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 .
Claims 1-11 and 14-23 are pending in this application.
Claims 15-20 stand withdrawn from further consideration as being directed to non-elected subject matter. Claims 1-11, 14, and 22-23 will presently be examined.
35 U.S.C. 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.
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 1-11, 14, and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over CN 1094682651 in view of Reif et al. (WO 2017/090049; hereinafter, Reif) and O’Connor et al. (WO 01/78530; hereinafter, O’Connor).
CN 109468265 teaches a method of extracting milk exosomes that does not utilize ultracentrifugation; instead, milk sample (e.g., bovine milk) is centrifuged at 2000g and 12,000g, milk protein removed, supernatant passed through a 0.22 µm membrane, and freeze dried to obtain bovine milk exosome powder. See abstract; claims 1-2; paragraphs 9-16, 25-28.
Reif (WO 2017/090049) discloses a composition comprising a milk formula and microvesicles isolated from natural milk such as bovine milk, which include exosomes (claims 1-3; page 4, lines 5-6, 12-13; page 5, lines 9-13; page 9, lines 21-30; page 11, lines 24-27). The exosomes comprise proteins and/or miRNA molecules (claims 7-10; page 4, lines 15-17), including miR-210 and miR-146a (pages 13-16). Lyophilized microvesicles are disclosed (claim 14; page 5, lines 3-4). Exosomes are isolated from skim fraction of milk, wherein milk is fractionated by centrifugation at 5000g, the skim fraction is centrifuged at 12,000g, and then the supernatant is filtered through, for example, 5 or 0.45 µm filters; the exosomes are then pelleted, which can be lyophilized (paragraph bridging pages 10-11; claim 14; page 5, lines 3-4). Example 6 discloses isolated exosomes from cow milk, and miRNAs were detected from isolated exosomes, which indicates intact exosomes (pages 49-50). Example 6 discloses further processing by dehydrating the isolated exosomes and adding to milk formulas in dehydrated form (page 50, lines 7-9). Reif discloses exosomes as having a diameter between 30 and 100 nm. Reif’s milk formula contains sufficient nutritional components such as protein, carbohydrates, and fat to serve as a nutritional source when provided in sufficient quantity (page 10, lines 4-7), which includes milk formula for infants (claim 15). Reif further discloses that miRNA content in various infant-milk formulas is significantly lower than that found in cow or human milk, or in most cases absent (page 18, lines 15-17) and commercial milk formulas lack essential components, which are present in natural milk (page 47, lines 23-29).
O’Connor (WO 01/78530) discloses infant formulas containing docosahexaenoic acid (DHA), arachidonic acid (AA), alpha-linolenic acid (ALA), and linolenic acid (LA). See claim 1. Known infant formulas contain protein, fat, carbohydrates, and other ingredients in liquid or powder form (page 15, Table A; pages 23-25). Dietary fiber such as soy polysaccharide can be added (page 23, line 19). Milk protein can be added (page 24, first paragraph).
CN 109468265 does not explicitly disclose the weight percentage of intact bovine milk-isolated powdered exosomes. However, the process taught by CN 109468265 avoids ultracentrifugation, and the centrifugation step of CN 109468265 is low at 2000g and 12,000g. Further, Reif’s comparably processed Example 6 discloses isolated exosomes from cow milk, and miRNAs were detected from isolated exosomes, which indicates intact exosomes.
It would have been obvious to the ordinary skilled artisan that the powdered bovine exosomes taught by CN 109468265 would have the claimed intact exosome features because all the steps of CN 109468265 would not be expected to damage exosomes. Taken with Reif’s teaching that miRNA content in various infant-milk formulas is significantly lower than that found in cow or human milk, or in most cases absent, it would have been obvious to add the bovine milk-isolated powder exosomes to solid infant formulas.
Claim 3 requires the powdered exosomes to comprise greater amount of miRNA after storage at 37 °C for 3 weeks than fresh milk exosomes after storage at 37 °C for 3 weeks. This claim is quite broad in that “fresh milk exosome” could mean significantly different things depending on the medium that the “fresh milk exosome” is in. Besides, does “fresh milk exosomes” include fresh milk, which would probably spoil in 3 weeks at such refrigerator temperature? For these reasons, it would have been obvious that the bovine milk-isolated powder exosomes taught by CN 109468265 would possess the characteristics recited in instant claim 3.
Claim 7 requires 0.001-10 wt% of bovine milk-isolated exosomes, based on the weight of the nutritional composition. Reif teaches that miRNA content in various infant-milk formulas is significantly lower than that found in cow or human milk, or in most cases absent, so it would have been well within the skill of the ordinary skilled artisan to adjust and optimize the amount of powdered, intact exosomes suggested by the combined teachings of the prior art as an additive to known infant-milk formulas.
In response to Applicant’s arguments filed on 6/11/2026, further discussion is set forth below regarding the claim-recited feature, “at least 50 wt % of the bovine milk-isolated powdered exosomes in the composition are intact” (claim 1) and “at least 70 wt % … are intact” (new claim 22). Applicant argues that even though the centrifugation steps of CN 109468265 are relatively low force, the instant specification discloses other mechanisms for membrane damage. Applicant notes that “the freeze drying step applied to the sample of CN ‘265 [CN 109468265 ] may have disrupted the membranes of any intact exosomes.” Applicant asserts this without evidence. In specification paragraphs 66 and 68, membrane disruption is disclosed as being caused by freezing and thawing the exosomes. There is no disclosure of thawing frozen exosomes by CN 109468265, so such disruption of exosome membranes would not have occurred.
Applicant argues that specification paragraphs 27, 30, 64, 66-68, 71 and “elsewhere” discuss mechanisms for membrane damage, but concrete discussions of damage identify (1) centrifugation “performed too forcefully” (paragraph 30), (2) not utilizing the step of orbital shaking in dissolving the exosome-containing pellet from centrifugation at 100,000 g by suspending the pellet in sterile PBS (paragraph 64), and (3) thawing the frozen exosomes prior to freeze drying (paragraphs 66-67). Applicant’s Example 1 (the only production method disclosed in the specification), is summarized below and compared with steps of CN 109468265:
Production of powdered exosomes: instant specification Example 1, paragraphs 63-66
Notable comments by Inventors
CN 109468265 –
Claim 1 in view of claim 2 (bovine milk)
Centrifuge milk at 12,000 g
4°C
for 15 mins
---
(1) Centrifuge milk at
2,000 g
4°C
for 30 mins
Centrifuge whey layer two more times, each at 12,000 g,
4°C,
for 30 mins
---
(2) Centrifuge at
12,000 g
4°C
for 30 mins
n/a
(3) Adjust pH of supernatant to 5.5-6.0
(4) Add rennet to supernatant to precipitate out milk protein under water bath conditions of 36-37°C
Filter clear whey fraction using 0.22 µm filter
---
Filter through 0.22 µm membrane
Centrifuge the microfiltered whey
at 100,000 g, 4°C, for 60 mins
to obtain exosome-containing pellet
Centrifugation performed too forcefully can damage exosome membrane (¶30)
n/a
Suspend the pellet in sterile PBS, incubate for 12-36 hours in orbital shaker at 4°C and 150 rpm
Without the orbital shaking step, aggregates appeared that required extensive pipetting to break up, which damaged exosomes (¶64)
Freeze the exosomes at -80°C for at least 2 hours
---
(5) Freeze dry into powder
(* no thawing is mentioned, and why would a skilled artisan thaw when the step is to freeze dry?)
Freeze dry the frozen exosomes “under conditions which maintain the exosomes in intact form” (¶65), including vacuum of less than 0.3 mbar for about 24 hours to ensure low moisture content.
Thawing of the frozen exosomes prior to the vacuum stage of the freeze drying damaged exosomes (¶66).
As can be seen from the above comparison, steps taught by CN 109468265 avoid all three exosome-damaging steps identified by Applicant: great centrifugation force, orbital shaking to dissolve pellets, and thawing. The greatest force used by CN 109468265 to perform centrifugation is 12,000 g, whereas Applicant used 100,000 g. There is no orbital shaking needed in the steps taught by CN 109468265 because there are no pellets to dissolve. As for thawing, there is no thawing disclosed prior to freeze drying – there would have been no motivation to carry out the unnecessary step of thawing when step (5) of CN 109468265 is to freeze dry. Step (5) of CN 109468265 is not “freeze, thaw, and then freeze dry.” Additionally, CN 109468265 discloses that its method steps “ensure that the functional components in the milk exosome are not destroyed to the greatest extent” (paragraph 28).
Applicant argues further in the response filed on 6/11/2026 that the “rejection lacks any rationale as to why one of ordinary skill in the art would be motivated to identify the various claimed features and the art provides no guidance or motivation that would have directed one of skill toward those features.” The Examiner cannot agree. CN 109468265 teaches a method of obtaining bovine milk-isolated powdered exosomes that does not have any of the steps identified by Applicant as causing exosome membrane damage. Applicant acknowledges that ultracentrifugation can damage exosomes, but Applicant applies 100,000 g, whereas CN 109468265 applies only 12,000 g. Thus, the powdered exosomes of CN 109468265 would necessarily have possessed the claimed features.
It is well established that “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.” In re Baxter Travenol Labs, 21 USPQ2d 1281, 1285 (Fed. Cir. 1991). In Baxter, the court held that even when the prior art did not expressly disclose hemolysis-suppression feature or property of a blood bag plasticizer, such unrecognized feature or property is insufficient for rebutting a prima facie case of obviousness over a prior art blood bag that utilized the same plasticizer. Id. See also Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Int. 1985) (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious”).
Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, because every element of the invention and the claimed invention as a whole have been fairly disclosed or suggested by the teachings of the cited references.
For these reasons, all claims must be rejected again. No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to JOHN PAK whose telephone number is (571)272-0620. The Examiner can normally be reached on Monday to Friday from 8:30 AM to 5 PM.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's SPE, Fereydoun Sajjadi, can be reached on (571)272-3311. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/JOHN PAK/Primary Examiner, Art Unit 1699
1 Machine translation was provided in the previous Office action of 3/11/2026. All references are to the machine translation.
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