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 .
Applicant’s amendment filed on 12/12/2025 has been entered.
Claims 1-20 are pending in the present application.
Applicant previously elected the following species: (i) a constitutive promoter; (ii) EFS as the constitutive promoter; and (ii) autoimmune disease.
Claims 6-7 and 10-18 were withdrawn previously from further consideration because they are drawn to non-elected species.
Accordingly, claims 1-5, 8-9 and 19-20 are examined on the merits herein with the above elected species.
Claim Rejections - 35 USC § 103
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.
Claims 1-4, 8-9 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Aggarwal et al (US 2009/0220464; IDS) in view of Atkinson et al (US 2007/0003518; IDS), Zhang et al (Diabetes 56:1316-1323, 2007; IDS) and Li et al (J. Hepatology 54:930-938, 2011; IDS) for the same reasons already set forth in the Non-Final Office Action dated 06/13/2025 (pages 3-6). The same rejection is restated below.
The instant claims encompass a method for treating a subject having a medical condition associated with inflammation and/or an unwanted immune response without an alpha1-antitrypsin (AAT) deficiency (e.g., an autoimmune disease such as type I diabetes as the elected species), wherein the method comprises administering genetically modified mesenchymal stem cells to the subject, wherein said genetically modified mesenchymal stem cells comprise an exogenous nucleic acid comprising (i) an AAT encoding region operably linked to (ii) a promoter or promoter/enhancer combination (e.g., EFS is the elected species for a constitutive promoter).
With respect to the elected species, Aggarwal et al disclosed at least a method of treating an autoimmune disease (e.g., Type I diabetes, multiple sclerosis, rheumatoid arthritis) in a mammal (e.g., human and non-human) comprising administering (e.g., intravenous, intraarterial or intraperitoneal administration) to the mammal an effective amount of mesenchymal stem cells (e.g., autologous or allogeneic) with or without genetic manipulation to treat the disease (see at least Brief Summary of the Invention; particularly paragraphs 6, 9-18, 41 and 97-101; and Fig. 7). Aggarwal et al also taught that the mesenchymal stem cells may be genetically engineered with one or more polynucleotides encoding a therapeutic agent that is dependent upon the disease being treated, the extent and the severity thereof, in the form of retroviral vectors, adenoviral vectors or adeno-associated virus vectors; and that the mesenchymal stem cells can also be used in combination with other therapeutic agents known in the art (paragraphs 98-100). Aggarwal et al also taught that it is believed that at least one mechanism by which the mesenchymal stem cells suppress autoimmune disease is by causing the release of interleukin-10 from regulatory T-cells (TReg cells) and/or dendritic cells (paragraph 10), and mesenchymal stem cells are also effective for treating inflammatory response in an animal via (i) promoting T-cell maturation to regulatory T-cells, thereby controlling inflammatory responses, and (ii) inhibiting T helper 1 cells, thereby decreasing the expression of IFN-γ (paragraph 20).
Aggarwal et al did not teach specifically a method of treating a subject having an autoimmune disease (e.g., Type I diabetes) using genetically modified mesenchymal stem cells comprising a recombinant expression vector encoding an alpha-1 antitrypsin (AAT).
Before the effective filing date of the present application, Atkinson et al already taught at least a method of treating diabetes (e.g., Type I diabetes) in a mammal by administering (e.g., intravenous, intramuscular or direct injection into pancreas) into said mammal a therapeutic effective amount of a rAAV particle comprising a promoter (e.g., a heterologous tissue-specific promoter, inducible promoter or a constitutive promoter such as a hybrid CMV promoter or a hybrid β-actin promoter) operably linked to a polynucleotide encoding AAT or a polynucleotide encoding IL-10 (Abstract; Summary of the Invention; particularly paragraphs [0013]-[0018], [0024]-[0027], [0201]-[0205], [[0207]-[0212], [0221], [0238]; and Figs. 6-9). Atkinson et al demonstrated in the spontaneous development of autoimmune diabetes NOD mouse model of human type I diabetes that 70% animals are Type I diabetes free at 30 wk of age when female NOD mice were intra-muscular injected with rAAV2-CB-AT vector at 4 wk of age (Fig. 8); and gene delivery of hAAT markedly reduced insulitis (Fig. 9). Atkinson et al also demonstrated that skeletal muscle transduction of female NOD mice with IL-10 completely abrogated diabetes, and rAAV-IL-10 transduction attenuated the production of insulin autoantibodies, quantitatively reduced pancreatic insulitis, maintained islet insulin content, and altered splenocyte cytokine responses to mitogenic stimulation (paragraphs [0201]-[0204], [0238]; Figs. 6-7). Atkinson et al also proposed ex vivo transduction of islets with rAAV vectors expressing AAT for protection from recurrent Type I diabetes (paragraphs [0207]-[0212]).
Additionally, Zhang et al also demonstrated in vitro that AAT significantly reduces TNF-α-induced and streptozotocin (STZ)-induced β-cell apoptosis, and that the antiapoptotic effects of AAT involves an inhibition of caspase-3 activity (Abstract; and Figs. 1-3). Zhang et al further demonstrated in STZ-induced diabetes in C57BL/6 mice that AAT-treated mice showed significantly lower blood glucose levels, a reduced rate of diabetes, a significantly lower number of apoptotic β-cells and more β-cells than saline-injected animals (Figs. 5-6).
Moreover, Li et al already demonstrated that adipose tissue-derived mesenchymal stem cells (AT-MSCs) can be transduced by recombinant AAV encoding human alpha-1 antitrypsin under the control of cytomegalovirus enhancer/chicken-β-actin promoter (rAAV1-CB-hAAT), and after transplanting to the mouse liver ex vivo transduced AT-MSCs expressed hAAT, and resulting in sustained serum levels of hAAT and no detected anti-hAAT antibody (see at least the Abstract). Li et al also noted that after systemic delivery, MSCs preferentially migrate to damaged tissue, and MSCs are also expected to be a targeting vehicle for cancer therapy because of selective engraftment of intravenously administered MSCs at the site of a tumor (page 935, right col, top of first paragraph). Li et al further stated “In summary, our current study tested the novel approach of using AT-MSCs as a vehicle to carry the wild type AAT gene. We showed (1) AT-MSCs can be transduced by rAAV1 vector; (2) AT-MSCs can serve as a platform for gene delivery to the liver; and (3) AT-MSCs mediated gene therapy can avoid host immune response to the transgene product and thus has a great potential for the treatment of genetic diseases, in which an immune response is unwanted” (page 937, left col, third paragraph).
It would have been obvious for an ordinary skilled artisan to modify the teachings of Aggarwal et al by also genetically modifying mesenchymal stem cells with a recombinant expression vector, including a recombinant retroviral vector, comprising a sequence encoding human AAT operably linked to a constitutive promoter to treat a subject having an autoimmune disease such as Type I diabetes, in light of the teachings of Atkinson et al, Zhang et al and Li et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modification because AAT has been demonstrated to be an effective therapeutic molecule for treating Type I diabetes via in vivo gene therapy and protein therapy by Atkinson et al and Zhang et al, respectively. Moreover, the primary Aggarwal reference already taught explicitly that the mesenchymal stem cells may be genetically engineered with one or more polynucleotides encoding a therapeutic agent in the form of retroviral vectors, adenoviral vectors or adeno-associated virus vectors. Furthermore, Li et al demonstrated successfully using AT-MSCs as a vehicle to carry the wild type AAT gene.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Aggarwal et al, Atkinson et al, Zhang et al and Li et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Aggarwal et al, Atkinson et al, Zhang et al and Li et al as set forth above is indistinguishable from the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Aggarwal et al (US 2009/0220464; IDS) in view of Atkinson et al (US 2007/0003518; IDS), Zhang et al (Diabetes 56:1316-1323, 2007; IDS) and Li et al (J. Hepatology 54:930-938, 2011; IDS) as applied to claims 1-4, 8-9 and 19-20 above, and further in view of Nagata et al (US 5,266,491; IDS) for the same reasons already set forth in the Non-Final Office Action dated 06/13/2025 (pages 6-8). The same rejection is restated below.
The combined teachings of Aggarwal et al, Atkinson et al, Zhang et al and Li et al were presented above. However, none of the cited references teach specifically using the short form of the human EEF1A1 eukaryotic translation elongation factor 1 alpha 1 (EFS) promoter as a constitutive promoter.
Before the effective filing date of the present application, Nagata et al already cloned and characterized a DNA fragment having a promoter region for a human polypeptide chain elongation factor-1α gene, including the 2.5 Kb fragment comprising the promoter sequence of SEQ ID NO: 1 (1,561 bp); the promoter sequence of SEQ ID NO: 1 (cloned in expression plasmid designated pEF-321-CAT); the promoter sequence of SEQ ID NO: 4 (the sequence consisting of nucleotides 373-1561 of SEQ ID NO: 1) as well as other truncated promoters cloned in expression plasmids designated as pEF220-CAT, pEF223-CAT, and pEF204-CAT (see at least the Abstract; col. 9 line 4 continues to line 28 of col. 13; col. 20 lines 5-27; SEQ ID NO: 1; SEQ ID NO: 4; Example 5 and Table 1). Nagata et al found that the expression plasmids have high applicability to a wide range of host cells with high expression efficiency in transient expression systems.
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to further modify the combined teachings of Aggarwal et al, Atkinson et al, Zhang et al and Li et al by also selecting and utilizing the full-length and/or any of the functional truncated forms of the human EEF1A1 promoters disclosed by Nagata et al as presented above to express the heterologous AAT transgene in the genetically modified mesenchymal stem cells to treat a subject having an autoimmune disease such as Type I diabetes.
An ordinary skilled artisan would have been motivated to further carry out the above modification because Nagata et al already cloned and characterized a DNA fragment having a promoter region for a human polypeptide chain elongation factor-1α gene, including the 2.5 Kb fragment comprising the promoter sequence of SEQ ID NO: 1 (1,561 bp); the promoter sequence of SEQ ID NO: 1 (cloned in expression plasmid designated pEF-321-CAT); the promoter sequence of SEQ ID NO: 4 (the sequence consisting of nucleotides 373-1561 of SEQ ID NO: 1) as well as other truncated promoters cloned in expression plasmids designated as pEF220-CAT, pEF223-CAT, and pEF204-CAT; and that these promoters are functional in a wide range of host cells with high expression efficiency at least in transient expression systems.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Aggarwal et al, Atkinson et al, Zhang et al, Li et al and Nagata et al; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Aggarwal et al, Atkinson et al, Zhang et al, Li et al and Nagata et al, as set forth above is indistinguishable from the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above 103 rejections in the Amendment dated 12/12/2025 (pages 4-10) along with the attached 1.132 Declaration of Dr. Felix Hermann dated 04/04/2018 have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
Applicant argued basically that the 1.132 Declaration outlines “unexpected synergistic” effect of the novel combination of transgenic AAT expression from AAT-MSCs, going beyond the isolated and additive effects of administering native MSCs and/or AAT protein. Specifically, the synergistic effect is apparent from the experiments related to type 1 diabetes as shown in Figures 4 and 5 of the Declaration. Additionally, Applicant argued that the specification stated that the homing of AAT-MSCs to the site of inflammation and the anti-inflammatory effects of expressed AAT provide an unexpected synergistic effect greater than the sum of each individual effect of native MSCs and AAT protein systemic application (paragraphs [0025]-[0026] and [0082]). Applicant also noted that it is not required that the specification describes the exact same model as employed in the Declaration to show unexpected effects, so long as it is tied to the claimed features and meets the usual requirements. Accordingly, the presently claimed method is “non-obvious”. Applicant further cited the 2021 publication of Song et al (Stem Cells Transl Med 10:320-331, 2020; 6 years after the effective filing date 01/08/2015 of the present application from a different group of investigators) to demonstrate that the unexpected synergistic effect due to the surprisingly beneficial properties of AAT-MSCs (e.g., increased self-renewal, better migration and multilineage differentiation abilities in comparison to native MSCs) in the context of type I diabetes treatment, which could not have been predicted from the combination of the cited references. Applicant also argued that these unexpected properties of AAT-MSCs would necessarily evident in the prior art is unfounded because the cited prior art does not disclose the claimed subject matter.
First, with respect to the issue that AAT-MSCs have a stronger therapeutic effect than native MSCs for the treatment of type I diabetes in a subject as shown in Figure 4 of the Declaration, since native MSCs alone can yield therapeutic effect in suppressing an autoimmune disease such as type I diabetes (via causing the release of interleukin-10 from regulatory T-cells (TReg cells) and/or dendritic cells; promoting T-cell maturation to regulatory T-cells; and/or inhibiting T helper 1 cells) as taught by the primary Aggarwal reference, coupled with AAT-mediated therapeutic effects in the form of a recombinant AAV particle or AAT protein alone for type I diabetes treatment (via reduction of insulitis; reduced β-cell apoptosis; and lowered blood glucose levels) as taught by the Atkinson reference and the Zhang reference, respectively; it would have been obvious for an ordinary skilled artisan that the combination of MSCs and AAT in the form of AAT-MSCs would yield a stronger therapeutic effect than native MSCs alone for the treatment of type I diabetes in a subject with a reasonable expectation of success. Thus, there is nothing that is unexpected and/or surprising. Particularly, Aggarwal et al already taught that the mesenchymal stem cells may be genetically engineered with one or more polynucleotides encoding a therapeutic agent; and Atkinson et al also proposed ex vivo transduction of islets with rAAV vectors expressing AAT for protection from recurrent Type I diabetes. Moreover, Li et al also taught using AT-MSCs as a vehicle to carry the wild type AAT gene that can avoid host immune response to the transgene product and thus has a great potential for the treatment of genetic diseases, in which an immune response is unwanted.
Second, with respect to the issue that AAT-MSCs have an unexpected synergistic effect that is beyond the isolated and additive effects of administering native MSCs and/or AAT protein for the treatment of type I diabetes in a subject as shown in Figure 5 of the Declaration, it is noted that the data was obtained from an experimental protocol that stated “On days 2 and 7 after cyclophosphamide treatment, mice received intravenous injections of native MSCs at doses of 1x105 cells/application or 1x106 cells/application, MSCs retrovirally transduced to express AAT at doses of 1x104 cells/application, 5x104 cells/application or 1x106 cells/application, or active AAT protein purified from human plasma at a concentration equal to the amount of AAT secreted from 1x106 AAT-MSCs in 48 hours as determined in in vitro experiments in cell culture supernatants” (Experimental design at page 10 of the Declaration). On day 2, in the group of animals treated with AAT protein alone the amount of administered AAT protein is equivalent to the amount of AAT secreted from 1x106 AAT-MSCs in 48 hours (2 days); but in the group of animals treated with 1x106 AAT-MSCs, these AAT-MSCs continue to secrete AAT for at least the next 5 days (120 hours). Then at day 7, in the group of animals treated with AAT protein alone the second amount of administered AAT protein is equivalent to the amount of AAT secreted from 1x106 AAT-MSCs in 48 hours (2 days); but in the group of animals treated with 1x106 AAT-MSCs, these additional AAT-MSCs along with AAT-MSCs from the first intravenous injection continue to secrete AAT for the next 30 days (see Figure 5 of the Declaration). Thus, the group of animals treated with 1x106 AAT-MSCs in the disclosed experimental design was treated with recombinant AAT proteins secreted from administered AAT-MSCs at much higher levels during the treatment period relative the group of animals treated with AAT proteins alone. Thus, an ordinary skill in the art would reasonably expect that AAT-MSCs have more therapeutic effects that are beyond the isolated and additive effects of administering native MSCs and/or AAT protein for the treatment of type I diabetes in a subject as shown in Figure 5 of the Declaration. Accordingly, there is no evidence of “unexpected synergistic” effect in Figure 5 of the Declaration as alleged by Applicant.
Third, simply stating in the specification that the homing of AAT-MSCs to the site of inflammation and the anti-inflammatory effects of expressed AAT provide an unexpected synergistic effect greater than the sum of each individual effect of native MSCs and AAT protein systemic application is not deemed to be sufficient to overcome the 103 rejection of record. Additionally, the issue is not about administering native MSCs and AAT protein for the treatment of type I diabetes in a subject because the primary Aggarwal reference already taught clearly that the mesenchymal stem cells may be genetically engineered with one or more polynucleotides encoding a therapeutic agent. Moreover, before the effective filing date of the present application (01/082015), it was already known that mesenchymal stem cells home to sites of injury and inflammation as evidenced at least by the review of Rustad et al (Advances in Wound Care, Volume 1; doi.org/10.1089/wound.2011.0314, 9 pages, 2012).
Fourth, with respect to the improved self-renewal, better migration and multilineage differentiation abilities of AAT-MSCs relative to MSCs as reported by the 2021 publication of Song et al, the modified MSCs resulting from the combined teachings of Aggarwal et al, Atkinson et al, Zhang et al, and Li et al as set forth in the above 103 rejection would also possess the same improved properties, regardless whether any of the cited art would have predicted any such improved properties. Please note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
1. Atkinson et al (US 8,758,761; IDS) already taught a method of treating type 1 diabetes using alpha-1 antitrypsin (AAT) together with mesenchymal stem cells (see at least issued claims 1, 3-4).
2. Bassi et al (Diabetes 61:2534-2545, 2012; IDS) demonstrated that ADMSC treatment reversed the hyperglycemia of early on-set diabetes in 78% of diabetic NOD mice, and this effect was associated with higher serum insulin, amylin, and glucagon-like peptide 1 levels compared with untreated controls (Abstract).
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s acting SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631