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 .
Status of the Claims
Claims 18-37 have been cancelled. New claims 38-41 have been added. Claims 1-17 and 38-41 are pending. Claims 8-17 and 41 have been withdrawn.
Claims 1-7 and 38-40 are currently under examination.
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.
Claims 1-7 and 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over Andries et al. (WO2019012100A1, Published 01/17/2019; cited in the IDS filed 03/09/2023) in view of Pramanick et al. (Pharma Times, 45(3), 65, Published March 2013).
Applicant’s Invention
Applicants’ claims are drawn to an intramuscular or subcutaneous injection, comprising: (a) a therapeutically effective amount of bedaquiline, or a pharmaceutically acceptable salt thereof, in micro- or nanoparticle form, and a surface modifier comprising polyethylene glycol 4000 (PEG4000); and (b) a pharmaceutically acceptable aqueous carrier.
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Regarding claim 1, Andries teaches the present invention is concerned with a pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of bedaquiline, or a pharmaceutically acceptable salt thereof, in the form of a suspension of micro- or nanoparticles comprising: (a) bedaquiline, or a pharmaceutically acceptable salt thereof, in micro- or nanoparticle form, and a surface modifier; and (b) a pharmaceutically acceptable aqueous carrier (page 3, lines 13-20). Andries further teach that suitable surface modifiers can be selected from polyethylene glycols (such as Carbowax 3550) (i.e., high molecular weight polyethylene glycol) (page 21, line 7).
Regarding claim 2, Andries teaches that suitable surface modifiers (i.e., wetting agent can be selected from polyethylene glycols (such as Carbowax 3550) (i.e., high molecular weight polyethylene glycol) (page 21, line 7). Andries further teaches if desired, two or more surface modifiers can be used in combination (page 21, lines 11-12).
Regarding claims 3 and 4, Andries teaches Particular surface modifiers are selected from poloxamers, a-tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, and salts of negatively charged phospholipids or the acid form thereof (page 21, lines 14-16).
Regarding claims 5 and 38, Andries teaches Bedaquiline can be used in its non-salt form or as a suitable pharmaceutically acceptable salt form, such as an acid addition salt form or base addition salt form (page 8, lines 5-7). Andries further teaches in particular, the fumarate salt is considered as the salt form which bedaquiline is able to form (page 8, lines 18-19).
Regarding claim 6, Andries teaches the pharmaceutical compositions of the invention comprise bedaquiline in nanoparticle form. The average effective particle size of the micro- or nanoparticles of the present invention may be below about 50 μm (pages 9-10, lines 35-37; lines 1-2).
Regarding claims 7, and 39-40, Andries teaches in one embodiment, the aqueous suspensions may comprise by weight, based on the total volume of the composition: (a) from 10% to 70% (w/v), or from 20% to 60% (w/v), or from 20% to 50% (w/v), or from 20% to 40% (w/v) of bedaquiline (or pharmaceutically acceptable salt thereof); (b) from 0.5% to 20 %, or from 2% to 15% or 20% (w/v), or from 5% to 15% (w/v) of a wetting agent (i.e., surface modifier); (c) from 0% to 10%, or from 0% to 5%, or from 0% to 2%, or from 0% to 1% of one or more buffering agents; (d) from 0% to 20 %, or from 2% to 15% or 20% (w/v), or from 5% to 15% (w/v) of a isotonizing agent (e) from 0% to 2% (w/v) preservatives; and (f) water for injection q.s. ad 100% (pages 25-26, lines 27-37; lines 1-2).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
Andries does not teach wherein the polyethylene glycol is PEG4000. However, this deficiency is cured by Pramanick et al.
In the analogous art of parenteral pharmaceutical compositions, Pramanick teaches Excipients are typically the major components in a drug product. Many formulations contain only a small percentage of the active drug molecules. Pharmaceutical excipients or additives are compounds added to the finished drug products to serve a specific function (introduction paragraph). Pramanick also teaches Polyethylene glycol (PEG): It provides good cake structure and increases viscosity of water, wherein apart from lyophilization, it is also used as a co-solvent and viscosity modifier in parenteral (page 66, fifth paragraph). Pramanick further teaches PEG 4000 in table 6 as solvents and co-solvents used in injectables (page 66, table 6).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the time of filing to have PEG4000 present in the pharmaceutical composition of Andries. One of ordinary skill in the art would have been motivated to do so because Pramanick teaches Polyethylene glycol (PEG): It provides good cake structure and increases viscosity of water, wherein apart from lyophilization, it is also used as a co-solvent and viscosity modifier in parenteral (page 66, fifth paragraph). Pramanick further teaches PEG 4000 in table 6 as solvents and co-solvents used in injectables (page 66, table 6). The skilled artisan would have had a reasonable expectation of success because Andries teaches the present invention is concerned with a pharmaceutical composition for administration by intramuscular or subcutaneous injection (i.e., parenteral) and Pramanick teaches using PEG 4000 as solvents and co-solvents in injectables, therefore, PEG4000 is suitable for intramuscular or subcutaneous injections which are parenteral.
With regards to claim 2, wherein the surface modifier comprises at least 75% by weight of the PEG4000 and the remainder is one or more other suitable surface modifiers, it would have been obvious to one of ordinary skill in the art to vary the amounts of each surface modifier to achieve the desired concentration of the surface modifiers. One would have understood in view of Andries that if desired, two or more surface modifiers can be used in combination (page 21, lines 11-12) and that based on the total volume of the composition: (b) from 0.5% to 20 %, or from 2% to 15% or 20% (w/v), or from 5% to 15% (w/v) of a wetting agent (page 25, lines 32-33). It would have been obvious to one of ordinary skill in the art to optimize the amount of the combined surface modifiers as taught by Andries to obtain the desired pharmaceutical composition. Determining optimal concentrations is routine experimentation and is practiced by one of ordinary skill. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). In addition, according to the MPEP, “It is to be presumed also that skilled workers would as a matter of course, if they do not immediately obtain desired results, make certain experiments and adaptations, within the skill of the competent worker.” (MPEP 716.07).
Response to Arguments
Applicant's arguments filed 04/27/2026 have been fully considered but they are not persuasive.
On pages 7-8 of Applicants remarks, Applicants argue that Pramanick discloses more than 100 excipients that may be utilized in pharmaceutical compositions, yet the Examiner has not provided any documents that alone, or in combination would have directed someone to select PEG4000 that is recited in Applicant’s claims. Applicants also argue that Pramanick is specifically directed to selected excipients for lyophilized drug products. Lastly, Applicants argue that Pramanick includes conflicting statements regarding the safety and use of polyethylene (PEG) excipients, therefore, there is no reason to believe that there would have been a motivation to use any PEG excipient, let alone PEG4000.
These arguments are not persuasive. The examiner points out that although Pramanick as a whole discloses more than 100 excipients, the Examiner cited the relevant section of Pramanick which teaches PEG 4000 in table 6 as solvents and co-solvents used in injectables (page 66, table 6). The Examiner further points out that table 6 of Pramanick teaches a finite number of solvents and co-solvents. The Examiner directs attention to Merck &Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Circ. 1989), which states with regards to its more than 1200 combinations: that the prior art “discloses a multitude of effective combinations does not render any particular formulation less obvious. This is especially true because the claimed composition is used for the identical purpose taught by the prior art.” "[P]icking and choosing may be entirely proper in the making of a 103, obviousness rejection." In re Arkley, 455 F.2d 586, 587 (CCPA 1972). Furthermore, it is noted that Applicants do not identify any secondary consideration demonstrating criticality or anything unexpected about the combination of two known prior art pharmaceutical agents. With regards to Applicants argument wherein Pramanick is specifically directed to selected excipients for lyophilized drug products, the Examiner points out that Pramanick is not limited to only lyophilized drug products, as Pramanick teaches this review deals with understanding of the physicochemical properties of excipients used in parenteral formulation development for solution, suspension and lyophilized drug products (abstract) and that table 6 which teaches the solvents and co-solvents used in injectables are recited in the section teaching excipients used in liquid injections (pages 69-70).
With regards to Applicants argument that Pramanick includes conflicting statements regarding the safety and use of polyethylene (PEG) excipients, therefore, there is no reason to believe that there would have been a motivation to use any PEG excipient, let alone PEG4000, the examiner points out that Pramanick teaches Table 6 which provides list of solvents, solubilizing agents and co-solvents which are currently in use in the approved formulations for injectables, wherein PEG4000 is taught. Therefore, the use of high molecular weight polyethylene glycols are known in the art to be used as solvents or co-solvents in injectables. The fact there may be some drawbacks that one of ordinary skill in the art would need to consider when using PEG excipients in a pharmaceutical formulations, it is taught as a well known excipient, therefore, the Examiner does not consider Pramanick’s statement about undesirable side effects when using PEG 400 a teaching away, but rather a caveat. The Examiner further points out that the primary prior art Andries further teach that suitable surface modifiers can be selected from polyethylene glycols (such as Carbowax 3550) (i.e., high molecular weight polyethylene glycol) (page 21, line 7). Therefore, the primary reference Andries already directs one of ordinary skill in the art to use high molecular weight polyethylene glycols in pharmaceutical composition for administration by intramuscular or subcutaneous injection as a suitable PEG excipient. Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See MPEP 2123 (II).
Double Patenting
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.
Claims 1-7 and 38-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-10 and 26 of copending Application No. 18/004,464 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘464 application claims render obvious the instant claims.
Inter alia the claims of the ‘464 application embrace A pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of an active pharmaceutical ingredient, or a pharmaceutically acceptable salt thereof, in the form of a suspension of micro- or nanoparticles comprising:(a) an active pharmaceutical ingredient, or a pharmaceutically acceptable salt thereof, in micro- or nanoparticle form, and a surface modifier; and (b) a pharmaceutically acceptable aqueous carrier, wherein the surface modifier comprises a high molecular weight polyethylene glycol. The ‘464 application also embraces wherein the surface modifier comprises at least 75% by weight PEG4000 and the remainder is one or more other suitable surface modifiers; wherein the one or more other suitable surface modifiers are poloxamers, a-tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, or salts of negatively charged phospholipids. The ‘464 application further embraces wherein the average effective particle of the active pharmaceutical ingredient, or a pharmaceutically acceptable salt thereof, micro- or nanoparticles is below about 50µm; wherein the pharmaceutical composition comprises by weight based on the total volume of the pharmaceutical composition: (a) from 10% to 70% (w/v), of active pharmaceutical ingredient (or pharmaceutically acceptable salt thereof, but where the w/v is calculated on the basis of its non-salt form); (b) from 0.5% to 20 % (w/v), of a wetting agent or surface modifier; (c) from 0% to 10% (w/v), of one or more buffering agents; (d) from 0% to 20 % (w/v), of a isotonizing agent (e) from 0% to 2% (w/v) preservatives; and (f) water for injection q.s. ad 100%. The ‘464 application continues to embrace wherein the active pharmaceutical ingredient is bedaquiline. The ‘464 application also embraces wherein the pharmaceutically acceptable salt thereof of the active ingredient is the fumarate salt.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's comment on page 8 of the remarks filed 04/27/2026 requesting that the
nonstatutory double patenting rejections be held in abeyance is noted.
Regarding Applicant's argument that the double patenting rejections should be held in abeyance, the double patenting rejections apply to the claims as they are currently written, therefore these double patenting rejections are maintained. Further, Applicants' request to hold the rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an objection or requirements as to form (see MPEP 37 CFR 1.111(b) and 714.02). Thus, the rejection is maintained in the absence of a terminal disclaimer.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AFUA BAMFOAA BOATENG whose telephone number is (703)756-1358. The examiner can normally be reached Monday - Friday 9:00am - 5:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571) 272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
AFUA BAMFOAA BOATENGExaminer, Art Unit 1617
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