DETAILED CORRESPONDENCE
This office action is in response to applicant’s filing dated September 10, 2025.
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 .
Status of Claims
Claims 1-3, 13, 16-18, 20, 24, and 25 are pending in the instant application. Acknowledgement is made of Applicant's remarks filed September 10, 2025. Claims 4-12, 14, 15, 19, 21-23, 26, and 27 were previously canceled.
Applicants elected with traverse Group I, drawn to a pharmaceutical composition comprising a therapeutically effective amount of each of linezolid, bedaquiline, and pretomanid or a pharmaceutically acceptable salt of each thereof, and a pharmaceutically acceptable carrier in the reply filed on October 19, 2018. The requirement is still deemed proper.
Claims 1-3, 13, 16-18, 20, 24, and 25 are presently under examination.
Priority
The present application is a national stage entry of PCT/US2016/055414 filed on October 5, 2016, which claims benefit of US Provisional Application No. 62/241,280 filed on October 14, 2015. The effective filing date of the instant application is October 14, 2015.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 28, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, except where marked with a strikethrough.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Maintained Objections and/or Rejections
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.
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.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-3, 13, 16-18, 20, 24, and 25 stand rejected under 35 U.S.C. 103 as being unpatentable over Devito et al (WO 2011/139832 A2, cited in a previous Office Action) in view of Zyvox® Prescribing Information (Pfizer, Pharmacia & Upjohn Company, May 2008, pp 1-35, hereinafter Zyvox®, cited in a previous Office Action), Sirturo™ Prescribing Information (Janssen Therapeutics, December 2012, pp 1-21, hereinafter Sirturo™, cited in a previous Office Action), and Diacon et al (Lancet, 2012; 380:986-93, cited in a previous Office Action).
Regarding claims 1 and 20, Devito teaches a composition for treating a mycobacterial infection in a patient comprising a pharmaceutically effective amount of an antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer (page 9, last paragraph); wherein the antibiotic compound or tautomer thereof or pharmaceutically acceptable salt or prodrug of said compound or tautomer is selected from an oxazolidinone antibiotic compound (page 12, last full paragraph); wherein oxazolidinone antimicrobial compounds include linezolid (page 16, 2nd paragraph). Devito further teaches a composition further comprising an additional pharmaceutical agent, particularly, one or more compounds typically used for treating, preventing, or reducing the risk of an infection caused or mediated by Mycobacterium tuberculosis or a nontuberculous mycobacterium and in particular those infections caused or mediated by resistant or highly virulent strain of a mycobacterium (page 12, 3rd paragraph) wherein the additional compounds include nitroimidazoles like PA-824 and new generation diarylquinolines like TMC207 (page 12, last paragraph). PA-824 is equivalent to pretomanid as evidenced by SciFinder (CAS Registry #187235-37-6) which lists PA-824 as an alternative name for pretomanid. TMC207 is equivalent to bedaquiline as evidenced by SciFinder (CAS Registry #843663-66-1) which lists TMC 207 as an alternative name for bedaquiline.
While the reference may not be anticipatory insofar as one must select linezolid from various oxazolidinone antimicrobial compounds and PA-824/pretomanid and TMC 207/bedaquiline from various additional pharmaceutical agents typically used for treating an infection caused or mediated by Mycobacterium tuberculosis as taught in Devito, it remains that it would have been obvious to a person of ordinary skill in the art, to have selected linezolid from the list of oxazolidinone antimicrobial compounds, and PA-824/pretomanid and TMC 207/bedaquiline from the list of additional pharmaceutical agents in order to arrive at a composition useful for an infection caused or mediated by Mycobacterium tuberculosis. The skilled person would have been motivated to do so by the unambiguous disclosure of each particular species of oxazolidinone antimicrobial compounds and additional pharmaceutical agents taught individually and alternatively as equally useful in a method of treating an infection caused or mediated by Mycobacterium tuberculosis. This conclusion is supported by the fact that it has long been held in patent prosecution that a reference should be considered as expansively as is reasonably possible in determining the full scope of the contents within its four corners.
Devito teaches supplementary active compounds (identified or designed according to the invention and/or known in the art) or tautomers thereof or a pharmaceutically acceptable salts or prodrugs of said compounds or tautomers also can be incorporated into the compositions; the formulations can conveniently be presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy/ microbiology (page 22, lines 32-33); formulations suitable for oral administration can be in the form of discrete units such as capsules, gelatin capsules, and tablets (page 24, lines 3-4). Thus, Devito suggests formulating the disclosed combinations into discrete compositions (i.e. separate compositions) or a single composition and that the formulations can be formulated as tablets. Moreover, Devito teaches throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate a single tablet consisting of linezolid and additional supplementary active compounds, PA-824 and TMC207 in view of the teachings of Devito.
Regarding the amount of linezolid of instant claim 1, Devito teaches generally an effective amount of dosage of active compound will be in the range of from about 0.01 to 100 mg/kg of body weight/day (page 28, 2nd full paragraph) and oxazolidinones were dosed orally at 50 mg/kg (page 35, 4th paragraph). Assuming an average weight of an adult is 60 kg, an amount of 0.01 to 100 mg/kg is equivalent to 0.6 mg to 6 g of linezolid. Moreover, Zyvox® teaches ZYVOX Tablets for oral administration contain 400 mg or 600 mg linezolid as film-coated compressed tablets (page 1; 4th paragraph); and dosage guidelines for Zyvox is 600 mg every 12 hr for adults for infection (Table 14). 600 mg every 12 hr reads on 600 mg bid or 1200 mg. MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed 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). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Regarding the amount of bedaquiline of instant claims 1-3, 13, 17, and 18, Devito does not teach the instantly claimed amounts. However, Sirturo™ teaches each tablet contains bedaquiline fumarate drug substance which is equivalent to 100 mg of bedaquiline (page 11, 2nd paragraph); and SIRTURO is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB) (page 1, 1st paragraph); and dosage and administration is 400 mg once daily (page 1, 2nd paragraph). 400 mg once daily reads on 400 mg. It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize the amount of bedaquiline taught by Sirturo™ as a starting point for optimizing the amount of bedaquiline, for use in a combination comprising linezolid, pretomanid, and bedaquiline with an expectation of success, since the prior art establishes that these amounts of bedaquiline are suitable for use as part of a combination therapy.
Regarding the amount of pretomanid of instant claims 1-3, 16-18, 24, and 25, Devito does not teach the instantly claimed amounts. However, Diacon teaches 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial (title); a 14-day EBA study in treatment naïve patients with sputum-microscopy smear-positive fully drug-susceptible pulmonary tuberculosis assessing various combinations of the new antituberculosis agents bedaquiline, PA-824, and moxifloxacin and the established agent pyrazinamide with a view to developing appropriate combinations for longer-term studies, leading to a tuberculosis regimen for management of drug-susceptible and MDR disease (page 987, left, 2nd paragraph); PA-824 was administered 200 mg a day (page 987, Panel 1).
Moreover, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize the amount of oxazolidinones taught by Devito and ZYVOX as a starting point for optimizing the amount of the oxazolidinone, linezolid; the amount of bedaquiline taught by Sirturo™ as a starting point for optimizing the amount of bedaquiline; and the amount of PA-824/pretomanid taught by Diacon for use in a combination comprising linezolid, pretomanid, and bedaquiline with an expectation of success, because the dosage is a result-effective variable, i.e. a variable that achieves a recognized result and therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Taken together, all this would result in the composition of claims 1-3, 13, 16-18, 20, 24, and 25 with a reasonable expectation of success.
Response to Arguments
Applicant argues:
Applicant submits that with the presently claimed invention, the criticality of the claimed dosage range(s) and the corresponding and exceptionally unexpected and desirable results provided thereby are unambiguously demonstrated at least with regard to Table 3 of the specification, and paragraph 6 et seq. of the Fotouhi Declaration, as previously argued (and argued herein). Applicant respectfully submits that the argument in the non-final Office Action that the evidence of an improved synergistic effect not being great enough, represents a continued mischaracterization and/or misunderstanding of Applicant's evidence as presented in the Fotouhi Declaration. In Table la of the Fotouhi Declaration, the Week 8 results for JPaL50 (0.39) are 72.7% better than for JPaAzi25 (1.43), where the Az (Radezolid) is present at a level that is 2.5 times (250%) greater than that of the L (Linezolid). It is submitted that a skilled artisan would unambiguously recognize and understand that these results are undeniably representative of a significant and exceptional synergistic effect associated with and provided by the presently claimed invention.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
MPEP 716.02 states:
Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). In the instant case, Devito teaches the combination of compounds can be a synergistic combination (page 4, 1st paragraph). Thus, Devito suggests combining the disclosed agents for a synergistic effect. Thus, it is not unexpected that combining linezolid, bedaquiline, and pretomanid would result in a synergistic effect. Moreover, it does not appear that the differences between the combinations are so great as to be unexpected.
In particular, in a review of the Declaration, the differences between the groups in Graphs A and B:
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do not appear to be so great as to be unexpected and of both statistical and practical significance.
Moreover, in a review of the data for JPaL50 and JPaL100 in which it appears that JPaL50 has a greater effect than JPaL100 (0.39±0.26 vs 0.66±0.39). The data provides comparison to JPaAz125. As noted in the response, JPaAz125 has a greater amount than that in JPaL50. It is not clear from the data provided if the results disclosed are due to differences in amounts of the compounds tested.
In a review of the data provided in the declaration, data for Linezolid treatment alone was not identified. Thus, it is not clear from the evidence provided if the differences were indeed unexpected and more than an additive effect.
Moreover, MPEP 716.02(c) states:
"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) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989). In the instant case, as set forth above, Devito suggests a composition for treating a mycobacterial infection in a patient comprising a pharmaceutically effective amount of an antibiotic compound, linezolid; further comprising an additional pharmaceutical agent, PA-824 and TMC207. Moreover, Devito teaches the combination of compounds can be a synergistic combination (page 4, 1st paragraph). Thus, Devito suggests combining the disclosed agents for a synergistic effect. Thus, it is not unexpected that combining linezolid, bedaquiline, and pretomanid would result in a synergistic effect. The fact that the combination of linezolid, PA-824/pretomanid and TMC 207/bedaquiline is useful for treating mycobacterial infection caused or mediated by Mycobacterium tuberculosis and that the combination has a synergistic effect is not unexpected. Thus, the teachings of cited references support the obviousness rejection set forth above.
Applicant argues:
With reference to paragraph 13 of the Fotouhi Declaration, the synergistic and desirable results provided by LZD (50 mg and 100 mg) in combination with BDQ and PA-824 (25 mg and 100 mg, respectively) as compared to AZD (radezolid, 125 mg) in combination with BDQ and PA-824 (25 mg and 100 mg, respectively), is additionally surprising in light of the data summarized in Table 1 of Devito et al. Examples of Devito et al., with regard to LORA IC90 results, the potency of radezolid (0.31 µg/ml) is at least 162 times greater than that of linezolid(>50µg/ml).
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The Examiner acknowledges that the data of Devito appears to support that radezolid is more potent than linezolid. However, the Examiner notes that the data of Devito was an in vitro assay in mycobacterial alamar blue assay (MABA) or in a low-oxygen recovery assay (LORA). However, the experiment disclosed in the declaration was conducted in BALB/c and C3HeB/FeJ mouse models of Mycobacterium tuberculosis. Thus, the in vitro data for radezolid and linezolid alone were conducted in a completely different assay and cannot be compared to the in vivo assay provided in the declaration. In a review of the data provided in the declaration, data for Linezolid treatment alone was not identified. Thus, it is not clear from the evidence provided if the differences were indeed unexpected and more than an additive effect. Thus, the examiner is unable to ascertain from the data provided that the claimed invention possesses unexpected properties.
Applicant argues:
It is argued in the non-final Office Action that it is not clear from the evidence provided if the differences were indeed unexpected and more than an additive effect. It is also argued in the non-final Office Action that "the in vitro data for radezolid and linezolid alone were conducted in a completely different assay and cannot be compared to the in vivo assay provided in the [Fotouhi] declaration." Attention is directed to paragraph 11 and Table 2 of the Fotouhi Declaration (provided as follows), which provides a comparison of treatment results for Linezolid alone and Radezolid (AZD 5487) alone, in which Radezolid alone provided improved results as compared to Linezolid alone (in the same assay) using amounts that correspond to the combination comparisons. Attention is further directed to paragraph 12 of the Fotouhi Declaration, which discusses the results of Linezolid alone and Radezolid alone, and correspondingly the surprising and significant synergistic effect provided by the combination of LZD (linezolid) at 50 mg and 100 mg each in combination with BDQ and PA-824 (25 mg and 100 mg, respectively), as compared to AZD (Radezolid, 125 mg) in combination with BDQ and PA-824 (25 mg and 100 mg, respectively).
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
In a review of Table 2 and Graph C, the Examiner notes that the data for linezolid appears to show great variability within the same dose, with points as low as about 4 and as high as about 8 with an average of 6.93.
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Again, it is noted that the doses tested are not the same dose (100 mg linezolid vs 125 mg). It is not clear from the data provided if the results disclosed are statistically significant. Moreover, as set forth above, Devito suggests a composition for treating a mycobacterial infection in a patient comprising a pharmaceutically effective amount of an antibiotic compound, linezolid; further comprising an additional pharmaceutical agent, PA-824 and TMC207. Moreover, Devito teaches the combination of compounds can be a synergistic combination (page 4, 1st paragraph). Thus, Devito suggests combining the disclosed agents for a synergistic effect. Thus, it is not unexpected that combining linezolid, bedaquiline, and pretomanid would result in a synergistic effect. The fact that the combination of linezolid, PA-824/pretomanid and TMC 207/bedaquiline is useful for treating mycobacterial infection caused or mediated by Mycobacterium tuberculosis and that the combination has a synergistic effect is not unexpected. Thus, the teachings of cited references support the obviousness rejection set forth above.
Applicant argues:
It is submitted that ZYVOX discloses pharmaceutical compositions that contain only linezolid, as the active pharmaceutical ingredient, in various dosage amounts. It is submitted that SIRTURO discloses pharmaceutical compositions that contain only bedaquiline, as the active pharmaceutical ingredient, in various dosage amounts. Diacon et al. discloses multiple-agent combinations for treating tuberculosis over the first 14 days of treatment, such as a combination of bedaquiline and pretomanid. See the Summary and Methods section (page 987, left column) of Diacon et al. Diacon et al. provides no disclosure or suggestion with regard to single or multiple-agent compositions that include linezolid. It is submitted that ZYVOX, SIRTURO, and Diacon et al., alone or in any combination, do not address or otherwise overcome the deficiencies of Devito et al. See paragraph 20 of the Fotouhi Declaration.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Arguments regarding Devito have been addressed above. Therefore, the rejection is maintained for the reasons set forth on the record and for those set forth in the response to the arguments above.
Conclusion
Claims 1-3, 13, and 16-18, 20, 24, and 25 are rejected.
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628