DETAILED ACTION
Applicant’s arguments and amendments filed on 12/29/2025 have been entered.
Claims 1, 5 and 7 have been amended.
Claims 2-4 have been cancelled and the limitations of cancelled claim 4 have been incorporated into the method of claim 1. Accordingly, a new 103 rejection is set forth to address amended claim 1.
In view of Applicant’s arguments and amendments, the scope of enablement, 112(b), 102 and ODP rejections are withdrawn.
Claims 1, 5 and 7 are examined in the instant application.
Withdrawn Objections/Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections or rejections not specifically reiterated are hereby withdrawn.
THIS ACTION IS NON-FINAL
Claim Rejections - 35 USC § 103 – New Grounds of Rejections
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, 5, and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Feral et al (WO 2019211285 A1, 4/30/2019; Published 11/07/2019) in view of Chang et al (KR 101860266B1 [KR 20180003999], 26 June 2017; published 24 May 2018; Ref. 1 of Foreign Patent Documents in IDS filed 10/13/2022; of record).
Regarding claim 1, Feral teaches a method for treating skin afflictions in a subject comprising a step of administering to said subject a therapeutically effective amount of small extracellular vesicles derived from dermal fibroblasts, wherein the sEVs are exosomes (claims 1 and 2 of Feral).
Feral continues to teach that the skin affliction refers to any of a number of skin ailments and infections that afflict the skin surface or deeper skin tissue, including skin disorders related to diabetes such as diabetic dermopathy (Detailed description, para 4).
Regarding claim 1 and 7, Feral teaches that the sEVs as obtained can be injected at the wound margin to increase the process of the wound healing and otherwise physically delivering a substance as it exists outside the body (e.g., sEVs containing CD98hc) into the subject, such as by mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery and/or any other method of physical delivery (p. 7, lines 7-14).
Feral does not teach:
that the exosomes are derived from thrombin-treated mesenchymal stem cells, and
that the mesenchymal stem cells are derived from cord blood.
(i) and (ii) Regarding exosomes derived from thrombin-treated cord blood mesenchymal stem cells, Chang teaches a pharmaceutical composition for treating skin wounds containing an exosome derived from thrombin-treated stem cells as an active ingredient (abstract; claim 1 of Chang).
Chang continues to teach that the stem cell is a stem cell selected from the group consisting of mesenchymal stem cells, human tissue-derived mesenchymal stromal cells, human tissue-derived mesenchymal stem cells and multipotential stem cell (see claim 2 of Chang) and that the mesenchymal stem cells are derived from cord, umbilical cord blood (see claim 3 of Chang). The reference also describes a method for treating skin wounds, comprising administering to an individual an exosome derived from a thrombin-treated stem cell and discusses the composition can be used for effective wound healing, particularly in those with issues with chronic wounds like diabetic patients (para 4 of Description).
Chang continues to teach that the damaged healing process can often be associated with diabetic complications, including severe limb amputation and even death (para 5 of Technical field). Approximately, 15% of diabetic patients suffer from chronic wounds that cannot be cured (same para).
Chang continues to teach that exosomes derived from stem cells, particularly exosome derived from stem cells treated with thrombin significantly increased the angiogenesis and skin wound healing effects of the exosomes (Description, para 14). The skin wound is treated by angiogenesis due to promotion of vascular endothelial cell growth. The exosome administration is characterized in that expression of a growth factor, an immunoregulatory factor, an antioxidant factor or an angiogenic factor is increased.
Chang continues to teach that the exosomes obtained in the thrombin-treated stem cells of the present invention exhibited significantly improved angiogenesis compared to the exosomes obtained in the non-thrombin-treated group (para 2 of Example 2-2). In addition, the exosomes obtained from fibroblast did not exhibit angiogenesis ability regardless of whether thrombin treatment was performed or not (same para). It was confirmed by the thrombin treatment that the exosome obtained in Example 1-1 was increased in expression of anti-inflammatory cytokines such as growth factor and IL-6 (Example 1-2, para 1). As shown in FIG. 3, it was confirmed that thrombin treatment induced brain-derived neurotropic factor (BDNF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), nerve growth factor (NGF) endothelial growth factor and IL-6 (Interleukin-6) expression increase in comparison with the control exosome, indicating that thrombin treatment enhances cell regeneration, vascular regeneration, and anti-inflammatory effects of stem-cell derived exosomes (Example 1-2, para 4).
Regarding claim 5, Chang teaches that the pharmaceutical composition further comprises a component selected from the group consisting of a culture medium, a cytokine, a growth factor and a gene (see claim 5 of Chang).
Regarding claim 7, Chang teaches that the agent is an injectable, an injection, a spray, a liquid or a patch (see claim 9 of Chang).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to treat skin diseases such as diabetic dermopathy via local administration of exosomes as taught by Feral, where the exosomes are derived from thrombin-treated cord blood mesenchymal stem cells as taught by Chang, to arrive at the instantly claimed invention. One of ordinary skill would have been motivated to simply substitute one known element (fibroblast-derived exosomes of Feral) for another (thrombin-treated MSC derived exosomes of Chang) with a reasonable expectation of advantageously significantly increasing the angiogenesis and skin wound healing effects as taught by Chang. One of ordinary skill, prior to the effective filing date, would have a reasonable expectation of success that the use of the exosomes of Chang would improve the method of Feral given that Chang teaches that thrombin-treated MSC-derived exosomes showed significantly improved angiogenesis, enhanced cell regeneration, vascular regeneration, and anti-inflammatory effects compared to fibroblast-derived exosomes.
Response to Arguments
Applicant’s arguments have been fully considered but are not persuasive.
On p. 10-15 of Remarks, Applicant argues in sum that while Chang describes exosomes derived from cord blood thrombin treated MSCs to treat skin wounds and a skin wound animal model, Chang does not teach the use of these exosomes for diabetic dermopathy. Applicant argues that the instant specification describes diabetic animal models treated with exosomes derived from cord blood thrombin treated MSCs and therapeutic effect manifested within 5 days (Fig. 4 of instant application). Applicant argues that the pathological and therapeutic mechanisms of ordinary wounds are different from diabetic dermopathy and that the exosomes of the instant claims exhibit both general wound healing efficacy and “superior therapeutic effects in diabetic dermopathy by supplying and modulating growth factors, promoting angiogenesis, activating fibroblasts to produce extracellular matrix, and exerting anti-inflammatory activity.” Applicant argues that the Office action does not provide clear and convincing evidence that locally administered exosomes, such as those instantly claimed, will necessarily lead to therapeutically effective treatment of diabetic dermopathy and be recognized by one of ordinary skill in the art. Applicant argues that Chang, at best, merely suggests use of these exosomes in healing those with chronic wounds.
While these arguments have been fully considered, they are not persuasive. First, newly cited reference Feral teaches that exosomes can be administered to treat a variety of skin afflictions, including diabetic dermopathy. While it does not teach that the exosomes are derived from mesenchymal stem cells,
Chang states (as recited above) exosomes obtained in the thrombin-treated stem cells of the present invention exhibited significantly improved angiogenesis compared to the exosomes obtained in the non-thrombin-treated group (para 2 of Example 2-2) and the exosomes obtained from fibroblast did not exhibit angiogenesis ability regardless of whether thrombin treatment was performed. "A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (see MPEP § 716.02(a)).
As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, does the prior art already contemplate or recognize Applicant’s purported unexpected effects of “supplying and modulating growth factors, promoting angiogenesis, activating fibroblasts to produce extracellular matrix, and exerting anti-inflammatory activity” as argued? Chang teaches that the thrombin treated MSC-derived exosomes increased expression of anti-inflammatory cytokines such as growth factor and IL-6 (Example 1-2, para 1). As shown in FIG. 3 of Chang, it was confirmed that thrombin treatment induced brain-derived neurotropic factor (BDNF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), nerve growth factor (NGF) endothelial growth factor and IL-6 (Interleukin-6) expression increase in comparison with the control exosome, indicating that thrombin treatment enhances cell regeneration, vascular regeneration, and anti-inflammatory effects of stem-cell derived exosomes. Moreover, even if Chang did not disclose these properties of thrombin treated MSC-derived exosomes, Applicant concedes that the exosomes of Chang are the same as the instant exosomes (“Chang . . . discloses pharmaceutical compositions including exosomes derived from cord blood thrombin treated MSCs for the treatment of skin wounds”; p. 11, para 2 of Remarks). As per MPEP 2112.01(II), “‘Products of identical chemical composition cannot have mutually exclusive properties.’ In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.” Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) (MPEP 2112.01(I)).
All of the teachings of Feral and Chang, both in their individual capacity and in combination, would impart to one of ordinary skill in the art before the effective filing date of the instant invention that: 1) exosomes derived from fibroblasts can be used to treat skin diseases, including those associated with diabetes like diabetic dermopathy, and 2) exosomes derived from thrombin treated mesenchymal stem cells are an improvement to exosomes derived from fibroblasts. Thus, Applicant’s arguments are not persuasive.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 5, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5 of U.S. Patent No. 12,239,695 B2 in view of Feral et al (WO 2019211285 A1, 4/30/2019; Published 11/07/2019).
Regarding claim 1, claim 1 of the ‘695 patent recites “A method of treating skin wound, comprising: administering to a subject in need thereof an effective amount of exosomes derived from thrombin-treated stem cells,” claim 2 recites “wherein the stem cells are selected from the group consisting of mesenchymal stem cells, human tissue-derived mesenchymal stromal cells, human tissue-derived mesenchymal stem cells and multipotent stem cells”, and claim 3 recite “wherein the mesenchymal stem cells are derived from . . . , umbilical cord blood”.
Regarding claim 5, claim 5 of the ‘695 patent recites “a supplementary ingredient selected from group consisting of a culture medium, a cytokine, a growth factor and a gene.”
The ‘695 patent does not teach that the exosomes are used to treat diabetic dermopathy.
However, Feral teaches a method for treating skin afflictions in a subject comprising a step of administering to said subject a therapeutically effective amount of small extracellular vesicles derived from dermal fibroblasts, wherein the sEVs are exosomes (claims 1 and 2 of Feral).
Feral continues to teach that the skin affliction refers to any of a number of skin ailments and infections that afflict the skin surface or deeper skin tissue, including skin disorders related to diabetes such as diabetic dermopathy (Detailed description, para 4).
Regarding 7, Feral teaches that the sEVs as obtained can be injected at the wound margin to increase the process of the wound healing and otherwise physically delivering a substance as it exists outside the body (e.g., sEVs containing CD98hc) into the subject, such as by mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery and/or any other method of physical delivery (p. 7, lines 7-14).
Thus, the instant claims are obvious variants of the method claim of the ‘695 patent in view of Feral given that Feral teaches that exosomes can be used to treat diabetic dermopathy.
Conclusion
No claim is allowed.
THIS ACTION IS NON-FINAL.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN C REGLAS whose telephone number is (571)270-0320. The examiner can normally be reached M-F 9-5.
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 Jr 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.
/DAVID A MONTANARI/Examiner, Art Unit 1632
/G.R./Examiner, Art Unit 1632
Prosecution Insights