DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Applicant’s amendment filed on 07/28/2025 has been entered.
Claims 1 and 6-23 are pending in the present application.
Applicant’s election without traverse Group II in the reply filed on 07/28/2025 is acknowledged.
Applicant also elected without traverse the species of graft versus host disease.
Accordingly, claims 1 and 21-22 are withdrawn from further considerations because they are directed to non-elected inventions. Claims 10-11 are also withdrawn from further consideration because they are drawn to non-elected species.
Therefore, claims 6-9, 12-20 and 23 are examined on the merits herein.
Claim Objections
Applicant is advised that should claim 9 be found allowable, claim 18 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 17 is objected to because of the phrase “selected from the group consisting of adherent marrow, periosteal cells……bone, or perichodrium”. It should be - - selected from the group consisting of adherent marrow, periosteal cells……bone, and perichodrium - -. This is because a group should contain more than one species.
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.
Claims 6-9, 12-20 and 23 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 a disease or disorder involving an activated immunological response in a human subject comprising administering to the subject a population of human mesenchymal stem cells that has TNF-alpha receptor Type I expression in an amount of at least 13 pg/106 cells;
does not reasonably provide enablement for a method of treating any other disease or disorder involving an immunological response in a human subject using non-human population of mesenchymal stem cells (e.g., murine, canine, swine or non-human primate mesenchymal stem cells) as claimed broadly. 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.
The instant specification is not enabled for the instant broadly claimed invention for the following reasons.
1. The breadth of the claims
The instant claims encompass a method of treating a disease or disorder involving a suppressive or activated immunological response (e.g., an activated immunological response that is associated with a graft-versus-host disease as the elected species) in a human subject comprising administering to the subject a population of mesenchymal stem cells derived from any species (e.g., murine, canine, swine, human, non-human primate and human MSCs), as long as it has TNF-alpha receptor Type I expression in an amount of at least 13 pg/106 cells. Dependent claim 16 encompasses the same method in which the population of mesenchymal stem cells has been frozen at any temperature before administering to the human subject. It is noting that the instant specification states specifically “In one embodiment, the mesenchymal stem cells are obtained from a mammal. The mammal may be a primate, including human and non-human primates” (paragraph [0014]).
2. The state and the unpredictability of the prior art
At about the effective filing date of the present application (01/13/2006), virtually nothing was known on the use of xenogeneic mesenchymal stem cells for treating any disease or disorder involving an immunological response, including graft-versus-host disease in a human subject, as evidenced at least by the teachings of Le Blanc et al (The Lancet 363:1439-1441, 2004; IDS), McIntosh et al (US 6,328,960; IDS), Pawliuk et al (US 2004/0241141; IDS), Glorioso et al (US 7,037,492; IDS), Maziarz et al (US 8,147,824; IDS), and Gonzalez De La Pena et al (US 8,440,177; IDS). Even in 2007, Mohiuddin (PLoS Medicine 4: 429-434, 2007; IDS) still disclosed that immunological barrier is still the most important hurdle preventing clinical xenotransplantation of organs/cells, and the mechanism of rejection is found to be more complex in large animals, and mechanisms of xenograft rejection include hyperacute rejection (HAR) occurring within minutes, delayed xenograft rejection/acute vascular rejection, intravascular coagulation, and cell-mediated rejection (page 429, middle column, last two paragraphs; and section titled “Mechanisms of Xenografts rejection in animal models”). Please also noting that the physiological art is recognized as unpredictable (MPEP 2164.03).
3. The amount of direction or guidance provided
Apart from investigating the role of TNFRI on the immunosuppressive human mesenchymal stem cells (hMSC) activity exclusively in vitro (Examples 1-2); the instant specification fails to provide sufficient guidance for a skilled artisan on how to use any xenogeneic population of mesenchymal stem cells for treating any disease or disorder involving an immunological response in a human subject, particularly for attaining desired therapeutic results, as encompassed by the instant claims. Especially, a xenogeneic population of mesenchymal stem cells would be vigorously rejected by various rejection mechanisms as disclosed in the review of Mohiuddin, such that the administered xenogeneic mesenchymal stem cells would not present in the treated human subject in an effective amount and/or present for a sufficient period of time long enough to yield any desired therapeutic effect such as inducing a reduced immune response against a human recipient by a graft for a human subject having a graft-versus-host disease. In a 2013 review of Griffin et al (Immunology and Cell Biology 91:40-51, 2013), they even reported anti-donor immune responses elicited by allogeneic mesenchymal stem cells, and proposed the concept of the immune privileged nature of allo-MSCs should be reconsidered (Abstract). There is also no evidence of record indicating or suggesting that the administered population of mesenchymal stem cells having TNF-α receptor Type I expression in an amount of at least 13 pg/106 cells could yield any therapeutic effect in treating a disease or disorder already involving a suppressive immunological response in a human subject, particularly human mesenchymal stem cells are already capable of suppressing immune responses and inflammation.
With respect to dependent claim 16, the instant specification also failed to provide an ordinary skilled artisan on how to use a population of mesenchymal stem cells that has been frozen in any manner and/or at any temperature before administering to the human subject for treating a disease or disorder involving an immunological response as claimed broadly. Particularly, the specification disclosed explicitly that hMSCs stored/frozen at -600C and at -500C have TNFR1 expression levels of less than 13 ng/106 cells, let alone stored/frozen at any temperature above -500C (see at least Fig. 2). Since the prior art at about the effective filing date of the present application (01/13/2006) failed to teach or provide any guidance regarding to the aforementioned issues, it is incumbent upon the present application to do so.
As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires:
That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.
Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maizel.).
Accordingly, due to the lack of sufficient guidance provided by the specification regarding to the issues set forth above, the unpredictability of the relevant arts, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of pre-AIA 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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 6-9, 12-20 and 23 are rejected under pre-AIA 35 U.S.C. 102 (b) as anticipated by or, in the alternative, under pre-AIA 35 U.S.C. 103(a) as obvious over McIntosh et al (US 6,328,960; IDS).
The instant claims encompass a method of treating a disease or disorder involving an immunological response (e.g., graft-versus-host disease) in a human subject comprising administering to the subject a population of mesenchymal stem cells that has TNF-alpha receptor Type I (TNFRI) expression in an amount of at least 13 pg/106 cells, 27.7 pg/106 cells, at least 37.5 pg/106 cells or at least 48.5 pg/106 cells (e.g., derived from a human donor).
With respect to the elected species, McIntosh et al already disclosed a method of reducing an immune response to a transplant in a recipient (e.g., a human, a baboon or a dog) by treating said recipient with an amount of mesenchymal stem cells effective to reduce or inhibit host rejection of the transplant; as well as a method of inducing a reduced immune response against a host by foreign tissue (e.g., graft versus host disease) by administering to a transplant recipient (e.g., a human, a baboon or a dog) suffering from graft versus host disease mesenchymal stem cells in an amount effective to inhibit or suppress the activated T cells in the transplant/donor tissue from mounting an immune response against the recipient, thereby reducing or eliminating a graft versus host response, wherein the mesenchymal stem cells are autologous or allogeneic to the transplant donor or autologous to the recipient or third party mesenchymal stem cells from the same species (see at least the Abstract; Summary of the Invention; particularly col. 5, line 7 continues to line 7 of col. 6; Examples; and issued claims 1-22). McIntosh et al stated explicitly “The recipient’s mesenchymal stem cells may be obtained from the recipient prior to the transplantation and may be stored and/or culture expanded to provide a reserve of mesenchymal stem cells in sufficient amount for treating an ongoing graft attack against host” (col. 6, lines 61-65); “[t]he mesenchymal stem cells can be obtained from the recipient, for example, prior to the transplant. The mesenchymal stem cells can be isolated and stored frozen until needed. The mesenchymal stem cells may also be culture-expanded to desired amounts and stored until needed” (col. 3, lines 59-64); and “Normally, co-culturing cells from different individuals results in a T cell response, manifested by activation and proliferation of the T cells, known as a mixed lymphocyte reaction (MLR). These unexpected results demonstrate that T cells are not responsive to mismatched mesenchymal stem cells. The lack of a proliferative response to human mesenchymal stem cells by allogeneic T cells was unexpected because human mesenchymal stem cells express surface molecules that should render them immunogenic, i.e., they express allogeneic class I MHC molecules. This discovery indicates that the mesenchymal stem cells are not immunogenic to the immune system. The inventors also discovered that mesenchymal stem cells can suppress an MLR between allogeneic cells. Mesenchymal stem cells actively reduced the allogeneic T cell response in mixed lymphocyte reactions in a dose dependent manner. In addition, mesenchymal stem cells from different donors did not exhibit specificity of reduced response with regard to MHC type. Thus, mesenchymal stem cells did not need to be MHC matched to the target cell population in the mixed lymphocyte reaction in order to reduce the proliferative response of alloreactive T cells to mesenchymal stem cells” (col. 5, lines 7-33). McIntosh et al also disclosed that mesenchymal stem cells can be isolated, preferably from bone marrow (e.g., needle bone marrow aspirates), purified, and expanded in culture to obtain sufficient numbers of cells for use (col. 8, lines 53-62); and harvested MSCs can be cryopreserved and stored in a liquid nitrogen storage freezer in the vapor phase (-120 to -1500C) (col. 13, lines 26-67). McIntosh et al also taught the mesenchymal stem cells can be administered at least systemically via parenteral administration or by intravenous injection (col. 8, lines 27-52). McIntosh et al characterized human mesenchymal stem cells obtained from normal human volunteers in suppressing the allogeneic response mixed lymphocyte reactions (MLR) (Example 2 and Fig. 2); inducing a state of hyporesponsiveness or unresponsiveness of T cells in secondary MLR (Examples 3-4 and Figs. 3-5); and they found that the selected hMSCs are highly effective with at least 90% suppressed proliferation in MLR (Fig. 2) and rendering 100% non-responsiveness to antigenic stimulation in the T cells in secondary MLR (Figs. 3-5). In example 8 demonstrating the feasibility and safety in dogs of the infusion of a moderately high dose of donor dog leukocyte antigen (DLA)-identical littermate canine mesenchymal stem cells (cMSC) at 10x106 cells/kg in an allogeneic marrow graft setting, McIntosh et al stated “In this model it was possible to detect skin graft-versus-host-disease (GVHD) by observing the redness of the eyes and ears of the animals. Using this indicator, it was determined that the animals that received mesenchymal stem cells had a lower incidence of and/or lower severity of GVDH compared to the control animals that were not treated with mesenchymal stem cells. These results demonstrate that allogeneic MSCs can support the rapid engraftment of bone marrow hematopoietic cells. No transfusion support was needed. There was no clinical evidence of GvHD. Platelet recovery was faster than in historical controls. There was evidence of chimerism in stromal cells after allogeneic transplantation. The option to engraft allogeneic tissue by using allogeneic MSCs broadens the range of transplant material usable in clinical transplant scenarios” (col. 23, lines 24-39).
Since the harvested/selected human mesenchymal stem cells of McIntosh et al to be administered in an effective amount to a human recipient of a graft/transplant are obtained from the same source (e.g., bone marrow aspirates) and particularly possess at least properties such as highly effective in reducing allogeneic T cell response in mixed lymphocyte reactions (MLR) (e.g., at least 90% suppressed proliferation), rendering 100% non-responsiveness to antigenic stimulation in the T cells in secondary MLR, prolonging of skin graft survival time (e.g., example 7), and supporting rapid engraftment of bone marrow hematopoietic cells with no clinical evidence of GvHD (e.g., example 8), such harvested/selected human mesenchymal stem cells from a normal human volunteer would inherently express endogenous cellular membrane-bound TNF-alpha receptor Type I in an amount of at least 13 pg/106 cells, 27.7 pg/106 cells, at least 37.5 pg/106 cells, or at least 48.5 pg/106 cells as evidenced at least by TNF-[Symbol font/0x61] receptor Type I expression levels of 53.8 pg/106 cells, 51.07 pg/106 cells, 53.2 pg/106 cells, 67.2 pg/106 cells, 39.6 pg/106 cells, 41.1 pg/106 cells, and 33.7 pg/106 cells for human bone marrow-derived mesenchymal stem cells obtained from 7 different human donors as shown by the present application (see at least Tables 3-4), along with the statement “The results from these experiments show that hMSCs with decreased expression of TNFRI lose their ability to suppress hPBMC proliferation in vitro. The data support the premise that the expression of TNFRI is an essential link to the suppression of PBMC proliferation by MSCs” (paragraph [0039]), and the mean TNFRI thresholds of 27.7 pg/106 cells and 48.5 pg/106 cells correspond to 69.9% and 75.3% inhibition hPBMC proliferation, respectively (Fig. 1). Accordingly, the step or harvesting/selecting human mesenchymal stem cells of McIntosh et al for administering to a human recipient of a graft/transplant that yield no clinical evidence of GvHD can be considered to be the same step of selecting a population mesenchymal stem cells based on expression of TNFRI in an amount of at least 13 pg/106 cells (dependent claims 9 and 18); and that such administered human mesenchymal stem cells of McIntosh et al would also suppress peripheral mononuclear cell (PBMC) proliferation, including CD3/CD28-induced PBMCs (dependent claims 19-20). It is also noting that the treatment method in claims 6-8, 12-20 and 23 comprises a single method step of administering; and the treatment method recited in dependent claims 13, 16 and 18 utilized a product-by-process.
MPEP 2112.01 (II) recites that “products of identical chemical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable.” Additionally, the Examiner notes that “the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004).
Accordingly, the McIntosh reference anticipates the instant claims.
Alternatively, although McIntosh et al did not explicitly disclose the harvested/selected human mesenchymal stem cells to be administered in an effective amount to a transplant human recipient to inhibit or suppress the activated T cells in the transplant/donor tissue from mounting an immune response against the recipient express TNF-alpha receptor Type I in an amount of at least 13 pg/106 cells, 27.7 pg/106 cells, at least 37.5 pg/106 cells, or at least 48.5 pg/106 cells, it would have been obvious at the effective filing date of the present application (01/13/2006) for an ordinary skilled artisan to recognize readily that the harvested/selected human mesenchymal stem cells from a healthy human donor would have express at least the recited TNF-alpha receptor Type I amounts with a reasonable expectation of success since they are obtained from the same source (e.g., bone marrow aspirates) and particularly possess at least properties such as highly effective in reducing allogeneic T cell response in mixed lymphocyte reactions (MLR) (e.g., at least 90% suppressed proliferation), rendering 100% non-responsiveness to antigenic stimulation in the T cells in secondary MLR, prolonging of skin graft survival time (e.g., example 7), and supporting rapid engraftment of bone marrow hematopoietic cells with no clinical evidence of GvHD (e.g., example 8); as evidenced at least by the endogenous TNF-[Symbol font/0x61] receptor Type I expression levels of 53.8 pg/106 cells, 51.07 pg/106 cells, 53.2 pg/106 cells, 67.2 pg/106 cells, 39.6 pg/106 cells, 41.1 pg/106 cells, and 33.7 pg/106 cells for human bone marrow-derived mesenchymal stem cells obtained from 7 different human donors shown by the present application (see at least Tables 3-4); along with the statement “The results from these experiments show that hMSCs with decreased expression of TNFRI lose their ability to suppress hPBMC proliferation in vitro. The data support the premise that the expression of TNFRI is an essential link to the suppression of PBMC proliferation by MSCs” (paragraph [0039]); and the mean TNFRI thresholds of 27.7 pg/106 cells and 48.5 pg/106 cells correspond to 69.9% and 75.3% inhibition hPBMC proliferation, respectively (Fig. 1). Accordingly, the step or harvesting/selecting human mesenchymal stem cells of McIntosh et al for administering to a human recipient of a graft/transplant that yield no clinical evidence of GvHD is indistinguishable from the step of selecting a population mesenchymal stem cells based on expression of TNFRI in an amount of at least 13 pg/106 cells (dependent claim 9); and that such administered human mesenchymal stem cells of McIntosh et al would also suppress peripheral mononuclear cell (PBMC) proliferation, including CD3/CD28-induced PBMCs (dependent claims 19-20). It is also noting that the treatment method in claims 6-8, 12-20 and 23 comprises a single method step of administering; and the treatment method recited in dependent claims 13, 16 and 18 utilized a product-by-process.
Please, also 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).
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 6-9, 13-15, 17-20 and 23 are rejected under 35 U.S.C. 103(a) as being unpatentable over Pawliuk et al (US 2004/0241141; IDS) in view of Glorioso et al (US 7,037,492; IDS).
The instant claims encompass a method of treating a disease or disorder involving an immunological response in a human subject comprising administering to the subject a population of mesenchymal stem cells that has TNF-alpha receptor Type I (TNFRI) expression in an amount of at least 13 pg/106 cells, 27.7 pg/106 cells, at least 37.5 pg/106 cells or at least 48.5 pg/106 cells (e.g., derived from a human donor). To the extent that the term “mesenchymal stem cells” encompasses both transfected and non-transfected mesenchymal stem cells as evidenced by the limitation “27.7 pg/106 cells” obtained from TNFRI anti-sense oligo-transfected human mesenchymal stem cells at the dose of 2.5 ug/mL (Table 4 of the application); and the term "TNF-alpha receptor Type I" encompasses both intact cellular membrane bound and soluble TNF-alpha receptor Type I; the following rejection is applied.
Pawliuk et al disclosed at least an ex vivo gene therapy method to treat arthritis (a disease or disorder involving an immunological response) by transfecting either autologous or allogeneic cells, including mesenchymal stem cells obtained from adipose tissue, bone marrow cells or synovial fibroblasts, ex vivo with a lentiviral vector containing a therapeutic gene such as a gene encoding soluble interleukin-1 receptors, soluble TNF-alpha receptors such as sTNF-R55 (TNF-alpha receptor Type I) and sTNF-R75 and others; and the transfected cells in a pharmaceutically acceptable carrier suitable for intravenous, intraperitoneal or parenteral administration are delivered to a subject, including a human patient (see at least Summary of the Invention, particularly paragraphs 14-15, 54, 61-64, 105, 112, 114-116; and claims 1-13). Pawliuk et al further taught the use of ELISA for quantitative assessment of expression level of a secreted therapeutic transgene mediated by the disclosed recombinant lentiviral vector with an exemplified expression level of IL-1Ra reaching a maximum of 2.35 ug/ml at MOI of 50 for 105 synovial cells (see at least example II and Figure 2A).
Pawliuk et al did not disclose explicitly a method comprising the step of selecting/using human mesenchymal stem cells expressing soluble TNF-alpha receptor Type I in an amount of at least 13 pg/106 cells.
At the effective filing date of the present application (01/13/2006), Glorioso et al already taught successfully an ex vivo method of treating a connective tissue disorder using a population of connective tissue cells (synovial cells) or non-connective tissue cells (bone marrow cells, hematopoietic progenitor cells) transduced with a recombinant viral vector encoding a therapeutic protein of interest such as, a soluble TNF-alpha receptor protein, a human interleukin-1 receptor antagonist protein (IRAP) or a soluble interleukin-1 receptor protein (see at least Summary of the Invention; col. 16, lines 3-57; col. 17, lines 11-21). Glorioso et al stated “For the ex vivo methods, all of the non-connective tissue cells can be injected into the bone marrow or blood-stream of the host following transduction. Both connective and non-connective tissue cells can be injected into the joint space, or any other area, of the host following transduction” (col. 16, lines 30-34). In an exemplification, Glorioso et al disclosed the transplantation of 106-107 synovial cells transduced with various recombinant vectors into a knee joint (see at least examples V, col. 25, lines 40-50; example XII, col. 33, lines 14-28; example XIII, col. 35, lines 22-30); and the amount of sTNF-alpha receptor type I expressed by 106 synovial cells is 50 ng (see at least example XVII and Table 3).
Accordingly, it would have been obvious for an ordinary skilled artisan at the effective filing date of the present application to modify the teachings of Pawliuk et al by also selecting/using at least a population of human mesenchymal stem cells expressing sTNF-alpha receptor Type I in the amount of 50 ng/106 cells to be administered/delivered into a human patient in need thereof, in light of the teachings of Glorioso et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modification because Glorioso et al already taught successfully the transplantation of at least 106 synovial cells transduced with a recombinant viral vector expressing 50 ng of sTNF-alpha receptor Type I protein into a joint of a subject in need thereof.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Pawliuk et al and Glorioso 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 Pawliuk et al and Glorioso et al as set forth above is indistinguishable and encompassed by from the broadly claimed method of the present application. With respect to claims 19-20, since the modified method has indistinguishable method step(s) and starting materials from the presently claimed invention, the administered mesenchymal stem cells expressing soluble TNF-alpha receptor Type I would also suppress peripheral mononuclear cell (PBMC) proliferation, including CD3/CD28-induced PBMCs.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
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 6-9, 12-20 and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,821,004.
Although the claims at issue are not identical, they are not patentably distinct from each other because a method of treating a disease or disorder involving an activated immunological response (e.g., graft versus host disease; see dependent claim 6) in a human subject comprising: (i) determining the amount of cellular membrane-bound TNFα receptor Type I expressed by at least one population of human mesenchymal stem cells; (ii) selecting a population of human mesenchymal stem cells that express cellular membrane-bound TNF-α receptor Type I in an amount of at least 27.7 pg/106 cells (e.g., at least 37.5 pg/106 cells or at least 48.5 pg/106 cells; see dependent claims 2-3); and (iii) administering to the subject the selected population of mesenchymal stem cells in claims 1-13 of U.S. Patent No. 11,821,004 anticipates the method of treating a disease or disorder involving an immunological response in a human subject in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus.
Claims 6-9, 12-20 and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,550,369 (IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because a method of treating graft-versus-host-disease (GVHD) in a human in need thereof comprising administering (e.g., via infusions, dependent claim 12) a therapeutic amount of culture-expanded mesenchymal stem cells (MSCs) (e.g., obtained from cryopreserved MSCs or from cord blood, dependent claims 3 and 13) comprising: (i) less than 0.75% CD45+ cells, (ii) at least 95% CD105+ cells, and (iii) at least 95% CD166+ cells, wherein the MSCs are capable of inhibiting IL2Rα expression by CD3/CD28-activated peripheral blood mononuclear cells PBMCs by at least 30% relative to a control, including the MSCs express at least 13 pg TNFRI per million MSCs (dependent claim 4) or the MSCs express about 13 pg to about 44 pg TNFRI per million MSCs (dependent claim 5), in claims 1-15 of U.S. Patent No. 10,550,369 anticipates the method of treating a disease or disorder involving an immunological response in a human subject in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus. It is noted that the administered MSCs in claims 1-15 of U.S. Patent No. 10,550,369 must have been selected based on expression of TNF-α receptor Type I expression prior to the administration; and they are identical to MSCs whose TNF-α receptor Type I expression has been determined using ELISA.
Claims 6-9, 15, 18-19 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-37 of copending Application No. 18/331,353 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because a method of treating steroid refractory acute Graft versus Host Disease (aGvHD) in a pediatric patient comprising intravenously administering eight biweekly therapeutic doses of 2x106 mesenchymal stem cells/kg (autologous or allogeneic MSCs, dependent claims 36-37); wherein the MSCs express at least 13 pg TNFR1 per million MSCs (dependent claim 30); wherein the MSCs express at least 108 pg TNFR1 per million MSCs (dependent claim 31); wherein the MSCs express about 13 pg to about 179 pg TNFR1 per million MSCs (dependent claim 32); wherein the MSCs express about 13 pg to about 44 pg TNFR1 per million MSCs (dependent claim 33); wherein the MSCs express 108 pg to 368 pg TNFR1 per million MSCs (dependent claim 34); wherein the MSCs express TNFR1 at a minimum of 272 pg/mL and a maximum of 1571 pg/mL (dependent claim 35) in claims 29-37 of copending Application No. 18/331,353 anticipates the method of treating a disease or disorder involving an immunological response in a human subject in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus. It is noted that the administered MSCs in claims 29-37 of copending Application No. 18/331,353 must have been selected based on expression of TNF-α receptor Type I expression prior to the administration; and that the administered MSCs also inherently suppress peripheral blood mononuclear cell (PBMC) proliferation, including CD3/cD28-induced PBMCs.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 13 and 16-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-37 of copending Application No. 18/331,353 (reference application) in view of McIntosh et al (US 6,328,960; IDS) and Pawliuk et al (US 2004/0241141; IDS).
The instant claims differ from claims 29-37 of copending Application No. 18/331,353 in
reciting specifically “wherein TNF-α receptor Type I expression has been determined using an enzyme-linked immunosorbent assay” (claim 13); “wherein the population of mesenchymal stem cells has been frozen before administered to the subject” (claim 16); and “wherein the mesenchymal stem cells are obtained from a sample selected from the group consisting of adherent marrow, periosteal cells, blood, skin, cord blood, muscle, fat, bone, or perichondrium” (claim 17).
Before the effective filing date of the present application (01/13/2006), McIntosh et al already disclosed a method of reducing an immune response to a transplant in a recipient (e.g., a human, a baboon or a dog) by treating said recipient with an amount of mesenchymal stem cells effective to reduce or inhibit host rejection of the transplant; as well as a method of inducing a reduced immune response against a host by foreign tissue (e.g., graft versus host disease) by administering to a transplant recipient (e.g., a human, a baboon or a dog) suffering from graft versus host disease mesenchymal stem cells in an amount effective to inhibit or suppress the activated T cells in the transplant/donor tissue from mounting an immune response against the recipient, thereby reducing or eliminating a graft versus host response, wherein the mesenchymal stem cells are autologous or allogeneic to the transplant donor or autologous to the recipient or third party mesenchymal stem cells from the same species (see at least the Abstract; Summary of the Invention; particularly col. 5, line 7 continues to line 7 of col. 6; Examples; and issued claims 1-22). McIntosh et al also disclosed that mesenchymal stem cells can be isolated, preferably from bone marrow (e.g., needle bone marrow aspirates), purified, and expanded in culture to obtain sufficient numbers of cells for use (col. 8, lines 53-62); and harvested MSCs can be cryopreserved and stored in a liquid nitrogen storage freezer in the vapor phase (-120 to -1500C) (col. 13, lines 26-67).
Additionally, Pawliuk et al disclosed at least an ex vivo gene therapy method to treat arthritis (a disease or disorder involving an immunological response) by transfecting either autologous or allogeneic cells, including mesenchymal stem cells obtained from adipose tissue, bone marrow cells or synovial fibroblasts, ex vivo with a lentiviral vector containing a therapeutic gene such as a gene encoding soluble interleukin-1 receptors, soluble TNF-alpha receptors such as sTNF-R55 (TNF-alpha receptor Type I) and sTNF-R75 and others; and the transfected cells in a pharmaceutically acceptable carrier suitable for intravenous, intraperitoneal or parenteral administration are delivered to a subject, including a human patient (see at least Summary of the Invention, particularly paragraphs 14-15, 54, 61-64, 105, 112, 114-116; and claims 1-13). Pawliuk et al further taught the use of ELISA for quantitative assessment of expression level of a secreted therapeutic transgene mediated by the disclosed recombinant lentiviral vector (see at least example II and Figure 2A).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the method of treating steroid refractory acute Graft versus Host Disease (aGvHD) in a pediatric patient in claims 29-37 of copending Application No. 18/331,353 by also utilizing a population of mesenchymal stem cells that has been frozen, the mesenchymal stem cells are obtained from bone marrow or adipose tissue, as well as using ELISA for determining TNFRI expression; in light of the teachings of McIntosh et al and Pawliuk et al as set forth above with a reasonable expectation of success.
An ordinary skilled artisan would have been motivated to carry out the above modifications because McIntosh et al already disclosed that mesenchymal stem cells can be isolated, preferably from bone marrow (e.g., needle bone marrow aspirates), purified, and expanded in culture to obtain sufficient numbers of cells for use (col. 8, lines 53-62); and harvested MSCs can be cryopreserved and stored in a liquid nitrogen storage freezer in the vapor phase (-120 to -1500C); while Pawliuk et al also disclosed at least an ex vivo gene therapy method to treat arthritis by transfecting either autologous or allogeneic cells, including mesenchymal stem cells obtained from adipose tissue, bone marrow cells or synovial fibroblasts, ex vivo with a lentiviral vector containing a therapeutic gene such as a gene encoding soluble interleukin-1 receptors, soluble TNF-alpha receptors such as sTNF-R55 (TNF-alpha receptor Type I) and sTNF-R75 and others, as well as using ELISA for quantitative assessment of expression level of a secreted therapeutic transgene.
The modified method resulting from claims 29-37 of copending Application No. 18/331,353 along with teachings of McIntosh et al and Pawliuk et al is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., whose telephone number is (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s 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