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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This is in response to Applicant’s amendment and response filed on November 18, 2025.
Claims 1, 2, 9, 11, 13, 18 and 21 are amended by Applicants’ amendment filed on 11/18/2025. .
Claims 1-2, 9, 11, 13, 18 and 21 are pending and have been considered on the merits. Claims 1, 11 and 21 are independent claims.
Therefore, claims 1-2, 9, 11, 13, 18, and 21 are examined in their merits to which the following grounds of rejection are applicable.
Priority
Applicant’s claim for the benefit of prior-filed provisional application 63/007,236 filed on 04/08/2020 and 63/006,835 filed 04/08/2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Thus, the earliest possible priority for the instant application is April 08, 2020.
Response to Arguments
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claim 1, 9, 11, 18, and 21 remain rejected and claims 2 and 13 are newly rejected under 35 U.S.C. 103 as being unpatentable over Vosough (2016, Archives of Iranian Medicine, 19 (2) 131-136; previously cited) in view of Donega (2014. Intranasal Administration of Human MSC for Ischemic Brain Injury in the Mouse: In Vitro and In Vivo Neuroregenerative Functions. PLoS ONE 9(11): e112339) and Jojo (2019. Formulation and optimization of intranasal nanolipid carriers of pioglitazone for the repurposing in Alzheimer’s disease using Box-Behnken design, Drug Development and Industrial Pharmacy, 45:7, 1061-1072).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 11/18/2025
The current claims can broadly be interpreted as a method comprising administering 50mg to 1000 mg of pioglitazone (PG) and about 2 x 107 to about 1.5 x 109 MSCs to an individual with neuroinflammation over the course of the treatment which could be in single or multiple dosages. Additionally, administration to the microglial cell occurs in vivo as a result of treatment as the administration routes are preferably intranasal and intracranial as shown by claims 2, 9, 13 and 18. Thus the administration to microglial cells is an indirect result of administration to the subject.
Regarding claims 1, 9, 11, 18 and 21, Vosough teaches a method of administering orally pioglitazone (PG) at a dose of 30mg per day for 12 months with MSCs administered twice over the course of 12 months at 6 month intervals via the intraportal vein to a human patient in order to treat fibrosis (i.e. inflammation) in patients with cirrhosis from hepatitis (i.e. inflammatory disease) (p. 132, 2nd column, Figure 1, Table 2). Vosough demonstrates the combined therapy of pioglitazone and MSCs.
Through Vosough’s method, the total dosage of PG administered is 360 mg over the course of the 12 months with MSC transplantation twice over 6-month intervals at a total of about 2 x 108 cells per dosage (Table 2). Therefore, a total of about 4 x 108 cells over the course of the study.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to adjust the dosage of pioglitazone to a range between 50mg and 1000 mg with a reasonable expectation of success based on the teachings of Vosough. If taking into consideration the duration of the study at month two a total of 60 mg has been administered, at month 3 a total of 90mg has been administered and so on. Therefore, for month 6 when the total of about 4 x 108 is administered, the total of 300mg of pioglitazone is administered as well. This falls within the claimed range.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
It is well settled that routine optimization is not patentable, even if it results in significant improvements over the prior art. In support of this position, attention is directed to the decision in In re Aller, Lacey, and Haft, 105 USPQ 233 (CCPA 1955): Normally, it is to be expected that a change in temperature, or in concentration, or in both, would be an unpatentable modification. Under some circumstances, however, changes such as these may impart patentability to a process if the particular ranges claimed produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art. In re Dreyfus, 22 C.C.P.A. (Patents) 830, 73 F.2d 931,24 USPQ 52; In re Waite et al., 35 C.C.P.A. (Patents) 1117, 168 F.2d 104, 77 USPQ 586. Such ranges are termed "critical" ranges, and the applicant has the burden of proving such criticality. In re Swenson et al., 30 C.C.P.A. (Patents) 809, 132 F.2d 1020, 56 USPQ 372; In re Scherl, 33 C.C.P.A. (Patents) 1193, 156 F.2d 72, 70 USPQ 204. However, even though applicant's modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art. In re Sola, 22 C.C.P.A. (Patents) 1313, 77 F.2d 627, 25 USPQ 433; In re Normann et al., 32 C.C.P.A. (Patents) 1248, 150 F.2d 708, 66 USPQ 308; In re Irmscher, 32 C.C.P.A. (Patents) 1259, 150 F.2d 705, 66 USPQ 314. More particularly, where 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 Swain et al., 33 C.C.P.A. (Patents) 1250, 156 F.2d 239, 70 USPQ 412; Minnesota Mining and Mfg. Co. v. Coe, 69 App. D.C. 217, 99 F.2d 986, 38 USPQ 213; Allen et al. v. Coe, 77 App. D. C. 324, 135 F.2d 11,57 USPQ 136. (Emphasis added). With regards to determining experimental parameters, such as time in culture, the court has held that "[d]iscovery of optimum value of result effective variable in known process is ordinarily within skill of art (In re Boesch and Slaney, 205 USPQ 215 (CCPA 1980)).
The adjustment of particular conventional working conditions (e.g., frequency of dosage administration) is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan having the cited reference before him/her.
Vosough does not teach where the MSCs are administered intranasally or intracranially.
Donega teaches intranasally administering 1x106 and 2x106 hMSCs to mice with brain damage from hypoxia ischemia (Abstract, p. 2, HI induction and intranasal MSC administration). The intranasal therapy resulted in decreased microglial activation and lesion size which is attributed to the hMSC secreted anti-inflammatory cytokines (p. 6, last paragraph; p. 7, 1st column). It is known in the art that inflammation is downregulated by MSCs (p. 6, 2nd column).
Therefore, it is inherent that the MSC therapy is reaches the microglial cells if administered intranasally.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer the MSCs of Vosough intranasally in order to effectively deliver the cells to the brain and treat neuroinflammation of microglial cells as taught by Donega with a reasonable expectation of success. An artisan would have been motivated to administer the MSCs intranasally as it is a known effective means to treat neuroinflammation and traumatic brain injury (Abstract, p. 6, last paragraph; p. 7, 1st column) .
However, these references do not teach wherein the pioglitazone is administered intranasally.
Jojo teaches optimizing the formula for pioglitazone for intranasal administration, utilizing 50 mg of pioglitazone in a lipid nanoparticle (Abstract, p. 1062, 2nd column). Jojo states that intranasal route is a non-invasive, direct route to the brain that bypasses the blood brain barrier and can result in a significantly high concentration of the drug in the brain from a lower dose (p. 1061-1062, bridging paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify the known method of administering pioglitazone orally as taught by Vosough, to an intranasal route as taught by Jojo with a reasonable expectation of success. An artisan would be motivated to do so as Jojo states that intranasal route is a non-invasive, direct route to the brain that bypasses the blood brain barrier and can result in a significantly high concentration of the drug in the brain from a lower dose (p. 1061-1062, bridging paragraph). Moreover, in view of the benefit of administering hMSCs intranasally to reach cells of the brain and treat neuroinflammation of microglial cells as taught by Donega, intranasal administration of pioglitazone (PG) as taught by Jojo should be reasonably expected to reach the brain and treat neuroinflammation of microglial cells.
Regarding the limitation of timing, Vosough does not teach administering pioglitazone about 3 to 7 days prior to the administration of MSCs, However, as discussed above, the duration and timing of dosages would be a routinely optimizable facet of the treatment. Additionally, Vosough does teach that for 1 day prior to the MSCs, pioglitazone is administered. Therefore, it would have been obvious to one of ordinary skill in the art to routinely optimize the pioglitazone to occur before the MSC administration at 3 to 7 days.
Regarding the limitation in claim 1 of decreasing IL-6, TNFa or CCL20, relative to pioglitazone alone or the mesenchymal stem cells alone, as the combined teachings of Vosough, Donega and Jojo teach each and every method step of the present claim, the result IL-6, TNFa or CCL20 would be inherent to the method. The same method steps yield the same results.
Regarding claims 2 and 13, Vosough, Donega, and Jojo make obvious claims 1 and 11. Moreover, Donega teaches that it is known in the art to administer MSCs intracranially which actively promotes proliferation and differentiation of neuronal and glial precursor cells as well as axonal regeneration (p. 1, 2nd column).
Regarding the limitation in claim 11 of reducing inflammation via decreasing expression of Iba1, as the combined teachings of Vosough, Donega and Jojo render obvious the method of claim 11, intranasal administration of PG and mesenchymal stromal cells should be reasonably expected to reach the brain and treat neuroinflammation of microglial cells and decrease expression of Iba1. The same method steps yield the same results.
Regarding the limitation in claim 21 of increasing anti-inflammatory cytokines such as PPARy and IL-10, pioglitazone is a known PPARy agonist (Vosough; Abstract), therefore, increasing PPARy should be reasonably expected as the combined teachings of Vosough, Donega and Jojo render obvious the same steps of claim 21.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicant’s arguments and amendments filed 11/18/2025 regarding the 103 rejections,
Applicant’s arguments and amendments have been considered; however they are not persuasive.
First, Applicant argues that the claims have been amended to further limit the claims to intranasal administration of PG, intracranial administration of MSCs, and treatment of neuroinflammation specifically.
Examiner has modified the claims in order to address these limitations. Specifically, Jojo has been incorporated to the above rejection in order to teach intranasal administration of pioglitazone to treat neuroinflammation.
Second, Applicant argues that Vosough is concerned with liver fibrosis and not neuroinflammation where components are administered directly into the portal vein, thus one would not combine with Donega as different diseases are treated.
In response to applicant's argument that the two references have different intended uses and therefore one would not combine, 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). Moreover, as neuroinflammation is now recited, Jojo is now incorporated which demonstrates pioglitazone’s applicability to neuroinflammation as well as Donegea shows MSCs are a known effective therapy for neuroinflammation. Vosough merely demonstrates that it is known in the art to treat inflammation generally with a combination of MSCs and pioglitazone together.
Third, Applicant argues that there is no teaching as to why an artisan would modify the dosage as the only reasoning stated is that it is a time-result effective variable.
The examiner disagrees. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. Moreover, the dosage taught by Vosough is within the range claimed and shows it is suitable for therapeutic use and Jojo which is now incorporated even teaches 50mg for intranasal administration, the same mode as the present invention.
Conclusion
No claims are allowed.
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.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634