9Notice 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 .
DETAILED ACTION
The amended claims filed on December 30, 2025, have been acknowledged. Claims 7-8 and 10-12 were cancelled. Claims 1, 5, and 9 were amended. Claims 1-6 and 9 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 63/065,728, filed on August 14, 2020. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-6 and 9 receive domestic benefit from U.S. provisional application No. 62/750,603, filed on August 14, 2020.
Oath/Declaration
Declaration under 37 CFR 1.132
The declaration under 37 CFR 1.132 filed by Dr. Woei-cherng Shyu on December 30, 2025 has been considered but is insufficient to overcome the rejections of instant claims based upon 35 U.S.C 103 as set forth in the current Office action for the following reasons:
First, the Shyu declaration is not commensurate in scope with the claimed invention. Specifically, the Shyu declaration refers to experiments where the therapeutic cell is an umbilical cord mesenchymal stem cell and does not identify the concentration of cells in the intravenous or intra-arterial injections nor the time interval between administrations. In contrast, claim 1 recites administering any therapeutic and requires that the intravenous administration comprises at least 10 times the amount of the therapeutic cell in the intra-arterial administration . As such the declaration does not show that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP § 716.
Furthermore, the claimed invention appears to work as expected. Although the results of the combined IA+IV administration show improved results compared to either alone, they appear additive and not synergistic. See MPEP § 716. As identified in the Affidavit, Figure 2A resulted in the volume of infarction of the control is 167±17 mm³, the volume of infarction of the IV-UMSC is 131±16 mm³, the volume of infarction of the IA-UMSC is 105±8 mm³, and the volume of infarction of the IA-IV-UMSC is 70±9 mm³. The difference between the control and IV administration is 36, the difference between the control and IA administration is 62, and the difference between the control and IA+IV administration is 97. When adding the difference between IV alone (36) and IA alone (62), this equates to a difference of 98, nearly identical to the experimental result from IA+IV administration (97). As such, this is considered an additive result.
Therefore, it would have been expected that combining IA+IV would improve the therapeutic effect as this would increase the concentration of therapeutic cells at the infarct and would, as expected, lead to a greater therapeutic effect.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1-5 and 7-8 under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20090246179 (Penn) is withdrawn in light of Applicant’s amendment to claim 1 to recite that second dose is 10 times the amount of the first dose.
New 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.
Claims 1-5 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20090246179 (Penn) and further in view of Watanabe et al. (Brain Circulation 2: 114-117. 2016) and United States Patent Application No. 20170020924 (Shyu). This is a new rejection made in response to Applicant’s amendments to claim 1 that is substantially similar to a previous rejection of record. Any aspect of Applicant’s traversal that is relevant to the rejection as newly written is addressed below.
Regarding claims 1-3, Penn teaches a method of treating a subject who experienced a stroke, the method comprising preparing a population of mesenchymal stem cells (MSCs) and administering the population to a subject with the stroke. The MSCs can be administered by a combination of arterial infusion and venous infusion (claims 1 and 5-7).
Penn does not identify an order for the arterial infusion and venous infusion. However, it would have been obvious to one of ordinary skill in the art that there are only two possible orders: intravenous infusion then intraarterial or intraarterial then intravenous as the infusions could not take place at the same time and would have to be done sequentially. Furthermore, selecting any order of steps was known to be obvious, In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.). See also Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.).
Therefore, as there are only two options, it would have been readily understood that one could perform the intraarterial infusion before the intravenous infusion.
Penn teaches that they treated rats with their method (Example, paragraphs 0098-0129).
Penn is silent regarding the dose of the intra-arterial and intravenous infusions.
However, Watanabe teaches that for treating ischemic stroke through intra-arterial administration of MSCs, 1 x 105 MSC cells is the maximum tolerated dose in rats. Watanabe teaches that IA MSC dose of 1 × 105 administered after 24 h could be very safe and effective in the treatment of cerebral ischemia in a rat model (115, column 1, paragraph 3).
Therefore, it would have been obvious to use a dose of 1 × 105 MSC cells for the intra-arterial administration as Watanabe teaches that this dose could be very safe and effective in the treatment of cerebral ischemia in a rat model.
Shyu teaches that they treated a rat stroke model with an intravenous injection of 2 x 106 MSCs improved neurological function (paragraphs 0099-0110).
Therefore, it would have been obvious to use a dose of 2 × 106 MSC cells for the intravenous administration as Shyu teaches that this dose was effective in improving neurological function in a cerebral ischemia rat model.
Thus, by using the doses of Watanabe and Shyu, this would equate to a second dose that is 20 times the first dose.
Regarding claim 4, Penn teaches that they isolated MSCs from bone marrow (paragraphs 0035 and 0100).
Regarding claim 5, Penn teaches that the infusion of MSCs can be performed about 1 day after the myocardial injury (Penn defines myocardial injury as including stroke (paragraphs 0031 and 0095). Furthermore, Watanabe, as stated supra, teaches that IA MSC dose of 1 × 105 administered after 24 h could be very safe and effective in the treatment of cerebral ischemia in a rat model (115, column 1, paragraph 3)
Response to Arguments
Applicant's arguments filed December 30, 2025, are acknowledged.
Applicant argues that their dosing strategy of administering a first dose of therapeutic cells intraarterially then a second dose intravenously represents a clinically meaningful dosing strategy that produces unexpected synergistic therapeutic effects in the treatment of cerebral ischemic injury. As demonstrated in the in vivo studies relating to the use for treating ischemia of the brain, the data provide clear, quantitative, and functional evidence of non-obviousness. Applicant cites the results of Figures 2 and 3 and the additional data shown in the Shyu Declaration to show that there is a synergistic effect (page 6, paragraph 1-page 10, paragraph 3).
Applicant's arguments and the cited Shyu Declaration have been fully considered but they are not persuasive.
As an initial matter, although Applicant argues unexpected results, the claims are not commensurate in scope with the experimental results cited by the Applicant. MPEP 716.02(d) discloses that 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) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
Regarding the claims at issue in the instant application, claim 1 encompasses treating stroke by administering a pharmaceutical composition comprising any therapeutic cell, with any first IA and second IV dose wherein the second IV dose is 10 times the amount of the first IA dose (encompassing an IA dose of 10 cells and a second IV dose of 100 cells), and with any time frame between injections. In contrast, the cited data from Figures 2-3 recite using mesenchymal stem cells isolated from the umbilical cord, adipose tissue, or bone marrow as the therapeutic cells at a first IA dose of 1 x 105 and a second IV dose at 1 x 106 administered 2 hours after the first IA dose. Regarding the data identified by the Shyu Declaration, the Shyu declaration refers to experiments where the therapeutic cell is an umbilical cord mesenchymal stem cell and does not identify the concentration of cells in the intravenous or intra-arterial injections nor the time interval between administrations. As such the arguments and declaration does not show that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP § 716.
Furthermore, although Applicant argues that cited data in Figures 2-3 and the declaration show a synergistic effect, this does not seem to be the case. Although the results of the combined IA+IV administration show improved results compared to either alone, they appear additive and not synergistic. See MPEP § 716. As identified in the Affidavit, Figure 2A resulted in the volume of infarction of the control is 167±17 mm³, the volume of infarction of the IV-UMSC is 131±16 mm³, the volume of infarction of the IA-UMSC is 105±8 mm³, and the volume of infarction of the IA-IV-UMSC is 70±9 mm³. The difference between the control and IV administration is 36, the difference between the control and IA administration is 62, and the difference between the control and IA+IV administration is 97. When adding the difference between IV alone (36) and IA alone (62), this equates to a difference of 98, nearly identical to the experimental result from IA+IV administration (97). As such, this is considered an additive result. Similarly, data in Figures 2B and 3A shows that the area of the largest infarction slice and % recovery in body swing test, respectively, was additive and not synergistic. In Figure 2B, the control was 16.8 mm2, the IV alone was 12.6 mm2, the IA alone was 9.6 mm2, and the IA+IV was 5.6 mm2. This equates to an overall difference between IA+IV administration and control of 11.2 mm2 while adding the results of IV alone (4.2) and IA (alone 7.2) equates to a difference of 11.4 mm2. In Figure 3A, Control was at 37.5%, IV alone was at 55%, IA alone was at 75%, and IA+IV was at 90%. This equates to an overall difference between IA+IV administration and control of 52.5% while adding the results of IV alone (17.5) and IA (alone 37.5) equates to a difference of 55%. Therefore, the results are considered additive and not synergistic, as claimed by the Applicant.
Furthermore, it would have been expected that combining IA+IV would improve the therapeutic effect as this would increase the concentration of therapeutic cells at the infarct and would, as expected, lead to a greater therapeutic effect.
As an additional matter, although Applicant argues that the order of administration is important and would not have been obvious, they only show that IA+IV led to an improved result over IV alone and IA alone, but do not test IV+IA to show whether the order of administration is important for the overall efficacy of treatment.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Furthermore, Applicant argues that Watanabe focuses solely on IA administration while Shyu focuses solely of IV administration and neither teaches combined IA and IV administration (page 8, paragraph 4-page 9, paragraph 6).
In response to 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). As recited in the rejection above, Penn provides support for performing both an intraarterial and intravenous administration of mesenchymal stem cells to treat stroke and Watanabe and Shyu provide support for specific concentrations for the IA and IV dose. Therefore, Applicant’s arguments are considered unpersuasive.
Claim 1 and 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20090246179 (Penn) and further in view of Watanabe et al. (Brain Circulation 2: 114-117. 2016) and United States Patent Application No. 20170020924 (Shyu) as applied to claims 1 and 5 above, and further in view of United States Patent Application No. 20180325957 (Kastrup).
The teachings of Penn, Watanabe, and Shyu are as discussed above.
Penn is silent regarding the timing of the second dose.
However, Kastrup teaches that using adipose derived mesenchymal stem cells to treat stroke and that adipose derived mesenchymal stem cells can undergo a 2-3 hour infusion as part of an intra-arterial injection (paragraphs 0023, 0148, and 0151).
As Kastrup teaches that the intra-arterial infusion can take 2-3 hours, it would have been obvious that the intravenous infusion could occur almost immediately after the end of the intra-arterial infusion which would be within the 2-4 hour interval of instant claim 6.
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 and are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9, 11, 13, 15, 18, and 20-21 of copending Application No. 17756247 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. This rejection is a new rejection made in response to Applicant’s amendments to claim 1 that is substantially similar to a previous rejection. Any aspect of Applicant’s traversal that is relevant to the rejection as newly recited is addressed below. Furthermore, Applicant’s argument regarding unexpected results has been addressed above.
Regarding claims 1-3, ‘247 claims a method of treating stroke by administering MSCs via an intraarterial injection in combination with an intravenous injection (claims 9, 13, 15, 18, and 20-21).
‘247 does not identify an order for the arterial infusion and venous infusion. However, it would have been obvious to one of ordinary skill in the art that there are only two possible orders: intravenous infusion then intraarterial or intraarterial then intravenous as the infusions could not take place at the same time and would have to be done sequentially. Furthermore, selecting any order of steps was known to be obvious, In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.). See also Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.).
Therefore, as there are only two options, it would have been readily understood that one could perform the intraarterial infusion before the intravenous infusion.
Regarding claim 4, ‘247 claims the MSCs can be derived from the umbilical cord, adipose, or bone marrow (claim 2).
Regarding claim 9, 247 claims that they administered about 1 x 104 cells for intracarotid (arterial) injection and about about 1 x 107 cells for intravenous injection.
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 filed December 30, 2025, are acknowledged.
Applicant argues that the ‘247 application relates to gene-engineered cells, whereas the present application concerns therapeutic cells administered through a specific dosing strategy. Therefore, the subject matter of the two applications is technically distinct (page 10, paragraph 5).
Applicant's arguments have been fully considered but they are not persuasive.
Although Application ‘247 is drawn to genetically engineered mesenchymal stem cells in part of the claims, ‘247 is also drawn to methods of treating stroke using those engineered MSCs. Therefore, the method of ‘247 is also drawn to administering a therapeutic cell (engineered MSCs) to treat stroke through intraarterial and intravenous administrations of the MSCs. Therefore, these are not considered technically distinct subject matter, as argued by the Applicant.
Claims 1 and 5-6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 9, 11, 13, 15, 18, and 20-21 of copending Application No. 17756247 as applied to claims 1 and 7 above and further in view of United States Patent Application No. 20180325957 (Kastrup). This rejection is repeated with regards to the Non-final Office action mailed on October 1, 2025. Applicant’s traversal has been addressed above.
The claims of ‘247 are as discussed above.
‘247 is silent regarding the timing of the second dose.
However, Kastrup teaches that using adipose derived mesenchymal stem cells to treat stroke and that adipose derived mesenchymal stem cells can undergo a 2-3 hour infusion as part of an intra-arterial injection (paragraphs 0023, 0148, and 0151).
As Kastrup teaches that the intra-arterial infusion can take 2-3 hours, it would have been obvious that the intravenous infusion could occur almost immediately after the end of the intra-arterial infusion which would be within the 2-4 hour interval of instant claim 6.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
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/KEENAN A BATES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631