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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/30/2026 has been entered.
Claim Status
Claims 8-11, 20, 27, and 29-37 are pending. Claims 24-26 and 28 were canceled; claims 31-37 were newly added; and claims 8-11 were amended in the Reply filed 3/30/2026. Claims 8-11, 20, 27, 29-30, 31, 33-34, 36, and 37 are withdrawn. Claims 32 and 35 are presently considered.
Election/Restrictions
Applicant’s election of Group II (Original claims 8-14 and 17-20) in the reply filed on March 4, 2022, was previously acknowledged; Applicant’s subsequent election of the species of “Example 2” in the response filed 8/15/2022, was previously acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The originally elected species has been consistently understood on record as follows: The originally elected species of Example 2 has been examined on record and understood to pertain to the inhibition of arrhythmia in an Opto-MTF murine model of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) “expressing the R4561I mutation”1,2, by intraperitoneal injection of AAV9-GFP-AIP and isoproterenol stimulation (wherein “GFP-AIP” comprises the AIP sequence of instant SEQ ID NO: 14 and is understood to have the sequence as shown at Fig. 6H to be CTnT-GFP-YKKALHRQEAVDCL, as detailed at 53-53 of the Specification).
Examiner notes that instant claims 8-11, 20, 27, 29-30, 31, 36, and 37 do not reasonably appear to read upon the originally elected species because (i) these claims depend directly or indirectly from independent claims 8 and 10, and (ii) independent claims 8 and 10 were amended in the Reply filed 3/30/2026 to require a mutation that was not present in the originally elected species. As consistently noted on the record, and not previously challenged by Applicant, the originally elected species is characterized by a single R4561I mutation, but the amended claims require additional mutations to be present3. Similarly, newly added claims 33-34 recite novel limitations that were not present in the originally elected species. Accordingly, claims 8-11, 20, 27, 29-30, 31, 33-34, 36, and 37 are understood to be directed to a different patient population, methodology, and species distinct from the originally elected species. Therefore, such claims would have been properly withdrawn as directed to non-elected species if presented earlier in prosecution.
Newly added claims 32 and 35 are understood to read upon the originally elected species4. In addition, newly added claims 32 and 35 continue reading upon the non-elected species previously examined and deemed obvious for reasons of record in the Actions mailed 2/22/2024, 10/07/2024, and 7/02/2025.
The originally elected species was previously deemed free of the prior art in the Action mailed 9/12/2022. Per MPEP § 803.02, examination was previously extended in the Action mailed 9/12/2022 to the non-elected species of method of administering KN-93 as disclosed by Liu et al. (see, e.g., Action mailed 9/12/2022). A brief summary of the prosecution history is provided below:
In the Reply filed 2/13/2023, Applicant amended the claims to exclude the previously examined non-elected species. Per MPEP § 803.02, examination was extended to the non-elected species of RyR2R4496C+/- mice (i.e., a CPVT mouse model) being administered a vector encoding the CaMKII peptide inhibitor of AIP in a manner sufficient to prevent ventricular tachycardia (see, e.g., Action mailed 4/18/2023).
Subsequently, in the Reply filed 2/06/2024, Applicant amended the claims to exclude the previously examined non-elected species by requiring an AAV vector and a promoter “suitable for” mammalian cardiac cells; per MPEP § 803.02, examination was extended to the non-elected narrow subgenus of species of RyR2R4496C+/- mice (i.e., a CPVT mouse model) being administered an AAV vector (e.g., AAV1, AAV6, AAV8, AAV9) encoding the CaMKII peptide inhibitor of AIP, wherein the AAV vector comprises a cardiac-specific promoter (e.g., MLC-2v or cTnT) (see, e.g., Action mailed 2/22/2024), which were deemed obvious in view of the prior art as applied below in the Action mailed 2/22/2024.
The amendments filed 7/22/2024 to claims 8-10 did not exclude the previously examined species of claimed embodiment, and therefore examination was not further extended in the Action mailed 10/07/2024.
The amendments filed 2/04/2025 did not exclude the previously examined species from the scope of amended, independent claims 8 and 10, and therefore examination was not further extended in the Action mailed 7/02/2025.
The amendments filed 3/30/2026 amended claims 8-11, 20, 27, and 29-30 in a manner that excluded both the previously examined species and the originally elected species (see explanation above). However, the amendments filed 3/30/2026 added new claims 32 and 35, which read upon both the originally elected species and also the previously examined species identified in the Action mailed 2/22/2024. Accordingly, claims 8-11, 20, 27, and 29-30 are withdrawn, and newly added claims 32 and 35 have been examined in view of the previously examined species of record, which has again been deemed obvious.
Per MPEP § 803.02, examination has not been extended unnecessarily to cover all nonelected species. Accordingly, the previously examined non-elected species is understood to continue to read upon newly added claims 32 and 35, and the non-elected species has again been deemed obvious.
Claims 8-11, 20, 27, 29-30, 31, 33-34, 36, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/4/2022.
Per MPEP § 803.02(III)(A), unless otherwise explicitly identified, examination has not been extended to additional non-elected species at this time.
Claims 32 and 35 are presently considered.
Denial of Priority
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, US Application 62/529,256 (filed 7/0/2017) fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The MPEP states that "[w]hile there is no in haec verba requirment, . . . . claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP § 2163.
Lack of Express Support
Claims 32 and 35 are representative of the pending claim scopes, and these newly added claims continue to recite and encompass subject matter that has previously been identified on record as not literally supported by the provisional. For example, the term “AAV” at newly added claim 32 and 35 is utilized to refer to a genus encompassing AAV6, AAV2i8, Anc80, and Anc82, which continue to lack literal support in the Pro’256. Accordingly, Pro’256 fails to provide literal support for the pending claim scope that is synonymous or equivalent in scope.
Lack of Implicit or Inherent Support
The MPEP states that "[w]hile there is no in haec verba requirment, . . . . claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP § 2163. In the absence of express support, the relevant issue is whether or not the claimed invention is supported by Pro’231 through implicit or inherent disclosures.
Upon review, zero inherent or implicit support commensurate in scope with the metes and bounds of the examined claims is found in Pro’256, at least because zero disclosures pertaining to methods of treatment of patients using AV6, AAV2i8, Anc80, and or Anc82 vectors appear on record commensurate in scope with the pending claims. According, the claim language presently claimed is not supported by the provisional document by synonymous or equivalent language.
Accordingly, Pro’256 fails to provide implicit or inherent support for the pending claim scope that synonymous or equivalent in scope, or otherwise commensurate in scope with the pending claims.
Conclusion
Accordingly, priority to US Application 62/529,256 (filed 7/0/2017) is denied for claims 32 and 35. Therefore, all currently examined claims have been accorded a priority date of 7/06/2018, which corresponds to the filing date of PCT/US18/41043 (filed 7/06/2018).
Information Disclosure Statement
The IDS filed 3/30/3026 is acknowledged.
Claim Interpretation and Examiner Notes
The claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Newly added claim 32 is representative of the pending claim scope, and currently recites:
32. (New) A method for treating, ameliorating, or reducing cardiac arrhythmia or catecholaminergic polymorphic ventricular tachycardia (CPVT) in a subject, the method comprising:
administering to a subject in need thereof an adeno-associated virus (AAV) vector comprising a polynucleotide encoding autocamtide-2-related inhibitory peptide (AIP) operably linked to a cardiac cell-specific promoter which targets expression of the AIP peptide inhibitor in a cardiac cell of the subject, wherein the cardiac cell in the subject comprises a mutated cardiac ryanodine channel (RYR2), and wherein expression of the AIP in the cardiac cell treats, ameliorates, or reduces the cardiac arrhythmia or CPVT in the subject.
The applicable claim interpretation is discussed below.
Regarding the transition statement: “Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
Regarding the preamble “for treating, ameliorating, or reducing cardiac arrhythmia or catecholaminergic polymorphic ventricular tachycardia (CPVT) in a subject”, the preamble is interpreted in view of MPEP §§ 2111, 2111.01(I)-(III), and 2111.02. Here, the preamble is understood to recite a purpose or intended use, fully satisfied by the positively recited steps set forth in the body of claim 32. Per MPEP § 2111.02(II), the preamble is deemed fully satisfied by any prior art method wherein a subject (e.g. any mammal) having a mutated RYR2 gene is administered (via any route) an AVV vector encoding AIP operably linked to a cardiac-specific promoter capable of expressing AIP in cardiac cells (see, e.g., instant claim 32).
Regarding the patient population: “Subject” is each understood to include animals and humans (see, e.g., Spec. filed 1/2/2020 at 14 at lines 23-34).
Regarding the CaMKII inhibitor being administered: “Autocamtide-2-related inhibitory peptide (AIP)” is understood to be a CaMKII peptide inhibitor, and is understood to read upon any prior art peptide sequence identified as AIP or Autocamtide-2-related inhibitory peptide.
Regarding the vector: “Adeno-associated virus (AAV) vector” as used at claim 32 is understood to be a genus of AAV vectors broader than the genus of AAV vectors set forth at dependent claim 35 (e.g., claim 35 is presumed to satisfy 35 USC §112(d)). Therefore, “AAV” at claim 32 is understood to read upon at least AAV6, AAV9, AAV2i8, Anc80, and Anc82, as recited at dependent claim 35.
Regarding the promoter: Newly added claim 32 recites a functionally defined promoter, namely a “cardiac cell-specific promoter” capable of “target[ing] expression of the AIP peptide inhibitor in a cardiac cell of the subject”. The only “promoters for cardiac muscle cell-specific expression” identified on record are the “cardiac troponin T promoter, the α-myosin heavy chain (α-MHC) promoter, the myosin light chain-2v (MLC-2v) promoter” and “the cardiac NCX1 promoter” (see, e.g., Spec. filed 1/02/2020 at 26 at lines 27-32, 35 at line 30 to p. 36 at line 4). However, as previously addressed earlier in prosecution, α-myosin heavy chain (α-MHC) promoter is not suitable for use with AAV vectors and is not enabled for reasons of record (see, e.g., Action mailed 2/22/2024 at 15-19). Accordingly, it is reasonably inferred that the functionally defined genus of promoters encompasses cardiac troponin T promoter (“cTnT”), the myosin light chain-2v (MLC-2v) promoter, and the cardiac NCX1 promoter.
“Cardiac troponin T promoter” may be written as “cTnT” (see, e.g., Spec. filed 1/02/2020 at 26 at lines 27-32, 35 at line 30 to p. 36 at line 4, p. 58 at lines 10-15), but is not associated with any sequence listing or NCBI number of record. For applying prior art, any prior art promoter identified as “cardiac troponin T promoter” or “cTnT” is understood to satisfy the element.
“Myosin light chain-2v promoter” may be written as “MLC-2v” (see, e.g., Spec. filed 1/02/2020 at 26 at lines 27-32, 35 at line 30 to p. 36 at line 4, p. 58 at lines 10-15), but is not associated with any sequence listing or NCBI number of record. For applying prior art, any prior art promoter identified as “Myosin light chain-2v promoter” or “MLC-2v” is understood to satisfy the element.
“Cardiac NCX1 promoter” may be written as “NCX1” (see, e.g., Spec. filed 1/02/2020 at 26 at lines 27-32, 35 at line 30 to p. 36 at line 4, p. 58 at lines 10-15), but is not associated with any sequence listing or NCBI number of record. For applying prior art, any prior art promoter identified as “NCX1” is understood to satisfy the element.
Accordingly, the phrase “a cardiac cell-specific promoter which targets expression of the AIP peptide inhibitor in a cardiac cell of the subject” is understood to be satisfied by any art-recognized cardiac troponin T promoter (“cTnT”), myosin light chain-2v (MLC-2v) promoter, or cardiac NCX1 promoter.
Regarding recitations of intended and expected results: Newly added claim 32 recites “wherein expression of the AIP in the cardiac cell treats, ameliorates, or reduces the cardiac arrhythmia or CPVT in the subject”, which is understood to recite intended or expected results that are necessarily satisfied by the performance of the positively recited steps set forth in the body of independent claim 325.
Additional claim interpretations are set forth below.
Maintained and Revised Rejection, as Necessitated by Applicant Amendments
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 32 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al.6 in view of US 2010/0285033 A17, Cuello et al.8, and Tilemann et al.9.
Claim interpretation: The applicable claim interpretation has been set forth above in a separate section, and those interpretations are incorporated herein. Additional claim interpretations are discussed below.
Regarding the general treatment of CPVT using a CaMKII inhibitor, and claims 32 and 35, Liu identifies that Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor gene (RyR2), and subsequently demonstrates that
“CaMKII inhibition with [a CaMKII inhibitor] completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2R4496C+/- mice”,
and concludes that
“CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT”
(see, e.g., Liu at title, abs; see also id. at 215 at col I at 1st partial ¶, 215-216 at §§ 3.1 CaMKII Inhibition prevents ventricular tachycardia in RyR2R4496C+/- mice). Therefore, the prior art provides guidance regarding the treatment of CPVT using “CaMKII inhibition”. Regarding cardiac ryanodine channels, mutations and modulations “associated with a cardiac arrhythmia”, and instant claims 32 and 35, Liu discloses and reduces to practice a method of treating subjects (i.e., RyR2R4496C+/- mice) having a mutation associated with cardiac arrhythmia (i.e., RyR2R4496C+/-10), by administering a CaMKII inhibitor to the subjects, wherein such CaMKII inhibitor is reasonably inferred to inhibit the phosphorylation of RyR2 by CaMKII (see, e.g., Liu at 214 at col II at 1st and 2nd ¶¶, 219 at §§ 3.8), and wherein the CaMKII inhibitor is administered to the mice (see Liu at 215-216 at §§ 3.1; see also id. at 215 at col I at 1st partial ¶, abs). Liu explicitly discloses that CaMKII inhibition prevents ventricular tachycardia in RyR2R4496C+/- mice (see, e.g., Liu at abs, 219 at §§ 3.8; see also id. at 215 at col I at 1st partial ¶, 221 at col II at §§ 4.4). Liu explicitly identifies that the model system utilized (i.e., RyR2R4496C+/- mice), is a “CPVT mouse model” (see, e.g., Liu at title, 221 at col II at §§ 4.4; see also id. at abs, explaining that CPVT is caused by mutations in RyR2). Regarding new claims 32, 35, and targeting a cardiac cell, such as a cardiomyocyte, Liu identifies that the disclosed tests targeted ventricular myocytes (see, e.g., Liu at 215 at §§2.1-2.3) and cardiac myocytes (see, e.g., Liu at 215 at §§2.4-2.5), and therefore all references to myocytes within Liu would be readily understood by artisans to refer to and pertain specifically to cardiac myocytes (see, e.g., Liu at 215-216 at §§ 3.1-3.4, 220 at Fig. 6, 221 at § 4.4; see also id. at 215 at col I at 1st partial ¶, abs). In summary, an artisan would readily infer that the mouse model was representative of CPVT in humans and other subjects and would readily appreciate that “CaMKII inhibition prevents ventricular tachycardia” in a subject with CPVT (see, e.g., Liu at title, abs, 215-216 at §§ 3.1, 221 at col II at §§ 4.4).
The primary reference differs from the instantly claimed invention as follows: Liu does not reduce to practice the administration to a subject of an adeno-associated virus (AAV) vector, such as AAV9, encoding the CaMKII inhibitor of AIP operably linked to an MLC-2v or cTnT promoter. Stated alternatively, although Liu does suggest administering the CaMKII inhibitor of AIP to subjects for the treatment of CPVT, Liu does not specifically teach administering AIP to subjects by specifically using an AAV delivery system designed for expression in mammalian cardiac cells.
The CaMKII inhibitor of AIP is a prior art element: Liu explicitly discloses AIP as a CaMKII inhibitor (see, e.g., Liu at abs, 215 at §2.3, Fig. 1 on 216, 216 at §§ 3.2-3.4), and therefore AIP is a prior art element that is known and art-recognized specifically as a CaMKII inhibitor (see id). In view of Liu, the use of any CaMKII inhibitor, including AIP, to treat or prevent arrhythmias in subjects with CPVT and having mutations in RyR2 would be obvious, because Liu explicitly teaches the general proposition that “CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT” (see, e.g., Liu at abs, 221 at § 4.4). Per MPEP § 2144.07(II), it is obvious to substitute art-recognized equivalents for the same purpose, and therefore the simple substitution of AIP in place of another CaMKII inhibitor does not render the claim scope non-obvious11.
The predicted and expected result of administering a CaMKII inhibitor to treat patients having CPTV was explicitly disclosed and taught in the prior art: Liu demonstrated that “CaMKII inhibition with [a CaMKII inhibitor] completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2R4496C+/- mice”, and concludes that “CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT”(see, e.g., Liu at title, abs; see also id. at 215 at col I at 1st partial ¶, 215-216 at §§ 3.1 CaMKII Inhibition prevents ventricular tachycardia in RyR2R4496C+/- mice). Accordingly, Liu provides a proof of principle that a CaMKII inhibitor “prevents ventricular tachycardia” in a CPVT mouse model with a RyR2 mutation (see, e.g., Liu at title, abs, 215-216 at §§ 3.1, 221 at col II at §§ 4.4), and Liu subsequently provides direct guidance and motivation to artisans by identifying that the broader class of “CaMKII inhibition” is “a promising therapeutic strategy for CPVT”, and that “CaMKII inhibition might be a novel target for the antiarrhythmic treatment of CPVT patients” (see, e.g., Liu at 221 at col II at §§ 4.4; see also id. at title, abs). Accordingly, an artisan would readily conclude that other CaMKII inhibitors capable of performing “CaMKII inhibition” would also provide “a promising therapeutic strategy for CPVT” (see, e.g., Liu at 221 at col II at §§ 4.4; see also id. at title, abs). Therefore, an artisan would readily appreciate, in view of Liu, that CaMKII inhibitors (including AIP) could be predictably and expectedly12 utilized to successfully treat CPVT13.
The use of gene therapy vectors for the delivery of CaMKII peptide inhibitors was already known, disclosed, and fully enabled in view of the prior art: US2010/0285033A1 teaches and discloses existing methods and practices utilized with CaMKII inhibitors (see, e.g., US’033 at title, abs, ¶¶[0002], [0005]-[0010], [0043], [0045]-[0047], [0049], [0050], [0058], [0107], [0130], claims 22-23). US’033, like Liu, explicitly identifies that autocamtide-2 related inhibitory peptide (“AIP”) is an art-recognized CaMKII inhibitor (see, e.g., US’033 at ¶¶[0005], [0043]), and therefore an artisan would readily appreciate that the disclosure of US’033 was applicable to AIP. US’033 specifically identifies that, circa 2010, such CaMKII peptide inhibitors could be administered using various delivery systems (see, e.g., US’033 at ¶[0006], [0086]), including aqueous compositions of gene therapy vectors “expressing any of the foregoing” CaMKII peptide inhibitors (see, e.g., US’033 at ¶¶[0086]), wherein such compositions explicitly include pharmaceutically acceptable carriers or aqueous mediums (see, e.g., id.; compare id. with instant claims 32 and 35). Therefore, delivery of CaMKII peptide inhibitors, such as AIP, via gene therapy vectors to patients is presumed fully enabled absent objective evidence to the contrary (see, e.g., MPEP § 2121(I); see, e.g., MPEP §§ 2123(I)-(II)).
An artisan attempting to make predictable variations of the Liu methodology of treating CPVT by administering CaMKII inhibitors would reasonably review the existing prior art applicable to CaMKII inhibitors and the usage of CaMKII inhibitors in heart tissue. Cuello, published circa 2016, discloses the state of the prior art for CaMKII inhibitors used in the treatment of heart disease (see, e.g., Cuello at title, abs, passim). Cuello acknowledges that “Proof-of-concept studies in mice and isolated human cardiac myocytes have successfully demonstrated the benefit of [CaMKII inhibitors] in several pathological cardiac conditions” (see, e.g., Cuello at 66 at col I at 1st partial ¶), and notes that
CaMKII targeting strategies have to take cardiac and isoform specificity into account. In this context, the establishment of a gene therapy approach seems “easier” than the development of pharmacological inhibitors. Also, gene therapy studies in large animals or even patients have already been tested . . .
(see, e.g., Cuello at 66 at col I at 1st partial ¶)
Accordingly, Cuello reasonably identifies that one of ordinary skill in the CaMKII inhibitor arts attempting to treat cardiac diseases circa 2016 would reasonably utilize “a gene therapy approach”. Cuello identifies “[d]ifficult hurdles that have to be envisaged” in order “to ultimately achieve clinical translatability”, and identifies the criticality of “appropriate cardiac-specific gene therapy approaches for the expression of inhibitory peptides” (see, e.g., Cuello at 66 at col I at 1st full ¶). Accordingly, Cuello identifies that although difficulties existed in human clinical settings, that “a gene therapy approach” was art-recognized as “easier” and that artisans circa 2016 readily appreciated that such gene therapy approaches required an “appropriate cardiac-specific gene therapy” (see, e.g., Cuello at 66 at col I at 1st partial ¶ to 66 at col II at 1st full ¶).
An artisan designing a “cardiac-specific gene therapy approach[]” as suggested by Cuello, would review the prior art for viable “cardiac-specific gene therapy” designs, including established Vector systems: Tilemann identifies “strategies for the treatment of heart failure by gene transfer” (see, e.g., Tilemann at title, abs, 777 at col I at 3rd ¶). Specifically, Tilemann identifies that adeno-associated viruses (AAVs) were well-known in the art, and have a “beneficial safety profile” (see, e.g., Tilemann at 778 at col II at § AAV Vectors in Cardiovascular Gene Transfer), have “low immunogenicity when compared with most other viral vectors” (see id), are “[n]onpathogenic” (see, e.g., Tilemann at Table 1 on 778), have “efficient cardiomyocyte transduction” (see id), and exhibit “persistent gene expression” (see id.). Tilemann specifically identifies that hundreds of AAV variants are known, but notes that some AAV serotypes exhibit “serotype-specific tissue and cell tropism” (see, e.g., Tilemann at 779 at col I at § Tropism of AAV Serotypes, Table 2 at 780). Tilemann explicitly identifies that
AAV1, AAV6, AAV8, and AAV9 show strong cardiac transduction, with AAV9 appearing to be the most cardiotropic. . .in rodents. . . in Rhesus Macaques AAV6 is superior . . .AAV1 can successfully transduce human cardiac tissue.
(see, e.g., Tilemann at 779 at col I at 1st full ¶, emphasis added).
Accordingly, an artisan attempting to design a gene therapy approach for delivering a CaMKII inhibitor, such as AIP, would select an appropriate AAV vector for the specific mammal being treated and for the specific delivery route (see, e.g., Tilemann at 779 at col I at 1st full ¶, Table 2 on 780, noting that AAV vector selection depends on delivery route and organism14). Accordingly, the usage of AAV vectors for cardiac-tissue specific gene therapy approaches would have been obvious because such approaches were art-recognized circa 2012, and were recognized as having numerous benefits (see, e.g., Tilemann at 778 at col II at § AAV Vectors, Table 1 on 778). Furthermore, AAV vectors did not have the drawbacks attributed for other vector systems and were appropriate for short sequences (see, e.g., Tilemann at Table 1 on 77815)
An artisan designing a “cardiac-specific gene therapy approach[]” as suggested by Cuello, would review the prior art for viable “cardiac-specific gene therapy” designs, including established cardiac specific promoters: Tilemann identifies an art-recognized problem, circa 2012, namely
…AAV vectors that do not transduce noncardiac tissues to some extent are thus far unavailable.
(see, e.g., Tilemann at 779 at col II at final ¶).
However, Tilemann identifies an art-recognized solution, known circa 2012, namely the usage of an “alternative and complementary approach to restrict transgene expression to the heart”, namely the usage of “cardiac specific promoters” (see, e.g., Tilemann at 780 at col I at 1st partial ¶). Tilemann explicitly identifies art-recognized cardiac-specific promoters suitable for use in AAV vectors, including “Myosin Light Chain-2 (MLC-2v) promoter” (a.k.a., MLC-2v promoter) (see, e.g., Tilemann at 780 at col I-II at bridging ¶, 781 at col I at 1st partial ¶) and the “cardiac Troponin T promoter” (a.k.a., cTnT promoter) (see, e.g., id; compare id with instant claims 21-23). Accordingly, an artisan designing a cardiac-specific AAV would reasonably utilize a cardiac-specific promoter such as MLC-2v or cTnT in order to predictably enhance cardiac-tissue specificity of the AAV-based gene therapy.
In summary, regarding the delivery of a CaMKII inhibitor peptide such as AIP using a gene therapy vector, in view of US’033, Cuello, and Tilemann, an artisan would readily appreciate that the CaMKII inhibitor peptides disclosed by Liu (i.e., AIP and KN-93) could be delivered using gene therapy techniques16, wherein an artisan would be reasonably directed to utilize an AAV serotype having a cardiac tropism, such as AAV1, AAV6, AAV8, or AAV917 (depending upon delivery route and mammal treated), and would further utilize such AAV vector with a cardiac-specific promoter (e.g., MLC-2v or cTnT), wherein such gene therapy vector would desirably and predictably have “efficient cardiomyocyte transduction, persistent gene expression, [and] low immunogenicity”18, and would successfully express a CaMKII inhibitor peptide (e.g., AIP) in cardiac cells with high specificity; the simple substitution of delivery of a CaMKII inhibitor using a cardiac-specific gene therapy approach in the prior art methods disclosed by Liu would predictably and expectedly yield a modified method of treating subjects in need thereof (e.g, RyR2R4496C+/- mice) having a mutation associated with cardiac arrhythmia (e.g., RyR2R4496C+/-19), wherein the CaMKII inhibitor so administered to subjects would predictably and expectedly treat CPVT as taught and suggested by Liu, because the expressed CaMKII inhibitor (e.g., AIP) would be reasonably inferred to inhibit the phosphorylation of RyR2 by CaMKII, as identified by Liu (see, e.g., Liu at 214 at col II at 1st and 2nd ¶¶, 219 at §§ 3.8). Accordingly, an artisan would readily appreciate that the methods taught and suggested by Liu could be modified to utilize cardiac-specific gene therapy approaches known in the prior art to achieve the same results disclosed and attributed by Liu to peptide CaMKII inhibitors.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reasons:
First, the claimed invention is the combination of prior art elements (i.e., CaMKII peptide inhibitors such as AIP, known AAV vectors with cardiac tropisms, known promoters with cardiac specificity) according to known methods (i.e., the methods of treating subjects with CPVT and RyR2 mutations by delivering peptide CaMKII inhibitors to cardiac cells as taught and suggested by Liu), using known peptide delivery methods (i.e., gene therapy vector approaches as taught by US’033, Cuello, and Tilemann) to yield predictable results, namely the treatment (or prevention) of ventricular tachycardia as taught and suggested by Liu; furthermore each component would merely perform its art-recognized function in combination as it does separately (see, e.g., MPEP § 2143(I)(A), (G)).
Second, the claimed invention is the simple substitution of one known CaMKII inhibitor (i.e., KN-93) and one known delivery method in the method of Liu for another art-recognized CaMKII peptide inhibitor (e.g., AIP) and another art-recognized delivery means available to peptides (i.e., gene therapy vectors approaches as taught by US’033, Cuello, and Tilemann), wherein such simple substitutions would yield predictable results, namely the treatment (or prevention) of ventricular tachycardia as taught and suggested by Liu (see, e.g., MPEP § 2143(I)(B), (G)).
Third, Liu provides direct guidance and motivation to artisans to utilize CaMKII inhibitors in the treatment of CPVT patients, because Liu identifies that CaMKII inhibition” is “a promising therapeutic strategy for CPVT”, and that “CaMKII inhibition might be a novel target for the antiarrhythmic treatment of CPVT patients”; accordingly such guidance would reasonably prompt artisans in the CPVT treatment field to make variations of the proof-of-principle taught by Liu as necessary to move such treatment to clinical usage in humans as is typical in the pharmaceutical industry, including variations using different CPVT subjects (or model systems), variations using different peptide CaMKII inhibitors known in the art (e.g., AIP), and variations using different delivery systems known in the art (i.e., gene therapy vector approaches as taught by US’033, Cuello, and Tilemann), wherein such variations would be predictable to one of ordinary skill in the art, and would be expected to treat (or prevent) ventricular tachycardia in such subjects exactly as taught and suggested by Liu (see, e.g., MPEP § 2143(I)(F), (G)).
Each component would merely perform its art-recognized function in combination as it does separately.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to follow a known method, of treating a known disease having a known cause in a known patient population, using a known class of drug, by administering such known drugs to the known patient population via a known means of administration in order to achieve a known and expected result that was explicitly predicted and taught by the prior art. More specifically, the use of known prior art vectors known to have cardiac tissue tropisms (e.g., AAV1, AAV6, AAV8, or AAV9) in combination with known prior art cardiac-specific promoters (e.g., MLC-2v or cTnT), would predictably yield an AAV gene therapy vector having high cardiac-tissue specificity exactly as taught and disclosed by the prior art.
To date, no evidence unexpected results commensurate in scope with the requirements of MPEP § 716.02 have been placed on record. To date, no evidence of inoperability of references commensurate in scope with the requirements of MPEP § 716.07 have been placed on record. To date, no evidence of commercial success commensurate in scope with the requirements of MPEP § 716.03 have been placed on record. To date, no evidence of long-felt need and failure of others commensurate in scope with the requirements of MPEP § 716.04 has been placed on record. To date, no evidence of skepticism commensurate in scope with the requirements of MPEP § 716.05 has been placed on record.
Accordingly, claims 32 and 35 are rejected as obvious.
Response to Arguments
Applicant's arguments filed 3/30/2026 have been fully considered but not found persuasive for reasons previously set forth on record in the Action mailed 7/02/2025 (see, e.g., Action mailed 7/02/2025 at pages 24-36), and the Examiner’s prior responses are fully incorporated herein. Examiner notes that numerous arguments have been rendered moot in view of the withdrawal of claims directed to non-elected species following the amendments filed 3/30/2026. Remaining arguments are addressed below.
Prior issues of record have not been clarified: Examiner previously noted that Applicant inadvertently mischaracterized the record regarding the reference of Barth20 and the Examiner’s position regarding the phrase “cardiac specific” as used in the art and by the instant Declarant (see, e.g., Reply filed 7/22/2024 at 6 at 4th ¶). The Examiner’s analysis of the term “cardiac specific” in the prior rejection under 35 USC 112(a) and 112(b) established that the instant Declarant’s own prior characterization was inconsistent with the usage of “cardiac specific” in the art as evidenced by the prior art references of Barth and Werfel21 (see, e.g., Affidavit filed 2/06/2024 at ¶6, noting that the Declarant’s interpretation of “suitable for” to imply absolute “cardiac-specificity” and capability to “prevent inhibition in off targets”; see Action mailed 2/22/2024 at 12-14). In sum, the Examiner’s position of record was that the Declarant’s apparent position was inconsistent with the prior art as evidenced by the prior art the Examiner placed on record. Although the amendments filed 7/22/2024 successfully addressed the prior issues under 35 USC 112(a) and 112(b), Applicant has not clarified their prior statements or the identification that such statements mischaracterized the record. In the absence of clarification, the Examiner’s position is presently undisputed.
Priority remains denied for reasons set forth above: Applicant traverses the prior denial of priority to US Provisional 62/529,256 (filed July 6, 2017) (see, e.g., Reply filed 3/30/2026 at § “Priority Claim” on pages 5-6). The traversal has been reviewed and fully considered (see, e.g., Reply filed 3/30/2026 at § “Priority Claim” on pages 5-6). It is the Examiner’s understanding that Applicant is alleging that the issue is resolved because the unsupported subjected matter (e.g., AAV6, AAV2i8, Anc80, and Anc82 vectors) was moved from an independent claim to a dependent claim. This does not rectify the issue because the pending claims continue to explicitly recite unsupported subject matter (e.g., AAV6, AAV2i8, Anc80, and Anc82 vectors), including the independent claim because “AAV” in the independent claim is not equivalent or synonymous to “AAV” as used in the provisional. Rather, the independent claims utilize “AAV” to define a genus of vectors explicitly including unsupported subject matter (e.g., AAV6, AAV2i8, Anc80, and Anc82 vectors), since the independent claim is broader than the dependent claim, and the dependent claim is presumed to satisfy the requirements of 35 USC §112(d). Accordingly, priority to US Provisional 62/529,256 (filed July 6, 2017) continues to be denied because the pending claim scope continues to read upon and encompass subject matter that was not literally, inherently, or implicitly disclosed by the priority document.
Applicable case law regarding Obviousness: Examiner notes that Applicant mischaracterized the relevant case law22, namely KSR, by alleging that
“…a cited reference must provide an explicit, apparent reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does (KSR Int’l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1731, 1741 (2007)….”
(see, e.g., Reply filed 2/04/2025 at 8 at final ¶).
This statement is incorrect and does not reflect the disclosure of the case cited. To the contrary, KSR literally identifies that test (i.e., TSM) requiring an “explicit” disclosure are not required:
The diversity of inventive pursuits and of modern technology counsels against confining the obviousness analysis by a formalistic conception of the words teaching, suggestion, and motivation, or by overemphasizing the importance of published articles and the explicit content of issued patents. . . . Granting patent protection to advances that would occur in the ordinary course without real innovation retards progress and may, for patents combining previously known elements, deprive prior inventions of their value or utility. . . . [A] court errs where, as here, it transforms general principle into a rigid rule limiting the obviousness inquiry23
Helpful insights, however, need not become rigid and mandatory formulas; and when it is so applied, the TSM test is incompatible with our precedents. The obviousness analysis cannot be confined by a formalistic conception of the words teaching, suggestion, and motivation, or by overemphasis on the importance of published articles and the explicit content of issued patents24
Accordingly, the Applicant’s mischaracterization of the holding of KSR is not accurate, credible, or persuasive. Per MPEP § 2143,
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious.
Consistent with the legal requirements and explicitly disclosed rationales capable of supporting a determination of obviousness as set forth in the MPEP, the instantly claimed invention has been rejected for explicitly recited and identified rationales supported by MPEP§§ 2143(I)(A)-(B), (F), and (G). Examiner has previously addressed the same or similar issues on record (see Action mailed 7/02/2025 at 25 at 1st full ¶; see also Action mailed 10/07/2024 at 22 at 1st full ¶; see also Action mailed 2/22/2024 at 30 at final ¶ to page 34 at 1st partial ¶). Examiner notes that Applicant does not dispute the Examiner’s prior position of record that the Applicant’s prior quotation of In re Kubin25 was taken out of context and erroneously relied upon to imply a non-existent and higher standard for establishing obviousness, which was a conclusion directly contradicted by the clear guidance of the MPEP (see, e.g., Action mailed 2/22/2024 at 30-34). Accordingly, mischaracterizations of the holdings of cases or the citation of cases without clear application of the holdings to the facts of the instant case are not persuasive to rebut prima facie obviousness. Here, the Examiner’s position is that a determination of obviousness may be made using any of the exemplary rationales set forth in the MPEP at §§ 2143(I) and 2144.
Prima facie obviousness has been established: It is the Examiner’s understanding that Applicant generally alleges, repeatedly and using different arguments, that the rejection does not render the claimed invention obvious due to lack of motivation to combine the known elements in the manner presently claimed, or otherwise that the rejection does not establish prima facie obviousness (see, e.g., Reply filed 3/30/2026 at 7 at 2nd full ¶, 12 at 1st full ¶, 20 at final ¶, 22 at 1st partial ¶, 23 at 1st partial ¶ to 1st full ¶, 25 at 1st full ¶, 25 at final ¶ to 27 at 1st full ¶). In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the Examiner has set forth multiple, explicit rationales supporting a determination of obviousness, including rationales under MPEP §§ 2143(I)(A), (B), (F), and (G). Here, all claimed structures were known in the art and are merely utilized in the claim to achieve their art-recognized function (e.g., AIP acts as a CaMKII inhibitor, the cardiac-specific promoters of cTnT and MLC-2v act as cardiac-specific promoters; AVV acts as a vector for gene therapy and protein delivery), and the general method of treating CPVT by administering a CaMKII inhibitor was already known and disclosed by the primary reference. Accordingly, the Examiner’s position is that it is obvious to use known prior art elements according to their known functions to achieve a known result; here, the claim scope is directed to the treatment of a known patient population with a known disease by administering a known compound encoded by a known AAV vector with a known cardiac-specific promoter, to achieve the exact outcome taught and suggested by the prior art (e.g., treatment of CPVT). Per KSR, all that is needed to sustain a determination of obviousness is:
A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007).
"[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976)).
Accordingly, here all components were known in the prior art, the function of each component was known in the prior art, the outcome of administering CaMKII inhibitors to subjects with CPVT were known, and one of skill in the art could combine such known components, and such combination yields “no more than one would expect from such an arrangement”. The Court has also stated that
“If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.”
KSR Int'l v. Teleflex Inc., 550 U.S. 398, 415 (2007), at 417.
Here, the claim is directed to a “predictable variation” of the treatment explicitly taught and disclosed by the primary reference because the claim is directed to the same treatment utilizing another CaMKII inhibitor delivered via a known means (e.g., known AAV vector with a known cardiac-specific promoter), and each component merely performs the exact function disclosed in the prior art. Accordingly, all proffered arguments alleging that a case of prima facie obviousness was not established have been fully considered but not found persuasive.
Reiterated arguments: Examiner notes that multiple arguments of record have been repeated or simply rephrased, but have been addressed previously on record and not found persuasive for reasons of record. Accordingly, the Examiner’s previous responses of record remain pertinent and are incorporated herein (see, e.g., Action mailed 7/02/2025 at pages 24-36; see also Action mailed 2/22/2024 at pages 30-44 and 44-57; see also Action mailed 10/07/2024 at pages 21-28).
All elements and features of the claimed invention were explicitly addressed, taught, and known in the prior art: Applicant generically alleges that the cited combination “does not teach or suggest all of the features and elements in applicant’s claims considered as a whole” (see, e.g., Reply filed 3/30/2026 at 7 at 2nd ¶), but Applicant fails to identify even a single structure or element that was not already taught and disclosed in the prior art (e.g., AIP was already known and merely acts as a CaMKII inhibitor, the cardiac-specific promoters of cTnT and MLC-2v were already known and merely act as cardiac-specific promoters; AVV vectors were already known and merely perform their art-recognized function for gene therapy and protein delivery; the use of CaMKII inhibitors to treat CPVT was already disclosed by the prior art; patients in need of treatment for CPVT were already known in the prior art). Accordingly, in the absence of any identification of any claimed element that was not addressed in the rejection and already known in the prior art, such arguments are conclusory in nature and not supported by objective evidence.
Proffered experimental evidence in the Declaration does not rebut prima facie obviousness because such evidence did not exist before the effective filing date of the claimed invention: It is the Examiner’s understanding that Applicant attempts to rebut a determination of prima facie obviousness based upon post-filed evidence (see, e.g., Reply filed 3/30/2026 at 10-11 at bridging ¶, 13 at 1st full ¶ to 19 at 2nd full ¶). This evidence and allegations have been fully considered, but not found persuasive because such arguments improperly rely upon improper hindsight; as explained at MPEP § 2143.02(III), prima facie obviousness depends upon a determination of obviousness in view of the prior art before the effective filing date of the claimed invention. Here, all assertions and conclusions alleging that prima facie obviousness circa July 2017 could not (or did not) exist because of post-filed evidence submitted years later (e.g., in 2026) is not persuasive to establish that a prima facie determination of obviousness was not properly made. However, such post-filed evidence may be utilized to establish the existence of secondary considerations sufficient to rebut a proper determination of prima facie obviousness (see, e.g., MPEP § 716). Accordingly, prima facie obviousness was properly established on record for explicitly recited and identified rationales under MPEP§§ 2143(I)(A)-(B), (F), and (G), as set forth in the rejection. As noted above, there is a reasonable expectation of success at the relevant time because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses, teaches, and reasonably suggests to artisans (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well within the ordinary skill in the art to follow a known method, of treating a known disease having a known cause in a known patient population, using a known class of drug (e.g., CaMKII inhibitor), by administering such known drugs to the known patient population via a known means of administration in order to achieve a known and expected result that was already predicted and explicitly expected by the prior art.
The prior art is not limited to only explicitly exemplified embodiments: It is the Examiner’s understanding that Applicant and Declarant attempts to rebut prima facie obviousness by narrowly interpreting the disclosure of Liu and alleging that it is only applicable for embodiments explicitly reduced to practice (see, e.g., Reply filed 3/30/2026 at 8 at 1st full ¶ to page 9 at last full ¶, suggesting that Liu is limited to a bolus injection of the CaMKII inhibitor of KN-92, and only discloses in vitro treatments of RYR2R4496+/- ventricular myocytes with the CaMKII inhibitor of AIP, and that Liu does not suggest the usage of AIP in vivo; see also id. at 10 at 1st full ¶, 11-12 at bridging ¶, 12-13 at bridging ¶, 20 at 2nd ¶, 20-21 at bridging ¶, 22-23 at bridging ¶, 24-25 at bridging ¶, 25 at 1st full ¶, 27 at 1st full ¶, 28 at 1st full ¶; see also Declaration filed 3/30/2026 at ¶¶9, 11) Arguments premised upon limiting the prior art to example reduced to practice are not persuasive because “[a] reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP §§ 2123(I)-(II)). Here, the explicit suggestions of Liu are clearly identified in the rejection, including the fact that Liu teaches and suggests that
“CaMKII inhibition with [a CaMKII inhibitor] completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2R4496C+/- mice”,
and that
“CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT”
(see, e.g., Liu at title, abs; see also id. at 215 at col I at 1st partial ¶, 215-216 at §§ 3.1 CaMKII Inhibition prevents ventricular tachycardia in RyR2R4496C+/- mice). Furthermore, such arguments amount to an improper dismissal of the level of ordinary skill in the CaMKII inhibitor arts; critically, the Court has stated that "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. In the instant case, simply extending a generic statement regarding a genus of compounds (e.g., CaMKII inhibitors) to other explicitly recited members of that genus of compounds (e.g., AIP, which is a CaMKII inhibitor), and expecting that the generic statement is correct, such as the statement that
“CaMKII inhibition with [a CaMKII inhibitor] completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2R4496C+/- mice”,
and that
“CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT”
(see, e.g., Liu at title, abs; see also id. at 215 at col I at 1st partial ¶, 215-216 at §§ 3.1 CaMKII Inhibition prevents ventricular tachycardia in RyR2R4496C+/- mice) is well-within the ordinary skill in the art. Arguments to the contrary are not reasonable, credible, or persuasive. Accordingly, all references are applicable for all that each teaches, discloses, and reasonably suggests to one of ordinary skill in the art (see, e.g., MPEP §§ 2123(I)-(II)).
Arguments addressing the teachings of individual references or less than the combination of all prior art references relied upon by the Examiner are not persuasive: It is the Examiner’s understanding that Applicant addresses the teachings of Liu in isolation (see, e.g., Reply filed 3/30/2026 at 7 at § “Liu, considered in its entirety, is distinct and different from the present claims and fails to make the present claims obvious” to 9 at final ¶; see also id. at 8 at 1st full ¶, 8-9 at bridging ¶, 9 at 1st full ¶, 10 at 1st full ¶, 11 at 1st full ¶, 11-12 at bridging ¶, 12 at 1st full ¶, 20 at 2nd ¶, 21-22 at bridging ¶, 24-25 at bridging ¶, 25 at 1st full ¶; 25-26 at bridging ¶, 26-27 at bridging ¶, 27 at 1st full ¶; 28 at 1st full ¶). Furthermore, it is the Examiner’s understanding that Applicant addresses the teachings of the references alone or fails to consider the combination of all references relied upon in the rejection (see, e.g., Reply filed 3/30/2026 at 12 at 1st full ¶ to 13 at 1st partial ¶, 21 at 1st full ¶ to 23 at 1st partial ¶). In response to applicant's arguments against individual references or otherwise arguments against less than the combined references relied upon by the Examiner, such arguments are not persuasive because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore, it is neither disputed nor dispositive of obviousness that individual references, considered alone or piecemeal with less than all references of record, do not anticipate or otherwise render obvious the instant claims, because such arguments address non-existent rejections (i.e., zero rejection under 35 USC 103 based on individual references, or less than the combined teachings of Liu, US’033 (Bayer), Cuello, and Tilemann have been placed on record). Here, the teachings of individual references, with citations, as relied upon by the Examiner have been placed on record, and the predicted and expected results have been explicitly set forth in the rejection, as supported by the prior art disclosure. All references are presumed fully enabled (see, e.g., MPEP §§ 2121(I)-(III)), and are applicable for all that each teaches, discloses, and reasonably suggests to one of ordinary skill in the art (see, e.g., MPEP §§ 2123(I)-(II)).
KN-93 and AIP are prior art elements, and were unambiguously identified in the prior art as CaMKII inhibitors: It is the Examiner’s understanding that Applicant is alleging that Liu and US’033 (“Bayer”) either
(i) do not teach that AIP and KN-93 are “art-recognized equivalents” for use as CaMKII inhibitors, or otherwise
(ii) do not teach that AIP would be understood to be a CaMKII inhibitor before the effective filing date of the claimed invention as required by MPEP § 2143.02(III)
(see, e.g., Reply filed 3/30/2026 at 10 at 1st full ¶ to 20 at 2nd full ¶). It is the Examiner’s understanding that Applicant offers three sources of evidence for such arguments, namely
(A) a declaration pertaining to inventor opinions regarding the teachings of the prior art (see, e.g., Reply filed 3/30/2026 at 10-11 at bridging ¶ to 13 at 1st full ¶, 19 at 2nd full ¶);
(B) post-filed evidence set forth in the same declaration (see, e.g., Reply filed 3/30/2026 at 10-11 at bridging ¶, to 13 at 2nd full ¶ to 19 at 2nd full ¶); and
(C) conclusory statements unsupported by objective evidence (see, e.g., Reply filed 3/30/2026 at 10 at 1st full ¶, 18 at 1st partial ¶, 20 at 1st full ¶ to 2nd full ¶, 20-21 at bridging ¶).
Regarding (A) and (B), the Declaration has been fully considered in a separate section, below, but not found persuasive for reasons set forth therein. In brief, opinion evidence is evaluated per MPEP § 716.01(c)(I)-(III), which explains that “an opinion as to a legal conclusion is not entitled to any weight”, but “the underlying basis for the opinion may be persuasive”; but post-filed evidence establishing that the full scope of the originally filed disclosure was not enabling, learned only after the effective filing date of the claimed invention as required by MPEP § 2143.02(III), does not rebut prima facie obviousness because obviousness is determined in view of the prior art before the effective filing date of the claimed invention. Regarding (C), conclusory statements made in the absence of any objective evidence addressing the merits of the rejection of record, are not persuasive because such argument amounts to an unsupported argument of counsel that are directly contradicted by the evidence of record. Such conclusory statements and opinions are outweighed by evidence of record objectively showing that AIP was, in fact, an art-recognized CaMKII inhibitor before the effective filing date of the claimed invention (see, e.g., Liu at abs, 215 at §2.3 reciting “The CaMKII inhibitor peptide (AIP) was loaded…”, Fig. 1 on 216, 216 at §§ 3.2-3.4; see also US’033 at ¶¶[0005], [0043], referring to “CaMKII inhibitors such as …AIP”). Here, the prior art of record objectively identifies that “CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT” (see, e.g., Liu at abs, 221 at § 4.4), wherein the predicted and expected result is explicitly taught by Liu, namely that “CaMKII inhibition is a powerful approach to prevent arrhythmogenesis in RyR2R4496C knock-in mic in vivo” (see, e.g., Liu at 219 at col I-II at § 4), and “CaMKII inhibition is a promising approach to prevent … arrhythmogenesis in the RyR2R4496C+/- CPVT mouse model” (see, e.g., Liu at 221 at col II at § 4.4). Such direct and unambiguous guidance provides artisans a reasonable expectation that CaMKII inhibitors, including AIP, could be predictably and expectedly utilized to treat and prevent arrhythmogenesis in the RyR2R4496C+/- CPVT mouse model. Accordingly, the proffered data by the Declarant and by the Applicant fail to rebut the objectively supported facts that (1) AIP and KN-93 were art-recognized CaMKII inhibitors, and (2) Liu explicitly teaches that, generally, CaMKII inhibitors, as a class of compounds, would have been predicted and expected to successfully treat and prevent arrhythmogenesis in the RyR2R4496C+/- CPVT mouse model exactly as taught and suggested by the prior art. Accordingly, the rationale described at MPEP § 2144.07(II), namely that it is obvious to substitute art-recognized equivalents for the same purpose, applies to all CaMKII inhibitors, including AIP26.
The Declaration is insufficient to rebut prima facie obviousness: It is the Examiner’s understanding that Applicant refers to a declaration filed 3/30/2026 that pertains to inventor opinions regarding the teachings of the prior art and post-filed evidence set forth in the same declaration (see, e.g., Reply filed 3/30/2026 at 10-11 at bridging ¶ to 13 at 1st full ¶, 19 at 2nd full ¶; see, e.g., id. at 10-11 at bridging ¶, to 13 at 2nd full ¶ to 19 at 2nd full ¶, reiterating post-filed evidence; see also id. at 10-11 at bridging ¶ referring to Dec. at ¶7; see also id. at 11 at 1st full ¶ referring to Dec. at ¶8; see also id. at 11-12 at bridging ¶ referring to Dec. at ¶9; see also id. at 12 at 1st full ¶ referring to Dec. at ¶10; see also id. at 12-13 at bridging ¶ referring to Dec. at ¶11; see also id. at 13 at 1st full ¶ referring to Dec. at ¶12; see also id. at 13 at final ¶ to 19 at 1st partial ¶ referring to Dec. at ¶¶13-16; see also id. at 19 at bridging ¶ referring to Dec. at ¶17; see also id. at 19 at final ¶ referring to Dec. at ¶18; see also id. at 21 at 2nd full ¶ referring to Dec. at ¶10; see also id. at 23 at final ¶ referring to Dec. at ¶11; see also id. at 24 at 1st full ¶ starting with “As a first matter” referring to Dec. at ¶12; see also id. at 25 at 1st full ¶ referring to Dec. at ¶13; see also id. at 26 at 1st partial ¶ referring to Dec. at ¶¶13-15; see also id. at 27 at 1st full ¶ referring to Dec. at ¶13; see also id. at 27-28 at bridging ¶ referring to Dec. at ¶¶14-17). The declaration has been fully considered in a separate section, below. In brief, the declaration is insufficient to rebut a determination of prima facie obviousness or otherwise to establish secondary considerations commensurate in scope with the requirements of MPEP § 716.
Unclaimed limitations are insufficient to distinguish the claimed invention relative to the prior art of record: It is the Examiner’s understanding that the Applicant refers to multiple aspects that do not reflect the pending claim scope and have unknown relevance to the invention as claimed. For example, the proffered arguments refer to limiting “off target” and “central nervous system (CNS) effects”, “transduction efficiency”, “heterogenous transduction” (see, e.g., Reply filed 3/30/2026 at 13 at 1st ¶), FKPB12.6 fused to AIP, “ventricular pacing”, “serial administration of isoproterenol…”, “CN19o and its derivatives” (see, e.g., Reply filed 3/30/2026 at 13-14 at bridging ¶), “AIP multimer AIPx5” (see, e.g., Reply filed 3/30/2026 at 14-15 at bridging ¶), CRD2959, pre-treatment, “appropriate serum levels” (see, e.g., Reply filed 3/30/2026 at 16 at 1st ¶), “isolated whole hear lysates from CRD2959-treated animals”, “CaMKII-mediated phosphorylation of …PLN” (see, e.g., Reply filed 3/30/2026 at 17 at 1st full ¶), “frequent post-pacing events (PPE)” (see, e.g., Reply filed 3/30/2026 at 17-18 at bridging ¶), etc., etc. In response to Applicant's arguments suggesting that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., unclaimed aspects noted above) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Proffered data is generally of unknown relevance to the claimed invention: Examiner acknowledges the proffered data at pages 14-15 (Fig. 1a-1d), 16-18 (Fig. 2a-2e), which appear to pertain to unclaimed inventions (e.g., the CaMKII inhibitor of “CRD2959” or the CaMKII inhibitor of CN19o at partially legible Figures 1a-1c; the CaMKII inhibitor of “CRD2959” at Figures 2a-2f) (see, e.g., Reply filed 3/30/2026 at 14-18). Although Figure 1(d) on 15 appears to show that a CaMKII inhibitor, namely AIP, can suppress “ventricular tachycardia (VT)/arrhythmia”, this information is consistent with the teachings and expectations of Liu (see, e.g., MPEP § 716.02(c)(II), noting that "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof."). Presumably, the data is provided to support the stated conclusions that (A) “CaMKII inhibition itself is insufficient to accurately predict arrhythmia suppression in CPVT models” (see, e.g., Reply filed 3/30/2026 at 18-19 at bridging ¶), that (B) “a priori, and without empirical, experimental data, it is unpredictable and nonobvious that treatment with any agent known or believed to inhibit CaMKII will effectively suppress arrhythmias or CPVT-associated ventricular arrhythmias” (see, e.g., Reply filed 3/30/2026 at 18-19 at bridging ¶), that (C) “known CaMKII inhibitors are not equivalent for the purposes of suppressing arrhythmias in vivo” (see, e.g., Reply filed 3/30/2026 at 19 at 1st ¶), and that (D) “these results indicate that it is not obvious that treatment with CaMKII inhibitor AIP in vivo by AAV vector delivery will effectively suppress CPVT-associated ventricular arrhythmia” (see, e.g., Reply filed 3/30/2026 at 19 at 2nd ¶). These conclusions, even if supported by the proffered data, are insufficient to rebut a determination of prima facie obviousness for the following reasons:
First, arguments that one CaMKII inhibitor works better than another is not surprising (see, e.g., MPEP § 716.02, noting that “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties”; see also MPEP § 2143.02(I), noting that a showing of efficacy is not required to establish obviousness), and does not rebut the predicted and expected results established by the prior art of record because such results show that the CaMKII inhibitor does, in fact, treat CVPT exactly as suggested by the prior art, which weighs in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II), noting that "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.").
Second, obviousness is determined "before the effective filing date of the claimed invention" (see, e.g., MPEP § 2143.02(III)), but such data has not been identified as extant and publicly available "before the effective filing date of the claimed invention". Accordingly, prima facie obviousness is not retroactively overcome by post-filed data. At best, such data may be utilized to rebut a determination of obviousness per a showing commensurate in scope with MPEP § 716.
Accordingly, such data does not rebut a determination of prima facie obviousness, because "before the effective filing date of the claimed invention", in view of the prior art of record, it would have been obvious to use a known CaMKII inhibitor encoded by a known AVV vector, with a known cardiac specific promoter, and to administer it to a known patient population to treat a known condition, exactly as taught and suggested by the prior art. Each component merely performs its art-recognized function.
References to alleged “potency” of AIP does not rebut a determination of prima facie obviousness: It is the Examiner’s understanding that Applicant refers to the “potency” of AIP multiple times (see, e.g., Reply filed 3/30/2026 at 12 at 1st full ¶, 21-22 at bridging ¶, 22-23 at bridging ¶, 23 at final ¶, 24-25 at bridging ¶), and suggests that such disclosure (i) establishes a teaching away (see, e.g., Reply filed 3/30/2026 at 12 at 1st full ¶, 21 at 1st full ¶ to 22 at 1st full ¶, “casts aspersions”, 23 at final ¶ “led the skilled practitioner away from the use of AIP”); (ii) lack of reasonable expectation of successful treatment of arrhythmias (see, e.g., Reply filed 3/30/2026 at 22-23 at bridging ¶, 23 at final ¶, 24-25 at bridging ¶); or otherwise (iii) lack of motivation to combine (see, e.g., Reply filed 3/30/2026 at 12 at 1st full ¶, 21-22 at bridging ¶, 22-23 at bridging ¶, 23 at final ¶, 24-25 at bridging ¶). These allegations are presumably premised upon a mischaracterization of a repeated quote found in US’033 (Bayer), which is quoted at pages 21-22 of the Reply filed 3/30/2026, and improper application of the requirements of obviousness as explained below:
First, the reliance upon US’033 for “potency” is misplaced because US’033 is cited in the rejection under 35 USC 103 to establish that AVV may be utilized to encode and deliver peptide-based CaMKII inhibitors in vivo to patients (see rejection, above). This teaching is not addressed by the references to “potency” because US’033 does not pertain to the treatment of cardiac arrhythmias or CPVT-associated ventricular arrhythmias as instantly claimed. Rather, US’033 pertains to other known and art-recognized applications of CaMKII inhibitors, namely for use in treating cancer and neurodegenerative diseases (see, e.g., US’033 at title, abs, claims). Accordingly, reference to “potency” in US’033 pertain to expectations regarding other diseases, but not arrhythmias.
Second, no “teaching away” from using AIP as a CaMKII inhibitor suitable for treating CPVT-associated ventricular arrhythmias appears in US’033 or any other prior art reference of record, because a reference to “low potency” relative to another compound, for cancer treatment, does not actually “criticize, discredit, or otherwise discourage the solution claimed” (see, e.g., MPEP § 2141.02(VI)), which is the treatment or prevention of arrhythmogenesis in the RyR2R4496C+/- CPVT mouse model (the non-elected species under examination) or otherwise the treatment of CPVT using CaMKII inhibitors generally as taught and suggested by the primary reference.
Third, allegations of “low potency” regarding treatment of other diseases is not germane to the treatment of arrhythmias as instantly claimed; and therefore such teachings do not weigh against a determination of a reasonable expectation of using AIP to successfully treat CPVT exactly as taught and suggested by the prior art.
Fourth, even assuming arguendo, that “potency” was a consideration for AIP, MPEP § 2121(I) explains that prior art is presumed fully enabled and operational for everything that it teaches or reasonably suggests, and explicitly identifies that “Efficacy is not a requirement for prior art enablement” (see, e.g., MPEP § 2121(III)), and that further explains that “Conclusive proof of efficacy is not required to show a reasonable expectation of success” (see, e.g., MPEP § 2143.02(I)), but rather Obviousness and a showing of reasonable expectation of success only requires “some degree of predictability” (see, e.g., MPEP § 2143.02(II)), wherein predictability is determined "before the effective filing date of the claimed invention" (see, e.g., MPEP § 2143.02(III)).
Fifth, clear motivation to arrive at the claimed invention was set forth explicitly in rejection under the rationales of MPEP§§ 2143(I)(A)-(B), (F), and (G); the rejection identified predicted and expected results supported by prior art disclosures made “before the effective filing date of the claimed invention” (see, e.g., MPEP § 2143.02(III)).
Accordingly, arguments alleging that the “potency is low” for AIP are not persuasive because the Applicant relies upon a quote from US’033, taken out of context, which pertains to ill-described level of “potency” in the context of an unclaimed disease relative to an unclaimed CaMKII inhibitor, but such statement is of unknown relevance to the instantly claimed methods of treating CPVT-associated ventricular arrhythmias; furthermore, even if proven relevant, such ill-defined “potency” issues are not required to establish obviousness or enablement of the prior art. Accordingly, arguments addressing “potency” of AIP have been fully considered but not found persuasive.
Conclusory arguments directly contradicted by cited art of record, are not persuasive in the absence of evidence and/or explanations reconciling such statements with evidence of record: It is the Examiner’s understanding that Applicant (and Declarant) allege
…it was not known whether the use of AA V to transduce cardiac cells would be pro-arrhythmic rather than anti-arrhythmic, as desired. Because AAV is known to have limited transduction efficiency and may result in heterogenous transduction of cardiac cells, there could consequently be an incomplete inhibition of CaMKII across the heart, which could potentially be more harmful than helpful, compared to no inhibition, in models of arrhythmia.
(see, e.g., Reply filed 3/30/2026 at 13 at 1st full ¶);
This line of arguments was previously raised (see, e.g., Arguments filed 2/06/2024 at 10 at penultimate ¶; see also Dec. filed 2/16/2024 at ¶6), and fully considered on record, but not found persuasive for reasons of record supported by objective evidence and references placed on record at that time (see, e.g., Reply filed 2/22/2024 at 35 at 1st full ¶, 36 at 1st full ¶ to 38 at 1st partial ¶, 48 at final ¶ to 56 at 1st ¶). In brief, such statements continue to not be persuasive for reasons already discussed on record (see, e.g., Reply filed 2/22/2024 at 36 at 1st full ¶ to 38 at 1st partial ¶, 48 at final ¶ to 56 at 1st ¶), which are incorporated into the instant response. For example, Hajjar27 and Denegri28 pertain to gene therapy, circa 2014. Hajjar identifies that AAV was considered for the treatment of CPVT circa 2014 (see, e.g., Hajjar at title, passim). Hajjar discloses
Cardiac gene therapy has been evaluated for >20 years, and recently, the application of adeno-associated viral vectors (AAVs) has accelerated the field because AAVs greatly increase the efficiency of prolonged cardiac gene expression after a single delivery compared with previous adenovirus and plasmid-based gene delivery technologies. Furthermore, the lack of human disease caused by AAV makes them an attractive candidate for clinical cardiac gene therapy.
(see, e.g., Hajjar at 2633 at col II at final ¶).
Hajjar explicitly identifies that, circa 2014, in murine models of CPVT, gene transfer with AAV serotype 9 encoding CASQ2 had been used successfully to treat arrhythmogenic phenotypes (see, e.g., Hajjar at 2634 at col I at 1st full ¶). Hajjar addresses the issue of “spatial heterogeneity” raised by Applicant (see, e.g., Reply filed 2/08/2024 at 9 at 1st full ¶, 9-10 at bridging ¶; see also Reply filed 3/30/2026 at 13 at 1st full ¶), and specifically notes that the treatment of arrhythmogenic phenotypes was successful
. . .despite the fact that only ≈40% of cardiomyocytes were infected by AAV9 gene delivery.
(see, e.g., Hajjar at 2633 at col II at final ¶).
Accordingly, the lack of 100% transduction of all cells, did not abrogate the successful treatment of a murine model of CPVT. The explanation for this observation is set forth in the prior art of Denegri, which is discussed in Hajjar. Critically, Denegri pertains to the treatment of CPVT in murine models using gene therapy and specifically an AAV serotype 9 encoding CASQ2 (see, e.g., Denegri at title, abs). Denegri notes that AAV9-CASQ2 only had an infection rate of about ≈40% (see, e.g., Denegri at 2679 at col II at 2nd full ¶), but was still successful in treating CPVT (see, e.g., Denegri at title, abs, passim). Denegri explains this as follows:
A puzzling question raised by our study is why, even though the AAV9-CASQ2 construct does not reach all cardiac cells, it induces a remarkable antiarrhythmic efficacy. We believe that biophysical properties that regulate the propagation of the action potential in the heart may provide an explanation for this apparently surprising effect. Accordingly, for a triggered action potential to elicit a premature ventricular complex, it has to be able to propagate to adjacent cells. Because action potential propagation follows the “source-sink” relationship, both active and passive properties of the cardiac tissue determine whether an action potential is able to travel from cell to cell. It is only when adjacent myocytes develop synchronous DADs that the summation of the multiple depolarizations allows propagation of a triggered action potential to the entire heart. The experimental demonstration of this concept has been provided in a most elegant in silico study by Xie et al.28 These authors calculated the number of adjacent cells required for a DAD to generate an action potential and showed that an afterdepolarization is suppressed unless a sufficient number of the neighboring myocytes develop an afterdepolarization on the same beat. Therefore, to prevent propagation of triggered beats, it is not required that all cells are rescued; it is enough that a fraction of them impair propagation of action potentials to prevent life-threatening arrhythmias.
(see, e.g., Denegri at 2680 at col I at 1st full ¶, emphasis added).
Accordingly, an artisan would readily appreciate that “spatial heterogeneity” resulting from less than 100% infection rates of cardiac cells would not abrogate efficacy of gene therapy in the treatment of CPVT in vivo (see, e.g., id). Accordingly, arguments amounting to mere speculation regarding “limited transduction efficiency and may result in heterogenous transduction of cardiac cells” in the absence of clearly addressing the ordinary skill in the art as evidenced by prior art already of record, is not persuasive for reasons of record. The prior art is presumed fully enabled for all that it teaches, discloses, and reasonably suggests to one of ordinary skill in the art (see, e.g., MPEP §§ 2123(I)-(II)), and no evidence commensurate in scope with the requirements of MPEP §§ 716.02, 716.03, 716.04, 716.04, 716.07, or 716.08 have been placed on record to date.
Statements contradicted by the literal disclosure of the art of record are not persuasive: Examiner notes that Applicant alleges that
…based on Liu, [] AIP peptide is not useful in vivo, does not successfully work in vivo, and/or does not successfully inhibit CaMKII activity to treat arrythmia and CPVT in an animal subject.
(see, e.g., Reply filed 3/30/2026 at 11 at 1st full ¶);
This statement and conclusion does not logically follow from the disclosure of Liu, which explicitly teaches and suggests that
“CaMKII inhibition with [a CaMKII inhibitor] completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2R4496C+/- mice”,
and that
“CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT”
And identifies that AIP is a CaMKII inhibitor (see, e.g., Liu at title, abs; see also id. at 215 at col I at 1st partial ¶, 215-216 at §§ 3.1 CaMKII Inhibition prevents ventricular tachycardia in RyR2R4496C+/- mice). No evidence commensurate in scope with the requirements of MPEP §§ 716.02, 716.05, or 716.07 has been placed on record at this time.
Conclusory statements unsupported by evidence are not persuasive: It is the Examiner’s understanding that Applicant applicants recites conclusory statements unsupported by objective evidence (see, e.g., Reply filed 3/30/2026 at 20-21 at bridging ¶, 22 at 1st partial ¶, opining what “the practitioner would be led to” or not led to; see id. at 23 at final ¶, opining that US’033 supports “a position in the art that AIP would not be considered to be a suitable candidate for treating CPVT” although US’033 is silent with respect to CPVT). If Applicant means to suggest the existence of skepticism of experts, such evidence should be filed per MPEP § 716.05 as evidence is required to establish skepticism of experts. In the absence of such evidence, such statements are understood to be unsupported conjecture of counsel. To date, no evidence commensurate in scope with the requirements of MPEP § 716.05 have been filed. If Applicant is attempting to allege that the prior art is not enabling or inoperable Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time. Critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability or establish skepticism of experts. The Examiner’s position is that the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)-(II)). Accordingly, Examiner disagrees and notes that the claimed inventions have been rejected as obvious for explicitly recited and identified rationales supported by MPEP§§ 2143(I)(A)-(B), (F), and (G). Conclusory arguments attempting to dismiss the merits of the rejection of record are not persuasive.
US’033 (Bayer) is analogous art: It is the Examiner’s understanding that Applicant is suggesting that “Bayer” constitutes non-analogous art (see, e.g., Reply filed 3/30/2026 at 21 at 1st full ¶ at 22 at 1st partial ¶, alleging that Bayer is directed to methods of treating different diseases). If Applicant means to allege that US’033 is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, US’033 pertains to CaMKII inhibitors and methods of delivering peptide-based CaMKII to subjects using AAV vectors, and therefore US’033 pertains to the particular problem with which the inventor was concerned, namely delivery means of the AIP peptide to subjects in need of treatment for CVPT as disclosed and suggested by the primary reference.
Applicant’s allegations, if correct, would suggest that the originally filed disclosure was not fully enabled: It is the Examiner’s understanding that Applicant is alleging that a high bar for an enabling disclosure in the instant art, which requires empirical evidence of operability (see, e.g., Reply filed 3/30/2026 at 8 at 1st partial ¶ to 9 at 1st partial ¶, 9 at final ¶, dismissing Liu as limited to the usage of AIP in vitro to RYR2R4496C+/- ventricular myocytes; 10-11 at bridging ¶ alleging that “mere CaMKII inhibition itself is insufficient to accurately predict arrhythmia suppression in CPVT models, which suggest that additional mechanism can contribute to arrhythmia suppression beyond CaMKII target engagement. . . it does not directly or necessarily follow that such agents can or will effectively inhibit, reduce, suppress, or treat CPVT and CPVT-associated arrhythmias”; 11 at 1st full ¶ alleging that “simply because an agent may inhibit CaMKII and be classified as a CaMKII inhibitor, not all CaMKII inhibitors can or would be ‘predictably and expectedly’ utilized to successfully treat CPVT” in view of Liu because “not every agent that may inhibit CaMKII behaves predictable following in vivo administration to a mammalian subject, or is able to achieve directed, successful, and effective treatment of arrythmia and CPVT if it is administered to a mammalian subject in vivo”; 11-12 at bridging ¶ alleging that if a reference “fails to present experiments” showing compounds “used to treat mice in vivo”, that such lack of experiments supports a conclusion that the compounds are “not useful in vivo, does not successfully work in vivo, and/or does not successfully inhibit CaMKII activity to treat arrythmia and CPVT in an animal subject”; 12 at 1st full ¶ to final ¶ alleging that gene therapy approaches are unpredictably “long and arduous”; 13 at 1st full ¶ alleging that AAV vectors may have “off target, e.g., central nervous system (CNS) effects”; 13-14 at bridging ¶ alleging that some CaMKII inhibitors “do not suppress CPVT-associated arrhythmia”; 18-19 at bridging ¶ alleging that the record supports “the premise that CaMKII inhibition itself is insufficient to accurately predict arrhythmia suppression in CPVT models, which suggests that additional mechanisms may contribute to arrhythmia suppression beyond mere CaMKII target engagement”; 18-19 at bridging ¶ alleging that “Therefore, a priori, and without empirical, experimental data, it is unpredictable and nonobvious that treatment with any agent known or believed to inhibit CaMKII will effectively suppress arrhythmias or CPVT associated ventricular arrhythmias”; at 20 at 1st ¶ alleging that “it cannot be reasonably expected that one CaMKII inhibitor can be substituted for another and the same results will be achieved, particularly when it cannot be determined a priori if a CaMKII inhibitor will suppress or treat arrhythmia or CPVT-associated arrhythmia, as supported by the Declaration”; at 23 at 1st partial ¶ alleging that “while different agents may be considered to be CaMKII inhibitors because they target CaMKII, it does not directly or necessarily follow that such agents can or will effectively inhibit, reduce, suppress, or treat CPVT and CPVT-associated arrhythmias”; 24 at 1st full ¶ starting with “As a first matter” alleging “it was not known whether the use of AAV to transduce cardiac cells would be pro-arrhythmic rather antiarrhythmic, as desired”; 27 at 1st full ¶ alleging “The successful activity of different agents . . . administered to a subject in vivo is not necessarily predictable or expected, given the nature of biological systems”; at 27-28 at bridging ¶ alleging that “CaMKII inhibition itself is not sufficient to accurately predict arrhythmia suppression in CPVT models”; at 28 at 1st partial ¶ alleging that “Accordingly, without empirical, experimental data, it is unpredictable and nonobvious that treatment with any agent known or believed to inhibit CaMKII will effectively suppress CPVT-associated ventricular arrhythmias”). If such statements were correct, then the originally filed disclosure and pending claim scope would be properly rejected as not fully enabling by Applicant’s own admission because the originally filed disclosure provided only “empirical, experimental data” relevant to in vivo treatment for the inhibition of arrhythmia in an Opto-MTF murine model of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) “expressing the R4561I mutation”29,30, by intraperitoneal injection of AAV9-GFP-AIP and isoproterenol stimulation (wherein “GFP-AIP” comprises the AIP sequence of instant SEQ ID NO: 14 and is understood to have the sequence as shown at Fig. 6H to be CTnT-GFP-YKKALHRQEAVDCL, as detailed at 53-53 of the Specification). However, (i) zero empirical evidence in humans or other mammals was disclosed at all, but continues to be claimed; (ii) zero empirical evidence utilizing AAV6, AAV2i8, Anc80, or Anc82 in any subject was disclosed at all, but continues to be claimed; (iii) zero empirical evidence utilizing any CPVT subject other than one characterized by a single R4561I was reduced to practice, but continues to be claimed; (iv) zero empirical evidence utilizing any “cardiac-specific promoter” other than CTnT was reduced to practice, but all other such promoters continue to be claimed; (v) zero empirical evidence in any model or subjects lacking isoproterenol stimulation were reduced to practice, but continues to be claimed; etc., etc. Accordingly, assertions that the prior art is highly unpredictable and therefore requires a high burden of empirical and experimental data would be applied to both the prior art and also applied to the instant disclosure. If such statements are correct, Applicant should confirm such statements in a subsequent action and clearly aver31 such statements by narrowing the pending claim scope to only encompass the single, disclosed embodiment that was actually empirically tested in vivo on record. However, if such statements are false, incorrect, over-generalized, or unreasonable in view of the ordinary level of skill in the art, Applicant is advised that it would facilitate prosecution if Applicant limited future arguments to objectively-supported statements commensurate in scope with Applicant’s own originally filed disclosure. For purposes of the instant action, such statements are not currently understood to reflect the state of the prior art because "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. In the instant case, simply extending the guidance regarding a genus of compounds (e.g., CaMKII inhibitors) to other explicitly recited members of that genus of compounds (e.g., AIP, which is a CaMKII inhibitor), and expecting that the generic statement to be reasonably predictive with a reasonable expectation of success, such as the statement that
“CaMKII inhibition with [a CaMKII inhibitor] completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2R4496C+/- mice”,
and that
“CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT”
(see, e.g., Liu at title, abs; see also id. at 215 at col I at 1st partial ¶, 215-216 at §§ 3.1 CaMKII Inhibition prevents ventricular tachycardia in RyR2R4496C+/- mice) is well-within the ordinary skill in the art. Accordingly, the Examiner’s position is that the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses, teaches, and reasonably suggests to artisans (see, e.g., MPEP §§ 2123(I)-(II)), which would include the usage of an art-recognized CaMKII inhibitor to prevent CPVT in subjects, wherein the art-recognized CaMKII inhibitor (e.g., AIP) could be delivered using known and cardiac-specific delivery means (e.g., AVV9 with a CnTn-promoter). Per SCOTUS, “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability” (see, e.g., KSR, 550 US at 417, 82 USPQ2d at 1396). Here, the claimed invention is the application of the methodology taught by the primary reference for AIP, wherein a gene therapy delivery system is utilized instead of direct delivery of the AIP peptide, wherein all elements of such gene therapy deliver systems for CaMKII inhibitors such as AIP were already known in the prior art (e.g., promoters, AAV vectors, etc.), and each prior art element merely performs its art-recognized function in combination as it does separately. Accordingly, such arguments are not persuasive.
It is the Examiner’s understanding that Applicant previously alleges that the Examiner should consider opinion evidence under MPEP § 716.01(c)(III) (see, e.g., Reply filed 2/04/2025 at 14-15 at bridging ¶). This is undisputed but of unknown relevance because all such evidence has been fully considered on record but not found persuasive for reasons of record which Applicant again fails to address (see also Action mailed on 2/22/2024 at 44-57, which is also fully incorporated herein), and no additional evidence under MPEP § 716.01(c)(III) has been submitted at this time. In addition, to date, Applicant has provided no objective supporting evidence for the speculative comments alleging that “the Liu lab, was unable to develop treatments . . . Liu and others were unable to solve this problem” (see, e.g., Reply filed 2/08/2024 at 10 at 2nd full ¶). As explained at MPEP § 716.01(c), to be of probative value such assertions “should be supported by actual proof”. To date, no evidence of inoperability of references commensurate in scope with the requirements of MPEP § 716.07 have been placed on record.
Examiner notes that Applicant previously alleged that the claimed invention solved a “Long-Felt but Unsolved Need in the Field, in the Face of Failures of Others” (see, e.g., Reply filed 2/08/2024 at 11 at 3rd full ¶ to 13 at 1st partial ¶), which was not found persuasive for reasons of record (see, e.g., Action mailed 2/22/2024 at 40-42), which are incorporated herein. Applicant failed to dispute the Examiner’s position set forth in the previous action. Therefore, the Examiner’s position is currently undisputed.
Accordingly, all arguments raised by the Applicant have been fully considered but not found persuasive for at least the reasons set forth above and set forth in the previous actions of record. Therefore, the rejection is maintained as revised above, and all revisions were necessitated by Applicant’s amendments.
Response to Declarations of Bezzerides under 37 C.F.R. §1.132
The affidavit under 37 CFR 1.132 filed 3/30/2026 is insufficient to overcome the rejections of record. A detailed explanation of why the affidavits or declarations are insufficient is provided below. The legal standards of review and consideration of Declarations under 37 C.F.R. §1.132 are discussed at MPEP § 716.01.
Interest of the Expert in the Outcome of the Case
Per MPEP 716.01(c)(III), in assessing the probative value of an expert opinion, the examiner must consider the interest of the expert in the outcome of the case. Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 227 USPQ 657 (Fed. Cir. 1985), cert, denied, 475 U.S. 1017 (1986). Here, the Declarant is a named inventor and therefore has a clear interest in the outcome of the case.
Nature of the Matter Sought to be Established
Per MPEP 716.01(c)(III), in assessing the probative value of an expert opinion, the examiner must consider the nature of the matter sought to be established. Ashland Oil, Inc., 776 F.2d 281.
Here, the Declaration presumably attempts to establish unexpected results (see, e.g., MPEP § 716.02), skepticism of experts (see, e.g., MPEP § 716.05), and/or inoperability of Liu (see, e.g., MPEP § 716.07). The requirements for establishing such data sufficient to rebut prima facie obviousness is set forth at MPEP §§ 716.01, 716.02, 716.05, and 716.07.
Opinions as to Legal Conclusions
It is the Examiner’s understanding that Declarant provides opinions regarding legal conclusions (see, e.g., Dec. filed 3/30/2026 at ¶¶7, 16, 17, 18, and 19). As an initial matter, Examiner notes that per MPEP 716.01(c)(III), any opinions expressed by Declarant regarding legal conclusions are not entitled to any weight. However, the underlying basis for any opinion as to legal conclusions has been fully considered as detailed below.
Presence or absence of factual support for the expert’s opinion
Per MPEP 716.01(c)(III), in assessing the probative value of an expert opinion, the examiner must consider the presence or absence of factual support for the expert’s opinion. Ashland Oil, Inc., 776 F.2d 281.
The declaration presents multiple opinions in the absence of objective supporting evidence: It is the Examiner’s understanding that Declarant provides multiple opinions ultimately suggesting that the instant invention is non-obvious (see, e.g., Dec. filed 3/30/2026 at ¶4 “based on my training and professional experience in the field of cardiology”, ¶5 “based on my years of experience and research”, ¶7 “in view of my professional experience and expertise”, ¶8 “Based on my expertise and years of experience in the field of cardiology”, ¶9 “I, as a person skilled in the art, concluded based on Liu, that the AIP peptide is not useful in vivo, does not successfully work in vivo, and/or does not successfully inhibit CaMKII activity to treat arrythmia and CPVT in an animal subject”, ¶11 “Based on my reading of the Lui and Cuello references”, ¶11 “it is my belief”, ¶17 “Our findings are highly surprising”, ¶18 “the present claims are non-obvious over the art”, ¶18 “It is my professional opinion and belief that, at the time of our invention, it was entirely unpredictable and surprising….”). Per MPEP § 716.01, “to be of probative value, any objective evidence should be supported by actual proof” (see, e.g., MPEP § 716.01(c)(I); see also Ex parte Gray, 10 USPQ2d 1922 (Bd. Pat. App. & Inter. 1989), noting that statement in publication dismissing the "preliminary identification of a human b-NGF-like molecule" in the prior art, even if considered to be an expert opinion, was inadequate to overcome the rejection based on that prior art because there was no factual evidence supporting the statement; see also In re Beattie, 974 F.2d 1309, 24 USPQ2d 1040 (Fed. Cir. 1992), noting that declarations of seven persons skilled in the art offering opinion evidence praising the merits of the claimed invention were found to have little value because of a lack of factual support); see also Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991), noting that conclusory statements that results were "unexpected," unsupported by objective factual evidence, were considered but were not found to be of substantial evidentiary value). Here, statements of opinions, unsupported (or contradicted by) factual evidence of record, have bee fully considered but are not found persuasive in the absence of supporting factual evidence addressing the actual evidence of record and the actual claimed invention of record.
Paragraphs ¶1-¶3 do not raise specific arguments, and are neither disputed nor dispositive of obviousness.
Paragraph ¶4 provides an opinion that “based on my training and professional experience in the field of cardiology” that “in vivo treatment of arrythmia and CPVT via CaMKII inhibition was fraught with problems” (see, e.g., Dec. filed 3/30/2026 at ¶4). Declarant provides no evidence of any existing “in vivo treatment of arrythmia and CPVT via CaMKII inhibition” that actually existed "before the effective filing date of the claimed invention" (see, e.g. MPEP § 2143.02(III)), other than Liu (see, e.g., Dec. filed 3/30/2026 at ¶4). However, the disclosure of Liu does not support the opinions set forth by the Declarant at ¶4, because Liu is silent regarding “lack of specificity for targeting cardiac cells” or “extra-cardiac toxicity of small molecule CaMKII inhibitors”. Accordingly, it is unclear what the factual basis for the Declarant’s opinion may be, or if such opinion is based upon only evidence obtained years after the effective filing date of the claimed invention.
Paragraph ¶5 provides an opinion that “Based on my years of experience and research…” that “mere CaMKII inhibition itself is insufficient to accurately predict arrhythmia suppression in CPVT models” (see, e.g., Dec. filed 3/30/2026 at ¶5). Declarant provides no supporting, objective evidence that actually existed "before the effective filing date of the claimed invention" (see, e.g. MPEP § 2143.02(III)), other than Liu (see, e.g., Dec. filed 3/30/2026 at ¶5), but Liu does not support the Declarant’s assertions. Presumably, the opinions are intended to be supported by “The experimental data and results described hereinbelow” (see, e.g., Dec. filed 3/30/2026 at ¶5). As an initial matter, the relevance of “accurately predict[ing] arrhythmia suppression in CPVT models” to the claimed invention is wholly unknown, and unexplained, since accuracy of predicting arrhythmia suppression in CPVT models is not a claimed limitation. Therefore, even assuming arguendo that the proffered data supported such conclusion, this conclusion does not differentiate the claimed invention over the prior art, and therefore is insufficient to rebut prima facie obviousness (see, e.g., MPEP § 716.01(b), noting that evidence directed to a non-claimed limitation lacks nexus with the claimed invention). Furthermore, the proffered evidence (e.g., Dec. filed 3/30/2026 at ¶¶13-15) appears to be post-filed evidence, and therefore did not exist "before the effective filing date of the claimed invention" (see, e.g. MPEP § 2143.02(III)), which means that the proffered evidence cannot refute that prima facie obviousness was properly established by the Examiner. Additional considerations of whether or not such proffered evidence is sufficient to rebut a proper determination of prima facie obviousness is discussed in more detail below. Finally, it is noted that the proffered evidence appears to support the conclusion that AIP can successfully treat CPVT, which supports a conclusion of obviousness because such result is the expected and predicted result in view of the disclosure of Liu (see, e.g. MPEP § 716.02(c)(II), noting that “Expected Beneficial Results Are Evidence of Obviousness”, not non-obviousness).
Paragraph ¶6 reiterates the Declarant’s understanding of the Office Action and rejection of record (see, e.g., Dec. filed 3/30/2026 at ¶6). The summary fails to reiterate the nuances of the rejection, evidence of record, explicit supporting citations, explicitly identified predicted and expected results, explicitly recited rationales supporting a determination of prima facie obviousness, etc., and therefore the Examiner directs Applicants to the full rejection, set forth above.
Paragraph ¶7 provides an opinion that “In view of my professional experience and expertise….I strongly disagree that I and my co-inventors” are claiming a “simple substitution of AIP in place of another CaMKII inhibitor” (see, e.g., Dec. filed 3/30/2026 at ¶7). This statement is understood to be an opinion regarding an ultimate legal conclusion; per MPEP 716.01(c)(III), any opinions expressed by Declarant regarding legal conclusions are not entitled to any weight, but the underlying basis for any opinion as to legal conclusions is fully considered. Here, a “simple substitution” rationale reflects only the rationale of MPEP § 2143(I)(B), but the rejection also recites and is based upon a determination of obviousness of the claimed invention in view of alternative rationales, such as MPEP §§ 2143(I)(A), (F), and (G). Notably, Declarant fails to identify that AAV, a cardiac-specific promoter, the CaMKII inhibitor of AIP, or CPVT patients did not exist in the prior art, or that the invention merely yields the exact results taught and suggested by Liu, wherein all prior art components (e.g., vector, promoter, AIP, etc.) merely perform the exact, result-recognized function taught and disclosed by the prior art. Critically, Declarant provides no supporting, objective evidence that actually existed "before the effective filing date of the claimed invention" (see, e.g. MPEP § 2143.02(III)), other than Liu (see, e.g., Dec. filed 3/30/2026 at ¶5), to support their opinions; however, Liu does not support the Declarant’s assertions. Accordingly, opinions unsupported by objective, supporting proof do not outweigh the explicit guidance provided by the prior art.
Paragraph ¶7 provides the following assertions:
“The claimed invention involves the in vivo use of the AIP peptide that has a unique targeting profile in vivo and is specifically delivered to the subject's cardiac cells in vivo via an AAV vector containing a polynucleotide encoding AIP.”
“The invention is distinct and different from the use of the small molecule CaMKII inhibitor KN-93 that is delivered to an animal in vivo via a bolus injection according to Liu.”
“The targeting profile of AIP is not the same as that of a small molecule such as KN-93.”
“In addition, the use of AIP in the claimed methods is distinct and different from the use of other peptides known to inhibit CaMKII.”
(see, e.g., Dec. filed 3/30/2026 at ¶7). Even assuming arguendo that each statement were true and properly corroborated by actual proof, such statements do not support a determination of non-obviousness or unexpected results. Such qualitative differences between two CaMKII inhibitors is expected (see, e.g., MPEP § 716.02, noting that “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.”). Here, the assertions are not accompanied by any objective evidence of any statistically or practically significant difference commensurate in scope with the pending claims (see, e.g., MPEP § 716.02(a), (b)(I)-(II), (c)(I)-(II), (d)). Accordingly, such statements are unsupported by objective supporting evidence, but, even if true, would not necessarily support a determination of non-obviousness unless such differences were more than what would be expected by an artisan.
Paragraph ¶8 provides an opinion that “Based on my expertise and years of experience in the field of cardiology, I point out that simply because an agent may inhibit CaMKII and be classified as a CaMKII inhibitor, not all CaMKII inhibitors can or would be ‘predictably and expectedly’ utilized to successfully treat CPVT” presumably because “not every agent that may inhibit CaMKII behaves predictably following in vivo administration” (see, e.g., Dec. filed 3/30/2026 at ¶8). First, Declarant provides no supporting, objective evidence that actually existed "before the effective filing date of the claimed invention" (see, e.g. MPEP § 2143.02(III)), other than Liu (see, e.g., Dec. filed 3/30/2026 at ¶5), to support their opinions; however, Liu does not support the Declarant’s assertions. Second, even assuming arguendo that the statements were correct, they are insufficient to rebut prima facie obviousness because such arguments appear to suggest that obviousness under 35 USC §103 requires “absolute predictability”, but MPEP § 2143.02(II) explicitly identifies that “Obviousness does not require absolute predictability”, but instead Obviousness only requires “at least some degree of predictability”. Third, the Examiner’s basis for predicted and expected results are premised upon the prior art elements (e.g., known vectors, known promoters, known CaMKII inhibitor, known patient population, etc.) simply acting exactly as taught and suggested by the prior art of record available "before the effective filing date of the claimed invention" (see, e.g. MPEP § 2143.02(III)). Fourth, the proffered data of record supports a determination of obviousness because the administration of the CaMKII inhibitor of AIP treats CPVT exactly as suggested by the prior art (see, e.g. MPEP § 716.02(c)(II), noting that “Expected Beneficial Results Are Evidence of Obviousness”, not non-obviousness).
Paragraph ¶9 alleges that “The cited references do not teach or suggest using AIP encoded by a vector for in vivo delivery in animals” (see, e.g., Dec. filed 3/30/2026 at ¶9).This statement is understood to be an opinion regarding an ultimate legal conclusion; per MPEP 716.01(c)(III), any opinions expressed by Declarant regarding legal conclusions are not entitled to any weight, but the underlying basis for any opinion as to legal conclusions is fully considered. All proffered evidence in support of such statements is considered herein, but not found persuasive in view of the rejection and evidence of record.
Paragraph ¶9 alleges that
…Liu reference uses only the small molecule KN-93 given in a bolus injection to mice generated by Liu. Liu does not disclose the use of the KN-93 small molecule inhibitor and the peptide AIP in the same way or in the same types of experiments. In fact, Liu utilizes different CaKMII inhibitors, depending on whether Liu conducts an in vivo experiment or an in vitro experiment.
(see, e.g., Dec. filed 3/30/2026 at ¶9).
Liu provides no protocol or method for administering AIP to animals in vivo.
(see, e.g., Dec. filed 3/30/2026 at ¶9).
It is neither disputed nor dispositive of obviousness that Liu is not an anticipatory reference or that Liu disclosed unclaimed embodiments; critically, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore, the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)). Accordingly, such statements are not disputed nor dispositive of obviousness.
Paragraph ¶9 further alleges that
Because Liu fails to present experiments in which both the KN-93 small molecule and the AIP peptide are used to treat mice in vivo, I, as a person skilled in the art, conclude based on Liu, that the AIP peptide is not useful in vivo, does not successfully work in vivo, and/or does not successfully inhibit CaMKII activity to treat arrythmia and CPVT in an animal subject.
(see, e.g., Dec. filed 3/30/2026 at ¶9).
This conclusion does not logically follow from the evidence provided because the combination of direct generic guidance along with the absence of a reduction to practice cannot be reasonably or credibly interpreted in a manner that directly contradicts the direct statements of the prior art reference. Here, Liu explicitly teaches and suggests that
“CaMKII inhibition with [a CaMKII inhibitor] completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2R4496C+/- mice”,
and that
“CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT”
and further identifies that AIP is a CaMKII inhibitor (see, e.g., Liu at title, abs; see also id. at 215 at col I at 1st partial ¶, 215-216 at §§ 3.1 CaMKII Inhibition prevents ventricular tachycardia in RyR2R4496C+/- mice), and provides evidence that AIP performs exactly as expected, consistent with such conclusions (see id). Accordingly, a conclusion that contradicts such statements and evidence does not logically flow from the disclosure of Liu, and is therefore neither credible or reasonable in view of the instant record. Accordingly, such Declarant opinions, directly contradicted by the objective evidence of record, are not persuasive.
Paragraph ¶10 provides an opinion that the prior art “cast aspersions on AIP as an inhibitor of CaMKII” based upon an uncited portion of US’033 (Bayer) pertaining alleging that “potency is low” relative to another CaMKII inhibitor in unrelated methods of treating unrelated diseases, without clarification is low potency meant 1.5% less efficacy, or 99% less efficacy in US’033 (see, e.g., Dec. filed 3/30/2026 at ¶10). Presumably, the Declarant is alleging that US’033 “teaches away” from the claimed invention.
First, the reliance upon US’033 for low “potency” is misplaced because US’033 is cited in the rejection under 35 USC 103 to establish that AVV may be utilized to encode and deliver peptide-based CaMKII inhibitors in vivo to patients (see rejection, above), and this teaching is undisputed.
Second, the reference by declarant to “potency” is misplaced because the reference in US’033 to potency does not pertain to the claimed treatment of cardiac arrhythmias or CPVT-associated ventricular arrhythmias as instantly claimed; rather the reference in US’033 pertains to unclaimed treatment methods of unclaimed diseases taught by US’033 (see, e.g., US’033 at title, abs, claims). Declarant fails to explain why an ill-defined “potency” with respect to unclaimed treatment of unclaimed diseases would be germane to the claimed invention.
Third, US’033 does not provide any “teaching away” from using AIP as a CaMKII inhibitor suitable for treating CPVT-associated ventricular arrhythmias because a generic and ill-explained reference to “low potency” relative to another compound, for cancer treatment, does not actually “criticize, discredit, or otherwise discourage the solution claimed” (see, e.g., MPEP § 2141.02(VI)), which is the treatment or prevention of arrhythmogenesis in the RyR2R4496C+/- CPVT mouse model (the non-elected species under examination) or otherwise the treatment of CPVT using CaMKII inhibitors generally as taught and suggested by the primary reference.
Fourth, even assuming arguendo, that “potency” was a consideration for AIP in the claimed treatment, MPEP § 2121(I) explains that prior art is presumed fully enabled and operational for everything that it teaches or reasonably suggests, and explicitly identifies that “Efficacy is not a requirement for prior art enablement” (see, e.g., MPEP § 2121(III)), and that further explains that “Conclusive proof of efficacy is not required to show a reasonable expectation of success” (see, e.g., MPEP § 2143.02(I)), but rather Obviousness and a showing of reasonable expectation of success only requires “some degree of predictability” (see, e.g., MPEP § 2143.02(II)), wherein predictability is determined "before the effective filing date of the claimed invention" (see, e.g., MPEP § 2143.02(III)).
Accordingly, the Declarant’s reliance upon the reference to “potency” in US’033 has been fully considered, but not found persuasive.
Paragraphs ¶¶10-11 are understood to suggest that the Cuello reference “teaches away” from gene therapy because Cuello discloses that “it will still be a long and arduous way to implement clinical CaMKII inhibition for heart failure” and that SERCA2a gene therapy clinical trial “failed” (see, e.g., Dec. filed 3/30/2026 at ¶¶10-11). This is not persuasive because Cuello does not provide any “teaching away” from using AIP as a CaMKII inhibitor suitable for treating CPVT-associated ventricular arrhythmias because a generic and ill-explained reference to “low potency” relative to another compound, for cancer treatment, does not actually “criticize, discredit, or otherwise discourage the solution claimed” (see, e.g., MPEP § 2141.02(VI)), which is the treatment or prevention of arrhythmogenesis in the RyR2R4496C+/- CPVT mouse model (the non-elected species under examination) or otherwise the treatment of CPVT using CaMKII inhibitors generally as taught and suggested by the primary reference. Although Cuello discloses challenges faced by artisans in the gene therapy arts, Cuello does not “teach away” from such approaches, but rather identifies known and relevant challenges in the field. More specifically, Cuello, published circa 2016, discloses the state of the prior art for CaMKII inhibitors used in the treatment of heart disease (see, e.g., Cuello at title, abs, passim). Cuello acknowledges that “Proof-of-concept studies in mice and isolated human cardiac myocytes have successfully demonstrated the benefit of [CaMKII inhibitors] in several pathological cardiac conditions” (see, e.g., Cuello at 66 at col I at 1st partial ¶), and notes that
CaMKII targeting strategies have to take cardiac and isoform specificity into account. In this context, the establishment of a gene therapy approach seems “easier” than the development of pharmacological inhibitors. Also, gene therapy studies in large animals or even patients have already been tested . . .
(see, e.g., Cuello at 66 at col I at 1st partial ¶, emphasis added)
Cuello reasonably identifies that one of ordinary skill in the CaMKII inhibitor arts attempting to treat cardiac diseases circa 2016 would reasonably utilize “a gene therapy approach”. Cuello identifies “[d]ifficult hurdles that have to be envisaged” in order “to ultimately achieve clinical translatability”, and identifies the criticality of “appropriate cardiac-specific gene therapy approaches for the expression of inhibitory peptides” (see, e.g., Cuello at 66 at col I at 1st full ¶). Accordingly, Cuello identifies that although difficulties existed in human clinical settings, that “a gene therapy approach” was art-recognized as “easier” and that artisans circa 2016 readily appreciated that such gene therapy approaches required an “appropriate cardiac-specific gene therapy” (see, e.g., Cuello at 66 at col I at 1st partial ¶ to 66 at col II at 1st full ¶). Accordingly, such statements direct artisans to use gene therapy but to research “appropriate cardiac-specific gene therapy approaches for the expression of inhibitory peptides” (see, e.g., Cuello at 66 at col I at 1st full ¶). Accordingly, Cuello does not “teach away” from the claimed invention.
Paragraph ¶11 iterates the opinion that “it is my belief, based on a consideration of the cited references, that one skilled in the art would be prompted to use a small molecule inhibitor such as KN-93 and not a peptide such as AIP for in vivo treatment….”(see, e.g., Dec. filed 3/30/2026 at ¶11). This conclusion does not logically follow the disclosure of Cuello, which explicitly identifies that gene therapy is “easier”:
CaMKII targeting strategies have to take cardiac and isoform specificity into account. In this context, the establishment of a gene therapy approach seems “easier” than the development of pharmacological inhibitors. Also, gene therapy studies in large animals or even patients have already been tested . . .
(see, e.g., Cuello at 66 at col I at 1st partial ¶, emphasis added);
Notably, Declarant’s opinion appears to not meaningfully consider the guidance of Cuello, which literally suggests to artisans that gene therapy approaches were easier than small molecule approaches
For the development of small pharmaceutical compounds, even more challenges have to be faced…
(see, e.g., Cuello at 66 at col I at 1st partial ¶, emphasis added)
The Declarant’s “belief” therefore, does not appear to be based upon the literal disclosure of the prior art, and no clear, objective supporting evidence for Declarant’s position is identified on the instant record.
Paragraph ¶12 appears to incorrectly allege
At the time of our invention involving the use of an AIP encoding polynucleotide in an AAV vector with a cardiac-specific promoter to inhibit CaMKII inhibition in the heart and limit off target, e.g., central nervous system (CNS) effects, it was not known whether the use of AA V to transduce cardiac cells would be pro-arrhythmic rather than anti-arrhythmic, as desired. Because AAV is known to have limited transduction efficiency and may result in heterogenous transduction of cardiac cells, there could consequently be an incomplete inhibition of CaMKII across the heart, which could potentially be more harmful than helpful, compared to no inhibition, in models of arrhythmia.
(see, e.g., Dec. filed 3/30/2026 at ¶12).
This line of arguments was previously raised (see, e.g., Arguments filed 2/06/2024 at 10 at penultimate ¶; see also Dec. filed 2/16/2024 at ¶6), and fully considered on record, but not found persuasive for reasons of record supported by objective evidence and references placed on record at that time (see, e.g., Reply filed 2/22/2024 at 35 at 1st full ¶, 36 at 1st full ¶ to 38 at 1st partial ¶, 48 at final ¶ to 56 at 1st ¶). In brief, such statements are not persuasive for reasons ofrecord (see, e.g., Reply filed 2/22/2024 at 36 at 1st full ¶ to 38 at 1st partial ¶, 48 at final ¶ to 56 at 1st ¶), which are incorporated into the instant response. For example, Hajjar32 and Denegri33 pertain to gene therapy, circa 2014. Hajjar identifies that AAV was considered for the treatment of CPVT circa 2014 (see, e.g., Hajjar at title, passim). Hajjar discloses
Cardiac gene therapy has been evaluated for >20 years, and recently, the application of adeno-associated viral vectors (AAVs) has accelerated the field because AAVs greatly increase the efficiency of prolonged cardiac gene expression after a single delivery compared with previous adenovirus and plasmid-based gene delivery technologies. Furthermore, the lack of human disease caused by AAV makes them an attractive candidate for clinical cardiac gene therapy.
(see, e.g., Hajjar at 2633 at col II at final ¶).
Hajjar explicitly identifies that, circa 2014, in murine models of CPVT, gene transfer with AAV serotype 9 encoding CASQ2 had been used successfully to treat arrhythmogenic phenotypes (see, e.g., Hajjar at 2634 at col I at 1st full ¶). Hajjar addresses the issue of “spatial heterogeneity” raised by Applicant and Declarant (see, e.g., Reply filed 2/08/2024 at 9 at 1st full ¶, 9-10 at bridging ¶; see Dec. filed 3/30/2026 at ¶12; see also Reply filed 3/30/2026 at 13 at 1st full ¶), and specifically notes that the treatment of arrhythmogenic phenotypes was successful
. . .despite the fact that only ≈40% of cardiomyocytes were infected by AAV9 gene delivery.
(see, e.g., Hajjar at 2633 at col II at final ¶).
Accordingly, the lack of 100% transduction of all cells, did not abrogate the successful treatment of a murine model of CPVT. The explanation for this observation is set forth in the prior art of Denegri, which is discussed in Hajjar. Critically, Denegri pertains to the treatment of CPVT in murine models using gene therapy and specifically an AAV serotype 9 encoding CASQ2 (see, e.g., Denegri at title, abs). Denegri notes that AAV9-CASQ2 only had an infection rate of about ≈40% (see, e.g., Denegri at 2679 at col II at 2nd full ¶), but was still successful in treating CPVT (see, e.g., Denegri at title, abs, passim). Denegri explains this as follows:
A puzzling question raised by our study is why, even though the AAV9-CASQ2 construct does not reach all cardiac cells, it induces a remarkable antiarrhythmic efficacy. We believe that biophysical properties that regulate the propagation of the action potential in the heart may provide an explanation for this apparently surprising effect. Accordingly, for a triggered action potential to elicit a premature ventricular complex, it has to be able to propagate to adjacent cells. Because action potential propagation follows the “source-sink” relationship, both active and passive properties of the cardiac tissue determine whether an action potential is able to travel from cell to cell. It is only when adjacent myocytes develop synchronous DADs that the summation of the multiple depolarizations allows propagation of a triggered action potential to the entire heart. The experimental demonstration of this concept has been provided in a most elegant in silico study by Xie et al.28 These authors calculated the number of adjacent cells required for a DAD to generate an action potential and showed that an afterdepolarization is suppressed unless a sufficient number of the neighboring myocytes develop an afterdepolarization on the same beat. Therefore, to prevent propagation of triggered beats, it is not required that all cells are rescued; it is enough that a fraction of them impair propagation of action potentials to prevent life-threatening arrhythmias.
(see, e.g., Denegri at 2680 at col I at 1st full ¶, emphasis added).
Accordingly, circa 2014, an artisan would readily appreciate that “spatial heterogeneity” resulting from less than 100% infection rates of cardiac cells would not abrogate efficacy of gene therapy in the treatment of CPVT in vivo (see, e.g., id). Accordingly, arguments amounting to mere speculation regarding “limited transduction efficiency and may result in heterogenous transduction of cardiac cells” in the absence of clearly addressing the ordinary skill in the art as evidenced by prior art already of record, is not persuasive for reasons of record. Accordingly, the Declarant’s statements at ¶12 appear directly contradicted by prior art already of record showing the state of the prior art circa 2014, but Declarant fails to reconcile their position and opinion with the references of record. Accordingly, Declarant’s position is unsupported by any objective evidence but is instead directly contradicted by the objective evidence already of record; therefore, such arguments and assertions are not persuasive.
At paragraphs ¶¶13-15, it is the Examiner’s understanding that Declarant provides evidence pertaining to an unknown structure referred to as “CN19o”, an unknown structure of “FKPB12.6 fused to AIP”, and AIP, wherein the data allegedly shows “that AIP delivered to animals in vivo surprisingly appears to have better anti-arrhythmic and anti-CPVT activity than other CaMKII inhibitors” (see, e.g., Dec. at ¶13), in an unclaimed model system requiring administration of isoproterenol, epinephrine, and caffeine by intra-peritoneal injection (see id). As an initial matter, even in the light most favorable to Declarant, by Declarant’s own admission, the proffered data of record supports a determination of obviousness because the administration of the CaMKII inhibitor of AIP treats CPVT exactly as suggested by the prior art (see, e.g. MPEP § 716.02(c)(II), noting that “Expected Beneficial Results Are Evidence of Obviousness”, not non-obviousness). The proffered data is not sufficient to establish unexpected results commensurate in scope with the requirements of MPEP § 716.02 because the proffered data is partially illegible (see, e.g., Dec. at ¶13 at Fig. 1b-c) and pertains to undisclosed and unknown structures (e.g., “CN19o”, ““FKPB12.6 fused to AIP”), in unclaimed embodiments (see, e.g., MPEP § 716.02(a) and (b), noting that Declarant has the burden to explain all proffered data per MPEP § 716.02(b)(II) and establish both statistical and practical significance). Furthermore, upon review, the proffered data appears to show that all tested CaMKII inhibitors did, in fact, treat CPVT exactly as suggested by the prior art (see, e.g. Dec. at ¶13; see also MPEP § 716.02(c)(II), noting that “Expected Beneficial Results Are Evidence of Obviousness”, not non-obviousness).
Paragraphs ¶¶14-15 are understood to pertain to an unclaimed invention using an unclaimed small molecule having an unknown structure, namely “CRD2959”, as discussed at ¶14, ¶15, and Figures 2a-2f, which are not all fully legible (see, e.g., Dec. at ¶¶14-15). Such data is of unknown relevance to the claimed invention because the claimed invention is not actually tested relative to CRD2959, and the proffered data is understood to include an in vitro model of cardiomyocytes (see, e.g., Dec. at ¶15). Such data does not satisfy the requirements of MPEP §§ 716.02, 716.05, or 716.07, because such data does not clearly satisfy MPEP § 716.01(b), because the data lacks a clear nexus with the claimed invention. Accordingly, Declarant fails to satisfy their burden (see, e.g., MPEP § 716.02(a) and (b), noting that Declarant has the burden to explain all proffered data per MPEP § 716.02(b)(II) and establish both statistical and practical significance).
Paragraph ¶16 appears to conclude, based on the data set forth at ¶¶13-15 that because of proffered evidence pertaining to an unknown small molecule that was not tested side-by-side with AIP, which was not publicly available before the effective filing date of the claimed invention as required by MPEP § 2143.02(III), and wherein the proffered evidence shows that the expected result pertaining to AIP shows the predicted and expected result in view of Liu (see, e.g. Dec. at ¶13; see also MPEP § 716.02(c)(II), noting that “Expected Beneficial Results Are Evidence of Obviousness”, not non-obviousness), that the proffered data shows that “a priori, and without empirical data, experimental data, it is unpredictable and nonobvious that treatment with any agent known or believed to inhibit CaMKII will effectively suppress CPVT-associated ventricular arrhythmias” (see, e.g. Dec. at ¶16). First, the data fails to establish that a proper, determination of prima facie obviousness was not established because the proffered data was only known to artisans after the effective filing date of the claimed invention as required by MPEP § 2143.02(III). Accordingly, prima facie obviousness was established. Second, the proffered data fails to establish unexpected results because the data fails to satisfy the requirements of MPEP § 716.01 and § 716.02. Specifically, as noted above, the proffered data lacks practical significance because the compared structures are unknown and undisclosed and therefore Declarant fails to satisfy MPEP §§ 716.02(b)(I)-(II). Furthermore, the relevance of the evidence at ¶¶14-15, which appears to pertain to an unclaimed invention using an unclaimed small molecule having an unknown structure, namely “CRD2959” (see, e.g., Dec. at ¶¶14-15) lacks a clear nexus with the invention as claimed as required by MPEP § 716.01(b). Third, the proffered data fails to establish inoperability of the prior art per MPEP § 716.07, because the proffered data literally shows that the known CaMKII inhibitor of AIP, known AVV vector, and known promoter merely yield the exact results taught and suggested in view of the prior art of record (see rejection). Accordingly, the prior art appears fully enabled. Note that the mere fact that Declarant successfully created some undisclosed structure “CRD2959” that did not function as expected is insufficient to establish inoperability of Liu or other references because the prior art is presumed fully enabled and operable for all that it discloses, and this presumption is not overcome by “a mere showing that it is possible to operate within the disclosure without obtaining the alleged product” (see, e.g., MPEP § 716.07; see also In re Weber, 405 F.2d 1403, 160 USPQ 549 (CCPA 1969)). Furthermore, per MPEP § 716.07
It is to be presumed also that skilled workers would as a matter of course, if they do not immediately obtain desired results, make certain experiments and adaptations, within the skill of the competent worker. The failures of experimenters who have no interest in succeeding should not be accorded great weight. In re Michalek, 162 F.2d 229, 74 USPQ 107 (CCPA 1947); In re Reid, 179 F.2d 998, 84 USPQ 478 (CCPA 1950).
Where the affidavit or declaration presented asserts inoperability in features of the reference which are not relied upon, the reference is still effective as to other features which are operative. In re Shepherd, 172 F.2d 560, 80 USPQ 495 (CCPA 1949).
Where the affidavit or declaration presented asserts that the reference relied upon is inoperative, the claims represented by applicant must distinguish from the alleged inoperative reference disclosure. In re Crosby, 157 F.2d 198, 71 USPQ 73 (CCPA 1946). See also In re Epstein, 32 F.3d 1559, 31 USPQ2d 1817 (Fed. Cir. 1994).
Accordingly, Liu and the other references continue to be presumed to be fully enabled. Fourth, regarding skepticism of experts sufficient to satisfy MPEP § 716.05, the MPEP notes that
"The skepticism of an expert, expressed before these inventors proved him wrong, is entitled to fair evidentiary weight, . . . as are the five to six years of research that preceded the claimed invention." In re Dow Chemical Co., 837 F.2d 469, 5 USPQ2d 1529 (Fed. Cir. 1988); Burlington Industries Inc. v. Quigg, 822 F.2d 1581, 3 USPQ2d 1436 (Fed. Cir. 1987) (testimony that the invention met with initial incredulity and skepticism of experts was sufficient to rebut the prima facie case of obviousness based on the prior art).
Here, zero evidence of the existence of any “skepticism of an expert”, expressed before the filing of the instant application, has been identified on record, because the manufactured doubt shown at ¶¶13-16 was unknown in the prior art. To the contrary, an artisan reading the prior art of record, including Hajjar34 and Denegri35, would readily and expectedly predict, in view of Liu, that the administration of a CaMKII inhibitor, including AIP, by any means (e.g., directly or by known gene therapy routes) would predictably and expectedly treat CPVT exactly as suggested by the prior art of record. In sum, the proffered evidence fails to establish unexpected results, inoperability of a prior art reference, or skepticism of experts commensurate in scope with the requirements of MPEP §§ 716, 716.01, 716.02, 716.05, or 716.07.
At paragraph ¶17 the Declarant provides the opinion that the results showing that AIP is “unexpectedly and surprising effective in suppressing arrhythmia in a CPVT model in vivo compared with “CN19o” is “highly surprising” (see, e.g. Dec. at ¶17). It is prima facie unclear why results showing that AIP functions exactly as expected in view of Liu is surprising or unexpected (see also MPEP § 716.02(c)(II), noting that “Expected Beneficial Results Are Evidence of Obviousness”, not non-obviousness). The conclusion that “it is not obvious…” (see, e.g. Dec. at ¶17) is directed to an ultimate legal conclusion, and Examiner notes that per MPEP 716.01(c)(III), any opinions expressed by Declarant regarding legal conclusions are not entitled to any weight. However, the underlying basis for any opinion as to legal conclusions has been fully considered but not found persuasive because the proffered data fails to satisfy the requirements of MPEP § 716.01 and § 716.02 as discussed above. Notably, it is not surprising nor unexpected that different CaMKII inhibitors have some differences (see, e.g., MPEP § 716.02). Furthermore, the selection of CN19o as a comparator is unexplained on record and the structure of the compound is unknown and therefore Declarant fails to satisfy MPEP §§ 716.02(b)(I)-(II). In addition, evidence showing that the prior art compound works exactly as predicted and expected in view of the prior art, supports a conclusion of obviousness per MPEP § 716.02(c)(II).
At paragraph ¶18 the Declarant provides opinions regarding an ultimate legal conclusion, and Examiner notes that per MPEP 716.01(c)(III), any opinions expressed by Declarant regarding legal conclusions are not entitled to any weight; notably, the paragraph at issue provides no new supporting evidence beyond that already considered above. Accordingly, such opinions are unsupported on record.
At paragraph ¶18 the Declarant opines
It is my professional opinion and belief that, at the time of our invention, it was entirely unpredictable and surprising that AAV delivery of AIP to cardiac cells in vivo would work to suppress arrhythmia until we provided the claimed methods.
(see, e.g., Dec. filed 3/30/2026 at ¶12).
This statement fails to explain “why” Declarant would believe this way in view of the prior art of record, which clearly includes prior art that explicitly teaches that CaMKII inhibitors could be utilized to treat CPVT, and such art explicitly included guidance informing artisans that peptide-based CaMKII inhibitors could be administered via known AAVs using known promoters, wherein such prior art components merely performed their art-recognized functions in combination that they do separately. Accordingly, such opinions are not persuasive because they are directly contradicted by art of record and unsupported by actual proof.
At paragraph ¶18 the Declarant opines
Indeed, at the time of our invention, one having skill in the art would have as readily believed that AAV delivery of AIP to cardiac cells in vivo would promote, rather than suppress, arrhythmia or would have no effect on arrhythmia suppression, without extensive empirical testing.
(see, e.g., Dec. filed 3/30/2026 at ¶12).
Declarant’s assertion is unsupported by any actual citation of any prior art teachings available before the effective filing date of the claimed invention as required by MPEP § 2143.02(III). In contrast, the assertion appears directly contradicted by Liu, which teaches and discloses that administration of CaMKII inhibitors to subjects would be predicted and expected to treat CPVT (see rejection). Accordingly, opinions unsupported by actual proof, which appear to be directly contradicted by objective evidence of record, are not persuasive.
The proffered data has been fully considered but deemed insufficient to rebut the presumption of obviousness because the proffered data does not establish results and evidence commensurate in scope with the requirements of MPEP §§ 716, 716.01, 716.02, 716.05, or 716.07 for the reasons discussed above.
Weighing Objective Evidence
Per MPEP § 716.01(d), the ultimate determination of patentability must be based on consideration of the entire record and notes that submission of evidence of patentability does not mandate a conclusion of patentability in and of itself. Accordingly, the Declaration has been fully considered but is not found persuasive because it does not establish unexpected results, skepticism of experts, or inoperability of a prior art reference commensurate in scope with the requirements set forth in the MPEP (see, e.g., MPEP §§ 716, 716.01, 716.02, 716.05, or 716.07).
Therefore, in view of the record as a whole, the Declaration is insufficient to overcome the rejections of record, which are maintained as set forth above.
Pertinent Prior Art and Examiner Notes
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Pellicena36 identifies known CaMKII inhibitors and identifies that such inhibitors were intended to treat arrhythmias circa 2014 (see, e.g., Pellicena at title, abs).
Schneider37 pertains to the usage of gene therapy in cardiovascular disease circa 1993 (see, e.g.. id. at title, abs, passim). Schneider states that
“…gene therapy no must be envisioned as one potential way to deliver therapeutic proteins (or alter the expression of a patient’s own proteins) for, inherently, any disease”
(see, e.g., Schneider at 1937 at col I at 1st ¶).
Pacak38pertains to the use of AAV Vectors for gene transfer in cardiac applications (see, e.g., Pacak at title, abs).
Wolfram39 pertains to and discusses general considerations for utilizing gene therapy to treat cardiovascular diseases circa 2013 (see, e.g., Wolfram, passim), including the usage of cardiac-specific promoters (see, e.g., id. at 3 at col II at 1st partial ¶).
Kreusser40 teaches and discloses a cardiac-specific AAV9 vector system “under control of the cardiac-specific myosin light chain promoter” (see, e.g., id. at abs) utilized to study CaMKII activity in heat failure models (id). Accordingly, cardiac-specific AAV9 vector systems using cardiac-specific promoters were known in the CaMKII arts prior to the effective filing date of the instant invention, and used successfully in animal models (see, e.g., id. at abs, 2 at col II).
Pacak200841 discloses and discusses AAV9 mediated transgene expression in cardiac tissue using cardiac-specific promoters, including cTnC and MLC-2 (see, e.g., Pacak2008 at title, abs).
Sasano42 pertains specifically to gene therapy methods, circa 2013, for the treatment of cardiac arrhythmias (see, e.g., Sasano at title, abs).
Barth43 identifies that even promoters enumerated at amended claims 8-10 and prior claims 21-23 are not absolutely “cardiac-specific”, but instead exhibit varying degrees of off-target expression in non-cardiac cell types (see, e.g., Barth at Fig. 2A-B on 958, comparing cardiac specificity of MLC-2v, α-myosin heavy chain promoter, NCX1 promoters, and showing that each of these promoters express in HUVEC, HEK293T, and Dermal fibroblasts as well as cardiac cells).
Werfel44 identifies that even promoters enumerated at amended claims 8-10 and prior claims 21-23 are not absolutely “cardiac-specific”, but instead exhibit varying degrees of off-target expression in non-cardiac cell types (see, e.g., Werfel at Fig. 2C on 18, 21 at col II at 1st full ¶, noting that even cTnT promoters in an AAV9 vector lead to off-target expression in liver, lung, kidney, and spleen cells).
Tilemann45 identifies that AAV vectors have a maximum packaging capacity of approximately 5 kb (see, e.g., Tilemann at Table 1 on 778) and specifically identifies that
The Myosin Heavy Chain Promoter, which has been used extensively in the generation of transgenic mice that express transgene specifically in cardiomyocytes, is not suitable for AAV vectors because it is 5.5 kb long.
(see, e.g., Tilemann at 780 at col II, emphasis added).
Bailey46 establishes that an artisan would readily appreciate that the MHC promoter referenced by Tilemann refers to α-MHC (see, e.g., Bailey at abs, at 2 at 1st full ¶, identifying that the α-MHC transgenic promoter system comprises a 5.5-kB region).
Hajjar47 and Denegri48 contradict the Applicant and Declarant’s previous allegations of lack of predictability pertaining to both the fields of Gene Therapy and Catecholaminergic Polymorphic Ventricular Tachycardia. Hajjar identifies that gene therapy, circa 2014, was being considered for the treatment of CPVT (see, e.g., Hajjar at title, passim). Hajjar discloses
Cardiac gene therapy has been evaluated for >20 years, and recently, the application of adeno-associated viral vectors (AAVs) has accelerated the field because AAVs greatly increase the efficiency of prolonged cardiac gene expression after a single delivery compared with previous adenovirus and plasmid-based gene delivery technologies. Furthermore, the lack of human disease caused by AAV makes them an attractive candidate for clinical cardiac gene therapy.
(see, e.g., Hajjar at 2633 at col II at final ¶).
Hajjar explicitly identifies that, circa 2014, in murine models of CPVT, gene transfer with AAV serotype 9 encoding CASQ2 had been used successfully to treat arrhythmogenic phenotypes (see, e.g., Hajjar at 2634 at col I at 1st full ¶). Hajjar addresses the issue of “spatial heterogeneity” raised by Applicant (see, e.g., Reply filed 2/08/2024 at 9 at 1st full ¶, 9-10 at bridging ¶), and specifically notes that the treatment of arrhythmogenic phenotypes was successful
. . .despite the fact that only ≈40% of cardiomyocytes were infected by AAV9 gene delivery.
(see, e.g., Hajjar at 2633 at col II at final ¶).
Accordingly, the lack of 100% transduction of all cells, did not abrogate the successful treatment of a murine model of CPVT. The explanation for this observation is set forth in the prior art of Denegri, which is discussed in Hajjar. Critically, Denegri pertains to the treatment of CPVT in murine models using gene therapy and specifically an AAV serotype 9 encoding CASQ2 (see, e.g., Denegri at title, abs). Denegri notes that AAV9-CASQ2 only had an infection rate of about ≈40% (see, e.g., Denegri at 2679 at col II at 2nd full ¶), but was still successful in treating CPVT (see, e.g., Denegri at title, abs, passim). Denegri explains this as follows:
A puzzling question raised by our study is why, even though the AAV9-CASQ2 construct does not reach all cardiac cells, it induces a remarkable antiarrhythmic efficacy. We believe that biophysical properties that regulate the propagation of the action potential in the heart may provide an explanation for this apparently surprising effect. Accordingly, for a triggered action potential to elicit a premature ventricular complex, it has to be able to propagate to adjacent cells. Because action potential propagation follows the “source-sink” relationship, both active and passive properties of the cardiac tissue determine whether an action potential is able to travel from cell to cell. It is only when adjacent myocytes develop synchronous DADs that the summation of the multiple depolarizations allows propagation of a triggered action potential to the entire heart. The experimental demonstration of this concept has been provided in a most elegant in silico study by Xie et al.28 These authors calculated the number of adjacent cells required for a DAD to generate an action potential and showed that an afterdepolarization is suppressed unless a sufficient number of the neighboring myocytes develop an afterdepolarization on the same beat. Therefore, to prevent propagation of triggered beats, it is not required that all cells are rescued; it is enough that a fraction of them impair propagation of action potentials to prevent life-threatening arrhythmias.
(see, e.g., Denegri at 2680 at col I at 1st full ¶, emphasis added).
Accordingly, an artisan would readily appreciate that “spatial heterogeneity” resulting from less than 100% infection rates of cardiac cells would not abrogate efficacy of gene therapy in the treatment of CPVT in vivo (see, e.g., id). Accordingly, the issue of “spatial heterogeneity” was known in the art circa 2014, tested in a murine model of CPVT, and shown not to be an issue, but instead resulted in the successful treatment of CPVT as evidenced by Hajjar and Denegri.
WO2016/168694 A149 establishes that the usage of AAV vector systems to treat CPVT had been taught and disclosed using a different peptide (see, e.g., WO’694 at title, abs, 4 at lines 3-20, 6 at lines 1-5, 15 at line 25 to page 16 at line 15, 17 at lines 5-18, claims 1-8), which expressly identified that using AAV9 “[g]reater than 60% of the heart can be transduced with AAV9” (see, e.g., WO’694 at 24 at lines 19-25).
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RANDALL L BEANE/ Primary Examiner, Art Unit 1654
1 See, e.g., Spec. filed 01/02/2020 at 52 at lines 28-32.
2 See, e.g., Action mailed 9/12/2022 at 2-3 at bridging ¶, noting that the originally elected species expressed an R4561I mutation; see also Action mailed 4/18/2023 at 2-3 at bridging ¶, noting that the originally elected species expressed an R4561I mutation; see also Action mailed 9/06/2023 at 3 at 2nd full ¶, noting that the originally elected species expressed an R4561I mutation; see also Action mailed 2/22/2024 at 3 at 2nd full ¶, noting that the originally elected species expressed an R4561I mutation; see also Action mailed 10/07/2024 at 2-3 at bridging ¶, noting that the originally elected species expressed an R4561I mutation.
3 See previous footnote and prosecution history.
4 See Requirement mailed 1/05/2022, noting that claims readable on the elected species must be identified “including any claims subsequently added” (see id. at 6-7 at bridging ¶).
5 See, e.g., MPEP § 2111.04, noting that “Claim scope is not limited by claim language that suggest or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and noting that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited’”.
6 Liu et al., Calmodulin kinase II inhibition prevents arrhythmias in RyR2(R4496C+/-) mice with catecholaminergic polymorphic ventricular tachycardia, J. Mol. Cell Cardiol., vol. 50(1):214-222 (online 2010 Oct. 23); hereafter “Liu”; cited in IDS filed 10/19/2021 as cite No. 4
7 Nov. 11, 2010; Bayer; cited in IDS filed 1/02/2020 as cite No. 3.
8 Cuello et al., Inhibition of cardiac CaMKII to cure heart failure: step by step towards translation? Basic Res Cardiol. 2016 Nov;111(6):66. (Epub 2016 Sep 28); hereafter “Cuello”; cited in previous action.
9 Tilemann et al., Gene therapy for heart failure. Circ Res. 2012 Mar 2;110(5):777-93; hereafter “Tilemann”; cited in previous action.
10 See, e.g., Liu at abs, 219 at §§ 3.8.
11 See also MPEP § 2144.07, which notes that the selection of a known material based on its suitability for its intended use supports a determination of obviousness because "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327 at 335, 65 USPQ 297, at 301 (1945).
12 Per MPEP § 2143.02(II), “Obviousness does not require absolute predictability”, but instead only “at least some degree of predictability is required”.
13 Per MPEP § 2143.02(I), “Conclusive proof of efficacy is not required to show a reasonable expectation of success”.
14 For example, Table 2 at page 780 of Tilemann demonstrates that for a mouse via IV administration, AAV9 would be selected, but for a canine via intramyocardial route, AAV6 would be selected.
15 AAV vectors are advantageously identified as having numerous benefits at Table 1, with the only drawback of packaging capacity, which is not an issue for short sequences, such as AIP.
16 See, e.g., US’033 at ¶¶[0005]-[0006], [0043], [0086]; see also, Cuello at 66 at col I at 1st partial ¶.
17 See, e.g., Tilemann at 779 at col I at § Tropism of AAV Serotypes, Table 2 at 780.
18 See, e.g., Tilemann at 779 at col I at § Tropism of AAV Serotypes, Table 2 at 780.
19 See, e.g., Liu at abs, 219 at §§ 3.8.
20 Barth et al. (Lentiviral vectors bearing the cardiac promoter of the Na+-Ca2+ exchanger report cardiogenic differentiation in stem cells. Mol Ther. 2008 May;16(5):957-64. doi: 10.1038/mt.2008.30. Epub 2008 Mar 18. PMID: 18388932; PMCID: PMC2717010; hereafter “Barth”; cited in previous action).
21 Werfel et al. (Rapid and highly efficient inducible cardiac gene knockout in adult mice using AAV-mediated expression of Cre recombinase. Cardiovasc Res. 2014 Oct 1;104(1):15-23. doi: 10.1093/cvr/cvu174. Epub 2014 Jul 31. PMID: 25082846; hereafter “Werfel”; cited in previous action).
22 See, e.g., Action mailed 2/22/2024 at 30-34, noting that In re Kubin was taken out of context and erroneously relied upon to imply a non-existent and higher standard for establishing obviousness, which was a conclusion directly contradicted by the clear guidance of the MPEP.
23 KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 402, 127 S. Ct. 1727, 1732, 167 L. Ed. 2d 705, 712, 82 U.S.P.Q.2d 1385, 1389, 2007 BL 12375, at *4 (2007).
24 KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 419, 127 S. Ct. 1727, 1741, 167 L. Ed. 2d 705, 722, 82 U.S.P.Q.2d 1385, 1396, 2007 BL 12375, at *15 (2007).
25 In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009).
26 See also MPEP § 2144.07, which notes that the selection of a known material based on its suitability for its intended use supports a determination of obviousness because "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327 at 335, 65 USPQ 297, at 301 (1945).
27 Hajjar et al. (Gene therapy for the treatment of catecholaminergic polymorphic ventricular tachycardia. Circulation. 2014 Jun 24;129(25):2633-5. doi: 10.1161/CIRCULATIONAHA.114.010586. Epub 2014 Jun 2. PMID: 24958749; PMCID: PMC5902314; hereafter “Hajjar”; cited in previous action mailed 2/22/2024.
28 Denegri et al. (Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age. Circulation. 2014 Jun 24;129(25):2673-81. doi: 10.1161/CIRCULATIONAHA.113.006901. Epub 2014 Jun 2. PMID: 24888331; hereafter “Denegri” ; cited in previous action mailed 2/22/2024.
29 See, e.g., Spec. filed 01/02/2020 at 52 at lines 28-32.
30 See, e.g., Action mailed 9/12/2022 at 2-3 at bridging ¶, noting that the originally elected species expressed an R4561I mutation; see also Action mailed 4/18/2023 at 2-3 at bridging ¶, noting that the originally elected species expressed an R4561I mutation; see also Action mailed 9/06/2023 at 3 at 2nd full ¶, noting that the originally elected species expressed an R4561I mutation; see also Action mailed 2/22/2024 at 3 at 2nd full ¶, noting that the originally elected species expressed an R4561I mutation; see also Action mailed 10/07/2024 at 2-3 at bridging ¶, noting that the originally elected species expressed an R4561I mutation.
31 See 37 CFR 1.56(b)(1)-(3); see also Teva Pharmaceuticals USA, Inc. v. Sandoz, Inc., 789 F. 3d 1335 (2015), at 1343, stating “We have said before, and reaffirm today, that past and future prosecution of related patents may be relevant to the construction of a given claim term”. See, also, Springs Window Fashions LP v. Novo Indus., L.P., 323 F.3d 989, 995 (Fed.Cir.2003), noting that “The public notice function of a patent and its prosecution history requires that a patentee be held to what he declares during the prosecution of his patent”.
32 Hajjar et al. (Gene therapy for the treatment of catecholaminergic polymorphic ventricular tachycardia. Circulation. 2014 Jun 24;129(25):2633-5. doi: 10.1161/CIRCULATIONAHA.114.010586. Epub 2014 Jun 2. PMID: 24958749; PMCID: PMC5902314; hereafter “Hajjar”; cited in previous action mailed 2/22/2024.
33 Denegri et al. (Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age. Circulation. 2014 Jun 24;129(25):2673-81. doi: 10.1161/CIRCULATIONAHA.113.006901. Epub 2014 Jun 2. PMID: 24888331; hereafter “Denegri” ; cited in previous action mailed 2/22/2024.
34 Hajjar et al. (Gene therapy for the treatment of catecholaminergic polymorphic ventricular tachycardia. Circulation. 2014 Jun 24;129(25):2633-5. doi: 10.1161/CIRCULATIONAHA.114.010586. Epub 2014 Jun 2. PMID: 24958749; PMCID: PMC5902314; hereafter “Hajjar”; cited in previous action mailed 2/22/2024.
35 Denegri et al. (Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age. Circulation. 2014 Jun 24;129(25):2673-81. doi: 10.1161/CIRCULATIONAHA.113.006901. Epub 2014 Jun 2. PMID: 24888331; hereafter “Denegri” ; cited in previous action mailed 2/22/2024.
36 Pellicena et al., CaMKII inhibitors: from research tools to therapeutic agents, Front. Pharmacol., vol 5:1-10 (20 February 2014; cited in previous action); hereafter “Pellicena”; cited in IDS filed 10/19/2021 as cite No. 6.
37 Schneider et al., The Advent of Adenovirus, Gene Therapy for Cardiovascular Disease, Circulation, vol. 88(4):1937-1942 (Oct. 1993); hereafter “Schneider”; cited in action mailed 9/06/2023.
38 Pacak et al., AAV vectors for cardiac gene transfer: experimental tools and clinical opportunities. Mol Ther. 2011 Sep;19(9):1582-90. doi: 10.1038/mt.2011.124. Epub 2011 Jul 26. PMID: 21792180; PMCID: PMC3182350; hereafter “Pacak”; cited in previous action.
39 Wolfram et al., Gene therapy to treat cardiovascular disease. J Am Heart Assoc. 2013 Aug 20;2(4):e000119. doi: 10.1161/JAHA.113.000119. PMID: 23963752; PMCID: PMC3828796; hereafter “Wolfram”; cited in previous action.
40 Kreusser et al., Inducible cardiomyocyte-specific deletion of CaM kinase II protects from pressure overload-induced heart failure. Basic Res Cardiol. 2016 Nov;111(6):65. doi: 10.1007/s00395-016-0581-2. Epub 2016 Sep 28. PMID: 27683174; cited in previous action; hereafter “Kreusser”
41 Pacak et al., Tissue specific promoters improve specificity of AAV9 mediated transgene expression following intra-vascular gene delivery in neonatal mice. Genet Vaccines Ther. 2008 Sep 23;6:13. doi: 10.1186/1479-0556-6-13. PMID: 18811960; PMCID: PMC2557000; hereafter “Pacak2008”; cited in previous action.
42 Sasano et al., Gene Therapy for Cardiac Arrhythmias. Acta Cardiol Sin. 2013 May;29(3):226-34. PMID: 27122711; PMCID: PMC4804834; hereafter “Sasano”; cited in previous action.
43 Barth et al. (Lentiviral vectors bearing the cardiac promoter of the Na+-Ca2+ exchanger report cardiogenic differentiation in stem cells. Mol Ther. 2008 May;16(5):957-64. doi: 10.1038/mt.2008.30. Epub 2008 Mar 18. PMID: 18388932; PMCID: PMC2717010; hereafter “Barth”; cited in previous action).
44 Werfel et al. (Rapid and highly efficient inducible cardiac gene knockout in adult mice using AAV-mediated expression of Cre recombinase. Cardiovasc Res. 2014 Oct 1;104(1):15-23. doi: 10.1093/cvr/cvu174. Epub 2014 Jul 31. PMID: 25082846; hereafter “Werfel”; cited in previous action).
45 Tilemann et al., Gene therapy for heart failure. Circ Res. 2012 Mar 2;110(5):777-93; hereafter “Tilemann”; cited in previous action.
46 Bailey et al., Cardiac stem cell genetic engineering using the αMHC promoter. Regen Med. 2009 Nov;4(6):823-33. doi: 10.2217/rme.09.51. PMID: 19903002; PMCID: PMC2869202; cited in previous action.
47 Hajjar et al., Gene therapy for the treatment of catecholaminergic polymorphic ventricular tachycardia. Circulation. 2014 Jun 24;129(25):2633-5. doi: 10.1161/CIRCULATIONAHA.114.010586. Epub 2014 Jun 2. PMID: 24958749; PMCID: PMC5902314; hereafter “Hajjar”; cited in previous action.
48 Denegri et al., Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age. Circulation. 2014 Jun 24;129(25):2673-81. doi: 10.1161/CIRCULATIONAHA.113.006901. Epub 2014 Jun 2. PMID: 24888331; hereafter “Denegri”; cited in previous action.
49 WO2016/168694 A1 (Oct. 20, 2016; cited in previous action).
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