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 .
The most recent claim set, dated April 27, 2026, is being considered. Claim 8 and 22 are newly canceled. Claims 1-3, 14-19, 23 and 24 are examined on their merits below.
Priority
The application is a continuation-in-part of application 17/085,695, filed Oct. 30, 2020; as such the earliest possible priority date is Oct. 30, 2020.
Information Disclosure Statement
The information disclosure statement filed April 1, 2025 was mistakenly asserted to fail to comply with the provisions of 37 CFR 1.98(a)(4) (lacking the appropriate size fee assertion). The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Rejections
The rejection of claims 14-19 under 35 U.S.C. 112, second paragraph for being indefinite is withdrawn in view of the claim amendments in the Response of April 27, 2026.
The rejection of claims 1-3 and 22-24 under 35 U.S.C. 102(a)(1) as being anticipated by Wong et al. is withdrawn in view of the claim amendments in the Response of April 27, 2026.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 14-19, 23 and 24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring composition without significantly more. This is a maintained rejection, amended to address the amended claims. The amended claims recite an exosome composition including a plurality of exosomes produced by a mesenchymal stem cell or fibroblast cell in a conditioned media and at least one extracellular matrix (ECM) component isolated from an ECM, all of which are obtained from the conditioned media having a concentration of ECM components that is at least 5x greater than the same exosome preparation prepared through ultracentrifugation of the conditioned media. This judicial exception is not integrated into a practical application because as shown in Fig. 1 of the application, the claimed cell product (exosomes and an extracellular matrix component) is naturally occurring and the process that is applied to collect this naturally occurring product does not alter the claimed product enough to distinguish it from its naturally occurring counterpart. In fact, for the exosomes and extracellular matrix product to be therapeutically useful, it must maintain a similarity to the naturally occurring product. (See para. [0003] of the published application). Para. [0098] of the specification indicates that the exosome composition is isolated from conditioned media produced by human mesenchymal stem cells. See also Han et al. (Stem Cells Internl, 2016), Fig 1, showing the exosomes. Note that the extracellular matrix is in and around the space between the cells and the exosomes, so adjacent to the exosomes in its naturally-occurring environment.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because each of the dependent claims further defines what is in the claimed cell product (or how it differs by using an isolation process that keeps the product more intact, e.g. closer to its naturally occurring product than counterparts that are isolated in a less intact manner).
Claim 24 recites that the exosome composition further includes a carrier or excipient. This additional element is not enough to amount to sufficiently more. Since no specific carrier or excipient is recited, a naturally occurring one, such as saline, would meet this limitation. Neither the exosome composition on its own, a carrier (such as saline) on its own, or the combination of the cells and saline (“carrier”) would amount to significantly more than the naturally occurring product, as the media is intended to maintain the exosomes, replicating the surrounding fluid that they encounter while in the human body. Additionally, neither the limitation that the ECM component is isolated (independent claim 1) nor the recitation of a carrier or excipient (claim 24) renders the claims markedly different from what exists in nature. Myriad clarified that not every change to a product will result in a marked difference, and that the mere recitation of particular words (e.g., “isolated” or “excipient or carrier”) in the claims does not automatically confer eligibility. Id. at 2119. See also Mayo, 132 S. Ct. at 1294 (eligibility does not “depend simply on the draftsman’s art”). There is no indication in the specification, nor have applicants provided any evidence that the claimed exosome composition including an exosome and a component isolated from an ECM in a carrier/excipient (e.g. saline or water) is markedly different from its naturally occurring counterpart.
Response to Arguments - 35 USC § 101
Applicant's arguments filed April 27, 2026 have been fully considered but they are not persuasive. Applicants assert that “the claimed composition is not merely an isolated natural product, but instead reflects a human-engineered composition with a quantitatively altered composition profile that does not occur in nature.” (pg. 9, first paragraph). Applicants appear to assert that the exosome preparation differs from that prepared by ultracentrifugation and that the claimed composition (note that the claim does not indicate how the claimed composition is prepared; rather, only that it is isolated from conditioned media and is more “enriched” in certain components than composition isolated from conditioned media that are ultracentrifuged) has different structural properties and different biological functionality, such as elevated regenerative or signaling properties. Applicants further assert that even if the isolated composition is naturally occurring, it has been integrated into a practical application because the claims require a “specific, non-natural formulation defined by quantitative enrichment relative to a defined preparation method.”
This is not found persuasive as the conditioned media from the culture of mesenchymal stem cells or fibroblasts or both (all natural products) has products within it, e.g. exosomes and ECM components (naturally occurring product as well), that applicants have isolated. Applicants appear to be comparing the claimed product to one that is made by ultracentrifugation and pointing out that they are selecting different components and concentrations by isolating these components without using ultracentrifugation. This would not change the fact that the isolated products are naturally occurring. Even if the claimed concentration or assortment of exosomes and ECM does not occur in nature, this difference, is not enough to distinguish the claimed composition from its naturally occurring counterpart. This is analogous to the contention rejected by the Supreme Court in Funk Bros. Seed Co. V. Kalo Inoculant Co. 333 U.S. 127, 131 (1948), where the court held that even though the combination of bacteria did not occur in nature, the combination of bacteria did not provide a different structural or functional characteristic than each bacteria possessed on its own.
"It is no more than the discovery of some of the handiwork of nature and hence is not patentable. The aggregation of select strains of the several species into one product is an
application of that newly-discovered natural principle. Each species has the same effect it
always had. The bacteria perform in their natural way." Id.
In the present claims if "bacteria" is replaced with "exosome and ECM components produced by mesenchymal stem cells and/or fibroblasts," the same reasoning applies. The (potentially) differently concentrated, claimed biological molecules function in their natural manner. Each component within the isolated conditioned media is structurally and functionally the same as that which is produced by the cell. The “collection” of these products (just as in the collection of bacteria in Funk) has not made them markedly different than their naturally occurring counterpart. While the composition as a whole appears to have elevated regenerative or signaling properties compared to a composition that is isolated using ultracentrifugation, each component of the composition is a naturally-occurring product and is structurally and functionally the same as it naturally-occurring counterpart. The collection of those components into the claimed composition is still not markedly different than the naturally-occurring counterpart. Rather, the increased therapeutic benefits of the composition come from the additive effect of each component functioning as it functions in its natural setting, just as in Funk.
Applicants further assert that even if the claims recite a product not markedly different than the naturally occurring product, the claimed recite significantly more than the naturally-occurring counterpart, again relying on the enrichment process that the claimed product uses (and again, that specific enrichment process is not recited in the claims; rather, the claims recite that the claimed product is present in a greater concentration than that found in a product prepared from the same conditioned media using ultracentrifugation.
This is not found persuasive. For the reasons explained above, the claimed composition is not markedly different from its naturally occurring counterpart. Even if the naturally occurring molecules are differently concentrated than they would be in a natural extracellular milieu, each biological molecule component is structurally and functionally the same as their naturally-occurring counterpart. Each component within the isolated conditioned media is structurally and functionally the same as that which is produced by the cell. As seen in Table 1 (specification, pgs. 75-124), the dozens and dozens of components that are compared between a commercial exosomes preparation (ultracentrifuged) and an exosome composition prepared without ultracentrifugation are all biological molecules that are found in and around cells, within living organisms.
The “collection” of these products (just as in the collection of bacteria in Funk) has not made them markedly different than their naturally occurring counterpart. As such, these claims do not recite significantly more. They recite a collection of naturally-occurring products, collected in a composition.
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.
Claim(s) 1-3, 14, 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Wong et al. (Arthroscopy, Aug., 2020) in view of Haraszti et al. (Molecular Therapy, 2018, cited in IDS filed on Jan. 31, 2023). This is a new rejection, to address amendments made to the claims.
The amended claims are directed to an exosome composition that includes a plurality of exosomes produced by MSCs or fibroblasts in a conditioned media and a least one extracellular matrix component isolated from an ECM where the exosome composition includes a concentration of the ECM component that is at least five times greater than a comparable exosome preparation prepared by ultracentrifugation.
The recitation that the “concentration of the ECM component that is at least five times greater than a comparable exosome preparation prepared by ultracentrifugation” is a product-by-process limitation. "[E]ven 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) (citations omitted) (emphasis added). MPEP 2113. Therefore, an exosome composition that has a plurality of exosomes produced by the claimed cells and an ECM component that is present at a concentration of five times that of what would be expected in an exosome preparation prepared by ultracentrifugation will meet the claimed limitations.
Example 1 in the specification details exosomes and ECM component collection using a filtration process that includes a tangential flow filtration system. The specification indicates that the exosome composition of Example 1 (which is prepared in a more specific way than the process recited by the claims) was analyzed and compared to a commercially available exosome preparation and that over 1900 compounds/growth factors/components found in extracellular matrix were elevated as compared to a commercial product. (see Example 2, para. [0163], Table 1 of published application).
With respect to independent claim 1, Wong et al. teach a composition that contains exosomes produced by MSCs and an isolated ECM component (hyaluronan) (Abstract, pg. 2217, 1st col, 1st full para. “…Intra-articular 1-mL injections of exosomes + HA (exosome + HA) or HA alone were administered…”). Wong further teach that the exosomes came from MSC conditioned medium that was size fractionated and concentrated by 50x by tangential flow filtration. (pg. 2216, “Exosomes”)
Wong et al. teach that 200 µg of exosomes suspended in 1 mL of 3% (w/v) HA. (pg. 22 17, 1st col., 1st full para.)
Wong does not explicitly teach that the concentration of the isolated ECM component in the mixture is 5x that of what would be found in an ultracentrifuged exosome preparation, though it is possible that Wong’s exosome preparation meets this limitation.
Haraszti et al. teach that exosomes produced by 3D cultures of MSCs and isolated using tangential flow filtrations (TFF) how higher yields and improved activity. (Title). Specifically, Haraszti et al. teach that this combination improves the yield of exosomes by 140-fold. (pg. 2839, 1st col, 1st partial para.).
Even if the composition taught by Wong does not have the claimed concentration, it would have been obvious to have optimized the extraction of the exosome preparation using 3D culture and TFF (as taught by Haraszti et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating this modification would have led to predictable results with a reasonable expectation of success because both Wong and Haraszti et al. teach isolation of exosomes using tangential flow filtration methods, Haraszti et al. teach that the combination of 3D culture and TFF improves the yield by 140-fold. Additionally, it would be prima facie obvious to have optimized the HA in the therapeutic exosome composition to reach a concentration where therapeutic benefit is maximized. As differences in concentration will not support patentability unless there is evidence that the specific concentration is critical to achieving an unexpected result (see MPEP 2144.05), the claimed increased concentration as compared to that achieved when preparing the composition using ultracentrifugation is deemed to be met.
With respect to claims 2 and 3, Wong et al. teach that hyaluronic acid and exosomes are present in the administered composition (“a glycoaminoglycan” and “hyluronan”). (Abstract, pg. 2217, 1st col, 1st full para.).
With respect to claim 14, as explained above, Even if the composition taught by Wong does not have the claimed concentration, it would have been obvious to have optimized the extraction of the exosome preparation using 3D culture and TFF (as taught by Haraszti et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating this modification would have led to predictable results with a reasonable expectation of success because both Wong and Haraszti et al. teach isolation of exosomes using tangential flow filtration methods, Haraszti et al. teach that the combination of 3D culture and TFF improves the yield by 140-fold. Additionally, it would be prima facie obvious to have optimized the HA in the therapeutic exosome composition to reach a concentration where therapeutic benefit is maximized. As differences in concentration will not support patentability unless there is evidence that the specific concentration is critical to achieving an unexpected result (see MPEP 2144.05), the claimed increased concentration as compared to that achieved when preparing the composition using ultracentrifugation is deemed to be met.
With respect to claim 23, Haraszti et al. teach that the range of administration of exosomes per animal (mouse) in preclinical small animal studies is 109 – 1011, or from about 100 million to 10 billion. (pg. 2842, 1st col., 1st full para.). It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the exosome + HA preparation taught by Wong et al. to incorporate including at least a billion exosomes because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Making this modification would have led to predictable results with a reasonable expectation of success because both Wong et al. and Haraszti are directed to use of therapeutic exosomes isolated using tangential flow filtration and Haraszti et al. teach that administering at least a billion exosomes is in an appropriate range for small animals. As such, a person of ordinary skill in the art would be motivated to form a composition that contained at least a billion exosomes for use in larger animals (such as the rabbits used by Wong et al (pg. 2216, “Animal Study Design and Surgical Procedure”) or for use in pre-clinical trials in humans.
With respect to claim 24, Wong et al. teach that the 1-mL injections of exosomes + HA contained 200 µg of exosomes, suspended in 1 mL of 3% (w/v) HA. (pg. 2217, 1st col, 1st full para.) While Wong et al. do not explicitly teach what the excipient or carrier the 3% HA is in, it would be understood by one of ordinary skill in the art that the HA and exosomes were suspended in a carrier.
Claims 1, 15-19 are rejected under 35 U.S.C. 103(a) as obvious over the combination of Kim et al. (Arthroscopy, Aug., 2020), in view of Haraszti et al. (Molecular Therapy, 2018, cited in IDS filed on Jan. 31, 2023). This is a new rejection, to address amendments made to the claims.
Kim et al. teach that ECM components such as DKK, Cadherin-13, and βig-h3 are present in the soluble fraction of conditioned medium of human bone marrow MSCs. (pg. 220, Table 2). Kim et al. teach that the conditioned medium can be divided into a soluble fraction and exosome fraction. (pg. 217, “Preparation of conditioned media (CM) and trypsin digestion”).
Kim et al. does not teach preparation of an exosome composition containing both exosomes and constituents from the soluble fraction.
Haraszti et al. teach that exosomes produced by 3D cultures of MSCs and isolated using tangential flow filtrations (TFF) how higher yields and improved activity. (Title). Specifically, Haraszti et al. teach that this combination improves the yield of exosomes by 140-fold. (pg. 2839, 1st col, 1st partial para.).
It would have been obvious to have produced an exosome composition containing both soluble fraction from conditioned medium from MSCs and exosomes and to have done so by 3D culturing the cells and using TTF for isolation because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating this modification would have led to predictable results with a reasonable expectation of success because Haraszti et al. teaches the doing so provides “a robust and scalable strategy” for exosome production. Once the 3D culture and TFF were performed to extract and optimize the exosomes, the soluble fraction could also be collected and added to the exosomes, thereby recreating the cellular milieu that MSCs are surrounded by in their natural environment. Such a product could be useful for studying MSCs or for MSC expansion and growth.
Response to Arguments – Prior Art Rejections
Applicant's arguments have been fully considered but they are not persuasive. Applicants assert that Wong et al. does not teach the claimed “enrichment” of the ECM component as compared to an exosome preparation prepared by ultracentrifugation.
This is not found persuasive because, as explained above, the claimed product is not limited by the actual method of production, rather the claims require a product that has an ECM component that is 5x increased as compared to that found in an ultracentrifuged exosome product (or 20x for claim 14). Wong et la., at least in view of Haraszti et al. teaches or renders obvious such a product, as Haraszti et al. teach that both 3D culture and TFF result in exosome preparations with much improved quality and result in a 140-fold increase in their yield of exosomes. It is therefore reasonable to assert that preparation of the exosome product in this manner, with the addition of therapeutic concentration of ECM components (as taught by Wong et al.) or inclusion of the claimed ECM components (as taught by Kim et al.) by including the soluble fraction of conditioned medium would render obvious the claimed exosome composition.
For at least these reasons, applicants’ arguments are not persuasive.
Conclusion
No claims are 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.
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/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
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