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
This Office Action is responsive to Applicant’s amendment and remarks, filed on 04/22/2026 in which claims 3, 15, and 30-21 were amended, claims 1-2, 4-9, 12-14, 16-19, and 23-27 were cancelled, and claims 32-33 were newly added. Claims 3, 10-11, 15, 20-22, and 28-33 are pending in the instant application and are examined on the merits herein.
Priority
This application is a National Stage Application of PCT/EP2020/086511 filed on 12/16/2020 and claims foreign priority to EPO 19216548.8 filed on 12/16/2019.
Withdrawn Rejections
Applicant’s amendment, filed on 04/22/2026, with respect to the rejection of claims 1 and 23-25 under 35 U.S.C. 102(a)(1) as being anticipated by Pruteanu et al (EP 3524237 A1, published 08/14/2019, IDS dated 11/06/2022) has been fully considered and is persuasive. Applicant has cancelled claims 1 and 23-25 rendering the rejection moot. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 04/22/2026, with respect to the rejection of claims 1, and 23-26 under 35 U.S.C. 103 as being unpatentable over Collins et al. (US 2015/0071904 A1, published 03/12/2015, PTO-892 dated 08/20/2025), has been fully considered and is persuasive. Applicant has canceled claims 1 and 23-26, rendering the rejections moot. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 04/22/2026, with respect to the rejection of claims 27 under 35 U.S.C. 103 as being unpatentable over Pruteanu et al. (EP 3524237 A1, published 08/14/2019, see IDS dated 11/06/2022) and Collins et al. (US 2015/0071904 A1, published 03/12/2015, PTO-892 dated 08/20/2025), has been fully considered and is persuasive. Applicant has canceled claims 27, rendering the rejection moot. The rejection is hereby withdrawn.
Rejections Necessitated by Amendment
The following are new ground(s) necessitated by Applicants' amendment, filed on 04/22/2026, wherein instant independent claims 3 and 15 were amended to alter the breadth and scope of the claim and wherein the remaining pending claims 10-11, 20-22, and 28-33 depend from said independent claims 3 and 15.
Modified and New Grounds of Rejection
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 3, 10-11, 30, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Collins et al (US 2015/0071904 A1, published 03/12/2015, see PTO-892).
Collins is drawn to compositions and methods comprising reactive oxygen species (ROS) target modulators that increase ROS flux and endogenous ROS production, thereby potentiating oxidate attack by antibiotics and biocides (abstract). Collins teachings that ROS production can be predictably enhanced in bacteria thereby increasing the bacteria’s susceptibility to oxidative attack. Collins created a model capable of predicting ROS production in E. coli and other bacteria. The metabolic network models were systematically perturbed and flux distributions analyzed to identify targets predicted to increase ROS production (paragraph 0005). Collins teaches a method for inhibiting a bacterial infection by increasing ROS production in a bacteria, the method comprising administering to a subject having or at risk for a bacterial infection an effective amount of a pharmaceutical composition comprising one or more ROS target modulator compounds and an antibiotic agent (paragraph 0007). A ROS target modulator compound could be an inhibitor of NADH dehydrogenase such as dicumarol (paragraph 0014). Any of the major classes of antibiotic agents in which bactericidal activity is potentiated or enhanced by inhibiting ROS production can be used with the ROS target modulators such as azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim (paragraph 0200). Therapeutic formulations of one or more ROS target modulator compounds with/without an antibiotic agent can be prepared by mixing an antibiotic agent and/or ROS target modulator compound having the desired degree of purity with one or more pharmaceutically acceptable carriers, excipients or stabilizers (paragraph 0302). The pharmaceutical composition may be administered as tablets and capsules in which case solid pharmaceutical excipients are used. The tablets can be coated (paragraph 0313). The composition may be administered as an inhalation mixture (paragraph 0324). Other examples of administration are creams, ointments, and lozenges (paragraph 0306).
Collins does not exemplify a composition containing both dicumarol and azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim.
It would have been prima facie obvious to select a composition comprising both dicumarol and azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim before the effective filing date of the claimed invention to arrive at the claimed invention. It would have been prima facie obvious for a person of ordinary skill in the art to select a composition containing both dicumarol and azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim because Collins teaches a pharmaceutical composition containing both a ROS target modulator and an antibiotic in which the bactericidal activity is enhanced by ROS production. One of ordinary skill in the art would have a reasonable expectation of success because Collins further teaches that dicumarol is a ROS target modulator and azithromycin, sisomicin, linezolid, dirithromycin, clindamycin and trimethoprim are antibiotics in which the bactericidal activity is enhanced by ROS production.
Regarding instant claim 3, it is noted that the prior art does not exemplify the composition can be used in the manner instantly claimed, for antagonizing a first bacterium that is a commensal species and not antagonizing the antibacterial effect of at least one second compound listed in instant claim 3. However, the cited recitations are considered an “intended use” of the claimed composition. The “intended use” of the claimed composition does not patentably distinguish the composition, per se, since the composition would be capable of performing the intended use. In order to be limiting, the intended use must create a structural difference between the claimed composition and the prior art composition. In the instant case, the intended use does not create a structural difference, thus the intended use is not limiting.
Regarding instant claim 10, it is noted that the prior art does not teach that the second compound is for the use in the treatment of a bacterial infection selected from the list of infections found in instant claim 10. However, the cited recitations are considered an “intended use” of the claimed composition. The “intended use” of the claimed composition does not patentably distinguish the composition, per se, since the composition would be capable of performing the intended use. In order to be limiting, the intended use must create a structural difference between the claimed composition and the prior art composition. In the instant case, the intended use does not create a structural difference, thus the intended use is not limiting.
Claims 15, 20-22, 28-29, 31 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Pruteanu et al (EP 3524237 A1, published 08/14/2019, see IDS dated 11/06/2022) and Collins et al (US 2015/0071904 A1, published 03/12/2015, see PTO-892).
Pruteanu is drawn to the repurposing of compounds for the treatment of infections and for modulating the composition of the gut microbiome (title). Pruteanu teaches that dicumarol is a compound for use in the modification of the growth of bacterial cells (claim 1). The bacterial cells are selected from Gram-positive bacteria, Gram-negative bacteria, Streptococcus, Staphylococcus, and Bacteroides (claim 2). The dicumarol may be administered to a human to modify the growth of bacterial cells in said subject wherein modifying the growth of bacterial cells results in the prevention and/or treatment of a disease (claim 3). Pruteanu teaches that the disease may be dysbiosis (claim 4). Pruteanu teaches that dicumarol may be used in a pharmaceutical composition for use in the prevention and/or treatment of a disease in a subject and/or in the modification of the composition of the microbiome of subject. The pharmaceutical composition may also contain a pharmaceutically acceptable additive, carrier, diluent, solvent, filter, lubricant, excipient, binder, and/or stabilizer (claim 14). Pruteanu tested the inhibitory effect of dicumarol and found that it was not specifically inhibitory to P. vulgatus and was inhibitory to streptococcus parasanguinis and streptococcus salivarius (Table 7, page 36).
Pruteanu does not teach the combined administration of dicumarol and a azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim. Pruteanu does not teach the specific pathogenic bacterium S. aureus or S. pneumoniae as recited in claim 25. Pruteanu does not teach the functional limitation of dicumarol antagonizing an antibacterial effect of a macrolide in a commensal species and not antagonizing the macrolide antibacterial effect on a pathogenic species.
The teachings of Collins are discussed above.
Collins further teaches the bacterial infection involves one or more of E. coli, Streptococcus pneumoniae, or Staphylococcus aureus (paragraph 0052). One of the key advantages of the method, uses and compositions of Collins is the ability of producing marked anti-bacterial effects in a human subject having a bacterial infection and thereby increasing bacterial sensitivity and susceptibility to a variety of antibiotic classes, as well as reducing toxicities and adverse effects. In some embodiments the dosage of the antibiotic administered may be reduced relative to the normally administered dosage (paragraph 0294).
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Pruteanu and Collins before the effective filing date of the claimed invention by modifying the method for treating dysbiosis with a composition containing dicumarol taught by Pruteanu to also co-administer azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim as taught by Collins to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the method for treating dysbiosis with a composition containing dicumarol taught by Pruteanu by co-administering azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim because Collins teaches the co-administration of dicumarol and azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim for improved anti-bacterial effect. One of ordinary skill in the art would have a reasonable expectation of success because Pruteanu teaches that dicumarol may be used to treat dysbiosis and can inhibit Streptococcus and Staphylococcus, which are pathogenic bacteria, but not inhibit P. vulgatus, which is a commensal bacteria, and Collins teaches that dicumarol may be used to improve the anti-bacterial effect of erythromycin towards the pathogenic bacterium S. aureus or S. pneumoniae. Additionally, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Therefore, although the functional limitation is not directly taught by Pruteanu or Collins, the combination of Pruteanu and Collins suggests that the combination of dicumarol and azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim to treat abnormalities in the gut microbiome, such as dysbiosis. The administration of the combination would naturally lead to the claimed results arising from the structural properties of dicumarol combined with azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim.
Response to Arguments
Applicant's arguments filed 04/22/2026 have been fully considered but they are not persuasive.
Regarding the rejection of claims 3, 10, 11, 23-26, and 30 under 35 U.S.C. §103 as being unpatentable over Collins, applicant argues that the claims no longer recite erythromycin and, instead, require a pharmaceutical composition comprising dicumarol in combination with a specifically defined set of antibiotics and that although Collins et al. generally discloses combining a ROS target modulator with an antibiotic, they fail to teach or suggest the specific combinations now claimed. Applicant further argues that Collins lists dicumarol among a large number of ROS target modulators and a large list of antibiotics without any guidance, preference or direction towards the particular selections. A prior art reference listing a variety of compounds does not inherently make a specific combination of those compounds obvious. A mere listing of compounds in a list, without additional motivation, suggestion, or teaching for specific combinations, is insufficient to make the combination obvious. The arguments are unpersuasive. Collins teaches the method of inhibiting a bacterial infection comprising administering to a subject a pharmaceutical composition comprising a ROS target modulator and antibiotic agent and further teaches that the target modulator can be dicumarol and the antibiotic can be azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim. It would have been obvious to select any of the disclosed ROS target modulators and antibiotics because they are all disclosed to have the same function and therefore one of ordinary skill would reasonably combine any of the listed ROS target modulators with any of the listed antibiotics to create a pharmaceutical composition.
Applicant argues that Collins teaches a composition to enhance ROS production to increase bacteria’s susceptibility to oxidative attack and is not directed to the intended use of the instant invention. The argument is not persuasive. Regarding the mode of action, the instant claims are composition claims, therefore the intended use is not limiting. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Regarding the rection of instant claims 15, 20-22, and 27-30 under 35 U.S.C. §103 as being unpatentable over Pruteanu and Collins, applicant argues that Pruteanu does not teach the combined administration of dicumarol and at least one second compound for use in treating dysbiosis, wherein dicumarol antagonizes the antibacterial effect of the recited at least one second compound in a commensal species and does not antagonize the antibacterial effect of the recited at least one second compound in a pathogenic bacterium. Applicant argues that neither Pruteanu or Collins provides a motivation to specifically select a combination of dicumarol and the at least one second compound for treating dysbiosis and that there would be no reasonable expectation to arrive at the combined use of dicumarol and the at least one second compound for the differential antagonistic behavior with respect to different bacterial populations. The argument is not persuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Collins teaches the co-administration of dicumarol and azithromycin, sisomicin, linezolid, dirithromycin, clindamycin, or trimethoprim for improved anti-bacterial effect.
Conclusion
No claims are allowed.
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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/S.L.S./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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