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 – 14 are pending.
Priority
This application claims foreign priority to Japanese Patent Application No. 2022-031332 filed 03/01/2022.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/11/2024 and 02/19/2026 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The use of the term Knockout, Lenti-X, GoStix, NucleoBond Xtra, NucleoSpin, PrimeScript, Ex Taq, Adeno-X, CalPhos Mammalian Transfection Kit, FACStarPLUS, Vectashield, MycoAlert, CellBanker, RNeasy SuperScript, CellTiter-Glo, GloMaxDiscover, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because the sentence structure is awkward. A suggested wording is “A composition that regenerates myelin sheath or proliferates Schwann cells comprising a culture supernatant from immortalized mesenchymal stem cells, wherein the immortalized mesenchymal stem cells comprise a telomerase reverse transcription enzyme (TERT) gene and two or three genes selected from the group consisting of Bmi-1, HPV 16-E6, and HPV 16-E7. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: in line 4, “a group consisting of” should read “the group consisting of” because of a grammatical error in reciting “a” instead of “the” when reciting a Markush group. Appropriate correction is required. See MPEP 2173.05(h) for language for reciting a Markush group.
Claim 2 is objected to because of the following informalities: in line 2, “HPVE16-E6” should read “HPV 16-E6” for consistency with claim 1. Appropriate correction is required.
Claim 3 is objected to because of the following informalities: in line 1, “claims” should read “claim” because only one claim is recited. Appropriate correction is required.
Claim 9 is objected to because of the following informalities: in line 2 “is central nerve one, and anyone” should read “is a central nervous system demyelinating disease, and any one” to correct grammar and based on Applicant’s specification at page 3, para. 0004. Appropriate correction is required.
Claim 9 is objected to because of the following informalities: in line 2, “a group consisting of” should read “the group consisting of” because of a grammatical error in reciting “a” instead of “the” when reciting a Markush group. Appropriate correction is required. See MPEP 2173.05(h) for language for reciting a Markush group.
Claim 10 is objected to because of the following informalities: in line 2 “is peripheral nerve one, and anyone” should read “is a peripheral neurogenic demyelinating disease, and any one” to correct grammar and based on Applicant’s specification at page 3, para. 0004. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: in line 2, “a group consisting of” should read “the group consisting of” because of a grammatical error in reciting “a” instead of “the” when reciting a Markush group. Appropriate correction is required. See MPEP 2173.05(h) for language for reciting a Markush group.
Claim 13 is objected to because the sentence structure is awkward. A suggested wording is “A pharmaceutical preparation for the treatment of chemotherapeutic agent-induced peripheral neuropathy comprising a culture supernatant from immortalized mesenchymal stem cells, wherein the immortalized mesenchymal stem cells comprise a telomerase reverse transcription enzyme (TERT) gene and two or three genes selected from the group consisting of Bmi-1, HPV 16-E6, and HPV 16-E7 Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5 and 9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 5, it is unclear what “them” in line 3 refers to.
Regarding claim 9, it is unclear whether “HTLB-1 related myelopathy” is a demyelinating disease and whether this should read HTLV-1 related myelopathy, which is known in the art as a demyelinating disease.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 9 and 10 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 does not further limit claim 7 because atopic myelitis is not known in the art to be a demyelinating disease. Therefore, recitation of atopic myelitis broadens the claim to include diseases that are not demyelinating diseases.
Claim 10 does not further limit claim 7 because herpes zoster is not known in the art to be a demyelinating disease. Therefore, recitation of herpes zoster broadens the claim to include diseases that are not demyelinating diseases.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Improper Markush Grouping
Claim 9 and 10 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of demyelinating diseases of claim 9 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: atopic myelitis is not a member of the recognized class of demyelinating diseases and therefore inclusion of atopic myelitis does not meet the requirements for a proper Markush grouping.
The Markush grouping of demyelinating diseases of claim 10 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: herpes zoster is not a member of the recognized class of demyelinating diseases and therefore inclusion of herpes zoster does not meet the requirements for a proper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Interpretation
Regarding the preamble of “that regenerates myelin sheath or proliferates Schwann cells” of claim 1, and the preamble of “for demyelinating disease” of claim 7, and the preamble of “for the treatment of chemotherapeutic agent-induced peripheral neuropathy” of claim 12, the preamble is not limiting because the body of the claim describes a complete invention (a particular culture supernatant also referred to as conditioned medium and SHED-CM, see Specification at para. 0003, 0037, 0104, and 0193) and the language recited solely in the preamble does not provide any distinct definition of any of the claimed inventions’ limitations, namely an intended use for that culture supernatant. Thus, the preamble of the claims is not considered a limitation and is of no significance to claim construction. For purposes of examination, claims 1, 7, and 12 and dependent claims 2 – 6, 8 – 11, 13, and 14 are considered to be limited to the claimed conditioned medium composition, regardless of the intended use of that composition.
For the purpose of applying prior art, “HPV16-E6” and “HPV16-E7” of claims 1, 2, and 12 are interpreted as HPV-E6 and HPV-E7 based on Applicant’s specification at para. 0127.
For the purpose of applying prior art, claim 6 is interpreted as the culture supernatant comprises a component that acts on c-MET where the component includes HGF based on Applicant’s specification at para. 0218.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1, 3, 4, 7, and 12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ashiba (Ashiba, Keisuke, et al. Inflammation and Regeneration 35.2 (2015): 057-060.), hereinafter Ashiba which is cited on the IDS filed 12/11/2024.
Claim 1 recites A composition that regenerates myelin sheath or proliferates Schwann cells, wherein the composition contains a culture supernatant of immortalized mesenchymal stem cells to which a gene set of telomerase reverse transcription enzyme (TERT) and two or three genes selected from a group consisting of Bmi-1 gene, HPV 16-E6 gene, and HPV 16-E7 gene are introduced.
Claim 7 recites A therapeutic pharmaceutical preparation for demyelinating diseases that comprises the composition claimed in claim 4 as an active ingredient.
Claim 12 recites A pharmaceutical preparation for the treatment of chemotherapeutic agent-induced peripheral neuropathy that comprises a composition as an active ingredient, wherein the composition contains a culture supernatant of immortalized mesenchymal stem cells to which a gene set of telomerase reverse transcription enzyme (TER T) and two or three genes selected from a group consisting of Bmi-1 gene, HPV 16-E6 gene, and HPV 16-E7 gene are introduced.
Regarding claims 1 and 12, Ashiba teaches a composition comprising conditioned media from immortalized mesenchymal stem cells that were immortalized by introducing hTERT, HPV E6 and HPV E7 genes (page 58, right col. para. 2; page 59, right col. para. 2). Ashiba teaches conditioned media is from stem cell culture that does not contain cells (page 58, left col. para. 2).
Regarding claims 3, 4, and 7, Ashiba teaches the composition comprising conditioned media from immortalized mesenchymal stem cells that were immortalized by introducing hTERT, HPV E6 and HPV E7 genes is prepared from immortalized human (claims 4 and 7) dental pulp-derived mesenchymal stem cells (claim 3) (page 58, right col. para. 2).
Therefore, Ashiba anticipates claims 1, 3, 4, 7, and 12.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 3, 4, 5, 7, and 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ashiba (Ashiba, Keisuke, et al. Inflammation and Regeneration 35.2 (2015): 057-060.), hereinafter Ashiba which is cited on the IDS filed 12/11/2024 in view of Yamashita (WO2017078176-A1; Filed 11/07/2016; Published 05/11/2017), hereinafter Yamashita which is cited on the IDS filed 12/11/2024. A machine translation of WO2017078176 is provided. The translation was performed on 09/02/2026 of pages 1 - 48 of the original document.
Ashiba anticipates claims 1, 3, 4, 7, and 12 as set forth above. Ashiba teaches the mesenchymal stem cells are immortalized with human TERT, HPV E6 and E7 (“hTERT”, “HPVE16-E6” and “HPV16-E7” of claim 2) genes (page 58, right col. para. 2) but does not teach “Bmi-1” of claim 2. Ashiba does not teach the gene set was introduced with virus vectors or culturing for 60 to 84 hours of claim 5. However, Ashiba teaches stem cells participate in tissue repair not only by generating daughter cells as new cellular components of the tissue being reconstructed but also by secreting biologically active molecules such as cytokines and growth factors to recruit and stimulate other types of cells (Abstract; page 58, left col. para. 2). Ashiba teaches administration of mesenchymal stem cell-conditioned media (MSC-CM) can be an effective therapy for repairing damaged tissues (page 58, right col. para. 1). Ashiba teaches active molecules secreted from MSCs can be used for treating diabetes mellitus (page 58, right col. para. 1). Ashiba teaches conditioned media of human dental pulp-derived stem cells was shown to promote functional recovery in a rat model of spinal cord injury (page 58, left col. last para.). Ashiba teaches for generating MSC-CM as a therapeutic agent to treat many patients, it is critical to maintain its quality with little lot-to-lot variability, which is challenging when working with primary MSCs (page 58, right col. para. 2). Ashiba teaches in order to resolve this issue, they immortalized human dental pulp-derived MSCs with TERT and HPV E6 and E7 genes (DP-iMSCs), and these cells maintain the molecular characteristics of primary MSCs (page 58, right col. para. 2; page 59, right col. para. 2). Ashiba teaches DP-iMSCs are expected to generate a large quantity of MSC-CM while maintaining the characteristics over time (page 59, right col. para. 2). Ashiba teaches DP-iMSCs make the mass production and mass distribution of MSC-CM feasible, and the MSC-CM can be administered in an allogeneic manner to treat many patients around the globe (page 59, right col. para. 2). Ashiba teaches dozens of genes encoding biologically active molecules (cytokines and growth factors) were commonly expressed in both primary MSCs and DP-iMSCs (page 59, left col. para. 1). Ashiba teaches differentially expressed genes between primary MSCs and DP-iMSCs reside in a set of genes termed regulation of cell proliferation, and this is consistent with the idea that the two MSCs are primarily different in the property of cell proliferation (page 59, left col. para. 1).
Regarding “Bmi-1” of claim 2, Yamashita teaches human dental pulp derived mesenchymal stem cells immortalized with the genes Bmi-1, HPV E6, HPV E7, and hTERT (page 57, para. 2 – 3; page 58, para. 1).
Regarding claim 5, Yamashita teaches the human dental pulp derived mesenchymal stem cells were immortalized with the genes Bmi-1, HPV E6, HPV E7, and hTERT by introducing the genes with virus vectors (page 42, last para.; page 43, para. 1; page 49, para. 1; page 50, para. 1; page 13, para. 2 – 3; page 24, last para.; page 25, para. 1; page 33, last para.; page 34, para. 1 – 3). Yamashita teaches culturing the cells for 3 (“for 60 to 84 hours”) to 5 days to select cells expressing the genes (page 50, para. 2; page 24, last para.; page 25, para. 1 – 2).
Yamashita teaches TERT is a gene that codes for an enzyme that lengthens telomere sequences, which shorten with age; E6 is known to reactivate TERT; and Bmi-1 is a polycomb gene and is known to be involved in the regulation of stem cell self-renewal and differentiation (page 12, para. 1). Yamashita teaches it was confirmed hTERT is expressed in human dental pulp stem cells whether three genes or four genes are introduced (page 61, para. 3; page 9, para. 2). Yamashita teaches the culture supernatant produced by non-immortalized cells contains growth factors but these growth factors can change as the cells age meaning that it is not possible to obtain culture supernatant with a consistent composition leading to the problem of not being able to provide therapeutic agents of stable quality (page 5, para. 1 – 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Ashiba regarding a composition comprising conditioned media from hTERT, E6, and E7 immortalized human dental pulp-derived MSCs where the MSCs express cytokines and growth factors with the teachings of Yamashita regarding immortalizing human dental pulp-derived MSCs with virus vectors encoding hTERT, E6, E7, and Bmi-1 genes to arrive at the claimed composition of culture supernatant from MSCs that are immortalized with Bmi-1, HPV E6, HPV E7, and hTERT. One would have been motivated to combine the teachings of Ashiba and Yamashita to provide culture supernatant with consistent levels of cytokines and growth factors for treating disease as Ashiba teaches administration of MSC-CM can be an effective therapy for repairing damaged tissues but for generating MSC-CM as a therapeutic agent to treat many patients, it is critical to maintain its quality with little lot-to-lot variability, which is challenging when working with primary MSCs and Yamashita teaches the culture supernatant produced by non-immortalized cells contains growth factors but these growth factors can change as the cells age meaning that it is not possible to obtain culture supernatant with a consistent composition leading to the problem of not being able to provide therapeutic agents of stable quality and Yamashita teaches Bmi-1 is a polycomb gene and is known to be involved in the regulation of stem cell self-renewal and differentiation. One would have a reasonable expectation of success in combining the teachings as Ashiba teaches conditioned media of human dental pulp-derived stem cells was shown to promote functional recovery in a rat model of spinal cord injury and Ashiba teaches primary MSCs and DP-iMSCs both showed expression of biologically active molecules but differed in genes for proliferation and Ashiba teaches DP-iMSCs make the mass production and mass distribution of MSC-CM feasible, and the MSC-CM can be administered in an allogeneic manner to treat many patients around the globe and Yamashita teaches it was confirmed hTERT is expressed in human dental pulp stem cells whether three genes or four genes are introduced.
Claim(s) 1, 3, 4, 6, 7, 9, 11 and 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ashiba (Ashiba, Keisuke, et al. Inflammation and Regeneration 35.2 (2015): 057-060.), hereinafter Ashiba which is cited on the IDS filed 12/11/2024 in view of Shimojima (Shimojima, Chiaki, et al. The Journal of Immunology 196.10 (2016): 4164-4171.), hereinafter Shimojima which is cited on the IDS filed 12/11/2024.
Ashiba anticipates claims 1, 3, 4, 7, and 12 as set forth above. Ashiba does not teach “at least a component that acts on c-MET” of claim 6 or “multiple sclerosis” of claim 9 or “dosage form” of claim 11. However, Ashiba teaches stem cells participate in tissue repair not only by generating daughter cells as new cellular components of the tissue being reconstructed but also by secreting biologically active molecules such as cytokines and growth factors to recruit and stimulate other types of cells (Abstract; page 58, left col. para. 2). Ashiba teaches administration of mesenchymal stem cell-conditioned media (MSC-CM) can be an effective therapy for repairing damaged tissues (page 58, right col. para. 1). Ashiba teaches conditioned media of human dental pulp-derived stem cells was shown to promote functional recovery in a rat model of spinal cord injury (page 58, left col. last para.). Ashiba teaches for generating MSC-CM as a therapeutic agent to treat many patients, it is critical to maintain its quality with little lot-to-lot variability, which is challenging when working with primary MSCs (page 58, right col. para. 2). Ashiba teaches in order to resolve this issue, they immortalized human dental pulp-derived MSCs with TERT and HPV E6 and E7 genes (DP-iMSCs), and these cells maintain the molecular characteristics of primary MSCs (page 58, right col. para. 2; page 59, right col. para. 2). Ashiba teaches DP-iMSCs are expected to generate a large quantity of MSC-CM while maintaining the characteristics over time (page 59, right col. para. 2). Ashiba teaches DP-iMSCs make the mass production and mass distribution of MSC-CM feasible, and the MSC-CM can be administered in an allogeneic manner to treat many patients around the globe (page 59, right col. para. 2). Ashiba teaches dozens of genes encoding biologically active molecules (cytokines and growth factors) were commonly expressed in both primary MSCs and DP-iMSCs (page 59, left col. para. 1).
Regarding claim 6, Shimojima teaches a composition of conditioned media from stem cells from human exfoliated deciduous teeth (SHED-CM) which is supernatant from cultured SHEDs contains HGF (page 4165, right col. para. 2 – 3; page 4167, left col. and right col. para. 1). Shimojima teaches HGF is one of the most abundant components of SHED-CM (page 4169, right col. para. 2).
Regarding “multiple sclerosis” of claim 9, Shimojima teaches SHED-CM improved disease scores in EAE which is a mouse model of multiple sclerosis (Abstract; page 4166, left col. last para. and right col. para. 1 – 3; Figure 1). Shimojima teaches SHED-CM induced modulation of the microenvironment resulted in suppressed demyelination (page 4169, right col. para. 1).
Regarding “liquids” and “injectables” of claim 11, Shimojima teaches SHED-CM is a liquid that was injected i.v. (page 4165, right col. para. 2).
Shimojima teaches demyelination occurs in multiple sclerosis and leads to sensory and motor paralysis, blindness, pain, incontinence, and dementia (page 4164, left col. and right col. para. 1). Shimojima teaches SHED-CM exerts similar therapeutic effects to those of SHEDs including remyelination of CNS (page 4164, right col. last para.). Shimojima teaches M2 macrophages promote remyelination and SHED-CM contains a set of M2-inducing molecules (page 4165, left col. para. 2 – 3). Shimojima teaches SHED-CM induced a shift in the macrophage phenotype from M1 to M2 (page 4169, right col. para. 1). Shimojima teaches HGF might cooperate with other factors in the SHED-CM to improve EAE (page 4170, left col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Ashiba regarding a composition comprising conditioned media from hTERT, E6, and E7 immortalized human dental pulp-derived MSCs where the MSCs express cytokines and growth factors with the teachings of Shimojima regarding SHED-CM contains HGF and when injected in liquid form improves symptoms in a mouse model of multiple sclerosis to arrive at the claimed preparation of culture supernatant from human dental pulp stem cells that are immortalized with HPV E6, HPV E7, and hTERT that contains HGF and that is an injectable liquid formulation for treating multiple sclerosis. One would have been motivated to combine the teachings of Ashiba and Shimojima to provide culture supernatant with consistent levels of cytokines and growth factors for treating multiple sclerosis as Ashiba teaches administration of MSC-CM can be an effective therapy for repairing damaged tissues but for generating MSC-CM as a therapeutic agent to treat many patients, it is critical to maintain its quality with little lot-to-lot variability, which is challenging when working with primary MSCs and Shimojima teaches demyelination in multiple sclerosis and EAE results in a range of clinical features including sensory and motor paralysis, blindness, pain, incontinence and dementia and Shimojima teaches HGF might cooperate with other factors in the SHED-CM to improve EAE. One would have a reasonable expectation of success in combining the teachings as Ashiba teaches primary MSCs and DP-iMSCs both showed expression of biologically active molecules and Shimojima teaches M2 macrophages promote remyelination and SHED-CM contains a set of M2-inducing molecules and Shimojima teaches the SHED-CM improved EAE which is a model of multiple sclerosis.
Claim(s) 1, 3, 4, 7, 8, 10, 11 and 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ashiba (Ashiba, Keisuke, et al. Inflammation and Regeneration 35.2 (2015): 057-060.), hereinafter Ashiba which is cited on the IDS filed 12/11/2024 in view of Makino (Makino, Eriko, et al. Journal of diabetes investigation 10.5 (2019): 1199-1208.), hereinafter Makino.
Ashiba anticipates claims 1, 3, 4, 7, and 12 as set forth above. Ashiba does not teach “10 to 90 weight %” of claim 8 or “diabetic neuropathy” of claim 10 or “dosage form” of claim 11. However, Ashiba teaches stem cells participate in tissue repair not only by generating daughter cells as new cellular components of the tissue being reconstructed but also by secreting biologically active molecules such as cytokines and growth factors to recruit and stimulate other types of cells (Abstract; page 58, left col. para. 2). Ashiba teaches administration of mesenchymal stem cell-conditioned media (MSC-CM) can be an effective therapy for repairing damaged tissues (page 58, right col. para. 1). Ashiba teaches active molecules secreted from MSCs can be used for treating diabetes mellitus (page 58, right col. para. 1). Ashiba teaches conditioned media of human dental pulp-derived stem cells was shown to promote functional recovery in a rat model of spinal cord injury (page 58, left col. last para.). Ashiba teaches for generating MSC-CM as a therapeutic agent to treat many patients, it is critical to maintain its quality with little lot-to-lot variability, which is challenging when working with primary MSCs (page 58, right col. para. 2). Ashiba teaches in order to resolve this issue, they immortalized human dental pulp-derived MSCs with TERT and HPV E6 and E7 genes (DP-iMSCs), and these cells maintain the molecular characteristics of primary MSCs (page 58, right col. para. 2; page 59, right col. para. 2). Ashiba teaches DP-iMSCs are expected to generate a large quantity of MSC-CM while maintaining the characteristics over time (page 59, right col. para. 2). Ashiba teaches DP-iMSCs make the mass production and mass distribution of MSC-CM feasible, and the MSC-CM can be administered in an allogeneic manner to treat many patients around the globe (page 59, right col. para. 2). Ashiba teaches dozens of genes encoding biologically active molecules (cytokines and growth factors) were commonly expressed in both primary MSCs and DP-iMSCs (page 59, left col. para. 1).
Regarding claim 8, Makino teaches the composition was 10x concentrated DPSC-CM and a dosage of 1 mL/rat was administered (page 1200, left col. para. 5 and right col. para. 3 – 4; page 1206, left col. last para.). Makino does not teach “10 to 90 weight % of the composition”. However, Makino teaches 10-fold concentrated DPSC-CM was prepared using a 3-kDa filter because the main proteins of the angiogenic, neurotrophic, and immunomodulated factors are larger than 3-kDa and this method is useful for reducing the administration volume without loss of efficacy (page 1206, left col. last para. and right col. para. 1). Makino teaches they need to further investigate the doses and timing of DPSC-CM injections, as well as the duration of efficacy in future experiments (page 1206, right col. para. 2). Therefore, it would be obvious to adjust the percentage of the DPSC-CM since it is a result-effective variable dependent on the desired volume of DPSC-CM administered, the concentrations of factors present, the number of doses administered, and the duration of efficacy.
Regarding “diabetic neuropathy” of claim 10, Makino teaches a composition of dental pulp stem cell conditioned media (DPSC-CM) for the treatment of diabetic polyneuropathy (Abstract; page 1200, right col. para. 2 – 4).
Regarding “liquids” and “injectables” of claim 11, Makino teaches the DPSC-CM is a liquid that was injected i.v. (page 1200, right col. para. 4).
Makino teaches therapeutic strategies targeting the cause of diabetic polyneuropathy are lacking and a particular need exists for radical treatments in cases in which diabetic polyneuropathy has progressed (page 1200, left col. para. 1). Makino teaches DPSCs are a kind of mesenchymal stem cell (page 1200, left col. para. 3). Makino teaches DPSC-CM significantly ameliorated nerve conduction velocity, nerve blood flow and intraepidermal nerve fiber density (page 1200, left col. para. 5; page 1201, right col. para. 3 – 6; page 1205, left col. para. 2). Makino teaches DPSC-CM has therapeutic effects on diabetic polyneuropathy through neuroprotective, angiogenic and anti-inflammatory actions (page 1206, right col. last para.; page 1207, left col. para. 1). Makino teaches the use of cell-free therapies, such as conditioned media from mesenchymal stem cells has specific advantages that include: (1) conditioned media was free from graft versus host disease, tumorigenicity and embolus formation and (2) large-scale production of conditioned media reduces the cost and maintains the high quality of conditioned media (page 1206, left col. para. 3). Makino teaches DPSC-CM will lead to a reduction in medical costs, maintenance of DPSC-CM quality by using selected DPSCs with high viability, and freedom from immune incompatibility and tumorigenicity (page 1207, left col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Ashiba regarding a composition comprising conditioned media from hTERT, E6, and E7 immortalized human dental pulp-derived MSCs where the MSCs express cytokines and growth factors with the teachings of Makino regarding dental pulp stem cell conditioned media for the treatment of diabetic polyneuropathy to arrive at the claimed preparation of culture supernatant from human dental pulp stem cells that are immortalized with HPV E6, HPV E7, and hTERT that is a liquid formulation containing 10 to 90 weight % when the total weight of the preparation is 100% for treating diabetic polyneuropathy. One would have been motivated to combine the teachings of Ashiba and Makino in a culture supernatant with consistent levels of cytokines and growth factors for treating diabetic polyneuropathy as Ashiba teaches administration of MSC-CM can be an effective therapy for repairing damaged tissues but for generating MSC-CM as a therapeutic agent to treat many patients, it is critical to maintain its quality with little lot-to-lot variability, which is challenging when working with primary MSCs and Makino teaches therapeutic strategies targeting the cause of diabetic polyneuropathy are lacking and a particular need exists for radical treatments in cases in which diabetic polyneuropathy has progressed. One would have a reasonable expectation of success in combining the teachings as Ashiba teaches primary MSCs and DP-iMSCs both showed expression of biologically active molecules and Makino teaches DPSC-CM significantly ameliorated nerve conduction velocity, nerve blood flow and intraepidermal nerve fiber density in a mouse model of diabetic polyneuropathy and Makino teaches DPSC-CM has therapeutic effects on diabetic polyneuropathy through neuroprotective, angiogenic and anti-inflammatory actions.
Claim(s) 1, 3, 4, 7, 10, and 12 – 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ashiba (Ashiba, Keisuke, et al. Inflammation and Regeneration 35.2 (2015): 057-060.), hereinafter Ashiba which is cited on the IDS filed 12/11/2024 in view of Boukelmoune (Boukelmoune, Nabila, et al. Brain, behavior, and immunity 93 (2021): 43-54), hereinafter Boukelmoune as evidenced by Muhammad (Muhammad, Suleiman Alhaji, et al. PLoS One 15.9 (2020): e0238449), hereinafter Muhammad.
Ashiba anticipates claims 1, 3, 4, 7, and 12 as set forth above. Ashiba does not teach “chemotherapeutic agent-induced peripheral neuropathy” of claim 10 or “anti-cancer agent” of claim 13 or “taxane preparation” of claim 14. However, Ashiba teaches stem cells participate in tissue repair not only by generating daughter cells as new cellular components of the tissue being reconstructed but also by secreting biologically active molecules such as cytokines and growth factors to recruit and stimulate other types of cells (Abstract; page 58, left col. para. 2). Ashiba teaches administration of mesenchymal stem cell-conditioned media (MSC-CM) can be an effective therapy for repairing damaged tissues (page 58, right col. para. 1). Ashiba teaches for generating MSC-CM as a therapeutic agent to treat many patients, it is critical to maintain its quality with little lot-to-lot variability, which is challenging when working with primary MSCs (page 58, right col. para. 2). Ashiba teaches in order to resolve this issue, they immortalized human dental pulp-derived MSCs with TERT and HPV E6 and E7 genes (DP-iMSCs), and these cells maintain the molecular characteristics of primary MSCs (page 58, right col. para. 2; page 59, right col. para. 2). Ashiba teaches DP-iMSCs are expected to generate a large quantity of MSC-CM while maintaining the characteristics over time (page 59, right col. para. 2). Ashiba teaches DP-iMSCs make the mass production and mass distribution of MSC-CM feasible, and the MSC-CM can be administered in an allogeneic manner to treat many patients around the globe (page 59, right col. para. 2). Ashiba teaches dozens of genes encoding biologically active molecules (cytokines and growth factors) were commonly expressed in both primary MSCs and DP-iMSCs (page 59, left col. para. 1). Ashiba teaches there is a potential risk of malignant transformation of transplanted stem cells and this can be circumvented by administering conditioned medium of stem cell culture containing biologically active molecules without transplanting the cells (page 58, left col. para. 1 – 2). Ashiba teaches allogeneic treatment with conditioned medium will not be hampered by graft rejection unlike the transplantation of allogenic cells (page 58, left col. para. 2).
Regarding “chemotherapeutic agent-induced peripheral neuropathy” of claim 10, “anti-cancer agent” of claim 13, and “taxane preparation” of claim 14, Boukelmoune teaches a composition of mesenchymal stem cells for treating chemotherapy-induced peripheral neuropathy (CIPN) (claim 10) induced by the anti-cancer agent (claim 13) paclitaxel (claim 14) (Figure 1; page 45, right col. para. 1; page 47, right col. para. 2; page 50, right col. para. 2; page 51, right col. para. 2). Applicant’s specification at para. 0010 states paclitaxel is a taxane.
Boukelmoune teaches CIPN is one of the most frequently reported adverse effects of cancer treatment and often persists long after treatment completion and has detrimental effects on a patient’s quality of life (Abstract; page 43). Boukelmoune teaches there are no effective FDA-approved treatments for CIPN and an efficacious therapeutic strategy is urgently needed (page 44, left col. para. 1). Boukelmoune does not teach the composition comprises culture supernatant from the MSCs. However, Boukelmoune teaches MSC-derived IL-10 is necessary for resolution of CIPN because IL10-/-MSCs did not have any positive effect on CIPN (page 46, right col. para. 3 – 4; Figure 6A; page 47, right col. para. 3). Boukelmoune teaches that the presence of IL-10R1 on sensory neurons is essential for resolution of CIPN because CIPN could not be reversed by MSC treatment in mice lacking IL-10 receptors (page 46, right col. para. 5; page 47, left col. para. 1; Figure 7A). Boukelmoune teaches that MSCs apart from producing IL-10 themselves may activate other resident cell types including macrophages to produce IL-10 (page 49, left col. para. 1).
The conditioned media of Ashiba would contain IL-10 because Muhammad teaches that conditioned media collected from culturing stem cells from human exfoliated deciduous teeth (SHED) contains IL-10 and the SHEDs express mesenchymal stem cell markers (Abstract; page 3, para. 4 – 5; page 4, para. 2; page 6, para. 4 and last para.; Figure 3B).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Ashiba regarding a composition comprising conditioned media from hTERT, E6, and E7 immortalized human dental pulp-derived MSCs where the MSCs express cytokines and growth factors with the teachings of Boukelmoune regarding MSC-derived IL-10 is necessary for resolution of CIPN to arrive at the claimed composition of culture supernatant from human dental pulp stem cells that are immortalized with HPV E6, HPV E7, and hTERT for treating CIPN. One would have been motivated to combine the teachings of Ashiba and Boukelmoune in a culture supernatant without MSCs and with consistent levels of cytokines and growth factors including IL-10 for treating CIPN as Ashiba teaches administration of MSC-CM can be an effective therapy for repairing damaged tissues but for generating MSC-CM as a therapeutic agent to treat many patients, it is critical to maintain its quality with little lot-to-lot variability, which is challenging when working with primary MSCs and Ashiba teaches there is a potential risk of malignant transformation of transplanted stem cells and this can be circumvented by administering conditioned medium of stem cell culture containing biologically active molecules without transplanting the cells and Boukelmoune teaches CIPN is one of the most frequently reported adverse effects of cancer treatment and often persists long after treatment completion and has detrimental effects on a patient’s quality of life and Boukelmoune teaches there are no effective FDA-approved treatments for CIPN and an efficacious therapeutic strategy is urgently needed and Boukelmoune teaches MSCs produce IL-10. One would have a reasonable expectation of success in combining the teachings as Ashiba teaches primary MSCs and DP-iMSCs both showed expression of biologically active molecules that includes IL-10 as evidenced by Muhammad and Boukelmoune teaches MSC-derived IL-10 is necessary for resolution of CIPN because IL10-/-MSCs did not have any positive effect on CIPN.
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 – 5, 7, 8, 11, and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 – 4 and 8 – 10 of copending Application No. 18561890 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they are not different from each other because they are both directed to the same composition, a conditioned medium derived from immortalized MSC which have been transduced with bmi-1, HPV-E6, HPV-E7, and TERT.
Instant claim 1 recites A composition that regenerates myelin sheath or proliferates Schwann cells, wherein the composition contains a culture supernatant of immortalized mesenchymal stem cells to which a gene set of telomerase reverse transcription enzyme (TERT) and two or three genes selected from a group consisting of Bmi-1 gene, HPV 16-E6 gene, and HPV 16-E7 gene are introduced.
Instant claim 12 recites A pharmaceutical preparation for the treatment of chemotherapeutic agent-induced peripheral neuropathy that comprises a composition as an active ingredient, wherein the composition contains a culture supernatant of immortalized mesenchymal stem cells to which a gene set of telomerase reverse transcription enzyme (TERT) and two or three genes selected from a group consisting of Bmi-1 gene, HPV 16-E6 gene, and HPV 16-E7 gene are introduced.
Reference claim 1 recites A preventive and/or therapeutic agent for pressure ulcer comprising conditioned medium of immortalized mesenchymal stem cells as an active ingredient, wherein bmi-1 gene, HPV-E6 gene, HPV-E7 gene, and TERT gene are introduced into the mesenchymal stem cells.
Reference claim 1 recites an identical composition to instant claims 1 and 12 because instant claims 1 and 12 recite that the cells can comprise the same four genes recited in reference claim 1. The only difference between reference claim 1 and instant claims 1 and 12 is the intended use of the composition.
Instant claim 2 maps to reference claim 1 because instant claim 2 requires all four of the recited genes recited in reference claim 1.
Instant claim 3 maps to reference claim 3 because both recite that the mesenchymal stem cells are dental pulp stem cells.
Instant claims 4, 5, and 7 map to reference claim 4 because both recite human dental pulp stem cells.
Instant claim 8 maps to reference claim 9 because instant claim 8 requires an additional component such that the preparation is 100% and reference claim 9 recites the agent further comprises one or more components selected from the group consisting of excipient, pH adjuster, diluent, and buffer.
Instant claim 11 maps to reference claims 8 and 10 because both recite the same forms of the preparation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/Z.M.B./Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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