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 .
Election/Restrictions
Claims 1, 4-7, 9, 13, 15-22, 24, 29-31, 35-39, 41-42, 44-46, 49-50, 53-54, 56-59, 63, 66-67, 69-71 are pending.
Applicant’s election without traverse of the species of i) fibroblast markers comprising the group CD44, CD49b, CD73, CD90, CD105, or combinations thereof; ii) contacting fibroblasts with hCG; iii) a second population comprising T cells, etc., iv) a sub-species of T cells, specifically, and v) a T cell with a CD4+ or CD8+ phenotype in the reply filed 01/21/2026 is acknowledged and made FINAL.
Claims 5, 20, 22, 29-31, 35-39, 41-42, 44-46, 49-50, 53-54, 56-59, 63, and 66-67 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/21/2026
Claims 1, 4, 6-7, 9, 13, 15-19, 21, 24, and 69-71 have been examined on their merits.
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.
Claims 1, 4, 6-7, 9, 13, 16-19, 21, 24, and 69-71 are rejected under 35 U.S.C. 103 as being unpatentable over O’Heeron et al. (WO2019108756A1, priority to 11/29/2018, on IDS 08/29/2022) in view of Gabrilovac et al. (Immunology Letters, 2004) as evidenced by Jiang et al. (Frontiers in Cell and Developmental Biology, 2018) and Nakamura et al. (Journal of Dermatological Science, 2016).
In regards to claims 1, 21, and 24, O’Heeron teaches methods for generating activated immune cells (claim 1). O’Heeron teaches that the cells are regulatory T cells (CD4+ Tregs) (claim 17, paragraph [0129]), which are a well-known type of immune modulatory cell. O’Heeron teaches that the method comprises contacting fibroblasts (a first cell population) with immune cells (a second cell population) to generate the activated immune cells (a third cell population). O’Heeron teaches that the cells can be administered to an individual in need (claim 41) and that these cells can be autologous (claim 208), and therefore, are necessarily obtained from a subject in need of therapy.
In regards to the type of fibroblasts, O’Heeron teaches the fibroblasts may be dermal (paragraph [0186]). As taught by Gabrilovac, CD13 is highly expressed by dermal fibroblasts (Abstract, p39). Therefore, the population of dermal fibroblasts, as taught by O’Heeron would be positive for this marker.
However, even if they did not, O’Heeron teaches that CD13 expressing MSCs can be used to treat disease (claims 139, 146, and 148). O’Heeron also teaches that while it is known in the art that while MSCs can be used in vitro to induce generation of Tregs, fibroblasts can be substituted for MSCs (paragraph [0139]). It is noted that it is well-understood in the art that MSCs and fibroblasts are a similar cell type, with overlapping marker expression, the difference being a greater differentiation potential with MSCs. Therefore, even if the fibroblasts as taught by O’Heeron were not CD13 positive, a person of ordinary skill in the art would have been motivated to select CD13 fibroblasts because they would be a closer substitute to the MSCs as identified by O’Heeron as being suitable to treat disease. Furthermore, because O’Heeron teaches that fibroblasts may be substituted for MSCs and because Gabrilovac teaches that CD13 is a known fibroblast marker, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 4, as evidenced by Jiang, CD90 is widely expressed on fibroblasts, including dermal fibroblasts (whole document).
In regards to claim 6, O’Heeron teaches that fibroblasts may be differentiated into mesodermal tissues (paragraph [0241]), and therefore, would have the property of being capable of differentiating into bone (a mesodermal tissue).
In regards to claim 7, O’Heeron teaches that the co-culture comprising T cells and fibroblasts may comprise an agent such as hCG (paragraph [0145]). Continuing, O’Heeron teaches that in specific embodiments, the fibroblasts are in solution with hCG (paragraph [0145]), which suggests that the fibroblasts specifically are contacted with hCG prior to co-culture with T cells.
Furthermore, see MPEP 2144.04 (IV)(C), the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Burhans, 154 F.2d 690, 69 USPQ 330(CCPA 1946); Selection of any order of mixing ingredients is prima facie obvious (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930)).
In regards to claims 9 and 13, in regards to whether the fibroblast population produces exosomes at a concentration of at least 10 ng/mL per million cells (as in claim 9) and whether those exosomes comprise the marker CD81, this is a property of exosomes and the claims do not require specific method steps for producing exosomes nor require culturing a specific number of cells. Rather, the claim suggests that the method steps of claim 1 are sufficient to cause fibroblasts to have these properties. In the instant case, since the method of O’Heeron performs these steps, this method would result in fibroblasts that produce CD81 positive exosomes as in claims 9 and 13. Furthermore, as evidenced by Nakamura, exosomes derived from fibroblasts express CD81 (Abstract, p30).
In regards to claims 16 and 17, as taught by O’Heeron, fibroblasts may be genetically edited to selectively excise inflammation evoking genes such as TNF-alpha (paragraph [0024]). A fibroblast with an excised inflammation gene such as TNF-alpha has an ability to inhibit secretion of TNF-alpha.
In regards to claim 18, O’Heeron teaches that fibroblasts may be cultured for at least 2 weeks (14 days (paragraph [0194]).
In regards to 19, while O’Heeron teaches that fibroblasts become “activated” (claim 1), activation does not imply differentiation of these cells, as they do not become another cell type. Indeed, O’Heeron also teaches that fibroblasts may be propagated for an indefinite period of time in continuous culture in an undifferentiated state (paragraph [0241]). Furthermore, this is a property of the fibroblasts, and claim 19 does not recite additional active method steps that prevent differentiation of fibroblasts. Instead, the claims suggest that the method of claim 1 is sufficient to result in fibroblasts that which are maintained in an undifferentiated state. Therefore, since the method of O’Heeron performs these steps, this method would be sufficient to maintain fibroblasts in an undifferentiated state absent evidence to the contrary.
In regards to claim 69, O’Heeron teaches that the contacting step may further comprise adding IL-2 (claim 37; paragraph [0228]).
In regards to claims 70 and 71, O’Heeron teaches that the subject has an autoimmune condition such as MS (claims 47, 81-82; paragraph [0109]).
Therefore, the combined teachings of O’Heeron and Gabrilovac renders the invention unpatentable as claimed.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over O’Heeron et al. (WO2019108756A1, priority to 11/29/2018, on IDS 08/29/2022) in view of Gabrilovac et al. (Immunology Letters, 2004) as applied to claim 1 above, and further in view of Advanced Biomatrix (Fironecin, available online 12/05/2019).
In regards to claim 15, O’Heeron teaches that the fibroblasts can be obtained from Wharton’s Jelly (paragraph [0186]). Therefore, the fibroblast population of O’Heeron can comprise these cells.
While O’Heeron is silent as to isolating “fibroblasts” specifically, O’Heeron teaches that MSCs derived from umbilical cord (which would include Wharton’s jelly, and which are similar cells to fibroblasts) can be obtained by enzymatically digesting the tissues, centrifuging, grown in plates with media comprising serum, and wherein adherent cells are selected (paragraph [0718]).
While in this specific embodiment, O’Heeron uses 10%, a person of ordinary skill in the art could have arrived at a concentration of 2% by routine optimization and the disclosure does not point to a criticality in this amount (see MPEP 2144.05(II)(A), 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). In the instant case, because O’Heeron teaches that serum can be used over a wide range, including 2% (paragraph [0202]) and because using low amounts of serum is typical in the art, a person of ordinary skill in the art could have arrived at a concentration of 2% by routine optimization with predictable results and a reasonable expectation of success.
In regards to coating plates with fibronectin, a person of ordinary skill in the art would have been motivated to do so in order to promote attachment of fibroblasts which are a known adherent cell type. Furthermore, because, as taught by Advanced Biomatrix, fibronectin for coating dishes and promoting attachment of adherent cells was readily available (see first page), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of O’Heeron, Gabrilovac, and Advanced Biomatrix renders the invention unpatentable as claimed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4, 6-7, 9, 13, 15-19, 21, 24, and 69-71 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 12,233,094B2 in view of O’Heeron et al. (WO2019108756A1, priority to 11/29/2018, on IDS 08/29/2022), Gabrilovac et al. (Immunology Letters, 2004), and Advanced Biomatrix (Fironecin, available online 12/05/2019).
While claims 1-13 of U.S. Patent No. 12,233,094B2 and the instant claims are not identical, they are not patentably distinct because both claims are drawn to methods comprising generating immune modulatory cells (of which regulatory T cells are a type) comprising contacting fibroblasts with T cells (Tregs, derived from CD4+ T cells).
While U.S. Patent No. 12,233,094B2 does not explicitly teach that the population of immune cells (T cells) is derived from a subject in need of therapy, a person of ordinary skill in the art would have been motivated to use T cells from a subject, because they would be autologous, and as autologous cells would have the greatest compatibility with a patient. Furthermore, because O’Heeron teaches that immune cells autologous to a patient in need can be contacted with immune cells (T cells, specifically) to generate an immune modulatory cell population (claims 41 and 208), it could have been done with predictable results and a reasonable expectation of success.
While U.S. Patent No. 12,233,094B2 is silent as to the specific phenotype of fibroblasts, O’Heeron teaches that CD13 expressing MSCs can be used to treat disease (claims 139, 146, and 148). O’Heeron also teaches that while it is known in the art that while MSCs can be used in vitro to induce generation of Tregs (immune modulatory cells), fibroblasts can be substituted for MSCs (paragraph [0139]). It is noted that it is well-understood in the art that MSCs and fibroblasts are a similar cell type, with overlapping marker expression, the difference being a greater differentiation potential with MSCs.
Therefore, a person of ordinary skill in the art would have been motivated to select CD13 fibroblasts because they would be a closer substitute to the MSCs as identified by O’Heeron as being suitable to treat disease. Furthermore, because O’Heeron teaches that fibroblasts may be substituted for MSCs and because Gabrilovac teaches that CD13 is a known fibroblast marker, it could have been done with predictable results and a reasonable expectation of success.
In regards to dependent claims 4, 6-7, 9, 13, 16-19, 21, 24, and 69-71, these are all known method steps for culturing fibroblasts as taught by O’Heeron as discussed in depth as above.
In regards to claim 15, while U.S. Patent No. 12,233,094B2 does not explicitly teach this step, as discussed above, O’Heeron teaches that the fibroblasts can be obtained from Wharton’s Jelly (paragraph [0186]).
In regards to the isolation steps, O’Heeron teaches that MSCs derived from umbilical cord (which would include Wharton’s jelly, and which are similar cells to fibroblasts) can be obtained by enzymatically digesting the tissues, centrifuging, grown in plates with media comprising serum, and wherein adherent cells are selected (paragraph [0718]). A person of ordinary skill in the art would have been motivated to use this method because O’Heeron teaches that it is suitable for obtaining mesenchymal cells. Furthermore, because fibroblasts are a mesenchymal cell type with similar characteristics to MSCs, it could have been done with predictable results and a reasonable expectation of success.
While in this specific embodiment, O’Heeron uses 10%, a person of ordinary skill in the art could have arrived at a concentration of 2% by routine optimization and the disclosure does not point to a criticality in this amount (see MPEP 2144.05(II)(A), 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). In the instant case, because O’Heeron teaches that serum can be used over a wide range, including 2% (paragraph [0202]) and because using low amounts of serum is typical in the art, a person of ordinary skill in the art could have arrived at a concentration of 2% by routine optimization with predictable results and a reasonable expectation of success.
In regards to coating plates with fibronectin, a person of ordinary skill in the art would have been motivated to do so in order to promote attachment of fibroblasts which are a known adherent cell type. Furthermore, because, as taught by Advanced Biomatrix, fibronectin for coating dishes and promoting attachment of adherent cells was readily available (see first page), it could have been done with predictable results and a reasonable expectation of success.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH (PAUL) MIANO whose telephone number is (571)272-0341. The examiner can normally be reached Mon-Fri from 8:30am to 5:30pm.
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, James (Doug) Schultz can be reached at (571) 272-0763. 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.
/JOSEPH PAUL MIANO/Examiner, Art Unit 1631