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 US application with the Serial Number 17/092,779, filed on 11/09/2020, now abandoned; which is a CON of PCT/US20/25705, filed on 03/30/2020; which claims benefit of the provisional application 62/826,676, filed on 03/29/2019.
Upon review of the specifications of the above US applications and the provisional application, it is determined that examined claims are only entitled to the filing date of 04/13/2023. This is because there is no written support in any of the above U.S. applications and provisional application for a method for preventing or treating chronic back pain, including discogenic back pain, in a subject in need thereof.
Claim Objections
Claim 11 is objected to because of the claim is not ended with a period.
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 1-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method for treating chronic back pain in a subject in need thereof, 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 and a second mammalian cell that does not comprise the exogenous nucleotide sequence and is a connective tissue cell;
does not reasonably provide enablement for a method for preventing chronic pain in a subject in need thereof 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 a method for preventing or treating chronic back pain in a subject in need thereof as claimed broadly for the reasons discussed below.
1. The breadth of the claims
Claims 1-22 encompass a method for preventing or treating chronic back pain in a subject in need thereof, 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 (e.g., a chondrocyte, a fibroblast, an epithelial cell, a human embryonic kidney cell, and a HEK-293 cell) comprising an exogenous nucleotide sequence encoding a protein having an intervertebral disc regenerating function (e.g., members of TGF-beta superfamily such as TGF-beta1, BMP-2, BMP-3, BMP-4, BMP-7/OP-1 and others) and a second mammalian cell that does not comprise the exogenous nucleotide sequence and is a connective tissue cell (e.g., a chondrocyte, a non-disc chondrocyte, a juvenile chondrocyte, or a primed chondrocyte).
2. The state and the unpredictability of the prior art
Before the filing date of the present application (04/13/2023), virtually nothing was known about a method for preventing chronic back pain in a subject in need thereof as evidenced at least by the teachings of Noh et al (WO 2009/117740; IDS), Freemont (Rheumatology 48:5-10, 2009), Kenon et al (BioMol Concepts 9:43-52, 2018; IDS) and Hodgkinson et al (JOR Spine 2:e1045; DOI: 10.1002/jsp2.1045; 15 pages, 2019; IDS). In a 2018 review, Kennon et al stated “Chronic low back pain is a critical health problem and a leading cause of disability in aging populations. A major cause of low back pain is considered to be a degeneration of the intervertebral disc (IVD)….The role of growth factors in IVD tissue engineering appears promising; however, further extensive research is needed at both basic science and clinical levels before its application is appropriate for clinical use” (Abstract). In a 2019 review, Hodgkinson et al still stated “Intervertebral disc (IVD) degeneration is a major contributing factor to chronic low back pain and disability, leading to imbalance between anabolic and catabolic processes, altered extracellular matrix composition, loss of tissue hydration, inflammation, and impaired mechanical functionality. Current treatments aim to manage symptoms rather than treat underlying pathology” (Abstract). Furthermore, please note that the physiological art is recognized as unpredictable (MPEP 2164.03).
3. The amount of direction or guidance provided
Apart from disclosing intradiscal injection of the mixed cell (a mix of human allogeneic chondrocytes and irradiated GP2-293 cells expressing exogeneous TGF-beta1 at the respective cell ratio of 3:1) treatment significantly alleviates discogenic low back pain in monosodium iodoacetate (MIA)-induced low back pain (LBP) rat model (see at least Examples VI-XI); the instant specification fails to provide sufficient guidance for an ordinary skilled artisan on how to prevent chronic back pain, including a discogenic back pain, in any subject in need thereof as encompassed broadly by the instant claims. There is no evidence of record indicating that a chronic back pain in any subject has been prevented. In a 2018 review, Kennon et al still disclosed that chronic low back pain is a critical health problem and a leading cause of disability in aging populations (first sentence of abstract). Even in a 2019 review, Kennon still taught that extensive research is needed at both basic science and clinical levels before its application is appropriate for clinical use (last sentence of abstract). Since the prior art before the filing date of the present application failed to provide sufficient guidance on how to prevent chronic back pain in a subject, it is incumbent upon the present application to do so. Given the state of the prior art discussed above, coupled with the lack of sufficient guidance provided by the present application, it would have required undue experimentation for a skilled artisan to make and use the present broadly claimed invention.
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 issue set forth above, the state and unpredictability of the relevant art, and the breadth of the instant 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 § 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 1-3, 12-18 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Noh et al (WO 2009/117740; IDS) in view of Freemont (Rheumatology 48:5-10; 2009).
The instant claims encompass a method for treating chronic back pain in a subject in need thereof, 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 (e.g., 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., a member of the TGF-beta superfamily such as TGF-beta1) and a second mammalian cell that does not comprise the exogenous nucleotide sequence and is a connective tissue cell (e.g., a chondrocyte).
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 via injection; 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 [00102]; Examples I and 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 explicitly treat a subject with a chronic back pain, including a discogenic back pain.
Before the filing date of the present application (04/13/2023), Freemont taught that molecular pathology has shown intervertebral disc (IVD) degeneration is a major cause of low back pain (Abstract). Freemont stated “Studies examining the problem from different directions (e.g. examination of volunteers [4] and patients [5], imaging investigations [6], trials of intervention [7]) have produced evidence implicating the intervertebral disc (IVD) in a significant proportion (at least 40%) of cases of chronic back pain, leading to the use of the term “discogenic back pain”. From the work that has been carried out to date two processes stand out as being important in the origins of discogenic back pain, disc degeneration and nociceptive nerve ingrowth into the normally aneural IVD” (page 5, left column, second and third paragraphs in the “Introduction” section). Freemont also stated “Overall, current data indicate that normal IVD matrix prevents nerve ingrowth into the IVD, but that in degeneration changes in the structure of aggrecan, coupled with altered IVD cell biology lead to nerve ingrowth into pain level IVD and that this is enhanced by the production of neurogenic cytokines during neovascularization of the degenerate IVD” (page 8, left column, last paragraph).
Accordingly, it would have been obvious for an ordinary skilled artisan to modify the teachings of Noh et al by also at least treating a subject with a chronic back pain, including discogenic back pain, in light of the teachings of Freemont as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modification because Freemont already taught that molecular pathology has shown intervertebral disc (IVD) degeneration is a major cause of low back pain.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Noh et al and Freemont; 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 and Freemont as set forth above is indistinguishable and encompassed by the presently claimed invention. Since the modified treatment method has the same method steps and starting materials as those of the presently claimed invention, particularly the treatment method of Noh et al is already useful for preventing or retarding degeneration of intervertebral disc at an intervertebral disc defect site in a mammal, such treatment method would naturally result at least in the reduction of discogenic back pain in the subject, reduction in the sensitivity of the subject to the discogenic back pain, and reduction of TrpV1 or TrpA1-depdnent calcium influx.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 4-11 are rejected under 35 U.S.C. 103 as being unpatentable over Noh et al (WO 2009/117740; IDS) in view of Freemont (Rheumatology 48:5-10; 2009) as applied to claims 1-3, 12-18 and 20-22 above, and further in view of Harpstead (US 6,479,066; IDS), Thomas et al (J. Pharm. Toxicologic. Methods 51:187-200, 2005; IDS), Masuda et al (The Spine Journal 4:3308-3408, 2004; IDS) and Strbo et al (WO 2018/071405).
The combined teachings of Noh et al and Freemont were presented above. However, none of the cited references teach specifically administering an effective amount of 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; and the human embryonic kidney cell or an epithelial cell is irradiated.
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).
Furthermore, 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 and Freemont 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 in the subject; as well as 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 the subject; in light of the teachings of Harpstead, Thomas et al, Masuda et al and Strbo et al as presented above.
An ordinary skilled artisan would have been motivated to further 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. Furthermore, 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, Freemont, 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, Freemont, 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.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Noh et al (WO 2009/117740; IDS) in view of Freemont (Rheumatology 48:5-10; 2009) as applied to claims 1-3, 12-18 and 20-22 above, and further in view of Ra et al (US 2010/0196329) and Strbo et al (WO 2018/071405).
The combined teachings of Noh et al and Freemont were presented above. However, none of the cited references 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 filing date of the present application (04/13/2023), 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 further modify the combined teachings of Noh et al and Freemont 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 further 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, Freemont, 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, Freemont, 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 1-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-22 of copending Application No. 18/134,401 (reference application) in view of Freemont (Rheumatology 48:5-10; 2009).
The instant claims differ from claims 1-12 and 14-22 of copending Application No. 18/134,401 in reciting specifically “A method for preventing or treating chronic back pain in a subject”.
Before the filing date of the present application (04/13/2023), Freemont taught that molecular pathology has shown intervertebral disc (IVD) degeneration is a major cause of low back pain (Abstract). Freemont stated “Studies examining the problem from different directions (e.g. examination of volunteers [4] and patients [5], imaging investigations [6], trials of intervention [7]) have produced evidence implicating the intervertebral disc (IVD) in a significant proportion (at least 40%) of cases of chronic back pain, leading to the use of the term “discogenic back pain”. From the work that has been carried out to date two processes stand out as being important in the origins of discogenic back pain, disc degeneration and nociceptive nerve ingrowth into the normally aneural IVD” (page 5, left column, second and third paragraphs in the “Introduction” section). Freemont also stated “Overall, current data indicate that normal IVD matrix prevents nerve ingrowth into the IVD, but that in degeneration changes in the structure of aggrecan, coupled with altered IVD cell biology lead to nerve ingrowth into pain level IVD and that this is enhanced by the production of neurogenic cytokines during neovascularization of the degenerate IVD” (page 8, left column, last paragraph).
Accordingly, it would have been obvious for an ordinary skilled artisan to modify the method for restoring a damaged or degenerating intervertebral disc in a subject in claims 1-12 and 14-22 of copending Application No. 18/134,401 by also applying the method for treating a subject with a chronic back pain, including discogenic back pain, in light of the teachings of Freemont as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modification because Freemont already taught that molecular pathology has shown intervertebral disc (IVD) degeneration is a major cause of low back pain; and the method for restoring a damaged or degenerating intervertebral disc in a subject of the copending Application No. 18/134,401 would be useful and applicable.
An ordinary skilled artisan would have a reasonable expectation of success in light of claims 1-12 and 14-22 of copending Application No. 18/134,401 along with the teachings of Freemont; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified treatment method resulting from claims 1-12 and 14-22 of copending Application No. 18/134,401 along with the teachings of Freemont as set forth above is indistinguishable and encompassed by the presently claimed invention. Since the modified treatment method has the same method steps and starting materials as those of the presently claimed invention, such treatment method would naturally result at least in the reduction of discogenic back pain in the subject, reduction in the sensitivity of the subject to the discogenic back pain, and reduction of TrpV1 or TrpA1-depdnent calcium influx.
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 1-22 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), Freemont (Rheumatology 48:5-10; 2009), 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 a method for preventing or treating chronic back pain in a subject; 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 chronic back pain is a discogenic back pain; the ratio of the first mammalian cells and the second mammalian cells; and a pharmaceutical carrier comprising about 10 to 20% (w/w) DMSO and about 1 to 5% (w/w) saccharose.
Before the filing date of the present application (04/13/2023), 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 via injection; 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 [00102]; Examples I and 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, Freemont already taught that molecular pathology has shown intervertebral disc (IVD) degeneration is a major cause of low back pain (Abstract). Freemont stated “Studies examining the problem from different directions (e.g. examination of volunteers [4] and patients [5], imaging investigations [6], trials of intervention [7]) have produced evidence implicating the intervertebral disc (IVD) in a significant proportion (at least 40%) of cases of chronic back pain, leading to the use of the term “discogenic back pain”. From the work that has been carried out to date two processes stand out as being important in the origins of discogenic back pain, disc degeneration and nociceptive nerve ingrowth into the normally aneural IVD” (page 5, left column, second and third paragraphs in the “Introduction” section). Freemont also stated “Overall, current data indicate that normal IVD matrix prevents nerve ingrowth into the IVD, but that in degeneration changes in the structure of aggrecan, coupled with altered IVD cell biology lead to nerve ingrowth into pain level IVD and that this is enhanced by the production of neurogenic cytokines during neovascularization of the degenerate IVD” (page 8, left column, last paragraph).
Moreover, Ra et al also 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).
Furthermore, 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, Freemont, 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; and 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; (ii) Freemont already taught that molecular pathology has shown intervertebral disc (IVD) degeneration is a major cause of low back pain; (iii) 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 (iv) 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, Freemont, Ra et al and Strbo et al is indistinguishable and encompassed by the presently claimed invention. Since the modified treatment method has the same method steps and starting materials as those of the presently claimed invention, such treatment method would naturally result at least in the reduction of discogenic back pain in the subject, reduction in the sensitivity of the subject to the discogenic back pain, and reduction of TrpV1 or TrpA1-depdnent calcium influx.
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 and 12-22 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), Freemont (Rheumatology 48:5-10; 2009), 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 a method for preventing or treating chronic back pain in a subject; a TGF-beta superfamily protein is TGF-beta1; the chondrocyte is primed by incubation with a cytokine such as TGF-beta1; the chronic back pain is a discogenic back pain; the ratio of the first mammalian connective tissue cells and the second mammalian connective tissue cells; and a pharmaceutical carrier comprising about 10 to 20% (w/w) DMSO and about 1 to 5% (w/w) saccharose.
Before the filing date of the present application (04/13/2023), 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 via injection; 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 [00102]; Examples I and 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, Freemont already taught that molecular pathology has shown intervertebral disc (IVD) degeneration is a major cause of low back pain (Abstract). Freemont stated “Studies examining the problem from different directions (e.g. examination of volunteers [4] and patients [5], imaging investigations [6], trials of intervention [7]) have produced evidence implicating the intervertebral disc (IVD) in a significant proportion (at least 40%) of cases of chronic back pain, leading to the use of the term “discogenic back pain”. From the work that has been carried out to date two processes stand out as being important in the origins of discogenic back pain, disc degeneration and nociceptive nerve ingrowth into the normally aneural IVD” (page 5, left column, second and third paragraphs in the “Introduction” section). Freemont also stated “Overall, current data indicate that normal IVD matrix prevents nerve ingrowth into the IVD, but that in degeneration changes in the structure of aggrecan, coupled with altered IVD cell biology lead to nerve ingrowth into pain level IVD and that this is enhanced by the production of neurogenic cytokines during neovascularization of the degenerate IVD” (page 8, left column, last paragraph).
Moreover, Ra et al also 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).
Furthermore, 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 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, Freemont, 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; and 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; (ii) Freemont already taught that molecular pathology has shown intervertebral disc (IVD) degeneration is a major cause of low back pain; (iii) 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 (iv) 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, Freemont, Ra et al and Strbo et al is indistinguishable and encompassed by the presently claimed invention. Since the modified treatment method has the same method steps and starting materials as those of the presently claimed invention, such treatment method would naturally result at least in the reduction of discogenic back pain in the subject, reduction in the sensitivity of the subject to the discogenic back pain, and reduction of TrpV1 or TrpA1-depdnent calcium influx.
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.
1. 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).
2. Moore et al (US 2013/0197094) disclosed administration of an effective amount of a TRPV1 compound at or near a target site to relieve pain caused by diverse sources, including postoperative pain, spinal disc herniation, discogenic back pain and joint pain (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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