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 .
Applicant’s arguments, filed 10 September 2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103 (Maintained Rejection)
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 1-5 and 7-13 are rejected under 35 U.S.C. 103 as being unpatentable over Mo et al. (US 2017/0290781 A1, 10/12/2017, ID reference) (hereinafter Mo).
Mo discloses a pharmaceutical preparation of a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, or prodrug thereof:
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where R1 and R2 are each independently selected from a C1-4 alkyl or a C3-6 cycloalkyl; and n is 1 or 2 ([0011]). Mo further discloses a specific embodiment wherein the pharmaceutical formulation is a fat emulsion comprising Compound 7:
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as the following pharmaceutical formulation:
Compound 7 5 g (i.e. 0.5 w/v% of claimed active ingredient)
Soybean oil 50 g (i.e. 5 w/v% of claimed oil ingredient)
Medium-chain triglyceride 50 g (i.e. 5 w/v% of claimed oil ingredient)
Egg-yolk lecithin 12 g (i.e. 1.2 w/v% of claimed emulsifier)
Glycerol 22.5 g (i.e. 2.25 w/v% of claimed osmotic pressure regulator)
Sodium oleate 0.3 g (i.e. 0.03 w/v% of claimed stabilizer)
Sodium hydroxide appropriate amount (i.e. claimed pH-adjusting agent)
Water for injection, added up to 1000 ml ([0328]). The fat emulsion has a pH of 3.0 to 10.0 ([0037]).
Mo further discloses wherein the pharmaceutical formulation comprises one or more antibacterials including methyl benzoate, sodium pyrosulfite, disodium edetate, and calcium sodium edetate ([0039]).
Accordingly, it would have been obvious to one of ordinary skill in the art to have formulated the various pharmaceutical preparations as instantly claimed since all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. See MPEP § 2143(I)(A).
Regarding the claimed amount of bacteriostat, 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. See MPEP § 2144.05(II)(A). Mo does not explicitly disclose the amount of disodium edetate (i.e. claimed bacteriostat). However, since antioxidants are pharmaceutical ingredients, it would have taken no more than the relative skill of one of ordinary skill in the art to have arrived at the claimed amounts of antioxidant (i.e. 0.0005 to 0.005% w/v) through routine experimentation based on the level of antioxidant effect desired.
Regarding claims 2-4, the cited compound reads on the compounds of instant claim 2 when R1 and R2 are each methyl and n is 1; instant claim 3, row 1 second structure; and Compound 3 of claim 4.
Regarding claims 1, 7, 11, and 12 reciting various amounts of various ingredients, the claimed ranges would have been obvious to one of ordinary skill in the art since they overlap with the ranges of the prior art. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 5, Mo further discloses wherein the prodrug of compound of formula (I) may be a compound of formula (II):
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wherein R1, R2 and n are as defined for the compound of formula (I); and Z+ may be H+ ([0105]).
It would have been obvious to one of ordinary skill in the art to have formulated the pharmaceutical formulations of Mo with the compound of formula (II) since it is a known and effective embodiment of formula (I) as taught by Mo.
Regarding claim 13, Mo further discloses wherein the pharmaceutical formulation may be used for inducing and maintaining anesthesia in an animal or human, for promoting sedative hypnosis of an animal or human, or for treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsion, and epilepsy ([0041]).
Response to Arguments
Applicant argues that the pharmaceutical preparation of the present application comprises a bacteriostatic agent at a low concentration distinct from any proposed by Mo, who discloses a specific pharmaceutical preparation in the form of a fat emulsion lacking a bacteriostatic agent in Example 21. Mo separately generically states that a pharmaceutical preparation may additionally include additives such as a bacteriostat in para. [0039], thus there is no suggestion that a bacteriostat could be introduced into a fat emulsion.
The Examiner does not find the argument persuasive. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. See MPEP 2123(I). Here, Mo discloses in para. [0036] that the pharmaceutical formulation is a fat emulsion, and in para. [0038] that the pharmaceutical formulation may further contain any one of or a mixture of antioxidants and antibacterials. Mo does not limit the inclusion of antioxidants and/or antibacterials to only aqueous formulations. Applicant appears to be relying on a narrow interpretation of the prior art (e.g., based on example 21) and thus the argument is unpersuasive.
Applicant argues adding a small amount of bacteriostats to a fat emulsion containing the active ingredient unexpected inhibited bacterial growth, as seen in Examples 3 and 4. Applicants also argue that adding such small amount of bacteriostat not only achieves bacteriostatic effects but also significantly improves the stability of the active ingredient as confirmed by Examples 3, 4, and 6. There is no teaching or suggestion in the prior art, including Mo, that a bacteriostat can improve the stability of the active ingredient in a fat emulsion.
The Examiner does not find the argument persuasive. "Prior art is not limited just to the references being applied, but includes the understanding of one of ordinary skill in the art. The prior art reference (or references when combined) need not teach or suggest all the claim limitations." See MPEP § 2141(III). In this instance, the usage of antioxidants and antibacterials including disodium edetate in fat emulsions is explicitly disclosed by Mo. From there, the determination of appropriate weight percentages of known components for their known function would seem to reasonably constitute no more than routine experimentation. See MPEP § 2144.05(II)(A). Applicant has not provided objective evidence to establish that the inclusion of the claimed bacteriostat concentrations are in fact really unexpected and of statistical and practical significance. See MPEP § 716.02. As such, the argument is unpersuasive.
Double Patenting (Previous Rejection)
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 1-5 and 7-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-54 of U.S. Patent No. 10,729,666 in view of Jansson et al. (“Propofol EDTA and Reduced Incidence of Infection”, 06/2006) (hereinafter Jansson). The patented claims differ from the instant claims insofar as not disclosing one of the instantly claimed bacteriostats. However, Jansson teaches that a water insoluble drug, such as propofol, formulated in a lipid vehicle (a soybean oil lipid emulsion), to support the growth of microorganisms (summary; p.362 left column). In order to reduce the risk of such bacterial contamination, anti-microbial additive EDTA (disodium edetate) is incorporated into the propofol formulation. EDTA is a suitable antimicrobial additive due to its ability to suppress the growth of microorganisms without compromising clinical safety, efficacy, or the stability of the emulsion (p.362 right column last ¶ to p.363 left column ¶1). The EDTA may be included in a concentration of 0.005% (p.364, right column, ¶3). Accordingly, it would have been obvious to one of ordinary skill in the art to have included an additive, such as EDTA, in a disclosed concentration, to suppress the growth of microorganisms without comprising safety, efficacy, or the stability of an active-containing lipid emulsion (i.e. fat emulsion) of the patented compositions, as taught by Jansson.
Response to Arguments
Applicant argues claims 1-54 of the ‘666 patent do not provide any teaching, suggestion or motivation to provide a fat emulsion comprising a bacteriostat in a concentration range of 0.0005 w/v% - 0.005 w/v%. as recited in claim 1 as amended. Moreover, one of skill in the art would have no expectation of success in inhibiting bacterial growth using such a low bacteriostat concentration, nor would one of skill in the art have any expectation of chemically stabilizing the compound of formula (I) as demonstrated in the present application. Janssen fails to remedy the failure of the claims of ‘666 patent as it provides no inkling that the stability of the compound of formula (I) would be improved in the present formulation.
The Examiner does not find the argument persuasive. As this is a 103 obviousness rejection, no one piece of prior art is required to teach each and every claim limitation. The ‘666 patent discloses a fat emulsion comprising a compound of formula (I) as claimed and an antibacterial such as disodium edetate. Jansson, discussed in detail above, provides the motivation to include the disodium edetate at a claimed amount in fat emulsions, such as those of propofol, to inhibit bacterial growth. See MPEP 2141(III).
Conclusion
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 LUCY M TIEN whose telephone number is (571)272-8267. The examiner can normally be reached Monday - Friday 10:00 AM - 6:00 PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Frederick Krass can be reached at (571) 272-0580. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LUCY M TIEN/Examiner, Art Unit 1612
/FREDERICK F KRASS/Supervisory Patent Examiner, Art Unit 1612