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 .
Applicant’s amendment and response filed on 12/3/2025 has been received and entered into the case.
Claims 2, 4-5, 7, 11, 14-16, 18-20, 22-23, 26-30, 33 and 35 have been canceled, claims 38-40 are newly added, and claims 1, 3, 6, 8-10, 12-13, 17, 21, 24-25, 31-32, 34 and 36-40 have been considered on the merits. All arguments have been considered.
Response to Amendment
The claim rejections under 35 USC 35 U.S.C. 112(a) have been withdrawn due to the instant amendment.
The claim rejection under 35 USC 35 U.S.C. 112(b) has been withdrawn due to the instant amendment.
The claim rejections under 35 USC 102 based on Molendijk or Ciccocioppo have been withdrawn due to the instant amendment.
The claim rejection under 35 USC 103 based on Ciccocioppo et al. has been withdrawn due to the instant amendment.
Claim Rejections - 35 USC § 112
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 13, 17, 21 and 34 are 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 13 is dependent on claim 11 which has been canceled. Thus, it is indefinite what subject matter claim 13 is referring to. For search purpose, claim 13 is interpreted to be dependent on claim 1.
Claim 17 is dependent on claim 11 which has been canceled. Thus, it is indefinite what subject matter claim 17 is referring to. For search purpose, claim 17 is interpreted to be dependent on claim 1.
Claim 21 is dependent on claim 11 which has been canceled. Thus, it is indefinite what subject matter claim 21 is referring to. For search purpose, claim 21 is interpreted to be dependent on claim 1.
Claim 34 discloses “20% HSA solution at a concentration of 25%, the HSA solution comprising 5% HSA and 15% buffer”. It is not clear what this phrase intends to point out. There are 3 concentrations referring to HSA, and they do not make any sense. It appears that “20% HSA solution at a concentration of 25%” refers that 20% of the solution mixture with the isotonic solution and DMSO is composed of 25% HSA solution. However, it is not clear what subject matter the phrase of “the HSA solution comprising 5% HSA and 15% buffer” intends to point out.
Based on the instant amendment, it appears that the composition is made of MSCs suspended in a solution comprising isotonic solution at 70% of the solution, DMSO at 10% of the solution, and HSA at 20% of the solution, rather than the percentages (i.e. 70%, 10%, and 20%) referring to the final concentration of each ingredients. However, the instant limitation is not clear if this interpretation is what applicant intends to point out. Clarification is required.
It appears that the “HSA solution comprising 5% HSA” is referring to the final concentration of HSA in the composition, and the final concentration would be 5% as 25% HSA solution is mixed when mixing with 80% of isotonic solution and DMSO solution at a 5-fold dilution (20%). However, it is not clear what this limitation is referring to. Furthermore, it is not clear how the 25% HSA solution comprises 5% HSA and 15% buffer? Clarification is required.
Applicant is advised to amend claim 34, for example, “…wherein the composition further comprises an isotonic solution, 10% DMSO and 5% human serum albumin (HSA).”
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 3, 8, 12-13, 17, 21, 24-25 and 31-32 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yang et al. (2015, Proceeding of Clinical Medicine; of record) as evidenced by CDC (2024; downloaded from www.cdc.gov/inflammatory-bowel-disease/about/ulcerative-colitis-uc-basics.html).
Regarding claims 1, 3, 8, 12, 23, 25, 31-32, Yang et al. teach a method of treating human patients having ulcerative colitis (UC), i.e. IBD, by multipoint-injection of MSCs under local submucosal with direct enteroscope view (Abstract). Yang et al. teach that five cases have reached complete remission, and 2 cases partial remission, with 100% effective rate.
Yang et al. do not particularly teach the local submucosal is the colon. However, the name of “colitis” refers to the inflammation in the colon, and it is well established in the art that UC causes inflammation in the large intestine, i.e. colon, and rectum according to CDC (p.2, Overview). Thus, a person skilled in the art would have at once envisaged that the local submucosal taught by Yang et al. would include the colon wall where UC is evident. The administration route of Yang et al. is considered to meet the directly into the submucosal layer of the colon of the subject.
Regarding the wherein clause directed to the treating comprises reducing or eliminating at least one symptom of the IBD or the subject has a partial clinical and/or endoscopic response/remission, these limitations do not require any active step to be carried out and directed to the outcome of the claimed method. Thus, the limitations do not provide any patentable weight in determining the patentability of the claimed method. Furthermore, the method taught by Yang et al. is identical to the claimed method, the results would be expected the same. This analysis is applicable to the wherein clause of claims 12-13, 17 and 21.
Regarding claim 24, as discussed above, Yang et al. teach the use of enteroscope, i.e. endoscope, for the injection of the MSCs.
Regarding claims 31-32, Yang et al. teach that 1x107 cells per point are injected to multiple points, and this teaching would meet the limitations.
Thus, the reference anticipates the claimed invention.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 3, 6, 8-10, 12-13, 17, 21, 24-25, 31-32 and 36-37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Forbes et al. (2014, Clinical Gastroenterology and Hepatology; IDS ref. NPL23) in view of Yang et al. (of record), Gregoire et al. (2018, Digestive and Liver Disease; IDS ref. NPL108) and Molendijk et al. (2012, Journal of Allergy)
Forbes et al. teach a method of treating luminal Crohn’s disease (CD) refractory to biologic therapy by administering allogeneic mesenchymal stem cells (MSCs) (see entire document). The subject having luminal CD taught by Forbes et al. is considered to meet the subject not having fistulizing CD. Forbes et al. teach that the MSCs are intravenous infused (Methods), however, they do not teach administering MSCs directly into the submucosal layer of the colon of the subject.
Yang et al. teach multipoint-injection of MSCs under local submucosal with direct enteroscope (endoscopic) view (Abstract).
It would have been obvious to a person skilled in the art to use the multipoint-injection of MSCs under local submucosal with direct enteroscope (i.e. endoscope) view taught by Yang et al. for the method of Forbes et al. with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to use the known method of submucosal injection taught by Yang et al. replacing the intravenous injection of Forbes et al. because Molendijk et al. teach one could speculate that compared to system infusion (e.g. intravenous injection), local injection would render higher numbers of cells reach the damaged tissue and therefore are more likely to perform their immunosuppressive and tissue regenerative functions (p.5, 1st col., last para. thru 2nd col., first para.). One skilled in the art would have a reasonable expectation of success in using local injection taught by Yang et al. for the method of Forbes et al. as Gregoire et al. teach that local and intravenous injections of MSCs have demonstrated their safety in fistulizing and luminal CD (p.1251, 2nd col.). Thus, by using the local injection taught by Yang et al. for the method of Forbes et al., the claimed limitation would be met. The combined teachings would also meet the subject matter of claim 24 directed to the use of endoscope.
Regarding the wherein clause directed to the treating comprises reducing or eliminating at least one symptom of the IBD or the subject has a partial clinical and/or endoscopic response/remission, these limitations do not require any active step to be carried out and directed to the outcome of the claimed method. Thus, the limitations do not provide any patentable weight in determining the patentability of the claimed method. Furthermore, the method taught by Forbes et al. in view of Yang et al., Gregoire et al. and Molendijk et al. is identical to the claimed method, the results would be expected the same. While this analysis is applicable to claims 12-13, 17 and 21,
Forbes et al. teach the outcome of the treatment in terms of CPR reduction (Table 3), endoscopic improvement (Table 2), and CDAI improvement as claimed (Table 2), and these teachings would meet the subject matter of claims 12-13, 17 and 21.
Regarding claim 6, Forbes et al. teach that the subject is refractory to biologic therapy or failed both infliximab and adalimumab (i.e. anti-TNF therapy) (p.66, 2nd col., Demographics; Table 1).
Regarding claim 10, some of the subjects treated by the method of Forbes et al. have colitis, i.e. CD is present in the colon, and the most of the subjects were with CDAI greater than 300 (see Table 1).
Regarding claims 31-32 directed to the 1x107 and 2x108 cells being administered, Forbes et al. teach the total dose of MSC (Table 1) which is around 1x107/kg via intravenous infusion. Furthermore, Yang et al. teach that 1x107 cells per point are injected to multiple points (see above). Thus, the combined teachings of Forbes et al. and Yang et al. would meet the limitations of claims 31-32.
Regarding claims 36-37 directed to the total dose being 7.5x107 or 1.5x108 cells, Forbes et al. do not particularly teach the limitation. However, it would have been obvious to a person skilled in the art to modify the total dosage of the MSCs utilized based on the number of sites/points being injected. For example, Yang et al. teach 1x107 cells per point and the injection is multipoint. Thus, the total dose of MSCs would be dependent on the number of sites being injected, and it can be routinely optimized for the desired outcome of effective treatment with a reasonable expectation of success. In the absence of criticality of the claimed total dose of MSCs, one skilled in the art would be able to arrive to the claimed dosage by routine optimization.
Regarding claims 38-40 directed to the subject having active moderate Crohn’s disease, active severe Crohn’s disease or having a CDAI between 200-450, the subject disclosed by Forbes et al. are considered to meet the limitation. This is because the patients disclosed in the method of Forbes et al. have CDAI in the range of 200 and up to 600 (see Table 2), and Forbes et al. teach that 15 patients are with moderate to sever active disease (p.69, Discussion).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Forbes et al. in view of Yang et al., Gregoire et al. and Molendijk et al. as applied to claim 1 above, and further in view of Itescu et al. (WO2018202853; IDS ref.; FP21).
Regarding claim 34, it is noted that the concentration of DMSO is not particularly claimed as the “10%” is considered the volume of DMSO at a unknown concentration in the solution mixture with 70% of the isotonic solution and 20% of the 25% HSA solution. The 25% HSA solution is not limiting as it is included in the composition at the final concentration of 5%. Thus, under the broadest reasonable interpretation, the limitation is interpreted as the composition further comprising isotonic solution, 10% DMSO, and 5% HSA. The “buffer” is considered met based on the isotonic solution (i.e. Plasma-Lyte). The concentration of the cells disclosed in the claim is considered as not liming because it is disclosed as optional.
Forbes et al. in view of Yang et al. do not teach the composition comprising MSCs further comprises isotonic solution, 10% DMSO and 5% HSA.
Itescu et al. teach the formulation or composition comprising mesenchymal lineage precursor or stem cells for treating inflammatory disorders including Crohn’s disease (Abstract; para. 21), and the composition can be cryopreserved in Plasma-Lyte-A, 25% HSA and DMSO (para. 20), and they also teach that the cryopreserved solution comprises about 5% human serum albumin (HSA) and about 10% DMSO (para. 236). Itescu et al. teach that the cryopreserved composition may be thawed and administered directly to the subject (para. 238).
It would have been obvious to a person skilled in the art to use the composition of Itescu et al. comprising the MLPSCs in Plasmalyte-A, 10% DMSO and 5% HSA for the method of Forbes et al. in view of Yang et al. with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because Itescu et al. teach that their composition can be utilized for treating Crohn’s disease.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
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, 3, 6, 8-10, 12-13, 17, 21, 24-25, 31-32, 34 and 36-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 7-8, 11, 14, 19, 23, 25, 34, 40-41, 45, 47-53 of copending Application No. 17/906150 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘150 application are directed to the identical method of treating IBD for the subject having refractory and non-fistulizing Crohn’s disease using the identical cell population, and the route of administration of the ‘150 application includes the administration to the colon which is identical to the instant application. The composition of the ‘150 application includes the identical isotonic solution (i.e. Plasma-Lyte A), DMSO and HSA.
Thus, the claims of the ‘150 application render the claims of the instant application obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
No claims are allowed.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631