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 action is in response to the papers filed January 26, 2026.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 26, 2026 has been entered.
Claims 4, 12-24, 56, 58, and 60 are pending in the application. No claims are amended, no claims are canceled and no new claims are added as set forth in the claim set filed April 21, 2025. Claims 4, 17 and 18 are independent claims.
The examiner acknowledges receiving an executed Declaration under 37 C.F.R. § 1.132 executed by Antoinette Konski on July 09, 2009 (“Koenig Decl. 2”), and filed on 03/28/2025.
Claims 4, 12-24, 56, 58, and 60 are pending the application and examined on the merits.
Priority
Applicant’s claim for the benefit of prior-filed provisional application 63/196,108 filed 06/02/2021 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 June 02, 2021.
Response to arguments
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 4, 12-14, 16-24, 56 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Sahenk (WO2020006458; IDS Reference filed 03/29/2023) as evidenced by ABSS (Sequence Alignment; WO2020006458, SEQ ID #1; accessed 3/12/2024) and Hagan (2017. The Jackson Laboratory. “When are mice considered old?”) in view of Yalvac (2017. Skeletal Muscle 7:27: 1-18; IDS Reference filed 03/29/2023).
Regarding claim 4, Sahenk teaches a recombinant adeno-associated virus (rAAV) comprising a polynucleotide which comprises a first AAV inverted terminal repeat (ITR), a promoter, a nucleotide sequence encoding a protein with calpain 3 (CAPN3) activity and a second AAV ITR wherein said polynucleotide is Sahenk’s SEQ ID NO: 1 (Claim 1, Claim 10, para. ). As evidenced by the alignment carried out by ABSS in the screen shot below, Sahenk (PCTUS19)’s is 7629 bp long, the first 3977 bps of Sahenk’s SEQ ID NO: 1 are a 100% identical match to SEQ ID NO:1 of the present invention. Therefore, Sahenk renders obvious a rAAV virus which comprises SEQ ID NO: 1 of the present invention. Sahenk further teaches that this rAAV comprising SEQ ID NO: 1 is administered to a subject in a method of treating limb girdle muscular dystrophy 2A (para. [0021] Claim 18, 19).
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Sahenk does not teach that the method further comprises the step of measuring the expression level of peroxisome proliferator activated receptor y coactivator 1 alpha (PGC1α) in a sample obtained from the subject having decreased levels of PGC1α after administration of a rAAV and that the result of the method showed an increase of PGC1α after administration and that the control level is that of the sample taken prior to the treatment, or an untreated sample.
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Yalvac teaches utilizing CAPN3-KO mice (the same mice as Sahenk where there is not expression of the calpain 3 and therefore no calpain 3 activity) and measuring PGC1α in muscles at 4- and 12-weeks post injection of cardiotoxin (CTX) (Figure 6). CTX induces muscle necrosis and regeneration in the mice to simulate early features of the dystrophic process in limb girdle muscular dystrophy type 2A (p. 2, 1st column, last paragraph). The baseline levels (i.e. control/standard level) were obtained from untreated limbs of the mouse at each interval (Figure 6, line 3). Additionally, Yalvac teaches that PGC1α is a key regular of mitochondrial biogenesis and a marker of mitochondria function in AMPK pathways. AMPK stimulates oxidative metabolism and slow type gene expression through PGC1α (p. 11, last paragraph; p. 14 1st column). As disclosed by Yalvac, absence or decreased levels of CAP3N results in decreased levels of PGC1α and is measured in Fig 6B in the CAP3N -KO which is restored by CTX injection. Moreover, Yalvac teaches that restoring CAPN3 in CAP3N -KO mice first injected with CTX and two weeks later with an AAV vector comprising CAPN3 gene under MCK muscle-specific promoter (page 7, col. 2 last para. bridging to page 8, col. 1, first paragraph) where “CAPN3 replacement via gene therapy in the CAPN3-KO muscle rescued defective regeneration, evidenced with toward normalization of fiber size and a decrease in the number of STO fiber population.” (page 8, col. 1, first paragraph.
Based on Yalvac’s teaching where absence or decreased levels of CAP3N results in decreased levels of PGC1α and where CAPN3 replacement via gene therapy rescued aberrant regeneration of muscle, it would have been prima facie obvious to one of ordinary skill in the art to measure PGC1α were lower levels is associated with defective muscle regeneration via taking a control from an untreated muscle from a subject with decreased levels of PGC1α and comparing it to that of a treated muscle in the method treatment of Sahenk with a reasonable expectation of success where administration of Sahenk’s SEQ ID NO: 1 for the treatment of limb girdle muscular dystrophy 2A should had been reasonable expected to enhance expression of PGC1α levels to rescue defective muscle regeneration in the treatment of limb girdle muscular dystrophy 2A .. Moreover, measuring PGC1α levels would have been beneficial in measuring mitochondrial function in treated subjects as PGC1α is a key regular of mitochondrial biogenesis and a marker of mitochondria function (Yalvac, p. 11, last paragraph). As each and every limitation is met by the combination of references, it would be obvious to one of ordinary skill in the art that the result of an increase of PGC1α would be present as the same method steps yield the same results.
Regarding claims 12 and 24, Sahenk teaches that the method comprises administering the rAAV are formulated into a composition which is then administered via intramuscular injection or intravenous injection (Claim 23, para. 0020).
Regarding claims 13 and 56, Sahenk teaches that the rAAV comprises one or more AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-7, AAV-8, AAV-9, AAV-10, AAV-11, AAV-12, AAV- 13, AAV rh.74 and AAV rh. 10 capsid proteins (para. 0019).
Regarding claims 14 and 58, Sahenk teaches the rAAV is administered to mice which 2 months of age and 6 months of age (Example 4-5). As evidenced by Hagan, 3-6 months is the equivalent of what humans consider a mature adult (Figure on p. 2). Therefore it is interpreted that the composition is administered to a young adult subject and a mature adult subject before middle age.
Regarding claim 16, although Sahenk does not explicitly teach that the administration of the rAAV encoding SEQ ID NO: 1 resulted in a switch from fast-twitch glycolytic fibers (FTG) to slow- twitch oxidative fibers (STO), as each and every limitation of the method is taught by Sahenk as well as the same rAAV, the result is an inherent outcome of the administration.
Regarding claim 17, as described above, Sahenk and Yalvac make obvious a method of treating limb girdle muscular dystrophy 2A in a subject comprising administering to the subject a recombinant rAAV wherein the rAAV comprises SEQ ID NO: 1 wherein the administration results in an increase in the level of PGC1alpha. Sahenk further teaches an improved phenotype or performance as a result of the treatment. Sahenk teaches improved performance such as increase in muscle contractability (para. 0083, 0088) or an improved performance in the run to exhaustion test (para. 0039, Fig 8). Sahenk further teaches an improved phenotype such as an increase in muscle fiber diameter (para. 0022-0023, para. 0032, Figures 1A-1F). Regarding the limitations of an increase in number of oxidative muscle fibers, a switch from FTG fibers to STO fibers, or an increase in the percentage of oxidative muscle fibers. These are all interpreted to be correlated to the switch from FTG to STO or FTO (oxidative fibers) (para. 0022, Table 4) which would increase the percentage of oxidative fibers in total and increase the number.
Regarding claim 18, as described above, Sahenk and Yalvac make obvious a method of treating limb girdle muscular dystrophy 2A in a subject comprising administering to the subject a recombinant rAAV wherein the rAAV comprises SEQ ID NO: 1 wherein the administration results in an increase in the level of PGC1alpha. Sahenk further teaches that the treatment of subjects via administration of the rAAV comprising SEQ ID NO: 1 resulted in 2.5-fold relative increase in CAPN3 (i.e. at least 10% increase) (Figure 5). Regarding the limitation that the increase is indicative of an increase in performance or phenotype, this is merely an interpretation of the results and would be inherent to the at least 10% increase.
Regarding claim 19 and 22, Sahenk teaches that in the run to exhaustion test mice treated reached about 120m compared to the wild type which reached 100m and the untreated which resulted in less than 60m (i.e. increase in performance) (Figure 8A). This is at least about 100% increase in the distance to run to exhaustion test.
Regarding claim 20, Sahenk further teaches an improved phenotype such as an increase in muscle fiber diameter (para. 0022-0023, para. 0032, Figures 1A-1F). Regarding the limitations of an increase in number of oxidative muscle fibers, a switch from FTG fibers to STO fibers, or an increase in the percentage of oxidative muscle fibers. These are all interpreted to be correlated to the switch from FTG to STO or FTO (oxidative fibers) (para. 0022, Table 4) which would increase the percentage of oxidative fibers in total and increase the number.
Regarding claim 21, Sahenk teaches that the method results in an increased muscle force generation which is measured via observing the maximum tetanic force response (Claim 20, para. 0087). Although Sahenk does not explicitly state that the improved performance is at least a 10% increase in maximum tetanic response, as each method step of Claim 1 is described in Sahenk with the same rAAV, inherently the tetanic response would also increase to at least 10% more than the untreated muscle fibers.
Regarding claim 23, Sahenk further teaches an improved phenotype such as an increase in muscle fiber diameter (para. 0022-0023, para. 0032, Figures 1A-1F), these fibers are STO, FTG or FTO (Table 1).
Therefore the invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicant’s arguments against the references of claims 4, 12-14, 16-24, 56 and 58 the previously set forth 103 rejections,
Applicant's arguments filed 10/30/2025 have been considered and are not persuasive.
Applicant reiterates previously stated arguments which have been addressed in the Final Rejection filed 07/31/2025 and also addressed in the Advisory Action filed 12/05/2025. In particular, Applicant states that none of the references teach or suggest the claimed method, particularly that there is no selection of a subject with a decreased level of PGC1alpha explicitly stated and that Yalvac does not remedy deficiencies based on the CTX treatment and not an administration of an rAAV.
Examiner disagrees and reiterates the arguments of the previous response that 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.
Sahenk teaches administration of a rAAV expressing a calpain 3 (CAPN3) protein for the treatment of girdle muscular dystrophy 2A. Sahenk does not teach that said administration is associated with increased level of PGC 1 alpha relative to the level of PGC 1 alpha before administration. Yalvac remedy the deficiencies of Sahenk by teaching that deceased expression of CAPN3 protein results in decreased levels of PGClalpha where CAPN3 replacement via gene therapy rescued aberrant regeneration of muscle and is measured in Fig 6B in the CAP3N -KO relative to the WT at 4 weeks and 12 weeks after post CTX injection,. Note that cardiotoxin (CTX) simulates the early features of the dystrophic process in limb-girdle muscular dystrophy type 2A (LGMD2A) (Yalvac Abstract).
Thus, it would have been obvious to observe and measure increased expression of PGC 1alpha in early features of the dystrophic process in LGMD2A as disclosed by Yalvac after administration of a rAAV expressing CAPN3 protein as taught by Sahenk. Furthermore, though Yalvac discloses upregulated expression of PGC1la in CAP3N -KO mice first injected with CTX and two weeks later with an AAV vector comprising CAPN3 gene, the instant claims require administering to a subject having decreased level of PGC1alpha with a recombinant adeno-associated virus (rAAV) comprising the nucleotide sequence of SEQ ID NO: 1. However, the instant claims are not so limited such that this is the only possible expression from the claimed adenoviral vector. The claims are "open" and thus lend themselves to administration of additional transgenes, or measurements of additional regulators.
Claims 15 and 60 remain rejected under 35 U.S.C. 103 as being unpatentable over Sahenk (supra) as evidenced by ABSS (supra) and Hagan (supra) in view of Yalvac (supra) as applied to claims 4 and 17 above and in further view of Hagan (2017. The Jackson Laboratory. “When are mice considered old?”; previously cited).
As discussed in the above 103 rejection, Sahenk and Yalvac teaches a recombinant adeno-associated virus (rAAV) comprising a polynucleotide which comprises a first AAV inverted terminal repeat (ITR), a promoter, a nucleotide sequence encoding a protein with calpain 3 (CAPN3) activity and a second AAV ITR wherein said polynucleotide is Sahenk’s SEQ ID NO: 1 (Claim 1, Claim 10) and measuring PGC1alpha in the muscle in the treated limb. As evidenced by the alignment carried out by ABSS in the screen shot below, Sahenk (PCTUS19)’s is 7629 bp long, the first 3977 bps are a 100% identical match to SEQ ID NO:1 of the present invention. Therefore, Sahenk teaches a rAAV virus which comprises SEQ ID NO: 1 of the present invention. This results in improved performance and phenotype.
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However, regarding claims 15 and 60, while the combined teachings of Sahenk and Yalvac do teach administration to mice which are 2 to 6 months old. Sahenk does not teach administering the therapy to human subjects which are a certain number of years old.
Hagan teaches that mice are widely used models for both aging and senescent because of their similarity to humans, however their maturational rate does not linearly correlate with humans as it occurs 150 times faster during the first month and 45 times faster over the next five months (p. 1; 3-6 months in a mouse subject is the equivalent of what humans consider a mature adult (Figure on p. 2). Therefore it is interpreted that the composition is administered to a young adult subject and a mature adult subject before middle age. Hagan further teaches that the equivalence of these subjects is a 2 month old mouse is less than 20 years old (a mouse at 3 months) and a mouse which is 6 months is at the end of the age range at around 30 years old in human age years (Figure on p. 2). This falls within the age range of 15 to 55 years as claimed in claims 15 and 60.
Based on these teachings, it would be obvious to administer the therapy of Sahenk to a human subject which is anywhere between about 20 to 30 years old (i.e. instead of the 2 to 6 month old mice with a reasonable expectation of success. Mice are widely used models for their similarity to humans and Hagan teaches that 3 to 6 months in mice is equivalent to 20 to 30 years old in humans (Figure on p. 2). Therefore, an artisan would be substituting known equivalent aged subjects for the same purpose of condition or disease treatment.
Therefore, the invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Double Patenting
Claims 4, 12-24, 56, 58, and 60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 18, of US Patent No. 12,391.928 (hereinafter ‘928) in view of Sahenk (WO2020006458; IDS Reference filed 03/29/2023) as evidenced by ABSS (Sequence Alignment; WO2020006458, SEQ ID #1; accessed 3/12/2024), ABSS2 (Sequence Alignment; US17/255,488, SEQ ID #1; accessed 3/12/2024), and Hagan (2017. The Jackson Laboratory. “When are mice considered old?”) and Yalvac (2017. Skeletal Muscle 7:27: 1-18; IDS Reference filed 03/29/2023)
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 01/26/2026 and 10/30/2025.
Regarding claim 4, 17, and 18, ‘928 teaches a recombinant adeno-associated virus comprising a polynucleotide which comprises nucleotides 1 to 3977 of SEQ ID NO: 1 (Claim 1, 18). As evidenced by ABSS2, this polynucleotide is 100% identical to the present invention.
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However, ‘928 does not teach that the rAAV is utilized in a method of treating muscular dystrophy nor the resulting mRNA expression of the treatment method.
Sahenk teaches a recombinant adeno-associated virus (rAAV) comprising a polynucleotide which comprises a first AAV inverted terminal repeat (ITR), a promoter, a nucleotide sequence encoding a protein with calpain 3 (CAPN3) activity and a second AAV ITR wherein said polynucleotide is Sahenk’s SEQ ID NO: 1 (Claim 1, Claim 10). As evidenced by the alignment carried out by ABSS in the screen shot below, Sahenk (PCTUS19)’s is 7629 bp long, the first 3977 bps are a 100% identical match to SEQ ID NO:1 of the present invention. Therefore Sahenk teaches a rAAV virus which comprises SEQ ID NO: 1 of the present invention.
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Sahenk further teaches that this rAAV comprising SEQ ID NO: 1 is utilized in a method of treating limb girdle muscular dystrophy 2A via administration to a subject (Claim 18, 19) wherein the treatment results in one or more of:
(a) an increased muscle fiber diameter,
(b) a decreased number of small lobulated muscle fibers,
(c) a decreased number of fibers with internal nuclei,
(d) a decreased endomysial connective tissue content,
(e) correction of muscle atrophy, and
(f) an increased muscle force generation. (Claim 20).
It would have been obvious to one of ordinary skill in the art to utilize the rAAV of ‘928 in a method of treatment for muscular dystrophy as taught by Sahenk with a reasonable expectation of success. As the rAAV is the same as Sahenk and the present invention, utilizing the ‘928 rAAV would result in all of the beneficial outcomes described by Sahenk such as increased muscle fiber diameter and increased function and performance (Claim 20). Furthermore, Sahenk teaches that the therapy resulted in 2.5 fold relative increase in CAPN3 (i.e. at least 10% increase) (Figure 5). Regarding the limitation that the increase is indicative of an increase in performance or phenotype, this is merely an interpretation of the results and would be inherent to the at least 10% increase. Thus utilizing ‘928 rAAV in the same method with same method steps would also provide the same inherent outcome.
‘928 and Sahenk do not teach that the method further comprises the step of measuring the expression level of peroxisome proliferator activated receptor y coactivator 1 alpha (PGC1α) in a sample obtained from the subject after administration of a rAAV, wherein an increase in PGC1α level compared to a control level of PGC1α is indicative of improved muscle function, the samples are taken before and after administration and that the control level is that of the sample taken prior to the treatment, or an untreated sample.
Yalvac teaches utilizing CAPN3-KO mice (the same mice as Sahenk) and measuring PGC1α in muscles at 4 and 12 weeks post injection of cardiotoxin (CTX) (Figure 6). CTX induces muscle necrosis and regeneration in the mice to simulate early features of the dystrophic process in limb girdle muscular dystrophy type 2A (p. 2, 1st column, last paragraph). The baseline levels (i.e. control/standard level) were obtained from untreated limbs of the mouse at each interval (Figure 6, line 3). Additionally, Yalvac teaches that PGC1α is a key regular of mitochondrial biogenesis and a marker of mitochondria function in AMPK pathways. AMPK stimulates oxidative metabolism and slow type gene expression through PGC1α (p. 11, last paragraph; p. 14 1st column).
Based on such teachings, it would have been prima facie obvious to one of ordinary skill in the art to measure PGC1α via taking a control from an untreated muscle and comparing it to that of a treated limb in the method treatment made obvious by Sahenk above with a reasonable expectation of success. Doing so, would be beneficial in measuring mitochondrial function in treated subjects as PGC1α is a key regular of mitochondrial biogenesis and a marker of mitochondria function (Yalvac, p. 11, last paragraph).
Therefore, the claims are rejected on the ground of non-statutory double patenting.
In response to Applicant’s request to hold the double patenting rejection in abeyance
Applicant has requested the double patenting rejection be held in abeyance. This request is denied.
The rejection has been modified to reflect the application status of ‘488 as a patented case.
According to MPEP 804, “As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only compliance with objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated.”
Conclusion
Claims 4, 12-24, 56, 58, and 60 are rejected.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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