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 .
DETAILED ACTION
This action is in response to the papers filed on February 24, 2026. Pursuant to the amendment filed February 24, 2026, claims 1-4, 10, and 45 are amended. Claims 6-8, 63-65, 68-70, 73, 91, and 92 have been canceled. Claim 1 is an independent claim.
Election/Restrictions
Applicant’s election without traverse of Group V, claims 1-8, 10, 11, 13, 36-38, 41-45, drawn to a method of treating any oral disease (or injury), presumably in a subject in need thereof, by administering to the mouth of the subject, presumably as a composition, a therapeutically effective amount of a composition comprising fibroblasts, in the reply filed
on February 24, 2026, is acknowledged.
Since searches for the elected Group V rendered results for Groups I-XIII, the restriction requirement between Groups I-XIII is hereby withdrawn, and the Groups are rejoined with the elected group.
In addition, Applicants' election of the following species, without traverse is also
acknowledged:
A. A species of treated disease: inflammation
B. A species of soft tissues:
C. A species of protease regulation: up-regulation of proteases
D. A species of fibroblast enhancement period and technique: hypoxia enhanced before administration
E. A species of fibroblast protein/cytokine/factor which is induced: HIF-1
F. A species of Toll-like receptor: TLR-3
Upon further consideration, the species of treated disease, soft tissue, protease regulation, fibroblast enhancement, protein/cytokine/factor, and Toll-like receptor are rejoined and examined together.
In view of the above noted withdrawal of the restriction requirement between Groups I- XIII and species election requirement, applicants are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Therefore, claims 1-5, 10-11, 13, 36-38 and 41-45 are currently under examination.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/071296 filed August 27, 2021. Applicants' claim for the benefit of a prior-filed application parent provisional application 63/071,333, filed August 27, 2020, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is August 27, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on February 21, 2023, January 29, 2026, and February 24, 2026 is acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim interpretation
Independent claim 1 recites the methodological step of treating one or more oral medical conditions, comprising the step of administering a therapeutically effective amount of a composition comprising a fibroblast population to the oral cavity of the individual. Dependent claim 36 further recites where the fibroblast is exposed to a condition, such as low oxygen or hypoxia at any point. Claim 13 further recites an optional alternative step of selecting CD73 positive cell for the fibroblast population administered. Claim 43 recites a step of culturing in the presence of a ligand.
Thus, under the broadest reasonable interpretation, the operative steps required by the claims are the administration of a composition comprising fibroblast to the oral cavity where, at any point, the cells were exposed to the recited environmental conditions, and further when the fibroblasts are exposed to a ligand or inflammatory stimulus during culture. The recitation of various oral conditions defines the intended use or context of the treatment but does not impose structural or procedural limitations beyond requiring that the method be suitable for the recited condition. Any recited functional language or intended results do not impose additional methodological steps but instead describe the expected or intended outcome of the administration or results of the natural cellular response to the environment.
Examples of claim language, that may raise a question as to the limiting effect of the language in a claim are “whereby” clauses. The claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. The determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a “whereby” clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention.” Id. However, the court noted (quoting Minton v. Nat ’l Ass ’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. See M.P.E.P. § 2111.04.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 4-5, 10-11, 36-38, and 41-42 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Häkkinen et al. (Cytotherapy. 2014 Sep;16(9):1171-86. Epub 2014 Jun 13.), evidenced by Mettraux et al. (J Periodontol. 1984 Sep;55(9):516-21.), Mendes et al. (Clin Exp Dent Res. 2018 Dec 14;4(6):241-248. eCollection 2018 Dec.), and Ryter et al. (J Breath Res. 2013 Mar;7(1):017111. Epub 2013 Feb 27.).
Regarding claims 1-3, Häkkinen discloses therapeutic utility of fibroblast cellular compositions administered to the oral cavity to treat gingival, or soft tissue gum, tissue deficiencies (pg. 1179, column 2, para. 2).
Regarding claim 4-5, Häkkinen discloses gingival fibroblasts function in tissue defense against the oral biofilm building at the tooth-gingiva interface (pg. 1177, column 1, para. 2).
Regarding claim 10-11, Häkkinen discloses the wound-healing in both gingiva and other parts of the oral mucosa are accelerated by factors including molecules that promote wound healing, including growth factors, like secretory leukocyte protease inhibitor (pg. 1172, column 2, para. 2). Additionally, Häkkinen discloses gingival fibroblasts produce high levels of the metalloproteinase species of protease inhibitor (pg. 1177, column 1, para. 2).
Regarding claims 36-38 and 41-42, the diseased oral cavity inherently posses localized hypoxic conditions in the inflamed or pathological oral state, as evidenced by the disclosure of Mettraux and Mendes (Abstract). Mettraux and Mendes evidence that diseased periodontal tissues, including periodontal pockets and inflamed oral sites, exhibit reduced oxygen tension and form localized hypoxic environments due to bacterial activity, inflammation, and limited oxygen diffusion. Hence, when fibroblasts are delivered to such sites, exposure to hypoxia necessarily occurs as a natural consequence of the environment, and any resulting hypoxia-induced cellular responses represent inherent properties of the administered cells in that setting. Additionally, carbon monoxide is a naturally occurring endogenous molecule is present in vivo and is only required to be ‘provided’ or present, evidenced by Ryter (Abstract).
Where the only apparent distinction is a non-structural property presumed to be inherent, the examiner may rely on inherency to anticipate or render obvious the claimed invention, see MPEP 2112. Accordingly, absent evidence that the claimed fibroblast cells are structurally different from those taught in Häkkinen, and that such differences result in a materially different therapeutic outcome or function, the claimed subject matter is properly rejected under 35 U.S.C. § 102/103.
When the claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978). Thus, under MPEP § 2112.02, a newly discovered property of a known product or an unrecognized result of a known process does not render the claim patentable. Furthermore, when the prior art discloses the same process applied to the same cell type, any functional or biological properties of the resulting treated cell population are inherent to that process, See MPEP § 2112 and § 2112.01
The recognition of inherent properties does not confer novelty where the underlying treatment is the same as that disclosed in the prior art and all method steps are the same. Thus, because prior art discloses the same treatment with the same cells for of the same diseases, and because the dependent claim features merely recite inherent biological consequences of that treatment, the prior art teaching the operative steps of the method fully anticipates the claimed subject matter under 35 USC§ 102. “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1-5, 10-11, 13, 36-38 and 41-45 are rejected under 35 U.S.C. 103 as being unpatentable over Häkkinen et al. (Cytotherapy. 2014 Sep;16(9):1171-86. Epub 2014 Jun 13.), in view of Ramos-Junior et al. (J Periodontol. 2020 Feb;91(2):253-262. Epub 2019 Aug 12.), Hou et al. (Cell Transplant. 2003;12(7):787-97.), Mettraux et al. (J Periodontol. 1984 Sep;55(9):516-21.), and further in view of Mendes et al. (Clin Exp Dent Res. 2018 Dec 14;4(6):241-248. doi: 10.1002/cre2.135. eCollection 2018 Dec.), evidenced by Ryter et al. (J Breath Res. 2013 Mar;7(1):017111. Epub 2013 Feb 27.).
Regarding claims 1-3, Häkkinen teaches therapeutic utility of fibroblast cellular compositions administered to the oral cavity to treat gingival, or soft tissue gum, tissue deficiencies (pg. 1179, column 2, para. 2).
Regarding claim 4-5, Häkkinen teaches gingival fibroblasts function in tissue defense against the oral biofilm building at the tooth-gingiva interface (pg. 1177, column 1, para. 2).
Regarding claim 10-11, Häkkinen teaches the wound-healing in both gingiva and other parts of the oral mucosa are accelerated by factor including molecules that promote wound healing, including growth factors, like secretory leukocyte protease inhibitor (pg. 1172, column 2, para. 2). Additionally, Häkkinen discloses gingival fibroblasts produce high levels of the metalloproteinase species of protease inhibitor (pg. 1177, column 1, para. 2).
Regarding claim 13, Häkkinen teaches the selection of fibroblasts (pg. 1177, column 2, last para.) for the applicable method. Häkkinen does not explicitly teach wherein the said fibroblast population comprises CD73-positive fibroblasts.
However, Ramos-Junior teaches human gingival fibroblasts express functional CD73 and CD73 activity regulates inflammatory signaling and anti-inflammatory effects (Abstract; pg. 7, para. 4; pg. 9, first para.). Thus, once fibroblasts are administered to an oral tissue environment, downstream effects such as growth factor production, inflammatory modulation are a result of the biological properties of the natural cellular responses to that environment.
Therefore, before the effective filing date of the instant application, the ordinary artisan would have recognized fibroblast naturally express CD73 and it would have been obvious to utilize fibroblast populations comprising CD73+ cells, or select for such cells, for utility in the method of treatment, as taught by Häkkinen, with a reasonable expectation in treating an oral condition, such as inflammation. The person of ordinary skill in the art would have found motivation to select for such cells in view of Ramos-Junior’s teachings that CD73 activity enhances anti-inflammatory responses and contributed to improved tissue outcomes, and recognition of the benefit of reducing inflammation and improving regeneration in oral or periodontal therapy.
Regarding claims 36-37 and 41-45, the operative step is exposure of the fibroblast cells to conditions, including hypoxia or deficient oxygen levels at any point in the life if the cell (before, during, or after). The cellular responses recited are the natural responses of the cell induced by the environmental factor.
Hakkinen teaches fibroblast-based approaches for oral tissue repair but does not specifically teach the exposure of the fibroblast to hypoxic conditions.
However, Hou teaches administering fibroblasts directly to periodontal defects and other diseased oral tissues, including methods of treating periodontal defects by administering autologous gingival fibroblast cells to sites within the oral cavity, including periodontal osseous defects (Abstract). The fibroblasts are taught to be delivered to pathological oral environments associated with inflammation and tissue degradation, including diseased periodontal tissue, resulting in improved clinical outcomes and tissue regeneration (Fig. 3-7).
Furthermore, the ordinary artisan would have recognized where the fibroblast was delivered or administered to an oral environment specified to be pathophysiological (such as states consistent with tooth loss, tooth decay, tooth impaction, gum disease, periodontitis, abscess, mouth ulcer, cold sore, rash, inflammation, leukoplakia, halitosis, infection, microbiome dysbiosis, bacterial microfilm, cancer) localized hypoxic microenvironments arise and periodontal pockets were known to be hypoxic environments, further in view of the teachings of Mettraux and Mendes.
Mettraux teaches that periodontal pockets associated with periodontal disease constitute anaerobic and low oxygen level environments, characterized by reduced oxygen tension due to bacterial biofilms, inflammation, and limited oxygen diffusion (Abstract; pg. 516, column 1, para. 1; Table 4-5).
Mendes further teaches that inflamed and diseased oral tissues, including periodontal lesion, exhibit reduced oxygen availability and hypoxia-driven biological responses (Abstract). Mendes teaches that inflamed periodontal tissues exhibit hypoxia as a result of inflammation and microbial activity, which leads to altered cellular responses and tissue remodeling. Mendes teaches that hypoxic conditions arise in periodontal lesions due to increased metabolic demand, vascular disruption, and bacterial biofilm formation (pg. 242, column 1, para. 2; pg. 246, column 2, para. 2-3). Moreover, Mendes demonstrates natural cellular responses to the hypoxic environment, such as HIF isoform induction and increases in VEGF (pg. 247, column 1, para. 1; pg. 244, column 2, para. 1; pg. 246, column 2, last para.).
Hence, before the effective filing date of the instant application, the ordinary artisan would have understood that fibroblasts administered to diseased oral sites, such as periodontal defects and inflamed tissues, would implicitly be placed into environments characterized by reduced oxygen tension or levels. Since, hypoxia was a recognized condition of such pathological oral environments, the ordinary artisan would have reasonably expected that the administered fibroblasts would be subjected to hypoxic conditions and would respond with well-established natural cellular mechanisms associated with and induced by low oxygen levels. The recited exposure of fibroblasts and the resulting inherent cellular responses to hypoxia, and the resulting cellular responses are natural and predictable results of administering fibroblasts to known hypoxic oral environments.
Regarding claim 38, the combined teachings of Häkkinen, Hou, Mettraux, and Mendes render claims 1, 36, and 37 obvious.
Additionally, the claim merely recites carbon monoxide is provided. Animals produce and exhale carbon monoxide so the ordinary artisan would expect carbon monoxide to be ‘provided.’ The Ryter disclosure evidence that carbon monoxide (CO), a low molecular weight gas, is a ubiquitous environmental product of organic combustion, which is also produced endogenously in the body and exhaled (Title; Abstract).
***
Claims 43-45 are rejected under 35 U.S.C. 103 as being unpatentable over Häkkinen et al. (Cytotherapy. 2014 Sep;16(9):1171-86. Epub 2014 Jun 13.), in view of Hou et al. (Cell Transplant. 2003;12(7):787-97.), Mettraux et al. (J Periodontol. 1984 Sep;55(9):516-21.), Mendes et al. (Clin Exp Dent Res. 2018 Dec 14;4(6):241-248. doi: 10.1002/cre2.135. eCollection 2018 Dec.), evidenced by Ryter et al. (J Breath Res. 2013 Mar;7(1):017111. Epub 2013 Feb 27.), and further in view of Mahanonda et al. (J Immunol. 2007 Jan 15;178(2):1151-7.).
The combined teachings of Häkkinen, Hou, Mettraux, and Mendes, are applied as above in the 102/103, the content of which are incorporated herein rendering obvious the limitations of claims 1 and 36.
Regarding claims 43-45, the combined teachings of Häkkinen, Hou, Mettraux, and Mendes render claims 1 and 36 obvious. Häkkinen teaches the culturing of fibroblast and the cells’ responsiveness to inflammatory signaling molecules (pg. 1177, column 1, para. 2 through column 2, para. 2). The combined teachings of Häkkinen, Hou, Mettraux, and Mendes do not specifically teach the species of Toll-like receptor (TLR) agonist.
However, Mahanonda teaches human gingival fibroblasts express multiple Toll-like receptors, including TLR1 and TLR9, and directly responds to stimulation with known TLR agonists such as LPS (TLR2/4), poly(I:C) (TLR3), and flagellin (TLR5). Mahanonda teaches stimulation of fibroblasts with these TLR ligands induces expression of IL-8 and IDO, which are key modulators of inflammatory and immune responses in periodontal tissue (Abstract; pg. 1151, column 1, para. 1-2).
Hence, the ordinary artisan would have recognized that exposing fibroblasts to TLR agonists prior to administration would have been a predictable method of modulating or preconditioning the cells to influence their therapeutic activity. In view of Häkkinen and Hou teaching fibroblast-based treatment of diseased oral tissues, and Mahanonda teaching that gingival fibroblasts directly respond to known TLR agonists with predictable modulation of inflammatory and immunoregulatory pathways, a person of ordinary skill in the art would have found it obvious to culture or expose fibroblasts to TLR agonists prior to administration to enhance or optimize their therapeutic activity, with a reasonable expectation of success.
Conclusion
Claims 1-5, 10-11, 13, 36-38 and 41-45 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOEL D LEVIN whose telephone number is (571)270-0616. The examiner be reached 8:00 am to 5:00 pm, Monday through Friday.
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, Christopher Babic can be reached at (571) 272-8507. 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.
/J.D.L./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
Prosecution Insights