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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/11/2026 has been entered.
Status of Claims
Claims 18-19, 21-27, and 29-31 are pending.
Claims 18 and 25-27 are currently amended. Claim 28 is currently cancelled.
Claims 18-19, 21-27, and 29 are examined on the merits herein.
Claims 30-31 are withdrawn from consideration as being drawn to inventions non-elected without traverse.
Status of Rejections
The cancellation of claim 28 and renders any rejections thereof moot.
The rejection of claims 18-19, 21-27, and 29 under 35 U.S.C. 112(a) is maintained. Applicant’s arguments are addressed following the rejection.
Claim Interpretation
The specification defines the phrase “healthy person” as “an asymptomatic human which has not developed any symptom of infection with a virus that uses ACE2 as a receptor” (p 19, para 40).
Claim 18 is drawn to a method of inhibiting an infection of a healthy person, wherein the method comprises administering a composition (1). The broadest reasonable interpretation of composition (1) as claimed includes a composition containing a culture supernatant, wherein the culture supernatant contains ACE2, as well as a composition containing ACE2 and a culture supernatant, wherein the culture supernatant does not comprise ACE2 prior to incorporation into the composition.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 18-19, 21-27, and 29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 recites the limitation “ACE2 on cells of human” in line 3. It is unclear what human cells are being referred to in this limitation. For the sake of compact prosecution, this limitation is interpreted as “ACE2 on cells of the healthy person.”
Claims 19, 21-27, and 29 are included in the rejection because they depend from claim 18.
Regarding claims 25-27: Claim 25 recites the limitation “inhibits binding of SARS-Co V-2 to ACE2 of a human between a spike protein of SARS-CoV-2 and ACE2 on the human cells” (lines 2-3). It is unclear what is referred to by “a human” (line 2) and “the human cells” (line 3). For example, “the human cells” could refer to cells of the healthy person, or to cells in the composition. Likewise, claim 26 recites “the human cell” in line 2, and claim 27 recites “a human cell” in lines 2-3, which are indefinite for the same reason as set forth for claim 25. For the sake of compact prosecution, reference to “a human” is interpreted as “the healthy person,” and reference to “human cells” is interpreted as “cells of the healthy person.”
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 18-19, 21-27, and 29 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
The breadth of the claims:
Claims 18-19, 21-27, and 29 are directed to a method of inhibiting an infection of a healthy person with SARS-CoV-2, wherein the inhibition is achieved by inhibiting binding between a spike protein of SARS-Co V-2 and ACE2 on cells of human (interpreted as cells of the healthy person).
Regarding “inhibiting an infection”: This phrase is not defined in the specification. The broadest reasonable interpretation of “inhibiting an infection” includes deterring the entry of a virus into a cell, deterring the multiplication of a virus upon its entry into a cell, and deterring the onset of symptoms caused by a virus.
Regarding “a healthy person”: A healthy person is defined in the specification as “an asymptomatic human which has not developed any symptom of infection with a virus that uses ACE2 as a receptor” (p 19, para 40). The specification further recites that “The healthy person also includes a human which is asymptomatically infected with a virus that uses ACE2 as a receptor regardless of whether the human is negative to infection.”
Regarding the origin of stem cells and cross-species administration: Claim 18 does not limit the origin of stem cells to a particular animal. The claims encompass culture supernatant obtained from any animal having dental pulp-derived stem cells (see Claim Interpretation), as well as extracellular vesicles obtained from any animal having dental pulp-derived stem cells, wherein the extracellular vesicles contain ACE2. Furthermore, the claims encompass cross-species administration of the composition (e.g., a composition containing a culture supernatant of dental pulp-derived stem cells from bats may be administered to a human subject). Claim 29 limits the stem cells recited in claim 18 to those of human origin.
Regarding the route of administration: The claims do not limit the route of administration of the composition to a healthy person. The specification recites that the route of administration “is not particularly restricted” (p 25, para 51), and gives examples including spraying or inhalation to the oral cavity, the nasal cavity or the respiratory tract, infusion, injection, and transdermal electroporation (p 25, para 51). Routes of injection routinely practiced in the art include intramuscular and intravenous injection. The claims encompass both systemic and non-systemic routes of administration.
The nature of the invention:
Broadly, the nature of all claims, which depend from claim 18, is a method for inhibiting infection of a healthy person with SARS-CoV-2. The method comprises administering a composition (1) containing a culture supernatant of dental pulp-derived stem cells or immortalized stem cells thereof, wherein the composition contains ACE2 (see Claim Interpretation), or a composition (2) containing exosomes derived from a culture supernatant of dental pulp-derived stem cells or immortalized stem cells thereof, wherein the extracellular vesicles contain ACE2.
Claim 19 limits the nature of invention to the use of a composition containing extracellular vesicles derived from the culture supernatant of dental pulp-derived stem cells.
Claim 29 limits the nature of invention to the use of a composition derived from human stem cells.
The state of the prior art:
Art published prior to the 7/17/2020 effective filing date suggest the use of mesenchymal stem cell (MSC) therapy for the treatment of COVID-19. However, the prior art does not disclose, or suggest, the use of MSC-based therapies for the prevention or inhibition of COVID-19 in healthy individuals that do not exhibit symptoms of COVID-19.
Regarding the use of a culture supernatant or extracellular vesicles derived from stem cells to prevent infection in a healthy person with SARS-CoV-2:
Golchin (2020, Stem Cell Reviews and Reports, 16: 427-433), published in April 2020, teaches that although no standard treatment for COVID-19 has been discovered to date, mesenchymal stem cell (MSC)-based immunomodulation treatment has been proposed as a therapeutic approach, with several clinical trials underway (Abstract). Golchin states that despite the ongoing clinical trials, there are no approved MSC-based approaches for the prevention and/or treatment of COVID-19 patients as of April 2020 (Abstract). Furthermore, the clinical trials discussed in Golchin pertain to the use of MSCs to treat patients with symptoms of COVID-19, not the prevention of infection in healthy patients.
Saldanha-Araujo (2020, Frontiers in Immunology, 11: 1563), published 07/03/2020, discloses 69 ongoing clinical trials investigating the application of stem cells to treat COVID-19 (Abstract). For example, one of the clinical trials comprises administering ExoFlo, which is a compound comprising exosomes derived from bone-marrow MSCs, to COVID-19 patients. In this clinical trial, 17 out of 24 patients recovered (p 6, col 2, para 4). The clinical trials discussed in Saldanha-Araujo comprise administering MSCs and/or their products to patients who are already ill from COVID-19; the patients are not healthy people as defined by the specification, and the clinical trials discussed in Saldanha-Araujo do not encompass a method of preventing COVID-19 in a healthy person by administering MSCs and/or their products.
Gentile (2020, Expert Opinion on Biological Therapy, 20(7): 711-716), published in March 2020, discloses that intravenous administration of MSCs to patients who are SARS-CoV-2 positive and exhibiting COVID-19 pneumonia is effective at reducing pneumonia in said patients (p 712, section 3). Gentile further discloses that 22 clinical trials are registered at the time of publication to evaluate MSCs as clinical treatment for patients with COVID-19 (p 714, section 4.3). However, the clinical trials discussed in Gentile pertain to the treatment of patients who are already ill from COVID-19, not to the prevention of SARS-CoV-2 infection in healthy patients.
Regarding the origin of stem cells and cross-species administration: The stem cells used in the clinical trials disclosed in Saldanha-Araujo and Gentile are derived from humans, and are administered to humans. Cross-species administration of MSCs are not discussed.
Regarding the route of administration: Saldanha-Araujo discloses that treatment with MSCs often comprises intravenous administration of allogeneic MSCs, whereupon a significant percentage of MSs become trapped in the lungs (p 4, col 1, para 2). Other strategies include the administration of MSC-derived exosomes via inhalation (Saldanha-Araujo, Fig 2 caption). Transdermal electroporation, as discussed in the specification of the instant application, are not discussed in the prior art as an established route of administration for MSC-based therapies.
The level of one of ordinary skill:
One of ordinary skill in the art is a research scientist, such as a virologist or molecular biologist, holding a postgraduate degree or equivalent experience.
The level of predictability in the art:
Regarding the use of a culture supernatant or extracellular vesicles derived from stem cells to inhibit infection in a healthy person with SARS-CoV-2: The art recognized the promise of MSC-based therapies in treating patients with symptoms of COVID-19 (see Golchin et al., Saldanha-Araujo et al., and Gentile et al.). However, these therapies were still in clinical trial stages prior to the effective filing date of 07/17/2020. Furthermore, the art does not recognize, or suggest, the use of MSC-based therapies for the prevention of infection in healthy people who do not exhibit symptoms of COVID-19. Treating existing symptoms of the COVID-19 illness, such as pneumonia, is different from preventing the entry of the SARS-CoV-2 virus into otherwise healthy cells, or preventing the onset of symptoms in asymptomatic individuals who have been infected with SARS-CoV-2. Therefore, there was a high level of unpredictability regarding the use of MSC-based therapies to prevent infection from SARS-CoV-2 in otherwise healthy individuals at the time the invention was made.
Regarding cross-species administration: The prior art discloses clinical trials that utilize allogeneic MSCs for the treatment of COVID-19. The prior art does not teach the administration of non-human stem cells, or culture supernatants or extracellular vesicles thereof, to human subjects for the treatment of COVID-19. Li (2012, Xenotransplantation, 19(5): 273-285) discloses that genetically modified porcine MSCs have been demonstrated to downregulate human T-cell response to pig antigens in vitro (Abstract), and that MSC function has been confirmed in several different cross-species models (Results and Discussion; Fig 1). However, Li teaches that the number of MSCs administered in the experimental models varied considerably depending on the species model, the disease to be treated, and mode of administration (local vs. systemic). Therefore, there was a high level of unpredictability regarding the use of cross-species administration of MSC-based therapies at the time the invention was made.
Regarding the route of administration: The prior art teaches that treatment with MSCs often comprises intravenous administration of allogeneic MSCs, but that other strategies include the administration of MSC-derived exosomes via inhalation (Saldanha-Araujo, Fig 2 caption). Saldanha-Araujo further teaches that a meta-analysis study suggests superior results following intratracheal administration of MSCs, compared to intravenous and intraperitoneal routes (p 5, col 2, para 2). This is further complicated by the fact that COVID-19 mainly acknowledged as a respiratory syndrome, but have systemic effects beyond the respiratory tract (Saldanha-Araujo, p 5, col 2, para 2). Therefore, there was a high level of unpredictability regarding the route of administration of MSC-based therapies at the time the invention was made.
Working examples and the amount of guidance:
The instant specification offers working examples of in-vitro binding assays. One is titled “Evaluation of Inhibition of Spike-ACE2 Binding of Culture Supernatants” (p. 27-29, para 57-61), which characterizes the binding affinity of the COVID spike protein to the ACE2 receptor complex in the presence of supernatants of dental pulp-derived stem cells (para 55) and adipose-derived stem cells (para 56). Another set of examples characterizes exosomes derived from stem cells (“Characteristics of Exosomes,” para 68), measures ACE2 expression in said exosomes (“Observation of ACE2 Expression,” para 69-70), and measures ACE2 concentrations in said exosomes (“Measurement of ACE2 Concentrations,” para 71-73). The specification does not offer working examples directed towards preventing or inhibiting infection of a healthy person with SARS-CoV-2, as recited in independent claim 18, or more broadly, any in-vivo working examples.
Moreover, the specification fails to provide guidance in correlating or applying data from the in-vitro assays to inhibiting or treating an infection in a person, wherein the infection is caused by SARS-CoV-2. Although the specification recites how this composition may be administered (e.g., para 51-53 discuss, among other things, the route and timing of administration), the specification lacks guidance on how the composition prevents infection in a healthy person.
The quantity of experimentation necessary:
Based on the content of the disclosure, undue experimentation is required to use the invention as claimed. As stated above, the experimental examples disclosed in the specification are assays demonstrating the capacity of supernatants or extracellular vesicles derived from stem cells to inhibit the binding of the COVID spike protein to the ACE2 receptor complex in vitro. However, the claims are drawn to an in-vivo method; more specifically, to a method of inhibiting an infection of a healthy person with SARS-CoV-2.
First, the in-vitro data disclosed in the Specification must be validated in vivo; that is, it is necessary to establish that stem-cell derived supernatants or extracellular vesicles are capable of inhibiting binding of the COVID spike protein to the ACE2 receptor complex in vivo. Given the changes in environments between in vitro and in vivo conditions, virus-receptor binding models that are established in vitro do not necessarily replicate in vivo. Additionally, demonstrating decreased binding between a virus and ACE2 receptor in the presence of a culture supernatant or extracellular vesicle in vivo is not the same as demonstrating the use of said supernatant or exosome as a medicament for inhibiting infection in animals. Additional experimentation is required to establish that the decreased binding between the virus and ACE2 receptor results in the prevention of infection of a healthy person. Especially given that the use of MSC-based therapies to prevent viral infections, including COVID, was not established in the art at the time the invention was made, this process requires significant experimentation. Given the state of the prior art, the optimal route of administration and cross-species administration of the MSC-based therapies must be further determined and refined through experimentation.
In conclusion, the disclosure does not support a method of administering a composition containing a culture supernatant or extracellular vesicles derives from stem cells to inhibit an infection of a healthy person with SARS-CoV-2, as recited in independent claim 18. The evidence provided in the instant specification, in light of the teachings available in the art, does not enable one skilled in the art to make and use the claimed invention without undue or reasonable experimentation. Therefore, the methods recited in claims 18-19, 21-27, and 29 are not enabled.
Response to Arguments
RE: Claim Interpretation
Applicant argues: In view of the accompanying amendment, claim 18 should be interpreted as being directed to a specific mechanism for inhibiting SARS-CoV-2 infection, namely inhibition of binding between the SARS-CoV-2 spike protein and ACE2 on human cells.
As amended, claim 18 no longer broadly recites merely "preventing infection" in the abstract. Rather, claim 18 expressly recites that the infection is inhibited by inhibiting binding between a spike protein of SARS-Co V-2 and ACE2 on human cells. Thus, the claimed method is tied to the ACE2-mediated viral-entry mechanism disclosed in the specification.
In response: Applicant’s argument that the amendment to claim 18 limits “inhibition” to “inhibiting binding between a spike protein of SARS-CoV-2 and ACE2 on cells of human (interpreted as cells of the healthy person)” is persuasive. However, it is noted that this amendment is not sufficient to overcome the rejection of the claims under 112(a) over the enablement requirement, which, as set forth in the rejection above, goes beyond the mere mechanism of inhibition. First, although the manner of “inhibition” is now defined in the claim, claim 18 further requires “inhibiting an infection of a healthy person.” The phrase “inhibiting an infection” is not defined in the claim or the specification, and is broader in scope than the mere mechanism of inhibition. Second, in the absence of a definition in the specification, “inhibition” in the context of “inhibiting an infection of a healthy person” in line 1 of claim 18 is interpreted as a synonym for “preventing an infection of a healthy person”; thus, although the amendment to claim 18 does narrow the claim, it is not sufficient to overcome the enablement requirement.
RE: Rejection under 35 U.S.C. § 112(a)
Applicant argues: As amended, independent claim 18 is directed to a method for inhibiting infection of a healthy person with SARS-CoV-2, wherein the inhibition is achieved by inhibiting binding between a spike protein of SARS-CoV-2 and ACE2 on human cells. Thus, the claim is not directed broadly to every possible method of preventing SARS-CoV-2 infection. Rather, the claim is directed to a specific ACE2-mediated decoy mechanism: inhibiting interaction between the SARS-CoV-2 spike protein and ACE2 on human cells.
The specification provides detailed support for this mechanism. The specification explains that SARS-CoV-2 binds to ACE2 on human cells through its spike protein, and that such binding is required for viral entry. The specification further explains that ACE2-containing microparticles, including exosomes, bind the virus and inhibit binding, entry, or fusion into ACE2-expressing cells. See, e.g., paragraphs [0041]-[0043]. The specification therefore expressly links the disclosed ACE2-containing compositions to the claimed functional result.
The working examples also directly support the claimed mechanism. Example 1 describes preparation of a culture supernatant of dental pulp-derived stem cells. Paragraphs [0057]-[0061] describe evaluation of inhibition of spike-ACE2 binding using a SARS-CoV-2 Spike-ACE2 binding assay, and the results show that the dental pulp-derived stem cell culture supernatant inhibited spike-ACE2 binding. Example 11 describes preparation of exosomes from the dental pulp-derived stem cell culture supernatant. Paragraphs [0063]-[0064] show that the dental pulpderived stem cell exosomes inhibited spike-ACE2 binding, with a binding inhibition rate of 40.8%, and that the inhibition rate increased when the amount of dental pulp-derived stem cell EVs was increased. Paragraphs [0069]-[0073] further show that the exosomes contained ACE2 and had ACE2 activity. These examples are directly aligned with the amended claim language.
The Examiner appears to require in vivo or human clinical data showing actual prevention of infection. However, § l 12(a) does not require clinical proof of efficacy. The enablement inquiry is whether the specification teaches a person of ordinary skill in the art to make and use the claimed
invention without undue experimentation, not whether the specification conclusively proves clinical success. Here, the specification teaches how to prepare the claimed culture supernatants, how to prepare exosomes from those supernatants, how to confirm ACE2 expression and activity, and how to evaluate inhibition of SARS-CoV-2 spike-ACE2 binding. The specification also identifies routes, timing, and conditions of administration. See, e.g., paragraphs [0051]-[0052].
In response: Applicant’s arguments have been fully considered, but are not persuasive. The amendment to claim 18 now limits the mechanism of inhibiting infection to inhibiting binding between a spike protein of SARS-CoV-2 and ACE2 on cells of human (interpreted as cells of the healthy person). However, as set forth in the body of the rejection above, this does not overcome the grounds of rejection under 35 U.S.C. § 112(a) regarding the enablement requirement. As set forth in the rejection, there are other outstanding issues of enablement including, but not limited to, cross-species administration and route of administration, as well as more broadly, the use of the method to inhibit SARS-CoV-2 infection in a healthy person. The in-vitro examples provided in the Specification do not provide guidance regarding these issues. Although the enablement requirement does not require clinical proof of efficacy, in the present instance, the disclosure, in light of the teachings of the prior art, does not enable a person of ordinary skill in the art to make and use the claimed invention without undue experimentation.
Applicant argues: Consideration of the Wands factors supports enablement. (Remarks, pages 8-10).
In response: Applicant’s arguments have been fully considered, but are not persuasive for the reasons set forth in the body of the rejection above.
RE: Affidavit or Declaration Under 37 CFR 1.132 and arguments thereto
The Declaration under 37 CFR 1.132 filed 05/11/2026 is insufficient to overcome the rejection of claims 18-19, 21-27, and 29 under 35 U.S.C. 112(a) based upon lack of enablement as set forth in the last Office Action because the Declaration consists of arguments, rather than objective evidence. Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Furthermore, although an affidavit or declaration which states only conclusions may have some probative value, such an affidavit or declaration may have little weight when considered in light of all the evidence of record in the application. In re Brandstadter, 484 F.2d 1395, 179 USPQ 286 (CCPA 1973). See MPEP § 716.01(C). In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of enablement fails to outweigh the evidence of non enablement.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RISA TAKENAKA/Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632
