DETAILED ACTION
Status of claim rejections
The rejection under 35 USC 112(b) is withdrawn in view of Applicant’s amendments to the claims in the response filed 09/22/25.
The rejection under 35 USC 103 is modified in view of Applicant’s arguments in the response filed 09/22/25.
This Action is NON-FINAL.
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.
First rejection
Claims 27, 38, 40-43, 52-53 are rejected under 35 U.S.C. 103 as being unpatentable over Oyama et al (WO 2018097226 A1, 31 May 2018; cited with English machine translation in applicant 10 Nov 2021 IDS; prior art of record; hereinafter “Oyama”), and further in view of Licari et al (US20070087320A1; hereinafter “Licari”), Thatte et al (CA2678486C; hereinafter “Thatte”), Hirose et al (WO2017065280A1; 20 April 2017; cited in Applicant’s 11/10/21 IDS; prior art of record; hereinafter “Hirose”) and Lee et al (Cryobiology Volume 50, Issue 1, February 2005, Pages 103-111; cited in Applicant 12/13/22; prior art of record; hereinafter “Lee”).
Oyama teaches a preservative solution for live cells or composition comprising live cells (title). Oyama teaches a method of preserving a sheet-like cell culture comprising immersing a sheet-like cell culture in a preservative solution (a method for preserving a cell in a liquid as in claim 27), where the solution of Oyama comprises synthetic vitamins in a physiological isotonic solution (see claims 1 and 7 of Oyama). Oyama also teaches that the vitamins include niacin/vitamin B3 and/or its derivatives (paragraph 0034) (as in claim 27) and other vitamins such as vitamin A, vitamin B1, vitamin B2, vitamin B5, vitamin C, vitamin E etc. (vitamin C/ascorbic acid as in claim 27) (paragraph 0034-0040). The cell(s) preserved can include living cells, such as myoblasts, mesenchymal stem cells, myocardial cells, fibroblasts, etc. (paragraph 0019). Oyama also teaches that the preservation solution can contain vitamin C as an essential vitamin in combination with an optional vitamin such as vitamin B3 (i.e., niacin) only (paragraph 0049). Thus, Oyama teaches a solution that does not comprise vitamin B2 or a derivative thereof or a salt thereof. Oyama further teaches that the temperature conditions during storage can be anywhere between 2-40 degrees Celsius (between 0 and 40 deg C as in claim 27; paragraph 0136) and that the cell culture can be stored anywhere between 4-200 hours (200 hours = approx. 8 days; between 1-15 days as in claim 27; see paragraph 0138).
The difference between Oyama and the instant claims is that Oyama does not explicitly teach that the solution comprises 10-5000 mg/L of niacin, a derivative of niacin, or a salt of niacin, or a salt of the derivative of niacin.
However, Licari teaches preservation solutions for living tissues, organs, and cells (see title, abstract, claim 1). Licari specifically teaches that the preservation medium contains independently or in combination: from 0.01 to 350 mg/l of vitamins necessary for the maintenance of cells and tissues, including nicotinamide (i.e., vitamin B3; a derivative of niacin as in claim 27) (see paragraphs 0036-40). Please note that the range as taught by Licari has amounts of nicotinamide which lie within the claimed range of 10-5000 mg/L. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (see MPEP 2144.05(I)).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the cell preservation solution of Oyama by including the concentration of nicotinamide as taught by Licari to arrive at the claimed invention. As Oyama teaches a preservative solution for live cells including niacin (vitamin B3) and Licari teaches a suitable concentration of nicotinamide (a derivative of niacin) that can be used in a medium to promote preservation of living cells, one of ordinary skill would have been motivated to make the modification with a reasonable expectation of success. One of ordinary skill to make the modification because Licari teaches that nicotinamide can advantageously be utilized in a cell medium necessary for the maintenance of cells and tissues.
Oyama and Licari do not teach the solution comprises 300-3000 mg/L of ascorbic acid.
However, Thatte (in a similar field of tissue and cell preservation) teaches solutions for preserving cardiac organs and tissues (see abstract; pg. 19-20). Thatte teaches the preservation solution is capable of providing protective ingredients that can help the tissues/cells resist the damaging effects of prolonged storage (see pg. 20). Thatte also teaches some potentially damaging processes that occur during storage includes reactive oxygen species are generated during storage; however, ascorbic acid (at 0.01-0.5 g/L; see claim 1) and reduced glutathione (i.e., reducing agents) present in the solution consume oxygen free radicals during storage (see pg. 20-21). Thatte teaches ascorbic acid at 0.01-0.5 g/L (i.e., 10-500 mg/L), which overlaps Applicant’s claimed range of 300-3000 mg/L. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) (see MPEP 2144.05).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the cell preservation solution of Oyama and Licari by optimizing the concentration of ascorbic acid as taught by Thatte to arrive at the claimed invention. As Oyama and Licari teach a preservative solution for live cells including niacin or derivative of niacin and Thatte teaches use of ascorbic acid in a solution that can be used for cell and tissue preservation, one of ordinary skill would have been motivated to make the modification with a reasonable expectation of success. One of ordinary skill to make the modification because Thatte teaches that ascorbic acid advantageously consume oxygen free radicals that can help the tissues/cells resist the damaging effects of prolonged storage.
Oyama, Licari, and Thatte do not teach that the cell is a platelet or megakaryocyte.
However, Hirose teaches a method for producing purified platelets (title, abstract). Hirose teaches that the platelets (the cell is a platelet as in claim 27) are produced from megakaryocyte cells (the cell is a megakaryocyte as in claim 27) cultured in vitro (pg. 2, paragraph 2). Hirose also teaches that when the megakaryocytes are cultured in vitro to produce platelets, it is necessary to separate and concentrate the platelets from the megakaryocytes (pg. 2, paragraph 4). Hirose also teaches that to separate and concentrate the platelets, a cell sorter cannot be used and centrifugation using a filter or hollow fiber membrane causes loss of platelet physiological activity and a recovery rate as low as 10% (pg. 2, paragraph 4). Hirose also teaches the use of a centrifugation step where the culture of megakaryocytes is centrifuged using a centrifugal force of 150 x g to 550 x g and a second centrifugation step of centrifuging the liquid component recovered in the first centrifugation step with a centrifugal force of 600 × g to 4000 × g (pg. 1, claim 1). Hirose teaches that the high-quality platelets can be purified from a megakaryocyte culture in a large amount at a high recovery rate, so that a large amount of safe platelet preparations with low risk of bacterial contamination can be obtained (pg. 2, paragraph 8; pg. 6; Example 3). Hirose further teaches that the purified platelets can be added to the megakaryocyte culture or after the centrifugation steps (pg. 3, paragraph 3; paragraph 8).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of preserving cells as taught by Oyama, Licari, and Thatte by preserving a platelet or megakaryocyte cell as taught by Hirose to arrive at the claimed invention. As the claimed invention relies on the preservation of mammalian cells using a preservation solution, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the mammalian cells of Oyama, Licari, and Thatte) for another (the platelet or megakaryocyte of Hirose) with a reasonable expectation of success (preserving a mammalian cell using a preservation solution). One of ordinary skill would have been motivated to make the substitution because Hirose teaches the successful purification of platelets from megakaryocytes, where the megakaryocytes/platelets are preserved in a preservation solution.
The difference between Oyama, Licari, Thatte, Hirose, and the instant claim is that none of the references explicitly teach the liquid further comprises albumin.
However, Lee teaches the effect of human serum albumin on the extended storage of human oral keratinocyte viability under mild hypothermia (title). Lee teaches that cell suspensions of oral keratinocytes in saline or DMEM supplemented with 10% albumin (albumin as in claim 27) showed higher viability after 24 and 72 h at 4 degrees Celsius in comparison to keratinocytes stored in saline or DMEM alone (pg. 106, col 1, paragraph 1; pg. 106; Fig. 1; pg. 107; Fig. 2). Lee further teaches that albumin has a lot of functions, including acting as a chelator, binding growth factors, antioxidant properties, and caused improved cell viability and stability (pg. 109, col 1-2).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of preserving cells as taught by Oyama, Licari, Thatte, and Hirose by including albumin in the preservation solution as taught by Lee to arrive at the claimed invention. As Lee teaches the effect of albumin on extended storage of keratinocyte cells, one of ordinary skill would have been motivated to add albumin to the solution of Oyama and Hirose with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Lee teaches that albumin advantageously is capable of causing improved cell viability and stability due to its chelating and antioxidant properties.
Regarding claim 38, Hirose also teaches that when the megakaryocytes are cultured in vitro to produce platelets, it is necessary to separate and concentrate the platelets from the megakaryocytes (a condensation step of condensing a culture product of megakaryocytes as in claim 38, step (A)) (pg. 2, paragraph 4) and the use of a centrifugation step where the culture of megakaryocytes is centrifuged using a centrifugal force of 150 x g to 550 x g and a second centrifugation step of centrifuging the liquid component recovered in the first centrifugation step with a centrifugal force of 600 × g to 4000 × g (pg. 1, claim 1). (as in claim 38, step (B)). As such, it also would have been prima facie obvious to one of ordinary skill to modify the method of preserving cells by including the concentration and centrifugation steps as taught by Hirose to arrive at the claimed invention. As Oyama teaches a method of preserving cells using a niacin and antioxidant solution, and Hirose teaches the production of purified platelets using a centrifugation and concentration step from megakaryocytes, one of ordinary skill would have been motivated to include the purification protocol with a reasonable expectation of success. One of ordinary skill would have been motivated to include the protocol because Hirose teaches the successful preparation of high-quality platelets from a megakaryocyte culture at a high recovery rate that advantageously has low risk of bacterial contamination.
Regarding claim 40, Lee teaches use of 10% albumin (see above). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) (see MPEP 2144.05).
Regarding claims 41-42, Oyama teaches that the preservation solution can include sugar, where the sugar is various concentrations of glucose (paragraph 0154).
Regarding claim 43, Oyama teaches that the cells can be preserved anywhere between 4-200 hours (200 hours = approx. 8 days) (paragraph 0138) and Hirose teaches the cell to be preserved can be a platelet or megakaryocyte (see above).
Accordingly, the claimed invention was prima facie obvious at the time of filing, especially in the absence of evidence to the contrary.
Second rejection
Claims 44-46, 48 and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Oyama, Licari, Thatte, and further in view of Nishimura et al (US 20160120170; 05 May 2016; cited in Applicant 11/10/21 IDS; prior art of record; hereinafter “Nishimura”).
As discussed above, Oyama teaches a preservative solution for live cells, including mesenchymal stem cells (see above, stem cell as in claim 44; mesenchymal stem cell as in claim 45) comprising ascorbic acid and vitamin B3 (i.e., niacin) where temperature conditions during storage can be anywhere between 2-40 degrees Celsius (between 0 and 40 deg C as in claim 44; paragraph 0136) and that the cell culture can be stored anywhere between 4-200 hours (200 hours = approx. 8 days; between 1 and 63 days as in claim 44).
Also as discussed above, Licari teaches a preservation medium that contains from 0.01 to 350 mg/l of vitamins necessary for the maintenance of cells and tissues, including nicotinamide (i.e., vitamin B3; a derivative of niacin (as in claim 44).
As further discussed above, Thatte teaches some potentially damaging processes that occur during storage includes reactive oxygen species are generated during storage; however, ascorbic acid (at 0.01-0.5 g/L; see claim 1) and reduced glutathione (i.e., reducing agents) present in the solution consume oxygen free radicals during storage (see pg. 20-21).
The difference between Oyama, Licari, Thatte, and the instant claims, is that none of the references explicitly teach that the solution has trehalose in an isotonic solution.
However, Nishimura teaches trehalose and dextran-containing solution for transplanting mammalian cells (title). Nishimura teaches a method of preserving a mammalian cell in an aqueous solution comprising 2-6% (w/v) of trehalose, lactate Ringer’s solution, and 4-7% (w/v) of dextran (the isotonic solution comprises trehalose as in claim 44; lactate Ringer’s as in claim 48; dextran as in claim 50) (see claim 1 and 6 of Nishimura). Nishimura also teaches that the mammalian cell to be preserved can be a mammalian T cell, such as human peripheral blood T cells, leukocytes, T cells, helper T cells, cytotoxic T cells, and γδ cells (the immunocyte is a T cell as in claim 46) (see claims 4, 8, and 9 of Nishimura; paragraph 0045). Nishimura teaches that trehalose has the properties of stabilizing cell membrane and suppressing cell damage (paragraph 0004), and a physiological aqueous solution containing dextran or trehalose can suppress the cell death and can increase the percentage of living cells (paragraph 0074-0075).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the method of preserving cells as taught by Oyama, Licari, and Thatte, by including dextran, trehalose, and lactate Ringer’s solution in the preservation solution to arrive at the claimed invention. As Nishimura teaches the preservation of mammalian cells in a solution that has dextran, trehalose, and lactate Ringer’s, one of ordinary skill would have been motivated to include dextran, trehalose, and lactate Ringer’s in the solution with reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Nishimura teaches that trehalose advantageously has the properties of stabilizing cell membrane and suppressing cell damage, and solutions containing dextran, trehalose, and lactate Ringer’s can suppress the cell death and can increase the percentage of living cells.
It also would have been prima facie obvious to preserve a T cell as taught by Nishimura to arrive at the claimed invention. As the claimed invention relies on the preservation of mammalian cells using a preservation solution, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the mammalian cells of Oyama, Licari, and Thatte) for another (the T cell of Nishimura) with a reasonable expectation of success (preserving a mammalian cell using a preservation solution). One of ordinary skill would have been motivated to make the substitution because Nishimura teaches that mammalian T cells can successfully preserved in a solution that has trehalose, dextran, and Ringer’s lactate solution.
Accordingly, the claimed invention was prima facie obvious at the time of filing, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments with respect to the Doorscholdt reference have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Please note that the response to argument below will only address arguments related to the other cited references.
On pg. 8-9, Applicant argues that a major feature of Licari is that the preservation medium contains no component of animal origin such as fetal bovine serum albumin but claim 27 requires albumin such that it would not be obvious to modify Oyama with Licari. Applicant argues that Licari discloses as many as 132 combinations of vitamins, such that it would not be obvious to select nicotinamide and ascorbic acid and in view of Licari’s disclosure regarding preserving human corneal cells, there is no reason to presume that ascorbate advantageously applicable to cells other than human corneal cells.
In response, the examiner disagrees. First, the disclosure of Licari discloses a preference of not using albumin because of a specific disadvantage: inability to guarantee their medical security with respect to prion diseases, in particular Creutzfeld-Jakob disease (see paragraph 0007). However, this reference does not disparage or discourage the use of albumin in preservation solutions generally. "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Also, the teachings of Licari (which was not used for its teachings regarding albumin) must also be viewed in light of the teachings of Lee which specifically teaches that albumin advantageously is capable of causing improved cell viability and stability due to its chelating and antioxidant properties (see rejection above). Thus, in light of the combination of Licari and Lee, one of ordinary skill would have been motivated to use albumin because of its advantageous properties. Second, Applicant’s argument regarding Licari’s disclosure of “as many as 132 combinations” is unpersuasive as Licari explicitly teaches a solution containing both ascorbic acid and nicotinamide (see paragraph 0040). Third, Applicant’s argument regarding “no reason to presume that ascorbate advantageously applicable to cells other than human corneal cells” is unpersuasive as Licari explicitly discloses the use of the preservation medium for living organs, biological tissues, and cells (see abstract; claims; throughout) and defines “living biological organs, cells, and tissues” as “components of human or animal origin” (see paragraph 0014) which would necessarily include any and all human organs, cells, and tissues (including platelets/megakaryocytes as instantly claimed). Thus, the rejections are maintained as set forth above.
On pg. 10-11 Applicant argues the rejections of claims 39-40, 44-46, 48 and 50 for much of the same reasons as set forth above.
In response, the examiner disagrees with Applicant’s arguments for the same reasons as set forth above. The combination of Oyama, Licari, Thatte, Hirose, and Lee teach Applicant’s claimed solution, and the additional references cited (Lee and Nishimura, respectively) render prima facie obvious the remaining claims for the reasons set forth in the 103 rejections above. Thus, the rejections are maintained.
Conclusion
NO CLAIMS ALLOWED.
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672