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 .
This action is in response to the papers filed May 20, 2026.
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. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 20, 2026 has been entered.
Claims 1-4 and 8-14 are pending in the application. No claims are canceled, claim 1 is amended and no new claims are added as set forth in the claim set filed May 20, 2026.
Therefore, claims 1-4 and 8-14 are examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/KR2021/005767 filed May 07, 2021.
Applicant’s claim for the foreign benefit of a prior-filed Korean Patent 10-2020-0054455 filed May 07, 2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Filing of a certified untranslated copy of the Korean Patent 10-2020-0054455, filed November 4, 2022 is acknowledged.
Thus, the earliest possible priority for the instant application is May 07, 2020.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1-4 and 8-14 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Applicant’s arguments and amendments filed 05/20/2026 have been considered and are persuasive. In particular, the amendments made to claim 1 further define the active steps.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 1-4 and 8-14 remain rejected under 35 U.S.C. 103 as being unpatentable over Sheyn (STEM CELLS TRANSLATIONALMEDICINE 2016;5:1447–1460) in view of Zhang (Biomaterials 41 (2015) 15-25; IDS Reference), Rungarunlert (World J Stem Cells 2009 December 31; 1(1): 11-21) and Carpenedo (STEM CELLS 2007;25:2224 –2234)
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 10/27/2025.
Regarding claim 1, 8 and 11, Sheyn teaches a method of making induced mesenchymal stem cells (iMSCs) from human induced pluripotent stem cells (iPSCs) (reading on pluripotent stem cells of claim 1 step (a) ) (Abstract; p. 1448, 2nd column). The iMSCs were made by seeding the iPSCs into 348 well plates with 10,000 cells per well and cultured to form embryoid bodies (EBs) (p. 1449, 1st column; Fig 1A), reading on claim 1 step (a).
PNG
media_image1.png
184
688
media_image1.png
Greyscale
The EBs were then transferred and cultured on 1% gelatin treated flasks (reading on culture vessel coated with an adhesive polymer of claim 1 step ( c)) where EBs attached and formed the aiMSCs or EBs did not attach and formed tiMSCs, both populations were compared to BM-MSCs (Figure 1, p. 1449, 1st column; p. 1449, 2nd column). Regarding step 1c, the EBs themselves are differentiated.
While Sheyn teaches partially step a) and partially step c) of the present invention, the reference does not teach step b) 3D culturing of EBs in a bioreactor under microgravity to form spheroids.
Zhang teaches that it is known in the art generally that spheroids can be obtained via three approaches: hanging drop, low-attachment culture, and dynamic culture, however dynamic culture is more suitable for large scale production of spheroids (p. 16, 2nd paragraph). Dynamic cultures involve spheroids that are grown in a spinner flask or a microgravity bioreactor (MB) which offers the benefits of reduced shear stress, reduction of damage caused by mechanical agitation, increased mass transfer which promotes the transport of nutrients and the removal of metabolites from spheroids growing in an MB. “Thus, these advantages of MB potentially increase cell viability of MSCs. Moreover, increasing evidence has demonstrated that MBs are useful in the scale-up of stem cells” (p. 16, 2nd paragraph). Moreover, Zhang teaches that the bioreactor is a microgravity bioreactor which rotates at a speed of 25 rpm for 5 days (p. 16, 1st column).
Based on the benefits of culturing embryoid bodies in microgravity bioreactor (MB) for large scale production of spheroids as taught by Zhang, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to include a step of culturing the EBs in a bioreactor with microgravity in the method of Sheyn as taught by Zhang before the differentiation of EB into mesenchymal stem cells by adherent culture with a reasonable expectation of success. An artisan would be motivated to do so as microgravity bioreactors offer the benefits of reduced shear stress, reduction of damage caused by mechanical agitation, increased mass transfer which promotes the transport of nutrients and the removal of metabolites from spheroids growing in an MB (Zhang, p. 16, 2nd paragraph). Moreover, Zhang shows microgravity forms spheroids, therefore culturing the EBs of Sheyn would form spheroids with a reasonable expectation of success.
However, Sheyn and Zhang do not teach the limitation of step a where in the aggregation of the cells to form EBs is induced through centrifugation as required in claim 1 line 9 .
Rungarunlert teaches that methods are known in the art which force aggregation of EBs through centrifugation in pluripotent cells such as embryonic stem cells and (Table 1; p. 15, 1st column). Forced aggregation through centrifugation improves the reproducibility of EB production (p. 15, 1st column). As shown in Table 1, forced aggregation of EBs is a known alternative method of forming EBs from pluripotent cells such as embryonic stem cells.
Based on these teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to further induce aggregation of pluripotent cells to form EBs of Sheyn through centrifugation as taught by Rungarunlert with a reasonable expectation of success. An artisan would have been motivated to aggregate the pluripotent cells to form EBs of Sheyn through the methods such as forced aggregation by centrifugation as taught by Rungarunlert because forced aggregation through centrifugation improves the reproducibility of EB production (p. 15, 1st column). As shown in Table 1, forced aggregation of cells is a known alternative method of forming EBs.
Regarding the limitation of 40-80 rpm, as well as the increase in rpm in claim 8, these references do not teach that the rpm is 40-80 where rotation speed increases by 5 rpm every day.
Carpenedo teaches culturing embryoid bodies formed from pluripotent stem cells in a microgravity bioreactor at speeds of 25, 40 and 55 rpm (p. 2225, 4th-5th paragraph). The study teaches that an inverse relationship between embryoid body (spheroids) formation size and rotary speed exists, for instance, a lower speed such as 25 rpm produces larger, fewer clusters of the spheroids and a higher speed such as 55 rpm produces smaller spheroids in greater amounts (p. 2233, 1st paragraph; p. 2226, last paragraph; Figure 1). “The ability to control the size of EBs may be necessary for creating robust, reproducible strategies for ES cell differentiation because cell differentiation is influenced by spatial and temporal patterns of cell-cell interactions, and thus the size of individual EBs formed may affect their differentiation profiles” (p. 2232, last paragraph). Therefore, the rotatory speed is a case of routine optimization.
In view of the benefits of to control the size of EBs by adjusting the rotation speed, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify the speed of the microgravity bioreactor as taught by Sheyn, Zhang and in order to routinely optimize the parameters of the cell culture as evidenced by Carpenedo. An artisan would be motivated to optimize this parameter as Carpenedo teaches “The ability to control the size of EBs may be necessary for creating robust, reproducible strategies for ES cell differentiation because cell differentiation is influenced by spatial and temporal patterns of cell-cell interactions, and thus the size of individual EBs formed may affect their differentiation profiles” (p. 2232, last paragraph).
It is well settled that routine optimization is not patentable, even if it results in significant improvements over the prior art. In support of this position, attention is directed to the decision in In re Aller, Lacey, and Haft, 105 USPQ 233 (CCPA 1955): Normally, it is to be expected that a change in temperature, or in concentration, or in both, would be an unpatentable modification. Under some circumstances, however, changes such as these may impart patentability to a process if the particular ranges claimed produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art. In re Dreyfus, 22 C.C.P.A. (Patents) 830, 73 F.2d 931,24 USPQ 52; In re Waite et al., 35 C.C.P.A. (Patents) 1117, 168 F.2d 104, 77 USPQ 586. Such ranges are termed "critical" ranges, and the applicant has the burden of proving such criticality. In re Swenson et al., 30 C.C.P.A. (Patents) 809, 132 F.2d 1020, 56 USPQ 372; In re Scherl, 33 C.C.P.A. (Patents) 1193, 156 F.2d 72, 70 USPQ 204. However, even though applicant's modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art. In re Sola, 22 C.C.P.A. (Patents) 1313, 77 F.2d 627, 25 USPQ 433; In re Normann et al., 32 C.C.P.A. (Patents) 1248, 150 F.2d 708, 66 USPQ 308; In re Irmscher, 32 C.C.P.A. (Patents) 1259, 150 F.2d 705, 66 USPQ 314. More particularly, where 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 re Swain et al., 33 C.C.P.A. (Patents) 1250, 156 F.2d 239, 70 USPQ 412; Minnesota Mining and Mfg. Co. v. Coe, 69 App. D.C. 217, 99 F.2d 986, 38 USPQ 213; Allen et al. v. Coe, 77 App. D. C. 324, 135 F.2d 11,57 USPQ 136. (Emphasis added). With regards to determining experimental parameters, such as time in culture, the court has held that "[d]iscovery of optimum value of result effective variable in known process is ordinarily within skill of art (In re Boesch and Slaney, 205 USPQ 215 (CCPA 1980)).
The adjustment of particular conventional working conditions (e.g. rotary speed/rpm) is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan having the cited reference before him/her.
Regarding claims 2 and 3, the combined teachings of Sheyn, Zhang, Rungarunlert, and Carpenedo render obvious claim 1. Moreover, Sheyn teaches a method of making induced mesenchymal stem cells (iMSCs) from human induced pluripotent stem cells (iPSCs) (i.e. pluripotent stem cells) (Abstract; p. 1448, 2nd column).
Regarding claim 4, as stated by the instant specification, “the term "three-dimensional culture" is a concept opposite to two-dimensional culture, and refers to culturing of cells in a floating state in a culture medium without adhesion to a substrate, etc. Thus, the term "three-dimensional culture" is used in the same meaning as "suspension culture”” (Specification p. 7). The combined teachings of Sheyn, Zhang, Rungarunlert, and Carpenedo render obvious claim 1. Moreover, Sheyn teaches the EBs are formed in non-adherent 384-well conical PCR plates (p. 1499, 1st column). Therefore, Sheyn reads on the claimed limitation.
Regarding claim 9 and 10, the combined teachings of Sheyn, Zhang, Rungarunlert, and Carpenedo render obvious claim 1. Moreover, Sheyn teaches the adhesive polymer the spheroids are cultured on is gelatin (p. 1449, 1st column).
Regarding claim 12, the combined teachings of Sheyn, Zhang, Rungarunlert, and Carpenedo render obvious claim 1. Moreover, Sheyn teaches utilizing the iMSCs to promote bone formation (i.e. treat bone disease) in vivo in mouse models where cells are resuspended in fibrin gel (p. 1451, 1st column). As the fibrin gel is the delivery vehicle, the cells are interpreted to be the active ingredient.
Regarding claim 13 and 14, the combined teachings of Sheyn, Zhang, Rungarunlert, and Carpenedo render obvious claim 1. Moreover, Sheyn teaches that a composition of their iMSCs might be advantageous due to their anti-inflammatory properties to be utilized for treatments or prevention of GvHD (p. 1458, 1st paragraph).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicant’s arguments and amendments filed 05/20/2026 regarding the 103 rejection previously set forth.
Applicant’s arguments and amendments filed 05/20/2026 have been considered, however, they are not persuasive.
Applicant argues that the amendment made to recite “consisting of” instead of “comprising” overcomes the rejection and details the method steps found within the specification. Applicant argues that the references taken alone or in any fair combination does not teach or suggest a method of producing mesenchymal stem cells via the performance of only steps (a)-(c) as claimed and points to Sheyn which teaches a treatment of EBs with TGF beta 1 to achieve iMSCs.
The examiner disagrees. The combination of the references as discussed in the prior office action filed 03/10/2026 read on steps (a)-(c). Regarding the new claim language, while this does limit the scope of the invention to the steps, the steps themselves are also extremely broad. In particular, the step of step (c) recites “a step of differentiating the spheroids into mesenchymal stem cells by adherent-culturing in a culture vessel coated with an adhesive polymer.” This encompasses the TGF beta step that Applicant points to. The step as seen in Figure 1A below, shows differentiating EBs to MSCs with TGF beta 1 treatment on an adhesive polymer.
PNG
media_image1.png
184
688
media_image1.png
Greyscale
Moreover, as the combination of the references of Zhang and Sheyn is utilized in the 103 rejection, the formation of spheroids occurs after the EB formation with the microgravity bioreactor of Zhang. As detailed in the rejection, microgravity bioreactors offer the benefits of reduced shear stress, reduction of damage caused by mechanical agitation, increased mass transfer which promotes the transport of nutrients and the removal of metabolites from spheroids growing in an MB (Zhang, p. 16, 2nd paragraph). Moreover, Zhang shows microgravity forms spheroids, therefore culturing the EBs of Sheyn would form spheroids with a reasonable expectation of success.
As all of the limitations are taught by the combination of references in the above 103 rejection, the method would produce spheroids (as in step (b)) and then be cultured in an adhesive polymer coated vessel as taught by Sheyn to read on step (c). Step (c) is broad enough to encompass the TGF beta 1 treatment as it is part of the differentiation culture into iMSCs.
New grounds of objections/rejections
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 11-14 are newly rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e. product of nature) without significantly more.
Claim 11 recites “mesenchymal stem cells produced by the method according to claim 1.”
Mesenchymal stem cells are a product of nature. A three part inquiry has been established to determine subject matter eligibility under 35 U.S.C. 101 for process claims that involve laws of nature. See Subject Matter Eligibility Guidance. This inquiry comprises answering:
Step 1: Is the claimed invention directed to one of the four statutory patent-eligible subject matter categories: process, machine, manufacture, or composition of matter?
Step 2A:
Prong one: Does the claim recite or involve one or more judicial exceptions? Judicial exceptions include abstract ideas, laws of nature/natural principles, natural phenomena, and natural products. ; and
Prong two: Whether the additional elements integrate the exception into a practical application? Does the additional element apply, rely or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Step 2B: Does the claim as a whole recite something significantly different than the judicial exception(s)?
In the instant application,
With respect to step 1, the claimed invention is directed to a product.
With respect to step 2A prong one, the claimed invention recites mesenchymal stem cells which are a product of nature.
With respect to prong two of the analysis, the claimed invention further recites a pharmaceutical composition for the treatment of various diseases wherein the MSCs are an active ingredient. This is not an integration of a practical application as there are no administration steps. Furthermore, there are no additional elements listed, merely an intended use for the MSCs and the potential to utilize the MSCs as an active ingredient. Therefore, additional limitations do not impose a meaningful limitation on the judicial exception.
With respect to prong 2B, claims 11-14 do not include additional elements that are sufficient to amount to significantly more than the judicial exception as there are no additional elements.
Therefore, claims 11-14 are rejected as being directed to a judicial reception.
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.
Claims 1-4 and 8-14 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.
Claim 1 recites “(b) a step of forming spheroids by three-dimensionally culturing the embryoid bodies in a bioreactor under microgravity; and (c) a step of differentiating the spheroids into mesenchymal stem cells by adherent culturing in a culture vessel coated with an adhesive polymer.” Claim 1 is missing a step between step (b) and (c) wherein the spheroids are transferred from a bioreactor to a cell culture vessel which renders the metes and bound of the invention indefinite as it is unclear how an artisan would culture spheroids in a bioreactor in any culture vessel.
Therefore, claim 1 and its dependent claims are rejected as indefinite.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 11-14 are newly rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sheyn (STEM CELLS TRANSLATIONALMEDICINE 2016;5:1447–1460).
Claim 11 is anticipated based on the scope of the claim limitations and that it is a product-by-process claim. Claim 11 recites “mesenchymal stem cells produced by the method according to claim 1,” however this process has no weight on the structure of the obtained composition. As the product recited only comprises the mesenchymal stem cells, the cells are not recited to be structurally different than other induced MSCs derived from pluripotent stem cells.
Regarding claim 11, Sheyn teaches MSCs produced from pluripotent stem cells (Abstract; p. 1448, 2nd column). According to MPEP 2113, “"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art.
As the limitations do not apply further structure to the mesenchymal stem cells, the product is taught by Sheyn.
Regarding claim 12, Sheyn teaches utilizing the iMSCs to promote bone formation (i.e. treat bone disease) in vivo in mouse models where cells are resuspended in fibrin gel (p. 1451, 1st column). As the fibrin gel is the delivery vehicle, the cells are interpreted to be the active ingredient.
Regarding claim 13 and 14, Sheyn teaches that a composition of their iMSCs might be advantageous due to their anti-inflammatory properties to be utilized for treatments or prevention of GvHD (p. 1458, 1st paragraph).
Therefore, the claims are anticipated by Sheyn.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA CONNORS whose telephone number is (571)272-7010. The examiner can normally be reached Monday - Friday (9AM-5PM).
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, MARIA LEAVITT can be reached at (571) 272-1085. 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.
/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
Prosecution Insights