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 .
Election/Restriction
Applicant’s election without traverse of Group III (claims 1-5 and 7) in the reply filed on 8/26/2025 is acknowledged.
Claims 8-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as
being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was
made without traverse in the reply filed on 8/26/2025.
Accordingly, claims 1-5 and 7-12 are pending and claims 1-5 and 7 have been examined herein.
Priority
The instant claims herein are examined utilizing the accepted effective filing date of 4/14/2020 for the basis of any prior art rejections.
Claim Objections
Claim 7 is objected to because of the following informalities:
Claim 7 recites, inter alia, “wherein the formulation of the composition is an injectable type, an infusion type, a spray type, a liquid type, or a patch type.” The examiner suggests amending the claim to remove “type” to make the claim grammatically correct.
Appropriate correction is required.
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 1-5 and 7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating an diabetic dermopathy in a diabetic subject comprising administering a pharmaceutical composition comprising thrombin-treated human umbilical cord blood mesenchymal stem cell-derived exosomes, does not reasonably provide enablement for (1) preventing any diabetic skin diseases using any stem cells or (2) treating diabetic skin disease or other acute wounds, with stem cell-derived exosomes other than umbilical cord blood mesenchymal stem cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considered whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirement, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d at 737, 8 USPQ2d 1400, 1404 (Fed. Cir.1988)).
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore, skepticism raised in the enablement rejection are those raised in the art by artisans of expertise.
Claims 1-5 and 7 are directed to a method of preventing or treating a diabetic skin disease comprising: administering a pharmaceutical composition comprising thrombin-treated stem cell- derived exosomes as an active ingredient to an individual. Claim 2 specifies that 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, pluripotent stem cells, and amniotic epithelial cells. Claim 3 specifies the mesenchymal stem cells are derived from the umbilical cord, cord blood, bone marrow, fat, muscle, skin, the amniotic membrane or placenta. Claim 4 specifies that the diabetic skin disease is selected from the group consisting of diabetic ulcers, eruptive xanthomatosis, cutaneous infection, diabetic dermopathy, skin fibroma, acanthosis nigricans, pruritus, scleredema diabeticorum, and granuloma annulare. Claim 5 specifies that the composition further comprising an auxiliary component selected from the group consisting of a culture medium, a cytokine, a growth factor, and a gene. Claim 7 specifies that the formulation of the composition is an injectable type, an infusion type, a spray type, a liquid type, or a patch type.
Nature of the invention:
A method of preventing or treating a diabetic skin disease comprising: administering a pharmaceutical composition comprising thrombin-treated stem cell- derived exosomes as an active ingredient to an individual.
The state of the prior art:
The state of the prior art for preventing any diabetic skin diseases using any stem cell-derived exosomes or (2) treating any diabetic skin diseases with any stem cell-derived exosomes was unpredictable before the effective filing date of the claimed invention. Administering various stem cell-derived exosomes via various administration routes was unpredictable before the effective filing date of the claimed invention.
The breadth of the claims:
The claims encompass using various thrombin-treated stem cell derived exosomes via various administration routes to treat or prevent various diabetic skin disorders in various individuals. Various diabetic skin disorders include diabetic dermopathy, diabetic ulcers, eruptive xanthomatosis, cutaneous infection, diabetic dermopathy, skin fibroma, acanthosis nigricans, pruritus, scleredema diabeticorum, granuloma annulare, etc. Various administration routes include direct injection, subcutaneous, intravenous, intramuscular, intrathecal, intraperitoneal, oral, topical, dermal, transdermal, inhalation, intranasal administration, etc. Various stem cell-derived exosomes include exosomes derived from various mesenchymal stem cells, induced pluripotent stem cells, embryonic stem cells, hematopoietic stem cells, neural stem cells, epithelial stem cells, etc.
The level of skill in the art:
The level of skill is high that requires a researcher with a PhD degree.
The working examples and guidance provided:
The specification discloses a working example in which human cord blood-derived mesenchymal stem cells where induced to secrete exosomes after treatment with thrombin (p. 16 of specification). The specification also discloses a working example which verified the therapeutic effect of the exosomes on diabetic dermatopathy. A diabetes-induced animal model was subjected to diabetic dermatopathy by making a wound with a certain size on its back. After making the wound, exosomes were directly applied to the lesion. The thrombin treated MSC-derived exosomes were able to treat the skin lesion and had a higher therapeutic effect not seen in exosomes not treated with thrombin (working example 2).
The specification fails to provide any working examples (in vitro, in vivo, or prophetic) in which any diabetic skin disorder embraced by the claims is prevented using any exosomes embraced by the claims of the instant method.
The specification fails to provide adequate guidance and evidence in which any other diabetic skin disorder (other than acute wound) is treated using the broad genus of exosomes embraced by the instantly claimed method (other than human umbilical cord mesenchymal stem cell derived exosomes).
The specification fails to provide adequate guidance and evidence for how to administer via various administration routes other than direct application to treat an acute wound in a diabetic subject.
The unpredictable nature of the art:
The specification defines “prevention” to include all actions of inhibiting a diabetic skin disease or delaying the onset thereof by administration of the pharmaceutical composition. However, there is no singular modality that can “prevent” any and all skin disorders in diabetics. Furthermore, no singular treatment modality can ameliorate symptoms of all skin disorders in diabetic subjects.
The American Diabetes Association (“Diabetes and Skin Complications”, accessed from the Internet 9/19/2025 from https://diabetes.org/about-diabetes/complications/skin-complications) teaches that there are several things to prevent skin problems such as keeping diabetes well managed, keep skin clean and dry, avoiding very hot baths and showers, preventing dry skin, treating cuts right away, keeping the home humid during colder months, seeing a dermatologist, and taking good care of feet (“Good skin care”). Diabetic dermopathy causes light brown, scaly patches that do not hurt, open up, or itch and are harmless and do not need to be treated. Necrobiosis lipoidica diabeticorum often starts as a dull, red, raised area (“Necrobiosis lipoidica diabeticorum”). After a while, it looks like a shiny scar with a violet border (same para). The blood vessels under the skin may become easier to see. Sometimes NLD is itchy and painful. Sometimes the spots crack open (same para). NLD is a rare condition and as long as the sores do not break open, you do not need to have it treated (same para). This shows that the art does not recognize ways to prevent diabetic skin disorders other than good hygiene practices.
Post-dated Wang et al (J Control Release. 12 Oct 2020; 329:894-906) states that although recent studies have demonstrated promising advances with exosome-based drug delivery systems, several challenges severely hinder further development of exosomes for clinical applications (abstract). Exosomes exhibit nonspecific biodistribution into unintended organs, including the liver, spleen, lung, kidneys, and pancreas and is a huge challenge for exosome-based drug delivery (p. 903, “Challenges . . . as a drug delivery carrier in vivo”, para 1). Developing exosomes as drug carriers for “non-conventional” therapeutic applications, e.g., transmucosal, conjunctival, ocular, cutaneous, pulmonary, delivery are rarely investigated. Challenges of developing drug delivery systems include understanding how exosomes can 1) penetrate physical barriers such as epithelial tight junctions in different tissues and 2) escape clearance by local tissue fluid and enzyme under physiological conditions (p. 903, “Challenges . . . as a drug delivery carrier in vivo”, para 3).
Post-dated Zhao et al (Biomed Pharmacother. 26 May 2020;128:110237) states that the technology of exosome production and quality control is flawed, the storage stability of exosome production are not clearly studied, and the specific functions of exosomes are not fully understood yet, so it is difficult to predict the long-term safety and efficacy of exosomes (p. 7, para 3).
Cheng et al (Stem Cells International, 19 Dec 2017; 2017:6305295) reports that exosomes are released in almost all types of extracellular fluids and exosomal content greatly depends on cellular origins. MSC-derived exosomes function largely via the constant transfer of miRNAs and proteins (more than 900 species), resulting in the alteration of a variety of activities in target cells via different pathways (p. 2, right column, lines 1-14). Cheng concludes that “while various clinical trials are underway to evaluate the safety and effectiveness of exosomes as therapeutic targets, many issues still remain . . . and how various loading and isolation strategies impact the potency of exosome-based drug delivery remain unanswered. Therefore, there is an urgent need to closely examine the following aspects of exosomes: (1) natural therapeutic potential; (2) biogenesis mechanism; and (3) circulation kinetics and biodistribution.
The extremely broad scope of the claims and lack of guidance in the specification exacerbates a
highly unpredictable art regarding using stem cell-derived exosomes to prevent or delay the onset of all diabetic skin disorders. While the results presented in the art do not necessarily preclude Applicant’s hypothesis, they certainly fail to support it in its totality that any thrombin-treated stem cell-derived exosomes can prevent or delay the onset of any and all diabetic skin disorders on its own. Applicants do not provide the details of how the “thrombin-treated stem cell-derived exosomes” as broadly claimed could be used to prevent diabetic skin disorder in subjects with diabetes, treat all diabetic skin disorders other than an acute wounds, nor is there a reduction to practice the instant method of preventing or delaying the onset of any and all diabetic skin disorders via various administration routes. It is noted that, though not controlling, the lack of working examples is a factor to be considered in a case involving both physiological activity and an underdeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, they run the risk that unless one of skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them (Ex parte Sudilosky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971)).
It has been established by legal decision that a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion. Tossing out the germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor or exemplified in the specification, reasonable detail must be provided in order to enable one of ordinary skill to understand and carry out the invention. It is true that a specification need not disclose what is well known in the art. However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph.
Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would not know how to practice the claimed invention and would require undue experimentation to practice over the full scope of the invention claimed.
The amount of experimentation necessary:
The specification only describes ameliorating an acute wound via direct application of human umbilical cord blood mesenchymal stem cell-derived exosomes that were treated with thrombin. One of ordinary skill in the art could not reasonably take these working examples and readily or immediately apply these exosomes in the claimed method to prevent diabetic skin disorders in any subject using any administration route as broadly embraced by the claims. These teachings do not reasonably support these exosomes as a potential preventative for any diabetic skin disorder and does not support these exosomes as a potential treatment (i.e., able to ameliorate symptoms only) other than an acute wound. One of ordinary skill in the art before the effective filing date of the claimed invention would be required to trial and error identify and select a “individual” from a broad genus of potential disease populations (both those with and without diabetic skin disorders), as well as from subpopulations of disease progression for treatment, preparation of various thrombin-treated stem cell-derived exosomes, administration of the various exosomes to various subjects via various administration routes, trial and error experimentation to determine whether sufficient exosomes reach the target sites in vivo, and trial and error experimentation to determine whether therapeutic effect can be provided to ameliorate various pathological symptoms of various diabetic skin disorders in vivo.
For the reasons set forth above, one skilled in the art before the effective filing date of the claimed invention would not be able to make and/or use the invention as claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of the art.
Claim Rejections - 35 USC § 112(b)
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.
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.
Claim 5 is 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 5 recites, inter alia, “further comprising an auxiliary component.” It is unclear what is meant by “an auxiliary component” particularly since the instant specification does not define what this means. Thus, the claim is indefinite.
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.
Claim(s) 1-3, 5, and 7 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by 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).
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).
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) (“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” as in instant claim 2). The mesenchymal stem cells are derived from cord, umbilical cord blood, bone marrow, fat, muscle, nerve, skin, amnion or placenta (see claim 3 of Chang) (“wherein the mesenchymal stem cells are derived from the umbilical cord, cord blood, bone marrow, fat, muscle, skin, the amniotic membrane or placenta” as in instant claim 3). The pharmaceutical composition further comprises an auxiliary component selected from the group consisting of a culture medium, a cytokine, a growth factor and a gene (see claim 5 of Chang) (“the composition further comprising an auxiliary component selected from the group consisting of a culture medium, a cytokine, a growth factor, and a gene” as in instant claim 5). The agent is an injectable, an injection, a spray, a liquid or a patch (see claim 9 of Chang) (“wherein the formulation of the composition is an injectable type, an infusion type, a spray type, a liquid type, or a patch type” as in instant claim 7). 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) (“a method of preventing or treating a diabetic skin disease comprising: administering a pharmaceutical composition comprising thrombin-treated stem cell-derived exosomes as an active ingredient to an individual” as in instant claim 1).
Thus, Chang anticipates the instant invention of claims 1-3, 5, and 7.
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 1-3 and 5 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. Although the claims at issue are not identical, they are not patentably distinct from each other because, if it were available as prior art, the ‘695 patent would anticipate the instant claims.
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,” which would anticipate “method of preventing or treating a diabetic skin disease comprising: administering a pharmaceutical composition comprising thrombin-treated stem cell- derived exosomes as an active ingredient to an individual” as in instant claim 1.
Claim 2 of ‘695 patent 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,” which would anticipate “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” as in instant claim 2.
Claim 3 of the ‘695 patent recites “wherein the mesenchymal stem cells are derived from umbilical cord, umbilical cord blood, bone marrow, fat, muscle, nerve, skin, amniotic membrane or placenta,” which would anticipate “wherein the mesenchymal stem cells are derived from the umbilical cord, cord blood, bone marrow, fat, muscle, skin, the amniotic membrane or placenta” as in instant claim 3.
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,” which would anticipate “the composition further comprising an auxiliary component selected from the group consisting of a culture medium, a cytokine, a growth factor, and a gene” as in instant claim 5.
Thus, the ‘695 patent would anticipate claims 1-3 and 5 of the instantly claimed invention and constitutes double patenting.
Conclusion
No claim is allowed.
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 7-3.
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.
/G.R./Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632