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 .
Claim Status
1. The amendment filed 02/26/2026 has been entered. Claims 1 – 8 and 11 – 13 remain pending and are under consideration. Claim 10 has been canceled.
Priority
2. This application is a National Stage filing under 35 U.S.C. § 371 of International Application No. PCT/US2021/024947, filed March 30, 2021, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Serial No. 63/002,274, filed on March 30, 2020.
3. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Provisional Application No. 63/002,274, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Provisional Application No. 63/002,274 fails to provide adequate support for “pyogenic disorder, Pyogenic Arthritis, Pyoderma gangrenosum and Acne (PAPA) recited in claim 1. Accordingly, claims 1 – 8 and 11 – 13, wherein the dependent claims require PAPA, are not entitled to the benefit of the prior application.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 02/26/2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
5. It is noted that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Withdrawn Claim Rejections
6. The rejection of claim 10 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 is rendered moot in view of Applicant’s cancellation of the claim.
7. The rejection of claims 1 – 8 and 11 – 13 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of Applicant’s amendment to claim 1 and arguments pointing out support for PAPA in the specification at page 18, line 9.
8. The rejection of claim 10 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancelation of the claim.
9. The rejection of claims 1, 2, and 7 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
10. The rejection of claims 3 – 6, 8, 11, and 13 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
11. The rejection of claim 12 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
Maintained Claim Rejections
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.
12. Claim 1 – 8 and 11 – 13 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 26 of copending Application No. 18120301 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by reference claim 26. Although maintained, note that the rejection is revised in light of the amendment to the claims.
Reference claim 26 of copending Application No. 18120301 recites a method of treating autoimmune disease, comprising administering to a subject having autoimmune disease an effective amount of ABCB5 positive dermal mesenchymal stem cells to treat the autoimmune disease, wherein ABCB5 positive dermal cells comprise at least 95% of the isolated preparation of ABCB5 positive dermal mesenchymal stem cells.
The instant specification states that PAPA is an auto-inflammatory disorder at page 18, lines 3 – 10 and as reference claim 26 broadly recites “autoimmune disease”, reference claim 26 anticipates instant claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
13. Claims 1 – 8 and 11 – 13 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22 – 24 of copending Application No. 18699716 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by reference claim 22. Although maintained, note that the rejection is revised in light of the amendment to the claims.
Reference claim 22 of copending Application No. 18699716 recites a method for treating a subject, comprising, administering to the subject a unit dose of a therapeutic cell solution, wherein the unit dose of a therapeutic cell solution is obtained from a device of claim 1 and claim 1 recites a device comprising a unit of use vial (1) comprising 10.4 x 106 ± 20% to 15.6 x 106 ABCB5+ stem cells per ml, wherein the unit of use vial (1) is a closed system cryogenic vial.
The instant specification states that PAPA is an auto-inflammatory disorder at page 18, lines 3 – 10 and as reference claim 22 broadly recites “treating a subject”, reference claim 22 anticipates instant claim 1.
This is a provisional nonstatutory double patenting rejection.
14. Claims 1 – 8 and 11 – 13 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11624054 to Frank (Frank ‘054). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by patent claim 1. Although maintained, note that the rejection is revised in light of the amendment to the claims.
Patent claim 1 of Frank recites a method, comprising administering to a subject an isolated preparation of ABCB5 positive immunomodulatory dermal mesenchymal stem cells in an effective amount to modulate immune molecule expression in cells of the subject, wherein ABCB5 positive dermal cells comprise at least 95% of the isolated preparation of ABCB5 positive immunomodulatory dermal mesenchymal stem cells.
The instant specification states that PAPA is an auto-inflammatory disorder at page 18, lines 3 – 10 and as reference claim 22 broadly recites “administering to a subject”, patent claim 1 anticipates instant claim 1.
Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
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.
15. Claims 1 – 8 and 11 – 13 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 for treating skin wounds in a subject with recessive dystrophic epidermolysis bullosa (RDEB) comprising systemically administering autologous, allogeneic, or xenogeneic dermal ABCB5+ mesenchymal stem cells in a dose of about 2 x 105 - 2 x 106 cells, does not reasonably provide enablement for treating any hyper-inflammatory disorder wherein the hyper-inflammatory disorder is pyogenic disorder Pyogenic Arthritis Pyoderma gangrenosum and Acne. 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 use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (a) the breadth of the claims, (b) the nature of the invention, (c) the state of the prior art, (d) the level or ordinary skill in the art, (e) the level of predictability in the art, (f) the amount of direction provided by the inventor, (g) the existence of working examples, and (h) the quantity of experimentation needed to make use of the invention based on the content of the disclosure. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
(a) The breadth of the claims: The claims broadly recite “treating” and “administering” and therefore the claims read on any outcome of any symptom of PAPA due to administering any dose of any of autologous, allogeneic, or xenogeneic ABCB5+ stem cells from any source (dermal or limbal) by any route. Consequently, the breadth of the claims is expansive.
It is noted that the instant rejection is based on absence of an enabling disclosure of treating PAPA by any route of administration of a composition of any source of ABCB5+ stem cells at any dose.
(b) The nature of the invention: The nature of the invention is treating a hyper-inflammatory disorder in a human subject by administering to the subject a composition comprising ABCB5+ stem cells (page 2, lines 20 – 32; page 18, lines 3 – 10).
(c) The state of the prior art:
Regarding PAPA, Cugno (Cugno, Massimo, et. al. American journal of clinical dermatology 18.4 (2017): 555-562.) teaches PAPA syndrome is a rare autosomal dominant disease that is characterized by aseptic inflammation of the skin and joints and painful, recurrent, sterile monoarticular arthritis with a prominent neutrophilic infiltrate may be the presenting sign of the disease and is associated with various mutations on chromosome 15q that affect the PSTPIP1 gene (page 556, right col. last para.; page 557, left col. para. 4; Table 1). Cugno teaches pyroderma gangrenosum (PG) in PAPA syndrome presents with single or multiple painful ulcers with violaceous, raised and undermined borders on the legs (page 557, left col. para. 2). Cugno teaches the inflammatory aspects of acne often predominate, but other dermatological manifestations described in the setting of PAP include psoriasis and rosacea (page 557, left col. para. 2). Cugno teaches increased amounts of IL-1beta and TNF-alpha have been found in PBMCs of patients with PAPA (page 557, left col. para. 3). Cugno teaches mutations in the PSTPIP1 gene of PAPA syndrome individuals may affect its function of phosphorylating proinflammatory molecules (page 557, left col. last para. and right col. para. 1).
Regarding treating PAPA syndrome, Cugno teaches given the rarity of PAPA syndrome, no randomized controlled clinical trials have yet investigated the efficacy of individual therapies (page 559, right col. para. 5). Cugno teaches medications targeting IL-1 and TNF-alpha are usually successful in managing the manifestations of PAPA syndrome with the most consistent responses observed with anti-TNF-alpha antagonists etanercept, adaliumumab, and infliximab (page 559, right col. last para.). Cugno teaches the response to anti-IL1 agent anakinra varies, but it seems to be more effective in managing joint manifestations than cutaneous disease (page 559, right col. last para.; page 560, left col. para. 1). Cugno teaches joint disease is responsive to corticosteroids but they may exacerbate acne (page 560, left col. para. 1). Cugno teaches topical and systemic retinoids have been shown to be effective in the management of the most severe forms of acne (page 560, left col. para. 1).
Regarding ABCB5+ cells, Schatton (Schatton, Tobias, et al. Cell reports 12.10 (2015): 1564-1574.) teaches human and murine skin contains ABCB5+ cells with mesenchymal stem cell phenotype (page 1565, right col. last para.; page 1566, left col. last para.; page 1572, right col. para. 2). Schatton teaches intravenous administration of syngeneic or allogeneic ABCB5+ dermal cells to mice and the cells inhibited alloantigen-dependent T cell proliferation in the mixed lymphocyte reactions in a dose-dependent manner and inhibited T cell proliferation in response to mitogens (page 1566, right col. last para.; page 1568, left col. para. 1). Schatton teaches intravenous administration of ABCB5+ cells prolongs cardiac survival in a cardiac allotransplantation model (page 1568, left col. para. 2).
Regarding ABCB5+ cells, Webber (Webber, Beau R., et al. Laboratory Investigation 97.10 (2017): 1218-1224) teaches transplantation of 5 x 105 human dermal ABCB5+ cells by injection into the facial vein of blistered mice as a treatment for RDEB (Abstract; page 1219, right col. para. 2 – 3). Webber teaches the mice transplanted with the cells survived longer than control mice (Figure 3b). Webber teaches ABCB5+ dermal mesenchymal stem cells ameliorated disease severity and suppression of innate immune responses in the mice mediated by macrophages appeared to potentially play a role (page 1223, left col. para. 2). Webber teaches ABCB5+ dermal mesenchymal stem cells are known to express PD-1; suppress T-cell proliferation; have the capacity to evade immune rejection; have capability to induce regulatory T cells; and have homing potential to localize to skin after systemic administration (page 1223, left col. last para. and right col. para. 1). Schatton teaches they were unable to document the presence of human ABCB5+ cells in the mice, which is consistent with the transient nature of transplanted MSCs and studies examining cell homing and localization will be necessary to maximize therapeutic outcome (page 1223, right col. para. 1). Schatton teaches it will be of interest to explore the therapeutic capacity of ABCB5+ cells in an immunocompetent setting (page 1223, right col. para. 1).
The state of the art teaches that PAPA syndrome patients have increased amounts of IL-1beta and TNF-alpha have been found in PBMCs. The state of the art teaches that treatment of the different symptoms of PAPA syndrome require different therapeutics and that treatment of one symptom can exacerbate another symptom. The state of the art teaches that intravenous administration of human dermal ABCB5+ mesenchymal stem cells can increase the survival of immunocompromised RDEB mice; however, the mechanism is unclear. The state of the art does not appear to provide any evidence as to the treatment of PAPA syndrome with ABCB5+ dermal mesenchymal stem cells, nor does the state of the art provide evidence that ABCB5+ dermal mesenchymal stem cells can decrease the levels of IL-1beta and/or TNF-alpha, which are found in PBMCs of PAPA syndrome patients.
(d) The level skill in the art:
The level of skill in the art of treating PAPA is high, as an artisan in this art needs specialized knowledge such as a postgraduate degree (Ph.D. and/or M.D.) given the complex nature of the immune system.
(e) The level of predictability in the art:
The use of ABCB5+ dermal MSCs for treating any or all symptoms of PAPA syndrome within the scope of the claim is not predictable because the prior art provides no evidence of treating PAPA syndrome with MSCs of any kind. Further, Cugno teaches the response to anti-IL1 agent anakinra varies, but it seems to be more effective in managing joint manifestations than cutaneous disease and Cugno teaches joint disease is responsive to corticosteroids but they may exacerbate acne. Webber teaches ABCB5+ dermal MSCs prolong survival in a mouse model of RDEB, but does not teach these cells reduce the levels of IL-1 or TNF-alpha. Thus, it is unpredictable whether ABCB5+ dermal MSCs used for RDEB can be used to treat PAPA syndrome even when the two conditions share symptoms of dermal wounds. The predictability of applying ABCB5+ dermal MSCs for treating any symptoms of PAPA syndrome encompassed by the instant claim would be low given that treating one symptom of PAPA syndrome can negatively affect another symptom and ABCB5+ dermal MSCs are not known to reduce TNF-alpha and/or IL-1.
(f) The amount of direction provided by the inventor:
The specification shows that ABCB5+ cells co-cultured with allogeneic PBMC CD14+ monocyte-derived macrophages activated with interferon gamma and lipopolysaccharide reduce M1 macrophage derived pro-inflammatory cytokines TNF-alpha and IL12/IL23p40, and increase M2 macrophage derived anti-inflammatory cytokine IL10 (page 22, lines 7 – 16). The specification shows that injection of ABCB5+ cells injected intradermally around the wound edges of non-immunosuppressed mice with iron-overload counteracts pro-inflammatory cytokine profile and increases production of anti-inflammatory cytokines in the mouse wounds (page 22, lines 17 – 29). The specification shows that injection of ABCB5+ cells into NSG mice humanized with PBMC and with iron overload increased human M2 macrophages and decreased pro-inflammatory macrophages (page 22, lines 30 – 32; page 23, lines 1 – 5). Therefore, there is a nexus between these results and the reduction of inflammatory cytokines and increase in anti-inflammatory cytokines mediated by dermal ABCB5+ mesenchymal stem cells (page 20, lines 30), but not to the full scope of the method as claimed. The specification does not provide any guidance on treating PAPA.
(g) The existence of working examples:
The specification shows that systemic administration of ABCB5+ stem cells into a mouse model of RDEB improved blistering and survival (page 23, lines 29 – 32; page 24, lines 1 – 18). The specification posits that the effect on RDEB mice was due to an amelioration of their inflammatory condition (page 24, lines 8 – 18). The specification does not teach the dose of stem cells administered; however, the specification teaches administering a single dose intravenously of 2 x 106 ABCB5+ cells to NSG mice where the cells were predominantly found at the injection site (skin and skeletal muscle) and some cells were found in the lung (page 24, lines 30 – 32; page 25, lines 1 – 7; Table 1; page 26, lines 19 – 30; Table 2).
Thus, the specification provides sufficient teachings only for the enablement of treating RDEB by intravenous administration of 2 x 106 ABCB5+ cells autologous, allogeneic, or xenogeneic dermal ABCB5+ mesenchymal stem cells. The specification does not provide any working examples of treating PAPA in any subject by administering ABCB5+ cells. The prior art provides no compensatory guidance, since there is no evidence of treating PAPA syndrome with MSCs. Therefore, undue experimentation would be required to practice the invention as broadly claimed.
(h) The quantity of experimentation needed to make use of the invention based on the content of the disclosure:
The amount of experimentation would be undue because it would require determining what symptoms of PAPA syndrome would be reasonably treated with ABCB5+ stem cells. Since, as discussed above, it is not routine to determine how ABCB5+ dermal MSCs will act on any symptom of PAPA syndrome, knowing only that the ABCB5+ dermal MSCs of the instant claims prolong survival in a mouse model of RDEB would mean that significant experimentation would be required to determine which symptoms of PAPA syndrome ABCB5+ dermal MSCs could treat and at what dose and at what dosing regimen. This is because one cannot extrapolate between the working example in the specification and the treatment of PAPA syndrome claimed and since there is little guidance with respect to the use of ABCB5+ dermal MSCs for treating PAPA syndrome. Thus, the full scope of claim 1 is not enabled by the disclosure.
Applicant’s Arguments/ Response to Arguments
16. Applicant Argues: Applicant asserts that the double patenting rejections should be withdrawn because the pending applications and patent do not disclose treatment of PAPA.
Response to Argument: This is not found persuasive because the pending applications and patent broadly recite autoimmune disease or treating and the instant specification states that PAPA is an auto-inflammatory disorder at page 18, lines 3 – 10 and therefore the pending applications and patent anticipate instant claim 1.
Applicant Argues: Applicant asserts that the previously cited teachings in the obviousness rejection of the claims does not teach PAPA of amended claim 1.
Response to Argument: The previous rejections of the claims over the prior art have been withdrawn in view of the amendment to claim 1 and therefore the arguments are moot. A new rejection of the claims under 35 U.S.C. 112(a) is set forth above.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZANNA M BEHARRY whose telephone number is (571)270-0411. The examiner can normally be reached Monday - Friday 8:45 am - 5:45 pm.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632
Prosecution Insights