DETAILED ACTION
This action is in reply to papers filed 8/6/2026. Claims 32-44 are pending and examined herein.
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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/6/2026 has been entered.
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230226153A1, Published 7/20/2023.
Withdrawn Claim Rejections
The 103 (a) rejection of claims 32-44 as being unpatentable over Engelhardt et al. (PgPub US20080249050A1, Published 10/9/2008) in view of Shabbir et al. (Transplantation 87(9):p 1275-1282, May 15, 2009.) and Bostick et al. (Hum Gene Ther . 2008 Aug;19(8):851-6 .) is withdrawn in view of the amendments made to independent claim 32.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 32-44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of inducing acquired immunological tolerance in a subject having Duchenne Muscular Dystrophy, wherein said method comprises a first step of systemically administering a first population of mesenchymal stem cells (MSCs) and an AAV9 vector, a second step of systemically administering a second population of MSCs seven days after the first step and a third step of locally introducing the recombinant AAV9 expression vector one day after the second step, wherein after introduction of the first population of mesenchymal stem cells (MSCs) and the first recombinant AAV9 expression vector, the host immune response is suppressed,
, does not reasonably provide enablement for any other embodiment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue.’ Not ‘experimentation;” (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
• (A) The breadth of the claims;
• (B) The nature of the invention;
• (C) The state of the prior art;
• (D) The level of one of ordinary skill;
• (E) The level of predictability in the art;
• (F) The amount of direction provided by the inventor;
• (G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
The Nature of the Invention: The inventive concept in the instant application is a method of acquiring immunological tolerance to an introduced AAV9 based vector by administering a first population of MSCs and an AAV9 vector and a second population of MSCs prior to the introduction of the AAV9 vector.
The Breadth of the Claims: The breadth of the claims is excessive with regard to the type of AAV vector introduced.
Amount of Direction Provided by Inventor/Working Examples: Pertinent to the instant invention are Examples 4 and 5. Starting at para. 193, the specification discloses the objective is to verify, in dogs, that immunological tolerance against immunogen to be introduced to recipient individual is induced by pretreatment using MSCs. First, the specification teaches AAV9 was introduced as an immunogen to each recipient, and this administration date was defined as a reference date (day 0). Next, 8 days before the reference date, MSCs and the immunogen AAV9 were intravenously administered as the first step of the method for inducing immunological tolerance. For a control, only AAV9 or only MSCs were intravenously administered. Subsequently, on the day before the reference date, MSCs were intravenously administered as the second step of the method for inducing immunological tolerance. This administration was not carried out for the control. On the reference date, the immunogen AAV9 was introduced by local administration. The specification teaches the introduced AAV9 causes luciferase gene expression.
Starting at para. 204, the specification discloses 4 weeks after the reference date, the tibialis anterior muscle was biopsied at the introduction sites. The results are shown in FIGS. 12A-C. FIG. 12A shows the results about Control−AAV. FIG. 12B shows the results about MSCs+AAV. FIG. 12C shows the results about Control-MSCs. In the MSCs+AAV treated by the method for inducing immunological tolerance of the present invention, the expression of the marker gene of luciferase derived from the immunogen AAV9 was observed (FIG. 12B). By contrast, in the Control−AAV pretreated with only AAV9 without the immunological tolerance induction treatment with MSCs, the expression of luciferase was not seen (FIG. 12A). Likewise, in the Control-MSCs that underwent neither administration nor introduction of AAV9-Luc, the expression of luciferase was not seen (FIG. 12C). At para. 207, the specification teaches these results indicate that immunological tolerance against the immunogen AAV9-Luc was induced in the individual that received the immunological induction treatment by the method of the present invention, and the introduced AAV9-Luc was not eradicated by immune response even 4 weeks after the introduction of the AAV9-Luc.
Using the steps of the above, Example 5 teaches 4 weeks after the date of intravenously administering the immunogen AAV9-μDys, the expression of microdystrophin was confirmed (FIG. 13C), as in the MSCs+AAV-Luc given luciferase. At para. 223, the specification teaches these results indicate that immunological tolerance against the immunogen AAV9-μDys was induced, and the introduced AAV9-μDys was not eradicated by immune response even 4 weeks after the introduction of the AAV9-μDys. Example 5 teaches the subjects were muscular dystrophy-affected dogs (DMD), and treated affected dogs (DMD/MSCs+AAV-μDys).
Each of these examples is pertinent to the claimed invention in view of (1) use of the immunogen AAV9 and (2) specific timing of the various steps. (1) is problematic because the breadth of the claim encompasses, inter alia, suppression of an immune response to any AAV vector. The specification only narrowly provides evidence for suppression of an AAV9 vector ~ AAV9-μDy and AAV9-Luc. Moreover, claim 32 fails to recite a first and second administration of MSCs and a first and second administration of AAVs. Even further, the claims fail to recite when the first and second administration of the cells and vectors are administered. This is problematic.
The State of the Prior Art: Halbert et al. (J Virol. 2000 Feb;74(3):1524–1532; Ref. G95 in IDS filed 5/28/2025) explored the use of AAV2 vectors pseudotyped with capsid proteins from AAV serotypes 2, 3, and 6 for readministration in the mouse lung. Halbert teach prior administration of an AAV2 vector completely blocked transduction by a second AAV2 pseudotype vector, prior administration of an AAV6 vector only partially inhibited transduction by a second administration of an AAV6 pseudotype vector (Abstract). Halbert notes that all animals exhibited a robust neutralizing immune response against the second AAV2 vector (Pg. 1526, Col. 2, para. 1). Costa-Verdera et al. (Hum Gene Ther. 2023 Sep;34(17-18):836-852.;Ref. G94 in IDS filed 5/28/2025) cautions against vector engineering and serotype switching. Indeed, Costa-Verdera teaches several methodologies can be used to engineer AAV capsids with better tissue tropism or the ability to cross physical barriers. Similarly, the development of non-natural variants and their selection against pooled human sera can help identify novel AAV capsids with low seroprevalence. In the context of vector readministration, serotype switch has been shown to be effective in preclinical models. While the effectiveness of the approach needs clinical validation, it should be kept in mind that the use of a different capsid for redosing purposes is highly resource intensive as in many ways it is equivalent to developing a new investigational gene therapy product (Pg. 843, paragraph bridging Col. 1-2).
Thus, both Halbert and Costa-Verdera provide evidence that not all AAV vectors can be readministered without induction of an immune response and/or undue burden.
Merino et al. (Cell Transplant. 2017 Jun; 26(6): 1017–1030; Ref. C4 in IDS filed 9/13/2023) makes clear that timing of pre-treatment with MSCs is important by noting that in the allogeneic kidney transplantation model, rats in which MSC infusion was 4 days (MSCs-4) and 7 days (MSCs-7) before kidney transplantation performed differently. While Merino notes that both MSC treatments decreased the percentage of T, B, and NK cells in PB, creatinine levels, survival, and histological parameters were better in MSCs-7 than in MSCs-4. Merino concludes that, in the renal allograft model, the optimal time schedule for MSC infusion before grafting was 7 days to prevent acute rejection (Abstract). Thus, Merino broadly provides evidence of criticality in the timing of the administration of MSCs prior to treatment.
The level of Predictability in the Art/Conclusion: The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. Due to the breadth of the claims which encompasses immune suppression of any AAV vector, the state of the art which establishes criticality in the timing of MSC administration for the purposes of immune suppression coupled, it would have required undue experimentation for one skilled in the art at the time of the invention to practice over the full scope of the invention claimed. Thus, limiting the claimed invention to the scope above would be proper.
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Conclusion
No claim is allowed.
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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632
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