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 .
Election/Restrictions
Applicant’s election of Group I (i.e., claims 1-14 drawn to a method of treating A. baumannii infection with a subtherapeutic dose of rifabutin and polymyxin) and Species A (i.e., a single and specific combination therapy indicating the following: 1. A single and specific polymyxin, Applicants’ Election: Polymyxin B; 1a. a single and specific subtherapeutic dose or range for the elected polymyxin, Applicants’ Election: the subtherapeutic dose of the polymyxin is between about 0.5mg/kg/day and about 0.8mg/kg/day; 2. A single and specific subtherapeutic dose of the rifabutin, Applicants’ Election: the subtherapeutic dose of rifabutin is between about 250 mg/day and about 400 mg/day) in the reply filed on 01/31/2024 are acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 14 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/31/2024.
Upon searching the elected species (i.e., Polymyxin B), additional species were found, e.g., colistin. Accordingly, for purposes of compact prosecution, the election of species is modified only to the extent of examining this additional species. Otherwise the election of species requirement is still retained.
Status of Claims
Claims 1-28 were originally filed on November 1st 2022. The amendment filed on January 31st, 2024 cancelled claims 15-28.
The amendment filed on June 14th 2024, amended claims 1, 3, 9-10, and 12-14; and added new claims 29-31.
The amendment filed on January 6th 2025, amended claims 1-8, 10, 13-14, 29-31; cancelled claims 9 and 12; and added new claim 32.
The amendment filed on November 19th 2025, amended claims 1, 7, 29 and 32; and cancelled claims 2-4 and 6.
Claims 1, 5, 7-8, 10-11, 13, 29-32 are currently pending and under consideration.
Priority
The present application claims the benefit under 35 U.S.C 119 (e) to U.S. Provisional Application No. 63/342,217 filed May 16th, 2022. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C 119 (e) or under 35 U.S.C 120, 121, or 365 (c ) is acknowledged.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 1, regarding the scope of “treating,” it is noted that the instant specification does not define what constitutes “treating.” Pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. The Merriam-Webster Dictionary, defines “treating” as a to act upon with some agent especially to improve or alter (see Merriam-Webster Dictionary, “treating,” available online at https://www.merriam-webster.com/dictionary/treat#:~:text=%3A%20to%20care%20for%20or%20deal,treat%20a%20metal%20with%20acid on 03/06/2024). As such the examiner is interpreting the scope of “treating” an A. baumannii infection in a subject as improving or altering the A. baumannii infection with a dose of rifabutin between about 150 mg/day and 550 mg/day and a dose of the polymyxin that results in an fCtrough below the level required for clinical efficacy if given alone, but the claimed doses do not encompass 100% prevention of the A. baumannii infection in a human subject.
Response to Arguments
1. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to the claim objections, have been fully considered and are persuasive. The claim objection to claim 30 has been withdrawn.
2. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to the claim objections, have been fully considered and are persuasive. The duplicate claim warning of claim 29, has been withdrawn.
3. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement (i.e., inhibition of bacterial growth), have been fully considered and are persuasive. The 35 U.S.C. 112(a) rejection of claims 1-8, 10-11, 13 and 30-32, has been withdrawn.
4. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement (i.e., new matter), have been fully considered and are persuasive. The 35 U.S.C. 112(a) rejection of claim 3, has been withdrawn.
5. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement (i.e., enablement), have been fully considered but are not persuasive. The 35 U.S.C. 112(a) rejection of claim 32, has been maintained.
6. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement (i.e., a large array of insufficient amounts/doses without any necessary dose that would be required to exhibit the instantly claimed function of inhibiting bacterial growth of A. baumannii in a subject), have been fully considered and are persuasive. The 35 U.S.C. 112(a) rejection of claims 1-5, 7-8, 10-11, 13 and 29-32, has been withdrawn.
7. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to the 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 join inventor regards as the invention (i.e., regarding the terms “providing” and “provided”), have been fully considered and are persuasive. The 35 U.S.C. 112(b) rejection of claims 1-5, 7-8, 10-11, 13 and 29-32, has been withdrawn.
8. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to the 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 join inventor regards as the invention (i.e., regarding the term “insufficient”), have been fully considered and are persuasive. The 35 U.S.C. 112(b) rejection of claims 1-5, 7-8, 10-11 and 13, has been withdrawn.
9. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to the 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 join inventor regards as the invention (i.e., regarding the term “sufficient”), have been fully considered and are persuasive. The 35 U.S.C. 112(b) rejection of claims 29-32, has been withdrawn.
10. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to the 35 U.S.C. 102 (a)(1) as anticipated by Cheng et al., Antimicrob Agents Chemother. 2021, vol. 6, issue 4, pp. 1-5 (herein after “Cheng”) as evidenced by Vicari et al., CID, 2013:56, pp.398-404 (herein after “Vicari”); have been fully considered and are persuasive. The 35 U.S.C. 102 (a)(1) rejection of claims 1, 6, 8, 11 and 29, has been withdrawn.
11. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to the 35 U.S.C. 103 as being obvious over Cheng et al., Antimicrob Agents Chemother. 2021, vol. 6, issue 4, pp. 1-5 (herein after “Cheng”) as applied to claim 1 above, in view of US 11,701,346 B2 filed on March 17, 2020 (herein after “Spellberg”); have been fully considered and are persuasive. The 35 U.S.C. 103 rejection of claims 1-4, has been withdrawn.
12. Applicants’ arguments, see Remarks, filed 11/19/2025, with respect to the 35 U.S.C. 103 as being obvious over Cheng et al., Antimicrob Agents Chemother. 2021, vol. 6, issue 4, pp. 1-5 (herein after “Cheng”) as applied to claim 1 above, and Sandri et al., CID, 2013:57, pp. 524-531. (herein after “Sandri et al.”); have been fully considered and are persuasive. The 35 U.S.C. 103 rejection of claims 5, 10, 13, and 30-31, has been withdrawn.
13. Applicants’ arguments, see Response, filed 11/19/2026, with respect to Nonstatutory Double Patenting have been fully considered but they are not persuasive. The Nonstatutory Double Patenting rejections to claims 1-13 and 29-31 are maintained.
Response to Amendment
The Declaration of Glenn E. Dale under 37 CFR 1.132 filed on 11/19/2025 is acknowledged but is rendered insufficient to overcome the rejection of claims 1, 5, 7-8, 10-11, 13 and 29-32 based upon Cheng et al., Antimicrob Agents Chemother. 2021, vol. 6, issue 4, pp. 1-5 (herein after “Cheng”) in view of US 11,701,346 B2 filed on March 17, 2020 (herein after “Spellberg”) and Sandri et al., CID, 2013:57, pp. 524-531. (herein after “Sandri et al.”), as set forth in the last Office action for the following reasons:
Declarant’s assertion of evidence of unexpected results in the prosecution of U.S. Patent Application No. 17/978,647 is found unpersuasive. The phase 2 study described in the abstract provided as part of the evidence (i.e. NCT05685615), describes that rifabutin for infusion (BV100) for the treatment of CRAB (carbapenem-resistant A. baumannii) has a potent antibacterial activity when administered at doses of 200mg or 300 mg q 12h (i.e., 400mg/day and 600 mg/day); when combined with polymyxin B. However, the Declarant’s arguments and the provided Abstract are silent about the dose of polymyxin B administered in combination with the low (i.e., 400mg/day) and high (i.e., 600 mg/day) doses of rifabutin. Declarant’s assertion that the achievement of the strong therapeutic effect of combining a low dose of 400mg/day of rifabutin with an unknown amount of polymyxin B is evidenced by the substantial survival benefit observed in the study, and by the response at test of cure obtained for the BV100 arms (i.e., 400mg/day and 600 mg/day). Additionally, the study compared the Best Available Therapy (BAT) which was 100% colistin (i.e., a polymyxin B analogue) based therapy; and that that the microbiological response at test of cure (ToC), was 75% in the BV100 arms and 50% in the BAT arm and that the clinical cure at ToC was 75% in the combined BV100 arms versus 30% in the BAT arm.
The Declarant argues that the effect of 75% at test of cure and 75% clinical cure at ToC in the BV100 arms compared to BAT was unexpected in view of published data by Duarte-Mangoni et al., 2013 and by Park et al., 2019; where colistin and rifampicin (i.e., an analog of rifabutin) were combined and no benefit on 28/30-day all-cause mortality was observed. The Declarant states that this is very much in contrary to the combination of BV100 plus Polymyxin B even at low doses of BV100. It is the Examiner’s understanding that the Declarant’s statement is in reference to a low dose of rifabutin and an unspecified dose of polymyxin B. Upon reviewing the published data by Duarte-Mangoni et al. 2013, it was confirmed that a dose of 160mg of colistimethate sodium every 8 hrs in combination to 600mg of rifampicin every 12 hrs was administered intravenously (see Duarte-Mangoni et al., pg. 350, right column, last paragraph). Similarly, the published data by Park et al. 2019 confirms that 100mg of colistin sodium methanesulfonate was administered intravenously every 8h; and rifampicin 600 mg was administered orally daily (see Park et al., pg. 67, right column, study protocol).
Pursuant to MPEP 716.02(e), an affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). "A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference." In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). In the instant case, Applicant/Declarant (i.e., Glenn E. Dale) fails to explain, note or evaluate the significance of dose/amount of colistin (i.e., an analog of polymyxin) when combined with the dose/amount of rifampicin (i.e., an analog of rifabutin). The Declarant fails to acknowledge the dose/amount of the polymyxin analog and its role on the strong therapeutic effect of the claimed antibiotic combination in the treatment of A. baumannii infection when compared to the published data by Duarte-Mangoni et al., 2013 and by Park et al., 2019 and the lack of strong therapeutic effect of the combination of antibiotics in the treatment of a subject infected with A. baumannii.
Moreover, pursuant to MPEP 716.02(d), whether the unexpected results are the results of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” The surprising and unexpected results reported by the Declarant are not commensurate in scope with the instant claims, because it is not readily apparent if the results obtained as part of the Phase 2 were obtained by administering a dose of polymyxin that results in an fCtrough below the level required for clinical efficacy of given alone. This uncertainty is due to the fact that the exact amount/dose of polymyxin combined with the doses of BV100 (200mg or 300mg q 12h) is unknown. Therefore, without further clarification of the critical amount/dose of polymyxin combined with the claimed dose of rifabutin (i.e., between 150mg/day and 550/day), a determination of whether the scope of instant claim 1 is commensurate in scope with the unexpected results cannot be made. Therefore, Declarant’s argument of surprising and unexpected results is not persuasive.
Maintained/Modified Rejections in light of Amendments
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
1. Claims 1, 5, 7-8, 10-11, 13 and 29-32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating an A. baumannii infection in a subject, comprising administering a dose of rifabutin and a dose of polymyxin, does not reasonably provide enablement for a method of treating an A. baumannii infection in a human subject infected with A. baumannii by administering a dose of rifabutin and a dose of a polymyxin wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day and wherein the dose of the Polymyxin, or species of polymyxin (i.e., polymyxin B), results in an fCtrough below the level required for clinical efficacy if given alone, as recited in instant claims 1 and 29.
Likewise, the specification does not reasonable provide enablement for a method of treating an A. baumannii infection in a subject, the method comprising administering to a human subject infected with A. baumannii a dose of rifabutin and a dose of a polymyxin selected from polymyxin B, colistin methane sulfonate, SPR206, QPX9003, MRX-8, and Pol7306, wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day, and wherein, the dose of polymyxin B is between about 0.5 mg/kg/day and about 0.8 mg/kg/day, the dose of colistin methane sulfonate is between about 0.8mg/kg/day and about 1.6 mg/kg/day, and the dose of SPR206, QPX9003, MRX-8, or Pol7306 results in an fCtrough inhibiting growth about 5% to about 50% of strains in a test panel of 100 or more recent A. baumannii clinical isolates, as recited in instant claim 32.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, "The Federal Circuit has repeatedly held that "the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation'." In re Wriqht, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)" (emphasis added). The "make and use the full scope of the invention without undue experimentation" language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: "A lack of enablement for the full scope of a claim, however, is a legitimate rejection." The principle was explicitly affirmed most recently in Auto. Tech. Int'l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortriqht, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessarily needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The eight In re Wands factors are applied to claims 1, 5, 7-8, 10-11, 13 and 29-32 as follows:
The Breadth of the Claims and The Nature of the Invention
Claims 1, 29 and 32 are drawn to “a method of treating A. baumannii infection in a human subject by administering a dose of rifabutin between about 150 mg/day and 550 mg/day and a dose of polymyxin (or a polymyxin species: i.e., polymyxin B, colistin methane sulfonate, SPR206, QPX9003, MRX-8 and Pol7306), wherein the dose of polymyxin B results in an fCtrough below the level required for clinical efficacy if given alone” as recited in claims 1 and 29. And “wherein the dose of polymyxin B is between about 0.5 mg/kg/day and about 0.8 mg/kg/day, the dose of colistin methane sulfonate is between about 0.8 mg/kg/day and about 1.6 mg/kg/day, and the dose of SPR206, QPX9003, MRX-8, or Pol7306 results in an fCtrough inhibiting growth about 5% to about 50% of strains in a test panel of 100 or more recent A. baumannii clinical isolates”, as recited in claim 32.
In other words, Applicants claim treating the A. baumannii infection in a human subject by administering several species and doses of polymyxin (i.e., polymyxin B, colistin methane sulfonate and SPR206, QPX9003, MRX-8 and POL) combined with a dose of rifabutin between about 150 mg/day and 550 mg/day. However, details disclosed in the specification do not show that a human subject infected with A. baumannii can be treated with a dose of rifabutin between about 150 mg/day and 550 mg/day and the combination of the polymyxins at the amounts recited in claim 1, 29 and 32.
Accordingly, claims 1, 29 and 32 are unduly broad with respect to treating A. baumannii infection in a human subject by providing a dose of rifabutin between about 150 mg/day and 550 mg/day and a dose of polymyxin B, colistin methane sulfonate, SPR206, QPX9003, MRX-8 and Pol7306; wherein the dose of polymyxin B is between about 0.5 mg/kg/day and about 0.8 mg/kg/day, the dose of colistin methane sulfonate is between about 0.8 mg/kg/day and about 1.6 mg/kg/day, and the dose of SPR206, QPX9003, MRX-8, or Pol7306 results in an fCtrough inhibiting growth about 5% to about 50% of strains in a test panel of 100 or more recent A. baumannii clinical isolates
The State of the Prior Art
With regard to the state of the art, it is known that a rifabutin oral dose of 900–1200 mg per day for 1 week is a rational choice for adjunctive therapy of A. baumannii infections (see Phillips et al., Open Forum Infectious Diseases, 2020, pp. 1-9 at pg. 1, abstract). This dosage maximizes AUC24 to drive efficacy while simultaneously minimizing toxicity (see Phillips et al., pg. 1, abstract). Furthermore, studies show significant inter-person variability of bioavailability with standard 300-mg daily oral dosing (see Phillips et al., pg. 2, left column, paragraph 4). Its Cmax is dose-dependent, ranging from 0.16 μg/mL after administration of a single 150-mg capsule to 0.9 μg/mL after a single 900-mg administration (see Phillips et al., pg. 2, right column, paragraph 1). Doses >900 mg/d were not associated with further increases in Cmax, ranging from 0.4 μg/mL to 1 μg/mL (see Phillips et al., pg. 2, right column, paragraph 1). Like its Cmax, rifabutin’s AUC24 increases in a dose dependent manner, approximately proportionate manner up to 900 mg per day (see Phillips et al., pg. 2, right column, paragraph 2 and Table 2). At 1200 mg, the AUC24 rises slightly and less than proportionately further (see Phillips et al., pg. 2, right column, paragraph 2). The drug’s AUC24 decreases with chronic use, with a 45% decrease observed in AUC after 21–28 days of daily oral administration (see Phillips et al., pg. 2, right column, paragraph 2).
Similarly, it is known that despite the renewed interest in polymyxin B for treatment of multidrug resistant Gram-negative bacteria, optimal dosing strategies remain unclear as they are largely based on population pharmacokinetics (see Avedissian et al., Antibiotics 2019, vol. 8, 31, pp. 1-11 at pg. 8, paragraph 1). Initial product labelling recommended dosing IV polymyxin B at 1.5–2.5 mg/kg/day divided into two daily doses (see Avedissian et al., pg. 8, paragraph 1). Tsuji et al. also disclose that an AUC across 24 hours at steady state target (AUC ss,24 hr) of 20-100 mg*hr/L, corresponding to a target average steady state plasma concentration (Css,avg) of 2-4mg/L, may be acceptable from a toxicity standpoint (see Tsuji et al., Pharmacotherapy 2019; vol 39 (1), pp.10–39 at pg. 14, left column, first paragraph). Additionally, it is known that colistin, a species of polymyxin, is increasingly used for the treatment of multidrug-resistant gram-negative infections (see Vicari et al., CID, 2013:56, pp.398-404, at pg. 398, Background). However, colistin dosing varies greatly and the optimal regimen is unknown (see Vicari et al., at pg. 398, Background). Similarly, Sandri et al., also teach that Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria (see Sandri et al., CID 2013:57, pp. 524-531 at pg. 524, Background). There are no scientifically based dosing guidelines for polymyxin B due to the lack of solid PK information (see Sandri et al., pg. 525, left column paragraph 2). Thus the state of the art recognizes the standard therapeutic doses of both rifabutin and polymyxin (i.e., polymyxin B and colistin) maintain a plasma concentration of each without causing toxicity, additionally, the state of the art also recognizes that there are no scientifically based dosing guides for the polymyxin species (i.e., Polymyxin B and Colistin). Therefore, the level of predictability in the art is dependent on many factors including inter-person variability of bioavailability, dose dependent efficacy of treatment, bacterial strain (i.e., multidrug-resistant, gram stain, etc.). Accordingly, the prior art demonstrates that the scope of claims 1, 29 and 32 encompass treating an A. baumannii infection in a human subject that would require undue experimentation given the many factors vary when providing polymyxin and rifabutin as a treatment.
The Level of Skill in the Art
Practitioners in this art (medical clinicians, pharmacists, doctors and/or pharmaceutical chemists, researches) would presumably be highly skilled in the art of treating an A. baumannii infection in a human subject.
The Level of Predictability in the Art
The court has indicated that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. (See In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970)). In the instant case, Applicants do not demonstrate that administering to a human subject infected with A. baumannii a dose of rifabutin and a dose of polymyxin, wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day and wherein the dose of polymyxin results in an fCtrough below the level required for clinical efficacy if given alone; treats the A. baumannii infection.
Applicants also fail to demonstrate that administering to a human subject infected with A. baumannii the dose of polymyxin B between about 0.5mg/kg/day and about 0.8 mg/kg/day, the dose of colistin methane sulfonate between about 0.8 mg/kg/day and about 1.6 mg/kg/day, and the dose of SPR206, QPX9003, MRX-8 and Pol7306 results in an fCtrough inhibiting growth about 5% to about 50% of strains in a test panel of 100 or more recent A. baumannii clinical isolates, treats the infection A. baumannii infection in a human subject.
Rather, Applicants only demonstrate that rifabutin in the presence of members of the polymyxin family of antibiotics at sub MIC (sub trough concentrations) show synergistic effect (see specification, Example 1, pg. 9-10 and FIGs. 1-2); that the combination of rifabutin with one of the polymyxin, provided together at low dosages is highly and rapidly bactericidal, indicating that the combination is synergistic and protects from resistance development (bacterial regrowth) (see specification, Example 2 and FIGs. 3-4); and that the combination of rifabutin with polymyxin B, provided together at low dosages, is highly and rapidly bactericidal, indicating that the combination is synergistic and protects from resistance development (bacterial growth) even at very low concentrations of rifabutin (see specification, Example 3 and FIGs. 5-6).
Thus, Applicants appear to rely on the assumption that by providing evidence based on the effects on number of strains and CFU depending on the dose and/or compound applied to the bacterial populations in vitro would treat an A. baumannii infection in a human subject. However, such an assumption cannot be made because there is no indication that treating a human subject by administering a dose of rifabutin, a dose of polymyxin B, a dose of colistin methane sulfonate and a dose of SPR206, QPX9003, MRX-8 and Pol7306 as claimed, treats the A. baumannii infection. Therefore, it is unpredictable that the claimed method would treat an A. baumannii infection in a human subject.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
The specification does not enable any person skilled in the art to which it pertains (i.e. treating an A. baumannii infection in a human subject) by administering a dose of rifabutin and a dose of a polymyxin wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day and wherein the dose of the Polymyxin, or species of polymyxin (i.e., polymyxin B), results in an fCtrough below the level required for clinical efficacy if given alone, as recited in instant claims 1 and 29.
Nor enables any person skilled in the art to which it pertains (i.e. treating an A. baumannii infection in a human subject) by administering a dose of rifabutin and a dose of a polymyxin selected from polymyxin B, colistin methane sulfonate, SPR206, QPX9003, MRX-8, and Pol7306, wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day, and wherein, the dose of polymyxin B is between about 0.5 mg/kg/day and about 0.8 mg/kg/day, the dose of colistin methane sulfonate is between about 0.8mg/kg/day and about 1.6 mg/kg/day, and the dose of SPR206, QPX9003, MRX-8, or Pol7306 results in an fCtrough inhibiting growth about 5% to about 50% of strains in a test panel of 100 or more recent A. baumannii clinical isolates, as recited in instant claim 32.
In other words, the specification does not enable any person skilled in the art to which it pertains, to make and/or use the invention commensurate in scope with the claims. There is a lack of adequate guidance from the specification or prior art with regard to the actual treatment of an A. baumannii infection by administering to a human subject the claimed antibiotic combinations (i.e., rifabutin and polymyxin or species of polymyxin at the claimed dose/amounts (i.e., 0.5 mg/kg/day and about 0.8 mg/kg/day; or about 0.8mg/kg/day and about 1.6 mg/kg/day) or at unspecified range amounts (i.e., fCtrough below the level required for clinical efficacy if given alone) without resorting to undue experimentation.
Absent a reasonable a priori expectation of success for treating an A. baumannii infection in a human subject by administering a dose of rifabutin and a dose of a polymyxin wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day and wherein the dose of the Polymyxin, or species of polymyxin (i.e., polymyxin B), results in an fCtrough below the level required for clinical efficacy if given alone; or by administering a dose of rifabutin and a dose of a polymyxin selected from polymyxin B, colistin methane sulfonate, SPR206, QPX9003, MRX-8, and Pol7306, wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day, and wherein, the dose of polymyxin B is between about 0.5 mg/kg/day and about 0.8 mg/kg/day, the dose of colistin methane sulfonate is between about 0.8mg/kg/day and about 1.6 mg/kg/day, and the dose of SPR206, QPX9003, MRX-8, or Pol7306 results in an fCtrough inhibiting growth about 5% to about 50% of strains in a test panel of 100 or more recent A. baumannii clinical isolates; one skilled in the art would have to extensively test many various combinations and/or amounts. Since each prospective embodiment, and indeed future embodiments as the art progresses, would have to be empirically tested, and those which initially failed tested further, an undue amount of experimentation would be required to practice the invention as it is claimed in its current scope, because the specification provides inadequate guidance to do otherwise.
The amount of direction or guidance presented in the specification is limited to that the combination of rifabutin with one of the polymyxin, provided together at low dosages is highly and rapidly bactericidal, indicating that the combination is synergistic and protects from resistance development (bacterial regrowth) as disclosed in the instant specification. Moreover, as noted in “Breadth of the Claims and Nature of the Invention" and “The Level of Predictability in the Art” Sections, treatment of an A. baumannii infection in a human subject with polymyxin and rifabutin is influenced by many factors, such as inter-person variability of bioavailability, dose dependent efficacy of treatment, bacterial strain (i.e., multidrug-resistant, gram stain, etc.). Thus, the data described in the Specification may not be indicative of valid results. In the absence of such information, a person of ordinary skill in the art would reasonably require an undue quantity of experimentation.
The Quantity of Experimentation Necessary
In light of the unpredictability surrounding the claimed subject matter, the undue breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. One wishing to practice the presently claimed invention would have to produce additional data and experimentation to determine whether an A. baumannii infection can be treated by administering the instantly claimed amounts of polymyxin and rifabutin.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 1, 29 and 32, in view of the Applicants’ entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the invention as claimed in claims 1, 5, 7-8, 10-11, 13 and 29-32 would not be enabled by the written disclosure for treating an A. baumannii infection in a human subject by administering a dose of rifabutin and a dose of polymyxin, does not reasonably provide enablement for a method of treating an A. baumannii infection in a human subject infected with A. baumannii by administering a dose of rifabutin and a dose of a polymyxin wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day and wherein the dose of the Polymyxin, or species of polymyxin (i.e., polymyxin B), results in an fCtrough below the level required for clinical efficacy if given alone.
Therefore, claims 1, 5, 7-8, 10-11, 13 and 29-32 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art in treating an A. baumannii infection in a human subject.
New Rejection Necessitated by Amendment
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.
2. Claims 1, 7, 10-11, 29 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over US 11,701,346 B2 filed on March 17, 2020 (herein after “Spellberg”) as evidenced by Vicari et al., CID, 2013:56, pp.398-404 (herein after “Vicari”); Lu et al., Infect Drug Resist. 2021 14:1979–1988 (herein after “Lu”) and Karakonstantis et al., Antibiotics 2021, 10, 1344 (herein after “Karakonstantis”).
Regarding claims 1, 29 and 32, Spellberg teaches methods and compositions related to the treatment of Acinetobacter infections in humans with rifabutin (see column 2, lines 39-42). Spellberg also teaches that the rifabutin is co-administered with colistin but not with another therapeutically active agent, and that the administered amount of the rifabutin with the colistin is effective for improving survival of the mammalian subject compared to a mammalian subject infected with the Acinetobacter who is not administered with a therapeutically active agent or who is administered with the rifabutin as a sole therapeutically active agent (see column 34, claims 1-2 and 14). Thereby corresponding to a method of treating an A. baumannii infection in a subject, the method comprising administering to a human subject infected with A. baumannii a dose of rifabutin and a dose of a polymyxin.
As evidenced by Vicari, it is known that colistin, a species of polymyxin, is increasingly used for the treatment of multidrug-resistant gram-negative infections (see pg. 398, Background).
Spellberg adds that in some embodiments, the rifabutin is administered in a dose of 60mg to 600mg per day (see column 2, lines 66-67 and column 34, claims 8-9 and 18). The MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Thereby corresponding to wherein the dose of rifabutin is between about 150mg/day and about 550mg/day. However, Spellberg does not expressly teach wherein the dose of the colistin (i.e., polymyxin) results in an fCtrough below the level required for clinical efficacy if given alone.
Lu’s work discusses the clinical efficacy of polymyxin B in patients infected with Carbapenem-Resistant Organisms (CROs) (see pg. 1971, Title). Lu teaches that in the International Consensus Guidelines for the Optimal Use of the Polymyxins published in 2019; the recommended daily dose of polymyxin B (PMB) is 1.25-1.50 mg/kg (q12h), and a loading dose of 2.0-2.5 mg/kg is suggested (see pg. 1985, left column, first paragraph). However, the median daily dose of PMB in Lu’s study was 0.86 mg/kg (q12h) (see pg. 1985, left column, first paragraph). Furthermore, the recommended dose given by the PMB manufacturer was 500000-1000000 IU divided into two administrations per day, and the median daily dose in Lu’s study was 1000000 IU (see pg. 1985, left column, first paragraph). Hence the daily dose in Lu’s study was lower than that recommended in guideless but in accordance with manufacturer’s instructions (see pg. 1985, left column, first paragraph). Lu also teaches that the recommended dose in the manufacturer’s instructions was lower than that in the guidelines (see pg. 1985, left column, first paragraph).
With respect to the clinical efficacy of the polymyxin if given alone; Lu’s study involved CRO-infected patients treated with PMB for ≥72 h, and the endpoint indicator was clinical efficacy, the characteristics (demographics, pathogenic bacteria, PMB treatment) between patients who had “clinical success” (CS) and “clinical failure” (CF) were compared (see pg. 1979, abstract). Lu’s Table 1, depicts the clinical characteristics and parameters of patients in the CS group and CF group after PMB treatment (see pg. 1982, Table 1). “CS” was defined as improvements of microbiologic and clinical symptoms and parameters including body temperature, APACHE II score, biochemistry indicators of infection (White blood cell count in adults ≤ 109, C-reactive protein ≤ 10mg/L, Procalcitonin < 0.05ng/mL, erythrocyte sedimentation rate < 15mm/h), twice negative culture results at least, control of infection symptoms and clinician documented improvements at the end of treatment (see pg. 1980, right column, paragraph 3). “CF” was defined as failure to meet all the criteria for CS and deterioration/persistence of infection symptoms or death (see pg. 1980, right column, paragraph 3). As it can be observed in Lu’s Table 1, the “failure” column depicts the loading dose (i.e., 50 mg/d), the maintenance dose (100mg/day), the total cumulative dose (800 mg/day), the dose per kg (i.e., 0.86 mg/kg/q12h) and the daily PMB dose (i.e., 100 mg) (see pg. 1982, Table 1). Thereby Lu’s administered polymyxin doses (i.e., loading dose, maintenance dose, total cumulative dose, dose per kg and daily PMB dose are suggestive of the dose of polymyxin that results in an fCtrough below the level required for clinical efficacy if given alone.
The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not Applicants' dose of the polymyxin results in an fCtrough below the level required for clinical efficacy if given alone, and if so to what extent, from the median daily dose of PMB in Lu’s study (i.e., 0.86 mg/kg (q12h). Lu’s loading dose (i.e., 50 mg/d), the maintenance dose (100mg/day), the total cumulative dose (800 mg/day), the dose per kg (i.e., 0.86 mg/kg/q12h) and the daily PMB dose (i.e., 100 mg) dose of polymyxin is similar to the claimed dose of polymyxin because the clinical efficacy of subjects that were administered Lu’s doses exhibited deterioration/persistence of infection symptoms or death (i.e., clinical failure). The cited art taken as a whole demonstrates a reasonable probability Lu’s dose of polymyxin is either identical or sufficiently similar to the claimed dose of the polymyxin that results in an fCtrough below the level required for clinical efficacy if given alone and that whatever differences exist are not patentably significant. Therefore, the burden of establishing novelty or unobviousness by objective evidence is shifted to applicants.
Additionally, Karakonstantis teaches a systematic review of antimicrobial combination options for pandrug-resistant Acinetobacter baumannii (see pg. 1, Title). Karakonstantis teaches that polymyxin-based combinations were the most studied, with several studies demonstrating synergy against eligible A. baumannii isolates (see pg. 5, second paragraph). Also that polymyxins may be combined, either as double or as triple combinations, with a variety of antimicrobials, including carbapenems, sulbactam, fosfomycin, rifampicin, rifabutin (which has recently been shown to be much more potent than rifampicin and may retain activity even against pandrug-resistant A. baumannii (PDRAB) (see pg. 8, paragraph 2). Synergy with many of these combinations was achievable at concentrations ≤ established breakpoints of resistance and demonstratable in animal models and/or dynamic in vitro PK/PD studies simulating human treatment regimens (see pg. 8, paragraph 3). However, synergy is not universal and not applicable to every A. baumannii strain (see pg. 8, paragraph 3). Clinically relevant synergy may be less likely for strains with very high MICs; for example, clinically-relevant synergy between polymyxins and carbapenems appears to be less likely for isolates with high carbapenem MIC (see pg. 8, paragraph 3). Moreover, as demonstrated Karakonstantis’ review, studies often fail to assess the clinical relevance of reported synergy, as evidenced by the evaluation for synergy at antimicrobial concentration unlikely to be clinically relevant or lack of reporting of concentrations at which synergy is present (see pg. 9, paragraph 2). For example, an FIC index ≤ 0.5 in checkerboard assay does not necessarily prove clinically relevant synergy if antimicrobials are synergistic at concentrations higher than those achievable in vivo at the site of the infection (see pg. 9, paragraph 2). Similarly, in time-kill assays antimicrobials should ideally be used in concentrations achievable at the site of infection, which is often not the case (see pg. 9, paragraph 2). Karakonstantis concludes that numerous antimicrobial combinations have been evaluated and several appear to be active at clinically relevant concentrations, at least against selected eligible A. baumannii isolates (see pg. 9, last paragraph). However, studies often do not report the concentrations at which synergy is observed or use antimicrobials at concentrations unlikely to be clinically relevant (see pg. 9, last paragraph).
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Spellberg’s method of treating Acinetobacter infections in humans with rifabutin co-administered with colistin by administering a lower than recommended dose of polymyxin, in order to arrive at the claimed invention. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because it was known that CRO-infected patients administered polymyxin alone at a loading dose of 50 mg/d, a maintenance dose of 100mg/day, a total cumulative dose of 800 mg/day, the dose per kg of 0.86 mg/kg/q12h and the daily PMB dose of 100 mg failed to meet all the criteria for clinical success (i.e., improvements of microbiologic and clinical symptoms and parameters including body temperature, APACHE II score, biochemistry indicators of infection (White blood cell count in adults ≤ 109, C-reactive protein ≤ 10mg/L, Procalcitonin < 0.05ng/mL, erythrocyte sedimentation rate < 15mm/h), twice negative culture results at least, control of infection symptoms and clinician documented improvements at the end of treatment), exhibited deterioration/persistence of infection symptoms or death as taught by Lu.
One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated with reasonable expectation of success to incorporate Lu’s teachings at part of Spellberg’s method of treating Acinetobacter infections in humans given that polymyxin-based combinations for pandrug-resistant Acinetobacter baumannii are the most studied because synergy between polymyxins combined with a variety of antimicrobials, including carbapenems, sulbactam, fosfomycin, rifampicin, rifabutin, was achievable at concentrations ≤ established breakpoints of resistance and demonstratable in animal models and/or dynamic in vitro PK/PD studies simulating human treatment regimens, as taught by Karakonstantis. One of ordinary skill would have been motivated with reasonable expectation of success given that numerous antimicrobial combinations have been evaluated and several appear to be active at clinically relevant concentrations, at least against selected eligible A. baumannii isolates; and given that studies often fail to assess the clinical relevance of reported synergy, as evidenced by the evaluation for synergy at antimicrobial concentration unlikely to be clinically relevant or lack of reporting of concentrations at which synergy is present as taught by Karakonstantis. Therefore, incorporating Lu’s teachings as part of a method of treating Acinetobacter infections in humans with rifabutin co-administered with colistin by administering a lower than recommended dose of polymyxin, would support the instantly claimed method by constituting some teaching, suggestion, or motivation in the prior art that would have let one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Regarding claim 7, Spellberg teaches that the rifabutin is administered in a dose of 60mg to 600mg per day (see column 2, lines 66-67 and column 34, claims 8-9 and 18). The MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Thereby corresponding to wherein the dose of rifabutin is between about 150mg/day and about 550mg/day.
Regarding claim 10, Lu teaches that the median daily dose of PMB was 0.86 mg/kg (q12h) (see pg. 1985, left column, first paragraph). Thereby corresponding to wherein the dose of the polymyxin is about 90mg/day or less as recited in instant claim 10.
Regarding claim 11, Spellberg teaches that the method comprises a time lag of at least about 4 h between administration of the rifabutin and administration of the colistin (see column 34, claim 4, lines 23-25). Thereby corresponding to wherein the rifabutin and the polymyxin are provided separately.
Regarding claim 13, Lu teaches that the median daily dose of PMB was 0.86 mg/kg (q12h) (see pg. 1985, left column, first paragraph). The MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Thereby corresponding to wherein the dose of the polymyxin is between about 0.8mg/kg/day and about 1.6 mg/kg/day, as recites in instant claim 13.
3. Claims 5 and 30-31 are rejected under 35 U.S.C. 103 as being obvious over US 11,701,346 B2 filed on March 17, 2020 (herein after “Spellberg”) as evidenced by Vicari et al., CID, 2013:56, pp.398-404 (herein after “Vicari”), and Lu et al., Infect Drug Resist. 2021 14:1979–1988 (herein after “Lu”) as applied to claim 1 above; and Sandri et al., CID, 2013:57, pp. 524-531. (herein after “Sandri et al.”).
See discussion of Spellberg and Lu above.
Spellberg teaches a method of treating a mammalian subject infected with Acinetobacter, comprising: administering to the mammalian subject a therapeutically effective amount of rifabutin and colistin (see column 34, claim 14).
Lu teaches that in the International Consensus Guidelines for the Optimal Use of the Polymyxins published in 2019; the recommended daily dose of polymyxin B (PMB) is 1.25-1.50 mg/kg (q12h), and a loading dose of 2.0-2.5 mg/kg is suggested (see pg. 1985, left column, first paragraph). However, the median daily dose of PMB in Lu’s study was 0.86 mg/kg (q12h) (see pg. 1985, left column, first paragraph). Furthermore, the recommended dose given by the PMB manufacturer was 500000-1000000 IU divided into two administrations per day, and the median daily dose in Lu’s study was 1000000 IU (see pg. 1985, left column, first paragraph). Hence the daily dose in Lu’s study was lower than that recommended in guideless but in accordance with manufacturer’s instructions (see pg. 1985, left column, first paragraph). Lu also teaches that the recommended dose in the manufacturer’s instructions was lower than that in the guidelines (see pg. 1985, left column, first paragraph). However, Spellberg nor Lu expressly teach wherein the dose of the polymyxin (i.e., colistin), is less than about half of a standard therapeutic dose as recited in instant claim 5.
Sandri teaches that Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria (see pg. 524, Background). However, there are no scientifically based dosing guidelines for polymyxin B due to the lack of solid pharmacokinetics (PK) information (see pg. 525, left column, paragraph 2). Sandri also teaches that that the physician-selected dose of polymyxin B was 0.45–3.38 mg/kg/day; 23 patients received the drug every 12 hours, whereas the patient who was prescribed the lowest daily dose received it every 24 hours (see pg. 526, left column, paragraph 3). The AUC over a day (AUC0–24 hours) from the population PK analysis was 66.9 ± 21.6 mg/hour/L (range, 16.4–117 mg/hour/L), and therefore the average steady-state plasma concentration (Css,avg, i.e., AUC0–24 hours/24 hours) was 2.79 ± 0.90 mg/L (range, 0.68–4.88 mg/L) (see pg. 526, left column, paragraph 4). Sandri adds that as polymyxin B total body clearance (CL) was not related to creatine clearance (CrCL), its daily doses should not be based on renal function (see pg. 529, left column, paragraph 2). This contrasts strongly with colistin wherein daily doses need to be tailored to renal function (see pg. 529, left column, paragraph 2). Therefore, the teachings of Spellberg when combined with the teachings of Sandri suggest the claim limitations recited in instant claim 5, wherein the dose of the polymyxin is less than about half of a standard therapeutic dose.
For claims 30-31 and the dose of polymyxin, it is noted that wherein a dose of a polymyxin results in an fCtrough below the level required for clinical efficacy if given alone is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Therefore, a dose of a polymyxin that results in an fCtrough below the level required for clinical efficacy if given alone, wherein the dose is any of the amounts recited in instant claims 30-31, is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal dose of a polymyxin needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to modify the dose of polymyxin as taught by Lu which resulted in clinical failure of CRO-infected subjects thereby resulting wherein the dose of the polymyxin is less than about half of a standard therapeutic dose, because an ordinary skilled artisan would have been able to utilize the teachings of Sandri to obtain various dose parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of a dose of a polymyxin that results in an fCtrough below the level required for clinical efficacy if given alone, wherein the dose is about 60mg/day as recited in claim 30 or is between about 0.5 mg/kg/day and about 0.8 mg/kg/day as recited in claim 31; would have been obvious at the time of Applicants' invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed limitations recited in instant claims 30-31..
Therefore one of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated with reasonable expectation of success to combine the teachings of Sandri with the teachings of Lu and administer a dose of 0.45 mg/kg/day or 0.86 mg/kg (q12h) of polymyxin B in order to arrive at the claimed method of treating an A. baumannii infection in a human subject, wherein the dose is less than about half of a standard therapeutic dose. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because patients who were prescribed the lowest daily dose of polymyxin ( i.e., 0.45 mg/kg/day) received the dose every 24hrs and because the average steady-state plasma concentration (Css,avg, i.e., AUC0–24 hours/24 hours) was 2.79 ± 0.90 mg/L (range, 0.68–4.88 mg/L). One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that subjects who received a median daily dose of 0.86 mg/kg (q12h) exhibited clinical failure (i.e., deterioration/persistence of infection symptoms or death) as taught by Lu. Therefore, incorporating a dose of 0.45 mg/kg/day of polymyxin as part of a rifabutin-colistin combination treatment of A. baumannii infection, would support a method of treating an A. baumannii infection in a subject, the method comprising a dose of polymyxin that is less than about half of a standard therapeutic dose by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
3. Claim 8 is rejected under 35 U.S.C. 103 as being obvious over US 11,701,346 B2 filed on March 17, 2020 (herein after “Spellberg”) as evidenced by Vicari et al., CID, 2013:56, pp.398-404 (herein after “Vicari”), and Lu et al., Infect Drug Resist. 2021 14:1979–1988 (herein after “Lu”) as applied to claim 1 above; and Cheng et al., Antimicrob Agents Chemother. 2021, vol. 6, issue 4, pp. 1-5 (herein after “Cheng”).
See discussion of Spellberg and Lu above.
Spellberg teaches a method of treating a mammalian subject infected with Acinetobacter, comprising: administering to the mammalian subject a therapeutically effective amount of rifabutin and colistin (i.e., polymyxin) (see column 34, claim 14). However, Spellberg does not expressly teach wherein the rifabutin and the polymyxin are provided in a single formulation.
Cheng teaches that interactions between rifabutin and colistin, the last-resort drug for carbapenem-resistant infections (see pg. 1, abstract). Rifabutin and colistin were synergistic in vitro and in vivo, and low-dose colistin significantly suppressed emergence of resistance to rifabutin (see pg. 1, abstract). Thus, this combination is a promising therapeutic option for highly resistant A. baumannii infections (see pg. 1, abstract). Cheng discloses the efficacy of rifabutin colistin combination treatment in vivo (see pg. 4, FIG. 3, Description). In particular, FIG. 3A depicts percent survival of mice infected with 1.2 x 107 to 3.9 x107 CFU of the hypervirulent (100% lethal dose [LD100] , 2 <107CFU) carbapenem-resistant A. baumannii HUMC1which were treated with PBS, 0.05mg/kg RBT, 0.005mg/kg COL, or a combination of RBT and COL (see pg. 4, FIG. 3A, Description). It is noted that the percent survival (i.e., 100%) corresponds to mice that were administered a sufficient dose of rifabutin (i.e., 0.05 mg/kg) and a dose of colistin (i.e., 0.005 mg/kg) together (see pg. 4, FIG. 3A). However when the dose of rifabutin (i.e., 0.05 mg/kg) and the dose of colistin (i.e., 0.005 mg/kg) were administered individually to the infected mice, the percent survival is below 100%; therefore the individual doses when administered individually are insufficient to inhibit bacterial growth (see pg. 4, FIG. 3A). Cheng’s FIG. 3 discloses the efficacy of rifabutin colistin combination treatment in vivo (see pg. 4), thereby corresponding to wherein the rifabutin and the polymyxin and provided in a single formulation.
The Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Spellberg with the teachings of Cheng in order to arrive at the claimed invention, wherein the rifabutin and the polymyxin are provided in a single formulation. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because it was known that rifabutin and colistin were synergistic in vitro and in vivo, and low-dose colistin significantly suppressed emergence of resistance to rifabutin as taught by Cheng. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because had a reasonable expectation of success given that the efficacy of rifabutin-colistin combination treatment in vivo against A. baumannii infection correlates with 100% survival as demonstrated by Cheng. Therefore administering rifabutin colistin combination treatment would support a method of treating an A. baumannii infection in a subject wherein the dose of rifabutin and the polymyxin are provided in a single formulation by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
1. Applicants’ arguments with respect to the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement (i.e., enablement), have been fully considered but are not persuasive for the following reasons:
Applicants assert that the specification provides ample guidance and representative examples to enable the full scope of claim 32 (see Remarks, filed 11/19/2025, pg. 7, first paragraph).
However, the 35 U.S.C. 112(a) rejection has been modified to include claims 1, 5, 7-8, 10-11, 13 and 29-32. As discussed in the rejection above, the specification does not reasonably provide enablement for a method of treating an A. baumannii infection in a human subject infected with A. baumannii by administering a dose of rifabutin and a dose of a polymyxin wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day and wherein the dose of the Polymyxin, or species of polymyxin (i.e., polymyxin B), results in an fCtrough below the level required for clinical efficacy if given alone, as recited in instant claims 1 and 29.
Nor does it provide reasonable provide enablement for a method of treating an A. baumannii infection in a subject, the method comprising administering to a human subject infected with A. baumannii a dose of rifabutin and a dose of a polymyxin selected from polymyxin B, colistin methane sulfonate, SPR206, QPX9003, MRX-8, and Pol7306, wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day, and wherein, the dose of polymyxin B is between about 0.5 mg/kg/day and about 0.8 mg/kg/day, the dose of colistin methane sulfonate is between about 0.8mg/kg/day and about 1.6 mg/kg/day, and the dose of SPR206, QPX9003, MRX-8, or Pol7306 results in an fCtrough inhibiting growth about 5% to about 50% of strains in a test panel of 100 or more recent A. baumannii clinical isolates, as recited in instant claim 32.
It is acknowledged that Figures 1, 2, and 4 provide data for polymyxin and colistin, as well as synthetic derivatives such as SPR206. However amended claims 1, 29 and 32 are not fully supported by the disclosure. As discussed in the 35 U.S.C. 112(a) rejection above, the level of predictability in the art with respect to the dose of a polymyxin is relatively high because there are no scientifically based dosing guidelines for polymyxin due to the lack of pharmacokinetic information and because is predictability also depends on many factors including inter-person variability of bioavailability, dose dependent efficacy of treatment, bacterial strain (i.e., multidrug-resistant, gram stain, etc.). Therefore, it is unpredictable that the claimed method would treat an A. baumannii infection in a human subject.
Additionally, the prior art applied in the 35 U.S.C 103 rejection also teaches that synergy is not universal and not applicable to every A. baumannii strain; clinically relevant synergy may be less likely for strains with very high MICs; for example, clinically-relevant synergy between polymyxins and carbapenems appears to be less likely for isolates with high carbapenem MIC; time-kill assays antimicrobials should ideally be used in concentrations achievable at the site of infection, which is often not the case. Accordingly, the 35 U.S.C. 112(a) rejection is maintained because the instant specification calls for a undue amount of experimentation to make and use the instantly claimed method of treating an A. baumannii infection in a subject.
2. Applicant's arguments with respect to the 35 U.S.C. 103 rejection of claims 1, 5, 7-8, 10-11, 13, 29-32, have been fully considered but they are not persuasive for the following reasons:
Applicants assert that the amended claims are nonobvious over the cited references, in particularly over Spellberg and Sandri . More specifically, Applicants attest that Spellberg’s disclosure of a 60-600 mg/day rifabutin dose is intended to be a therapeutic dose and that Spellberg does not provide teaching or motivation to select a dose from this range that is intentionally ineffective on its own (see remarks, filed 11/19/2025, pg. 11, second to last paragraph). And that Sandri’s disclosure of 0.45-3.38 mg/kg/day polymyxin B dose is descriptive and observational, and is the de facto standard-of-care doses that physicians prescribed with therapeutic intend (see remarks, filed 11/19/2025, pg. 11, last paragraph). Thus, Applicants argue that the cited references when properly understood in their respective contexts, teach away from the “subtherapeutic synergy” strategy explicitly recited in the amended independent claims (see remarks, filed 11/19/2025, pg. 11, paragraph 2).
It is the Examiner’s understanding that Applicants are suggesting that the dose of rifabutin taught by Spellberg (i.e., 60-600 mg/day) and the dose of polymyxin taught by Sandri (i.e., 0.45-3.38 mg/kg/day) teach away from the “subtherapeutic synergy” strategy recited in the amended claims. However, pursuant to MPEP 2123 (II), “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
Spellberg’s and Sandri’s teachings are not reverse teachings that stand in opposition to the claimed invention as Applicants attest. Rather they are preferred embodiments. Additionally, the prior art applied (i.e., Lu et al. and Karakonstantis et al.) in the current 35 U.S.C. 103 rejection supports the obviousness rejection of claims 1, 5, 7-8, 10-11, 13, and 29-32 over Spellberg and Sandri.
As discussed in the obviousness rejection above, Lu teaches the clinical efficacy of polymyxin B in patients infected with Carbapenem-Resistant Organisms (CROs) (i.e., A. baumannii), wherein the median daily dose of polymyxin was 0.86 mg/kg (q12h), a dose lower than the recommended International Consensus Guidelines for the Optimal Use of the Polymyxins published in 2019but in accordance with manufacturer’s instructions. Lu evaluated the clinical failure or clinical success of CRO-infected subjects where subjects who failed to meet all the criteria for clinical success (i.e., improvements of microbiologic and clinical symptoms and parameters including body temperature, APACHE II score, biochemistry indicators of infection (White blood cell count in adults ≤ 109, C-reactive protein ≤ 10mg/L, Procalcitonin < 0.05ng/mL, erythrocyte sedimentation rate < 15mm/h), twice negative culture results at least, control of infection symptoms and clinician documented improvements at the end of treatment) and exhibited deterioration/persistence of infection symptoms or death.
Karakonstantis systematic review of antimicrobial combination options for pandrug-resistant Acinetobacter baumannii revealed that synergy is not universal and not applicable to every A. baumannii strain; that synergy studies often fail to assess the clinical relevance of reported synergy, as evidenced by the evaluation for synergy at antimicrobial concentration unlikely to be clinically relevant or lack of reporting of concentrations at which synergy is present; that numerous polymyxin-based combinations have been evaluated and several appear to be active at clinically relevant concentrations, at least against selected eligible A. baumannii isolates; that an FIC index ≤ 0.5 in checkerboard assay does not necessarily prove clinically relevant synergy if antimicrobials are synergistic at concentrations higher than those achievable in vivo at the site of the infection; and that in time-kill assays antimicrobials should ideally be used in concentrations achievable at the site of infection, which is often not the case.
Therefore, the amended claims are obvious over the cited references, because an ordinary skilled artisan would have been motivated with reasonable expectation of success after reading Spellberg, Sandri, Lu and Karakonstantis to treat a human subject infected with A. baumannii with doses intended to be therapeutic.
3. Applicants’ arguments with respect to the Objective Evidence of Non-Obviousness: Unexpectedly Superior Results in Human Clinical Trials (see remarks, filed 11/19/2025, pp. 12-13), have been fully considered but they are not persuasive for the following reasons:
Pursuant to MPEP 716.02(c)(II), expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). Additionally, pursuant to MPEP 2143.02(II), obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). In other words, it is not a requirement for the therapeutic doses of Spellberg and Sandri to exhibit a synergistic effect because the prior art has already demonstrated that that numerous polymyxin based combinations have been evaluated and several appear to be active at clinically relevant concentrations as taught by Karakonstantis.
As discussed in the “Response to Amendment” section above, the Declarant’s arguments and the provided Abstract of phase 2 study NCT05685615 are silent about the dose of polymyxin B administered in combination with the 400mg/day (i.e., low) dose of rifabutin and the 600 mg/day (i.e., high) dose of rifabutin. The Examiner notes that the “powerful, objective evidence of non -obviousness” submitted in the declaration of Glenn E. Dale under 37 CFR 1.132 is congruent with the teachings of Karakonstantis; that synergy studies often lack reporting of concentrations at which synergy is observed or use antimicrobials at concentrations unlikely to be clinically relevant. Accordingly, the results provided by the declarant are expected and thereby obvious.
Furthermore, even if the unexpected results were evidence of unobviousness; pursuant under MPEP 716.02(d), whether the unexpected results are the results of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”
With respect to claim 1, the scope of the claimed method comprises administering a composition wherein the dose of rifabutin is between about 150 mg/day and 550 mg/day and wherein the dose of the Polymyxin results in an fCtrough below the level required for clinical efficacy if given alone. Thus, the scope of claim 1 encompasses administration of rifabutin doses ranging between 135mg/day and 165mg/day (i.e., about 150mg/day) and 495mg/day and 605mg/day (i.e., about 550mg/day). When reviewing the evidence provided in the specification, the specification does not support details pertaining to the specifics of the composition (i.e., dose of rifabutin) that improves or alters an A. baumannii infection in a human subject. Instead, the instant specification teaches amounts at antimicrobial concentrations that aid in determining the MIC data and time-kill curve data for both antibiotics as depicted in figures 1-6 of the instant specification. Therefore, the unexpected results are not commensurate in scope with the instant claims.
Accordingly, claims 1, 5, 7-8, 10-11, 13, 29-32 stand rejected under 35 U.S.C. 103.
Maintained/Modified Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
5. Claims 1, 5, 7-8, 10-11, 13 and 29-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 8-9, 11, 14 and 19 of US 11,207,305 (Trebosc et al.) Date of Patent: Dec. 28, 2021, in view of US 11,701,346 B2 filed on March 17, 2020 (herein after “Spellberg”), Lu et al., Infect Drug Resist. 2021 14:1979–1988 (herein after “Lu”), Karakonstantis et al., Antibiotics 2021, 10, 1344 (herein after “Karakonstantis”), and Sandri et al., CID, 2013:57, pp. 524-531. (herein after “Sandri et al.”).
U.S. US 11,207,305 A1 claims:
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(See U.S. US 11,207,305 claims 1-2, 4, 8-9, 11, 14 and 19). As such, the US 11,207,305 claimed invention encompasses the instant method of treating an A. baumannii infection in a subject, the method comprising providing to a subject infected with A. baumannii rifabutin (as recited in instant claim 1) and a second antibiotic selected from the group consisting of colistin (as a species of polymyxin as recited in instant claim 1) and cefiderocol. However, U.S. 11,207,305 does not claim wherein the dose of rifabutin is between about 150mg/day and about 550mg/day and wherein the dose of the polymyxin results in an fCtrough below the level required for clinical efficacy if given alone as recited in instant claims 1 and 29, or the specific doses as recited in instant claims 1, 5, 7, 10, 13 and 30-32.
Regarding instant claims 1, 5, 7, 10, 13 and 29-32 and a dose of rifabutin and a dose of polymyxin, please see discussion of Spellberg, Lu and Sandri above along with the motivation to combine them. Briefly, an ordinary skilled artisan would be motivated to optimize a dose of rifabutin and a dose of polymyxin B or colistin with a reasonable expectation of success given that low doses of these antibiotics were known to inhibit bacterial growth of A. baumannii. Therefore, the U.S. 11,207,305 claimed invention is not patentably distinct from the instantly claimed invention.
6. Claims 1, 5, 7-8, 10-11, 13 and 29-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-15, and 20-21 of U.S. 11,766,425 (Trebosc et al.) in view of US 11,701,346 B2 filed on March 17, 2020 (herein after “Spellberg”), Lu et al., Infect Drug Resist. 2021 14:1979–1988 (herein after “Lu”), Karakonstantis et al., Antibiotics 2021, 10, 1344 (herein after “Karakonstantis”), and Sandri et al., CID, 2013:57, pp. 524-531. (herein after “Sandri et al.”).
US 11,766,425 Claims:
(See US 11,766,425 claims 1-4, 6-15 and 20-21) As such, the U.S. 11,766,425 claimed invention encompasses the instant method of treating an A. baumannii infection in a subject, the method comprising providing, to a subject infected with A. baumannii rifabutin (as recited in instant claim 1) and a second antibiotic selected from the group consisting of a polymyxin (as recited in instant claim 1). However, US 11,766,425 does not claim wherein the dose of rifabutin is between about 150mg/day and about 550mg/day and wherein the dose of the polymyxin results in an fCtrough below the level required for clinical efficacy if given alone as recited in instant claims 1 and 29, or the specific doses as recited in instant claims 5, 7, 10, 13 and 30-32.
As discussed in the 103 rejection above the dose of rifabutin is between about 150mg/day and about 550mg/day and wherein the dose of the polymyxin results in an fCtrough below the level required for clinical efficacy if given alone, wherein the dose of rifabutin is any of the amounts recited in instant claims 7, and the dose of polymyxin is any amount recited in instant claims 5, 10, 13, 30-32 are clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal dose of rifabutin needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to modify the dose of polymyxin as taught by Lu and Sandri for treating Acinetobacter infections in humans, thereby resulting the dose of the polymyxin results in an fCtrough below the level required for clinical efficacy if given alone, because an ordinary skilled artisan would have been able to utilize the teachings of Spellberg, Lu and Sandri to obtain various dose parameters with a reasonable expectation of success.
Therefore, the U.S. US 11,766,425 claimed invention is not patentably distinct from the instantly claimed invention.
7. Claims 1-8, 10-11, 13 and 29-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4 and 8-9, 14, and 18-19 of copending Application No. 18/465,226 (Trebosc et al. US Publication No. 20240000759 A1) in view of view of Cheng et al., Antimicrob Agents Chemother. 2021, vol. 6, issue 4, pp. 1-5 (herein after “Cheng”); US 11,701,346 B2 filed on March 17, 2020 (herein after “Spellberg”), and Sandri et al., CID, 2013:57, pp. 524-531. (herein after “Sandri et al.”).
Copending Application No. 18/465,226 claim set filed on 03/18/2025:
(see Copending Application No. 18/465,226 claims 1-2, 4, 8-9, 14 and 18-19 filed on 03/18/2025). As such, the copending application No. 18/465,226 claimed invention encompasses the instant method of treating an A. baumannii infection in a subject, but does not claim wherein the dose of rifabutin is between about 150mg/day and about 550mg/day and wherein the dose of the polymyxin results in an fCtrough below the level required for clinical efficacy if given alone as recited in instant claims 1 and 29, or the specific doses as recited in instant claims 5, 7, 10, 13 and 30-32.
As discussed in the 103 rejection above the dose of rifabutin is between about 150mg/day and about 550mg/day and wherein the dose of the polymyxin results in an fCtrough below the level required for clinical efficacy if given alone, wherein the dose of rifabutin is any of the amounts recited in instant claims 7, and the dose of polymyxin is any amount recited in instant claims 5, 10, 13, 30-32 are clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal dose of rifabutin needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to modify the dose of polymyxin as taught by Lu and Sandri for treating Acinetobacter infections in humans, thereby resulting the dose of the polymyxin results in an fCtrough below the level required for clinical efficacy if given alone, because an ordinary skilled artisan would have been able to utilize the teachings of Spellberg, Lu and Sandri to obtain various dose parameters with a reasonable expectation of success. Therefore, the ‘266 copending application encompasses the claimed method.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Regarding Applicants’ argument with respect to nonstatutory double patenting, have been considered but are not persuasive for the following reasons:
Applicants assert that because the pending claims are directed to a specific, non-obvious method of use involving a subtherapeutic dosing regimen that yield unexpectedly superior results in human subjects, the instant claims are patentably distinct from the broad combinations of the reference claims (see remarks, filed 11/19/2025, at pg. 15, second to last paragraph).
Applicants’ attention is directed to the “Response to Amendment” and to the U.S.C 103 rejection above.
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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/CLAUDIA ESPINOSA/ Patent Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654