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 . 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.
Election/Restrictions
Applicants elected polymyxin B and histone H2A for treating patients in a hospital or surgical patient without traverse in the reply filed on 2 Oct, 2024.
Claims Status
Claims 1-8, 10, 13-19, 22 and 24-26 are pending.
Claims 1, 2, 8, 24, and 25 have been amended.
Claims 3, 6, 7, 13, 14, and 17 have been withdrawn from consideration due to an election/restriction requirement.
Withdrawn Rejections
The rejection of claims 1, 2, 4, 5, 8, 19, 24, and 25 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph due to uncertainty as to when the concentration of the histones/polymyxin must be within the claimed range is hereby withdrawn due to amendment.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 8, 22, and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims have been amended to require 1 mM magnesium concentration. The issue is how this is measured. Several claims (4-7, 18) require in vivo administration. Yet the plasma Mg concentration is less than 1 mM (Jahnen-Dechent et al, Clin. Kidney J. (2012) 5(Suppl 1) pI3-I14, table 2, pi5, 1st column, middle of page). Jahnen-Dechent et al states that accurate clinical tests for the assessment of magnesium status are lacking (pi8, 2nd column, 3d paragraph). This makes it unclear what the patient population for the claims are.
response to applicant’s arguments
Applicants state that they have amended around this rejection.
Applicant's arguments filed 9 Feb, 2026 have been fully considered but they are not persuasive.
Jahen-Dechent et al, as noted in the rejection, states that clinical tests for Mg status are lacking. This makes it unclear if a given patient has a free Mg concentration that meets the claim limitations.
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.
Claim(s) 2,4, 5, 10, 15, 16, 18, 19, 25, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Class et al (US 20010046976, cited by applicants) in view of Hoeksema et al (Future Microbiol. (2016) 11(3) p441-453) and Daugelavicius et al (Antimicrob. Agents. Chemother. (2000) 44(11) p2969-2978).
Class et al describe antimicrobial histones (title). This is histone H1, which can be in a composition suitable for administration to tissue with a second antimicrobial, such as histone H2A or polymyxin suitable for administration to tissue (paragraph 8), which is a pore forming agent. The material can be administered topically or parenterally. Use of such formulations in the context of surgery is mentioned (paragraph 113).
The difference between this reference and the claims is that this reference does not use the specific pore forming agent claimed by applicants, and does not discuss dosages.
Hoeksema et al discuss histones as part of host defense (title). The antimicrobial activity of histones has long been known (p442, 2nd column, 1st paragraph). Histone H2A (applicant’s elected histone) has a wide range of activity, killing both gram positive and gram negative bacteria, viruses, fungi, and some parasites, as does histone H1 of Class et al (table 1, p444, bottom of page), although the fungi are species dependent (p445, 1st column, 3d paragraph). This reference discusses histones as antimicrobial compounds.
Daugelavicius et al research the effects of polymyxin B with the E. coli cell envelope (title). While pores were formed by this antibiotic at above 20 µg/mL, the flux of compounds through the cell membrane increased greatly even at an order of magnitude lower concentration (abstract). Note that 2 µg/mL was the lowest concentration tested, and it showed increased permeability if the bacterial cell membrane (fig 1, p2971, top of page), suggesting that even lower concentrations may be effective. This reference discusses the effects of polymyxin B on a gram negative bacterium.
Therefore, it would be obvious to use the histone H2A of Hoeksema et al instead of the histone H1 of Class et al as a simple substitution of one known element (histone H1) for another (histone H2A) yielding expected results (antimicrobial activity). As Hoeksema et al shows that both histones have a broad spectrum of activity, an artisan in this field would attempt this substitution with a reasonable expectation of success. Alternatively, Class et al list both histone H2A and polymyxins as compounds that can be added to the histone H1 formulation, making adding both obvious (MPEP 2144.06(I)).
Furthermore, it would be obvious to use polymyxin B, as Deugelavicius et al teach that this is an effective antimicrobial and has effects at low concentration. As this is a well known antimicrobial and a member of a class of antimicrobials mentioned by Class et all, an artisan in this field would attempt this therapy with a reasonable expectation of success.
Class et al and Hoeksema et al render obvious either substituting histone H2A for histone H1, or adding it to the mixture with polymyxin. Thus, the combination of references renders obvious claims 2, 10, 18, and 22.
Class et al mentions surgery, rendering obvious claims 4 and 5.
Deugelavicius et al render obvious using polymyxin B as the polymyxin of Class et al, rendering obvious claims 15, and 19.
In general, differences in concentration are not a patentable distinction absent secondary considerations, because it is assumed that a person of skill in the art will optimize that parameter. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”) (MPEP2144.05.II). Note that Deugelavicius et al show that polymyxin B has activity at concentrations similar to that claimed by applicants. Thus, the combination of references renders obvious claims 16 and 26.
response to applicant’s arguments
Applicants argue that the compositions would not be expected to work in the presence of Mg ions, that both histones and polymyxin are toxic, so would not be used in a patient, that none of the references disclose the claimed concentrations, that the polymyxin concentration is lower than would be expected to be effective, and that it is unexpected that the formulation show synergistic behavior.
Applicant's arguments filed 9 Feb, 2026 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to Mg concentration and synergy have been presented previously, and are not persuasive for reasons of record.
Applicants argue that both histones and polymyxin are toxic, so a person of skill in the art would not use them. However, everything is toxic in a large enough dose; even water is poisonous if enough is taken (Hilton, CHHE blog post of 4 Jan, 2016). The idea of optimizing the dose is to avoid subtherapeutic dosages while preserving safety (Le Tourenau et al, J. Natl. Canc. Inst. (2009) 101 p708-720, p708, 1st column, 2nd paragraph). The mere fact that a compound has toxicity is not sufficient to prevent its use as a drug; if that was the standard, no drugs would ever be used.
Applicants argue that none of the claimed concentrations are disclosed. However, applicants have not explained why the rationale behind the rejection of the claimed dosages, that it is standard to optimize concentrations, is invalid or incorrect. Every drug and drug combination used must have undergone a dose optimization; that is the point of the phase I clinical trial (Le Tourneau et al, abstract); a person of skill in the art would be familiar with how to do such an optimization.
Applicants argue that the amount of polymyxin used would be considered too low to be effective. Applicants appear to be conflating antimicrobial effects of this drug with permeabilization discussed by Daugelavicius et al. That reference shows that the lowest concentration tested, which is slightly higher than that of applicants, still permeabilized microbes. It is not clear why applicants feel that it is surprising that the concentration they used is lower than would be expected to work.
New Rejections
Claim Rejections - 35 USC § 112(b)
The legal basis for rejections under this statute was given above, and will not be repeated here.
Claims 1, 8, and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 has the active method step of “administer” the histone. This verb is not commonly used outside of in vivo (drugs are not typically “administered” to petri dishes). However, there is no patient described and the preamble is broad enough to include in vitro embodiments. This makes it unclear if the active method step limits the claims to in vivo embodiments or not.
Claim Rejections - 35 USC § 103
The legal basis for rejections under this statute were given above, and will not be repeated here.
Claim(s) 1, 2, 4, 5, 8, 10, 15, 16, 18, 19, 22, and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over Class et al (US 20010046976, cited by applicants) in view of Hoeksema et al (Future Microbiol. (2016) 11(3) p441-453), Daugelavicius et al (Antimicrob. Agents. Chemother. (2000) 44(11) p2969-2978), and Nishikawa et al (Acute Med. Surg. (2018) 5 p222-229).
The teachings of Class, Hoeksema et al, and Daugelavicius et al were given above, and will not be repeated here. Please note that those references render obvious claims 2,4, 5, 10, 15, 16, 18, 19, 25, and 26.
The difference between these references and the remaining claims is that these references do not specify a free magnesium level of over 1 mM.
Nishikawa et al discuss hypermagnesemia patients (title). These patients had very high levels of plasma Mg, averaging 6 mg/dL (p223, 1st column, 2nd paragraph), corresponding to 2.5 mM (0.06 g/L/24 g/mole). This was measured using a weak chelating agent (p223, 1st column, 1st paragraph), indicating that free Mg levels were what was measured. Several of these patients had infections, such as pneumonia, urinary tract infections, or bloodstream infection (table 1, p225, all of page).
Therefore, it would be obvious to treat the infections of Nishikawa et al with the histones and polymyxins of Class et al, Hoeksema et al, and Daugelavicius et al, to provide an antimicrobial effect as described by those references. As these compounds are known in the art for this purpose, an artisan in this field would attempt this therapy with a reasonable expectation of success.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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, Melissa can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658