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 with traverse of Group I, claims 1-9, 11-12, 15-16, 19-23, in the reply filed on 5/15/2024 remains acknowledged.
Applicant's election with traverse of:
(i) the combination of:
1) isopropyl myristate as emollient oil (claim 1 and claims dependent therefrom);
2) glyceryl monocaprylate as surfactant (claim 1 and claims dependent therefrom);
3) chlorhexidine gluconate as antimicrobial compound (claim 1 and claims dependent therefrom);
4) glycerol (claim 8); and
5) benzyl alcohol (claim 16),
in the reply filed on 5/15/2024 remains acknowledged (Examiner previously noted that claim 1 also requires water, in addition to the elected species under 1), 2) and 3), above).
Claims 12, 17-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 5/15/2024.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 1-9, 11, 15-16, 19-23 remain rejected under 35 U.S.C. 103 as being unpatentable over Tamarkin et al. (US 2008/0260655 A1; 2008; cited in a prior Office action), in view of Zhang (“Development and Evaluation of Novel Biocompatible Microemulsion Formulations for Transdermal Drug Delivery”, Master of Science (Research) thesis, School of Biological Sciences, University of Wollongong, 2016; https://ro.uow.edu.au/theses/4962; cited in a prior Office action); and Ruth et al. (“Phase studies and particle size analysis of oil-in-water phospholipid microemulsions”; 1995; International Journal of Pharmaceutics; 116: 253-261; cited in a prior Office action).
Claim 12 has been amended, and no longer reads on the elected composition; thus, claim 12 has been withdrawn, and, accordingly, the rejections of claim 12 are no longer applied.
Tamarin teaches, inter alia, microemulsions, when water is present in a composition [0250]; which, in some embodiments are non-alcoholic or substantially so [0251].
In an embodiment the non-aqueous solvent is monooctanoin (a.k.a., Applicant elected glyceryl monocaprylate) [0187]. Glyceryl stearate (monostearate) is also taught as a surfactant [0326], (bottom table on p. 41, second table on p. 42, bottom table p. 44), [0656], [0658], and is used in water in oil emulsions [0660] 1a & 1b, [0662], 2a, [0663], 3a. Preferable non-ionic surfactants include a monoglyceride [0319] (a class that each of monoctanoin and glyceryl monostearate fall into). Each of the emulsions contain water.
Regarding hydrophobic solvents, ester oils are taught, including Applicant elected isopropyl myristate [0279]. This compound is also taught as an “emollient”, possessing a softening or soothing effect, especially when applied to body areas such as the skin [0287], and is an oil [0301], claim 29, No. 13.
Regarding active agents, antibacterial agents taught include chlorohexidine [0428], and chlorhexidine gluconate has some degree of solubility in water [0451], claim 30.
Additionally, the preference for low or no alcohol including ethanol, is taught to be less than about 5%, preferably less than about 2%, and more preferably less than about 1%, is taught due to the skin irritating effect [0192]. These levels (or absence of ethanol and other short chain alcohols) read on the permitted amounts of lower monohydric alcohols of claims 1 and 4.
While Tamarkin teaches each elected component, isopropyl myristate, as an ester oil and emollient, monooctanoin (glyceryl monocaprylate), and the similar compound glyceryl monostearate, as surfactant (suggesting monooctanoin would also function as a surfactant), and chlorhexidine gluconate as water soluble antibacterial active agent, and water, their combination would require picking and choosing from different portions of this publication. Additionally, microemulsions are taught, but their droplet particle size is not specified.
Zhang discusses microemulsion (ME) formulations for transdermal drug delivery (title). MEs can form spontaneously, are thermodynamically stable and possess high solubilization capacity for drug compounds (i; abstract, 1st paragraph).
Medium chain monoglycerides (MCM) are discussed as transdermal drug delivery (8, section 1.3); they are fatty acid monoesters of glycerol (section 1.3.1). mono-glycerides are commonly added to food products in small quantities as emulsifiers and considered GRAS compounds (section 1.3.2).
Regarding transdermal permeation enhancers, MCM have enhanced the transdermal permeation rate of numerous drug compounds. Applicant elected Glyceryl monocaprylate (C8) significantly improved the transdermal delivery rate of pentazocine compared with other permeation enhancers (i.e., isopropyl myristate solution alone, carboxylic acids, non-ionic surfactants, l-menthol, alcohols, glycol and urea) from Applicant elected isopropyl myristate solution system (IPM); two derivatives of glyceryl monocaprylate (glyceryl diglycerides and glyceryl triglycerides) were proved to have no permeation enhancement effect of pentazocine. While the highest flux was reached for glyceryl monocaproate (GEFA-C6), when comparing Applicant elected glyceryl monocaprylate (GRFA-C8) and glyceryl monocaproate (GRFA-C6), the former is suitable as a permeation enhancer because of its safety and odorless properties (9: section 1.3.3).
Section 1.3.4 (p. 10) discusses broad spectrum antimicrobial properties of MCM.
The formation and structure of MEs are discussed in 1.4.1 (p. 10-11). MEs are defined as a single, optically isotropic structured solution of surfactant, oil and water is called a microemulsion. MEs can be formed with a wide range of oil-surfactant-water compositions and can be either water-in-oil (W/O) or oil-in-water (O/W) with a characteristic droplet size of 150 nm or less. As it is difficult to predict ME formation based on the complex physical-chemical interactions between components, pseudo-ternary phase diagrams are commonly used to determine the specified oil-surfactant-water concentrations ranges required for the formation of MEs (p. 10).
Monophasic ME are of consideration as potential drug delivery vehicle in this study since they are stable, can be easily prepared and have high capacity for a wide range drug solubilization, including lipophilic and hydrophilic compounds in the one formulation (p. 11, top).
Section 1.4.2 discusses properties that render MEs as ideal liquid vehicles for drug delivery since the small droplets have better ability to adhere to membranes and to transport bioactive molecules in a more controlled fashion; MEs can be administered, including topically on the skin.
Section 1.5 (p. 12) documents MCM, as known transdermal penetration enhancers for a range of compounds, and displaying broad spectrum antimicrobial activity against a variety of human pathogens, provides a combination of activities that may be useful in the development of novel antimicrobial formulations for topical use. MEs are stable mixtures of oils, surfactants and water and are ideal for the development of topical formulations containing MCM and water-soluble drug compounds.
Zhang discusses how to prepare microemulsions, which have sizes under 150 nm, rendering obvious sizes of claim 1 and 2 obvious as overlapping with the prior art size range. Among preferred MCM permeation enhancers is Applicant elected glyceryl monocaprylate (GRFA-C8), and its combination with isopropyl myristate, demonstrated to have enhanced transdermal permeation of drugs. The discussion of MEs leads to an expectation of improved solubilization of active agents, including
Ruth teaches systems composed of egg or soya lecithins, ethanol, isopropyl myristate and water, where stable oil-in water microemulsion regions were identified. Droplet sizes of the microemulsions were between approx. 10 and 60 nm, and increased with increasing volume fraction of isopropyl myristate (abstract); see also phase diagrams. Ruth documents isopropyl myristate is a preferable oil material, in microemulsions, and documents the effects of varying concentrations including relative IPM amounts, which are engineering parameters to size microemulsion droplets particle sizes within the range 10-60 nm, rendering obvious this range.
Thus, it would have been obvious to one of ordinary skill in the art to combine glyceryl monocaprylate (taught by Tamarkin as monooctanoin, and reasonably expected to act as surfactant/emulsifier), together with isopropyl myristate (taught by Tamarkin as oil, and emollient), which are preferable based on Zhang (and isopropyl myristate is preferred by Ruth as an oil component of microemulsions), to combine with water as the three components necessary to form microemulsions. It would further have been obvious to solubilize Applicant elected chlorhexidine gluconate, taught by Tamarkin as having some degree of solubility in water, and taught by Tamarkin as an antibacterial agent within the microemulsion. Selection of this active compound would have been obvious
It is noted that Applicant’s election indicates that glyceryl monocaprylate has the recited HLB value of claims 1 & 23; thus, and obvious formulation containing this surfactant/emulsifier satisfies the HLB limitations.
Regarding claim 3, the microemulsions appear to be liquids at room temperature, rendering obvious this characteristic.
Regarding claim 5, chlorhexidine gluconate is taught to be antimicrobial, and Zhang teaches GRFA-C8 is also antimicrobial. Accordingly, the elected composition is presumed to have the characteristics recited in this claim, absent evidence to the contrary.
Regarding amounts of water of claim 6-7, and amounts of lipophilic component of claim 9, the amount of chlorhexidine gluconate of claim 11 & 15, it would have been obvious to construct a ternary phase diagram, in the manner used by Zhang (see chapter 3), or the manner used by Ruth (Figures 1-2), where water (or water and glycerol and benzyl alcohol) replace the ethanol/water side of Ruth figures and glyceryl monocaprylate replaces the lecithin sides of Ruth figures, to determine ME regions. Absent evidence to the contrary, this optimization of microemulsions would have resulted in workable ranges within the scopes of each of these claimed ranges.
Examiner notes that GTCC in oil phase was used by Zhang, in amounts as high as 57% (Table 31), rendering majority concentration of isopropyl myristate (higher emollient oil than surfactant amount, reading on claim 19), when it is used as oil component. Water ranges from 10-86%, rendering obvious amounts throughout this range. MCM amounts of 19% render obvious similar amounts of the glyceryl monocaprylate (this compound has at least 80% glycerol monocaprylate, and reads on claims 21 & 23). The dissolved active compound concentration would also have been determined via dissolution based on the obvious optimization via ternary phase diagrams, then evaluation of amount of chlorhexidine gluconate that will dissolve in MEs formed.
As pointed out in MPEP 2144.05 II, generally differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding the elected glycerol component of claim 8 and the elected benzyl alcohol component of claim 16, each of these components are taught by Tamarkin as other non-aqueous solvents, preferably added in small amounts [0186], [0355]; and can be considered potent solvents [0387]. Thus, each of their additions, giving the elected embodiment of the claims, would have been obvious, motivated to further enhance solvation capacity of the obvious chlorohexidine gluconate in the formulated microemulsions.
Applicant again argues:
about Table 1 data in the specification, that with CHG (at 2.3%) a clear, stable isotropic microemulsion forms, demonstrating CHG is both an antimicrobial compound and a cosurfactant. Without CHG the formulation separated into two phases upon standing, citing Figures 2 A and 3B.
This is not persuasive. Examiner provided evidence that CHG is known as both an antimicrobial compound, and a surfactant. Even though the evidence provided states these properties, Applicant somehow alleges that this is not true.
Examiner notes that alternate sources may also be used to verify these properties. For instance, the chemical book webpage: Chlorhexidine Gluconate: A Comprehensive Overview for Chemistry Professionals_Chemicalbook states that this compound is a guanidine disinfectant, is a cationic surfactant with strong broad-spectrum antibacterial and bactericidal effects. MPEP 2112.01 (II) indicates if the composition is physically the same, it must have the same properties
However, knowledge of these properties is not needed to formulate microemulsions. The rejection clearly relies on the teachings of microemulsions; these are taught by Tamarkin, Zhang and Ruth. Construction of ternary phase diagram would have been obvious, to identify amounts of components where microemulsions form and are stable. The fact that Applicant has identified conditions (e.g., with and without 2-2.3 % CHG) to have different formulation properties, would correspond to locations in the obvious ternary phase diagram, which are routinely evaluated in the art of microemulsion formulations. Applicant pointing out characteristics from this diagram does not render the instant claimed topical antimicrobial composition to be patentable over the cited references.
Furthermore, even if the evidence of the cited tables were taken to be unexpected (not the position being adopted), the specification data is limited to specific combinations of ingredients, each present at specific disclosed amounts. There is no claim rejected that correspond to the combination of ingredients (claim 1, for instance has multiple listings of alternative ingredients for emollient oil, for surfactant, for amphiphilic component, permitting unspecified lower alcohols up to about 10%, each of these ingredients at the disclosed amounts. MPEP 716.02 indicates the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). In the instant case, there is no commensurate in scope correlation between rejected claims and the evidence argued.
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 TIMOTHY P THOMAS whose telephone number is (571)272-8994. The examiner can normally be reached M-Th 6:30-5:00.
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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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TIMOTHY P. THOMAS
Primary Examiner
Art Unit 1614
/TIMOTHY P THOMAS/Primary Examiner, Art Unit 1614