DETAILED ACTION
This action is in reply to papers filed 12/09/25 and 12/15/25 and IDS filed 01/15/26 and 11/25/25. Claims 18-19 and 21-19 are pending and examined herein.
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 .
Election/Restrictions
Applicant previously elected without traverse Group I, drawn to claims 18-29. Claims 30-31 are withdrawn from further consideration as being drawn to a non-elected invention.
Withdrawn Objections and Rejections
The objections to claims 18, 25 and 27-28 are withdrawn in light of the amendment to the claims.
The rejections of claims 18 and 26 under 35 U.S.C. 112(b) are withdrawn in light of the amendment to the claims.
The rejection of claim 21 under 35 U.S.C. 112(d) is withdrawn in light of the amendment to independent claim 18, which now recites “produced by a culture supernatant” (line 11) instead of the previous “derived from a culture supernatant.” The limitation “produced by,” as recited in amended claim 18, differs from the limitation “purified from” in line 2 of claim 21, and thus the amendment effectively differentiates dependent claim 21 from independent claim 18.
The cancellation of claim 20 and renders any rejections thereof moot.
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 preventing infection of a healthy person, wherein the method comprises administrating 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(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 28 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This is a new rejection, which is necessitated by the amendment to independent claim 18.
Claim 18, as amended, is drawn to a method for preventing infection of a healthy person with SARS-CoV-2. SARS-CoV-2 is the coronavirus that causes COVID-19 (see para. 2 of PgPub), and therefore, the limitation of “wherein the infection is COVID-19” in claim 28 does not further limit the subject matter of independent claim 18. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 and 21-29 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 and 21-29 are directed to a method of preventing infection of a healthy person with SARS-CoV-2.
Regarding “preventing infection”: This phrase is not defined in the specification. The broadest reasonable interpretation of “preventing 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: The claims do 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 preventing 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 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 prevent 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 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 preventing 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 preventing 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 preventing 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 prevent 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 and 21-29 are not enabled.
Response to Arguments
Rejection under 35 U.S.C. § 112(a)
Applicant argues: The specification provides extensive disclosure enabling the amended claim. It contains detailed working examples showing inhibition of SARS-CoV-2 spike protein binding to ACE2 using both culture supernatants of dental pulp-derived stem cells and purified exosomes derived from those supernatants. Examples 1 and 11, along with the associated assay description at paragraphs [0055] through [0064], provide explicit experimental evidence that dental pulp- derived stem cell supernatants and exosomes inhibit SARS-CoV-2 spike-ACE2 binding, with exosomes exhibiting inhibition rates exceeding 40 percent, as shown in Figure 2. The specification further explains that exosomes derived from these stem cells express and contain ACE2, as discussed in paragraphs [0016], [0017], and [0018], and thus function as decoys that bind SARS-CoV-2 and prevent viral entry into cells, as further described in paragraphs [0041] and [0042]. The amended claim is now limited precisely to this experimentally confirmed embodiment.
In response: Applicant’s arguments have been fully considered, but are not found persuasive. As set forth above in the rejection under 35 U.S.C. 112(a), the examples in the specification are limited to in vitro assays, whereas the claims are drawn to an in vivo method of preventing infection of a healthy person with SARS-CoV-2. Therefore, although the previous concerns regarding the type of virus (now limited to SARS-CoV-2) and species of subject (now limited to human) are rendered moot in light of the amendments to claim 18, the specification still does not enable the method of claim 18 as claimed.
Applicant further argues: The Examiner's prior concerns regarding excessive breadth and unpredictability are no longer applicable. The original claims encompassed numerous ACE2-using viruses, various human and nonhuman animals, multiple stem cell types, cross-species administration, and heterogeneous extracellular vesicle populations. The amended claim no longer includes any of these broad elements. SARS-CoV-2 is the only virus recited, human subjects are the only permitted recipients, the stem-cell source is narrowed to dental pulp-derived cells (with which all key experimental data were obtained), and the vesicles are limited to exosomes, the specific microparticle species repeatedly characterized in the specification. The specification describes the preparation of culture supernatants of dental pulp-derived stem cells in detail, including culture conditions, serum removal, and screening steps at paragraphs [0021] through [0032]. It also provides detailed procedures for isolating exosomes from such supernatants through centrifugation and filtration, including methodological parameters at paragraph [0033]. These teachings allow a skilled artisan to make the precise composition required by the amended claim without undue experimentation.
In response: Applicant’s arguments have been fully considered, but are not found persuasive. As set forth above in the rejection under 35 U.S.C. 112(a), the examples in the specification are limited to in vitro assays. Undue experimentation is required to carry out the method of claim 18, which is drawn to an in vivo method of preventing infection of a healthy person with SARS-CoV-2. Furthermore, the concern regarding cross-species administration still remains in amended claim 18, as claim 18 does not require that the dental pulp-derived stem cells in the composition are derived from a human.
Applicant further argues: The specification also offers substantial guidance for using the claimed compositions in humans. Paragraphs [0040] through [0043] describe the meaning of a "healthy person," the mechanism by which SARS-CoV-2 infects cells through ACE2, and how exosomes containing ACE2 can block or reduce infection. Paragraphs [0051] and [0052] describe permissible routes, timing, and conditions of administration to humans, including inhalation, spray, and injection, all of which are routine for those skilled in the art. The level of detail provided across these passages is more than sufficient to enable the claimed method.
In response: Applicant’s arguments have been fully considered, but are not found persuasive. As set forth above in the rejection under 35 U.S.C. 112(a), although the specification does describe modes of administration to humans (e.g., para 51-53), these paragraphs merely describe how a composition may be administered, not how the administration of said composition results in the claimed effect of preventing infection of a healthy person with SARS-CoV-2.
Applicant further argues: Considering the Wands factors, the amended claim is narrow, highly predictable, and directly supported by working examples. The quantity of experimentation required is minimal because all critical elements-how to obtain dental pulp-derived stem cell supernatants, how to isolate exosomes, how to measure ACE2 concentrations, how to evaluate SARS-CoV-2 spike binding inhibition, and how to administer the composition to humans-are fully described in the specification. The state of the art at the time of filing included well-established methods for culturing dental pulp-derived stem cells, producing exosomes, and conducting spike-ACE2 binding assays. A person of ordinary skill, equipped with the detailed methods disclosed in paragraphs [0055] through [0064] and the supporting biological mechanisms in paragraphs [0041] and [0042], would have been able to make and use the claimed invention without undue experimentation.
In response: Applicant’s arguments have been fully considered, but are not found persuasive. As set forth above in the rejection under 35 U.S.C. 112(a) and in the preceding responses to arguments, the specification fails enable a method for preventing infection of a healthy person with SARS-CoV-2 by administering the composition as recited in claim 18. Although the specification discloses how to obtain dental pulp-derived stem cell supernatants, how to isolate exosomes, how to measure ACE2 concentrations, how to evaluate SARS-CoV-2 spike binding inhibition, and potential modes of administration, it does not disclose how administration of said composition results in the claimed effect of preventing infection of a healthy person with SARS-CoV-2. Therefore, there is a high level of unpredictability and undue experimentation required to carry out the method as claimed.
Conclusion
THIS ACTION IS MADE FINAL. 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 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
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632