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 .
Applicant's amendments to the claims and arguments filed on 05-22-2026 have been received and entered. Claims 1, 14 have been amended. Claims 4-5, 8, 10-11, 16, 23 have been canceled. Claims 1-3, 6-7, 9, 12-15, 17-22 are pending in the instant application. Receipt is acknowledged of the 37 C.F.R. 1.132 declaration by Dr. Wang that was submitted on 11-03-2025. The declaration has been fully considered and discussed below.
Election/Restrictions
Applicant’s election of Group I (claims 1-7, 9-15, and 17-19) in the reply filed on 12-09-2024 is acknowledged. 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)).
Claims 20-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12-09-2024.
Claims 1-3, 6-7, 9, 12-15, and 17-19 are under consideration.
Priority
Instant application is a 371 of PCT/US2020/032433 filed on 05/12/2020 that claims priority from US provisional application 62/848,230 filed on 05/15/2019.
Withdrawn- Claim Rejections - 35 USC § 112
Claim 1-3, 6-7, 9, 12-15, and 17-19 were 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. In view of applicant’s amendments, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Maintained in modified form-Claim Rejections - 35 USC § 103- necessitated by amendments
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.
Claims 1-3, 6-7, 9, 12-15, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Motlagh et al. (Pub. No.: US 2013/0216495 Al, Pub. Date: Aug. 22, 2013) in view of Pasha et al (TRANSFUSION 2017;57;1744–1754, doi:10.1111/trf.14136) as evidenced by Houze et al (Pub. No.: US 2015/0071886 A1, Pub. Date: Mar. 12, 2015).
Claim interpretation:
The specification of the claimed invention teach that the therapeutic cells include umbilical cord blood cells, and the therapeutic composition or cells comprise CD34+ (Page 3, lines 9-12). Also, claim 12 of the claimed invention recite: The umbilical cord blood cells are CD34+ cells. Thus, the umbilical cord blood cells are interpreted as encompassing CD34+ cells.
The specification of the claimed invention teaches that “Such an electrolyte solution may for example be PLASMA-LYTE A or PLASMA-LYTE 148, which has an osmolarity of about 294 or 295 mOsmol/liter. PLASMALYTE A or PLASMA-LYTE 148 contains about 90 mM NaCl, about 5 mM KCl, about 1.5 mM MgCl2, about 27 mM Sodium Acetate Trihydrate, and about 23 mM Sodium Gluconate. While PLASMA-LYTE A has a pH of about 7.4, PLASMA-LYTE 148 has a pH of about 6.0.” (Page 11, lines 12-16). Thus, PLASMA-LYTE A or PLASMA-LYTE 148 is interpreted to have an osmolarity of about 294 or 295 mOsmol/liter and contains about 90 mM NaCl, about 5 mM KCl, about 1.5 mM MgCl2, about 27 mM Sodium Acetate Trihydrate, and about 23 mM Sodium Gluconate. PLASMA-LYTE A has a pH of about 7.4, and PLASMA-LYTE 148 has a pH of about 6.0.
It is also noted that PLASMA-LYTE is a registered trademark of Baxter International Inc. It is a brand name for a group of intravenous (IV) balanced crystalloid solutions, including Plasma-Lyte A and Plasma-Lyte 148, used for fluid and electrolyte replacement. The trademark has been registered and used by Baxter for decades, with the first filing dating back to 1959.
Regarding to claim 1, Motlagh et al teach a cell population comprising CD34+ cells (Abstract) and the pharmaceutical composition comprises (i) a cell population comprising CD34+ cells, (ii) a plasma protein and (iii) an isotonic solution comprising at least one salt ([0007], page 1). Motlagh et al teach “The cell population is isolated from any adult, fetal or embryonic tissue comprising the desired cell population” ([0060], page 6) and “The cell population is isolated from any biological sample suspected of containing CD34+cells”([0062], page 6). Motlagh et al teach “the isotonic solution is or is substantially the same as any one of: Plasma-Lyte® A, Plasma-Lyte® 148, …..” ([0102], page 10). Motlagh et al teach “the pharmaceutical composition of the invention provides a stable environment for the CD34+ cells, such that the CD34+ cells may be stably stored at a non-freezing temperature (e.g., but without limitation to 1 to 30 degrees Celsius or 2 to 8 degrees Celsius) …… at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more of the cells of the cell population are viable cells after storage in the pharmaceutical composition for a period of time from about 1 hour to about 5 days and/or at a temperature within the range of 1 to 30 degrees Celsius” ([0107], page 11).
Motlagh et al teach in exemplary embodiments, the pharmaceutical compositions comprise ….. at least about 108 cells ([0106], page 11). Additionally, Table 11 teaches average WBC counts x 107 cells/mL ([0330], page 28) (For the claimed: (i) about 1 x 107 to 1 x 109 /ml umbilical cord blood cells).
Motlagh et al also teach in exemplary aspects, the isotonic solution is or is substantially the same as any one of: Plasma-Lyte® A, Plasma-Lyte® 148, Plasma-Lyte® 56, Normosol®-R, Isolyte® P, Lactated Ringer's solution (also known as Hart- mann solution), Ringer's solution, and 5% Dextrose in water (D5W) ([0102], page 10) (Note: For element with charge of one, 1 mEq/L is equal to 1 mmol/L) (For the claimed: (ii) a pharmaceutically acceptable carrier solution that (a) contains about 25-30 mM acetate and about 20-25 mM gluconate).
Motlagh et al teach the isotonic solution of the pharmaceutical composition has an osmolality of about 240 mOsmol/L to about 350 mOsmol/L ([0011], page 1-2) (For the claimed: (ii) (b): “has an osmolality of about 270 to 320 mOsmol/L”).
Also, Applicant’s own disclosure provides evidences for PLASMA-LYTE A or PLASMA-LYTE 148 that encompasses the cited pharmaceutically acceptable carrier solution in the claim: an osmolarity of about 294 or 295 mOsmol/liter and contains about 90 mM NaCl, about 5 mM KCl, about 1.5 mM MgCl2, about 27 mM Sodium Acetate Trihydrate, and about 23 mM Sodium Gluconate (see instant disclosure Page 11, lines 12-16). Additional evidence can be found in the Houze et al reference that PLASMA-LYTE A encompasses the cited pharmaceutically acceptable carrier solution in the claim: Houze et al teach progenitor cells of mesodermal lineage and their use in therapy (Abstract). One suitable carrier or diluents is Plasma-Lyte A. This is a sterile, nonpyrogenic isotonic solution for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2·3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2·6H2O). It contains no antimicrobial agents. The pH is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0) ([0148], page 10).
Note: Given 100 mL:
Sodium Chloride (NaCl): 526 mg/100ml => 5.26g/l (NaCl: 58.44 g/mol)
Sodium Gluconate (C₆H₁₁NaO₇): 502 mg/100ml => 5.02g/l (C₆H₁₁NaO₇ : 218.14 g/mol)
Sodium Acetate Trihydrate (C₂H₃NaO₂·3H₂O): 368 mg/100ml => 3.68g/l (C₂H₃NaO₂·3H₂O: 136.08 g/mol)
Potassium Chloride (KCl): 37 mg/100ml => 0.37g/l (KCl: 74.55 g/mol)
Magnesium Chloride (MgCl₂·6H₂O): 30 mg/100ml => 0.3g/l (MgCl₂·6H₂O: 203.30 g/mol)
Concentrations in mM:
NaCl: 5.26/58.44 = 90.0 mM
Sodium Gluconate: 5.02/218.14 = 23.0 mM
Sodium Acetate Trihydrate: 3.68/136.08 = 27.0 mM
KCl: 0.37/74.55 = 5.0 mM
MgCl₂·6H₂O: (0.3/203.3 )= 1.48 mM
Regarding to the limitation “wherein, after the therapeutic composition being stored at 2-6 °C for at least 84 hours, the umbilical cord blood cells exhibit greater than 70% viability”, it is noted that Motlagh et al teach cell population comprising CD34+ cells (Abstract) and any adult, fetal or embryonic tissue ([0060], page 6) stored in the composition such as Plasma-Lyte® A ([0102], page 10) for a period of time from about 1hour to about 5 days and/or at a temperature within the range of 1 to 30 degrees Celsius with at least 95% or more of the cells of the cell population are viable cells after storage in the pharmaceutical composition for a period of time of about 2 days and/or at a temperature within the range of 2 to 8 degrees Celsius ([0107], page 11). However, Motlagh et al do not teach pharmaceutically acceptable carrier solution for use specifically with umbilical cord blood cells. Pasha et al cure the deficiency.
Pasha et al teach development and testing of a stepwise thaw and dilute protocol for cryopreserved umbilical cord blood units (CBUs) (Title). Pasha et al stated that “We show that in the presence of HA, PLASMALYTE A effectively maintains viability of white blood cells (WBCs) and CD34+ cells above the thresholds set by regulatory bodies and preserves potency of thawed CBUs” (Page 1745, left column, 3rd para.). Pasha et al teach “Consistent with the greater viability of UCB cells with PLASMA-LYTE A, the net number of viable CD45+ and CD34+ cells was generally greater with PLASMA-LYTE A (data not shown). In support of this, combined analysis of all time points revealed significant increase in the net number of viable CD45+(+6%, p = 0.0463) and CD34+ cells (+12%, p = 0.0026) with PLASMA-LYTE A (Page 1748, left column, last para.).
Pasha et al also teach CBUs used had a minimum volume of 50 mL and a total nucleated cell (TNC) count greater than 0.9 x 109 (Page 1745, left column, last para). Note: (0.9 x 109)/50 = 0.018 x109 = 1.8x107.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the cell composition of Motlagh et al by using cell composition and method of Pasha et al to significant increase in the net number of viable umbilical cord blood units such as CD34+ cells as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Pasha et al teach that “PLASMA-LYTE A diluent provided superior viability of CD45+ and CD34+ cells than dextran 40 and recovered more colony-forming units” (Abstract), and “PLASMALYTE A effectively maintains viability of white blood cells (WBCs) and CD34+ cells above the thresholds set by regulatory bodies and preserves potency of thawed CBUs.” (Page 1745, left column, 3rd para.). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Pasha et al were successful in increasing net number of viable CD45+ and CD34+ cells with PLASMA-LYTE A with detailed instructions and data.
Additionally, regarding to the limitation “wherein, after the therapeutic composition being stored at 2-6 °C for at least 84 hours, the umbilical cord blood cells exhibit greater than 70% viability”: Applicant’s own disclosure provides evidences for using PLASMA-LYTE A with the umbilical cord blood cells exhibit greater than 70% viability when being stored at 2-6 °C for long period of time in Figs. 1A-1D “the cells packaged and shipped in PLASMA-LYTE A at 4 °C ("P-cold") showed higher viability (by acridine orange/propidium iodide (AO/PI) stain), total CFU numbers, total nucleated cells (TNC) recovery, and cells expressing CD34/CD45 markers than other conditions, such as PLASMA-LYTE A at room temperature ("P-rt"), saline at room temperature ("S-rt"), and saline at 2-8 °C (''S-cold"). For example, after about 72 hours (3 days) of shipping or storage, the cells packaged and shipped in PLASMA-LYTE A at 2-8 °C ("P-cold") exhibited greater than 80% viability, greater than 80% TNC recovery, more than 90 CPU/plate (per 3xl04 cells plated), and greater than 0.5% CD34+/CD45+ cells.” (See the instant disclosure, page 23, lines 7-14)
Motlagh et al do not teach/mention DMSO. Thus, a person of ordinary skill in the art would not look for and add DMSO in the composition. Additionally, Pasha et al teach “The most commonly used method of UCB preparation at transplant centers is the so-called thaw and dilute protocol that reduces the concentration of the cryoprotectant dimethyl sulfoxide (DMSO) to minimize its toxicity to grafts and side effects to patients.”. Thus, it is indicating that the concentration of DMSO in umbilical cord blood (UCB) preparation was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to perform the reducing DMSO concentration into only a trace amount a plurality of times out of the course of routine optimization, in order to minimize its toxicity to grafts and side effects to patients (For the claimed: (ii) (b): “wherein the therapeutic composition is free of DMSO or contains a trace amount of DMSO”).
Regarding to claim 2, Motlagh et al teach the isotonic solution comprises electrolytes or ions at a concentration which is the same as that found in plasma, e.g., but without limitation to, human plasma. Plasma contains 145 mEq/L sodium (Na+), 110 mEq/L chloride (Cl-), 4-5 mEq/L potassium (K+), 2 mEq/L magnesium (Mg2+) ([0086], page 8). It is noted that:
145 mEq/L sodium (Na+) =145 mmol/L sodium (Na+) (charge of one)
110 mEq/L chloride (Cl-) = 110 mmol/L chloride (Cl-) (charge of one)
4-5 mEq/L potassium (K+) = 4-5 mmol/L potassium (K+) (charge of one)
2 mEq/L magnesium (Mg2+) = 1 mmol/L magnesium (Mg2+) (charge of two)
Regarding to claim 3, Motlagh et al teach that in exemplary aspects, the isotonic solution is calcium-free ([0011], page 2). In exemplary aspects, the isotonic solution is one which is free of lactate ([0101], page 10)
Regarding to claim 6, Motlagh et al also teach the isotonic solution is or is substantially the same as any one of: Plasma-Lyte® A, Plasma-Lyte® 148, and contents of Isotonic Solutions (mEq/L): Plasma-Lyte A: 140 mM Na+ (140 mEq/L) ([0102], page 10 and see the table below (also on page 10))
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Regarding to claim 7, Motlagh et al teach in certain aspects, the isotonic solution has a pH of about 5 to about 9 or a pH of about 7.0 ([0098], page 10).
Regarding to claim 9, Motlagh et al teach in exemplary embodiments, the pharmaceutical compositions comprise at least about at least about 108 cells ([0106], page 11). Additionally, Tables 11 teaches average WBC counts 11.9 x 107 cells/mL ([0330], page 28). Thus, one of ordinary skill in the art would be motivated and able to select about 1 x 108 cells/ml of therapeutic cells for generating a composition.
Regarding to claim 12, Motlagh et al teach a cell population comprising CD34+cells isolated from peripheral blood of a subject ([0002], page 1).
Regarding to claim 13-14, Motlagh et al teach the plasma protein in the pharmaceutical composition of the invention is serum albumin and in certain aspects, the serum albumin is human serum albumin. In some embodiments, human serum albumin is present in the pharmaceutical composition at a concentration ranging from about 0.5% (w/v) to about 10% (w/v) ([0076], page 8).
Regarding to claim 15, Motlagh et al teach the pharmaceutical composition of the invention provides a stable environment for the CD34+ cells, such that the CD34+ cells may be stably stored at a non-freezing temperature (e.g., but without limitation to 1 to 30 degrees Celsius or 2 to 8 degrees Celsius) ([0107], page 11).
Regarding to claim 17-18, Motlagh et al teach a pharmaceutical composition comprising (i) a cell population comprising CD34+ cells, (ii) a plasma protein, and (iii) an isotonic solution comprising at least one salt, said isotonic solution comprising acetate, gluconate, or both acetate and gluconate (Abstract). The pharmaceutical composition is packaged in a ready to use and/or non-reusable container, such as a syringe, vial or bag ([0014], page 2). Cells obtained through the methods described herein …. are optionally administered via a cell delivery matrix , and the cell delivery matrix in certain embodiments comprises any one or more of polymers and hydrogels comprising collagen, fibrin, chitosan, matrigel ([0135], page 14).
Regarding to claim 19, Motlagh et al teach the pharmaceutical composition described herein is formulated for parenteral administration …… ([0129], page 13). The parenteral formulations are in various aspects presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze dried (lyophilized) condition ([0132], page 14).
Response to Arguments
Applicant's arguments filed on 05-22-2026 and Dr. Wang’s declaration filed on 11-03-2025 have been fully considered but they are not persuasive.
1. Applicant disagrees that the cited references either alone or in combination do not disclose or suggest the therapeutic composition of amended independent claim 1:
Motlagh et al. is silent with respect to a therapeutic composition comprising about 1 x 107 to 1 x 109 cells/ml umbilical cord blood cells preserved in a pharmaceutically acceptable carrier solution having the specific formulation recited in amended claim 1, wherein the carrier solution preserves the cells at a concentration of about 1 x 107 to 1 x 109 cells/ml and results in increased cell survival rate.
Pasha et al. is entirely silent with respect to a concentration of "about 1 x 107 to 1 x 109 cells/ml umbilical cord blood cells" as recited in amended claim 1. Pasha et al. merely describes that "CBUs used had a minimum volume of 50 ml and TNC count greater than 0.9 x 109," which is a concentration of l .8x 107 /ml. See Pasha et al., page 1745, Materials and Methods. Critically, the 50 mL volume refers to the original cord blood unit as collected-not a PLASMA-LYTE A solution. Thus, the actual concentration of cells in the PLASMA-LYTE A solution at the time of Pasha et al.'s viability measurements would have been substantially lower than 1.8 x 107 cells/mL, well below the claimed concentration range.
Pasha et al. does not address whether PLASMA-LYTE A preserves umbilical cord blood
cells at a concentration of 1 x 107 to 1 x 109 cells/ml during shipping or storage. Simply because Pasha et al. finds that PLASMA-LYTE A can be used as a post-thaw diluent does not suggest that PLASMA-LYTE A can serve as a pharmaceutically acceptable carrier solution for packaging and shipping umbilical cord blood cells at 1 x 107 to 1 x 109 cells/ml and result in increased cell survival rate as recited in amended claim 1.
(See remarks, page 6-7).
Response to Arguments:
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case:
Motlagh et al teach “the pharmaceutical composition comprises (i) a cell population comprising CD34+ cells, (ii) a plasma protein and (iii) an isotonic solution comprising at least one salt” ([0007], page 1). Motlagh et al teach “the pharmaceutical composition of the invention provides a stable environment for the CD34+ cells, such that the CD34+ cells may be stably stored at a non-freezing temperature (e.g., but without limitation to 1 to 30 degrees Celsius or 2 to 8 degrees Celsius) …… at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more of the cells of the cell population are viable cells after storage in the pharmaceutical composition for a period of time from about 1 hour to about 5 days and/or at a temperature within the range of 1 to 30 degrees Celsius” ([0107], page 11). Motlagh et al teach “The cell population is isolated from any adult, fetal or embryonic tissue comprising the desired cell population” ([0060], page 6) and “ the cell population is isolated from any biological sample suspected of containing CD34+cells” ([0062], page 6). Motlagh et al also teach “in exemplary aspects, the isotonic solution is or is substantially the same as any one of: Plasma-Lyte® A, Plasma-Lyte® 148, …..” ([0102], page 10). Motlagh et al teach in exemplary embodiments, the pharmaceutical compositions comprise ….. at least about 108 cells ([0106], page 11).
Motlagh et al do not teach pharmaceutically acceptable carrier solution for use specifically with umbilical cord blood cells. Pasha et al cure the deficiency. Pasha et al stated that “We show that in the presence of HA, PLASMALYTE A effectively maintains viability of white blood cells (WBCs) and CD34+ cells above the thresholds set by regulatory bodies and preserves potency of thawed CBUs” (Page 1745, left column, 3rd para.). Pasha et al teach “Consistent with the greater viability of UCB cells with PLASMA-LYTE A, the net number of viable CD45+ and CD34+ cells was generally greater with PLASMA-LYTE A (data not shown). In support of this, combined analysis of all time points revealed significant increase in the net number of viable CD45+(+6%, p = 0.0463) and CD34+ cells (+12%, p = 0.0026) with PLASMA-LYTE A (Page 1748, left column, last para.). One of ordinary skill in the art would have been motivated to combine references because Pasha et al teach that “PLASMA-LYTE A diluent provided superior viability of CD45+ and CD34+ cells than dextran 40 and recovered more colony-forming units” (Abstract), and “PLASMALYTE A effectively maintains viability of white blood cells (WBCs) and CD34+ cells above the thresholds set by regulatory bodies and preserves potency of thawed CBUs.” (Page 1745, left column, 3rd para.).
Applicants argue that “the actual concentration of cells in the PLASMA-LYTE A solution at the time of Pasha et al.'s viability measurements would have been substantially lower than 1.8 x 107 cells/mL, well below the claimed concentration range”. It is noted that 1.8 x 107 cells/mL is well within the range of “about 1 x 107 to 1 x 109 cells/ml” recited in the claim. It seems applicant implicitly interpret that viability of 1.8 x 107 cells/mL would somehow fall out of the recited limitation of “about 1 x 107 to 1 x 109 cells/ml”. However, first, the instant claims do not specify 1 x 107 to 1 x 109 cells/ml is the “70% viability” population concentration. Second, according to teaching Motlagh et al, “at least 70%, at least 75%, …. at least 95% or more of the cells of the cell population are viable cells after storage in the pharmaceutical composition for a period of time from about 1 hour to about 5 days and/or at a temperature within the range of 1 to 30 degrees Celsius” ([0107], page 11). Thus, even 70% of 1.8 x 107 cells/mL is 1.26 x 107 cells/mL which is still within the recited range.
2. Applicant argues that the claimed therapeutic composition exhibits unexpected results: These unexpected results include the ability to be shipped under conditions such as room or ambient temperature at a high concentration over an extended period of time (e.g., 12 to 72 hours). As demonstrated in Examples 1 and 2 of the application, cells packed and stored at a concentration of cells at about I x I09 in PLASMA-LYTE at 4 °C "showed higher viability (by acridine orange/propidium iodide (AO/PI) stain), total CFU numbers, [and] total nucleated cells (TNC) recovery." See Specification, page 23, lines 7-9 and FIGS. IA-IC. Furthermore, FIGS. IA-ID show that cells packed and shipped in PLASMA-LYTE A at 2°C-8°C ("P-cold") exhibited greater than 80% viability, greater than 80% TNC recovery, more than 90 CFU/plate (per 3xI04 cells plated), and greater than 0.5% CD34+/CD45+ cells
The unexpected results of the claimed therapeutic composition are distinct from the findings in Pasha et al. The use of PLASMA-LYTE A as a thawing diluent (as in Pasha et al.) with the use of PLASMA-LYTE A as a carrier solution for packaging and shipping cells to preserve them at high concentrations. These are fundamentally different applications with different technical challenges
The Examples in Motlagh et al. were performed using CD34+ cells mobilized from peripheral blood and do not involve umbilical cord blood cells. Notably, Motlagh et al. uses concentrations of cells such as 5.0x 106 cells/mL and 7.5x 106 cells/mL that are well below the concentration range of umbilical cord blood cells recited in amended claim 1.
(remarks, page 7-8)
Response to Arguments:
As per MPEP 716.02, Allegations of Unexpected Results : Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Motlagh et al teach “the pharmaceutical composition of the invention provides a stable environment for the CD34+ cells, such that the CD34+ cells may be stably stored at a non-freezing temperature (e.g., but without limitation to 1 to 30 degrees Celsius or 2 to 8 degrees Celsius) …… at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more of the cells of the cell population are viable cells after storage in the pharmaceutical composition for a period of time from about 1 hour to about 5 days and/or at a temperature within the range of 1 to 30 degrees Celsius” ([0107], page 11). Motlagh et al teach in exemplary embodiments, the pharmaceutical compositions comprise ….. at least about 108 cells ([0106], page 11). Motlagh et al teach “The cell population is isolated from any adult, fetal or embryonic tissue comprising the desired cell population” ([0060], page 6) and “The cell population is isolated from any biological sample suspected of containing CD34+cells”([0062], page 6).
Thus, a person of ordinary skill in the art before the effective filing date of the rejected claims would expect the pharmaceutical compositions comprise at least about 108 CD34+ cells isolated from any adult, fetal or embryonic tissue would %, at least 95% or more of the cells of the cell population are viable cells after storage in the pharmaceutical composition for a period of time from about 1 hour to about 5 days and/or at a temperature within the range of 1 to 30 degrees Celsius.
The Pasha et al reference provide evidence for using PLASMA-LYTE A for cryopreserved umbilical cord blood units (CBUs): Pasha et al teach “Consistent with the greater viability of UCB cells with PLASMA-LYTE A, the net number of viable CD45+ and CD34+ cells was generally greater with PLASMA-LYTE A (data not shown). In support of this, combined analysis of all time points revealed significant increase in the net number of viable CD45+(+6%, p = 0.0463) and CD34+ cells (+12%, p = 0.0026) with PLASMA-LYTE A (Page 1748, left column, last para.). Pasha et al teach that “PLASMA-LYTE A diluent provided superior viability of CD45+ and CD34+ cells than dextran 40 and recovered more colony-forming units” (Abstract), and “PLASMALYTE A effectively maintains viability of white blood cells (WBCs) and CD34+ cells above the thresholds set by regulatory bodies and preserves potency of thawed CBUs.” (Page 1745, left column, 3rd para.).
3. Applicant argues that the therapeutic composition of claim 1 addresses a long-felt unmet need: The non-obviousness of the therapeutic composition of claim I is further evidenced by the fact that it addresses a long-felt unmet need. As stated in the previously filed Wang Declaration dated October 29, 2025, [T]he claimed therapeutic composition is non-obvious in that it addresses an unmet need by enabling packing and/or shipping of high concentrations of stem/pluripotent cells or preparations containing such cells at room or ambient temperature over an extended period of time. Conventional stem/ pluripotent cells packaging and shipping do not allow one to ship cells at such high cell concentrations. To obtain therapeutic composition with such high cell concentrations, clinicians have to further process the cells to increase the cell numbers and/or concentrations ( the Wang Declaration, paragraph 10)
(Remarks, page 8-9).
Response to Arguments:
The shipping of any CD34+ cells isolated from any adult, fetal or embryonic tissue ([0060], page 6) and with high concentration of at least about 108 cells ([0106], page 11) in the isotonic solution such as PLASMA-LYTE A ([0102], page 10) from about 1hour to about 5 days and/or at a temperature within the range of 1 to 30 degrees Celsius with at least 95% or more of the cells of the cell population are viable cells ([0107], page 11) have been taught as described above in the teaching of Motlagh et al. Additionally, Motlagh et al stated that “this Example evaluated the stability of selected CD34+ cells (that were mobilized from donors that received 5 µg/kg/day G-CSF for 5 days) after being concentrated in potential injection medias (i.e., Formulations A, B or C), loaded into syringes and shipped in commercially available shipping containers with monitored temperature conditions of 1 to 10° C. daily for three days. The goal of the study was to determine under which condition(s) the stability of the cells was maintained. In summary, the following key observations were made during this study: 1) The primary acceptance criteria for determining if the stability of the cells was maintained was based on viability of the cells with a percentage viability of greater than 80% considered acceptable. Cells stored in Formulations B and C, respectively, maintained high levels of viability for up to three days with an average viability of approximately 94%- 95% at Day 3. ….” ([0381]-[0382], page 33). Thus, Motlagh et al ‘s goals are to addressing increase viability CD34+ cells in large quantity during shipping using isotonic solution such as PLASMA-LYTE A ([0102], page 10) as same as the claimed invention.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHOA NHAT TRAN whose telephone number is (571)270-0201. The examiner can normally be reached M-F (9-5).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, PETER PARAS can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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