DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant should note that the instant application has been reassigned to a new examiner and now resides in Art Unit 1617.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/20/2016 has been entered.
Claim Status
Pursuant to the amendment dated 05/20/2026, claim 2 has been cancelled. Claims 1 and 3-9 are pending and under current examination.
All rejections not reiterated are withdrawn.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 3-9 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al. (TW201620498; publication date: 06/16/2016; citing the English machine translation) in view of Matic (Stability Of Bovine Milk Exosomes And Their Effect On Proliferation Of Raw 264.7 Cells, May 2019; of record) and further in view of Panich et al., (Ultraviolet Radiation-Induced Skin Aging: The Role of DNA Damage and Oxidative Stress in Epidermal Stem Cell Damage Mediated Skin Aging, April 11, 2016; of record) and Samuel et al. (Scientific Reports 7:5933; publication year 2017).
Liang discloses that colostrum is a milk that is produced within three days after calving and has higher nutrient content, lower fat, and a large number of immune and growth factors (page 1). Liang teaches a method of applying an effective does of the colostrum to skin for scavenging free radicals and that the colostrum can be further utilized in manufacturing cosmetic compositions or pharmaceutical compositions for anti-oxidation or anti-aging (abstract). Liang discloses further that the colostrum can be fractionated by centrifugation at low temperature and the speed of centrifugation affects the substances present in each layer (page 2, example 1). Further molecular sieves are used to separate the components of the colostrum. The colostrum itself is the active in Liang’s invention, i.e. it does not serve as a carrier for a drug.
Liang does not expressly teach application of isolated exosomes per se and does not discuss the intended outcome recited in the instant claims of protection form UV-induced oxidative damage of cells.
Matic discloses exosomes isolated from commercially available fat-free milk (Great Value brand) by differential centrifugation. Milk was centrifuged at 13,000 x g at 4 °C for 30 min in 250 mL centrifuge bottles. The whey was collected, transferred into polycarbonate 26.3 mL Beckman centrifuge tubes, and centrifuged at 100,000 x g at 4 °C for 60 min. The final supernatant was collected, transferred to 26.3 mL centrifuge tubes and centrifuged at 135,000 x g at 4 °C for 90 min. The supernatant was discarded, and the pellet was washed with PBS twice. The exosome pellet was collected and resuspended in PBS. Isolated exosomes were sterile filtered through 0.22 µm filters and the protein concentration was adjusted to 6 mg/mL (pages 31-32, 2.3.2 Isolation of exosomes). Matic teaches that reactive oxygen species are generated under oxidative stress and that exosome treatment significantly reduced the ROS production when compared to untreated cells. There was no significant difference in ROS production between the cell treated with 100 µg/mL and 200 µg/mL exosomes (i.e., an effective amount) (page 72, 3.4.3 Bovine milk exosomes reduced production of ROS in RAW 264.7 cell under hypoxic conditions). The application of milk exosomes as a potential functional food ingredient (i.e., functional health food) depends on the ability of exosomes to survive human digestion and to reach intestines and circulation in an intact form (page 40, 2.4.3 Bovine milk exosomes resist pepsin-pancreatin hydrolysis). It was found that exosomes are resistant to simulated digestive conditions (page 42, first paragraph).
Thus, in view of Matic, one having ordinary skill would have recognized that milk exosomes retain the ability to inhibit ROS.
Panich teaches that ultraviolet radiation (UVR) is a major cause of stem cell DNA damage and can contribute to depletion of stem cells (ESCs and mesenchymal stem cells) leading to photoinduced skin aging (Abstract). UV-A-induced ROS (reactive oxygen species) is responsible for ESCs DNA damage. Accumulated oxidative damage to biomolecules in the cells, caused by repetitive exposure to environmental insults, in particular UVR, may compromise their self-renewal capacity and promote loss of ESC numbers, resulting in premature aging (page 6, 6. UV-Induced Oxidative Stress: A Major Assault on Skin and a Potential Preventive and Therapeutic Target for Antioxidants in Skin Photoaging). Production of the DNA toxic ROS from UV-A leads to damage of dermal fibroblasts, resulting in skin aging (page 5, Figure 1). Exposure of human skin fibroblasts, an important cellular component of skin microenvironment, to UVR produced ROS has been shown to result in oxidative stress and high level of ROS was also reported to induce skin fibroblasts to secrete high levels of matrix metalloproteinases (MMPs), which caused extensive ECM remodeling in dermal layers. However, due to the transient nature of ROS, it is possible to ameliorate its effect and protect the skin from premature aging. Pharmacologically, ROS has been considered as a potential target for photoaging prevention and therapies (page 7, fourth and fifth paragraphs).
Samuel teaches that colostrum contains exosomes that have many biologically active substances important for immune response and growth (abstract).
Thus, one having ordinary skill in the art would have understood that components of colostrum that have been isolated by centrifugation and filtration can be applied to skin to mitigated oxidative damage, that exosomes from milk, a substance closely related to colostrum retain the antioxidant properties, and that UV-irradiation causes oxidative stress on the skin and that colostrum contains many bioactive substances. It would have been prima facie obvious to apply exosomes isolated from colostrum to the skin in order to inhibit UV-induced oxidative damage. The artisan of ordinary skill would have been motivated to do so in order to isolate the most potent antioxidant elements from the colostrum described by Liang. The skilled artisan would have had a reasonable expectation of success because milk exosomes were recognized to retain antioxidant properties and because methods to isolate different fractions of colostrum by centrifugation and filtration had been established as of the instant effective filing date. With regard to the intended outcome, a significant reduction in ROS production in cells would result in inhibited UV-induced oxidative damage of cells. With regard to the particular fraction of colostrum that contains isolated exosomes as delimited by the product by process language recited in the instant claims, as discussed above, methods of isolating microvesicles from other components of milk or colostrum by adjusting centrifugation speed and by filtration were established as of the instant effective filing date and one having ordinary skill would have been motivated to test the exosome fraction because the exosome fraction of the closely related substance, milk, showed antioxidant activity. It would have been a matter of routine for one of ordinary skill to experiment with the conditions under which the most potent antioxidant substances in the colostrum can be isolated. "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."). See MPEP 2141.03 and 2144.05(II)(A).
Regarding claims 3-7, the steps of isolating the exosomes from colostrum are considered product by process language as the claims are directed to a method of use rather than a method of manufacture. Matic discloses bovine derived exosomes prepared by substantially the same process as instantly claimed. Even though product-by- process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process, In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), see MPEP 2113. Moreover, as pointed out above, it would have been prima facie obvious to optimize the conditions under which the most potent components of colostrum are contained using routine methods such as centrifugation and filtration.
Regarding claim 8, as noted above, Liang teaches application of colostrum to skin, which contains dermal fibroblasts, and also it would have been obvious to treat human dermal fibroblasts (i.e., cells) with an effective amount of colostrum exosomes isolated since DNA toxic ROS from UV-A results in oxidative stress damage of human dermal fibroblasts as taught by Panich, and as discussed above, an effective amount of the exosomes of Matic significantly reduced the ROS production in cells.
Claims 3-7 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al. (TW201620498; publication date: 06/16/2016; citing the English machine translation) in view of Matic (Stability Of Bovine Milk Exosomes And Their Effect On Proliferation Of Raw 264.7 Cells, May 2019; of record) and further in view of Panich et al., (Ultraviolet Radiation-Induced Skin Aging: The Role of DNA Damage and Oxidative Stress in Epidermal Stem Cell Damage Mediated Skin Aging, April 11, 2016; of record )and Samuel et al. (Scientific Reports 7:5933; publication year 2017) as applied to claims 1 and 3-9 above, and further in view of Izumi et al., (EP 3192518 A1, July 19, 2017; Morinaga Milk Industry, cited by applicant on IDS), Bolen et al. (US 2018/0193270 A1, July 12, 2018; of record) and Thery et al. (Journal of Extracellular Vesicles, 2018; of record).
Instant claims 3-7 have been rejected as being obvious over Liang, Matic, Panich, and Samuel as set forth supra. However, purely arguendo, for the purposes of complete prosecution, and for the purposes of this ground of rejection only, the product by process language of instant claims 3-7 is also obvious as follows:
However, Izumi discloses a method for isolating exosomes from milk, comprising: a centrifugation step of centrifuging raw milk so as to remove fat and cells at 4 degrees Celsius; a step of removing centrifuged fat and cells; a step of adjusting the pH to 4.6 by adding 10% acetic acid and precipitating casein; a step of centrifuging the milk in which casein is precipitated at 4,500 × g and 4°C for 30 minutes, and collecting a supernatant; and a step of filtering the collected supernatant by using a 0.22 µm filter ([0046]), reading on claims 3-4 and 6-7.
Bolen teaches methods of producing exosomes (Abstract) from milk ([0009]) by a first step of centrifugation ([0970] – [0972]), then a first filtration step to further remove fat and cells therefrom ([0973 – 0979]), then a dilution step of adding distilled water to the filtered milk as needed (approximately 10 mL) in order to satisfy manufacturer instructions for properly filled/balanced tubes ([0980]), reading on claim 3.
Thery teaches that for the separation of extracellular vesicles (i.e. exosomes), there is no single optimal separation method, so choose based on the downstream applications and scientific question (Table 1, page 13). Thery et al. teaches the k factor can be determined from the rotor type, tube/adapter, and centrifuge speed and must sometimes be adjusted (Table 1, subparagraph a). Thery et al. teaches for filtration techniques; one must take care to remove cells and other large membranous structures prior to ultrafiltration and that the pore size of the matrix should be taken into account (Table 1 subparagraph b). Thery et al., teaches that time and temperature are also factors that may require adjustment during the exosome separation process (Table 1, Examples for classical technique). A person of ordinary skill in the art, with a reasonable expectation of success, would have been able to adjust the k factor and time of the first centrifugation step to encompass 4,000 to 6,000 x g for 20 to 40 minutes as recited in claim 4, the desired mesh size of the strainer to 20 to 60 µm or 30 to 50 µm as recited in claims 3 and 5, an equal amount of distilled water added to the filtered milk or goat milk as recited in claim 3, and the temperature to room temperature as recited in claim 7 in the instant application with repeated experimentation and a reasonable expectation of success based on the teachings of Thery.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the exosome preparation processes of Izumi and Bolen to prepare the exosomes taught by Liang/Matic/Panich/Samuel motivated by the desire to optimize the separation process according to the downstream application of the exosomes (Thery, Table 1) and to adjust the volume of liquid in the tubes in order to satisfy manufacturer instructions for properly filled/balanced tubes (Bolen, ([0980]).
Response to Arguments
Applicant's arguments filed 05/20/2026 have been fully considered but they are not persuasive.
On pages 4 and 5, Applicant argues that colostrum is a completely different product than commercial milk.
This argument has been addressed by the new grounds of rejection above.
On page 5, Applicant argues that exosomes from colostrum are effective in the claimed method and may offer advantages of over exosomes isolated from commercial milk. Applicant points to the specification as establishing that exosomes from colostrum had a greater immunity-enhancing effect as compared to exosomes isolated from commercial milk, citing data and figures contained in the specification.
Please refer to MPEP 716.02(b) which details the burden on Applicant to establish that results in a side-by-side comparison to the closest prior art are unexpected and significant. Specifically, Applicant must establish that differences in results are in fact unexpected and unobvious and are of both practical and statistical significance. Additionally, evidence of unexpected properties must be commensurate in scope with the claims.
In the instant case, the result does not appear to have been unexpected as colostrum was known in the prior art to have potent antioxidant properties (see Liang), which would provide protection from UV damage. Moreover, there is no nexus between the instant claim language and the allegedly unexpected result because the instant claims are directed to reducing oxidative damage due to UV exposure, rather than to affecting inflammation. Thus, the significance of the data with regard to the instant method is not clear.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 3-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 14 and 21, 23, 24, 26, 28, 30, 31, 33, 35, 37, and 38 of co-pending Application No. 17/780391;
claims 1-3, 5, 6, and 9-20 of copending Application No. 18/133,886; and
claims 1-9 of co-pending Application No. 18/133,901
in view of Liang et al. (TW201620498; publication date: 06/16/2016; citing the English machine translation), Matic, (Stability Of Bovine Milk Exosomes And Their Effect On Proliferation Of Raw 264.7 Cells, May 2019) (hereinafter Matic) and Panich et al., (Ultraviolet Radiation-Induced Skin Aging: The Role of DNA Damage and Oxidative Stress in Epidermal Stem Cell Damage Mediated Skin Aging, April 11, 2016) (hereinafter Panich).
The co-pending applications claims 14, 26, and 33 teach a method comprising applying a therapeutically effective amount of exosomes isolated from colostrum to the skin of the subject (see e.g. page 13 of the ‘886 application for the scope of the term “administering”); and the ‘901 applicant embraces application to the skin of the scalp in the form of a shampoo. The claims do not expressly recite a limitation regarding inhibiting UV-induced oxidative damage of cells, comprising treating the cells with an effective amount for inhibiting UV-induced oxidative damage, as recited in instant claim 1.
As an initial matter, the examiner notes that the exosomes derived from colostrum are applied to the skin in the cited copending applications and therefore the intended outcomes are deemed inherent absent evidence to the contrary.
Moreover, the state of the prior art renders obvious administering colostrum exosomes with the intention of mitigating oxidative damage due to UV exposure: Liang discloses that colostrum is a milk that is produced within three days after calving and has higher nutrient content, lower fat, and a large number of immune and growth factors (page 1). Liang teaches a method of applying an effective does of the colostrum to skin for scavenging free radicals and that the colostrum can be further utilized in manufacturing cosmetic compositions or pharmaceutical compositions for anti-oxidation or anti-aging (abstract). Liang discloses further that the colostrum can be fractionated by centrifugation at low temperature and the speed of centrifugation affects the substances present in each layer (page 2, example 1). Further molecular sieves are used to separate the components of the colostrum. The colostrum itself is the active in Liang’s invention, i.e. it does not serve as a carrier for a drug.
Matic teaches that reactive oxygen species are generated under oxidative stress and that exosome treatment significantly reduced the ROS production when compared to untreated cells. There was no significant difference in ROS production between the cell treated with 100 µg/mL and 200 µg/mL exosomes (i.e., an effective amount) (page 72, 3.4.3 Bovine milk exosomes reduced production of ROS in RAW 264.7 cell under hypoxic conditions). Panich teaches that ultraviolet radiation (UVR) is a major cause of stem cell DNA damage and can contribute to depletion of stem cells (ESCs and mesenchymal stem cells) and damage of stem cell niche, eventually leading to photoinduced skin aging (Abstract). Exposure of human skin fibroblasts, an important cellular component of skin microenvironment, to UVR produced ROS has been shown to result in oxidative stress and high level of ROS was also reported to induce skin fibroblasts to secrete high levels of matrix metalloproteinases (MMPs), which caused extensive ECM remodeling in dermal layers. However, due to the transient nature of ROS, it is possible to ameliorate its effect and protect the skin from premature aging. Pharmacologically, ROS has been considered as a potential target for photoaging prevention and therapies (page 7, fourth and fifth paragraphs).
Regarding claim 1, it would be obvious to one of ordinary skill in the art to utilize exosomes derived from colostrum for the intended use of inhibiting UV-induced oxidative damage of cells, comprising treating the cells with an effective amount for inhibiting UV-induced oxidative damage, with a reasonable expectation of success because bovine milk exosomes reduce production of ROS and UVR produced ROS has been shown to result in oxidative damage, as taught by Liang, Matic, and Panich.
The colostrum exosomes are manufactured by the same method in the ‘391 application as in the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant argues that all OTDP rejections should be withdrawn in view of Applicant’s arguments regarding Matic and Panich.
Applicant’s arguments have been fully considered but are not found to be persuasive. The Examiner submits that Applicant’s argument with regards to Matic and Panich is addressed in the new grounds of rejection. Therefore, these rejections are maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE PEEBLES whose telephone number is (571)272-6247. The examiner can normally be reached Monday through Friday: 9 am to 3 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571)272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATHERINE PEEBLES/Primary Examiner, Art Unit 1617
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