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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/11/2026 has been entered.
Election/Restrictions
Applicant’s election of Group III, with the addition of HPC-M, HPC-G, PEG-400, ethanol, and water, as the composition species, in the reply filed on 10/30/2024 is acknowledged and maintained.
Priority
This application is a national stage filing under 35 U.S.C. § 371 of International PCT
Application PCT/PT2020/050009, filed February 18, 2020, which claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application, U.S.S.N. 62/807,680, filed on February 19, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/11/2026 has been considered by the examiner.
Claims Status
Claims 57, 109-113, and 115-133 are pending. Claims 1-56, 58-108, and 114 are canceled. Claims 111-113, 123-126, and 128-132 are withdrawn. Because claims 130 depends on withdrawn claim 129 and claims depending directly or indirectly from claim 129 are also withdrawn. Claims 57, 109, 110, 115-122, 127, and 133 are examined in accordance to the elected species.
Action Summary
Claims 57, 109, 110, 115-122, 127, and 130-133 are rejected under 35 U.S.C. 103 as being unpatentable over Krekeler et al (US2013/0216594 A1) in view of Ashland (Klucel hydroxypropyl cellulose, 2017, pages 1-24), Wang et al (WO2018/004576 A2), and Lockwood et al (US10,946,169 B2), are withdrawn in light of Applicant’s amendment (the composition is a solution under ambient conditions).
New 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 (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.
Claims 57 and 115-119 are rejected under 35 U.S.C. 103 as being unpatentable over Krekeler et al. (US2013/0216594 A1; hereinafter “Krekeler”) in view of Ashland (KlucelTM hydroxypropyl cellulose, 2017, pages 1-24; hereinafter “Ashland”).
Claim 57 recites a composition comprising both of a hydroxypropyl cellulose M (“HPC-M” and a hydroxypropyl cellulose G (“HPC-G”), wherein HPC-M is present at 0.3-4 wt% and HPC-G is present at 0.6-3.5 wt%; ethanol, a propanol, a butanol, or a mixture thereof at 10-80 wt%; inclusive, by weight; water at 20-75 wt%, wherein the composition is a solution under ambient conditions; and wherein the total concentration of all components is 100%, inclusive, by weight.
Krekeler teaches a process for preparing at pharmaceutical composition comprising forming a suspension of at least one pharmaceutical ingredient (A) in a solvent or solvent mixture (B), adding at least one gel former (C) that is swellable in the solvent or solvent mixture, and optionally allowing the suspension to swell. (See claim 1.) Krekeler teaches that gel former may be selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, Klucel® Klucel®E. Klucel®L, Klucel®J. Klucel® G, Klucel® M. Klucel(R) H, Klucel® EF, Klucel® LF, Klucel® JF, Klucel® GF, Klucel® MF, Klucel® HF, Klucel® EX, Klucel® LXF, Klucel® JXF, Klucel® GXF, Klucel® MXF, Klucel® HXF, ethyl cellulose, or mixtures thereof. (See ¶¶ [0029], [0083]; claim 10.) Krekeler therefore expressly contemplates the use of Klucel G and Klucel M, including mixtures of those HPC materials. Klucel G corresponds to HPC-G and Klucel M corresponds to HPC-M.
Krekeler further teaches that klucel hydroxypropyl cellulose is nonionic, water-soluble cellulose ether that is soluble in both aqueous and organic solvents. (See ¶ [0083]).
Krekeler additionally teaches solvent systems comprising C1-C5 alkanols, particularly ethanol, isopropanol, and mixtures thereof. (See ¶¶ [0026], [0070], [0082]; claims 7-8). Krekeler also expressly contemplates aqueous solvents systems, including water (see, e.g., ¶¶ [0069], [0071]). Thus, Krekeler teaches the use of the claimed types of HPC materials together with the claimed classes of aqueous and alcohol solvents.
Krekeler thus teaches the use of the claimed HPC-M and HPC-G materials, mixtures thereof, water, lower alcohol solvents. Krekeler, however, does not expressly disclose a composition containing both Klucel M and Klucel G at the respective concentrations of 0.3-4 wt% and 0.6-3.5 wt%, together with the recited alcohol and water concentrations wherein the resulting composition is a solution at ambient conditions.
Ashland remedies these deficiencies. Specifically, Ashland teaches KLucel HPC combines water solubility with organic solvent solubility and has excellent solubility in water and in a wide range of polar organic solvents and teaches solution formation in ethanol and aqueous/alcohol solvent systems. (See pp. 7-8, §4.2, and Table 4) Significantly, Asland expressly evaluates 2wt% Kluce G in water, ethanol, and an ethanol/water system, thereby demonstrating solution behavior of the G grade in the very classes of solvent required by claim 57. (See p. 8, Table 4.) Ashland additionally teaches under its discussion of aqueous Klucel HPC solution that, at room temperature, solution of Klucel HPC may be prepared over a wide range of viscosities depending upon the concentration and viscosity grade employed. (See p. 9, §4.3.1 and Fig. 4) Ashland’s Figure 4 provides concentration-dependent solution-viscosity information for different Klucel viscosity grades, including M and G. The M-grade concentration region shown by Ashland, including approximately 2.5-3 wt.%, falls within claim 57’s HPC-M range of 0.3-4 wt%. Likewise, Ashland’s G-grade concentration region, including approximately 2-6 wt5, overlaps claim 57’s HPC-G range of 0.6-3.5 wt%.
Accordingly, the rejection does not depend merely upon reducing Krekeler’s dry weight gel-former concentration through unsupported routine optimization. Ashland independently teaches Klucel M solution concentration within the claimed M-grade range and Klucel G solution concentrations overlapping the claimed G-grade range.
Ashland further teaches that the viscosity-concentration curves for Klucel HPC dissolved in organic liquids such as ethanol and methanol follow the same general pattern as those in water. (See p. 15, §4.3.9.1) Ashland additionally expressly discusses aqueous alcohol Klucel HPC solutions and teaches that the viscosity of such solutions varies with solvent composition, including a 7 parts water: 3 parts alcohol by weight system. (See p.15, §4.3.9.2.)
Thus, Ashland provides affirmative evidence that the claimed HPC materials form solutions under ambient/room-temperature conditions at concentrations falling within or overlapping the claimed ranges and in water/alcohol solvent environment relevant to claim 57.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to employ Krekeler’s disclosed mixture of Klucel M and Klucel G at concentration within the solution-concentration region taught by Ashland and in an aqueous/alcohol solvent system as taught by Krekeler and Ashland.
One would have been motivated to do so because Krekeler expressly identifies Klucel M and Klucel G, including mixtures thereof, as suitable pharmaceutical gel-forming materials and expressly teaches that Klucel is soluble in aqueous and organic solvents, while Ashland provides formulation-specific teachings concerning the concentration at which the M and G grades form solutions and expressly demonstrates Klucel solution behavior in water, ethanol, and aqueous-alcoholic systems. Thus, the proposed modification represents use of Krekeler’s expressly identified Klucel materials under solution-formulation conditions expressly taught by the manufacturer of those materials.
The combination therefore does not require changing the principle of operation of Krekeler. Rather, the skilled artisan would be applying known solution properties of Krekeler’s expressly identified Klucel materials to formula those materials in a known compatible solvent system.
One of ordinary skill would have had a reasonable expectation of successfully obtaining a solution under ambient conditions because Krekeler itself teaches Klucel HPC is soluble in both aqueous and organic solvents, see ¶ [0083], and Ashland expressly teaches room-temperature Klucel solutions, concentration-dependent solution behavior of the M and G grades, and Klucel solutions in water, ethanol, and aqueous-alcohol systems. See pp. 8-9, Table 4, and Fig. 4; p. 15, §4.3.9.1-4.3.9.2.
The fact that Krekeler’s process initially describes a suspension does not compel a contrary conclusion. Krekeler explains that the suspension results from selecting a solvent or solvent mixture in which the ingredient to be formulated is insoluble or poorly soluble. (See ¶ [0071]-[0072].) That does not establish that Klucel polymer itself is insoluble; to the contrary, Krekeler expressly states that Klucel is soluble in aqueous and organic solvents. (See ¶ [0083].)
Moreover, claim 57 does not require the poorly soluble pharmaceutical ingredient responsible for Krekeler’s suspension. Accordingly, the proposed modification does not require converting Krekeler’s poorly soluble active ingredient into a solution. The relevant issue is whether the components positively required by claim 57 would have been obvious as a solution, and Ashland affirmatively teaches solution formation by those Klucel materials.
Accordingly, claim 57 is unpatentable over Krekeler in view Ashland.
With respect to claim 115, the claim further limits HPC-M to 0.3-1.8 wt%. Ashland teaches that Klucel solution viscosity is concentration dependent and provides concentration-viscosity curves for the individual Klucel grades, including M. (See p. 9, §4.3.1, Fig. 4.)
Having been taught that the M-grade concentration controls solution viscosity and that the polymer systems, one of ordinary skill would have been led to select a lower M concentration where a lower-viscosity solution was desired. Thus, to the extent to the narrower 0.3-1.8 wt% range does not directly overlap the principal M concentration depicted by Ashland, selection of the concentration within that lower region would have constituted optimization of an expressly recognized result-effective variable, namely polymer concentration as it affects solution viscosity.
The skilled artisan would reasonable have expected success because Ashland teaches the concentration dependence of M-grade solution viscosity and does not identify a lower-concentration solubility barrier.
With respect to claim 116, HPC-G is limited to 0.6-1.8 wt%. Ashland’s figure 4 likewise expressly teaches concentration-dependent solution behavior for the G grade. (See p. 9, §4.3.1, Fig. 4. Selection of a lower G concentration to obtain corresponding lower solution viscosity would have been routine optimization of the expressly disclosed concentration/viscosity relationship.
With respect to claim 117, compound (ii) is ethanol. Krekeler expressly teaches ethanol as a particular suitable C1-C5 alkanol solvent. (See ¶¶ [0026]-[0070], [0082]; claim 8.) Ashland independently teaches Klucel HPC solutions in ethanol and aqueous ethanol systems. (See p. 8, Table 4, p. 15, §4.3.9.1-4.3.9.2.) Selection of ethanol therefore is expressly suggested by both references.
With claim 118, ethanol is present at 36-40 wt%. Ashland expressly teaches aqueous-alcohol Klucel solutions and identifies solvent composition as a parameter affecting solution viscosity. (See p.15, §4.3.9.2. Ashland specifically describes a 7-parts water; 3-parts alcohol by-weight system. The skilled artisan therefore would have understood the water/alcohol ratio to be an adjustable formulation parameter and would have been motivated to adjust the ethanol
Proportion to obtain desired solution properties while remaining within a solvent system in which Ashland teaches Klucel HPC to be soluble.
Thus, selection of an ethanol concentration within 36-40 wt% would have been routine optimization of the expressly recognized aqueous-alcohol solvent-composition variable.
With respect to claim 119, water is present at 50-66 wt%. For substantially the same reasons, Ashland expressly teaches aqueous-alcohol Klucel solutions and that the properties of such solutions vary as a function of aqueous/alcohol solvent composition. (See p 15, §4.3.9.2.) Krekeler independently teaches water as an aqueous solvent. (See ¶ [0089]-[0072].)
It therefore would have been obvious to select the relative water content within the claimed range wile maintaining an aqueous/alcohol solvent environment known to dissolve Klucel HPC.
Claims 109, 120-122, 127, and 133 are rejected under 35 U.S.C. 103 as being unpatentable over Krekeler et al. (US2013/0216594 A1; hereinafter “Krekeler”) in view of Ashland (KlucelTM hydroxypropyl cellulose, 2017, pages 1-24; hereinafter “Ashland”) as applied to claims 57 and 115-119, and further view of Kottayil et al. (WO2009/020666 A1, hereinafter “Kottayil”).
The teachings of Krekeler and Ashland have been discussed above.
Krekeler and Ashland collectively render obvious the composition of claim 57 for the reasons set forth above. However, Krekeler teaches the pharmaceutical ingredient is readily soluble in an aqueous solvent system. (See claim 8.)
Kottayil teaches aqueous pharmaceutical liquid formulations containing a pharmaceutical active, particularly a cannabinoid such as dronabinol, together with pharmaceutically acceptable cosolvents to maintain physical stability of the formulation. Kottayil teaches ethanol and polyethylene glycol as suitable cosolvents and teaches low-molecular-weight PEG, particularly PEG-400, for use in such pharmaceutical liquid formulations. (See claims 1-7; and Examples 4-5.) Kottayil also discloses the organic cosolvent will be present in an amount effective to have the cannabinoid substantially solubilized in the organic cosolvent that can contain ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, and combinations. (See ¶¶ [00165]-[00166].) The corresponding disclosure reports successful formulations containing dronabinol, ethanol, PEG-400, and aqueous buffer.
With respect to claims 109 and 133, Kottayil expressly teaches cannabinoid, including dronabinol, as the pharmaceutically active and teaches active-agent concentration including 1-30 wt% dronabinol, which falls wholly within claim 109’s 01-50 wt% range and claim 133’s 0.1-5 wt%. Thus, unlike the previous reliance upon Krekeler’s active concentration based upon dry composition weight, the present rejection relies upon Kottayil’s express teaching of an active in liquid pharmaceutical formulation in an amount falling within the claimed range.
It would have been obvious to further include such a pharmaceutical active in the Krekeler/Ashland solution because Krekeler itself concerns pharmaceutical formulations containing ingredients and Kottayil expressly demonstrates the successful incorporation of an active into aqueous/cosolvent pharmaceutical solutions. One would have reasonably expected success because Kottayil provides actual pharmaceutical liquid formulation containing the relevant classes of aqueous and organic solvent that can dissolve the active.
With respect to claim 120 requiring PEG at 0.1-18 wt%. Kottayil teaches PEG as a pharmaceutical cosolvent and teaches PEG amounts including about 1-40 wt%, 1-30 wt%, and 1-25 wt% of the aqueous pharmaceutical formulation. (See ¶ [00169].)
It would have been obvious to include PEG in the pharmaceutical solution because Kottayil teaches PEG as a pharmaceutically acceptable cosolvent useful in formulating/solubilizing the active ingredient in the aqueous formulation. The skilled artisan would reasonably have expected success because Kottayil expressly reports successful PEG-containing pharmaceutical liquid formulations.
With respect to claim 121 requiring the PEG to be PEG-400. Kottayil teaches lower-molecular-weight and identifies PEG-400 for the aqueous pharmaceutical formulations. Examples 4-5 expressly employ PEG-400 in dronabinol-containing aqueous formulations. Thus, PEG-400 is expressly suggested by the reference.
With respect to claim 122 requiring PEG at 0.6-8 wt%. Kottayil’s publication ranges beginning at about 1 wt% overlap the claimed range from approximately 1-8 wt%. Moreover, Example 5 expressly teaches a formulation containing 5 % PEG-400, directly within the claimed 0.6-8 wt% range. (See Example 5 and Tble 4.) Accordingly, claim 122 is not dependent merely upon optimization; the prior art expressly provides a PEG-400 concentration failing within the claimed range.
With respect to claim 127 requiring the active to be a pharmaceutical agent, nutraceutical agent, supplement, or cosmetic agent. Kottayil expressly teaches dronabinol as a pharmaceutically active agent. Because claim 127 recites the alternatives disjunctively, disclosure of the pharmaceutical-agent alternative satisfies the limitation.
Claim 110 is rejected under 35 U.S.C. 103 as being unpatentable over Krekeler et al. (US2013/0216594 A1; hereinafter “Krekeler”) in view of Ashland (KlucelTM hydroxypropyl cellulose, 2017, pages 1-24; hereinafter “Ashland”) as applied to claims 57 and 115-119, and further view of Lockwood et al. (US2011/0232234 A1; hereinafter “Lockwood”).
Krekeler in view Ashland renders obvious the underlying composition of claim 57 for the reasons set forth above.
Neither Krekeler nor Ashland is relied upon as expressly teaching the additional Kit/instructions limitation.
Lockwood expressly teaches a medical procedure Kit comprising printed instructions. Lockwook ¶ [0118] teaches that printed instructions can be attached to, dispensed upon, or disposed within the tray and that instructions inform healthcare provider how to use the kit, including how to use the device contained therein. Lockwood further teaches pictorial, step-by-step instructions for using the medical procedure kit. (See ¶¶ [0118], [0210].)
It would have been obvious to one of ordinary skill in the art to provide the pharmaceutical composition rendered obvious by Krekeler and Ashland together with instructions for its use, as taught by Lockwood.
One would have been motivated to do so because Lockwood expressly teaches that inclusion of instructions with a medical kit communicates how the contents are to be properly used. Providing instructions with the pharmaceutical composition would therefore predictably facilitate proper use and administration of the composition.
One of ordinary skill in the art would have had a reasonable expectation of success because the proposed modification requires no alteration of the chemical composition. The pharmaceutical composition continues to perform the same pharmaceutical/formulation function, while the printed instructions continue to perform their established informational function. Lockwood expressly demonstrates successful packaging of medical products with instructions explaining their use.
Importantly, Lockwood is relied upon only for the additional “kit” and “instructions for using the composition” limitations of claim 110. Lockwood is not relied upon to establish the HPC-M and HPC-G concentrations, alcohol concentration, water concentration, or the solution-under-ambient-conditions requirement. Those features are supplied by Krekeler and Ashland as discussed for claim 57, thus, and argument that Lockwood does not remedy an alleged compositional deficiency in Krekeler does not address the actual basis for combination.
Applicant’s arguments and Response to Applicant’s arguments
Applicant’s argument (05/04/2026) filed in response to the prior Office Acton have been fully considered but are not persuasive of patentability. The previous rejection has been withdrawn and replaced with this new rejection in view of the amended claims and Applicant’s arguments. In particular, the Examiner has considered the newly added limitation of claim 57 requiring that “the composition is a solution under ambient conditions.” The rejection, as presently set forth, relies upon the teachings of Krekeler and Ashland as a whole and does not rely upon the previously stated dry-weight calculations to establish the concentrations recited in the claimed liquid composition.
Applicant argues that Krekeler is directed to a suspension and that there would
have been no reason to modify Krekeler’s suspension to provide the presently claimed solution under ambient conditions.
In response, Applicant’s argument is not persuasive because it does not address the basis for the rejection as presently formulated and improperly treat Krekeler’s suspension of a poorly soluble active ingredient as though the hydroxypropyl cellulose components themselves necessarily remain suspended. Krekeler expressly teaches that the gel former may comprise Klucel® G, Klucel® M, or mixtures thereof (see, e.g., ¶ [0083].) Krekeler further expressly characterizes Klucel hydroxypropyl cellulose as a water-soluble cellulose ether that is soluble in both aqueous and organic solvents. Krekeler additionally teaches aqueous solvent systems and organic solvent systems comprising lower alkanols, including ethanol and isopropanol.
The fact that Krekeler deliberately maintains a poorly soluble or insoluble pharmaceutical ingredient in dispersed or suspended form does not negate Krekeler’s separate express teaching concerning the solubility of the Klucel hydroxypropyl cellulose itself. Indeed, Krekeler explains that the suspension results from selection of a solvent or solvent mixture in which the particular active ingredient is poorly soluble or insoluble. The physical state of that active ingredient therefore does not establish that klucel G and klucel M cannot be dissolved in the solvent system.
Moreover, independent claim 57 does not require the poorly soluble pharmaceutical ingredient responsible for Krekeler’s suspension. Claim 57 is directed to a composition comprising the recited HPC-M and HPC-G, alcohol, and water components and requires the resulting composition to be a solution under ambient conditions. Accordingly, the rejection does not require converting Krekeler’s suspended pharmaceutical ingredient into a dissolved pharmaceutical ingredient.
Ashland directly addresses the solution behavior of the hydroxypropyl cellulose components. Ashland teaches that klucel HPC is soluble in water below approximately 45oC, has excellent solubility in a wide range of polar organic solvents including ethanol, and can be prepared as solutions in aqueous and organic solvent systems. Ashland further expressly teaches that, at room temperature, klucel HPC solutions can be prepared over a wide range of viscosities and concentrations and provides concentration-dependent viscosity information for such solutions. Ashland additionally discusses aqueous alcohol klucel HJPC systems, including ethanol/water systems.
Thus, the proposed combination does not depend upon an unsupported assumption that Krekeler’s suspension would somehow become a solution. Rather, Krekeler identifies the claimed klucel grades and their solubility in aqueous and organic solvents, while Ashland expressly teaches preparation and behavior of klucel HPC solutions in those solvent environments at room temperature.
Accordingly, one of ordinary skill in the art would have had reason to employ the klucel M/G mixture disclosed by Krekeler in the aqueous/alcohol solution systems taught by Ashland and would have reasonably expected the HPC components to form a solution under ambient conditions. Applicant has not identified evidence establishing that the claimed HPC concentrations would have unexpectedly prevented solution formation in the aqueous/alcohol solvent systems taught by Ashland.
Applicant argues that Krekeler’s 5-25 wt% gel-former disclosure is based upon the
dry weight of the composition and therefore does not establish the presently claimed HPC-M and HPC-G concentrations based upon the total liquid compositions.
In response, Applicant’s argument is not persuasive. The Examiner acknowledges that Krekeler expresses certain gel-former amounts relative to the dry weight of the composition. The rejection as presently formulated does not depend upon converting Krekeler’s dry-weight percentages into hypothetical percentages of the claimed liquid composition. Rather, Krekeler is relied upon for its express identification of Klucel G and Klucel M, including mxitures thereof, as suitable hydroxypropyl cellulose materials and for its teachings concerning their use in the relevant solvent/formulation environment. Ashland is additionally relied upon for its teachings concerning klucel HPC solution concentrations and the relationship between polymer concentration and solution viscosity.
Ashland expressly evaluates Klucel HPC solutions as a function of HPC solids concentration and teaches that solution viscosity depends upon polymer concentration and molecular weight/grade. Thus, the concentration of Klucel HPC in solution was a known formulation parameter available to the ordinary skilled artisan. To the extent the claimed concentration ranges overlap the concentration disclosed or suggested by Ashland, the overlapping ranges support a prima facie case of obviousness. See MPEP 2144.05.
Accordingly, Applicant’s criticism of the prior dry-weight calculations does not overcome the rejection as presently formulated because that calculation is longer relied upon to establish the claimed concentrations.
Applicant argues that Krekeler teaches away from the claimed amount of water and
that there would have been no reason to increase the amount of water to arrive at the presently claimed composition.
In response, Applicant’s argument is not persuasive. A reference teaches away when its disclosure would have discouraged one of ordinary skill in the art from following the path taken by the applicant or would have led the artisan in a direction divergent from the claim invention. A mere preference for another embodiment does not, itself, constitute a teaching away. In the present case, Krekeler ‘s discussion of disadvantages associated with certain aqueous formulations, particularly in connection with particular poorly soluble pharmaceutical ingredients and the processing of films containing such ingredients, does not amount to a general teaching that water cannot or should not be used with klucel G or klucel M. To the contrary, Krekeler expressly identifies aqueous solvent systems and expressly states that klucel HPC is water soluble.
More importantly, Ashland affirmatively teaches aqueous klucel HPC solutions and aqueous-alcohol Klucel HPC systems, including ethanol/water systems. Ashland therefore provides an affirmative technical reason for the skilled artisan to employ water together with alcohol in formulating soluble klucel HPC materials.
The rejection also does not rely upon the prior statement that an artisan necessarily would have increased the amount of water because a pharmaceutical active ingredient was water insoluble, nor does the rejection rely upon the proposition that selecting 50% ethanol necessarily requires the remaining 50% to be water. Instead, the rejection relies upon the express aqueous and aqueous-alcohol solution teachings of the cited references.
Thus, the prior art, considered as whole, does not criticize, discredit, or otherwise discourage the claimed aqueous/alcohol solvent environment. Rather, Asland expressly demonstrates its suitability for klucel HPC solutions. Applicant’s teaching away argument is therefore not persuasive.
Applicant argues that the Examiner has not provided sufficient motivation to modify
Krekeler to arrive at the claimed concentration and that the previously state reasoning concerning increased viscosity, film thickens, and rapid disintegration is unsupported.
In response, Applicant’s argument is not persuasive. The rejection presently formulated does not depend upon the proposition that increasing viscosity necessarily increases film thickness or that a particular film thickness necessarily produces rapid disintegration.
The reason for the proposed modification instead arises directly from the formulation teachings of the references. Krekeler identifies klucel M and klucel G, including mixture thereof, as suitable HPC materials and teaches their compatibility with aqueous and organic solvent systems. Ashland provides practical formulation guidance concerning the preparation of klucel HPC solutions, including the effect of polymer grade and concentration upon solution viscosity.
Thus, one of ordinary skill in the art seeking to formulate Krekeler’s disclosed klucel M/G materials in an aqueous/organic solvent vehicle would have had reason to select the respective amounts of these polymers from the workable concentrations taught by Ashland in order to obtain a solution having an appropriate viscosity for the intended pharmaceutical formulation. The concentrations of the polymer were known formulation variables whose effects on solution viscosity were expressly taught by Ashland.
The Supreme Court has made clear that the obviousness inquiry is flexible and may be supported by combining known elements according to known methods to obtain predictable results or by applying a known technique to a known product ready for improvement. See MPEP §§ 2141 and 2143. Here, the proposed modification uses known klucel HPC grades disclosed by Krekeler under solution-formulation conditions expressly taught by Ashland for those materials.
Further, one of ordinary skill in the art would have had a reasonable expectation of success because Ashland expressly reports successful preparation and characterization of klucel HPC solutions at room temperature and in aqueous, organic, and aqueous-alcohol solvent environments. The proposed modification therefore would not have require speculation concerning whether klucel HPC was capable of forming the claimed type of solution.
Applicant argues that the additional references, including Lockwood do not cure the
deficiencies of Krekeler and that there would have no reason to combine the cited reference to arrive at the claimed invention.
In response, Applicant’s argument is not persuasive because it treats each secondary reference as though it must be independently supply all limitations allegedly absent from Krekeler. Obviousness, however, is determined from the collective teachings of the references and the claimed invention as a whole.
With respect to claim 57 and the claims depending therefrom that do not add the PEG, active-agent, and kit limitations for which additional references are applied, the rejection relies upon Krekeler in view of Ashland. Ashland is relied upon for its express teachings concerning concentrations, aqueous, and organic solvent solubility, aqueous-alcohol systems, and room-temperature solution behavior. Thus, Ashland directly addresses the additional “solution under ambient conditions” limitation added by Applicant.
For claims adding an active pharmaceutical agent and/or PEG limitations, Kottayil is relied upon only for those additional limitations. Kottayil expressly teaches room-temperature-stable aqueous pharmaceutical solutions containing a pharmaceutical active agent together with aqueous and organic solvent; identifies ethanol and polyethylene glycol as suitable pharmaceutical cosolvents; expressly identifies PEG-400 as the most preferred PEG; and teaches quantitative amounts of the active agent and PEG on a formulation-weight basis. The reference further explains that PEG and the organic cosolvent are employed to solubilize water-insoluble pharmaceutical active agents. Thus, its teachings provide both a reason for incorporating the additional components and a reasonable expectation that these components would function successfully in a pharmaceutical solution.
The quantitative disclosures of Kottayil also overlap the claimed active-agent and PEG ranges. Where a claimed range overlaps or lies within a range disclosed by the prior art, a prima facie case of obviousness ordinarily exists absent persuasive evidence of criticality, teaching away, or unexpected results. See MPEP § 2144.05. Applicant has not identified evidence establishing that the presently claimed overlapping concentrations produce a critical or unexpected result relative to the prior art ranges.
With respect to claim 110, Lockwood is not relied upon to establish any deficiency concerning the composition of claim 57. Krekeler in view of Ashland renders obvious the underlying composition for the reasons stated in the rejection. Lockwood is relied upon solely for the additional limitation of claim 110 requiring a kit comprising the composition, and instructions for using the composition. Accordingly, an argument that Lockwood does not disclose the HPC concentrations, aqueous/alcohol solvent systems, or solution-under-ambient-conditions limitations does not address the reason Lockwood is applied.
The proposed combinations therefore do not constitute an attempt to reconstruct Applicant’s invention using unrelated disclosures. Each secondary reference is applied for a specific teaching that directly corresponds to an additional limitation and is technically compatible with the formulation teachings of the preceding references. The references collectively concern pharmaceutical formulations and the selection of use of components and conditions for preparing such formulations. The proposed modifications employ the respective components for their known functions and would have produced predictable pharmaceutical-formulation results.
Conclusion
Applicant’s arguments have been fully considered. To the extent certain arguments identify shortcomings in the manner in which the prior rejection was previously articulated-particularly the reliance upon dry-weight calculations or certain statements concerning water content, viscosity, film thickness, and disintegration-the rejection has been withdrawn and does not depend upon these propositions.
The rejection presently relies upon the express teaching of the references concerning the claimed components, solution behavior, solvent systems, concentrations, and known pharmaceutical functions. The Examiner therefore maintains the new formulated rejection under 35 U.S.C. § 103 for the reasons set forth above in the new ground of rejection.
Conclusion
Claims 57, 109, 110, 115-122, 127, and 130-133 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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