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 .
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1, 4-5, 9-14, and 16; drawn to a method facilitating neointima formation over an endovascular device) in the reply filed on May 7, 2024, is acknowledged.
Claims 17, 20-21, 25-27, 32-34, and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II and III), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 7, 2024.
Applicant’s election of the following species in the reply filed on February 17, 2026, is acknowledged.:
a. umbilical cord blood as the source of the HSCs
b. a cell population of stem cell clones co-positive for LNGFR and Thy-1 and features a coefficient of variation for forward scatter in flow cytometry of 40% or less
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
In light of the Applicant’s elected species, claim 17 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Rejoinder
The species election requirement for species A: the source of the HSCs has been reconsidered in view of the prior art and has been withdrawn.
DETAILED ACTION
The amended claims filed on February 17, 2026, have been acknowledged. Claims 1-14 and 26-28 were cancelled. Claims 15-25 are pending and examined on the merits.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from JP2021-024794 filed on February 19, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received August 17, 2023. While a certified copy of the foreign patent application is provided with the instant application, a certified English translation of said foreign patent application has not been provided.
Information Disclosure Statement
The information disclosure statements (IDS) filed on September 21, 2023, May 23, 2024, August 9, 2024, October 21, 2024, August 11, 2025, and February 27, 2026, have been considered.
Specification
The use of the term Strensiq, 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 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 15-25 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.
The term “high-purity mesenchymal stem cells” in claims 15, 20, and 22 is a relative term which renders the claim indefinite. The term “high-purity mesenchymal stem cells” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what level of purity is required to reach high-purity.
Applicant is recommended to identify the mesenchymal stem cells as undergoing selection (as identified on page 2, paragraph 4 of the specification).
The term “rapidly proliferating mesenchymal stem cells” in claims 20-23 is a relative term which renders the claim indefinite. The term “rapidly proliferating mesenchymal stem cells” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what level of proliferation is required to reach rapidly proliferating.
It is recommended that the Applicant refer to the cells by their marker expression (Thy-1+ and LNGFR+) and leave out the unclear functional characteristics.
Claims 24-25 recite the limitation "the cell" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 15 refers to mesenchymal stem cells and hematopoietic stem cells. As can be seen in claims 16 and 20, these refer specifically to the hematopoietic stem cells or mesenchymal stem cells, respectively. It is unclear which cells are “the cells” in claims 24-25 since there are two possible cells that “the cells” could be referencing.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 15 and 17-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Taketani et al. (Cell Transplantation 24: 1931–1943, 2015; referenced in IDS).
Taketani teaches a method of treating hypophosphatasia comprising administering allogeneic bone marrow transplantation (which would contain hematopoietic stem cells) followed by multiple allogeneic mesenchymal stem cell transplantations (4 or 9 administrations depending on the patient). The number of transplanted MSCs ranged from 1.0 to 2.0 × 106 cells per kilogram of body weight. The MSCs, dissolved in 20 ml of phosphate-buffered saline (Gibco), were intravenously administered. As can be seen in Figure 5, osteocalcin levels after HSC and MSC administration increased (whole document). As osteocalcin is known to be secreted by osteoblasts, the number of osteoblasts in the patients were increased.
Regarding the high-purity mesenchymal stem cells limitation, as identified in the 112b above, high-purity mesenchymal stem cells is an unclear term. Taketani teaches that they expanded MSCs ex vivo in their aseptic cell-processing center. Approximately 20–40 ml of the donor-derived BM was used for culture expansion of MSCs in a flask. The adherent cells became nearly confluent after 10 to 12 days and were passaged using a trypsin-like enzyme solution into another flask. After several days, the first passaged cells were collected using the TrypLE Select and used for transplantation. In some cases, to acquire enough cell numbers, the first passaged cells were further passaged once, and the second passaged cells were used for the transplantation. The expression pattern of cell surface antigens was mesenchymal type (page 1932, column 2, paragraph 3-page 1933, column 2, paragraph 2). Therefore, the MSCs of Taketani are considered to fall within the limitation high-purity mesenchymal stem cells.
Claims 15 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Carrancio et al. (PLoS ONE 6: 1–9, 2011).
Carrancio teaches that they wanted to determine how mesenchymal stem cells (MSC) could improve bone marrow (BM) stroma function after damage. As part of this, 64 NOD/SCID recipients were transplanted with CD34+ cells (HSCs) administered either by intravenous (IV) or intrabone (IB) route, with or without BM derived MSCs
Carrancio teaches that in order to test the role of the injection site of hematopoietic cells and MSC in hematopoietic engraftment, human HSC cells were intravenous (IV) or intrabone marrow (IB) administrated while human MSC were exclusively IB injected under the following conditions: 1) 2 x 106 IV CD34+ cells; 2) 2 x 106 IV CD34+ cells and 5 x 105 IB MSC; 3) 2 x 106 IB CD34+ cells; 4) 2 x 106 IB CD34+ cells and 5 x 105 IB MSC. Intravenously injected cells were resuspended in a 200 μl of PBS and slowly injected by the tail vein. For IB injection, a 27-gauge needle was inserted into the joint surface of the right femur, and human cells were injected into the BM cavity in a total volume of 20 μl. (abstract, page 1, column 2, paragraph 3-page 2, column 1, paragraph 1, and page 5, column 2, paragraph 6-page 8, column 1, paragraph 2). 5 x 105 IB MSC in a total volume of 20 μl equates to 2.5 x 107 cells/mL. As can be seen in Figure 4, human cells expressed osteocalcin after HSC and MSC administration (page 3, column 1, paragraph 3-paragraph 7). As osteocalcin is known to be secreted by osteoblasts, the number of osteoblasts in the mice were increased.
Regarding the high-purity mesenchymal stem cells limitation, as identified in the 112b above, high-purity mesenchymal stem cells is an unclear term. Carrancio teaches that MSCs from BM samples could be expanded in all cases. All of them adhered to plastic surfaces, were capable of differentiating into adipocytes, osteoblasts and chondrocytes, expressed the antigens CD44, CD73, CD90, CD105, and CD166 and were negative for hematopoietic antigens thus fulfilling the criteria proposed for MSC definition by the International Society for Cellular Therapy (ISCT) (Figure 1). In order to test the role of the injection site of hematopoietic cells and MSC in hematopoietic engraftment, human HSC cells were intravenous (IV) or intrabone marrow (IB) administrated while human MSC were exclusively IB injected under the following conditions: 1) 2 x 106 IV CD34+ cells; 2) 2 x 106 IV CD34+ cells and 5 x 105 IB MSC; 3) 2 x 106 IB CD34+ cells; 4) 2 x 106 IB CD34+ cells and 5 x 105 IB MSC (page 1, column 2, paragraph 3-page 2, column 1, paragraph 1, and page 5, column 2, paragraph 6-page 8, column 1, paragraph 2). Therefore, the MSCs of Carrancio are considered to fall within the limitation high-purity mesenchymal stem cells.
Claims 15-17 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 20110059050 (Cetrulo) as evidenced by Carrancio et al. (PLoS ONE 6: 1–9, 2011).
Cetrulo teaches a method of administering hematopoietic stem cells and mesenchymal stem cells to treat disorders that can be treated with HSC transplantation. The HSC may be obtained from cord blood or bone marrow. The HSC and the mesenchymal cells are isolated, and/or partially purified from their source. The mesenchymal cells are administered before, during and after the hematopoietic stem cells. In another embodiment, the mesenchymal cells are administered during and after the hematopoietic stem cells. In still another embodiment, the mesenchymal cells are administered after the hematopoietic stem cells. The mesenchymal cells may be administered on a regular basis or schedule including but not limited to daily, weekly, biweekly, or monthly. The method results in more rapid engraftment compared to transplantation of the hematopoietic stem cells in the absence of the mesenchymal cells (paragraphs 0007-0034).
Regarding the high-purity mesenchymal stem cells limitation, as identified in the 112b above, high-purity mesenchymal stem cells is an unclear term. Cetrulo teaches that the mesenchymal cells are isolated, and/or partially purified from their source (paragraphs 0012 and 0044-0047). Therefore, the MSCs of Cetrulo are considered to fall within the limitation high-purity mesenchymal stem cells.
Carrancio evidences that in order to test the role of the injection site of hematopoietic cells and MSC in hematopoietic engraftment, human HSC cells were intravenous (IV) or intrabone marrow (IB) administrated while human MSC were exclusively IB injected under the following conditions: 1) 2 x 106 IV CD34+ cells; 2) 2 x 106 IV CD34+ cells and 5 x 105 IB MSC; 3) 2 x 106 IB CD34+ cells; 4) 2 x 106 IB CD34+ cells and 5 x 105 IB MSC (abstract, page 1, column 2, paragraph 3-page 2, column 1, paragraph 1, and page 5, column 2, paragraph 6-page 8, column 1, paragraph 2). As can be seen in Figure 4, human cells expressed osteocalcin after HSC and MSC administration (page 3, column 1, paragraph 3-paragraph 7). As osteocalcin is known to be secreted by osteoblasts, the number of osteoblasts in the mice were increased.
Therefore, the method of Cetrulo would also lead to an increase in osteoblasts as both methods involve engraftment of the transplanted HSCs and MSCs in bone marrow for reconstitution of the hematopoietic lineages.
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.
Claims 15 and 20-23 are rejected under 35 U.S.C. 103 as being unpatentable over Taketani et al. (Cell Transplantation 24: 1931–1943, 2015) as applied to claim 15 above, and further in view of Mabuchi et al. (Stem Cell Reports 1: 152–165. 2013; referenced in IDS).
The teachings of Taketani are as discussed above.
Taketani does not teach that their MSCs are rapidly proliferating mesenchymal stem cells nor wherein they express LNGFR and Thy-1.
However, Mabuchi teaches mesenchymal stem cells that express LNGFR+THY-1+ reveal functionally distinct subpopulations of mesenchymal stem cells. Mabuchi also reported an improved prospective clonal isolation technique and reveal that the combination of three cell-surface markers (LNGFR, THY-1, and VCAM-1) allows for the selection of highly enriched clonogenic cells (one out of three isolated cells). Rapidly expanding clones (RECs) exhibited robust multilineage differentiation and self-renewal potency. Furthermore, RECs exhibited higher cellular motility compared with the other clones. The combination marker LNGFR+THY-1+VCAM-1hi+ (LTV) can be used selectively to isolate the most potent and genetically stable MSCs, i.e. RECs (Whole document).
Moreover, Mabuchi teaches flow-cytometric analysis and sorting were performed. Analysis of cell populations expressing varying combinations of LNGFR and THY-1 on their surface from the different tissues routinely demonstrated 99% purity by flow cytometry (Page 162, column 2, paragraph 3). The measurements of cell size (forward scatter) and complexity (side scatter) were performed in Figure S5D (Page 158, column 2, paragraph 1 and Figure S5D). Mabuchi teaches that a single LNGFR+THY-1+ cell can be divided into three functionally distinct subpopulations termed RECs, MECs, and SECs. Among them, RECs exhibited robust multilineage differentiation and self-renewal potency. Mabuchi therefore considers RECs to be the most primitive and undifferentiated population in CFU-Fs (Page 161, column 2, paragraph 2). Mabuchi teaches that RECs were uniformly small and spindle-shaped (Page 156, column 2, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used rapidly expanding LNGFR+/Thy-1+ MSC clones as the MSC cells in the method of treating hypophosphatasia of Taketani to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use LNGFR+/Thy-1+ MSC clone REC cells in the method with a reasonable expectation of success because Mabuchi teaches an explicit advantage of the LNGFR+THY-1+ REC cells are the most potent and genetically stable MSCs with robust multilineage differentiation and self-renewal potency. Therefore, these cells would be capable of producing more osteoblasts and other support cells in the bone marrow to improve treatment in hypophosphatasia patients. Furthermore, Taketani identifies the LNGFR+Thy-1+ cells of Mabuchi as a possible cell type for use in developing an isolated MSC culture system to establish a suitable MSC transplant procedure, including for treating hypophosphatasia (page 1941, column 2, paragraph 1). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the coefficient of variation of the forward scatter of the cell population in flow cytometry is 40% or less, it is noted that the specification of the claimed invention discloses that the coefficient of variation for forward scatter is used an indicator for selection. The coefficient of variation (CV) is the standard deviation divided by the mean, and is a value used to relatively evaluate the variability of data set in different units and the relationship between data and variability with respect to the mean (paragraphs 0035-0038). The specification discloses that “A cell population with a CV value of 40% or less is a cell population composed of cells that are uniform in size (paragraph 0038)
Given flow-cytometry, the measurements of cell size (forward scatter), and the resulting RECs cell population uniformly in size and shape with improved functionality were taught by Mabuchi, a person of ordinary skill in the art would have been motivated to select REC cells with similar size and shape distribution (uniformity) with robust multilineage differentiation and self-renewal potency because polymorphic and larger nuclei were associated with moderately expanding and slowly expanding MSC clones (page 156, column 2, paragraph 2). Therefore, it would have been obvious to use flow-cytometry to achieve a uniform cell population with as low of a coefficient of variation as reasonably possible (e.g., 40% or less) to ensure that only REC cells are within the cell population and not any of the polymorphic, slower proliferating subpopulations.
Claims 15, 20-23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Carrancio et al. (PLoS ONE 6: 1–9, 2011) as applied to claim 15 above, and further in view of Mabuchi et al. (Stem Cell Reports 1: 152–165. 2013).
The teachings of Carrancio are as discussed above. Carrancio, as stated supra, teaches that in order to test the role of the injection site of hematopoietic cells and MSC in hematopoietic engraftment, human HSC cells were intravenous (IV) or intrabone marrow (IB) administrated while human MSC were exclusively IB injected under the following conditions: 1) 2 x 106 IV CD34+ cells; 2) 2 x 106 IV CD34+ cells and 5 x 105 IB MSC; 3) 2 x 106 IB CD34+ cells; 4) 2 x 106 IB CD34+ cells and 5 x 105 IB MSC. Intravenously injected cells were resuspended in a 200 μl of PBS and slowly injected by the tail vein. For IB injection, a 27-gauge needle was inserted into the joint surface of the right femur, and human cells were injected into the BM cavity in a total volume of 20 μl. (abstract, page 1, column 2, paragraph 3-page 2, column 1, paragraph 1, and page 5, column 2, paragraph 6-page 8, column 1, paragraph 2). 5 x 105 IB MSC in a total volume of 20 μl equates to 2.5 x 107 cells/mL.
Carrancio does not teach that their MSCs are rapidly proliferating mesenchymal stem cells nor wherein they express LNGFR and Thy-1.
However, Mabuchi teaches mesenchymal stem cells that express LNGFR+THY-1+ reveal functionally distinct subpopulations of mesenchymal stem cells. Mabuchi also reported an improved prospective clonal isolation technique and reveal that the combination of three cell-surface markers (LNGFR, THY-1, and VCAM-1) allows for the selection of highly enriched clonogenic cells (one out of three isolated cells). Rapidly expanding clones (RECs) exhibited robust multilineage differentiation and self-renewal potency. Furthermore, RECs exhibited higher cellular motility compared with the other clones. The combination marker LNGFR+THY-1+VCAM-1hi+ (LTV) can be used selectively to isolate the most potent and genetically stable MSCs, i.e. RECs (Whole document).
Moreover, Mabuchi teaches flow-cytometric analysis and sorting were performed. Analysis of cell populations expressing varying combinations of LNGFR and THY-1 on their surface from the different tissues routinely demonstrated 99% purity by flow cytometry (Page 162, column 2, paragraph 3). The measurements of cell size (forward scatter) and complexity (side scatter) were performed in Figure S5D (Page 158, column 2, paragraph 1 and Figure S5D). Mabuchi teaches that a single LNGFR+THY-1+ cell can be divided into three functionally distinct subpopulations termed RECs, MECs, and SECs. Among them, RECs exhibited robust multilineage differentiation and self-renewal potency. Mabuchi therefore considers RECs to be the most primitive and undifferentiated population in CFU-Fs (Page 161, column 2, paragraph 2). Mabuchi teaches that RECs were uniformly small and spindle-shaped (Page 156, column 2, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used rapidly expanding LNGFR+/Thy-1+ MSC clones as the MSC cells in the method of reconstituting hematopoietic cells in the bone marrow of Carrancio to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use LNGFR+/Thy-1+ MSC clone REC cells in the method with a reasonable expectation of success because Mabuchi teaches an explicit advantage of the LNGFR+THY-1+ REC cells are the most potent and genetically stable MSCs with robust multilineage differentiation and self-renewal potency. Therefore, these cells would be capable of producing more osteoblasts and other support cells in the bone marrow to improve reconstitution of hematopoietic lineage cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the coefficient of variation of the forward scatter of the cell population in flow cytometry is 40% or less, it is noted that the specification of the claimed invention discloses that the coefficient of variation for forward scatter is used an indicator for selection. The coefficient of variation (CV) is the standard deviation divided by the mean, and is a value used to relatively evaluate the variability of data set in different units and the relationship between data and variability with respect to the mean (paragraphs 0035-0038). The specification discloses that “A cell population with a CV value of 40% or less is a cell population composed of cells that are uniform in size (paragraph 0038)
Given flow-cytometry, the measurements of cell size (forward scatter), and the resulting RECs cell population uniformly in size and shape with improved functionality were taught by Mabuchi, a person of ordinary skill in the art would have been motivated to select REC cells with similar size and shape distribution (uniformity) with robust multilineage differentiation and self-renewal potency because polymorphic and larger nuclei were associated with moderately expanding and slowly expanding MSC clones (page 156, column 2, paragraph 2). Therefore, it would have been obvious to use flow-cytometry to achieve a uniform cell population with as low of a coefficient of variation as reasonably possible (e.g., 40% or less) to ensure that only REC cells are within the cell population and not any of the polymorphic, slower proliferating subpopulations.
Claims 15 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Taketani et al. (Cell Transplantation 24: 1931–1943, 2015) as applied to claim 15 above, and further in view of United States Patent Application No. 20110059050 (Cetrulo).
The teachings of Taketani are as discussed above. Taketani, as stated supra, teaches a method of treating hypophosphatasia comprising administering allogeneic bone marrow transplantation (which would contain hematopoietic stem cells) followed by multiple allogeneic mesenchymal stem cell transplantations (4 or 9 administrations depending on the patient). The number of transplanted MSCs ranged from 1.0 to 2.0 × 106 cells per kilogram of body weight (whole document).
Taketani does not teach wherein the cells are administered at a dose of 1 x 107 cells per kg body weight and is repeated weekly for 4 weeks.
Cetrulo teaches a method of administering hematopoietic stem cells and mesenchymal stem cells to treat disorders that can be treated with HSC transplantation. The HSC may be obtained from cord blood or bone marrow. The HSC and the mesenchymal cells are isolated, and/or partially purified from their source.The mesenchymal cells are administered after the hematopoietic stem cells. The mesenchymal cells may be administered on a regular basis or schedule including weekly. The method results in more rapid engraftment compared to transplantation of the hematopoietic stem cells in the absence of the mesenchymal cells (paragraphs 0007-0034).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the frequency of MSC administrations of Taketani to perform 4 weekly administrations to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Taketani already teaches that 4-9 administrations can be performed for treating hypophosphatasia and graft versus host disease following bone marrow transplantation. Furthermore, Cetrulo teaches that HSC and MSC transplantation can include regular administration of mesenchymal stem cells, including weekly. Therefore, it would have been obvious that four mesenchymal stem cell administrations could occur weekly.
Regarding the dosage, Taketani, as stated supra, teaches that they administered 1.0 to 2.0 × 106 cells per kilogram of body weight. Although Taketani does not teach a dose of 1 x 107, the MPEP 2144.05(i) states that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Waite, 168 F.2d 104, 108, 77 USPQ 586, 590 (CCPA 1948); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Swenson, 132 F.2d 1020, 1022, 56 USPQ 372, 374 (CCPA 1942); In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); Gentiluomo v. Brunswick Bowling and Billiards Corp., 36 Fed. App'x 433 (Fed. Cir. 2002)(non-precedential)(disagreeing with argument that overlapping ranges were required to find a claim prima facie obvious); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.). Therefore, it would have been obvious that a dose of 1.0 × 107 cells per kilogram of body weight could be used instead of the 1.0 to 2.0 × 106 cells per kilogram of body weight of Taketani. Furthermore, Taketani has already shown that a dosage of 1.0 to 2.0 × 106 cells per kilogram of body weight was successful at treating hypophosphatasia. Therefore, it would have been reasonable to expect that increasing the dose to 1.0 × 107 cells per kilogram of body weight would also successfully treat hypophosphatasia. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
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/KEENAN A BATES/Examiner, Art Unit 1631
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