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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/17/2026 has been entered.
Amended claims 1-18 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Claims 6-7 and 10-18 were withdrawn previously from further consideration because they are drawn to non-elected species.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, amended claims 1-5 and 8-9 are examined on the merits herein with the above elected species.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it contains the phrase “said genetically modified mesenchymal stem cells” on line 4 of the abstract. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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.
Amended claims 1-4 and 8-9 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). This is a modified rejection.
The instant claims encompass a method for treating Type I diabetes in a subject, 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 also stated “It is believed that the mesenchymal stem cells migrate to inflamed lung tissue due to increased production of TNF-alpha and/or MCP-1, which are chemo-attractants for mesenchymal stem cells” (last sentence of paragraph [0032]); and “The inflammation and/or epithelial damage which may be treated in accordance with this aspect of the present invention includes, but is not limited to, inflammation and/or epithelial damage caused by a variety of diseases and disorders, including, but not limited to, autoimmune disease, rejection of transplanted organs, burns, cuts, lacerations, and ulcerations, including skin ulcerations and diabetic ulcerations” (paragraph [0040]).
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 (01/08/2015), 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 (modified AAT-MSCs) 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. Additionally, 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 (ex vivo gene therapy). Moreover, Li et al already 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. Additionally, since MSCs preferentially migrate to damaged and/or inflamed tissues, an ordinary skill in the art would also have a reasonable expectation that the systemically administered, modified AAT-MSCs would target and deliver two complementary and potent therapeutic agents, namely MSCs and AAT that act via different mechanisms, at the damaged and/or inflamed tissues in a subject with Type I diabetes to yield an enhanced or effective therapeutic effect relative to non-genetically modified MSC treatment alone or two separate treatments of MSCs and AAT (unlike MSCs, AAT protein does not have the property of homing to damaged and/or inflamed tissues and/or subjected to proteolytic degradation via a systemic administration).
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 and 8-9 above, and further in view of Nagata et al (US 5,266,491; IDS).
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 (01/08/2015), 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 modified 103 rejections in the Amendment dated 07/17/2026 (pages 5-12) along with the attached 1.132 Declaration of Dr. Manfred Stangl dated 07/17/2026 have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
A. AAT-MSCs exhibit stronger therapeutic effects than native MSCs alone.
Applicant argued that just because MSCs possess therapeutic activity and AAT possesses therapeutic activity, any observed improvement must necessarily have been predictable; and this reasoning improperly relies upon hindsight. Applicant refers the examiner to the previously submitted Hermann Rule 132 Declaration dated April 4, 2018, demonstrating that administration of only 5 x 104 AAT-MSCs completely prevented diabetes development in the NOD mouse model, whereas substantially larger doses (105 and 106) of unmodified MSCs produced materially weaker effects (Figure 4); and this is an unexpected superior magnitude of improvement that constitutes evidence of non-obviousness. Applicant also argued that Type I diabetes immunotherapy has historically been characterized by unpredictable outcomes, particularly in the context of cell-based and gene-modified therapies; and the high degree of unpredictability in this field further weighs against a finding that the observed therapeutic effects would have been reasonably expected, particularly the magnitude of therapeutic improvement demonstrated.
First, comparing the therapeutic results mediated by AAT-MSCs and those of MSCs alone is like comparing oranges and apples. Nevertheless, an ordinary skill in the art would reasonably expect that the therapeutic results medicated by AAT-MSCs would be much stronger than those of MSCs alone at the same cell dosage because AAT-MSCs deliver to the targeted damaged and/or inflamed tissues two independent, complementary, and potent therapeutic agents (MSCs and recombinant AAT secreted from MSCs) that act via different mechanisms instead of one therapeutic agent in the form of MSCs alone. Specifically, Aggarwal et al taught that mesenchymal stem cells suppress autoimmune disease (e.g., Type I diabetes) 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). In complementary to the therapeutic effects mediated by mesenchymal stem cells, AAT-mediated therapeutic effects in the form of a recombinant AAV particle or AAT protein alone for type I diabetes treatment are via reduction of insulitis, reduced β-cell apoptosis, and lowered blood glucose levels as taught by the Atkinson reference and the Zhang reference, respectively. Thus, administration of only 5 x 104 AAT-MSCs completely prevented diabetes development in the NOD mouse model, whereas substantially larger doses (105 and 106) of unmodified MSCs produced materially weaker effects as shown in Figure 4 of the previously submitted Hermann Rule 132 Declaration dated April 4, 2018 is a result of the additional complementary therapeutic effects mediated by recombinant AAT secreted from AAT-MSCs at targeted damaged and/or inflamed tissues. Thus, there is nothing that is unexpected or surprising or unpredictable. Particularly, Atkinson et al already 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); while Zhang et al also 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, the prior art in the form of Atkinson et al (US 8,758,761; IDS) already disclosed a method of treating type 1 diabetes using the combination of alpha-1 antitrypsin (AAT) and mesenchymal stem cells (see at least issued claims 1 and 3-4).
Second, with respect to Applicant’s argument on impermissible hindsight reconstruction Examiner would like to recite a paragraph from in re Oetiker, 977, F.2d 1443, 1448 (Fed. Cir. 1992).
"[T]here must be some teaching, reason, suggestion, or motivation found "in the prior art" or "in the prior art references" to make a combination to render an invention obvious within the meaning of 35 U.S.C. 103 (1998). Similar language appears in a number of opinions and if taken literally would mean that an invention cannot be held to have been obvious unless something specific in a prior art reference would lead an inventor to combine the teachings therein with another piece of prior art. This restrictive understanding of the concept of obviousness is clearly wrong…. While there must be some teaching, reason, suggestion, or motivation to combine existing elements to produce the claimed device, it is not necessary that the cited references or prior art specifically suggest making the combination…. In sum, it is off the mark for litigants to argue, as many do, that an invention cannot be held to have been obvious unless a suggestion to combine the prior art teachings is found in a specific reference."
Although the cited artisans do not specifically point out a motivation to in their disclosure, an ordinarily skilled artisan would have been able to identify the need for the combination of the teachings without the disclosure of the instant application. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Please refer to the above modified 103 rejections for more details along with the motivations provided why an ordinary skill in the art would have combined at least the teachings of Aggarwal et al, Atkinson et al, Zhang et al and Li et al.
B. AAT-MSC-treated animals may have received substantially greater cumulative AAT exposure than animals administered purified AAT protein.
With respect to the results presented in Figure 5 of the Hermann Rule 132 Declaration dated April 4, 2018, Applicant referred the Examiner to the Rule 132 Declaration of Dr. Manfred Stangl dated July 16, 2026, establishing that the effective 5 x 104 AAT-MSC treatment produced approximately 0.5 μg AAT during 48 hours, while the protein treatment subjects received approximately 10 μg AAT in total during the corresponding 48 hours (twenty-fold more AAT); and yet the AAT protein treatment was markedly less effective than treatment with only 5 x 104 AAT-MSCs. Dr. Stangl even assumed continued cell viability and AAT secretion at the measured in vitro rate throughout the approximately 30-day study period, the two administered 5 x 104 AAT-MSC doses would be expected to produce approximately 12.75 μg AAT in total, which remains below the approximately 20 μg of purified AAT administered to the protein-control group. Accordingly, Applicant argued that the superior efficacy of the AAT-MSC treatment cannot be reasonably attributed to systemic administration of a larger quantity of AAT which contradicts the Examiner’s reasoning; and this result would not have been expected by a person of ordinary skill in the art based on the prior art cited in this application.
The results presented in Figure 5 of the Hermann Rule 132 Declaration dated April 4, 2018 demonstrated that after a period of 30 days AAT-MSCs are more efficient than MSCs and AAT protein in preventing diabetes development in a mouse model of cyclophosphamide-accelerated diabetes mellitus type I. An ordinary skill in the art would also reasonably expect that AAT-MSCs treatment is more efficient than MSCs and AAT protein treatments for the following reasons:
(i) Although a larger quantity of AAT is systemically administered, but an effective amount of AAT at the targeted damaged and/or inflamed tissues of type I diabetes may be significantly less than the AAT level secreted by AAT-MSCs because AAT protein itself does not possess a homing ability to targeted damaged and/or inflamed tissues of type I diabetes. Moreover, systemically administered AAT is also subjected to proteolytic degradation in the blood stream before it reaches targeted damaged and/or inflamed tissues, with the half-life of AAT is 8.7 days as reported by Pla et al (Arch Bronconeumol. 42:553-556, 2006; see at least Abstract). Thus, the initial total amount of administered 20 μg AAT purified AAT in the protein-control group is significantly degraded during the 30-day study period.
(ii) AAT-MSCs deliver to the targeted damaged and/or inflamed tissues of type I diabetes two independent, complementary, and potent therapeutic agents (MSCs and recombinant AAT secreted from MSCs) that act via different mechanisms instead of one therapeutic agent in the form of MSCs alone or AAT protein alone. Specifically, Aggarwal et al taught that mesenchymal stem cells suppress autoimmune disease (e.g., Type I diabetes) 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). In complementary to the therapeutic effects mediated by mesenchymal stem cells, AAT-mediated therapeutic effects in the form of a recombinant AAV particle or AAT protein alone for type I diabetes treatment are via reduction of insulitis, reduced β-cell apoptosis, and lowered blood glucose levels as taught by the Atkinson reference and the Zhang reference, respectively.
Accordingly, the effect in Figure 5 of the Hermann Rule 132 Declaration is neither surprising nor unexpected.
C. Specification statements and MSC homing.
With respect to the Examiner’s cited Rustad reference as evidence of MSC homing to sites of injury and inflammation, Applicant argued that the reference does not disclose treatment of Type 1 diabetes, nor does it discuss AAT, AAT-modified MSCs, or genetically engineered MSCs expressing therapeutic transgenes; and with respect to the present claims the Rustad reference is considerable remote. Nevertheless, the Examiner’s previous argument does not address the actual basis upon which unexpected results have been presented. Particularly, the Hermann Declaration demonstrates prevention of diabetes development using low-dose AAT-MSC administration under conditions where both native MSCs and purified exhibited substantially lower efficacy, regardless of whether MSC homing was known in the context of wound healing and inflammation.
First, Aggarwal et al already stated “It is believed that the mesenchymal stem cells migrate to inflamed lung tissue due to increased production of TNF-alpha and/or MCP-1, which are chemo-attractants for mesenchymal stem cells” (last sentence of paragraph [0032]); and “The inflammation and/or epithelial damage which may be treated in accordance with this aspect of the present invention includes, but is not limited to, inflammation and/or epithelial damage caused by a variety of diseases and disorders, including, but not limited to, autoimmune disease, rejection of transplanted organs, burns, cuts, lacerations, and ulcerations, including skin ulcerations and diabetic ulcerations” (paragraph [0040]). Additionally, 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). Thus, both the teachings of Aggarwal et al and Li et al taught that MSCs are capable of targeting or homing to damaged and/or inflamed tissues, including those of autoimmune disease such as Type I diabetes. The review of Rustad et al (Advances in Wound Care, Volume 1; doi.org/10.1089/wound.2011.0314, 9 pages, 2012) further supported both of the teachings of Aggarwal et al and Li et al on the issue that mesenchymal stem cells possess the ability to home to sites of injury and inflammation.
Second, with respect to the “unexpected” results please refer to the Examiner’s responses in Sections A-B above for details.
D. Reliance upon inherency and the Song publication.
Applicant argued that the relevant question is whether a person of ordinary skill in the art, at the time of filing, would have reasonably expected the biological properties later reported by Song et al as a result from expression of AAT in mesenchymal stem cells, and the prior art provides no such teaching or reasonable expectation. Applicant argued that the Song publication serves as an independent scientific confirmation of the unexpected nature of the biological and therapeutic effects associated with expression of AAT in MSCs. Specifically, nothing in Aggarwal, Atkinson, Zhang, or Li suggests that expression of AAT would beneficially alter the biology of the MSCs themselves, improve stemness-related properties, increase proliferative capacity, enhance migration, or improved therapeutic efficacy in the NOD diabetes model relative to unmodified MSCs. Applicant argued that unexpected properties discovered in a claimed composition constitute powerful objective evidence of non-obviousness, even where the individual structural elements may be identified in hindsight. Additionally, Applicant argued that Song provides an independent scientific basis supporting why the therapeutic effects observed in the Hermann Declaration may exceed what would have been predicted from either MSC therapy alone or AAT administration alone; and the Song publication supports the conclusion that AAT-MSCs are not merely MSCs carrying an AAT transgene, but cells whose biological properties are unexpectedly improved by AAT expression. Moreover, Applicant argued that Aggarwal taught genetically modified MSCs expressing therapeutic proteins, Atkinson taught AAT for treating Type 1 diabetes; Li taught MSCs as vehicles for delivering AAT; and the cited references do not teach treatment of Type I diabetes in a subject as claimed. Accordingly, it is entirely unreasonable to assert that the prior art products “are the same or substantially the same” as the claimed invention.
First, 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, once again 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 modified 103 rejection would also possess the same improved properties, regardless whether any of the cited art would have predicted any such improved properties; particularly Li et al already prepared adipose tissue-derived mesenchymal stem cells (AT-MSCs) transduced with recombinant AAV encoding human alpha-1 antitrypsin under the control of cytomegalovirus enhancer/chicken-β-actin promoter (rAAV1-CB-hAAT). 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). It is noted the present application also fails to describe any of 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.
Second, as set forth in the above 103 rejection since MSCs preferentially migrate to damaged and/or inflamed tissues, an ordinary skill in the art would also have a reasonable expectation that the systemically administered, modified AAT-MSCs resulting from the combined teachings of Aggarwal et al, Atkinson et al, Zhang et al, and Li et al would target and deliver two complementary and potent therapeutic agents, namely MSCs and AAT that act via different mechanisms, at the damaged and/or inflamed tissues in a subject with Type I diabetes to yield an enhanced or effective therapeutic effect relative to non-genetically modified MSC treatment alone or two separate treatments of MSCs and AAT (unlike MSCs, AAT protein does not have the property of homing to damaged and/or inflamed tissues and/or subjected to proteolytic degradation via a systemic administration). Moreover, the prior art in the form of Atkinson et al (US 8,758,761; IDS) already disclosed a method of treating type 1 diabetes using the combination of alpha-1 antitrypsin (AAT) and mesenchymal stem cells (see at least issued claims 1 and 3-4).
Third, please also refer to the Examiner’s responses to alleged unexpected results in both the Hermann and Stangl Declarations in Sections A-B above for details.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
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.
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.
Patent applicants with problems or questions regarding electronic images that can be viewed in the Patent Application Information Retrieval system (PAIR) can now contact the USPTO’s Patent Electronic Business Center (Patent EBC) for assistance. Representatives are available to answer your questions daily from 6 am to midnight (EST). The toll-free number is (866) 217-9197. When calling please have your application serial or patent number, the type of document you are having an image problem with, the number of pages and the specific nature of the problem. The Patent Electronic Business Center will notify applicants of the resolution of the problem within 5-7 business days. Applicants can also check PAIR to confirm that the problem has been corrected. The USPTO’s Patent Electronic Business Center is a complete service center supporting all patent business on the Internet. The USPTO’s PAIR system provides Internet-based access to patent application status and history information. It also enables applicants to view the scanned images of their own application file folder(s) as well as general patent information available to the public.
/QUANG NGUYEN/Primary Examiner, Art Unit 1631
Prosecution Insights