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 .
The Examiner for this Application has changed. Please direct all future correspondence to Juliana Candelaria, AU 1634. Additional contact information can be found at the end of this paper.
Applicant's claim amendment and response received on 09/05/2025 has been entered.
Claim 4-20 have been canceled. Claims 1-3 and 21-24 are currently pending and under examination in the instant application. An action on the merits follows.
Amendments to the Specification and to the Drawings
Applicant’s substitution specification received on 09/05/2025 has not been entered because it does not comply with 37 CFR 1.121(b) because deletion of matter in the specification constitutes new matter. Issues with the substitution specification include:
Deletion of subject matter related to the inclusion of an anion channel activator as part of the culture with the conditioned media and;
Deletion of the brief descriptions of Figure 3A-C, Figure 4A-D, and Figure 5A-F.
Amended brief description of figures does not accurately described figures (i.e. amended figures in drawings do not match corresponding brief description in specification)
The examiner additionally raises issues related to deletion of subject matter constituting new matter. See MPEP 608.04(a) - Matter Not Present in Specification, Claims, or Drawings on the Application Filing Date [R-10.2019]. In brief, MPEP 608.04(a) recites: “new matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method” emphasis added by examiner).
The examiner additionally notes the history of patent examination for this application as it relates to the specification. Examiner notes that prior amended specifications were not indicated to be entered by the previous examiner’s office actions and, in particular, amended specification filed 01/18/2023 lacks a marked-up version with its filing. It appears that amended specification filed 01/18/2023 is identical to amended specifications filed 09/28/2023 and 09/05/2025, all of which have not been entered.
Applicant’s amendments to the drawings received on 09/05/2025 has not been entered because it does not comply with 37 CFR 1.121(d) because (1) A marked-up copy of any amended drawing figure, including annotations indicating the changes made, may be included. The marked-up copy must be clearly labeled as "Annotated Sheet" and must be presented in the amendment or remarks section that explains the change to the drawings. (2) A marked-up copy of any amended drawing figure, including annotations indicating the changes made, must be provided when required by the examiner.
The filed drawings of 09/05/2025 suggest removal of Figure 3A-C, Figure 4A-D, and Figure 5A-F. Therefore, an “Annotated Sheet” must clearly depict these changes.
The examiner notes that the applicant’s filing of “Amendments to the Drawings” on 09/05/2025 states “The drawings have been amended to delete the Figs. 3a to 5f.” However, upon review of the drawings submitted 09/05/2025, the examiner notes that Figs. 3a to 5f were indeed deleted and proceeding figures were re-numbered accordingly (for instance, previously presented Figure 6a is now Figure 3a). However, many of the figures were additionally amended to remove data. Specifically, Figures 3A-F, 5A-C, 6A-C, and 7B-D were amended to remove data. The examiner points applicant to the aforementioned MPEP statement above regarding issues related to deletion of subject matter constituting introduction of new matter (See MPEP 608.04(a) - Matter Not Present in Specification, Claims, or Drawings on the Application Filing Date [R-10.2019]).
The examiner additionally notes that prior filed amendments to the drawings were not indicated to be entered by the previous examiner’s office actions.
In an effort to maintain compact prosecution, the examiner notes that even if the applicant amends the drawings, there remains differences between the previously presented and current drawings such that the issue of new matter remains present.
Claim Rejections - 35 USC § 103
Claims 1-3 and 21-24 remain rejected under 35 U.S.C. 103 as being unpatentable over Menon et al. (Stem Cells, 2007; 25:520-528) in view of Michielsen et al. (Oncolmmunology, 2012; 1:5 751-753) and Kodack et al. (Cell Reports, 2017; 21:3298-3309).
Response to Arguments
Applicant's arguments filed 09/05/2025 have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant argues that while Menon et al teaches mesenchymal stem cells (MSCs) exposed to conditioned medium from tumor cells exhibit increased in vitro and in vivo migration, the tumor cells used in Menon are standard immortalized cell lines and not derived from patients, as recited in claim 1 of the instant application. The applicant further argues that while Menon analyzed in vivo migration of MSCs to tumors, there was no experimental evidence that the MSCs were “educated” by tumor-cell-conditioned media. The applicant further argues that Menon only used established cancer cell line C85, not patient-derived cancer cells, for MSC education and they did not perform any cross-analysis, therefore there is no indication of educating MSCs using autologous cell cultures from a patient to be treated. Applicant further argues that Menon suggests the MSCs tumor-targeting ability is unlikely to be tumor specific and that nothing in Menon suggests tumor type-dependent chemotaxis.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., necessity to perform cross-analysis to demonstrate cells are “educated” tumor type-dependent chemotaxis) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Nevertheless, claim 1 of the instant application does not disclose the feature of needing to perform a cross-analysis or any confirmation to demonstrate the stem cells are “educated” and more likely to migrate to tumors. The examiner’s interpretation of the term “educated” means that the cells have been primed in a particular manner by exposure to factors present in the culture environment. Indeed, the specification recites “educating is performed by treating the stem cell with cell culture medium of in vitro cell culture of cancer cells obtained from the subject” (para [0014]). Similarly, claim 1 of the instant application does not disclose that the cells would need to specifically demonstrate tumor type-dependent chemotaxis and that MSCs homing is necessitated. Rather, claim 1 simply recites that the stem cells are prepared to be educated by culturing in cell culture medium of in vitro cell culture of cancer cells obtained from a patient and they have “cancer targeting” ability. The examiner is interpreting “cancer targeting” to mean that the stem cell encompasses the ability to have an effect on a cancer. There is no recitation that the cells are required to have any functional property following culture with the conditioned media, such as tumor type-dependent chemotaxis or enhanced tumor cell chemotaxis or that MSC homing is necessitated, nor does it recite that one would need to test and ensure that the cells are “educated”. Therefore, in view of the aforementioned claim interpretations, the teachings of Menon teach exposing MSCs to conditioned culture media derived from cultured tumor cells, injection of MSCs demonstrating in vivo migration to tumor microenvironment, and that migration is enhanced when MSCs are exposed to conditioned media derived from cultured tumor cells. It is further noted that the teachings of Menon are not read in a vacuum, but rather in view of the teachings of the secondary references Michielsen and Kodack.
The applicant then argues that the teachings of Michielsen, while teaching tumor-conditioned medium may reflect the tumor microenvironment more accurately than cancer cell lines, does not teach stem cells or addresses cell migration, education, or therapeutic targeting. Moreover, Michielsen teaches that dendritic cell maturation is inhibited using tumor conditioned media from colorectal cancer explants. In regards to the teachings of Kodak, the applicant argues that that Kodak does not teach stem cell education, let alone modifying stem cells using patient’s own tumor culture to achieve improved migration.
However, in response to applicant’s argument 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). Further, 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). 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 the instant case, Menon was cited as the primary reference for teaching in vitro cell culture of cancer cells, harvesting the culture medium from the in vitro cell culture of said cancer cells (i.e. conditioned medium) and using the harvested culture media from said cancer cells for MSC in vitro culture. Moreover, Menon was cited for teaching injecting MSCs into tumor-bearing animals such that MScs migrate to tumors in vivo. The rejection of record acknowledged that Menon did not teach obtaining cell culture medium from in vitro cell culture of cancer cells (i.e. conditioned medium) from a patient and culturing stem cells in the conditioned medium such that they become “educated” and are injected into the cancer patient. However, the rejection of record did cite Michielsen who teaches using tumor-conditioned media from tumor explants obtained from patients would be beneficial as it reflects the inflammatory milieu of the tumor rather than a cancer cell line. Moreover, the rejection of record cited Kodack who teaches development of personalized medicine using cell cultures from tumor biopsies and that matching therapeutics to genetic mutations (which can cause cancer/tumors) is limited as there is incomplete understanding of the relationship between tumor genotype and drug sensitivity. While Kodack does not teach stem cells, stem cell education, or cancer targeting specifically, Kodack teaches the need for using patient-specific tumor cell cultures and a relationship between tumor cells, their conditioned media, and developing therapeutics, such as stem cells for cancer-targeting.
Therefore, it is maintained that in view of the motivation provided by Menon to use conditioned media from in vitro culture cancer cell lines for MSC in vitro culture and injecting MSCs into tumor-bearing animals (i.e. cancer patient) to target tumors, the motivation of Michielsen to use tumor explants to generate conditioned media as it better reflects the microenvironment of tumors compared to cell lines, and motivation of Kodack to develop personalized therapies using tumor biopsies, it would have been prima facie obvious to the skilled artisan to use cell culture medium of in vitro cultured cancer cells derived from a patient to culture stem cells such that they become “educated” by the conditioned media and then inject the stem cells to the cancer patient as a personalized treatment for targeting cancer in vivo.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 Juliana Candelaria whose telephone number is (571)272-5488. The examiner can normally be reached Monday - Friday 8am - 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.
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/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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