DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This is the fifth Office action on the merits of the claims.
All citations to the Manual of Patent Examining Procedure (MPEP) refer to Revision 01.2024, which was released in November 2024.
Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 22 January 2026 has been entered.
Status of the Claims
Applicant amended claims 1-3, 5, and 7-11. Claims 4 and 6 were cancelled previously by Applicant. Claims 1-3, 5, and 7-11 are pending and under consideration.
Status of the Rejections
The rejection of claims 7-11 under 35 U.S.C. 112(b) as being indefinite is maintained.
The rejection of claims 1-3, 5, and 7-11 under 35 U.S.C. 103 as being unpatentable over Luan (“Engineering exosomes as refined biological nanoplatforms for drug delivery.” Acta Pharmacologica Sinica 38.6 (2017 April 10): 754-763) in view of Xu (“Green factory: plants as bioproduction platforms for recombinant proteins.” Biotechnology advances 30.5 (2012): 1171-1184) and, optionally, Batrakova (“Using exosomes, naturally-equipped nanocarriers, for drug delivery.” Journal of Controlled Release 219 (2015): 396-405) and Kim (WO 2004/014954 A1) is maintained. Applicant’s argument is considered in paragraphs 36-39 of this Office action.
Claim Rejections – 35 U.S.C. 112(b)
The following is a quotation of 35 U.S.C. 112(b):
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.
Claims 7-11 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter that the inventors regard as the invention.
Regarding claim 7, what is required by the generic step of “preparing” the plant exosomes? For example, is merely placing the plant exosomes in a syringe configured for intramuscular administration sufficient to satisfy the claim? Similarly, what (if anything) is actually required to prepare the exosomes for oral or topical administration? The same concern applies to each of the remaining routes of administration recited in the claim. This ambiguity renders claim 7 indefinite. MPEP § 2173.04 (“a genus claim that could be interpreted in such a way that it is not clear which species are covered would be indefinite (e.g., because there is more than one reasonable interpretation of what species are included in the claim)”).
Regarding claims 8-11, what—if anything—is actually required by the generic step of “preparing plant exosomes to carry immunomodulatory drug” (claim 8)? For example, does claim 8 require loading the plant exosomes with the immunomodulatory drug? What is required in claim 9 to “prepare” the plant exosome “as adjuvants”? Similarly, what is even required to “prepare” the plant exosomes as a nutritional supplement to modulate the immune system (claim 10) or to “use” the plant exosomes for autoimmune diseases, etc. (claim 11)? Does the latter require administration to a patient? These ambiguities respectively render claims 8-11 indefinite.
Claim Rejections – 35 U.S.C. 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 1-3, 5, and 7-11 are rejected under 35 U.S.C. 103 as being unpatentable over Luan (“Engineering exosomes as refined biological nanoplatforms for drug delivery.” Acta Pharmacologica Sinica 38.6 (2017 April 10): 754-763) in view of Xu (“Green factory: plants as bioproduction platforms for recombinant proteins.” Biotechnology advances 30.5 (2012): 1171-1184) and, optionally, Batrakova (“Using exosomes, naturally-equipped nanocarriers, for drug delivery.” Journal of Controlled Release 219 (2015): 396-405) and Kim (WO 2004/014954 A1).
Luan is directed to exosomes and their role in drug delivery.
Luan discloses that “[e]xosomes can be used for DNA, RNA, and protein delivery.” Figure 2, page 759, at caption (C).
Luan discloses: “Utilizing exosomes is one of the most promising methods for delivering macromolecular proteins (Figure 2C). Proteins can be loaded into exosomes through genetic engineering of the donor cells or through direct loaded into the exosomes. In the first method, donor cells are transfected with a plasmid carrying the gene of interest. Consequently, the cells synthesize the protein encoded by the inserted gene, and these proteins are subsequently secreted into the extracellular vesicles. At this stage, the extracellular vesicles can be isolated by collecting the cell culture supernatant and then purified.” (Emphasis added) Page 760, left column.
Luan discloses that “exosomes isolated from fruits and plants have been explored as alternative options for clinical use because they come from reliable sources and have better safety profiles.” (Emphasis added) Page 756, left column. “Exosomes derived from food have garnered attention, owing to the obvious conclusion that these exosomes are known to be commonly ingested and thus are generally considered safe.” Id. “In addition, agricultural products such as fruits and milk are relatively economically practical and scalable sources from which to isolate exosomes.” (Emphasis added) Id.
Although Luan discloses advantages of exosomes isolated from fruits and plants (page 756, left column), Luan is silent as to whether a fruit or other plant cell can be selected as the donor cell for the genetic engineering process disclosed later therein (page 760, left column). As explained below, the following reference compensates for this deficiency: Xu.
Xu is directed to plants as bioproduction platforms for recombinant proteins.
Xu teaches: “Plants possess exceptional biosynthetic capacity including the ability to use the sun (photosynthesis) and/or very simple media to support significant biomass and protein accumulation. Their potential for low-cost production of high quality and bioactive recombinant protein is well documented. Plants successfully perform the majority of post-translational modifications important for many complex eukaryotic proteins and provide tremendous flexibility in bioproduction platforms that differentially address production scale, cost, safety, and regulatory issues.” (Internal citations omitted) Page 1172 at Section 1.
Xu teaches: “Many proteins of mammalian origin have been expressed in plants, yielding a product with full function. These include monoclonal antibodies (mAbs), vaccine antigens, therapeutic enzymes, blood proteins, cytokines, growth factors and growth hormones (see examples in Table 2). Bioactivity of these proteins often requires protein folding, disulfide bond formation, subunit assembly, proteolytic cleavage, and/or glycosylation, highlighting the ability of plants to process complex human/mammalian proteins. Plant-made antibodies (Plantibodies ®) have received considerable interest as they are made at much lower cost in plants than in mammalian cells without the associated risks of potentially harboring animal pathogens.” (Emphasis added) Page 1172 at Section 2.1; see also Table 2 at page 1173 (vaccines for H5N1 and H1N1, respectively).
Xu teaches: “Because of the safety and economic concerns of using mammalian cell cultures, plant-made therapeutic proteins are receiving renewed interest by pharmaceutical companies. In fact, several plant-made mammalian proteins such as human lactoferrin and lysozyme (Ventria Bioscience), human aprotonin (ProdiGene), mammalian gastric lipases (Meristem Therapeutics), and human intrinsic factor (Cobento Biotechnology, Aarhus, Denmark) are now on the market.” (Internal citations omitted) Page 1179 at Section 5.2.
Xu teaches: “In contrast to other expression systems such as bacterial, mammalian cell and yeast, plant expression systems encompass diverse forms including whole-plants, suspension cells, hairy roots, moss, duckweed, microalgae, etc. (Fig. 1). Each of the platforms has its own strengths and weaknesses and is often best suited for certain classes of recombinant proteins based on the market, scale, cost, and upstream and downstream processing constraints of the particular protein product. A multiplicity of plant species can serve as hosts for plant-based bioproduction that comprise platforms ranging from in vitro cell and plant tissue cultures to whole plants grown under glass and in the field.” (Emphasis added) Page 1172 at Section 1.
Xu teaches that seeds, fruits, and leaves are among the options available for targeted production of recombinant proteins. Page 1180 at Figure 2; see also page 1173 at Figure 1. Additionally, the caption to Figure 2 teaches: “Because they are common to all plant platforms, the advantages of plants over other production systems, e.g., eukaryotic protein processing, lack of human pathogens, scalability options, are not listed here.” (Emphasis added) Page 1180.
Before the effective filing date of the claimed invention, the teachings of Xu would have motivated a person having ordinary skill in the art to modify Luan by selecting a fruit cell or other plant cell as the donor cell in the genetic engineering process disclosed therein on page 760 (left column), in an effort to produce medically-relevant recombinant proteins (e.g., vaccine antigens) for human use in a manner that is safer and more economical. MPEP § 2144.07 (the selection of a known material based on its suitability for its intended use can support a prima facie obviousness determination). The foregoing modification would have been undertaken with a reasonable expectation of success, especially considering Luan’s disclosure that “exosomes isolated from fruits and plants have been explored as alternative options for clinical use because they come from reliable sources and have better safety profiles” (page 756, left column). MPEP § 2143.02(I) (“Where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success.”).
The following two optional references provide additional (but non-critical) support for the examiner’s position that there would have been a reasonable expectation of success in modifying Luan with the teachings of Xu: Batrakova and Kim.
Batrakova (2015) reinforces that it was known in the art, before the effective filing date of the claimed invention, to transfect donor cells with DNA that codes for a therapeutic protein and, thereafter, harvest exosomes containing that therapeutic protein following their secretion from the transfected donor cells, as shown in Figure 3C (page 400) reproduced below:
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Kim (WO 2004/014954 A1), which is directed to “exosome containing exogenous antigen through gene transfection” (title), establishes that it was known in the art, before the effective filing date of the claimed invention, to transfect donor cells with a gene encoding an exogenous protein antigen and, thereafter, harvest exosomes containing that protein antigen following their secretion from the transfected donor cells, as shown in Figure 1 reproduced on the next page:
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In sum, claims 1 and 2 are prima facie obvious. MPEP § 2143.01 (“Obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so.”).
Regarding claim 3, Xu identifies plant tissue cultures as a strategy used to boost protein yields in plants. Page 1172 at Table 1.
Regarding claim 5, Luan discloses purification of exosomes by gradient centrifugation. Page 757, left column. Luan additionally discloses the following protocol for purification via ultracentrifugation: “In consecutive rounds of centrifugation and pouring off, the RCF (g) and the centrifugation time are increased to pellet smaller particles. After first 200×g and 2000×g centrifugations, pellets that contain dead cells and cell debris are discarded, and the supernatant is kept for the next step. In contrast, after the 100 000×g centrifugations, pellets (containing EVs) are kept, and supernatants are discarded.” Figure 1, page 755, at caption.
Regarding claim 7, Xu discloses oral vaccination. Page 1179, right column. Moreover, a person having ordinary skill in the art — following a review of Section 5.2 (pages 1179-1180) of Xu — would have readily envisaged intramuscular (IM) vaccination because that has been the most common route of vaccine administration for decades. MPEP § 2131.02(III) (“a generic disclosure will anticipate a claimed species covered by that disclosure when the species can be ‘at once envisaged’ from the disclosure”).
Regarding claims 8-10, Xu teaches recombinant human lysozyme (immunomodulator) and recombinant human lactoferrin (adjuvant). Page 1179 at Section 5.2. Xu suggests that either of those recombinant proteins may be regarded also as nutraceuticals (claim 10). Id. Additionally or alternatively, Luan teaches that exosomes can be used to carry curcumin, among other small therapeutic molecules. Page 756, left column, and page 758, right column; see also page 759 at Figure 2. Curcumin is both an immunomodulator and a nutraceutical. Id.
Regarding claim 11, Xu teaches pr-antiTNF, a biosimilar version of etanercept (EnbrelTM) for the treatment of rheumatoid arthritis (Section 5.2 at page 1180), which is an autoimmune disease.
Response to Applicant’s Argument
The following remarks are provided in response to the argument raised by Applicant on pages 6-7 of the Reply filed 22 January 2026:
The isolated sentence from Luan asserted by Applicant on page 6 of the Reply refers to naturally-occurring exosomes, which in this context are exosomes secreted by un-transfected food cells (i.e., cells from food, such as milk, that have not been transfected). Luan at page 756 (right column). The exosomes secreted by those food cells do not carry recombinant protein antigens or other similar immunostimulatory agents. However, the remainder of that same paragraph in Luan expresses optimism for using exosomes secreted by plant cells, especially fruit cells, to carry and deliver anti-cancer agents with considerable efficiency, including when tumor-targeting ligands are added to the exosomal surface. Luan at page 756 (paragraph bridging the left and right columns). By analogy, if one were to transfect a fruit cell with a gene encoding an exogenous protein antigen and, thereafter, harvest the secreted exosomes carrying the resulting recombinant protein antigen, it would have been reasonable to expect that those exosomes would be capable of inducing an immune response (see Kim (WO 2004/014954 A1) as applied above). This is supported by Luan, which discloses: “Utilizing exosomes is one of the most promising methods for delivering macromolecular proteins (Figure 2C). Proteins can be loaded into exosomes through genetic engineering of the donor cells or through direct loaded into the exosomes.” Page 760, left column. Thus, the examiner concludes that Luan, when considered in its entirety, does not teach away from Applicant’s claimed invention. MPEP § 2141.02(VI) (“A prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention.”).
In closing, the examiner notes that the claims do not which identify which immunomodulatory gene is used to transfect the cells of the plant sample. See, e.g., claim 1. Indeed, it is striking none of the claims even requires that the plant cells are transfected with an immunomodulatory gene (or a vector comprising an immunomodulatory gene). The extreme breadth of the claims remains a very significant obstacle to progressing this application to allowance.
The foregoing §103 rejection is maintained.
* * *
Conclusion
Claims 1-3, 5, and 7-11 are rejected.
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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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/P.A./
21 February 2026
/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611