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 .
Claims 1-22 are pending in the present application, and they are examined on the merits herein.
Priority
The present application is a CIP of 17/092,779, filed on 11/09/2020, now abandoned; which is a CON of PCT/US2020/025705, filed on 03/30/2020; which claimed the provisional application with the Serial Number 62/826,676, filed on 03/29/2019.
Since the provisional application 62/826,676 has written support for the specific concept of using human embryonic kidney cells or epithelial cells transfected with a gene encoding a protein having intervertebral disc regenerating function for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site of a mammal in need thereof, the instant claims have an effective filing date of 03/29/2019.
Claim Objections
Claim 11 is objected to because the claim is not ended with a period.
Claim 20 is objected to because of the misspelled term “increaseing”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 12-18 and 20-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Noh et al (WO 2009/117740; IDS).
The instant claims are drawn to a method for restoring a damaged or degenerating intervertebral disc in a subject in need thereof, comprising administering a composition comprising a mixed cell population to an intervertebral disc site of the subject, wherein the mixed cell population comprises a first mammalian cell comprising an exogenous nucleotide sequence encoding a protein having an intervertebral disc regenerating function and a second mammalian cell that does not comprise the exogenous nucleotide sequence and is a connective tissue cell.
Noh et al already disclosed at least a method for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site (e.g., torn or herniated) of a mammal, the method comprises: a) inserting a gene encoding a protein having intervertebral disc regenerating function (e.g., a member of TGF-beta superfamily such as TGF-beta1, BMP-2, BMP-3, BMP-4, BMP-7/OP-1 and others) into a first mammalian connective tissue cell, and b) transplanting a mixture of the mammalian connective tissue cell of a) and unmodified second mammalian connective tissue cell into the intervertebral disc defect site; preferably the method does not use a scaffolding or any supporting structure for the cells; wherein the first and second mammalian connective tissue cell may be chondrocyte (e.g., non-disc chondrocyte, juvenile chondrocyte, and specifically the chondrocyte for the second mammalian connective tissue cell is a primed chondrocyte) or fibroblast; and either or both the first and second connective tissue cell may be autologous or allogeneic relative to the mammalian subject or to each other (paragraphs [0002], [0005], [0007], [0035]-[0036], [0043], [0047], [0052]; and Example IV). Noh et al also taught that the ratio of cells that have not been transfected or transduced with a gene encoding a member of the transforming growth factor beta superfamily to cells that have been transfected or transduced with a TGF superfamily gene may be in the range of about 3-20 to 1, 3-10 to 1 or about 10 to 1 (paragraph [0028]). Noah et al also stated “ When these fibroblastic chondrocytes are incubated or “primed” with a cytokine such as a protein from the TGF-beta superfamily, the cells regain their chondrocytic characteristics, which include production of collagen” (paragraph [0046]); “An advantage of using primed cells in retardation of intervertebral disc degeneration is the ease of creating usable chondrocytes for introduction into the intervertebral disc for production of collagen and otherwise maintenance of the cartilaginous matrix” (paragraph [0047]); and “Alternatively, the cells may be incubated with the cytokine of interest for a time and the combination may be administered to the site of defect without separating out the cytokine” (paragraph [0050]). Noh et al further disclosed that a compound for parenteral administration to a patient in a therapeutically or prophylactically effective amount that includes a TGF-beta superfamily protein and a suitable pharmaceutically acceptable carrier (paragraphs [0058]-[0059]). Noh et al also taught that the connective tissue cell may be stored frozen in 10% DMSO in liquid nitrogen (paragraph [0063]), or in an exemplary cryopreservative media of DMEM, FBS and DMSO in a 5:4:1 ratio (last sentence of paragraph [00117]). In Example IV. 1, Noh et al taught the use of X-ray radiograph to obtain a disc height index of the intervertebral disc to measure its morphology, its level of degeneration or regeneration (paragraphs [0008], [00102]; and Fig. 1D-F); as well as the use of MRI (magnetic resonance image) radiograph to show healing, the slowing, retardation or prevention of degeneration of injured disc (paragraphs [0008], [[0093], 00102]; and Fig. 1A-C). Since the above disclosed treatment method of Noh et al has the same method step and starting materials as those encompassed by the presently claimed invention, such method would inherently result in an improved collagen matrix, proteoglycan or the water content of the damaged or degenerating intervertebral disc.
Accordingly, the teachings of Noh meet every limitation of the instant claims. Therefore, the reference anticipates the instant claims.
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, 4-5 and 7-11 are rejected under 35 U.S.C. 103 as being unpatentable over Noh et al (WO 2009/117740; IDS) in view of Harpstead (US 6,479,066; IDS), Thomas et al (J. Pharm. Toxicologic. Methods 51:187-200, 2005; IDS) and Masuda et al (The Spine Journal 4:3308-3408, 2004; IDS).
Noh et al already disclosed at least a method for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site (e.g., torn or herniated) of a mammal, the method comprises: a) inserting a gene encoding a protein having intervertebral disc regenerating function (e.g., a member of TGF-beta superfamily such as TGF-beta1, BMP-2, BMP-3, BMP-4, BMP-7/OP-1 and others) into a first mammalian connective tissue cell, and b) transplanting a mixture of the mammalian connective tissue cell of a) and unmodified second mammalian connective tissue cell into the intervertebral disc defect site; preferably the method does not use a scaffolding or any supporting structure for the cells; wherein the first and second mammalian connective tissue cell may be chondrocyte (e.g., non-disc chondrocyte, juvenile chondrocyte, and specifically the chondrocyte for the second mammalian connective tissue cell is a primed chondrocyte) or fibroblast; and either or both the first and second connective tissue cell may be autologous or allogeneic relative to the mammalian subject or to each other (paragraphs [0002], [0005], [0007], [0035]-[0036], [0043], [0047], [0052]; and Example IV). Noh et al also taught that the ratio of cells that have not been transfected or transduced with a gene encoding a member of the transforming growth factor beta superfamily to cells that have been transfected or transduced with a TGF superfamily gene may be in the range of about 3-20 to 1, 3-10 to 1 or about 10 to 1 (paragraph [0028]). Noah et al also stated “ When these fibroblastic chondrocytes are incubated or “primed” with a cytokine such as a protein from the TGF-beta superfamily, the cells regain their chondrocytic characteristics, which include production of collagen” (paragraph [0046]); “An advantage of using primed cells in retardation of intervertebral disc degeneration is the ease of creating usable chondrocytes for introduction into the intervertebral disc for production of collagen and otherwise maintenance of the cartilaginous matrix” (paragraph [0047]); and “Alternatively, the cells may be incubated with the cytokine of interest for a time and the combination may be administered to the site of defect without separating out the cytokine” (paragraph [0050]). Noh et al further disclosed that a compound for parenteral administration to a patient in a therapeutically or prophylactically effective amount that includes a TGF-beta superfamily protein and a suitable pharmaceutically acceptable carrier (paragraphs [0058]-[0059]). Noh et al also taught that the connective tissue cell may be stored frozen in 10% DMSO in liquid nitrogen (paragraph [0063]), or in an exemplary cryopreservative media of DMEM, FBS and DMSO in a 5:4:1 ratio (last sentence of paragraph [00117]). In Example IV. 1, Noh et al taught the use of X-ray radiograph to obtain a disc height index of the intervertebral disc to measure its morphology, its level of degeneration or regeneration (paragraphs [0008], [00102]; and Fig. 1D-F); as well as the use of MRI (magnetic resonance image) radiograph to show healing, the slowing, retardation or prevention of degeneration of injured disc (paragraphs [0008], [[0093], 00102]; and Fig. 1A-C).
Noah et al did not teach specifically a method for restoring a damaged or degenerating intervertebral disc in a subject in need thereof, comprising administering a mixed cell population to an intervertebral disc site of the subject, wherein the mixed cell population comprises a human embryonic kidney cell or an epithelial cell comprising an exogenous nucleotide sequence encoding a protein having an intervertebral disc regenerating function (e.g., TGF-β1 protein) and chondrocytes that do not comprise the exogenous nucleotide sequence.
Before the effective filing date of the present application (03/29/2019), Harpstead already taught using human epithelial cells (HeLa), human embryonic kidney cells (HEK), Chinese hamster ovary cells (COS) and other known cell lines derived from tumors or from stem cells that have been developed to divide indefinitely, which provide an unlimited source standardized, genetically homogenous cells in a device to be implanted at a site (e.g., intraperitoneal fat sites, subcutaneous sites, intervertebral discs) in a patient in need thereof (see at least col. 5, line 65 continues to line 65 on col. 7; and issued claims 1, 20-21). Harpstead also disclosed that the implanted cells are capable of producing a therapeutic substance (e.g., BMP, NGF and others) that has a beneficial effect on the host, and that the implanted cells can be genetically engineered transformed cells (col. 6, line 28 continues to line 26 of col. 7).
Additionally, Thomas et al also disclosed that HEK293 cell line is of epithelial origin and it has been extensively used as an expression tool for recombinant proteins; and some of the principal attributes which have made the HEK cell a popular choice include: (i) quick and easy reproduction and maintenance, (ii) amenability to transfection using a wide variety of methods, (iii) high efficiency of transfection and protein production, and (iv) faithful translation and processing of proteins (see at least the Abstract).
Moreover, Masuda et al already reviewed the prior art literature and reported that growth factors such as TGF-beta1, BMP-2, OP-1/BMP-7 in the form of a recombinant protein and/or a recombinant expression vector increased proteoglycan and/or collagen synthesis, and/or increased cell proliferation in intervertebral disc cells in numerous cell and organ culture systems and in vivo models (see at least the Abstract; and particularly Tables 1-2 and section titled “The gene transfer approach using growth factors” on page 3368). Masuda et al concluded “From the data reviewed above, the application of growth factors, either by direct injection of the protein into the NP or the AF or by the transplantation of IVD cells transfected with therapeutic genes by viral or nonviral gene therapy, is clearly possible as an effective therapeutic approach in the treatment of IVD degeneration” (page 3388, left column, top of first full paragraph).
Accordingly, it would have been obvious for an ordinary skilled artisan to modify the teachings of Noh et al by also selecting and using human embryonic kidney cells or epithelial cells such as HEK-293 cells that are inserted/transfected with a gene encoding a protein having intervertebral disc regenerating function such as a member of TGF-beta superfamily (e.g., TGF-beta 1, BMP) to be transplanted in a mixture with unmodified chondrocytes to induce/enhance cartilage, proteoglycans synthesis and/or cell proliferation of endogenous intervertebral disc cells and/or increased cartilage and proteoglycan production provided by co-implanted unmodified chondrocytes at an intervertebral disc defect site of a mammalian subject in need of treatment, in light of the teachings of Harpstead, Thomas et al and Masuda et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because Harpstead already taught successfully using human epithelial cells (HeLa), human embryonic kidney cells (HEK) which provide an unlimited source of standardized, genetically homogenous cells, including transformed/genetically modified cells, that produce a therapeutic substance in a device to be implanted (e.g., at intervertebral site) in a patient in need thereof; while Thomas et al taught that HEK293 cell line is of epithelial origin and it has many positive attributes that include: (i) quick and easy reproduction and maintenance, (ii) amenability to transfection using a wide variety of methods, (iii) high efficiency of transfection and protein production, and (iv) faithful translation and processing of proteins. Moreover, Masuda et al already reviewed the prior art literature and reported that growth factors such as TGF-beta1, BMP-2, OP-1/BMP-7 in the form of a recombinant protein and/or a recombinant expression vector increased proteoglycan and/or collagen synthesis, and/or increased cell proliferation in intervertebral disc cells in numerous cell and organ culture systems and in vivo models.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Noh et al, Harpstead, Thomas et al and Masuda et al; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified treatment method resulting from the combined teachings of Noh et al, Harpstead, Thomas et al and Masuda et al as set forth above 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.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Noh et al (WO 2009/117740; IDS) in view of Harpstead (US 6,479,066), Thomas et al (J. Pharm. Toxicologic. Methods 51:187-200, 2005; IDS) and Masuda et al (The Spine Journal 4:3308-3408, 2004; IDS) as applied to claims 1, 4-5 and 7-11 above, and further in view of Strbo et al (WO 2018/071405).
The combined teachings of Noh et al, Harpstead, Thomas et al and Masuda et al were presented above. However, none of the cited references teach specifically that the human embryonic kidney cell or an epithelial cell is irradiated.
Before the effective filing date of the present application (03/29/2019), Strbo et al already taught the use of HEK293 cells that are transfected with the gp96-Ig-ZIKV antigen expression vector for the treatment of a flavivirus infection in a subject, wherein the transfected HEK293 cells were first irradiated (12,000 rads), then suspended in freezing medium comprising 10% DMSO, and 25% human serum albumin prior to subcutaneous administration to a patient (see at least Abstract; particularly paragraphs [0037]-[0039]).
Accordingly, it would have been obvious for an ordinary skilled artisan to further modify the combined teachings of Noh et al, Harpstead, Thomas et al and Masuda et al by also irradiating the human embryonic kidney cell or an epithelial cell comprising an exogenous nucleotide sequence encoding a protein having an intervertebral disc regenerating function in a mixed cell population prior to administering the mixed cell population to a subject in need thereof, in light of the teachings of Strbo et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modification because Strbo et al already taught successfully the use of irradiated HEK293 cells that were transfected with the gp96-Ig-ZIKV antigen expression vector for the treatment of a flavivirus infection in a subject.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Noh et al, Harpstead, Thomas et al, Masuda et al and Strbo et al; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified treatment method resulting from the combined teachings of Noh et al, Harpstead, Thomas et al, Masuda et al and Strbo et al as set forth above 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.
Claims 1, 13, 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Noh et al (WO 2009/117740; IDS) in view of Ra et al (US 2010/0196329) and Strbo et al (WO 2018/071405).
Noh et al already disclosed at least a method for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site (e.g., torn or herniated) of a mammal, the method comprises: a) inserting a gene encoding a protein having intervertebral disc regenerating function (e.g., a member of TGF-beta superfamily such as TGF-beta1, BMP-2, BMP-3, BMP-4, BMP-7/OP-1 and others) into a first mammalian connective tissue cell, and b) transplanting a mixture of the mammalian connective tissue cell of a) and unmodified second mammalian connective tissue cell into the intervertebral disc defect site; preferably the method does not use a scaffolding or any supporting structure for the cells; wherein the first and second mammalian connective tissue cell may be chondrocyte (e.g., non-disc chondrocyte, juvenile chondrocyte, and specifically the chondrocyte for the second mammalian connective tissue cell is a primed chondrocyte) or fibroblast; and either or both the first and second connective tissue cell may be autologous or allogeneic relative to the mammalian subject or to each other (paragraphs [0002], [0005], [0007], [0035]-[0036], [0043], [0047], [0052]; and Example IV). Noh et al also taught that the ratio of cells that have not been transfected or transduced with a gene encoding a member of the transforming growth factor beta superfamily to cells that have been transfected or transduced with a TGF superfamily gene may be in the range of about 3-20 to 1, 3-10 to 1 or about 10 to 1 (paragraph [0028]). Noah et al also stated “ When these fibroblastic chondrocytes are incubated or “primed” with a cytokine such as a protein from the TGF-beta superfamily, the cells regain their chondrocytic characteristics, which include production of collagen” (paragraph [0046]); “An advantage of using primed cells in retardation of intervertebral disc degeneration is the ease of creating usable chondrocytes for introduction into the intervertebral disc for production of collagen and otherwise maintenance of the cartilaginous matrix” (paragraph [0047]); and “Alternatively, the cells may be incubated with the cytokine of interest for a time and the combination may be administered to the site of defect without separating out the cytokine” (paragraph [0050]). Noh et al further disclosed that a compound for parenteral administration to a patient in a therapeutically or prophylactically effective amount that includes a TGF-beta superfamily protein and a suitable pharmaceutically acceptable carrier (paragraphs [0058]-[0059]). Noh et al also taught that the connective tissue cell may be stored frozen in 10% DMSO in liquid nitrogen (paragraph [0063]), or in an exemplary cryopreservative media of DMEM, FBS and DMSO in a 5:4:1 ratio (last sentence of paragraph [00117]). In Example IV. 1, Noh et al taught the use of X-ray radiograph to obtain a disc height index of the intervertebral disc to measure its morphology, its level of degeneration or regeneration (paragraphs [0008], [00102]; and Fig. 1D-F); as well as the use of MRI (magnetic resonance image) radiograph to show healing, the slowing, retardation or prevention of degeneration of injured disc (paragraphs [0008], [[0093], 00102]; and Fig. 1A-C).
Noah et al did not teach specifically using a pharmaceutical carrier comprising about 10 to 20% w/w DMSO and about 1 to 5% w/w saccharose (sucrose).
Before the effective filing date of the present application (03/29/2019), Ra et al already disclosed at least a cell therapeutic composition comprising adipose-tissue derived mesenchymal stem cells and sucrose as an excipient, and wherein the composition further additionally comprising DMSO as the excipient (Abstract; Summary of the Invention; particularly paragraphs [0010]-[0014]). Ra et al stated “[w]hen the inventive cell therapeutic compositions containing adipose tissue-derived stem cells were stored under frozen storage conditions, the composition containing physiological saline, sucrose, albumin and cryopreservative DMSO showed the highest cell viability upon thawing, and it was observed that the addition of albumin and sugar components to the cell therapeutic composition protected the cells during the freezing and thawing of the cell to improve the viability of the cells” (paragraph [0048]). Ra et al demonstrated that the cell viability in frozen storage conditions was further increased in a formulation comprising physiological saline, PBS or Harman-D solution, as a base, 2% sucrose and 5% albumin and 10% DMSO (Example 7, particularly paragraph [0065] and Table 3).
Additionally, Strbo et al already taught the use of HEK293 cells that are transfected with the gp96-Ig-ZIKV antigen expression vector for the treatment of a flavivirus infection in a subject, wherein the transfected HEK293 cells were first irradiated (12,000 rads), then suspended in freezing medium comprising 10% DMSO, and 25% human serum albumin prior to subcutaneous administration to a patient (see at least Abstract; particularly paragraphs [0037]-[0039]).
Accordingly, it would have been obvious for an ordinary skilled artisan to modify the teachings of Noh et al by also using a frozen storage medium comprising about 10 % (w/w) DMSO and about 2% saccharose/sucrose (w/w) as a pharmaceutical carrier for the mixed cell population, in light of the teachings of Ra et al and Strbo et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because: (i) Ra et al already demonstrated that the cell viability for a stem cell therapeutic composition in frozen storage conditions was increased in a formulation comprising physiological saline, PBS or Harman-D solution, as a base, 2% sucrose and 5% albumin, and 10% DMSO; and (ii) Strbo et al already taught successfully the use of irradiated HEK293 cells that were transfected with the gp96-Ig-ZIKV antigen expression vector in a freezing medium comprising 10% DMSO and 25% human serum albumin for subcutaneous administration into a patient in need of a flavivirus infection treatment.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Noh et al, Ra et al and Strbo et al; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified treatment method resulting from the combined teachings of Noh et al, Ra et al and Strbo et al as set forth above 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer
Claims 1-19 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 18/134,383 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because a method for preventing or treating chronic back pain in a subject in need thereof (e.g., the subject has an intervertebral disc defect, the chronic back pain is a discogenic back pain; see dependent claim 13), comprising administering an effective amount of a composition comprising a mixed cell population to an intervertebral disc site of the subject, wherein the mixed cell population comprises a first mammalian cell comprising an exogenous nucleotide sequence encoding a protein having an intervertebral disc regenerating function (e.g., TGF-beta superfamily, TGF-beta1; see dependent claims 2-3 and 4-5) and a second mammalian cell that does not comprise the exogenous nucleotide sequence and is a connective tissue cell, including the first mammalian cell is a human embryonic kidney cell or an epithelial cell, and the second mammalian cell is a chondrocyte (see dependent claims 4-11) in claims 1-22 of copending Application No. 18/134,383 anticipates the claimed genus 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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5, 7-8, 12 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 16-18 and 21-22 of copending Application No. 17/599,831 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because a method for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site of a mammal comprising: a) inserting a gene encoding a protein having intervertebral disc regenerating function into a first mammalian cell to produce a transduced first mammalian cell, and b) transplanting a mixture of the transduced first mammalian cell of a) and second mammalian cell into the interverbal disc defect site, wherein the protein is a TGF-beta superfamily protein (e.g., TGF-beta1; see dependent claim 22), and wherein said first mammalian cell is a human embryonic kidney cell, and said second mammalian cell is a chondrocyte (e.g., a non-disc chondrocyte, a juvenile chondrocyte, or a primed chondrocyte; see dependent claims 16-17) in claims 13, 16-18 and 21-22 of copending Application No. 17/599,831 anticipates the claimed genus 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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 4-5, 7-8 and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of copending Application No. 18/900,083 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because a method for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site of a mammal, comprising: a) inserting a gene encoding a protein having intervertebral disc regenerating function (e.g., TGF-beta superfamily protein; dependent claim 2) into a first mammalian cell to provide a transduced first mammalian cells; and b) transplanting a mixture of the transduced first mammalian cell of a) and an unmodified second mammalian cell into the intervertebral disc defect site of the mammal, wherein the first mammalian cell is human embryonic kidney cells or epithelial cells, and wherein the second mammalian cell is connective tissue cells (e.g., chondrocyte such as a non-disc chondrocyte, a juvenile chondrocyte or a primed chondrocyte; see dependent claims 3-5) in claims 1-7 of copending Application No. 18/900,083 anticipates the claimed genus 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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2 and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of copending Application No. 18/900,011 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because a method for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site of a mammal, comprising: a) inserting a gene encoding a protein having intervertebral disc regenerating function (e.g., TGF-beta superfamily protein; dependent claim 2) into a first mammalian connective tissue cell to provide a transduced first mammalian connective tissue cell; and b) transplanting a mixture of the transduced first mammalian cell of a) and an unmodified second mammalian connective tissue cell (e.g., wherein the first and second connective tissue cells are chondrocytes such as a non-disc chondrocyte, a juvenile chondrocyte or a primed chondrocyte; see dependent claims 3-5) into the intervertebral disc defect site in claims 1-7 of copending Application No. 18/900,011 anticipates the claimed genus 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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 13, 20 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 18/134,383 (reference application) in view of Noh et al (WO 2009/117740; IDS).
The instant claims differ from claims 1-22 of copending Application No. 18/134,383 in reciting specifically “wherein the method improves structural recovery by increasing the disc height index of the damaged or degenerating intervertebral disc as measured by X-ray analysis” (claim 20); and “wherein the method improves structural recovery at an intervertebral disc defect site as measured by a magnetic resonance imaging analysis of the intervertebral disc defect site” (claim 22).
Before the effective filing date of the present application (03/29/2019), Noh et al already disclosed at least a method for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site (e.g., torn or herniated) of a mammal, the method comprises: a) inserting a gene encoding a protein having intervertebral disc regenerating function (e.g., a member of TGF-beta superfamily such as TGF-beta1, BMP-2, BMP-3, BMP-4, BMP-7/OP-1 and others) into a first mammalian connective tissue cell, and b) transplanting a mixture of the mammalian connective tissue cell of a) and unmodified second mammalian connective tissue cell into the intervertebral disc defect site; preferably the method does not use a scaffolding or any supporting structure for the cells; wherein the first and second mammalian connective tissue cell may be chondrocyte (e.g., non-disc chondrocyte, juvenile chondrocyte, and specifically the chondrocyte for the second mammalian connective tissue cell is a primed chondrocyte) or fibroblast; and either or both the first and second connective tissue cell may be autologous or allogeneic relative to the mammalian subject or to each other (paragraphs [0002], [0005], [0007], [0035]-[0036], [0043], [0047], [0052]; and Example IV). In Example IV. 1, Noh et al further taught the use of X-ray radiograph to obtain a disc height index of the intervertebral disc to measure its morphology, its level of degeneration or regeneration (paragraphs [0008], [00102]; and Fig. 1D-F); as well as the use of MRI (magnetic resonance image) radiograph to show healing, the slowing, retardation or prevention of degeneration of injured disc (paragraphs [0008], [[0093], 00102]; and Fig. 1A-C).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the treatment method in claims 1-22 of copending Application No. 18/134,383 by also analyzing X-ray radiographs to measure increasing disc height index of the damaged or degenerating intervertebral disc, as well as analyzing MRI radiographs to measure improved structural recovery at an intervertebral disc defect site; in light of the teachings of Noh 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 Noh et al already taught the use of X-ray radiograph to obtain a disc height index of the intervertebral disc to measure its morphology, its level of degeneration or regeneration; as well as the use of MRI (magnetic resonance image) radiograph to show healing, the slowing, retardation or prevention of degeneration of injured disc.
The modified treatment method resulting from claims 1-22 of copending Application No. 18/134,383 along with teachings of Noh 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.
Claims 1-4, 6-11, 13-20 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of copending Application No. 18/900,083, or claims 13, 16-18 and 21-22 of copending Application No. 17/599,831 (reference application) in view of Noh et al (WO 2009/117740; IDS), Ra et al (US 2010/0196329) and Strbo et al (WO 2018/071405).
The instant claims differ from claims 1-7 of copending Application No. 18/900,083, or claims 13, 16-18 and 21-22 of copending Application No. 17/599,831 in reciting specifically at least that the human embryonic kidney cell or an epithelial cell is irradiated; the chondrocyte is primed by incubation with a cytokine such as TGF-beta1; the damaged or degenerating intervertebral disc is a herniated disc or a thinning disc; the ratio of the first mammalian cells and the second mammalian cells; a pharmaceutical carrier comprising about 10 to 20% (w/w) DMSO and about 1 to 5% (w/w) saccharose; using X-ray analysis to measure increased the disc height index of the damaged or degenerating intervertebral disc; and using magnetic resonance imaging analysis to measure improved structural recovery at an intervertebral disc defect site.
Before the effective filing date of the present application (03/29/2019), Noh et al already disclosed at least a method for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site (e.g., torn or herniated) of a mammal, the method comprises: a) inserting a gene encoding a protein having intervertebral disc regenerating function (e.g., a member of TGF-beta superfamily such as TGF-beta1, BMP-2, BMP-3, BMP-4, BMP-7/OP-1 and others) into a first mammalian connective tissue cell, and b) transplanting a mixture of the mammalian connective tissue cell of a) and unmodified second mammalian connective tissue cell into the intervertebral disc defect site; preferably the method does not use a scaffolding or any supporting structure for the cells; wherein the first and second mammalian connective tissue cell may be chondrocyte (e.g., non-disc chondrocyte, juvenile chondrocyte, and specifically the chondrocyte for the second mammalian connective tissue cell is a primed chondrocyte) or fibroblast; and either or both the first and second connective tissue cell may be autologous or allogeneic relative to the mammalian subject or to each other (paragraphs [0002], [0005], [0007], [0035]-[0036], [0043], [0047], [0052]; and Example IV). Noh et al also taught that the ratio of cells that have not been transfected or transduced with a gene encoding a member of the transforming growth factor beta superfamily to cells that have been transfected or transduced with a TGF superfamily gene may be in the range of about 3-20 to 1, 3-10 to 1 or about 10 to 1 (paragraph [0028]). Noah et al also stated “ When these fibroblastic chondrocytes are incubated or “primed” with a cytokine such as a protein from the TGF-beta superfamily, the cells regain their chondrocytic characteristics, which include production of collagen” (paragraph [0046]); “An advantage of using primed cells in retardation of intervertebral disc degeneration is the ease of creating usable chondrocytes for introduction into the intervertebral disc for production of collagen and otherwise maintenance of the cartilaginous matrix” (paragraph [0047]); and “Alternatively, the cells may be incubated with the cytokine of interest for a time and the combination may be administered to the site of defect without separating out the cytokine” (paragraph [0050]). Noh et al further disclosed that a compound for parenteral administration to a patient in a therapeutically or prophylactically effective amount that includes a TGF-beta superfamily protein and a suitable pharmaceutically acceptable carrier (paragraphs [0058]-[0059]). Noh et al also taught that the connective tissue cell may be stored frozen in 10% DMSO in liquid nitrogen (paragraph [0063]), or in an exemplary cryopreservative media of DMEM, FBS and DMSO in a 5:4:1 ratio (last sentence of paragraph [00117]). In Example IV. 1, Noh et al taught the use of X-ray radiograph to obtain a disc height index of the intervertebral disc to measure its morphology, its level of degeneration or regeneration (paragraphs [0008], [00102]; and Fig. 1D-F); as well as the use of MRI (magnetic resonance image) radiograph to show healing, the slowing, retardation or prevention of degeneration of injured disc (paragraphs [0008], [[0093], 00102]; and Fig. 1A-C).
Additionally, Ra et al already disclosed at least a cell therapeutic composition comprising adipose-tissue derived mesenchymal stem cells and sucrose as an excipient, and wherein the composition further additionally comprising DMSO as the excipient (Abstract; Summary of the Invention; particularly paragraphs [0010]-[0014]). Ra et al stated “[w]hen the inventive cell therapeutic compositions containing adipose tissue-derived stem cells were stored under frozen storage conditions, the composition containing physiological saline, sucrose, albumin and cryopreservative DMSO showed the highest cell viability upon thawing, and it was observed that the addition of albumin and sugar components to the cell therapeutic composition protected the cells during the freezing and thawing of the cell to improve the viability of the cells” (paragraph [0048]). Ra et al demonstrated that the cell viability in frozen storage conditions was further increased in a formulation comprising physiological saline, PBS or Harman-D solution, as a base, 2% sucrose and 5% albumin and 10% DMSO (Example 7, particularly paragraph [0065] and Table 3).
Moreover, Strbo et al already taught the use of HEK293 cells that are transfected with the gp96-Ig-ZIKV antigen expression vector for the treatment of a flavivirus infection in a subject, wherein the transfected HEK293 cells were first irradiated (12,000 rads), then suspended in freezing medium comprising 10% DMSO, and 25% human serum albumin prior to subcutaneous administration to a patient (see at least Abstract; particularly paragraphs [0037]-[0039]).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the treatment method in claims 1-7 of copending Application No. 18/900,083, or claims 13, 16-18 and 21-22 of copending Application No. 17/599,831 by also having the above “features” recited in the claims of the present application; in light of the teachings of Noh et al, Ra et al, and Strbo 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: (i) Noh et al already taught to treat an intervertebral disc defect site (e.g., torn or herniated) of a mammal; the ratio of cells that have not been transfected or transduced with a gene encoding a member of the transforming growth factor beta superfamily to cells that have been transfected or transduced with a TGF superfamily gene may be in the range of about 3-20 to 1, 3-10 to 1 or about 10 to 1; the chondrocytes may be incubated with the cytokine of interest (e.g., TGF-beta1) for a time and the combination may be administered to the site of defect without separating out the cytokine; the use of X-ray radiograph to obtain a disc height index of the intervertebral disc to measure its morphology, its level of degeneration or regeneration; as well as the use of MRI (magnetic resonance image) radiograph to show healing, the slowing, retardation or prevention of degeneration of injured disc; (ii) Ra et al already demonstrated that the cell viability for a stem cell therapeutic composition in frozen storage conditions was increased in a formulation comprising physiological saline, PBS or Harman-D solution, as a base, 2% sucrose and 5% albumin, and 10% DMSO; and (iii) Strbo et al already taught successfully the use of irradiated HEK293 cells that were transfected with the gp96-Ig-ZIKV antigen expression vector in a freezing medium comprising 10% DMSO and 25% human serum albumin for subcutaneous administration into a patient in need of a flavivirus infection treatment.
The modified treatment method resulting from claims 1-7 of copending Application No. 18/900,083, or claims 13, 16-18 and 21-22 of copending Application No. 17/599,831 along with teachings of Noh et al, Ra et al and Strbo 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.
Claims 1-3, 13-20 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of copending Application No. 18/900,011 (reference application) in view of Noh et al (WO 2009/117740; IDS), Ra et al (US 2010/0196329) and Strbo et al (WO 2018/071405).
The instant claims differ from claims 1-7 of copending Application No. 18/900,011 in reciting specifically at least that a TGF-beta superfamily protein is TGF-beta1; the chondrocyte is primed by incubation with a cytokine such as TGF-beta1; the damaged or degenerating intervertebral disc is a herniated disc or a thinning disc; the ratio of the first mammalian connective tissue cells and the second mammalian connective tissue cells; a pharmaceutical carrier comprising about 10 to 20% (w/w) DMSO and about 1 to 5% (w/w) saccharose; using X-ray analysis to measure increased the disc height index of the damaged or degenerating intervertebral disc; and using magnetic resonance imaging analysis to measure improved structural recovery at an intervertebral disc defect site.
Before the effective filing date of the present application (03/29/2019), Noh et al already disclosed at least a method for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site (e.g., torn or herniated) of a mammal, the method comprises: a) inserting a gene encoding a protein having intervertebral disc regenerating function (e.g., a member of TGF-beta superfamily such as TGF-beta1, BMP-2, BMP-3, BMP-4, BMP-7/OP-1 and others) into a first mammalian connective tissue cell, and b) transplanting a mixture of the mammalian connective tissue cell of a) and unmodified second mammalian connective tissue cell into the intervertebral disc defect site; preferably the method does not use a scaffolding or any supporting structure for the cells; wherein the first and second mammalian connective tissue cell may be chondrocyte (e.g., non-disc chondrocyte, juvenile chondrocyte, and specifically the chondrocyte for the second mammalian connective tissue cell is a primed chondrocyte) or fibroblast; and either or both the first and second connective tissue cell may be autologous or allogeneic relative to the mammalian subject or to each other (paragraphs [0002], [0005], [0007], [0035]-[0036], [0043], [0047], [0052]; and Example IV). Noh et al also taught that the ratio of cells that have not been transfected or transduced with a gene encoding a member of the transforming growth factor beta superfamily to cells that have been transfected or transduced with a TGF superfamily gene may be in the range of about 3-20 to 1, 3-10 to 1 or about 10 to 1 (paragraph [0028]). Noah et al also stated “ When these fibroblastic chondrocytes are incubated or “primed” with a cytokine such as a protein from the TGF-beta superfamily, the cells regain their chondrocytic characteristics, which include production of collagen” (paragraph [0046]); “An advantage of using primed cells in retardation of intervertebral disc degeneration is the ease of creating usable chondrocytes for introduction into the intervertebral disc for production of collagen and otherwise maintenance of the cartilaginous matrix” (paragraph [0047]); and “Alternatively, the cells may be incubated with the cytokine of interest for a time and the combination may be administered to the site of defect without separating out the cytokine” (paragraph [0050]). Noh et al further disclosed that a compound for parenteral administration to a patient in a therapeutically or prophylactically effective amount that includes a TGF-beta superfamily protein and a suitable pharmaceutically acceptable carrier (paragraphs [0058]-[0059]). Noh et al also taught that the connective tissue cell may be stored frozen in 10% DMSO in liquid nitrogen (paragraph [0063]), or in an exemplary cryopreservative media of DMEM, FBS and DMSO in a 5:4:1 ratio (last sentence of paragraph [00117]). In Example IV. 1, Noh et al taught the use of X-ray radiograph to obtain a disc height index of the intervertebral disc to measure its morphology, its level of degeneration or regeneration (paragraphs [0008], [00102]; and Fig. 1D-F); as well as the use of MRI (magnetic resonance image) radiograph to show healing, the slowing, retardation or prevention of degeneration of injured disc (paragraphs [0008], [[0093], 00102]; and Fig. 1A-C).
Additionally, Ra et al already disclosed at least a cell therapeutic composition comprising adipose-tissue derived mesenchymal stem cells and sucrose as an excipient, and wherein the composition further additionally comprising DMSO as the excipient (Abstract; Summary of the Invention; particularly paragraphs [0010]-[0014]). Ra et al stated “[w]hen the inventive cell therapeutic compositions containing adipose tissue-derived stem cells were stored under frozen storage conditions, the composition containing physiological saline, sucrose, albumin and cryopreservative DMSO showed the highest cell viability upon thawing, and it was observed that the addition of albumin and sugar components to the cell therapeutic composition protected the cells during the freezing and thawing of the cell to improve the viability of the cells” (paragraph [0048]). Ra et al demonstrated that the cell viability in frozen storage conditions was further increased in a formulation comprising physiological saline, PBS or Harman-D solution, as a base, 2% sucrose and 5% albumin and 10% DMSO (Example 7, particularly paragraph [0065] and Table 3).
Moreover, Strbo et al already taught the use of HEK293 cells that are transfected with the gp96-Ig-ZIKV antigen expression vector for the treatment of a flavivirus infection in a subject, wherein the transfected HEK293 cells were first irradiated (12,000 rads), then suspended in freezing medium comprising 10% DMSO, and 25% human serum albumin prior to subcutaneous administration to a patient (see at least Abstract; particularly paragraphs [0037]-[0039]).
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the treatment method in claims 1-7 of copending Application No. 18/900,011 by also having the above “features” recited in the claims of the present application; in light of the teachings of Noh et al, Ra et al, and Strbo 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: (i) Noh et al already taught to treat an intervertebral disc defect site (e.g., torn or herniated) of a mammal; the ratio of cells that have not been transfected or transduced with a gene encoding a member of the transforming growth factor beta superfamily to cells that have been transfected or transduced with a TGF superfamily gene may be in the range of about 3-20 to 1, 3-10 to 1 or about 10 to 1; the chondrocytes may be incubated with the cytokine of interest (e.g., TGF-beta1) for a time and the combination may be administered to the site of defect without separating out the cytokine; the use of X-ray radiograph to obtain a disc height index of the intervertebral disc to measure its morphology, its level of degeneration or regeneration; as well as the use of MRI (magnetic resonance image) radiograph to show healing, the slowing, retardation or prevention of degeneration of injured disc; (ii) Ra et al already demonstrated that the cell viability for a stem cell therapeutic composition in frozen storage conditions was increased in a formulation comprising physiological saline, PBS or Harman-D solution, as a base, 2% sucrose and 5% albumin, and 10% DMSO; and (iii) Strbo et al already taught successfully the use of irradiated HEK293 cells that were transfected with the gp96-Ig-ZIKV antigen expression vector in a freezing medium comprising 10% DMSO and 25% human serum albumin for subcutaneous administration into a patient in need of a flavivirus infection treatment.
The modified treatment method resulting from claims 1-7 of copending Application No. 18/900,011 along with teachings of Noh et al, Ra et al and Strbo 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.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Song et al (Tissue Engineering 10:665-672, 2004; IDS) disclosed regeneration of hyaline articular cartilage with irradiated transforming growth factor Beta1-producing fibroblasts (abstract).
Conclusions
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.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631
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