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 . Claims included in the prosecution are claims 30, 31, 35, 38, 39, 41, 50 and 51.
Applicants' arguments, filed 08/24/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
1. Claims 30, 35, 38, 39, 41 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Huigens et al. (WO 2017/053696 A2, Mar. 30, 2017) (hereinafter Huigens) in view of Zhanel et al. (Subinhibitory antimicrobial concentrations: A review of in vitro and in vivo data, 1992) (hereinafter Zhanel).
Huigens discloses halogenated quinoline derivatives, such as compounds of Formula (I’):
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The halogenated quinoline derivates may be useful in preventing or treating a microbial infection (e.g., a bacterial infection) in a subject (abstract). RG and RE are each a halogen. RC may be H. RH may be
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, wherein RD and RB may each be H, RA may be a substituted or unsubstituted alkyl, and RK’ may be a substituted or unsubstituted C1-6 alkyl (claim 1). Halogens include chlorine (-Cl) (¶ [0066]). RA may be specifically Me (¶ [00124]). Examples of C1-6 alkyls include methyl (¶ [0046]). The compound may be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which are different from the compound and may be useful as, e.g., combination therapies (¶ [00246]). Exemplary additional pharmaceutical agents include a tetracycline (e.g., doxycycline) (¶ [00247]). The bacterium may be a multidrug-resistant bacterium. The bacterium may be a Gram-positive bacterium. The bacterium may be a Streptococcus species, such as Streptococcus pneumoniae (¶ [00267]).
Huigens differs from the instant claims insofar as not disclosing wherein the zinc ionophore is administered to a subject in an amount that is subinhibitory to the bacterial infection in the absence of the antibiotic.
However, Zhanel discloses wherein antimicrobial activity is not an “all or none” effect. An increase in the rate and extent of antimicrobial action is usually observed over a wide range of antimicrobial concentrations. Subinhibitory antimicrobial concentrations are well known to product significant antibacterial effects, and various antimicrobials at subinhibitory concentrations have been reported to inhibit the rate of bacterial growth (abstract).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to have administered the compound of Huigens in amount that is subinhibitory to the bacterial infection since the compound is useful in preventing or treating a microbial infection and a subinhibitory concentration is a known and effective concentration for antimicrobials to inhibit the rate of bacterial growth as taught by Zhanel.
In regards to instant claim 30 reciting wherein the zinc ionophore confers sensitivity of the bacterium to the antibiotic and increases the amount of zinc in the bacterium, the prior art discloses substantially the same compound as the claimed invention. Therefore, the compound of the prior art necessarily confers sensitivity of the bacterium to the antibiotic and increases the amount of zinc in the bacterium like the claimed invention.
2. Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Huigens et al. (WO 2017/053696 A2, Mar. 30, 2017) (hereinafter Huigens) in view of Zhanel et al. (Subinhibitory antimicrobial concentrations: A review of in vitro and in vivo data, 1992) (hereinafter Zhanel), and further in view of Jordan et al. (US 7,846,919, Dec. 7, 2010) (hereinafter Jordan), as evidenced by Barnham et al. (US 2008/0161353, Jul. 3, 2008) (hereinafter Barnham).
The teachings Huigens and Zhanel are discussed above. Huigens and Zhanel do not teach wherein the compound is in combination with a pharmaceutically acceptable zinc (II) salt.
However, Jordan discloses a composition for use in treating epithelial lesions formed of a combination of ingredients comprising 8-hydroxyquinoline and zinc bonded to said 8-hydroxyquinoline (claim 1). The zinc is provided in the composition as zinc chloride (claim 4).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to have the compound of Huigens in combination with zinc chloride motivated by the desire to additionally treat epithelial lesions since the combination of an 8-hydroxyquinoline and zinc treats epithelial lesions as taught by Jordan.
As evidenced by Barnham, the compound of Huigens is 8-hydroxyquinoline derivative PBT 1033 (pages 9 and 65):
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3. Claim 50 is rejected under 35 U.S.C. 103 as being unpatentable over Huigens et al. (WO 2017/053696 A2, Mar. 30, 2017) (hereinafter Huigens) in view of Zhanel et al. (Subinhibitory antimicrobial concentrations: A review of in vitro and in vivo data, 1992) (hereinafter Zhanel), Jordan et al. (US 7,846,919, Dec. 7, 2010) (hereinafter Jordan), and further in view of Nguyen et al. (Structures of the copper and zinc complexes of PBT2, a chelating agent evaluated as potential drug for neurodegenerative diseases, Nov. 4, 2016) (hereinafter Nguyen).
The teachings of Huigens, Zhanel, and Jordan are discussed above. Huigens, Zhanel, and Jordan do not disclose wherein the compound and the zinc (II) salt are in the form of a zinc (II) coordination complex.
However, Nguyen discloses Zn(PBT2)2Cl (Figure 5 motif B).
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Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. Jordan discloses wherein the combination of an 8-hydroxyquinoline and zinc treats epithelial lesions. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to incorporated Zn(PBT2)2Cl as the halogenated quinoline derivative of Huigens since it is a known and effective 8-hydroxyquinoline in combination with zinc as taught by Nguyen.
Response to Arguments
Applicant argues that the current specification teaches the opposite at paragraph [0319]; namely, that a sub-inhibitory concentration of the zinc ionophore PBT2 alone failed to reduce the bacterial burden at the site of infection.
The Examiner does not find Applicant’s argument to be persuasive. Paragraph [0319] does not disclose wherein a sub-inhibitory concentration of zinc ionophore PBT2 alone fails to reduce the bacterial burden at the site of infection. Paragraph [0319] discloses results from using a sub-inhibitory concentration of PBT2+zinc(II) ions. Thus, Applicant has not provided objective evidence showing wherein a sub-inhibitory concentration of zinc ionophore PBT2 alone fails to reduce bacterial burden. Moreover, paragraph [0319] describes Figure 3 of the instant specification. Figure 3 does show wherein a sub-inhibitory concentration of the zinc ionophore PBT2+Zn reduces some bacterial burden. Applicant even argues on page 8 of the remarks wherein Figure 3 demonstrates wherein a sub-inhibitory amount of the zinc ionophore in the presence of zinc did not significantly reduce the bacterial burden, but the combination of PBT2+Zn+Tet significantly reduced the number of bacteria at the site of infection. Not significantly reducing bacterial burden does not mean bacterial burden is not reduced at all. Thus, Applicant’s argument that a sub-inhibitory concentrations of the zinc ionophore without an antibiotic would not reduce bacterial burden is not persuasive. Also, even if an antibiotic is required, as discussed in the rejection, Huigens does teach addition of an antibiotic such as doxycycline. As such, Applicant’s argument is unpersuasive.
Applicant argues that they have surprisingly discovered that administration of a sub-inhibitory amount of the zinc ionophore or a or a sub-inhibitory amount of the zinc ionophore in combination with zinc provides significant advantages in the treatment of bacterial infections.
The Examiner does not find Applicant’s argument to be persuasive. Applicant shows in Fig. 3 wherein the combination of PBT2+Zn+Tet is more effective at reducing bacterial burden compared to PBT2+Zn. Applicant shows in Fig. 4 wherein PBT2+Collstin is more effective at reducing bacterial burden compared to PBT2. Thus, zinc ionophore alone or in combination with zinc does not appear to provide significant advantages. Zinc ionophore alone or in combination with zinc with the addition of an antibiotic appears to provide advantages. However, such showing does not appear to be unexpected. Paragraph [00245] of Huigens discloses wherein the compounds can be administered in combination with additional pharmaceutical agents to improve their potency or efficacy. Huigens discloses in paragraph [00246] wherein suitable additional pharmaceutical agents include an antibiotic, such as doxycycline. Thus, one of ordinary skill in the art would reasonably expect the combination of zinc ionophore alone or with zinc with the additional of an antibiotic to have improved reduction of bacterial burden compared to zinc ionophore alone or with zinc. Applicant has not shown wherein use of a sub-inhibitory amount is critical. As such, Applicant’s argument is unpersuasive.
Conclusion
Claims 30, 31, 35, 38, 39, 41, 50 and 51 are rejected.
Claims 36 and 40 have been withdrawn.
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 TRACY LIU whose telephone number is (571)270-5115. The examiner can normally be reached Mon-Fri 9 am - 5 pm.
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/TRACY LIU/Primary Examiner, Art Unit 1614
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