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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 28, 2026, has been entered.
DETAILED ACTION
The amended claims filed on May 28, 2026, have been acknowledged. Claims 2-3, 6-8, and 10-12 were cancelled. Claims 1 and 4 were amended. Claims 1, 4-5, and 9 are pending and examined on the merits.
Applicant’s response has been considered. Rejections and/or objections not reiterated from the previous office action mailed March 2, 2026, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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, 4-5, 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 May 28, 2026, 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:
As an initial matter, it is noted that although the Shyu declaration states that the examiner has requested a declaration to better consider and/or understand the arguments and results (page 2, paragraph 2), no such request was made.
The Shyu declaration argues that they have submitted supplementary experimental data demonstrating that IV administration at 26 hours alone does not achieve the same degree of infarct volume reduction as the claimed IA-IV administration regimen. The supplementary experimental data submitted herewith were generated using the same experimental procedures as those described in test Experiment I, "Use for treating the ischemia condition of the brain," set forth in the present application, except that an additional IV-alone group at 26 hours was included. Based on the cited data, the results indicate that IV administration at 26 hours alone did not materially reduce infarction volume relative to the corresponding control group. By contrast, the claimed IA-IV administration regimen, in which the two doses are separated by a 2-4 hour interval, provides improved therapeutic outcomes. The data above further indicate that the therapeutic outcome in this in vivo ischemic stroke model is sensitive to the timing of administration, and that even a change in administration timing may materially affect the experimental results. As a result, these results show that the claimed IA-IV administration regimen produces a markedly greater reduction in infarct volume than either IA administration alone or IV administration alone, thereby evidencing an unobvious therapeutic effect (page 2, paragraph 3-page 4, paragraph 2).
The arguments of the Shyu Declaration have been fully considered but they are not persuasive.
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 (UMSC) and the IV-UMSC cells alone are administered 26 hours after the stroke and does not identify the concentration of cells in the intravenous or intra-arterial injections. In contrast, claim 1 recites administering any mesenchymal stem cell at any dose and at any point in time after the stroke as long as the time between the IA dose and IV dose is 2-4 hours. As such the declaration does not show that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP § 716.
Furthermore, although the administration of IA and IV UMSCs may be synergerstic when compared to administering IV alone at hour 26 post stroke and IA alone at hour 24 post stroke, this does not appear to be the case at all time points as the data provided in the instant specification (Figures 2-10) show that 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 Shyu declaration from December 30, 2025, 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, as identified in the Shyu declaration from May 28, 2026, the data indicate that the therapeutic outcome is sensitive to the timing of administration, and that even a change in administration timing may materially affect the experimental results.
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.
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 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20090246179 (Penn) and further in view of Brazzini et al. (J Vasc Interv Radiol 21:443–451. 2010). This is a new rejection made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been considered but is unpersuasive in response to the new rejection of record and based on the response to the Shyu declaration addressed above.
Regarding claim 1, 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 is silent regarding the timing of the second dose.
However, Brazzini teaches that they administered bone marrow stem cells through intraarterial infusion to treat Parkinson’s Disease and saw improvements in the patients that received the mesenchymal stem cell infusion. The stem cells were manually infused in small pulses for a period of approximately 90–120 minutes. None of the treated patients (N=77) had major complications as a result of the infusion procedure, and all left the hospital after evaluation the next morning (whole document).
As Brazzini teaches that they were able to safely perform intraarterial infusion of mesenchymal stem cells for 120 minutes to treat a brain disorder, it would have been obvious that a similar intraarterial infusion procedure could be used for treating stroke patients as it was already shown to be a safe and effective treatment targeting the brain. Furthermore, 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 1.
Regarding claim 4, Penn teaches that they isolated MSCs from bone marrow (paragraphs 0035 and 0100) and Barzzini, as stated supra, teaches that they administered bone marrow mesenchymal stem cells (whole document).
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).
Claim 1 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20090246179 (Penn) and Brazzini et al. (J Vasc Interv Radiol 21:443–451. 2010) as applied to claim 1 above, 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.
The teachings of Penn and Brazzini are as discussed above.
Penn is silent regarding the dose of the intraarterial 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. Watanabe further discusses the translational potential of these results in humans (whole document).
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.
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.
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 and 4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 9, 11, 13, 15, 18, and 20-21 of U.S. Patent No. 12674141 and further in view of Brazzini et al. (J Vasc Interv Radiol 21:443–451. 2010). 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 and the allowance of the previously identified reference application 17756247. Applicant’s traversal has been considered but is unpersuasive in response to the new rejection of record and based on the response to the Shyu declaration addressed above.
Regarding claim 1, ‘141 claims a method of treating stroke by administering MSCs via an intraarterial injection in combination with an intravenous injection (claims 1, 9, 13, 15, 18, and 20-21).
‘141 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.
‘141 is silent regarding the timing of the second dose.
However, Brazzini teaches that they administered bone marrow stem cells through intraarterial infusion to treat Parkinson’s Disease and saw improvements in the patients that received the mesenchymal stem cell infusion. The stem cells were manually infused in small pulses for a period of approximately 90–120 minutes. None of the treated patients (N=77) had major complications as a result of the infusion procedure, and all left the hospital after evaluation the next morning (whole document).
As Brazzini teaches that they were able to safely perform intraarterial infusion of mesenchymal stem cells for 120 minutes to treat a brain disorder, it would have been obvious that a similar intraarterial infusion procedure could be used for treating stroke patients as it was already shown to be a safe and effective treatment targeting the brain. Furthermore, 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 1.
Regarding claim 4, ‘141 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 106 cells for intracarotid (arterial) injection and about 1 x 107 cells for intravenous injection (claim 21).
Claims 1 and 5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 9, 11, 13, 15, 18, and 20-21 of U.S. Patent No. 12674141 and further in view of Brazzini et al. (J Vasc Interv Radiol 21:443–451. 2010) as applied to claim 1 above and further in view of United States Patent Application No. 20090246179 (Penn). This is a new rejection made in response to Applicant’s amendments to claim 1.
The claims of ‘141 are as discussed above.
‘141 is silent regarding the timing of the first dose.
However, 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 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).
As Penn teaches that the infusion of MSCs can occur about 1 day after the stroke, it would have been obvious that the intraarterial infusion could occur 24 hours after the stroke as this was a known time frame for beginning the MSC treatment to treat the stroke.
Conclusion
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
