker identifies the presence of pathogenic gram-negative bacteria.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to compare the amount of 2-hydroxymyristate and 3-hydroxymyristate present in the sample because Gibbons teaches comparing 2-hydroxymyristate to a reference value, and Weil teaches 3-hydroxymyristate values to a baseline. One of ordinary skill in the art would reasonably expect that comparing the amount of 2-hydroxymyristate to the amount of 3-hydroxymyristate would predictably result in a ratio of 2-hydroxymyristae to 3-hydroxymyristate, and it was known in the art at the time of invention that bacterial lipid A contains both 2-hydroxymyristate and 3-hydroxymyristate.
While the references do not explicitly teach a ratio of 2-hydroxymyristate to 3-hydroxymyristate of greater than 0.01, it would have been obvious to one of ordinary skill in the art to determine a ratio as discussed above and then conclude whether a strain is pathogenic based on the value, because Gibbons teaches measuring both 2-hydroxymyristate and 3-hydroxymyristate, and also teaches comparing 2-hydroxymyristate to a reference value. One of ordinary skill in the art would reasonably expect that selecting the amount of 3-hydroxymyristate as the reference value in the method of Gibbons would predictably result in the determination of a ratio of 2-hydroxymyristate to 3-hydroxymyristate that one of ordinary skill in the art could then determine to be greater than 0.01.
Regarding claims 14-16, Gibbons teaches the bacteria Escherichia coli strain K12 (abstract).
Bartholomew teaches the bacteria Acinetobacter baumannii (title).
Gibbons and Bartholomew do not teach wherein the bacterium belongs to the genus Enterobacter (claims 14 and 15) or the species Enterobacter cloacae complex (claim 16).
However, Munford teaches the LPSx (lipid As) produced by commensals such as Klebsiella pneumoniae, Enterobacter cloacae, and E. coli have closely similar structures, and they elicit the same inflammatory responses with similar potencies (p.456, 1st column top paragraph). Munford further teaches that LPS preparations obtained from clinical isolates of Acinetobacter baumannii were potently proinflammatory towards human cells (p.457, 1st column 2nd paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Gibbons to replace the E. coli strain taught by Gibbons with the Enterobacter cloacae strain taught by Munford, because Munford teaches that Enterobacter cloacae and E. coli have closely similar lipid As structures and elicit the same inflammatory response with similar potencies, and further that Acinetobacter baumannii also was proinflammatory towards human cells. Each of Gibbons, Munford and Bartholomew teach the detection of lipopolysaccharide lipid A from gram-negative bacteria. One of ordinary skill in the art would reasonably expect that replacing E. coli with Enterobacter cloacae would predictably result a method for predicting the pathogenicity of a gram-negative bacteria of the Enterobacteriaceae family, because each of E. coli, Acinetobacter baumannii and Enterobacter cloacae are gram-negative bacteria, and it would amount to a simple replacement of one gram-negative bacteria strain for another, and it was known in the art at the time of invention that Enterobacter cloacae, Acinetobacter baumannii and E. coli lipid As had closely similar structures.
Regarding claim 18, for the purposes of prior art, the limitation “a method for predicting the resistance of strains of Enterobacter cloacae to antibiotics” is interpreted as an intended result, as there are no additional method steps recited. Thus, the method of Gibbons in view of Bartholomew and Munford would render the ability to predict the resistance of Enterobacter cloacae to antibiotics because Gibbons teaches the active method steps of measuring the amount of 2-hydroxymyristate present in the lipopolysaccharide of the bacteria and comparing with a reference value, and both Gibbons and Bartholomew identify the lack of 2-hydroxylation as a measure of sensitivity to cationic antimicrobial peptides. The method is obvious for the reasons set forth above.
Regarding claim 21, Gibbons teaches that 200 mL of bacteria was harvested by centrifugation at 4C; the cell pellet was resuspended in 80mL of phosphate-buffered saline to which was added 100mL of chloroform and 200mL of methanol to extract glycerophospholipids (relevant to further comprising a prior step of isolating the bacteria from the sample) (p.32942, 1st column 2nd paragraph).
Maintained rejection: Claims 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Gibbons et al. (“Oxygen Requirement for the Biosynthesis of the S-2-Hydroxymyristate Moiety in Salmonella typhimurium Lipid A”, The Journal of Biological Chemistry, 2000, Vol. 275, No. 42, pp.32940-32949; previously cited) in view of Munford (“Sensing Gram-Negative Bacterial Lipopolysaccharides: a Human Disease Determinant?”, Infection and Immunity, 2008, Vol. 76, No. 2, pp.454-465; previously cited), Bartholomew et al. (“2-Hydroxylation of Acinetobacter baumannii Lipid A Contributes to Virulence”, Infection and Immunity, 25 March 2019, Vol. 87, No.4, article e00066-19, 17 pages; previously cited) and Weil et al. (“Circulating levels of 3-hydroxymyristate, a direct quantification of endotoxaemia in noninfected cirrhotic patients”, Cirrhosis and Liver Failure, 2019, Vol.39, Issue 1, pp.106-114) as applied to claim 13 above, and further in view of Jayol et al. (“Rapid Detection of Polymyxin-Resistant Enterobacteriaceae from Blood Cultures”, Journal of Clinical Microbiology, 2016, Vol. 54, Issue 9, pp.2273-2277; previously cited).
The teachings of Gibbons et al., Munford, Bartholomew and Weil et al. are discussed above.
Regarding claims 19-20, Gibbons, Munford, Bartholomew and Weil do not teach wherein bacteria are present in a biological sample (claim 19) or wherein the biological sample is from a mammal and is selected from blood (claim 20).
However, Jayol teaches the rapid detection of polymyxin-resistant Enterobacteriaceae from blood cultures (title, abstract). Jayol teaches clinical blood cultures recovered from nonduplicate patients that were detected as positive by the BacT/Alert 3D blood culture system and stained as gram-negative (relevant to wherein the biological sample originates from a mammal, and is selected from blood) (p.2275, 1st column – Clinical blood cultures). Jayol teaches that rapid identification and antimicrobial susceptibility testing are essential for guiding clinicians in the selection of the most appropriate treatment for patients with bloodstream infections (p.2273, 1st column 2nd paragraph). Jayol further teaches that mortality rates from sepsis in intensive care units ranges from 20 to 60% worldwide, and inappropriate initial therapy for septic shock occurs in about 20% of patients resulting in 5-fold reduction in survival (p.2273, 1st column, 2nd paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Gibbons, Munford, Bartholomew and Weil to replace the bacterial culture sample taught by Gibbons and Munford with a clinical blood sample taught by Jayol. One of ordinary skill in the art would have been motivated to determine the presence of bacteria in a blood sample because Jayol teaches that doing so allows a clinician to rapidly determine the best way to treat a blood infection. One of ordinary skill in the art would have found it beneficial to have a rapid test to help improve the mortality rates due to sepsis in the hospital.
Response to Arguments
Applicant argues that the office action incorporates the teaching of Weil to highlight the measurement of 3-hydroxymyristate, which is absent from the other cited prior art (See Remarks dated 4/28/2026, p.8 paragraph 2). Applicant argues that Weil discloses measuring 3-hydroxymyristate only to detect endotoxemia and as a potentially promising tool for monitoring non-infected patients with cirrhosis (See Remarks dated 4/28/2026, p.8, paragraph 3).
Applicant argues that measurement of 3-hydroxymyristate reflects the presence of bacteria, but does not indicate whether those bacteria are virulent or pathogenic (See Remarks dated 4/28/2026, p.8, paragraph 4). Applicant argues that LPS from bacteria generally contain 3-hydroxymyristate but not necessarily 2-hydroxymyristate, and Weil is silent on this distinction (See Remarks dated 4/28/2026, p.8 paragraph 5).
Applicant further argues that none of the cited prior art describes or suggests comparing measurements of 2-hydroxymyristate and 3-hydroxymyristate, or discloses using a ratio of 2-hydroxymyristate and 3-hydroxymyristate greater than 0.01 to assess the pathogenicity of a strain of Gram-negative bacteria belonging to the Enterobacteriaceae family and thereby guide treatment of infected patients (See Remarks dated 4/28/2026, paragraph 6). Applicant argues that it would not have been obvious to one of ordinary skill in the art to measure the amount of 2-hydroxymyristate and measure the amount of 3-hydroxymyristate, and compare the amount of 2-hydroxymyristate and 3-hydroxymyristate present in the sample (See Remarks dated 4/28/2026, p.8 last paragraph to p.9 top paragraph). Applicant argues that one of ordinary skill in the art would not have expected that comparing the amount of 2-hydroxymyristate to the amount of 3-hydroxymyristate would predictably result in a ratio of 2-hydroxymyristate to 3-hydroxymyristate, much less than determining a ration and then concluding whether a strain is pathogenic based on the value (See Remarks dated 4/28/2026, p.9 top paragraph). Applicant argues that the combination of the cited prior art fails to teach every element of the claimed invention, and the combination of Munford, Bartholomew, Weil and/or Jayol does not provide the motivation to provide the proposed modification of Gibbons, and bringing in the isolated teaching of Munford, Bartholomew, Weil and/or Jayol would amount to improperly picking and choosing features from different references without regard to the teachings of the references as a whole; and (See Remarks dated 4/28/2026, p.9, 1st full paragraph).
Applicant's arguments filed April 28, 2026 have been fully considered but they are not persuasive.
As discussed in the rejection above, Gibbons teaches that recognition of LPS by mammalian cells activates innate immune responses. Gibbons teaches purifying 2-hydroxymyristate-modified Lipid A from E. coli using chromatography and TLC. Munford teaches that the lipid A moiety retains certain features in almost all gram-negative bacteria, and it is this structure that animals can sense to detect the presence of many gram-negative bacteria in their tissues. Bartholomew teaches that 2-hydroxylation of Acinetobacter baumannii lipid A contributes to virulence. Weil teaches the lipid A structure of LPS is composed of primary esterified acyl chains, most frequently represented in the different bacterial strains by 3-hydroxymyristate (3-HM), and teaches LPS concentration was determined at baseline by direct quantification of 3-hydroxymyristate (3-HM) by high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS/MS assay). One of ordinary skill in the art would have been motivated to use 2-hydroxymyristate as an identifying feature of pathogenicity because Bartholomew teaches that the lipid A structure can be modified by pathogens which may result in resistance to cationic antimicrobial peptides. One of ordinary skill in the art would have been motivated to measure 3-hydroxymyristate because Weil teaches that lipid A structure of LPS is most frequently represented in different bacterial strains by 3-hydroxymyristate. One of ordinary skill in the art would have found it beneficial to do so because both Gibbons and Bartholomew teach that there is a role of 2-hydroxylation as a parker of pathogenicity, and Munford teaches that the lipid A moiety retains certain features in almost all gram-negative bacteria that can be sensed by animals.
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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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/DEEPA MISHRA/Examiner, Art Unit 1657
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