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 .
Priority
This application, filed on 10/30/2020, claims priority from U.S. Provisional Application No. 62/664,884, filed on 04/30/2018 and 62/730,993 filed on 09/13/2018.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 03/26/2021, 03/22/2022, 02/28/2023, 06/15/2023, 08/24/2023, 04/24/2024 and 03/13/2025 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits, except where noted.
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/08/2024 has been entered.
The Amendments and Applicant’s Arguments submitted on 02/05/2025 have been received and its contents have been carefully considered.
Claim 14 was amended, and claims 4-6 and 11 were previously cancelled. Claims 1-3, 7-10 and 12-16 are pending.
Withdrawn Claim Rejections - 35 USC § 103
Claims 1-3, 7-10, and 12-16 rejected under 35 U.S.C. 103 as being unpatentable over M. Draper et al. (WO 2016/154332 A1, 09/29/2016) in view of J. Lashinsky et al. (Infect Dis Ther. 2017 Jun;6(2):199-211. doi: 10.1007/s40121-017-0153-2), is withdrawn in view of Applicant’s persuasive argument submitted on 02/05/2025 against Draper. Applicant argues that Minocycline was one of the early tetracycline antibiotics that Draper was looking to replace with structurally distinct compounds different from minocycline.
Rejection Maintained
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 7-10, and 14-15 rejected under 35 U.S.C. 102(a)(1) as being anticipated by W. Alfouzan, et al. (International Journal of Antimicrobial Agents, Volume 50, Issue 6, 2017, Pages 715-717, ISSN 0924-8579, https://doi.org/10.1016/j.ijantimicag.2017.06.026, “Alfouzan” cited in the previous PTO-892 dated 08/01/2023).
With respect to claims 1-3, Alfouzan discloses a method of treatment of multidrug-resistant bacterial infection including the risk of resistance emergence, against strains of Acinetobacter baumannii by administering minocycline intravenously at a daily dose of 400 mg, [Abstract]. Alfouzan discloses that I.V. minocycline dose of 400 mg/day is administered. [Alfouzan, pg. 717, col. 1, para. 2].
An I.V. dose of 400 mg/day meets the amended claim 1 limitation of “a single dose of from 250 mg to 1000 mg”, because an I.V. is a single dose. Moreover, Alfouzan teaches administration of 200 mg dose of minocycline to achieve the required fAUC exposures with minocycline 76% protein binding. [Pg. 716, col. 1, 3rd para.]. Alfouzan teaches that “Intravenous minocycline dosed at 200 mg/day has been reported as having an AUC0–8h of 67–86 mg/L, and with minocycline 76% protein binding, an fAUC of 18–40 would seem reasonable for a 200 mg IV dose to translate into a pharmacodynamics breakpoint. However, for many strains such exposures are likely to change population profiles and may be associated with the emergence of resistance, and higher doses of MNO have been used in small groups of patients with non-infectious diseases, e.g., 10 mg/kg/day to a maximum dose of 700 mg daily has been used in stroke patients; this provides an AUC24 of 347.7 mg/L.h or an fAUC of 55–110 mg/L ・ [Pg. 717, col. 1, 2nd para.]. Furthermore, Alfouzan teaches that favorable outcome for the treatment of carbapenem-resistant A. baumannii with an intravenous minocycline dose of 400 mg/day has been reported, which support the recommendation of an increased minocycline dose (e.g., 700 mg/day) to avoid the emergence of resistance and to increase the ability to suppress the bacterial load. Therefore, Alfouzan disclosure meets the limitations of claims.
Alfouzan’s dose of 400 mg of minocycline meets the limitations of claims 7-8.
With respect to claims 9-10, Alfouzan discloses that single-compartment dilutional pharmacokinetic model determine that an increased minocycline dose of more than 400 mg/day should be considered when treating Acinetobacter baumannii infections, [Abstract], and a daily dose of 700 mg should be used to avoid the emergence of resistance and to increase the ability to suppress the bacterial load. Moreover, Alfouzan discloses that minocycline dose of 700 mg daily has been used in stroke patients, [Pg. 717, col. 1, 2nd para.], which indicated that higher doses of minocycline has been tested for safety and tolerability. A dose of more than 400 mg or 700 mg reads on claims 9 and 10 doses of 500-1000 mg and 600-1000 mg.
With respect to claims 12, 14, and 15, Alfouzan discloses that higher doses of MNO have been used in small groups of patients with non-infectious diseases, e.g., 10 mg/kg/day to a maximum dose of 700 mg daily has been used in stroke patients. [Pg. 717, col. 1, 2nd para.]. 10 mg/kg is equivalent to 600 mg in human with average weight of 60 kg (10mg/kg x 60kg = 600 mg). Note that 60 kg is the known pharmacologic average weight of human. Alfouzan discloses that the dose frequency was fixed at every 12 h and various concentrations of drug were added to achieve the required fAUC exposures. [Pg. 716, col. 1, 4th para.]. A dose every 12 hours meet the limitation of two times a day.
Response to Arguments
Applicant argues:
Alfouzan refers to 400 mg/day as being the maximum standard 24-hour dose for intravenous minocycline. Alfouzan at abstract (“the maximum standard 24-hr doses of intravenous MNO are used (400 mg/day)’). This does not refer to the testing conducted as part of the research disclosed in the paper but refers instead to the standard maximum daily dose for intravenous minocycline at the time as evidenced by reference to the Minocin® label in” a person of ordinary skill in the art would have understood that the 400 mg/day dose referred to the maximum dosage over the course of 24 hours and that the daily dose was not administered as a single dose over 24 hours but administered in multiple doses, typically at 12-hour intervals. Alfouzan explicitly discloses that the “dose frequency was fixed at every 12 h” and [t]he modelled concentrations were based on the serum pharmacokinetics of a 200 mg dose of MNO” for the dose ranging experiments set forth in the publication. Alfouzan at 716. Alfouzan never discloses or suggests changing dosing frequency from once every 12 hours to once a day. Accordingly, the daily doses referred to in Alfouzan were not for a single dose over 24 hours but for multiple doses administered at 12 hour intervals. Remarks at page 2.
Examiner response:
This argument is not persuasive because while the cited section of Alfouzan, pharmacokinetics, is describing the dosing as every 12 h, there are no explicit or implicit teachings that the doses 400 mg or 700 mg were divided into two doses. It’s not proper to interpret administering an IV dose of 400 as two IV doses of 200 each. Moreover, the pharmacokinetics section teaches that various concentrations of drug were added to achieve the required fAUC exposures. It is not necessary that this AUC exposure is achieved by dividing the various concentration of the IV doses. The reference must be regarded for its teachings and multiple interpretations of its teachings is improper. Alfouzan clearly teaches administering a higher “single” dose of minocycline e.g., 400 mg and 700 mg. This is clearly taught by Alfouzan as Alfouzan teaches administration of different doses of minocycline including 200 mg to achieve the required fAUC exposures. [Pg. 716, col. 1, 3rd para.], and found that 200 mg is favorable to the 100 mg dose as 200 mg IV dose translates into a pharmacodynamics breakpoint. However, for many strains, such exposures are likely to change population profiles and may be associated with the emergence of resistance. In view of this, Alfouzan found that higher single dose of IV minocycline would bring higher exposure and better treatment of carbapenem-resistant A. baumannii, and avoid the emergence of resistance and to increase the ability to suppress the bacterial load. Specifically, Alfouzan teaches that “higher doses of MNO have been used in small groups of patients with non-infectious diseases, e.g., 10 mg/kg/day to a maximum dose of 700 mg daily has been used in stroke patients; this provides an AUC24 of 347.7 mg/L.h or an fAUC of 55–110 mg/L. [Pg. 717, col. 1, 2nd para.]. This teachings of Alfouzan clearly implied that a single dose of 200 mg is increased to 700 mg. moreover, there is no teaching in Alfouzan that the intervenors 400 mg/day is divided to two intravenous doses. Alfouzan discloses that minocycline dose of 700 mg daily has been used in stroke patients, without any teaching that the dose of 700 mg/day is divided into multiple doses. The pharmacokinetics experiments were performed with dose every 12 hours [Alfouzan, pg. 716, 4th], however, Alfouzan discloses explicitly that minocycline is administered as an intravenous dose of 400 mg/day. As such, claim 1 remains anticipated by Alfouzan.
New Rejection
Claim Rejections - 35 USC § 103
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 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.
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.
Claims 13 and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by W. Alfouzan, et al. (International Journal of Antimicrobial Agents, Volume 50, Issue 6, 2017, Pages 715-717, ISSN 0924-8579, https://doi.org/10.1016/j.ijantimicag.2017.06.026, “Alfouzan” cited in the previous PTO-892 dated 08/01/2023) as applied above to claims 1-3,7-10 and 12, in view of J. Lashinsky et al. (Infect Dis Ther. 2017 Jun;6(2):199-211. doi: 10.1007/s40121-017-0153-2, “Lashinsky” cited in the IDS dated 03/26/2021).
As discussed above, Alfouzan discloses a method of treating one or more bacterial infection in a
subject, wherein the infection is carbapenem-resistant, comprising intravenously administering
minocycline to the subject in need thereof at a single dose of from 250 mg to 1000 mg, wherein
the single dose of minocycline is administered from one to four times daily.
Alfouzan discloses that the dose frequency was fixed at every 12 h and various concentrations of drug were added to achieve the required fAUC exposures. [Pg. 716, col. 1, 4th para.].
While Alfouzan discloses that the minocycline doses of 400 mg and 700 mg, and the dose frequency was every 12 hours, Alfouzan does not disclose administering minocycline three times daily from about 1 day to at least 4 weeks.
However, in the same field of endeavor of treating carbapenem-resistant bacterial infection using tetracyclines, Lashinsky teaches the use of minocycline to overcome drug-resistant of Acinetobacter baumannii and in the treatment of infections due to Acinetobacter baumannii. [Abstract].
Lashinsky teaches administration of one-time intravenous dose of 200 mg of minocycline. [Pg. 203, col. 1, last para.]. Lashinsky recommended against dose adjustment downward based on the pharmacokinetics of minocycline. [Pg. 204, 1st para.].
Lashinsky teaches pharmacokinetic studies wherein patients received 200-400 mg daily dose of intravenous minocycline showed that higher doses and intravenous administration could lead to increased exposures further leading to enhanced bactericidal activity. [Pg. 204, col. 2, 2nd para.].
Lashinsky teaches that the patients received minocycline intravenously, at dose of 100 mg twice daily, with or without a loading dose of 200 mg, IV minocycline 200 mg twice daily, an oral minocycline of 200 mg every 6 h, and the treatment was administered for a duration that ranged between 2 days to 7 weeks, according to the source of infection. [Pg. 205, col. 2, 1st para.].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to combine the references and administer the 400 mg, 600 mg, or 700 mg of minocycline taught by Alfouzan two or three times daily from about 1 day to at least 4 weeks in view of Lashinsky. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because discloses that the minocycline doses of 400 mg and 700 mg, and the dose frequency was every 12 hours, and Lashinsky teaches that the patients received minocycline twice daily, and every 6 h for 2 days to 7 weeks. One of ordinary skill in the art would have been motivated to adapt Lashinsky protocol and administered minocycline every 6 hours for at least about 4 weeks because Lashinsky teaches that this administration protocol produced an overall, the clinical success rate of monotherapy or combination treatment of 78.2%, and microbiological cure in 4 studies of from 50% and 89%. [Pg. 205, col. 2, 1st para.]. MPEP 2144.05.II.A explains: “Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Conclusion
Claims 1-3, 7-10, and 12-16 are rejected.
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/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/
Supervisory Patent Examiner, Art Unit 1622