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 .
Claim Status
Claims 1-37 and 39 are rejected.
Claims 38 and 40 have been cancelled.
Claim Objections
Claims 8-9, 11, 17-21 and 24-25 are objected to because of the following informalities:
Claim 8: “wherein (a) comprises” in line 1 should be replaced with --wherein step (a) comprises--.
Claim 9: “wherein (a) comprises” in line 1 should be replaced with --wherein step (a) comprises--.
Claim 11: “wherein (b) comprises” in line 1 should be replaced with --wherein step (b) comprises--.
Claim 17: “wherein (d) comprises” in line 1 should be replaced with --wherein step (d) comprises--.
Claim 18: “wherein (d) comprises” in line 1 should be replaced with --wherein step (d) comprises--.
Claim 19: “wherein (e) comprises” in line 1 should be replaced with --wherein step (e) comprises--.
Claim 20: “wherein (e) comprises” in line 1 should be replaced with --wherein step (e) comprises--.
Claim 21: “wherein (e) comprises” in line 1 should be replaced with --wherein step (e) comprises--.
Claim 24: “wherein (e) comprises” in line 1 should be replaced with --wherein step (e) comprises--.
Claim 25: “wherein (e) comprises” in line 1 should be replaced with --wherein step (e) comprises--.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-37 and 39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitations: “optionally performing one or more ultracentrifugation steps after (d)” in line 8; “optionally (e) and optionally for about 15-120 minutes” in lines 10-11; and “optionally performing tangential flow filtration to obtain a retentate, wherein the retentate is optionally ultracentrifuged via one or more ultracentrifugation steps or stored at -80 degrees C, and separating out fractions of the retentate, optionally via column separation, after the retentate is optionally ultracentrifuged or stored at -80 degrees C” in lines 12-16. These limitations are indefinite because it is not clear if what follows the word “optionally” is being claimed.
Claim 36 recites the limitation "the formulation" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-37 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Izumi et al. (EP 3192518B1) [hereinafter Izumi] in view of Bolen et al. (WO 2020/010161A1) [hereinafter Bolen].
With respect to claim 1, Izumi discloses a method for preparing an exosome from milk (see paragraph 0024), including the steps of: a. centrifuging a biological fluid under conditions suitable to separate fats from one or more other components of the biological fluid [see paragraphs 0022, 0025, and 0046]; b. removing the separated fats from the biological fluid [see paragraphs 0022, 0025, and 0046]; after step (b) centrifuging the remaining biological fluid one or more times [see paragraphs 0022, 0025, and 0046]; d. filtering the remaining biological fluid after step (c) [see paragraphs 0022, 0025, and 0046]; e. performing one or more ultracentrifugation steps after (d) [see paragraphs 0022, 0025, and 0046]; and (g) after (f), optionally performing tangential flow filtration to obtain a retentate, wherein the retentate is optionally ultracentrifuged via one or more ultracentrifugation steps or stored at -80 degrees C, and separating out fractions of the retentate, optionally via column separation, after the retentate is optionally ultracentrifuged or stored at -80 degrees C, wherein the method comprises step (e) or step (g) but not both [see paragraphs 0022, 0025, and 0046].
Izumi lacks skimming any noticeable separated fats after each centrifuging in step (c); and f. chelating divalent cations with about 10 mM to about 100 mM EDTA at about 30-42 degrees Celsius after (d). It is submitted that the centrifuging disclosed in Izumi is considered indistinguishable from the recited centrifuging, and appears to be capable of including skimming any noticeable separated fats after each centrifuging in step (c) [see paragraphs 0022, 0025, and 0046]. Bolen teaches that it is known in the art to utilize a chelating agent such EDTA, which appears to be capable of being used at the recited mM and temperature range, to chelate divalent cations such as Ca ^2+, and remove casein micelles in a method of isolating milk vesicles or exosomes from unpasteurized milk [see Pg. 2 Lns. 20-25, Pg. 15 Lns. 20-30, Pg. 92 Lns. 17-31, and Pg. 94 Lns. 5-14]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi with the EDTA teaching of Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method comprising skimming any noticeable separated fats after each centrifuging in step (c): and f. chelating divalent cations with about 10 mM to about 100 mM EDTA at about 30-42 degrees Celsius after (d) involves only routine skill in the art, for the purpose of removing fats, and chelating Ca^2+ ions in the method, and thereby isolating exosomes with a desirable fat and casein concentration [see Bolen Pg. 2 Lns. 20-25, Pg. 15 Lns. 20-30, Pg. 92 Lns. 17-31, and Pg. 94 Lns. 5-14].
With respect to claim 2, Izumi lacks wherein chelating divalent cations occurs with about 30 mM EDTA. Bolen teaches that it is known in the art to utilize a chelating agent such EDTA, which appears to be capable of being used at the recited mM, to chelate divalent cations such as Ca ^2+, and remove casein micelles in a method of isolating milk vesicles or exosomes from unpasteurized milk [see Pg. 2 Lns. 20-25, Pg. 15 Lns. 20-30, Pg. 92 Lns. 17-31, and Pg. 94 Lns. 5-14]. It would have been obvious to one of ordinary skill in the art to modify Izumi with the EDTA teaching of Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein chelating divalent cations occurs with about 30 mM EDTA involves only routine skill in the art, for the purpose of chelating an effective amount of Ca^2+ ions in the method, and thereby isolating exosomes with a desirable casein concentration [see Bolen Pg. 2 Lns. 20-25, Pg. 15 Lns. 20-30, Pg. 92 Lns. 17-31, and Pg. 94 Lns. 5-14].
With respect to claim 3, Izumi lacks wherein chelating divalent cations occurs at about 37 degrees Celsius. Bolen teaches that it is known in the art to utilize a chelating agent such EDTA, which appears to be capable of being used at the recited temperature, to chelate divalent cations such as Ca ^2+, and remove casein micelles in a method of isolating milk vesicles or exosomes from unpasteurized milk [see Pg. 2 Lns. 20-25, Pg. 15 Lns. 20-30, Pg. 92 Lns. 17-31, and Pg. 94 Lns. 5-14]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi with the EDTA teaching of Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein chelating divalent cations occurs at about 37 degrees Celsius involves only routine skill in the art, for the purpose of chelating an effective amount of Ca^2+ ions in the method, and thereby isolating exosomes with a desirable casein concentration [see Bolen Pg. 2 Lns. 20-25, Pg. 15 Lns. 20-30, Pg. 92 Lns. 17-31, and Pg. 94 Lns. 5-14].
With respect to claim 4, Izumi discloses wherein the biological fluid is mammalian milk [see paragraphs 0022, 0025, and 0046].
With respect to claim 5, Izumi discloses wherein the biological fluid is unpasteurized, [since the milk disclosed in Izumi appears to be unpasteurized see paragraphs 0022, 0025, and 0046].
With respect to claim 6, Izumi discloses wherein steps (a) and (b) together are repeated 1-5 times [see paragraphs. 0022, 0025, and 0046].
With respect to claim 7, Izumi discloses wherein step (a), (b), (c), (d), (e), (g), or any combination thereof is performed at about 4 degrees Celsius (see paragraphs 0022, 0025, and 0046].
With respect to claims 8-9, Izumi lacks wherein (a) comprises centrifuging the biological fluid at about 2,000-3,000 rcf; and wherein (a) comprises centrifuging the biological fluid at about 2,500 rcf. It is submitted that the centrifuging disclosed in Izumi is considered indistinguishable from the recited centrifuging, and appears to be capable of utilizing the recited rcf range [see paragraphs 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi with the teaching of Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein (a) comprises centrifuging the biological fluid at about 2.000-3,000 rcf involves only routine skill in the art, for the purpose of utilizing the recited centrifuging in the method, and thereby removing desired fats or cells from the milk or biological fluid [see Izumi paragraphs. 0022, 0025, and 0046].
With respect to claim 10, Izumi discloses wherein step (a) is repeated 1-3 times [see paragraphs. 0022, 0025, and 0046].
With respect to claim 11, Izumi discloses wherein (b) comprises a first centrifugation followed by a second centrifugation [see paragraphs. 0022, 0025, and 0046].
With respect to claim 12, Izumi as modified by Bolen lacks wherein the first centrifugation comprises centrifuging the remaining biological fluid at about 13,500-15,500 rcf for about 45-75 minutes. It is submitted that the centrifuging disclosed in Izumi is considered indistinguishable from the recited first centrifugation, and appears to be capable of centrifuging the remaining biological fluid at about 13,500-15,500 rcf for about 45-75 minutes [see paragraphs. 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein the first centrifugation comprises centrifuging the remaining biological fluid at about 13,500-15,500 rcf for about 45-75 minutes involves only routine skill in the art, for the purpose of utilizing the recited centrifuging in the method, and thereby removing desired fats or cells from the milk or biological fluid [see Izumi paragraphs. 0022, 0025, and 0046].
With respect to claim 13, Izumi as modified by Bolen lacks wherein the first centrifugation comprises centrifuging the remaining biological fluid at about 14,500 rcf for about 60 minutes. It is submitted that the centrifuging disclosed in Izumi is considered indistinguishable from the recited first centrifugation, and appears to be capable of centrifuging the remaining biological fluid at about 14,500 rcf for about 60 minutes [see paragraphs. 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein the first centrifugation comprises centrifuging the remaining biological fluid at about 14,500 rcf for about 60 minutes involves only routine skill in the art, for the purpose of utilizing the recited centrifuging in the method, and thereby removing desired fats or cells from the milk or biological fluid [see Izumi paragraphs. 0022, 0025, and 0046].
With respect to claim 14, Izumi as modified by Bolen lacks wherein the second centrifugation is performed on the biological fluid remaining after the first centrifugation and wherein the second centrifugation is performed at about 24,800-26,800 rcf for about 45-75 minutes. It is submitted that the first and second centrifuging disclosed in Izumi is considered indistinguishable from the recited first centrifugation and second centrifugation, and appears to be capable of including a second centrifugation performed on the biological fluid remaining after the first centrifugation and wherein the second centrifugation is performed at about 24,800-26,800 rcf for about 45-75 minutes [see paragraphs 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein the second centrifugation is performed on the biological fluid remaining after the first centrifugation and wherein the second centrifugation is performed at about 24,800-26,800 rcf for about 45-75 minutes involves only routine skill in the art, for the purpose of utilizing the recited first and second centrifugation in the method, and thereby removing desired fats, cells, and casein from the milk or biological fluid [Izumi paragraphs. 0022, 0025, and 0046].
With respect to claim 15, Izumi as modified by Bolen lacks wherein the second centrifugation is performed on the biological fluid remaining after the first centrifugation and wherein the second centrifugation is performed at about 25,800 rcf for about 60 minutes. It is submitted that the first and second centrifuging disclosed in Izumi is considered indistinguishable from the recited first centrifugation and second centrifugation, and appears to be capable of including a second centrifugation performed on the biological fluid remaining after the first centrifugation and wherein the second centrifugation is performed at about 25,800 rcf for about 60 minutes [see paragraphs 0022, 0025, and 0046). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein the second centrifugation is performed on the biological fluid remaining after the first centrifugation and wherein the second centrifugation is performed at about 25,800 rcf for about 60 minutes involves only routine skill in the art, for the purpose of utilizing the recited first and second centrifugation in the method, and thereby removing desired fats, cells, and casein from the milk or biological fluid [Izumi paragraphs. 0022, 0025, and 0046].
With respect to claim 16, Izumi as modified by Bolen lacks wherein the second centrifugation is repeated 1-3 times with each repetition being performed on the remaining biological fluid from the centrifugation immediately prior. It is submitted that the second centrifuging disclosed in Izumi is considered indistinguishable from the recited second centrifugation, and appears to be capable of including second centrifugation repeated 1-3 times with each repetition being performed on the remaining biological fluid from the centrifugation immediately prior (see paragraphs. 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein the second centrifugation is repeated 1-3 times with each repetition being performed on the remaining biological fluid from the centrifugation immediately prior involves only routine skill in the art, for the purpose of utilizing the recited second centrifugation in the method, and thereby removing desired fats, cells, and casein from the milk or biological fluid [Izumi paragraphs 0022, 0025, and 0046].
With respect to claim 17, Izumi discloses wherein (d) comprises filtering the remaining biological fluid through one or more filters in series ranging from about a 0.45 micron filter to about a 0.22 micron filters [see paragraphs 0022, 0025, and 0046].
With respect to claim 18, Izumi discloses wherein (d) comprises filtering the remaining biological fluid through an about 0.45 micron filter followed by filtering the remaining biological fluid through an about 0.22 micron filter [see paragraphs 0022, 0025, and 0046].
With respect to claim 19, Izumi discloses wherein (e) comprises 2 or more serial ultracentrifugation steps, wherein each step is performed on the remaining biological fluid from the prior ultracentrifugation [see paragraphs 0022, 0025, and 0046].
With respect to claim 20, Izumi as modified by Bolen lacks wherein (e) comprises an ultracentrifugation step performed at about 45,000-55,000 rcf, an ultracentrifugation step performed at about 65,000-75,000 rcf, an ultracentrifugation step performed at about 90,000-110,000 rcf, or a combination thereof. It is submitted that the first and second ultracentrifuging disclosed in Izumi is considered indistinguishable from the recited ultracentrifugation steps, and appears to be capable of including an ultracentrifugation step performed at about 45,000-55,000 rcf, an ultracentrifugation step performed at about 65,000-75,000 rcf, an ultracentrifugation step performed at about 90,000-110,000 rcf, or a combination thereof [see paragraphs. 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein (e) comprises an ultracentrifugation step performed at about 45,000-55,000 rcf, an ultracentrifugation step performed at about 65,000-75,000 rcf, an ultracentrifugation step performed at about 90,000-110,000 rcf, or a combination thereof involves only routine skill in the art, for the purpose of utilizing the recited first and second ultracentrifugation steps in the method, and thereby removing desired fats, cells, and casein from the milk or biological fluid [Izumi paragraphs 0022, 0025, and 0046].
With respect to claim 21, Izumi as modified by Bolen lacks wherein (e) comprises an ultracentrifugation step performed at about 50,000 rcf, an ultracentrifugation step performed at about 70,000 rcf, an ultracentrifugation step performed at about 100,000 rcf, or a combination thereof. It is submitted that the first and second ultracentrifuging disclosed in Izumi is considered indistinguishable from the recited ultracentrifugation steps, and appears to be capable of including an ultracentrifugation step performed at about 50,000 rcf, an ultracentrifugation step performed at about 70,000 rcf, an ultracentrifugation step performed at about 100,000 rcf, or a combination thereof [see paragraphs 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein (e) comprises an ultracentrifugation step performed at about 50,000 rcf, an ultracentrifugation step performed at about 70,000 rcf, an ultracentrifugation step performed at about 100,000 rcf, or a combination thereof involves only routine skill in the art, for the purpose of utilizing the recited ultracentrifugation stops in the method, and thereby removing desired fats, cells, and casein from the milk or biological fluid [Izumi paragraphs 0022, 0025, and 0046].
With respect to claim 22, Izumi as modified by Bolen lacks wherein the one or more of the one or more ultracentrifugation steps are each performed for about 45-75 minutes. It is submitted that the first and second ultracentrifuging disclosed in Izumi is considered indistinguishable from the recited ultracentrifugation steps, and appears to be capable of including one or more ultracentrifugation steps are each performed for about 45-75 minutes [see paragraphs 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein the one or more of the one or more ultracentrifugation steps are each performed for about 45-75 minutes involves only routine skill in the art, for the purpose of utilizing the recited ultracentrifugation steps in the method, and thereby removing desired fats, cells, and casein from the milk or biological fluid [Izumi paragraphs 0022, 0025, and 0046].
With respect to claim 23, Izumi as modified by Bolen lacks wherein the one or more of the one or more ultracentrifugation steps are each performed for about 60 minutes. It is submitted that the first and second ultracentrifuging disclosed in Izumi is considered indistinguishable from the recited ultracentrifugation steps, and appears to be capable of including one or more ultracentrifugation steps are each performed for about 60 minutes [see paragraphs 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein the one or more of the one or more ultracentrifugation steps are each performed for about 60 minutes involves only routine skill in the art, for the purpose of utilizing the recited ultracentrifugation steps in the method, and thereby removing desired fats, cells, and casein from the milk or biological fluid [Izumi paragraphs 0022, 0025, and 0046].
With respect to claim 24, Izumi as modified by Bolen lacks wherein (e) comprises a final ultracentrifugation step performed at about 115,000-145,000 rcf, for about 90-150 minutes and wherein the resulting fluid is discarded, and the remaining pellet is resuspended in a suitable volume of a suitable solution prior to (f). It is submitted that the second ultracentrifuging disclosed in Izumi is considered indistinguishable from the recited final ultracentrifugation step, and appears to be capable of comprising a final ultracentrifugation step performed at about 115,000-145,000 rcf, for about 90-150 minutes and wherein the resulting fluid is discarded, and the remaining pellet is resuspended in a suitable volume of a suitable solution prior to (f) [see paragraphs. 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein (e) comprises a final ultracentrifugation step performed at about 115,000-145,000 rcf, for about 90-150 minutes and wherein the resulting fluid is discarded, and the remaining pellet is resuspended in a suitable volume of a suitable solution prior to (f) involves only routine skill in the art, for the purpose of utilizing the recited final ultracentrifugation step in the method, and thereby removing desired fats, cells, and casein from the milk or biological fluid [Izumi paragraphs 0022, 0025, and 0046].
With respect to claim 25, Izumi as modified by Bolen lacks wherein (e) comprises a final ultracentrifugation step performed at about 130,000 rcf, for about 120 minutes and wherein the resulting fluid is discarded, and the remaining pellet is resuspended in a suitable volume of a suitable solution prior to (f). It is submitted that the second ultracentrifuging disclosed in Izumi is considered indistinguishable from the recited final ultracentrifugation step, and appears to be capable of comprising a final ultracentrifugation step performed at about 130,000 rcf, for about 120 minutes and wherein the resulting fluid is discarded and the remaining pellet is resuspended in a suitable volume of a suitable solution prior to (f) [see paragraphs 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein (e) comprises a final ultracentrifugation step performed at about 130,000 rcf, for about 120 minutes and wherein the resulting fluid is discarded, and the remaining pellet is resuspended in a suitable volume of a suitable solution prior to (f) involves only routine skill in the art, for the purpose of utilizing the recited final ultracentrifugation step in the method, and thereby removing desired fats, cells, and casein from the milk or biological fluid [Izumi paragraphs 0022, 0025, and 0046].
With respect to claim 26 Izumi lacks wherein the tangential flow filtration of (g) is performed using ultrafiltration membrane with a cutoff ranging from about 250 kDa to about 750 kDa. Bolen teaches that it is known in the art to utilize tangential flow filtration, Amicon filtration, i.e. ultrafiltration, to separate particles of up to 300 kDa [see Pg. 6, Lns. 8-10; Pg. 19, Lns. 1-2; Pg. 100, Lns. 2-12]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi with the filtration teaching of Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method comprising tangential flow filtration of (g) is performed using ultrafiltration membrane with a cutoff ranging from about 250 kDa to about 750 kDa involves only routine skill in the art, for the purpose of removing fats and thereby isolating exosomes with a desirable fat and casein concentration [Bolen Pg. 6, Lns. 8-10; Pg. 19, Lns. 1-2; Pg. 100, Lns. 2-12]. Further, wherein the tangential flow filtration of (g) is performed using ultrafiltration membrane with a cutoff ranging from about 250 kDa to about 750 kDa [since (g) is an optional step in claim 1 see paragraphs. 0022, 0025, and 0046].
With respect to claim 27, Izumi lacks wherein the tangential flow filtration of (g) is performed using a 250 kDa ultrafiltration membrane. Bolen teaches that it is known in the art to utilize tangential flow filtration, Amicon filtration, i.e. ultrafiltration, to separate particles of up to 300 kDa [see Pg. 6, Lns. 8-10; Pg. 19, Lns. 1-2; Pg. 100, Lns. 2-12]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi with the filtration teaching of Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method comprising wherein the tangential flow filtration of (g) is performed using a 250 kDa ultrafiltration membrane involves only routine skill in the art, for the purpose of removing fats and thereby isolating exosomes with a desirable fat and casein concentration (Pure Pg. 6, Lns. 8-10; Pg. 19, Lns. 1-2; Pg. 100, Lns. 2-12]. Further, wherein the tangential flow filtration of (g) is performed using a 250 kDa ultrafiltration membrane [since (g) is an optional step in claim 1 see paragraphs 0022, 0025, and 0046].
With respect to claim 28, Izumi lacks wherein the tangential flow filtration of (g) is performed at a flow rate of about 5-15 mL per minute. Bolen teaches that it is known in the art to utilize tangential flow filtration, Amicon filtration, i.e. ultrafiltration, to separate particles of up to 300 kDa [see Pg. 6, Lns. 8-10; Pg. 19, Lns. 1-2; Pg. 100, Lns. 2-12]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi with the filtration teaching of Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method comprising wherein the tangential flow filtration of (g) is performed at a flow rate of about 5-15 mL per minute involves only routine skill in the art, for the purpose of removing fats and thereby isolating exosomes with a desirable fat and casein concentration [Pure Pg. 6, Lns. 8-10; Pg. 19, Lns. 1-2; Pg. 100, Lns. 2-12]. Further, wherein the tangential flow filtration of (g) is performed at a flow rate of about 5-15 mL per minute [since (g) is an optional step in claim 1 see paragraphs 0022, 0025, and 0046].
With respect to claim 29, Izumi lacks wherein the tangential flow filtration of (g) is performed at a flow rate of about 10 mL per minute. Bolen teaches that it is known in the art to utilize tangential flow filtration, Amicon filtration, i.e. ultrafiltration, to separate particles of up to 300 kDa [see Pg. 6, Lns. 8-10; Pg. 19, Lns. 1-2; Pg. 100, Lns. 2-12]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi with the filtration teaching of Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method comprising wherein the tangential flow filtration of (g) is performed at a flow rate of about 10 mL per minute involves only routine skill in the art, for the purpose of removing fats and thereby isolating exosomes with a desirable fat and casein concentration (Pure Pg. 6, Lns. 8-10; Pg. 19, Lns. 1-2; Pg. 100, Lns. 2-12]. Further, wherein the tangential flow filtration of (g) is performed at a flow rate of about 10 mL per minute [since (g) is an optional step in claim 1 see paragraphs 0022, 0025, and 0046].
With respect to claim 30, Izumi as modified by Bolen discloses wherein in step (g) when the amount of remaining biological fluid reaches about ten percent of its starting volume before tangential flow filtration the retentate is diafiltered with a suitable buffer [since (g) is an optional step in claim 1 see paragraph 0022, 0025, and 0046].
With respect to claim 31, Izumi as modified by Bolen discloses ultracentrifuging the retentate when the retentate reaches about 20 percent of the starting diafiltration amount [since the ultracentrifuging of the retentate in (g) is an optional step in claim 1 see paragraphs 0022, 0025, and 0046].
With respect to claim 32, Izumi as modified by Bolen discloses wherein the ultracentrifugation is performed at about 115,000- 145,000 rcf for about 90-150 minutes at about 4 degrees Celsius [since the ultracentrifuging of the retentate in (g) is an optional step in claim 1 see paragraphs 0022, 0025, and 0046].
With respect to claim 33, Izumi as modified by Bolen discloses wherein the ultracentrifugation is performed at about 130,000 rcf for about 120 minutes at about 4 degrees Celsius [since the ultracentrifuging of the retentate in (g) is an optional step in claim 1 see paragraphs 0022, 0025, and 0046].
With respect to claim 34, Izumi as modified by Bolen discloses wherein the retentate is stored at -80 degrees C after the retentate reaches about 20 percent of the starting diafiltration amount and prior to column separation [since the storing of the retentate in (g) is an optional step in claim 1 see paragraphs 0022, 0025, and 0046].
With respect to claim 35, Izumi as modified by Bolen lacks wherein the method yields an exosmal concentrate that is at least 7.5 percent, 8 percent, 8.5 percent, 9 percent, 9.5 percent, 10 percent, 10.5 percent, 11 percent, 11.5 percent, 12 percent, 12.5 percent, 13 percent, 13.5 percent, 14 percent, 14.5 percent, 15 percent, 15.5 percent, 16 percent, 16.5 percent, 17 percent, 17.5 percent, 18 percent, 18.5 percent, 19 percent, 19.5 percent, or at least 20 percent of the starting volume of milk. It is submitted that the exosome fraction obtained in Izumi is considered indistinguishable from the recited exosmal concentrate, and appears to be capable of having the recited percents of the starting volume of milk (see paragraphs 0022, 0025, and 0046]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi as modified by Bolen, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable method, wherein the method yields an exosmal concentrate that is at least 7.5 percent, 8 percent, 8.5 percent, 9 percent, 9.5 percent, 10 percent, 10.5 percent, 11 percent, 11.5 percent, 12 percent, 12.5 percent, 13 percent, 13.5 percent, 14 percent, 14.5 percent, 15 percent, 15.5 percent, 16 percent, 16.5 percent, 17 percent, 17.5 percent, 18 percent, 18.5 percent, 19 percent, 19.5 percent, or at least 20 percent of the starting volume of milk involves only routine skill in the art, for the purpose of recovering a desired exosmal concentrate in the method, and thereby obtaining an effective exosome fraction for use as an anti-inflammatory agent [Izumi paragraphs 0022, 0025, and 0046]
With respect to claim 36, Izumi lacks loading the exosomes of the formulation resulting from the method with one or more cargos. Bolen teaches that it is known in the art to utilize milk exosomes loaded with a cargo for oral delivery of a therapeutic agent [see Pg. 2 Lns 20-29]. It would have been obvious to one of ordinary skill in the art at the time of the invention to modify Izumi with the loading teaching of Bolen, for the purpose of loading the exosomes with a cargo in the method, and thereby providing a therapeutic agent for oral delivery [Bolen Pg. 2 Lns 20-29].
With respect to claim 37, Izumi as modified by Bolen discloses a formulation having exosomes, wherein the formulation is produced at least in part by the method [see Bolen Pg. 2 Lns 20-29].
With respect to claim 39, Izumi as modified by Bolen discloses administering a formulation to a subject in need thereof (see Bolen Pg. 1 Lns 9-16).
Conclusion
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/MADELINE GONZALEZ/Primary Examiner, Art Unit 1773