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 sixth 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 25 May 2026 has been entered.
Status of the Claims
Applicant amended claim 1, cancelled claims 7-11, and added one new claim, i.e., claim 12. Claims 4 and 6 were cancelled previously by Applicant. Claims 1-3, 5, and 12 are pending and under consideration.
Status of the Rejections and Objections
The objection to claim 12 is new.
The rejection of claims 7-11 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s cancellation of all those claims.
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 Journal of Controlled Release 219 (2015): 396-405) and Kim (WO 2004/014954 A1) is withdrawn in view of Applicant’s narrowing amendment to claim 1 requiring that “the plant sample is selected from the group consisting of pomegranate, leek, celery, horseradish, warty-leaved rhubarb, and ginger.”
The rejection of claims 1-3 and 5 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), Shoseyov (US 2017/0283822 A1) 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 new. The examiner notes that Shoseyov is newly cited.
The rejection of claim 12 under 35 U.S.C. 103 as being unpatentable over Luan in view of Xu, Shoseyov and, optionally, Batrakova and Kim, as applied above to claims 1-3 and 5, and further in view of Yamawaki (US 2018/0275029 A1) is new. The examiner notes that Yamawaki is newly cited.
Objection to the Claims
Claim 12 is objected to because of the following informality: The abbreviations “PEG” and “DEX” are not defined in the claim. Appropriate correction is required.
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 and 5 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), Shoseyov (US 2017/0283822 A1) 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). Furthermore, Luan is silent as to whether the plant donor cell can be selected from among “pomegranate, leek, celery, horseradish, warty-leaved rhubarb, and ginger” (claim 1, as recently amended).
As explained below, the following two references compensate for this deficiency: Xu and Shoseyov.
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: “Antibodies and vaccines are the two major classes of plant-made therapeutic proteins that are under commercial development.” (Emphasis added) Page 1179 at Section 5.2. “Subunit vaccine antigens produced in plants have received the most attention in the molecular farming community.” (Emphasis added) Id.
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.
Shoseyov is directed to “methods for producing polypeptides with a modified glycosylation pattern in plant cells.” Title.
Shoseyov teaches: “The polypeptides may be intracellular polypeptides (e.g., a cytosolic protein), transmembrane polypeptides, or secreted polypeptides.” (Emphasis added) Para. [0163].
Shoseyov teaches: “Exemplary vaccines that can be produced by the subject compositions and methods include but are not limited to vaccines against various influenza viruses (e.g., types A, B and C and the various serotypes for each type such as H5N2, HIN1, H3N2 for type A influenza viruses), HIV, hepatitis viruses (e.g., hepatitis A, B, C or D), Lyme disease, and human papillomavirus (HPV).” (Emphasis added) Para. [0164].
Shoseyov teaches: “According to a specific embodiment the plant cell is a root cell such as selected from the group consisting of Agrobacterium rihzogenes transformed root cell, celery cell, ginger cell, horseradish cell and carrot cell.” (Emphasis added) Para. [0115].
Before the effective filing date of the claimed invention, the teachings of Xu and Shoseyov, respectively, would have motivated a person having ordinary skill in the art to modify Luan by selecting a celery cell, a ginger cell, or a horseradish cell as the plant donor cell in the genetic engineering process disclosed therein on page 760 (left column), in an effort to produce medically-relevant vaccine antigens and other immunomodulatory recombinant proteins (e.g., antibodies) 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 and Shoseyov: 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.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Luan in view of Xu, Shoseyov and, optionally, Batrakova and Kim, as applied above to claims 1-3 and 5, and further in view of Yamawaki (US 2018/0275029 A1).
Although Luan discloses purification of exosomes by gradient centrifugation and by ultracentrifugation, Luan is silent as to whether the exosomes can be purified by a two-phase system. Consequently, Luan does not satisfy claim 12.
Yamawaki is directed to a two-phase system for concentrating extracellular vesicles (EVs).
In claims 1-20, Yamawaki teaches a method of purifying EVs that is at least substantially identical to the method recited in claim 12 of the present application. Applicant is additionally referred to paragraphs [0036]-[0045] of Yamawaki, which teach the method in even greater detail than is recited in Applicant’s claim 12. In Figures 1A and 1B (reproduced below), Yamawaki shows how the PEG and DEX phases cooperate to concentrate the EVs.
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Yamawaki identifies exosomes as an exemplary species of EV that can be purified utilizing the method taught therein. Para. [0016].
Before the effective filing date of the claimed invention, a person having ordinary skill in the art would have been motivated to modify Luan by purifying the exosomes using the two-phase PEG/DEX process taught in Yamawaki (instead of gradient centrifugation or ultracentrifugation) in the course of routine experimentation. Therefore, claim 12 is prima facie obvious. MPEP § 2144.06(II) (substituting equivalents known for the same purpose).
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Conclusion
Claims 1-3, 5, and 12 are rejected.
Claim 12 is also objected to.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER ANTHOPOLOS whose telephone number is 571-270-5989. The examiner can normally be reached on Monday – Friday (9:00 am – 5:00 pm). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany P. Barham, can be reached on Monday – Friday (9:00 am – 5:00 pm) at 571-272-6175. The fax number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.A./
27 June 2026
/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
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