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 .
Claim Status
Claims 23, 25, 27, 29-37, 39-42 and 45-48 are pending with claims 23, 25, 27, 29-32, 39-42 and 45-48 being examined with claims 33-37 deemed withdrawn. Claims 1-22, 24, 26, 28, 38 and 43-44 are canceled.
Response to Amendment
As to the claim amendments and remarks filed on 12/05/2025, the previous 12(b) rejection is withdrawn Applicant amended the claims to provide proper antecedent basis for the claimed features.
The previous 112(a) rejection is withdrawn. Applicant amended claims 23, 42 and 46 to address the deficiencies. However, upon examination of the claim amendments a new 112(a) rejection is has been filed and will be addressed below.
The previous claim objection is withdrawn. Applicant has amended claim 42 to address the deficiency. However, upon examination of the claim amendments a new 112(a) rejection has been filed and will be addressed below.
The previous drawing objection is moot. Applicant canceled the resealable nature of the container to address the issue.
As to the remarks, the examiner has found the Applicant’s arguments not persuasive and will be addressed below.
Claim Objections
Claim 40 is objected to because of the following informalities:
Claim 40 has an improper claim identifier. The identifier in claim 40 reads (Currently amended), however, claim 40 is not amended and should read (Previously presented).
Claim 47 is objected to because of the following informalities:
Claim 47 has an improper claim identifier. The identifier in claim 47 reads (Previously presented); however, since claim 47 is amended the claim identifier should read (Currently amended).
Appropriate correction is required.
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 23, 25-27, 29-32, 42 and 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Pharmaguideline (Pharmaguideline.com; hereinafter; “Pharmaguideline” previous of record) in view of Leigh (WO 2013144374 A1; hereinafter; “Leigh” previous of record), further in view of Faurie (US 20080067194 A1 previous of record), Bio-Rad (youtube.com; hereinafter “Bio-Rad” previous of record), Zuluaga (Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics; hereinafter “Zuluaga” previous of record), and Schuerer (Implications for Ophthalmic Formulations: Ocular Buffers Showed varied Cytotoxic Impact on Human Corneal-Limbal and Human Conjunctival Epithelial Cells; hereinafter “Schuerer” previous of record).
The expression “highly consistent” is deemed definite since applicant’s specification explicitly defines “highly consistent” as between +/- 0.015 and +/- 0.010 g (Spec., Pg. 8, lines 23-30).
Regarding claim 23, Pharmaguideline teaches a method for preparing media for physiologically relevant in vitro drug dissolution testing and drug solubility testing (Pharmaguideline; Title). Pharmaguideline teaches a buffer solution preparation that can be used in microbiological assay of antibiotics.
It is known in the art that process of microbiological assays of antibiotics are used to determine potency and concentration of pharmaceutical-grade antibiotics for injection and a statistical method to assess the in vitro equivalence of generic products with respect to the innovator (Zuluaga; fig. 2, 3 and 4), the method consisting essentially of the steps of:
providing a concentrate of a buffer solution comprising a defined concentration of one or more buffer agents inside a plastic or elastic deformable (Pharmaguideline; example 3, teaches a concentrated hydrochloric acid that is diluted with water with a defined concentration of 0.2M);
dispensing from said plastic or elastic deformable container into a second separate container a predetermined quantity (aliquot) of the buffer concentrate Pharmaguideline teaches dispensing from one container to a second container a predetermined aliquot of the buffer solution;
diluting the said predetermined quantity of the concentrate with a predetermined quantity of a solvent to produce the buffer solution comprising the defined concentration of the one or more buffer agents (Pharmaguideline; example 3 dilute with water);
wherein step (b) comprises dispensing an amount of the concentrate and step (c) comprises diluting the concentrate by a factor from 3 to 50 (Pharmaguideline example 3) and step (c) comprises diluting the concentrate by a factor from 3 to 50 (Pharmaguideline teaches 7.292 grams of HCl and when converted to milliliters equals 6.18mL of HCL using the equation mass/density=volume (7.292g/1.18g/mL = 6.18mL),
such that the buffer solution comprising the defined concentration of the one or more buffer agents has a pH from 1 to 9 (Pharmaguideline; example 3 the hydrochloride solution prepared of 0.2 M has a pH of 7 as can be calculated using the formula: pH= -log[H+]).
Pharmaguideline fails to teach the steps of (b) dispensing from a plastic or elastic deformable container into a second separate container a predetermined quantity (aliquot) of the buffer concentrate, said plastic or elastic deformable container having a nozzle within which there is an orifice or aperture configured to dispense the said predetermined quantity of the concentrate in a dropwise manner and/or in a controlled stream, the nozzle being configured to dispense drops having a highly consistent mass and/or volume, the drops having a mass of between 0.02 g and 0.25 g, and the deviation of the droplet mass from the mean droplet mass is less than 0.015 g;
said plastic or elastic deformable container enabling application of pressure of different magnitudes to control the rate at which the concentrate is dispensed, wherein a high magnitude of pressure rapidly dispenses the concentrate in a continuous stream and a lower magnitude of pressure accurately dispenses a final amount of concentrate in a dropwise manner, and wherein upon dispensing of the predetermined quantity of the concentrate the plastic or elastic deformable container nozzle is closed for later use.
However, Faurie teaches the analogous art of a plastic or elastic container
(Faurie; Abstract “nozzle is sealingly obstructed with a cap”) wherein the container (Faurie; [0011] “container with walls reversibly elastic”) includes a nozzle (Faurie; fig. 1. 5) that has an orifice that allows liquid to be dispensed in a dropwise manner (Faurie; Title) the orifice or aperture of the nozzle having an aspect ratio of between 1:5 and 1:1 (Faurie; fig. 1. 15 and fig. 3 illustrates a circular orifice; implicit of an aspect ratio of between 1:5 and 1:1), and the nozzle having a lid or seal to open and close the nozzle (Faurie; fig. 1. 6); the nozzle orifice or aperture configured to dispense the said predetermined quantity of the concentrate in a dropwise manner and/or in a controlled stream, the nozzle being configured to dispense drops having a highly consistent mass and/or volume, the drops having a mass of between 0.02 g and 0.25 g, and the deviation of the droplet mass from the mean droplet mass is less than 0.015 g.
Examiner notes that the applicant has not defined what specific solution is
dispensed in a dropwise manner from the deformable container therefore, the
drops mass would vary according to the solutions molality. Without some
statement of criticality or showing of unexpected results, to one of ordinary skill in
the art before the effective filing data of the invention it would have been obvious
to weigh the buffer solution or determine the weight through routine mathematical
experimentation to determine the drops mass;
said plastic or elastic deformable container enabling application of pressure of different magnitudes to control the rate at which the concentrate is dispensed (Faurie; [0018] “the liquid passes by effect of the compression exerted in the container by deformation of the walls”), wherein a high magnitude of pressure rapidly dispenses the concentrate in a continuous stream and a lower magnitude of pressure accurately dispenses a final amount of concentrate in a dropwise manner (Faurie; [0014]), and wherein upon dispensing of the predetermined quantity of the concentrate the plastic or elastic deformable container nozzle is closed for later use (Faurie; [0013]).
It would have been obvious to include a nozzle on the deformable container to provide dropwise and /or stream dispensing.
Alternatively, if Faurie’s nozzle is not taken as configured to dispense the defined concentration in a dropwise manner and/or in a controlled stream, Bio-Rad teaches a plastic or elastic deformable container (Bio-Rad) wherein enabling application of pressure of different magnitudes creates a continuous stream or a dropwise solution (Bio-Rad; minute 1:23-1:26).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s container to be an elastic container having a nozzle wherein a liquid can be dispensed from as taught by Faurie because Faurie teaches and elastic container (Faurie; Abstract and [0011) that includes a nozzle (Faurie; fig. 1. 5) and wherein liquid is dispensed from the resealable elastic container (Faurie; Title).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s container to be plastic or elastic deformable container (transfer pipette) as taught by Bio-Rad because Bio-Rad teaches a transfer pipette which is capable of dispensing in a continuous stream or a dropwise solution (Bio-Rad; minute 1:23-1:26).
This would allow to dispense an aliquot of sample and to reseal the elastic deformable container to prevent sample contamination.
Pharmaguideline fails to teach the method for preparing a buffer solution comprises dissolving the at least one osmolality adjusting agent therein.
However, Leigh teaches the analogous art of preparing a biorelevant media (Leigh; Title) that includes one osmolality adjusting agent is sodium chloride (Leigh; page 34 lines 21-22).
It would have been obvious to dissolve the sodium chloride osmolality adjusting agent to provide uniform distribution in the buffer concentrate sample.
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s buffer solution to include an osmolality adjusting agent as taught by Leigh because Leigh teaches adding sodium chloride to the buffer solution as a conventional osmolality adjusting agent. (Leigh; page 34 lines 21-22).
Pharma guideline also fails to teach a buffer with a buffer capacity from 0 mM/1/pH to 100 nM/1/pH and an osmolality from 25 mOsm/kg to 700 mOsm/kg, and
(d) adding to the concentrate or the diluted buffer solution biological surfactants comprising at least one of bile salts, phospholipids, fatty acids and their salts and products of lipolysis.
However, Leigh teaches the analogous art preparing a biorelevant media that includes buffer solution wherein the buffer has a buffer capacity from 0 mM/l/pH to 100 mM/l/pH (Leigh; [0208]), and an osmolality from 25 mOsm/kg to 700 mOsm/kg (Leigh; page 31, line 18).
To one of ordinary skill in the art it would have been obvious to prepare a buffer with a buffer capacity in the range from 0 mM/l/pH to 100 mM/l/pH an osmolality from 25 mOsm/kg to 700 mOsm/kg as taught by Leigh because Leigh teaches a buffer of physiological relevance with a buffer capacity between 2.5 mM/I/pH and 6.0 mM/I/pH an osmolality from 25 mOsm/kg to 700 mOsm/kg (Leigh; page 31, line 18). This would allow to prepare a canine fasted state simulated intestinal fluid (FaSSIF).
Leigh teaches (d) adding to the concentrate or the diluted buffer solution biological surfactants comprising at least one of bile salts, phospholipids, fatty acids and their salts and products of lipolysis (Leigh; [0016).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s buffer solution to include biological surfactants comprising at least one of bile salts as taught by Leigh because Leigh teaches adding to the concentrate or the diluted buffer solution biological surfactants comprising at least one of bile salts, phospholipids, fatty acids and their salts and products of lipolysis (Leigh; [0016).
The modification allows to simulate physiological fluids under fasted state conditions (Leigh; [0016]).
using the diluted buffer solution containing the biological surfactants comprising the at least one of bile salts, phospholipids, fatty acids and their salts and products of lipolysis for physiologically relevant in vitro drug dissolution testing and drug solubility testing.
This limitation recited an intended use of the claimed invention since the limitation does not further structurally limit the invention as claimed. Leigh further teaches using biorelevant gastric media for simulating physiological fluids under fasted state conditions (Leigh; [0016]), wherein the buffer media is a buffer (Leigh; [0063]). Thus, it is fully expected that Leigh would use the buffer solution. Therefore, Leigh meets the structural limitations of the claim (see MPEP 2114).
Regarding claim 25, modified Pharmaguideline teaches the method according to claim 23 (see above), wherein the solvent comprises water (Pharmaguideline; example 3).
Regarding claim 27, modified Pharmaguideline teaches the method according to claim 23 (see above) to include a concentrated solution (see above).
Modified Pharmaguideline fails to teach wherein step (b) comprises diluting the concentrate by a factor of 10 to 50.
However, Leigh teaches the analogous art of preparing a biorelevant media that includes buffer solution where the concentrate is diluted by a factor of 2 to 100 (Leigh; page 36 lines 11-12).
To one of ordinary skill in the art before the effective filing date it would have been obvious to modify Pharmaguideline’s concentrated solution to have a dilution factor from 2 to 100 as taught by Leigh because Leigh teaches the preparation of the relevant media solution is diluted by a factor of 6 (Leigh; page 36 line 12 “10 mL÷ 1.622 g = 6.16g/mL). Overlapping ranges are prima facie evidence of obviousness. It would have been obvious to one having ordinary skill in the art to have selected diluting the concentrate by a factor of from 10 to 50 that corresponds to the claimed range because it would provide an optimal diluting ratio of the components of the solution to provide a suitable solution compatible with biofluids.
Regarding claim 29, modified Pharmaguideline teaches the method according to claim 23 (see above), to include a buffer solution (see above).
Pharmaguideline fails to teach one or more osmolality adjusting agents is/are selected from sodium chloride, potassium chloride, magnesium chloride, calcium chloride, aluminum chloride, monosaccharides, disaccharides, polyols, and carbohydrates.
However, Leigh teaches the analogous art of preparing a biorelevant media wherein the osmolality adjusting agent is sodium chloride (Leigh; page 34 lines 21-22).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s buffer solution to include an osmolality adjusting agent as taught by Leigh because Leigh teaches adding sodium chloride to the buffer solution as a conventional osmolality adjusting agent. (Leigh; page 34 lines 21-22).
Regarding claim 30, modified Pharmaguideline teaches the method according to claim 23 (see above), wherein the one or more buffer agents is/are selected from the anhydrous and/or hydrate forms: Pharmaguideline teaches hydrochloric acid as a buffer agent (Pharmaguideline; example 3).
Regarding claim 31, modified Pharmaguideline teaches the method according to claim 23 (see above) to include a plastic or elastic deformable container (see above).
Modified Pharmaguideline fails to teach the plastic or elastic deformable container has an internal volume of less than 2.0 L.
However, Bio-Rad teaches dispensing from a 1mL transfer pipette (Bio-Rad; [0:25]).
Alternatively, Faurie teaches a plastic or elastic resealable container (Faurie; Title) for packaging eyedrops (eyedropper) (Faurie; [0010]) wherein the plastic or elastic container has an internal volume (Faurie; fig. 1. 15 and [0039] “this container forms a volume 15”).
It would have been obvious for the plastic or elastic deformable container in Faurie to have an internal volume of less than 2.0 L. as eye droppers are normally smaller than 2.0 L.
To one of ordinary skill in the art it would have been obvious to modify Pharmaguideline’s deformable container to have an internal volume of 1mL as taught by Bio-Rad because Bio-Rad teaches dispensing a small volume in a dropwise manner (Bio-Rad; [1:24]).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s deformable container to have an internal volume of less than 2.0 L as taught by Faurie because Faurie teaches a plastic or elastic deformable resealable container (eyedropper) (Faurie; Abstract and [0010]) wherein the plastic or elastic container has an internal volume (Faurie; fig. 1. 15).This would allow to have and amount of solution ready to dispense in a dropwise manner.
Regarding claim 32, modified Pharmaguideline teaches the method according to claim 23 (see above) wherein the pH of the buffer solution prepared is from 1.2 to 8.5 (Pharmaguideline; example 3, the hydrochloride solution prepared of 0.2 M has a pH of 7 as can be calculated using the formula: pH= -log[H+]).
Regarding claim 42, modified Pharmaguideline teaches a method for preparing a buffer solution comprising a defined concentration of one or more buffer agents for use in physiologically relevant in vitro drug dissolution testing, drug solubility testing and/or drug profiling (Pharmaguidline; Title). Pharmaguideline teaches preparing a buffer solution of a defined concentration of one or more buffer agents that can be used in microbiological assay of antibiotics.
It is known in the art that process of microbiological assays of antibiotics are used to determine potency and concentration of pharmaceutical-grade antibiotics for injection and a statistical method to assess the in vitro equivalence of generic products with respect to the innovator (Zuluaga; fig. 2, 3 and 4), the method consisting essentially of the steps of:
preparing a concentrate of a buffer solution, wherein the concentrate comprises one or more buffer agents and one or more osmolality adjusting agents dissolved therein (Pharmaguideline; example 3, teaches a concentrated hydrochloric acid that is diluted with water with a defined concentration of 0.2M);
dispensing the prepared concentrate of the buffer solution into a plastic or elastic deformable container. Pharmaguideline teaches dispensing from one container to a second container a predetermined aliquot of the buffer solution (Pharmaguideline; “the composition of standard buffer solutions”).
determining the defined concentration of the one or more buffer agents in the buffer solution based on factors comprising a desired buffer capacity and a desired osmolality.
It would have been obvious to determine the defined concentration based on buffer capacity using potentiometric titration to know the buffer concentration, and desired osmolality can be calculated;
dispensing from the plastic or elastic deformable container into a second separate container a predetermined quantity (aliquot) of the buffer concentrate (Pharmaguideline; example 3).
diluting the said defined concentration of the concentrate with a predetermined quantity of a solvent to produce the buffer solution comprising the defined concentration of the one or more buffer agents (Pharmaguideline; example 3);
wherein step (d) comprises dispensing an amount of the concentrate (Pharmaguideline; example 3) and step (e) comprises diluting the concentrate by a factor from 3 to 50 (Pharmaguideline teaches 7.292 grams of HCl and when converted to milliliters equals 6.18mL of HCL using the equation mass/density=volume (7.292g/1.18g/mL = 6.18mL), wherein the buffer solution comprising the defined concentration of the one or more buffer agents has a pH from 1 to 9 (Pharmaguideline; example 3 the hydrochloride solution prepared of 0.2 M has a pH of 7 as can be calculated using the formula: pH= -log[H+]).
Pharmaguideline fails to teach a plastic or elastic deformable container having a nozzle within which there is an orifice or aperture configured to dispense the said defined concentration of the concentrate in a dropwise manner and/or in a controlled stream, the nozzle being configured to dispense drops having a highly consistent mass and/or volume, the orifice or aperture of the nozzle having an aspect ratio of between 1:5 and 1:1 and the nozzle having a lid or seal to open and close the nozzle, the drops having a mass of between 0.02 g to 0.25 g, and the deviation of the droplet mass from the mean droplet mass is less than 0.015 g, said plastic or elastic deformable container enabling application of pressure of different magnitudes to control the rate at which the concentrate is dispensed, wherein a high magnitude of pressure rapidly dispenses the concentrate in a continuous stream and a lower magnitude of pressure accurately dispenses a final amount of concentrate in a dropwise manner, and wherein upon dispensing of the predetermined quantity of the concentrate the plastic or elastic deformable container is re-sealed for re-use.
However, Faurie teaches the analogous art of a re-sealable plastic or elastic container
(Faurie; Abstract “nozzle is sealingly obstructed with a cap”) wherein the container (Faurie; [0011] “container with walls reversibly elastic”) wherein the elastic container includes a nozzle (Faurie; fig. 1. 5) that has an orifice that allows liquid to be dispensed in a dropwise manner (Faurie; Title) the orifice or aperture of the nozzle having an aspect ratio of between 1:5 and 1:1 (Faurie; fig. 1. 15 and fig. 3 illustrates a round container with what appears to be a matching round nozzle with an aspect ratio of between 1:5 and 1:1) and the nozzle having a lid or seal to open and close the nozzle (Faurie; fig. 1. 6); the nozzle orifice or aperture configured to dispense the said predetermined quantity of the concentrate in a dropwise manner and/or in a controlled stream, the nozzle being configured to dispense drops having a highly consistent mass and/or volume, the drops having a mass of between 0.02 g and 0.25 g, and the deviation of the droplet mass from the mean droplet mass is less than 0.015 g.
Examiner notes that the applicant has not defined what specific solution is
dispensed in a dropwise manner from the deformable container therefore, the
drops mass would vary according to the solutions molality. Without some
statement of criticality or showing of unexpected results, to one of ordinary skill in
the art before the effective filing data of the invention it would have been obvious
to weigh the buffer solution or determine the weight through routine mathematical
experimentation to determine the drops mass;
said plastic or elastic deformable container enabling application of pressure of different magnitudes to control the rate at which the concentrate is dispensed (Faurie; [0018] “the liquid passes by effect of the compression exerted in the container by deformation of the walls”), wherein a high magnitude of pressure rapidly dispenses the concentrate in a continuous stream and a lower magnitude of pressure accurately dispenses a final amount of concentrate in a dropwise manner (Faurie; [0014]), and wherein upon dispensing of the predetermined quantity of the concentrate the plastic or elastic deformable container nozzle is re-sealed for later use (Faurie; [0013]);
It would have been obvious to include a nozzle on the deformable container to provide dropwise and /or stream dispensing.
Alternatively, if Faurie’s nozzle is not taken as configured to dispense the defined concentration in a dropwise manner and/or in a controlled stream, Bio-Rad teaches a plastic or elastic deformable container (Bio-Rad) wherein enabling application of pressure of different magnitudes creates a continuous stream or a dropwise solution (Bio-Rad; minute 1:23-1:26).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s container to be an elastic container having a nozzle wherein a liquid can be dispensed from as taught by Faurie because Faurie teaches and elastic container (Faurie; Abstract and [0011) that includes a nozzle (Faurie; fig. 1. 5) and wherein liquid is dispensed from the resealable elastic container (Faurie; Title).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s container to be plastic or elastic deformable container (transfer pipette) as taught by Bio-Rad because Bio-Rad teaches a transfer pipette which is capable of dispensing in a continuous stream or a dropwise solution (Bio-Rad; minute 1:23-1:26).
This would allow to dispense an aliquot of sample and to reseal the elastic deformable container to prevent sample contamination.
Pharmaguideline also fails to teach a buffer capacity from 0 mM/1/pH to 100 mM/1/pH; and an osmolality from 25 mOsm/kg to 700 mOsm/kg, and
(f) adding to the concentrate or the diluted buffer solution biological surfactants comprising at least one of bile salts, phospholipids, fatty acids and their salts and products of lipolysis;
However, Leigh teaches the analogous art preparing a biorelevant media that includes buffer solution wherein the buffer has a buffer capacity from 0 mM/l/pH to 100 mM/l/pH (Leigh; [0208]), and an osmolality from 25 mOsm/kg to 700 mOsm/kg (Leigh; page 31, line 18).
To one of ordinary skill in the art it would have been obvious to prepare a buffer with a buffer capacity in the range from 0 mM/l/pH to 100 mM/l/pH an osmolality from 25 mOsm/kg to 700 mOsm/kg as taught by Leigh because Leigh teaches a buffer of physiological relevance with a buffer capacity between 2.5 mM/I/pH and 6.0 mM/I/pH an osmolality from 25 mOsm/kg to 700 mOsm/kg (Leigh; page 31, line 18). This would allow to prepare a canine fasted state simulated intestinal fluid (FaSSIF); and
using the diluted buffer solution containing the biological surfactants comprising the at least one of bile salts, phospholipids, fatty acids and their salts and products of lipolysis for physiologically relevant in vitro drug dissolution testing and drug solubility testing.
This limitation recited an intended use of the claimed invention since the limitation does not further structurally limit the invention as claimed. Leigh further teaches using biorelevant gastric media for simulating physiological fluids under fasted state conditions (Leigh; [0016]), wherein the buffer media is a buffer (Leigh; [0063]). Thus, it is fully expected that Leigh would use the buffer solution. Therefore, Leigh meets the structural limitations of the claim (see MPEP 2114).
Regarding claim 45, modified Pharmaguideline teaches the method according to claim 42 (see above) to include preparing a buffer solution (see above).
Modified Pharmaguideline fails to teach the method of preparing a buffer solution further comprises preparing a physiologically relevant fasted state or fed state media containing bile salts and lecithin from the buffer solution.
However, Leigh teaches the analogous art preparing a biorelevant media that includes preparing a physiologically relevant fasted state or fed state media containing bile salts and lecithin (Leigh; page 17, lines 1-4) from the buffer solution (Leigh; page 19, lines 15-16).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s buffer solution to prepare a physiologically relevant fasted state or fed state media containing bile salts and lecithin from the buffer solution as taught by Leigh because Leigh teaches preparing a physiologically relevant fasted state or fed state media containing bile salts and lecithin from the buffer solution (Leigh; page 17, lines 1-4 and page 19,lines 15-16). Leigh teaches the biorelevant media is designed to reflect gastric and intestinal fluids (Leigh; page. 2, lines 14-15). Gastric and intestinal fluids are known in the art to be buffers.
Regarding claim 46, modified Pharmaguideline teaches the method according to claim 42 (see above), wherein the concentrate is prepared by dissolving the one or more buffer agents (Pharmaguideline; example 3 teaches hydrochloric diluted with water).
Modified Pharmaguideline fails to teach the one or more osmolality adjusting agents are dissolved in a solvent to prepare the concentrate and the step of dispersing the prepared concentration comprises dispensing a defined quantity of the concentrate into the plastic or elastic deformable container.
However, Leigh teaches the analogous art of preparing a biorelevant media that includes a buffer and osmotic components (Leigh; [0063]) that includes one or more osmolality adjusting agents dissolved therein (Leigh; [0177]-[0178] and [0247]). Leigh [0240]).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to include an osmolality adjusting agent to Pharmaguideline’s buffer solution as taught by Leigh because Leigh teaches a method of preparing an aqueous buffer solution that contains osmotic components comprising sodium chloride (Leigh; [0240]). The addition of an osmolality agent to Pharmaguideline’s buffer solution would allow to adjust the solutions osmolality.
It would have been obvious to disperse the prepared concentration comprising dispensing a defined quantity of the concentrate into the plastic or elastic deformable container so as to have the buffer concentrate readily available.
Regarding claim 47, Pharmaguideline teaches a method for preparing a buffer solution comprising a defined concentration of one or more buffer agents Pharmaguideline; (Title) teaches preparing a buffer solution on example 3 of a defined concentration of hydrochloric acid 0.2 M, the method consisting essentially of the steps of:
(a) filling a plastic or elastic deformable container with a buffer concentrate Pharmaguideline teaches filling a container to transfer to a second container a predetermined aliquot of the buffer solution (“the composition of standard buffer solutions”);
(b) dispensing from said plastic or elastic deformable container into a second separate container a predetermined quantity (aliquot) of the buffer concentrate. Pharmaguideline teaches dispensing from one container to a second container a predetermined aliquot of the buffer solution (The composition of standard buffer solutions”);
wherein step (b) comprises dispensing an amount of the concentrate Pharmaguideline teaches dispensing from one container to a second container a predetermined aliquot of the buffer solution;
diluting the said predetermined quantity of the concentrate with a predetermined quantity of a solvent to produce the buffer solution comprising the defined concentration of the one or more buffer agents (Pharmaguideline; example 3);
and step (c) comprises diluting the concentrate by a factor from 3 to 50,such that the buffer solution comprising the defined concentration of the one or more buffer agents has a pH from 1 to 9 and a buffer capacity from 0 mM/1/pH to 100 mM/1/pH; and an osmolality from 25 mOsm/kg to 700 mOsm/kg (Pharmaguideline teaches 7.292 grams of HCl and when converted to milliliters equals 6.18mL of HCL using the equation mass/density=volume (7.292g/1.18g/mL = 6.18mL),;
Pharmaguideline fails to teach the steps of (b) dispensing from a plastic or elastic deformable container into a second separate container a predetermined quantity (aliquot) of the buffer concentrate, said plastic or elastic deformable container having a nozzle within which there is an orifice or aperture configured to dispense the said predetermined quantity of the concentrate in a dropwise manner and/or in a controlled stream, the nozzle being configured to dispense drops having a highly consistent mass and/or volume, the drops having a mass of between 0.02 g and 0.25 g, and the deviation of the droplet mass from the mean droplet mass is less than 0.015 g;
Pharmaguideline fails to teach the plastic or elastic deformable container having a nozzle within which there is an orifice or aperture configured to dispense the said predetermined quantity of the concentrate in a dropwise manner and/or in a controlled stream, the nozzle being configured to dispense drops having a highly consistent mass and/or volume, the orifice or aperture of the nozzle having an aspect ratio of between 1:5 and 1:1 and the nozzle having a lid or seal to open and close the nozzle, the drops having a mass of between 0.02 g and 0.25 g, and the deviation of the droplet mass from the mean droplet mass is less than 0.015 g, said plastic or elastic deformable container enabling application of pressure of different magnitudes to control the rate at which the concentrate is dispensed, wherein a high magnitude of pressure rapidly dispenses the concentrate in a continuous stream and a lower magnitude of pressure accurately dispenses a final amount of concentrate in a dropwise manner.
However, Faurie teaches the analogous art of a plastic or elastic container
(Faurie; Abstract “nozzle is sealingly obstructed with a cap”) wherein the plastic or elastic container (Faurie; [0011] “container with walls reversibly elastic”) includes a nozzle (Faurie; fig. 1. 5) that has an orifice that allows liquid to be dispensed in a dropwise manner (Faurie; Title) the orifice or aperture of the nozzle having an aspect ratio of between 1:5 and 1:1 (Faurie; fig. 1. 15 and fig. 3 illustrates a round container with what appears to be a matching round nozzle with an aspect ratio of between 1:5 and 1:1) and the nozzle having a lid or seal to open and close the nozzle (Faurie; fig. 1. 6); the nozzle orifice or aperture configured to dispense the said predetermined quantity of the concentrate in a dropwise manner and/or in a controlled stream, the nozzle being configured to dispense drops having a highly consistent mass and/or volume, the drops having a mass of between 0.02 g and 0.25 g, and the deviation of the droplet mass from the mean droplet mass is less than 0.015 g.
Examiner notes that the applicant has not defined what specific solution is
dispensed in a dropwise manner from the deformable container therefore, the
drops mass would vary according to the solutions molality. Without some
statement of criticality or showing of unexpected results, to one of ordinary skill in
the art before the effective filing data of the invention it would have been obvious
to weigh the buffer solution or determine the weight through routine mathematical
experimentation to determine the drops mass;
said plastic or elastic deformable container enabling application of pressure of different magnitudes to control the rate at which the concentrate is dispensed (Faurie; [0018] “the liquid passes by effect of the compression exerted in the container by deformation of the walls”), wherein a high magnitude of pressure rapidly dispenses the concentrate in a continuous stream and a lower magnitude of pressure accurately dispenses a final amount of concentrate in a dropwise manner (Faurie; [0014]), and wherein upon dispensing of the predetermined quantity of the concentrate the plastic or elastic deformable container nozzle is closed for later use (Faurie; [0013]).
It would have been obvious to include a nozzle on the deformable container to provide dropwise and /or stream dispensing.
Alternatively, if Faurie’s nozzle is not taken as configured to dispense the defined concentration in a dropwise manner and/or in a controlled stream, Bio-Rad teaches a plastic or elastic deformable container (Bio-Rad) wherein enabling application of pressure of different magnitudes creates a continuous stream or a dropwise solution (Bio-Rad; minute 1:23-1:26).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s container to be an elastic container having a nozzle wherein a liquid can be dispensed from as taught by Faurie because Faurie teaches and elastic container (Faurie; Abstract and [0011) that includes a nozzle (Faurie; fig. 1. 5) and wherein liquid is dispensed from the resealable elastic container (Faurie; Title).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s container to be plastic or elastic deformable container (transfer pipette) as taught by Bio-Rad because Bio-Rad teaches a transfer pipette which is capable of dispensing in a continuous stream or a dropwise solution (Bio-Rad; minute 1:23-1:26).
This would allow to dispense an aliquot of sample and to reseal the elastic deformable container to prevent sample contamination
Pharmaguideline fails to teach the method for preparing a buffer solution comprises dissolving the at least one osmolality adjusting agent therein.
However, Leigh teaches the analogous art of preparing a biorelevant media (Leigh; Title) that includes one osmolality adjusting agent is sodium chloride (Leigh; page 34 lines 21-22).
It would have been obvious to dissolve the sodium chloride osmolality adjusting agent to provide uniform distribution in the buffer concentrate sample.
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s buffer solution to include an osmolality adjusting agent as taught by Leigh because Leigh teaches adding sodium chloride to the buffer solution as a conventional osmolality adjusting agent. (Leigh; page 34 lines 21-22).
Pharmaguideline also fails to teach adding to the concentrate or the diluted buffer solution biological surfactants comprising at least one of bile salts, phospholipids, fatty acids and their salts and products of lipolysis.
However, Leigh teaches the analogous art preparing a biorelevant media (Leigh; Title) that includes buffer solution (Leigh; [0047]) that includes adding to the concentrate or the diluted buffer solution biological surfactants comprising at least one of bile salts (Leigh; [0016]).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s buffer concentrate solution to add biological surfactants comprising at least one of bile salts as taught by Leigh because Leigh teaches a biorelevant media (Leigh; Title) that includes buffer solution (Leigh; [0047]) that includes adding to the concentrate or the diluted buffer solution biological surfactants comprising at least one of bile salts (Leigh; [0016]).
The modification allows to simulate physiological fluids under fasted state conditions in the stomach (Leigh; [0016]); and
using the diluted buffer solution containing the biological surfactants comprising the at least one of bile salts, phospholipids, fatty acids and their salts and products of lipolysis for physiologically relevant in vitro drug dissolution testing and drug solubility testing.
This limitation recited an intended use of the claimed invention since the limitation does not further structurally limit the invention as claimed. Leigh further teaches using biorelevant gastric media for simulating physiological fluids under fasted state conditions (Leigh; [0016]), wherein the buffer media is a buffer (Leigh; [0063]). Thus, it is fully expected that Leigh would use the buffer solution. Therefore, Leigh meets the structural limitations of the claim (see MPEP 2114).
Regarding claim 48, modified Pharmaguideline teaches the method according to claim 23 (see above) to include a nozzle (see above).
Modified Pharmaguideline fails to teach the nozzle is selected from the group consisting of:(i) a ribbed twist open close cap nozzle with bore seal;(ii) a polypropylene disc top cap with crab claw seal;(iii) a ribbed push pull cap with bore seal;(iv) a smooth polypropylene flip open close cap with expanded polyethylene liner; or (v) a smooth polypropylene flip top cap and crab claw seal.
However, Faurie teaches the analogous art of a plastic or elastic container that includes a cap (Faurie; Abstract “nozzle is sealingly obstructed with a cap”) wherein the container (Faurie; [0011] “container with walls reversibly elastic”) wherein the nozzle is selected from the group consisting of:(i) a ribbed twist open close cap nozzle (Faurie; [0034] “the cap is preferably a screw cap”) with bore seal], [0044] “the cap comprises a pip 15 penetrating the nozzle”).
To one of ordinary skill in the art the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s nozzle to be ribbed twist open close with bore seal cap nozzle as taught by Faurie because Faurie teaches a plastic or elastic container that includes a cap (Faurie; Abstract “nozzle is sealingly obstructed with a cap”) wherein the container (Faurie; [0011] “container with walls reversibly elastic”) wherein the nozzle is selected from the group consisting of:(i) a ribbed twist open close cap nozzle (Faurie; [0034] “the cap is preferably a screw cap”) with bore seal], [0044] “the cap comprises a pip 15 penetrating the nozzle”).
The modification allows to sealingly obstruct the nozzle with the cap (Faurie; Abstract).
Claim 39 is rejected under 35 U.S.C. 103 and is being unpatentable over Pharmaguideline (Pharmaguideline.com; hereinafter; “Pharmaguideline” previous of record) in view of Bio-Rad (youtube.com; hereinafter “Bio-Rad” previous of record) further in view of Leigh (WO 2013144374 A1; hereinafter; “Leigh” previous of record), further in view of Zuluaga (Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics; hereinafter “Zuluaga), further in view of Schuerer (Implications for Ophthalmic Formulations: Ocular Buffers Showed varied Cytotoxic Impact on Human Corneal-Limbal and Human Conjunctival Epithelial Cells; hereinafter “Schuerer”), and further in view of Borns (US20160017405 A1 hereinafter; “Borns” previous of record).
Regarding claim 39, modified Pharmaguideline teaches the method according to claim 27 (see above) to include a concentrated solution (see above).
Modified Pharmaguideline fails to teach wherein step (b) comprises diluting the concentrate by a factor of 20 to 40.
However, Borns teaches the analogous art of nucleic acid hybridization compositions that includes a concentrated stock solution that is diluted by a factor of 2-fold to 20-fold (Borns; [0015]).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s concentrated solution to dilute it by a factor of 1 to 20 as taught by Born because Born teaches diluting the stock solution yields the composition at a concentration for use (Borns; [0015]). Overlapping ranges are prima facie evidence of obviousness. It would have been obvious to one having ordinary skill in the art to have selected the portion of 20 to 40 that corresponds to the claimed range because the greater the concentration of the concentrate the higher the dilution factor will be. In re Malagari, 184 USPQ 549 (CCPA 1974).
Claim 40 is rejected under 35 U.S.C. 103 and is being unpatentable over Pharmaguideline (Pharmaguideline.com; hereinafter; “Pharmaguideline” previous of record) in view of Bio-Rad (youtube.com; hereinafter “Bio-Rad” previous of record) further in view of Leigh (WO 2013144374 A1; hereinafter; “Leigh” previous of record), further in view of Zuluaga (Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics; hereinafter “Zuluaga), further in view of Schuerer (Implications for Ophthalmic Formulations: Ocular Buffers Showed varied Cytotoxic Impact on Human Corneal-Limbal and Human Conjunctival Epithelial Cells; hereinafter “Schuerer”).and further in view of Globe Scientific (amazon.com hereinafter; “Globe Scientific” previous of record).
Regarding claim 40, modified Pharmaguideline teaches the method according to claim 31 (see above) to include a plastic or elastic deformable container (see above).
Modified Pharmaguideline fails to teach the plastic or elastic deformable container has an internal volume of 5 mL to 1.5 L.
However, Globe Scientific teaches the analogous art of a plastic or elastic deformable container that has an internal volume of 7mL (Globe Scientific; fig. 1).
To one of ordinary skill in the art before the effective filing date of the invention it would have been obvious to modify Pharmaguideline’s plastic or elastic deformable container to have a larger internal volume as taught by Globe Scientific because the deformable container can contain a larger sample volume.
Claim 41 is rejected under 35 U.S.C. 103 and is being unpatentable over Pharmaguideline (Pharmaguideline.com; hereinafter; “Pharmaguideline” previous of record) in view of Bio-Rad (youtube.com; hereinafter “Bio-Rad” previous of record) further in view of Leigh (WO 2013144374 A1; hereinafter; “Leigh” previous of record), further in view of Zuluaga (Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics; hereinafter “Zuluaga), further in view of Schuerer (Implications for Ophthalmic Formulations: Ocular Buffers Showed varied Cytotoxic Impact on Human Corneal-Limbal and Human Conjunctival Epithelial Cells; hereinafter “Schuerer”).and further in view of Halverson et al. (US 20100248216 A1; hereinafter; “Halverson” previous of record).
Regarding claim 41, modified Pharmaguideline teaches the method according to claim 40 (see above) to include a plastic or elastic deformable container (see above)
Modified Pharmaguideline fails to teach the deformable container has an internal volume of 50 ml to 1.0 L.
However, Halverson teaches the analogous art of a plastic or elastic deformable sample preparation container (Halverson; [0003]) with an internal volume of 50 mL to 250 mL (Halverson; [0055]).
To one of ordinary skill in the art it would have been obvious to modify modified Pharmaguideline’s plastic or elastic deformable container to have an internal volume of 50 mL to 250 mL as taught by Halverson because Halverson teaches the container can vary in capacity (Halverson; [0055]). It would have been obvious to use a larger deformable container than the pipette of Bio-Rad when one needed to prepare a large volume of buffer, yet still needed accuracy in the measurements.
Response to Arguments
Applicant’s arguments, filed on 12/05/2025, with respect to the prior art rejections over Pharmaguideline in view of Bio-Rad further in view of Leigh have been fully considered and are persuasive The rejections have been modified in accord with the amendment.
With respect to claims 23, 42 and 47, Applicant argues Pharmaguideline alone or in combination with Leigh, Faurie, Bio-Rad, Zuluaga and Schuerer describe or suggest at least the nozzle being configured to dispense drops having a highly consistent mass and/or volume, the orifice or aperture of the nozzle having an aspect ratio of between 1:5 and 1:1 and the nozzle having a lid or seal to open and close the nozzle and (2) adding to the concentrate or the diluted buffer solution biological surfactants, comprising at least one of bile salts, phospholipids, fatty acids and their salts and products of lipolysis.
Examiner disagrees. Faurie has a plastic or elastic deformable container that includes a nozzle configured to dispense drops, the orifice or aperture of the nozzle having an aspect ratio of between 1:5 and 1:1 since it is circular.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Leigh teaches adding to the concentrate or the diluted buffer solution biological surfactants, comprising at least one of bile salts, phospholipids, fatty acids and their salts and products of lipolysis.
With respect to claim 23, Applicant also argues Pharmaguideline is in such a remote field that a person skilled in the art would not consider the teachings.
Examiner disagrees, Pharmaguideline teaches a method for preparing a buffer solution as claimed by Applicant.
In response to applicant's argument that Pharmaguideline is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Pharmaguideline teaches a method for preparing media for physiologically relevant in vitro drug dissolution testing and drug solubility testing (see claim 1 above).
Applicant further argues Pharmaguideline would only allow dropwise dispensing of fluid using a pipette and not from a deformable container with a nozzle.
Examiner disagrees. Faurie teaches dispensing of fluid in a dropwise manner using a deformable container with a nozzle. Further, Bio-Rad also teaches a plastic or elastic deformable container (Bio-Rad) wherein enabling application of pressure of different magnitudes creates a continuous stream or a dropwise solution (Bio-Rad; minute 1:23-1:26).
Applicant further argues Pharmaguideline emphasizes the criticality of storing the buffer solution, not the buffer concentrate.
Examiner notes that Applicant is not claiming storage of the buffer concentrate or the buffer solution.
Conclusion
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.
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/A.R./Examiner, Art Unit 1798
/CHARLES CAPOZZI/Supervisory Patent Examiner, Art Unit 1798