DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 1 and 112-128 are pending.
This action is in response to the amendment filed 06/16/2026, in which claim 1 was amended, and claim(s) 112-128 were newly added.
Applicant’s arguments filed 06/16/2024 have been thoroughly reviewed, but are not persuasive for the reasons that follow. Any rejections and objections not reiterated in this action have been withdrawn. This action is FINAL.
Claim(s) 1 and 112-128 are under consideration.
Priority
Acknowledgement is made that this application is a 371 of PCT/US2022/011429 filed 01/06/2022 and claims priority based on provisional application filed as 63/135,121 on 01/08/2021.
All claims are given the priority date of 01/08/2021.
Information Disclosure Statement
Receipt of the information disclosure statement on 06/16/2026 is acknowledged. The signed and initialed PTO-1449 form(s) has/have been mailed with this action.
Response to Arguments – Specification
The previous objection to the specification for containing (a) minor informalities, (b), trademarks/tradenames, and (c) a hyperlink (see pages 2-4 of Office action filed 01/26/2026), has been withdrawn in view of Applicant’s amendments filed 06/16/2026.
Claim Objections - New
Claim 127 is objected to because of the following informalities: LGE is an acronym for “late gadolinium enhancement”, it would be remedial to spell this out prior to using the acronym.
Appropriate correction is required.
Response to Arguments - Claim Interpretation
In the previous Office action filed 01/26/2026, an interpretation for the word “inhibiting” was provided on page 4. This claim interpretation is moot in view of Applicant’s amendment to claim 1 removing “inhibiting”.
Response to Arguments - Claim Rejections - 35 USC § 112(a) – Written Description
The previous rejection of claim 1 under 35 U.S.C 112(a) for written description has been withdrawn in view of Applicant’s amendments of the claim filed 06/16/202026.
In brief, Applicant amended claim 1 to recite “. . . a nucleic acid encoding a human sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a). . .” instead of the broad genus of “a nucleic acid encoding SERCA polypeptide”.
Response to Arguments - Claim Rejections - 35 USC § 112(a) – Enablement
The previous rejection of claim 1 under 35 U.S.C 112(a) for Enablement has been withdrawn in view of Applicant’s amendments of the claim filed 06/16/2026.
In brief, Applicant amended claim 1 to recite (a) a particular muscular dystrophy (i.e. DMD and BMD); (b) a particular delivery formulation (i.e., AAV); (c) a particular SERCA polypeptide (i.e., SERCA2A); and (d) removed inhibiting (interpreted as preventing) from the claim language. In addition, Applicant amended the claim to recite “Human” as the subject, and that the method is for treating cardiomyopathy.
Response to Arguments - Claim Rejections - 35 USC § 102
The rejection of claim 1 under 35 U.S.C. 102 (a)(1) as being anticipated by Yue et al (Abstract title: AAV-SERCA2A EXPRESSION AMELIORATED CARDIOMYOPATHY IN THE MDX1, Article title: 15th International Congress on Neuromuscular Diseases July 6-10, 2018, Vienna, Austria, Journal of Neuromuscular Diseases, published on June 25th, 2018, Vol 5, Issue s1 pages S3-S383; cited on 892 filed 01/26/2026) is withdrawn in view of Applicant’s amendments of the claims in the reply filed 06/16/2016.
In brief Applicant overcame this rejection by adding “human” into the claim language of claim 1.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 112-116, 118-121, 123-126 and 128 are rejected under 35 U.S.C. 103 as being unpatentable over Jessup et al (Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): A Phase 2 Trial of Intracoronary Gene Therapy of Sarcoplasmic Reticulum Ca2+-ATPase in Patients With Advanced Heart Failure, Circulation, Vol 124, Issue 3, Pages 304-313; published June 27th, 2011) as evidenced by ClinicalTrials (NCT00454818 - Efficacy and Safety Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure; pages 1-16; Last updated 08/20/2014) and evidenced by Hajjar et al (Design of a Phase 1/2 Trial of Intracoronary Administration of AAV1/SERCA2a in Patients With Heart Failure; Journal of Cardiac Failure, Vol 14, Iss 5, pages 355-367, published June 2008) in view of Yue et al (supra). This is a new rejection, necessitated by the amendment to the claims filed 06/16/2026.
Regarding claim(s) 1, 112-113, and 115, Jessup et al teaches a clinical trial of intracoronary infusion of varying doses of SERCA2. More specifically, “The 39 CUPID trial participants were randomized and received intracoronary infusion of AAV1/SERCA2a or placebo, allocated in numbers shown in Table 1, . . .”, (p. 307, col 1, para 1).
Wherein Figure 1 discloses doses of AAV1/SERCA, i.e., 6x1011, 3x1012, and 1x1013 (p. 306).
Regarding claim 114, Jessup et al does not explicitly disclose whether or not the infusion is a single dose, however, this is evidence by ClinicalTrials. ClinicalTrials discloses the clinical trial information related to Jessup et al (Clinical trial registration disclosed on page 304 of Jessup et al). ClinicalTrials discloses on page 8 that these were single dose infusions of the viral vector.
Regarding claim 116, Jessup et al does not explicitly disclose that the promoter of the nucleic acid is CMV, however, Jessup et al teaches, “Detailed information about the phase 1 and 2 study designs and results of the phase 1 trial have been published previously.20,21”, (p.305, col 1, para 3). Wherein citation 20 is Hajjar et al which discloses that the promoter of the polynucleotide is CMV (see Fig. 1).
Regarding claim(s) 118 and 119, Jessup et al teaches, “Administration of nitroglycerin (either intracoronary bolus before infusion or intravenous before and during infusion or both) was routinely performed.”, (p. 305, col 2, para 3).
Regarding claim(s) 120 and 121, Jessup et al teaches screening for neutralizing antibodies against AAV1 (p. 305, col 1, para 2; and figure 1).
Regarding claim(s) 124 and 125, Jessup et al teaches measuring cardiac function via left ventricular function/remodeling (see table 2).
Regarding claim 126 and 128, Jessup et al teaches improvement in LVESV in figure 2, and more specifically, “There was no appreciable change in EF; however, both LV end-systolic volume and LV end-diastolic volume were substantially improved at 6 months after infusion in the high-dose group compared with placebo. . .”, (p. 310, col 1, para 3).
Jessup et al does not explicitly teach (a) that the patient experiencing cardiomyopathy has DMD or BMD (claim 1) or (b) that the administration provides an improvement in a symptom or measure of the DMD or BMD in the human subject (claim 123).
Yue et al teaches “Loss of dystrophin leads to Duchenne muscular dystrophy (DMD). Increased cytosolic calcium levels play a critical pathogenic role in the development DMD cardiomyopathy. Cytosolic calcium can be removed by the sarco/endoplasmic reticulum calcium ATPase (SERCA). SERCA activity is reduced in dystrophic muscle.”, (Background section).
Regarding claim(s) 1 and 123, Yue et al teaches, “. . . AAV-9 SERCA2a treatment
also reduced the serum CK level, a marker of muscle damage. Importantly, SERCA2a treatment
significantly improved heart function. . . Conclusion: Our results suggest that AAV-9 SERCA2a gene therapy is a promising approach to treat DMD cardiomyopathy.”, (see Results and Conclusion, p. S189-S190).
Serum CK level reading on a measure of DMD or BMD.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Jessup et al, i.e., administering AAV1/SERCA2a to human patients with advanced heart failure with the teachings of Yue et al, i.e., administering AAV9/SERCA2a to mice to treat Duchenne muscular dystrophy (DMD) cardiomyopathy, to yield the predictable results of treating human patients with DMD-related cardiomyopathy by administering AAV1/SERCA2a. One would be motivated to combine such teachings because Yue et al teaches that AAV9 SERCA2a treatment to mice reduces CK serum and improves heart function, along with suggesting that AAV9-SERCA2a gene therapy is a promising approach to treat DMD cardiomyopathy and Jessup et al teaches that AAV1-SERCA2a treats advanced heart failure. One could look the teachings of Jessup et al and Yue et al and arrive at the claimed invention with a high likelihood of success.
Accordingly, claim(s) 1, 112-116, 118-121, 123-126 and 128 are unpatentable over Jessup et al as evidenced by ClinicalTrials and as evidenced by Hajjar et al in view of Yue et al.
Claim(s) 117 and 122 are rejected under 35 U.S.C. 103 as being unpatentable over Jessup et al (supa) as evidenced by ClinicalTrials (supra) and as evidenced by Hajjar et al (supra) in view of Yue et al (supra) as applied to claim(s) 1, 112-116, 118-121, 123-126 and 128 above, and further in view of Zsebo (US 2008/0076730 A1; published March 27th, 2008; on IDS filed 09/27/2024 as citation 5).
Of note: Claim 122 depends from 117.
Regarding claim 122, as mentioned in the above rejection, the combination of Jessup et al and Yue et al teach a method of treating cardiomyopathy in a human subject with DMD, comprising: administering a polynucleotide comprising a nucleic acid encoding a human SERCA2A polypeptide to the human subject with DMD.
Jessup et al as evidenced by both ClinicalTrials and Hajjar et al in view of Yue et al do not teach viral particles/DNase resistant particles (DRP) doses of 3x1013.
Regarding claim 117, Zsebo teaches a range of doses, of which teaches 3x1013 viral particles (see para [0060]).
Therefore, it would have been obvious to try to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the single high dose (1x1013) AAV1-SERCA2a infusion to treat cardiomyopathy in a human subject with DMD as taught by the combination of Jessup et al as evidence by both ClinicalTrials and Hajjar et al in view of Yue et al, with 3x1013 as taught by Zsebo, to yield the predictable results of administering a dose of the AAV vector that is 3x1013 viral genome particles. One would be motivated to make such a modification because Jessup et al teaches that the high dose is the only group that met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months), and that mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P=0.05) on high-dose treatment versus placebo all with no untoward safety findings (abstract). Thus, one could look to the teachings of Jessup et al in combination with the teachings of Zsebo and select a higher dosage of viral genome particles and arrive at a dosage of 3 times that of the only significant dosage (i.e., 1x1013), and arrive at the modified dosage with a high likelihood of success.
Accordingly, claim(s) 117 and 122 are unpatentable over Jessup et al as evidenced by ClinicalTrials and as evidenced by Hajjar et al in view of Yue et al in further view of Zsebo.
Claim 127 is rejected under 35 U.S.C. 103 as being unpatentable over Jessup et al (supa) as evidenced by ClinicalTrials (supra) and as evidenced by Hajjar et al (supra) in view of Yue et al (supra) as applied to claim(s) 1, 112-116, 118-121, 123-126 and 128 above, and further in view of Puchalski et al (Late Gadolinium Enhancement: Precursor to Cardiomyopathy in Duchenne Muscular Dystrophy? Int J Cardiovasc Imaging, vol 25, issue 1, pages 1-11, published January 2009).
Jessup et al as evidenced by both ClinicalTrials and Hajjar et al in view of Yue et al do not teach wherein the left ventricular structure and/or function is assessed by LGE cardiac MRI.
Regarding claim 127, Puchalski et al teaches, “LGE by CMRI is able to detect fibrosis in selective regions of myocardium in patients with DMD. Unfavorable LV remodeling, with a corresponding decreased ejection fraction, is associated with the presence of LGE.”, (para 4, page 1). Further, “The presence of LGE correlated with LV size and function independent of age. Correlating LGE with function was important since DMD patients have a progressive decrease in LV systolic function that is age-related and well described [19] [9] [20] [21] [22] [10] [23] [24]. In perhaps the largest longitudinal study of this patient population, Nigro et al reported the results of cardiac evaluations in 328 patients with DMD of varying ages who were followed for 3 to 11 years [19]. These investigators found evidence of cardiomyopathy in no patient less than 10 years of age, approximately 30% of patients age 10 to 14 years, 53% of patients 14 to 18 years of age, and nearly 98% of patients over 18 years of age. We found that while our population of relatively young DMD patients had normal LV systolic function as a group, the sub-group with LGE had significantly reduced LV function and increased LV size. The severity of LV enlargement and decreased LV function was more pronounced when LGE involved a greater proportion of the LV myocardium. This suggests a role for identifying myocardial fibrosis at an early age to allow earlier treatment in the hope of delaying the progression or development of dilated cardiomyopathy, as has been demonstrated by Duboc and colleagues with a randomized trial using perindopril.”, (p.5 para 2),
Therefore, it would have been obvious to try to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the combined Jessup et al in view of Yue et al, i.e., treating cardiomyopathy in patients with DMD via administering AAV1/SERCA2a with the teachings of Puchalski et al, i.e., assaying left ventricular structure via LGE cardiac MRI, to arrive at the claimed invention of measuring improvement of left ventricular structure by LGE cardiac MRI. One would be motivated to combine such teachings because Puchalski et al teaches that (1) LGE by CMRI is able to detect fibrosis in selective regions of myocardium in patients with DMD and (2) LGE is correlated with LV size and function independent of age. Thus, one could look to the teachings of the Jessup et al in view of Yue et al and combine with Puchalski to arrive at the claimed invention of monitoring improvement of LGE in patients with a high likelihood of success.
Accordingly, claim 127 is rejected for being unpatentable over Jessup et al as evidenced by ClinicalTrials and as evidenced by Hajjar et al in view of Yue et al and further in view of Puchalski et al.
Conclusion
No claims 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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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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