DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Applicant’s Request for Continued Examination, Amendment and Arguments/Remarks received on 07 April 2026 have been entered.
Claims 1-2, 5, and 7-8 were previously pending in the application. New claims 9-12 have been added by Applicant. Claims 1-2, 5, and 7-12 are currently pending in the application. Claims 1, 2, 5, and 8 are independent claims.
The election of Group I, drawn to a refrigerated storage liquid for storing human or animal stem cells or embryos in a non-frozen state and a refrigerated storage method, remains in effect in the instant application. The following election of species remains in effect in the instant application:
Claims 2 and 7-8 remain withdrawn from consideration as being directed to a nonelected invention, there being no allowable generic or linking claim. Claims 11-12 are newly withdrawn from consideration as being directed to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 5, and 9-10 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/JP2020/041313, filed 05 November 2020, which claims priority to JP2019-203124, filed 8 November 2019. Filing of a certified copy of the JP2019-203124, filed 12 April 2022 is acknowledged.
Thus, the earliest possible priority for the instant application is 8 November 2019.
Claim Objections
Amended claim 1 is newly objected to because of the following informalities: amended claim 1 now recites “wherien” in line 21, which appears to be a typographical misspelling of “wherein”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Amended, previously presented, and new claims 1, 5, and 9-10 are newly 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. Previously presented and new claim 5 and 10 are included in this rejection due to their dependence on or encompassing of independent claim 1 and/or claim 9.
Amended independent claim 1 newly recites “from at least one of” in lines 3 and 6, wherein each of the lists recited in lines 3-5 and 6-8 are joined by the linker term “or”, which is indefinite because it is unclear whether the lists recited are open or closed groups. As such, the metes and bounds of the claims cannot be determined.
New claim 9 recites, “wherein the polyvinyl alcohol is in a quantity of 5% by weight of the refrigerated storage liquid”, which is indefinite because a quantity of 5% by weight corresponds to 50 g/L, which conflicts with the limitation of claim 1, upon which claim 9 depends, which recites “5 to 25 g/L of polyvinyl alcohol”. As such, the metes and bounds of the claims cannot be determined.
Claim Rejections - 35 USC § 112(a) - Scope of Enablement
The rejection of amended and previously presented claims 1 and 5 under 35 U.S.C. 112(a) for a scope of enablement where the specification,
while being enabling for a refrigerated storage liquid comprising:
potassium ions in a range of 30 to 80 mmol/L;
sodium ions in a range of 30 to 80 mmol/L, an ion-based molar ratio of the sodium ions to the potassium ions being in a range of 0.5 to 1.3;
wherein the potassium ion species are introduced into the storage liquid as potassium chloride, potassium dihydrogen phosphate, potassium hydroxide, dipotassium hydrogen phosphate, and/or potassium citrate, and
wherein the sodium ion species are introduced into the storage liquid as sodium chloride, sodium dihydrogen phosphate, sodium pyruvate, sodium hydroxide, L-tyrosine disodium salt dihydrate, sodium bicarbonate, and/or sodium phosphate monobasic anhydrous; and
L-alanyl-L-glutamine;
does not reasonably provide enablement for a refrigerated storage liquid comprising any potassium ion species, any sodium ion species, and any dipeptide as a substitute of L-alanyl-L-glutamine;
is withdrawn in view of Applicant’s amendments to the claims such that claim 1 now recites the specific potassium ion counterions and the specific sodium ion counter ions as identified as enabled in the prior actions as well as claim 1 now not reciting “or another dipeptide substitute”.
Claim Rejections - 35 USC § 103
The rejection of amended and previously presented claims 1 and 5 under 35 U.S.C. 103 as being unpatentable over Zeng & Lu [CN105284787A, published 03 February 2016, IDS, cited in a prior action]; in view of Cheng & Deng [CN108651442A, published 16 October 2018, IDS, cited in a prior action]; ThermoFisher Scientific [2015, 11130- MEM Amino Acids Solution (50X) liquid, retrieved on 21 May 2025 from the Internet: < https://web.archive.org/web/20150905203426/https ://www.thermofisher.com/us/en/home/technical-resources/media-formulation.164.html>, archived 05 September 2015, hereafter referred to as ”ThermoFisher Scientific (11130)”, cited in a prior action]; ThermoFisher Scientific [2015, MEM Amino Acids Solution (50X), retrieved on 21 May 2025 from the Internet: < https://web.archive.org/web/20151110134244/http://www.thermofisher.com/order/catalog/product/11130051>, archived 10 November 2015, hereafter referred to as ”ThermoFisher Scientific (MEM Amino Acids)”, cited in a prior action]; ThermoFisher Scientific [2015, GlutaMAXTM Supplement, retrieved on 21 May 2025 from the Internet: <https://web.archive.org/web/20150920232153/https://www.thermofisher.com/order/catalog/product/35050061>, archived 20 September 2015, hereafter referred to as ”ThermoFisher Scientific (GlutaMAXTM)”, cited in a prior action], Mori & Hara [2016, Journal of Bioscience and Bioengineering, 121(5), 584-590]; and Asada et al. [2002, Theriogenology, 58, 1199-1208], is maintained over amended and previously presented claims 1 and 5 and newly applied to new claim 9. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended claim 1 to recite specific potassium and sodium counterions, which encompass species taught by Zeng, including dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium citrate, and sodium chloride.
Additionally, Applicant amended claim 1 to remove “or another dipeptide substitute” and to narrow the range of essential amino acid concentrations to 80 to 150 mg/L.
Cheng, ThermoFisher Scientific (11130), ThermoFisher Scientific (MEM Amino Acids) together provide teachings for including essential amino acids at 162.4 mg/L, which does not fall within the recited range of 80-150 mg/L, but differs only by 12.4 mg/L (8.3%) from the upper end of the recited range.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 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%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05.
As such, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to include essential amino acids in a cell storage liquid in the range of about 162.4 mg/L as taught by Cheng, ThermoFisher Scientific (11130), and ThermoFisher Scientific (MEM Amino Acids) to promote the viability of the cells. Additionally, modification of the essential amino acid concentration to a range of between 80 and 150 mg/L would be readily achievable through routine experimentation and motivated by the normal desire of scientists or artisans to improve upon what is already generally known. Further, Applicant has not provided any evidence of the criticality of the claimed range which would render the range non-obvious over the prior art teachings of 162.4 mg/L.
Accordingly, Applicant’s amendments do not overcome a finding of obviousness under 35 U.S.C. 103.
Regarding new claim 9, Mori was cited for teaching hydrogels for the culture of neural stem/ progenitor cells (NSPCs) to maintain adherent NSPCs in an undifferentiated state [abstract], wherein the lowest concentration tested (e.g., 3.75% (w/v) or 37.5 g/L) gave the best results in terms of generating NSPC clusters similar to those in neurosphere cultures and maintained cells in an undifferentiated state while showing very little deformation upon impregnation [column 11 ¶ 4, Figure 2]. Mori also teaches that NSPCs grown in softer PVA hydrogels spread very little and spontaneously formed neurosphere-like hemispherical cell clusters [column 11 ¶ 5]. Additionally, Mori teaches that their soft PVA hydrogel can be applied not only to the culture but also to the shipping and storage of stem cells [column 12 ¶ 1]. Mori further teaches that the proliferation rate of cells grown on the soft PVA gel having 3.75-7.5% (w/v) PVA was approximately 70% of that of neurospheres in suspension [abstract]. Therefore, given the teachings of Mori of the improved maintenance of stemness of stem cells cultured in low percent hydrogels and the teaching to include the PVA hydrogel for shipping and storage of stem cells, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to include PVA at a low percentage (e.g., around 3.75-7.5%) to help maintain the cells in an undifferentiated state during storage.
Also, as discussed above, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. Applicant has not provided any evidence of the criticality of a 5% by weight concentration of PVA in the refrigerated storage liquid. In fact, the instant specification teaches testing PVA in the range of 0.5% to 5%, wherein 0.5% PVA combined with 30 mM to 90 mM mannitol provided viabilities of the cells after refrigerated storage which were higher than those obtained by the storage liquid containing hydroxyethyl starch at a concentration of 5% [0116]. Further, Figure 12B shows wherein 5% PVA resulted in lower viability than each of 0.5%, 1.0%, and 2.5% PVA across mannitol concentration of 30-90 mM. Accordingly, the instant disclosure does not teach a criticality of 5% PVA concentration for the instant invention as claimed.
Therefore, given the motivation taught by Mori to include PVA at a low percentage (e.g., around 3.75-7.5%) to help maintain the stem cells in an undifferentiated state during storage, it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the storage liquid of Zeng to include PVA at a concentration of 5% by weight with a reasonable expectation of success.
Applicant argues that:
Zeng range of 3 to 10 mM explicitly applies only to a vitamin C and vitamin E combination;
the amendment of claim 1 to recite a concentration range of essential amino acids of 80 to 150 mg/L, which is the most particular and narrow of the listed ranges in the specification, renders any argument that “differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” inapplicable;
Asada fails to teach and/or suggest using mannitol instead of ethylene glycol (EG) and sucrose (ES1);
Asada fails to teach and/or suggest using the solution for non-frozen state refrigerated storage instead of vitrification storage;
Mori fails to teach and/or suggest using the PVA or using the PCA in a culture medium;
claim 9 recites “wherein the polyvinyl alcohol is in a quantity of 0.5% by weight of the refrigerated storage liquid”, and Mori teaches PVA hydrogels at 3.75%, which is significantly less than the claimed concentration; and
An unexpectedly superior effect has been achieved by simultaneously adopting PVA and mannitol as disclosed at least at [0089] and Figs. 12A and 12B of the subject application, including that use of 0.5% by weight PVA provides a significantly more viable product than mere use of HES and a significantly more viable product than use of the other PVA values tested.
However, this is not agreed.
In response to Applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). 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). Further, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, regarding Applicant’s argument 1), note that the claims as written do not exclude the inclusion of vitamin C along with the vitamin E, and so do not exclude a combination of vitamin C and vitamin E. Note also that the translation provided by Applicant along with the IDS filed 18 June 2025, which indicates that it was obtained from Espacenet, recites, “vitamin C and vitamin E can be added at 3-10 mmol/L” and “when antioxidants are used together, they can be added in a low amount within the above range” [0019]. Therefore, by teaching “when antioxidants are used together”, Zeng is providing for the option to use only one or the other of the two antioxidants recited (i.e., vitamin C or vitamin E). Additionally, a teaching to add an amount in the low range when used together does not necessitate that the amount used when added individually max out the recited range. As such, Zeng teaches to add vitamin C in an amount (3-10 mmol/L) which substantially overlaps with the claimed range of 0.5 to 8 mM. Therefore, it would have been obvious to an ordinarily skilled artisan to select an amount of vitamin E anywhere within the cited range of 3-10 mmol/L, including within the overlapping range of 3-8 mmol/L.
Regarding Applicant’s argument 2), note that amending the claim to recite the narrowest recited range disclosed in the specification is not a teaching of the criticality of the claimed range. Accordingly, such an amendment does not preclude an argument that differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. Further, Applicant has not provided any evidence of the criticality of the claimed range of 80 to 150 mg/L of essential amino acids. As such, the prior art teachings to use essential amino acids at a concentration of 162.4 mg/L are sufficiently close such that the difference amounts to a difference obtainable by routine experimentation and does not support the patentability of the claimed invention.
Regarding Applicant’s argument 3), note that Asada was not relied on for teaching the use of mannitol in the refrigerated storage liquid. The use of mannitol in concentrations of 40-50 mmol/L was taught by the base reference Zeng. Asada was cited for teaching the motivation to include PVA at a concentration of about 0.5% (w/v) (e.g., about 5 g/L) to improve the survivability of the embryos.
Regarding Applicant’s argument 4), note “refrigerated” and “for storing human or animal stem cells or embryos in a non-frozen state” represent intended use of the claimed product. Applicant is reminded that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure (e.g., storage liquid) is capable of performing the intended use (e.g., ) storing human or animal stem cells or embryos in a non-frozen state, then it meets the claim. It is a general rule that merely discovering and claiming a new benefit to an old process cannot render the process again patentable. In re Woodruff, 919 F. 2d 1575, 1577-78, 16 USPQ2d 1934, 1936-37 (Fed.Cir. 1990); In re Swinehart, 439 F.2d 210, 213, 169 USPQ 226, 229 (CCPA 1971); and Ex Parte Novitski, 26 USPQ2d 1389, 1391 (Bd. Pat. App. & Int. 1993).
Not also that Asada was not relied on for teaching using the solution for non-frozen state refrigerated storage instead of vitrification storage. As discussed above, Asada was cited for teaching the motivation to include PVA at a concentration of about 0.5% (w/v) (e.g., about 5 g/L) to improve the survivability of embryos. Additionally, Zeng was cited for teaching a refrigerated storage liquid, wherein the cells are stored at 4 oC [0042].
Regarding Applicant’s argument 5), note that the instant claims recite a refrigerated storage liquid and not a culture media per se. Mori was cited for teaching the beneficial effects of PVA on stem cells in promoting the maintenance of an undifferentiated state, and to use the PVA in the storage of stem cells.
Further, as discussed in the prior action, Asada was cited for teaching that 0.5% (w/v) PVA in liquid media improves the survivability and activity of stored embryos such that an ordinarily skilled artisan would have been motivated to include PVA at a concentration of about 0.5% (w/v) (e.g., about 5 g/L) to improve the survivability of embryos.
Regarding argument 6), note that the PVA concentration recited in new claim 9 is 5% by weight and not 0.5% by weight. Additionally, as discussed above, Mori teaches a range of 3.75-7.5% PVA (which encompasses the claim 5%) provides beneficial effects for maintaining stem cells in an undifferentiated state. Therefore, the concentration range taught by Mori is not significantly less than the claimed concentration.
Regarding Applicant’s argument 7), that an unexpectedly superior effect has been achieved by simultaneously adopting PVA and mannitol as disclosed at least at [0089] and Figs. 12A and 12B of the subject application, and that use of 0.5% by weight PVA provides a significantly more viable product than mere use of HES and a significantly more viable product than use of the other PVA values tested, note firstly that claim 9 as filed recites 5% PVA and not 0.5% PVA.
As discussed in the prior action, instant Figures 12A and 12B show relative viability for samples treated with 5% HES or various concentrations of PVA (with or without various mannitol concentrations). Figure 12A shows that each of the PVA concentrations tested had viabilities which were comparable to the viability of the cells in 5% HES. Figure 12B shows that the further addition of mannitol to the PVA-comprising media resulted in viabilities which were still similar to the viabilities of the cells in 5% HES, with most conditions having lower viability. None of the PVA and PVA + mannitol storage solutions resulted in viabilities which were significantly improved from that obtained with the 5% HES solution. The only indication of significance provided in Figure 12B are the presence of error bars; the large range of the error bars depicted for all of samples, including the 0.5% and 5% PVA samples, indicate that they are not significantly different from the 5% HES control. Further, although the 0.5% PVA samples with 30 mM or 90 mM mannitol may be marginally statistically significant relative to the respective 5% PVA samples, the 5% PVA samples themselves have non-significantly lower viability compared to the 5% HES control sample.
Applicant did not provide any data for conditions which resulted in lower viability nor any other data which would suggest that the observed viability levels were in fact unexpected.
Applicant argued in the prior action that the observed high viability for cells stored in solutions comprising PVA and/or PVA+ mannitol is surprising because it has been traditionally believed that such viability was not obtainable [page 7 ¶ 2]. However, Applicant still has not provided any evidence for that “traditional” belief. As such, the argument amounts to an argument of counsel. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration. Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. MPEP 716.01(c). Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art.
It is also noted that any evidence of unexpected results must be commensurate in scope with the claimed invention, and that a greater, or greater than additive, effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected MPEP 716.02 (a) and (d). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
In the instant case, the evidence provided is not commensurate in scope with the claimed invention. The brief description of Figure 12A indicates that the graph shows protective effects of PVA in place of HES in an experiment in the same manner as that of Figure 6A, which was in the same manner as 2A with the concentration of Trolox changed (e.g., addition of 0.1 mM, 1.0 mM, 2.0 mM or 5.0 mM Trolox to the HTM1 solution). The brief description of 2A indicates that it was performed as in 1A, which indicates that the storage media (HTM1) was obtained by mixing the UW solution and the clinical-research use medium of StemFit® AK02N at a ratio of 2:1 [0019-0044]. Therefore, the solutions tested for the generation of data presented in Figure 12A comprising the HTM1 solution, 0-5 mM Trolox, and 0.25%, 0.5%, 1.0%, or 2.5% PVA without mannitol.
The Brief description for Figure 12B indicates the effects of further adding mannitol in addition to PVA in an experiment done in the same manner with that of Figure 12A [0045]. As such, the solutions tested for the generation of data presented in Figure 12B comprise the HTM1 solution supplemented with 0-5 mM Trolox; 0.5%, 1.0%, 2.5%, or 5% PVA; and 0 mM, 30 mM, 60 mM, or 90 mM mannitol. Note that all of the concentrations of PVA shown in Figure 12A performed comparably. Also, all of the concentrations of mannitol shown in Figure 12B performed comparably with no condition resulting in viability significantly higher than the HES 5% control condition.
The specification teaches that the HTM1 solution comprises 55.5 mM Na+, 85.1 mM K+, and an Na+/K+ ratio of 0.7. The specification also teaches that the HTM1 solution was made by adding 5 mM Trolox and 5-fold concentration (x5, 10 mM) GlutaMAX® [0108, 0111], however, the effect of these additions on the final volumes/ concentrations of other components, whether the concentrations taught are starting or final concentrations, and the volumes added were not taught.
The specification alternatively in Examples 13 and 14 alternatively teach that the data presented in Figures 12A and 12B were generated using HTM-alpha (UW solution + MEM-alpha, 2:1) without HES and supplemented with PVA with or without mannitol [0115-0116]. Note that Table 3 teaches that HTM-alpha has the same salt concentrations as HTM1 [0081]. Example 13 teaches, “the other components are same with those in the HTM-alpha (UW Solution + MEM-alpha, 2:1) while polyvinyl alcohol (PVA) in the range of 0.25% to 2.5% (weight) were added in the storage liquids used here” [0115], suggesting the lack of addition of Trolox, vitamin E, L-alanyl-L-glutamine, and/or other dipeptide substitute.
Therefore, the specification does not teach the extent to which the disclosed concentrations for HTM1 or HTM-alpha may be changed with the alterations in Trolox, vitamin E, L-alanyl-L-glutamine, other dipeptide substitute, PVA, and/or mannitol concentrations. The specification does not clearly teach how much (if any) Trolox, vitamin E, L-alanyl-L-glutamine, or other dipeptide substitute is included in the solutions tested in Figures 12A and 12B. Accordingly, the specification does not teach that the solutions used to produce the data provided in Figures 12A and 12B are commensurate in scope with amended independent claim 1.
Therefore, Applicant’s arguments are not found to be persuasive and do not overcome a finding of obviousness under 35 USC 103 over Zeng in view of Cheng, ThermoFisher Scientific (11130), ThermoFisher Scientific (MEM Amino Acids), ThermoFisher Scientific (GlutaMAXTM), Mori, and Asada, and the rejection is maintained.
New claim 10 is newly rejected under 35 U.S.C. 103 as being unpatentable over Zeng & Lu [CN105284787A, published 03 February 2016, IDS, cited in a prior action]; in view of Cheng & Deng [CN108651442A, published 16 October 2018, IDS, cited in a prior action]; ThermoFisher Scientific [2015, 11130- MEM Amino Acids Solution (50X) liquid, retrieved on 21 May 2025 from the Internet: < https://web.archive.org/web/20150905203426/https ://www.thermofisher.com/us/en/home/technical-resources/media-formulation.164.html>, archived 05 September 2015, hereafter referred to as ”ThermoFisher Scientific (11130)”, cited in a prior action]; ThermoFisher Scientific [2015, MEM Amino Acids Solution (50X), retrieved on 21 May 2025 from the Internet: < https://web.archive.org/web/20151110134244/http://www.thermofisher.com/order/catalog/product/11130051>, archived 10 November 2015, hereafter referred to as ”ThermoFisher Scientific (MEM Amino Acids)”, cited in a prior action]; ThermoFisher Scientific [2015, GlutaMAXTM Supplement, retrieved on 21 May 2025 from the Internet: <https://web.archive.org/web/20150920232153/https://www.thermofisher.com/order/catalog/product/35050061>, archived 20 September 2015, hereafter referred to as ”ThermoFisher Scientific (GlutaMAXTM)”, cited in a prior action], Mori & Hara [2016, Journal of Bioscience and Bioengineering, 121(5), 584-590]; and Asada et al. [2002, Theriogenology, 58, 1199-1208]; and further in view of Beutler & Kuhl [1988, Transfusion, 28(4), 353-357] and Petrenko et al. [2014, CryoLetters, 35(3), 239-246].
Zeng in view of Cheng, ThermoFisher Scientific (11130), ThermoFisher Scientific (MEM Amino Acids), ThermoFisher Scientific (GlutaMAXTM), Mori, and Asada teach the limitations of independent claim 1 and new claim 9.
Zeng was cited for teaching the inclusion of mannitol at a concentration of 40-50 mmol/L [0009]. None of Zeng, Cheng, ThermoFisher Scientific (11130), ThermoFisher Scientific (MEM Amino Acids), ThermoFisher Scientific (GlutaMAXTM), Mori, nor Asada teach the inclusion of mannitol at a concentration of 90 mmol/L.
Beutler teaches the storage of red blood cells at 4 oC for 6 weeks in the presence or absence of supplemented mannitol [column 2 ¶ 2, column 4 ¶ 2]. Beutler further teaches that at the end of 6 weeks in the presence of 82.4 mM mannitol, the volume of red blood cells had increased less than 1% and only 0.38% of cells had lysed, in contrast to in the absence of mannitol in which the volume of the red blood increased by 12% and with 1.03% of the cells had lysed [column 4 ¶ 2]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a concentration of mannitol about 82.4 mM in a refrigerated storage liquid for storing cells to reduce cellular lysis.
Petrenko teaches that cryoprotective solutions supplemented with mannitol in concentrations of 100 mM, 200 mM, 300 mM and 500 mM each resulted in significant improvement of mesenchymal stem cell (MSC) survival rate after cryopreservation compared to a control medium, and that the cryoprotective effect did not significantly depend on the concentration of mannitol in the freezing medium [column 6 ¶ 3, column 7 ¶ 1, Figure 1]. Therefore, an ordinarily skilled artisan would have been motivated to use mannitol at a concentration of 100-500 mM for the preservation of stem cells in a storage medium to increase the survival rate of the stem cells.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 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%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). See MPEP 2144.05.
In the instant case, Applicant has provided data for the effects of mannitol concentration on stem cell viability in Figure 12B, wherein the viability obtained for mannitol concentrations of 30 mM, 60 mM, and 90 mM are not significantly different from each other. Therefore, Applicant has not demonstrated a criticality for a concentration of 90 mM mannitol which would make it nonobvious over teachings for concentrations of 82.4 mM and 100 mM mannitol. Additionally, modifications to alter the mannitol concentration from the concentrations taught by Zeng (40-50 mM), Beutler (82.4 mM), and Petrenko (100 mM) to arrive at the instantly claimed 90 mM amounts to routine optimization and does not support the patentability of the claimed invention.
Given the teachings and motivations of Beutler to use a concentration of mannitol about 82.4 mM in a refrigerated storage liquid for storing cells to reduce cellular lysis and the teachings and motivations of Petrenko to use mannitol at a concentration of 100-500 mM for the preservation of stem cells in a storage medium to increase the survival rate of the stem cells; it would have been prima facie to an ordinarily skilled artisan at the time of filing the instant application to modify the refrigerated storage liquid of Zeng to comprise mannitol at a concentration of 90 mM with a reasonable expectation of success.
Insofar as applicant’s arguments apply to this new grounds of rejection, Applicant argues that the mannitol concentration taught by Zeng of 40-50 mM is significantly less than the claimed concentration. However, this is not agreed.
As described above, Beutler teaches to use a concentration of mannitol about 82.4 mM and Petrenko teaches to use mannitol at a concentration of 100-500 mM. Therefore, the cited references teach concentrations of mannitol which are substantially similar to the claimed concentration such that it would have been obvious to an ordinarily skilled artisan at the time of filing the instant application to select a mannitol concentration of 90 mM.
Therefore, Applicant’s arguments do not overcome a finding of obviousness under 35 U.S.C. 103 over Zeng in view of Cheng, ThermoFisher Scientific (11130), ThermoFisher Scientific (MEM Amino Acids), ThermoFisher Scientific (GlutaMAXTM), Mori, and Asada, and further in view of Beutler and Petrenko.
Conclusion
No claim is allowed.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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