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 .
DETAILED ACTION
Amendments
In the reply filed 02/11/2026, Applicant has amended claims 1 and 22.
Claim Status
Claims 1, 10-17, 20, 22, 30-31, 34-36, 39-40, 44-47, 51, 53-55, 57-59 and 62-66 are pending.
Claims 12-17, 20, 36, 40, 44-47, 53-55, 57-59 and 62-65 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. The election was made with traverse in the reply filed on 01/19/2024.
Claims 1, 10-11, 22, 30-31, 34-35, 39, 51 and 66 are considered on the merits.
Withdrawn Claim Rejections - 35 USC § 112(a)
The prior rejection of claim 22 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of Applicant’s amendment to the claim to recite the CASQ2 transgene encodes a protein comprising an amino acid sequence comprising SEQ ID NO: 1.
Maintained Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1, 10-11, 22, 30-31, 34-35, 39, 51 and 66 stand rejected under 35 U.S.C. 103 as being unpatentable over Denegri et al., (Circulation. 2014;129:2673-2681. Cited in IDS 10/05/2020) in view of Priori et al., (Circ Res. 2011;108:871-883), Kubalova et al., (J Physiol. 2004; 561(2): 515-524) and Sequence Alignment (between instant SEQ ID NO: 1 or 2 with human CASQ2 protein or mRNA published on NCBI 11/17/2006 and 04/20/2008, p. 1-10. Prior art of record).
With respect to claim 1, Denegri teaches a method of treating CPVT comprising administering a therapeutically effective amount of a composition comprising a transgene encoding CASQ2 (title, abstract). Denegri teaches an recombinant AAV9 viral construct is made to carry a transgene encoding wild-type CASQ2 gene (p. 2674, right col, para “Viral construct”), and a therapeutically effective amount of the CASQ2 virus is administered to a mouse model of CPVT (p. 2674, right col, para “AAV9-CASQ2 infection”). Denegri teaches the AAV9-CASQ2 delivery achieved a striking reduction in isoproterenol-induced delayed afterdepolarizations (DADs) and triggered activity (TA) (p. 2677, left col, last para, see Fig 4) and showed a highly significant suppression of the arrhythmic events (p. 2677, right col, para 2, see Fig 5), thus teaches a method of treating CPVT.
However, Denegri teaches treating a recessive CPVT caused by CASQ2 R33Q mutation but is silent on treating a dominant CPVT caused by a gain-of-function mutation in endogenous RYR2.
Nevertheless, Denegri teaches RYR2 mutations cause dominant CPVT and CASQ2 mutations cause recessive CPVT, and both RyR2 and CASQ2 mutations share “the same final pathway of sarcoplasmic reticulum (SR) Ca2+ overload, spontaneous diastolic SR Ca2+ release, and Ca2+ oscillations after adrenergic stimulation that represent a highly arrhythmogenic situation” (referring to Reference #24, p. 2678, right col, para “Discussion”, and also see p. 2673-2674, left col, para 1-2), and teaches the AAV9-CASQ2 delivery achieved a highly significant suppression of the arrhythmic events (p. 2677, right col, para 2).
Priori, being the Reference #24 of Denegri, summarizes the molecular basis and the pathophysiological mechanisms of CPVT caused by RyR2 and CASQ2 mutations (e.g., abstract).
In regard to the new limitation of a gain-of-function mutation in endogenous RYR2 gene, Priori summarizes the human mutations in the RYR2 protein linked to CPVT (see Figs 3-4) and teaches all of these mutations show a consistent behavior characterized by an enhanced response to luminal Ca2+ activation, and the CPVT RyR2 mutations preferentially sensitize the channel to luminal Ca2+ activation (p. 876, right col, para 1), thus teaches the new limitation of a gain-of-function mutation in RYR2 gene that causes dominant CPVT.
Priori teaches a unifying theory for dominant CPVT caused by mutant RyR2 and recessive CPVT caused by mutant CASQ2 (see Fig 6). Priori teaches mutations in RyR2 lower the Store Overload Induced Ca2+ Release (SOICR) threshold (Fig 6C), whereas mutations in CASQ2 reduce Ca2+ buffering capability (Fig 6A). During SR Ca2+ overload, the free luminal Ca2+ level is more likely to exceed the RyR2 mutation-lowered SOICR threshold (Fig 6C, bottom) or the threshold lacking SR Ca2+ buffering by CASQ2 mutations resulting in a fast recovery of SR free Ca2+ after each Ca2+ release (Fig 6A, bottom), leading to tachycardias (see Fig 6 legend and p. 879, left col, last para). Priori teaches a promising approach for suppressing CPVT is the prevention of SR Ca2+ overload (p. 880, left col, 1st full para), and refers to Kubalova et al (Reference #91) demonstrating that changing the level of CASQ2 protein markedly alter the dynamics of SR Ca2+ recovery after SR Ca2+ release and the frequency of SOICR (p. 879, right col, 2nd full para).
Kubalova, being the Reference #91 of Priori, teaches overexpressing CASQ2 by an adenovirus vector in ventricular myocytes results in a significant increase in the Ca2+ interwave intervals, and the rate of [Ca2+]SR recovery following Ca2+ release increases ∼3-fold in CASQ2-overexpressing myocytes (e.g., abstract; p. 519, left col, bottom half, also see Fig 4D), suggesting overexpressing CASQ2 prolongs the period for SR free Ca2+ recovery after SR Ca2+ release.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating CPVT comprising administering a therapeutically effective amount of a composition comprising a transgene encoding CASQ2 in which the CPVT is a recessive CPVT caused by CASQ2 mutation disclosed by Denegri, by substituting the recessive CPVT with a dominant CPVT caused by a gain-of-function mutation in RYR2 as suggested by Denegri, Priori and Kubalova with a reasonable expectation of success. Since Denegri teaches both dominant CPVT caused by RyR2 mutations and recessive CPVT caused by CASQ2 mutations share “the same final pathway of sarcoplasmic reticulum (SR) Ca2+ overload, spontaneous diastolic SR Ca2+ release, and Ca2+ oscillations after adrenergic stimulation that represent a highly arrhythmogenic situation” (p. 2678, right col, para “Discussion” and p. 2673-2674, left col, para 1-2), since Priori teaches a unifying theory for dominant CPVT caused by mutant RyR2 and recessive CPVT caused by mutant CASQ2 (see Fig 6) and suggests a promising approach for suppressing CPVT by the prevention of SR Ca2+ overload (p. 880, left col, 1st full para) and refers to Kubalova et al demonstrating changing the level of CASQ2 protein markedly alter the dynamics of SR Ca2+ recovery after SR Ca2+ release and the frequency of SOICR (p. 879, right col, 2nd full para), and since Kubalova teaches overexpressing CASQ2 in ventricular myocytes results in a significant increase in the Ca2+ interwave intervals and a 3-fold increase in the rate of [Ca2+]SR recovery following Ca2+ release (e.g., abstract; p. 519, left col, bottom half, also see Fig 4D), one of ordinary skill in the art would have had a reason to substitute the subject with the dominant CPVT caused by RYR2 mutations in Denegri’s method of CASQ2 gene therapy in order to prolong the period for SR free Ca2+ recovery after SR Ca2+ release and thus to reduce the frequency of SOICR and suppress CPVT as suggested by Kubalova and Priori.
Furthermore, with respect to a reasonable expectation of success, it would be predictably obvious to treat dominant CPVT caused by RYR2 mutations when practicing the method of Denegri. In re O' Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988) (citations omitted) (The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful.). Therefore, one of ordinary skill in the art could have pursued the known potential option of using CASQ2 gene therapy of Denegri to treat dominant CPVT caused by RYR2 mutations with a reasonable expectation of success. This reasonable expectation of success is supported by: (1) the reference of Denegri et al. contained a detailed enabling methodology for CASQ2 gene therapy on recessive CPVT that could easily be applied to other CPVTs (i.e., a dominant CPVT caused by RYR2 mutations), (2) Priori provides suggestions that both recessive and dominant CPVTs share a unifying mechanism of SR Ca2+ overload and refers to Kubalova demonstrating that changing the level of CASQ2 protein markedly alter the dynamics of SR Ca2+ recovery after SR Ca2+ release and the frequency of SOICR (p. 879, right col, 2nd full para), and (3) the success of making and using CASQ2 overexpression in cardiomyocytes prolongs the period for SR free Ca2+ recovery after SR Ca2+ release as taught by Kubalova suggest modification of the method of CASQ2 gene therapy of Denegri to treat dominant CPVT caused by RYR2 mutations would be successful.
However, Denegri teaches the method of treating CPVT in a mouse model, but Denegri in view of Priori and Kubalova, does not specifically teach treating CPVT in a human patient.
Nevertheless, Denegri teaches in CPVT patients, caused either by RyR2 mutations or by CASQ2 mutations, the recurrence of life-threatening arrhythmic episodes on medications is quite common despite compliance with β-blocker therapy, thus there is a need for new therapeutic approaches and for the identification of a cure for this disease (p. 2674, left col, para 3) and their disease model replicates what happens in the human form of the disease (p. 2678, right col, last para). Denegri teaches the preclinical data provide the rational for envisioning viral gene transfer as a novel therapeutic approach in CPVT patients (p. 2681, para “Clinical perspective”). Furthermore, Priori summarizes the human mutations in the RYR2 protein (see Fig 3) and contemplates the therapeutic approaches to CPVT in human patients (see p. 880).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating dominant CPVT in a mouse model suggested by Denegri in view of Priori and Kubalova, by substituting with a human dominant CPVT patient as suggested by Denegri and Priori with a reasonable expectation of success. Since Denegri teaches there is a need for new therapeutic approaches and for the identification of a cure for CPVT in human patients (p. 2674, left col, para 3) and their disease model replicates what happens in the human form of CPVT (p. 2678, right col, last para) thus their preclinical data provide the rational for envisioning viral gene transfer as a novel therapeutic approach in CPVT patients (p. 2681, para “Clinical perspective”), and since Priori summarizes the human mutations in the RYR2 protein (see Fig 3) and contemplates the therapeutic approaches to CPVT in human patients (see p. 880), one of ordinary skill in the art would have had a reason to substitute with a human dominant CPVT patient having a RyR2 mutation in the method of Denegri in view of Priori and Kubalova, in order to provide a novel therapeutic approach in CPVT human patients as suggested by Denegri (p. 2681, para “Clinical perspective”).
With respect to claim 10 directed to the mutation in RYR2 resulting in an increase in cytosolic calcium release in a cardiac myocyte, as stated supra, Priori teaches mutations in RyR2 lower the SOICR threshold (Fig 6C) thus during SR Ca2+ overload, the free luminal Ca2+ level is more likely to exceed the RyR2 mutation-lowered SOICR threshold (Fig 6C, bottom), leading to severe Ca2+ spillover into cytosol (see Fig 6 and legend). Priori teaches this enhanced SOICR has been observed in cardiomyocytes isolated from various knock-in mice harboring CPVT RyR2 mutations (p. 876, last para). Accordingly, one of ordinary skill in the art would have appreciated that the mutation in RYR2 would have resulted in an increase in cytosolic calcium release (i.e., Ca2+ spillover into cytosol) in a cardiac myocyte contacted with a RYR2 agonist (i.e., leading to SR Ca2+ overload).
With respect to claim 11 directed to the mutation in RYR2 being selected from a list of mutations, as stated supra, Priori summarizes the human mutations in the RYR2 protein (see Figs 3-4), including, e.g., L433P and R176Q/T2504M located in the N-terminal region of the channel; mutations S2246L and R2474S located in the central region; and Q4201R, N4104K, R4496C, I4867M, N4895D, and V4653F located in the C-terminal region. All of these mutations show a consistent behavior characterized by an enhanced response to luminal Ca2+ activation (p. 876, right col, para 1). Accordingly, one of ordinary skill in the art would have appreciated that the gain-of-function mutation in RYR2 would have been selected from the list of mutations in the instant claim.
With respect to claim 22 directed to the CASQ2 having an amino acid sequence comprising SEQ ID NO: 1, as stated supra, Denegri teaches a transgene encoding mouse wild-type CASQ2 gene (p. 2674, right col, para “Viral construct”), which has a sequence (NCBI Reference Sequence: NP_033944.2) that is about 91% identical to the amino acid sequence of SEQ ID NO: 1.
Since Denegri, in view of Priori and Kubalova, suggests to treat a human patient, it would have been obvious to use a transgene comprising human wild-type CASQ2 gene sequence encoding a human wild-type CASQ2 protein in treating human patients. The human wild-type CASQ2 protein has a sequence (NCBI Reference Sequence: NP_001223.1, prior art of record) that is 100% identical to the amino acid sequence of SEQ ID NO: 1 as shown in previously attached Sequence Alignment file (p. 1-2).
Accordingly, it would have been obvious for one of ordinary skill in the art to have chosen the human CASQ2 amino acid sequence of SEQ ID NO: 1 with a reasonable expectation of success. One would have had a reason to do so because it was a well-known sequence disclosed in the prior art as shown in attached Sequence Alignment file (p. 6-7). Furthermore, it is noted that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
With respect to claim 30 directed to the composition comprising a vector, claim 31 directed to the vector comprising a viral vector, claim 34 directed to the viral vector comprising an AAV, and claim 35 directed to the AAV comprising an AAV9, and claim 39 directed to the AAV comprising a recombinant capsid protein, as stated supra, Denegri teaches a composition comprising a recombinant AAV9 viral construct is made to carry a transgene encoding CASQ2 (p. 2674, right col, para “Viral construct”), thus teaches claims 30-31, 34-35 and 39.
With respect to claim 51 directed to the method further comprising measuring expression of triadin or junctin in a cardiac cell in the patient following the administration of the composition, Denegri teaches measuring expression of triadin and junctin in a cardiac cell in the mouse model following the administration of the composition (p. 2675, left col, para 2 “Immunoblotting”, see Fig 2 and Fig 6).
With respect to claim 66 directed to the CASQ2 transgene comprising a nucleic acid sequence comprising SEQ ID NO: 2, as discussed above, since Denegri, in view of Priori and Kubalova, suggests to treat a human patient, it would have been obvious to use a transgene comprising human wild-type CASQ2 cDNA in treating human patients. The human wild-type CASQ2 cDNA has a sequence (NCBI Reference Sequence: NM_001232.2, prior art of record, p. 8-10) that is 100% identical to the nucleic acid sequence of SEQ ID NO: 2 as shown in attached Sequence Alignment file (p. 3-5).
Accordingly, it would have been obvious for one of ordinary skill in the art to have chosen the human wild-type CASQ2 cDNA nucleic acid sequence of SEQ ID NO: 2 with a reasonable expectation of success. One would have had a reason to do so because it was a well-known sequence disclosed in the prior art as shown in attached Sequence Alignment file (p. 8-10). Furthermore, it is noted that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 02/11/2026 are acknowledged.
Applicant argues that the cited art, taken alone or in combination, fails to teach or suggest each element of Applicant's amended claims. Moreover, one of ordinary skill in the art would be neither motivated to combine these references to arrive at the claimed invention nor be imbued with a reasonable expectation of success for practicing the claimed invention armed with only the teachings of the asserted art (Remarks, p. 8, and detailed argument follows).
Applicant’s arguments have been fully considered but they are not persuasive. The detailed response are as follows.
Applicant first argues that these limitations in amended claim 1 are neither taught nor disclosed by the proposed combination of references. (Remarks, p. 9, para 1).
As discussed above, in regard to the new limitation of a gain-of-function mutation in endogenous RYR2 gene, Priori summarizes the human mutations in the RYR2 protein linked to CPVT (see Figs 3-4) and teaches all of these mutations show a consistent behavior characterized by an enhanced response to luminal Ca2+ activation, and the CPVT RyR2 mutations preferentially sensitize the channel to luminal Ca2+ activation (p. 876, right col, para 1), thus teaches the new limitation of a gain-of-function mutation in RYR2 gene that causes dominant CPVT.
Applicant additionally argues that nothing in Priori suggests the use of CASQ2 as a therapeutic approach for dominant RyR2-mut CPVT. (Remarks, p. 9, para 3).
As discussed above, Denegri teaches the use of CASQ2 as a therapeutic approach for treating recessive CPVT. The difference between Denegri and the instant invention is that the instant invention uses the CASQ2 gene therapy for treating dominant CPVT caused by a gain-of-function mutation of RYR2 gene.
Priori is cited to teach a unifying theory (SOICR) for dominant CPVT caused by mutant RyR2 (i.e., claimed by the instant invention) and recessive CPVT caused by mutant CASQ2 (taught by Denegri) (see Fig 6 and p. 879, last para). Priori proposes a promising approach for suppressing CPVTs by preventing SR Ca2+ overload (p. 880, left col, 1st full para). Priori teaches “The level of CASQ2 has also been suggested to be important in modulating the activity of RyR2” and refers to Kubalova et al demonstrating that changing the level of CASQ2 protein markedly alter the dynamics of SR Ca2+ recovery after SR Ca2+ release and the frequency of SOICR (p. 879, right col, 2nd full para).
Kubalova teaches overexpressing CASQ2 by a virus vector (a similar approach used by Denegri) in ventricular myocytes results in a significant increase in the Ca2+ interwave intervals, and the rate of [Ca2+]SR recovery following Ca2+ release increases ∼3-fold (e.g., abstract; p. 519, left col, bottom half, also see Fig 4D), indicating overexpressing CASQ2 slows down the SR free Ca2+ recovery.
Accordingly, one of ordinary skill in the art would have expected that slowing down the SR Ca2+ recovery thus reducing the SOICR (by overexpressing CASQ2 as suggested by Denegri and Kubalova) would have suppressed CPVTs caused by SOICR, which is a common mechanism for both RyR2-mut CPVT and CASQ2-mut CPVT suggested by Priori.
Applicant additionally argues that the Office has selectively pulled this from Priori without considering the reference as a whole. The Office cannot extract a statement from Priori out of context and give it a meaning it would not have had to one of ordinary skill in the art. Similarly, the Office cannot rely on a single aspect of Priori and use it with hindsight to find obviousness (Remarks, p. 9, last para).
As a first matter, it is noted that Applicant does not specifically point out how the examiner selectively pulls, extracts out of context, a single aspect of Priori. On the contrary, Priori summarizes the review with “In vitro studies and development of knock-in mice have provided important information that have advanced the field and suggest that SOICR is likely to be the common mechanism for a variety of mutations in these 2 genes (i.e., RYR2 and CASQ2 genes). The field has been particularly productive in bringing advancements to the clinics where new therapies have already been introduced. Advances in our understanding of the regulation of intracellular Ca2+ in health and disease will facilitate the development of novel risk stratification and management scheme to improve survival and quality of life of CPVT patients.” (p. 880, last section “Summary”. Underlined by examiner).
Applicant further argues that the Office selectively omits that Priori teaches a second promising approach, which is the resolution of the defect in Store Overload Induced Ca2+ Release (SOICR) by RyR2 modulation (Priori at page 880, first full paragraph). Moreover, the Office also overlooks that Priori provides several examples of both approaches including β-blockers, flecainide, a Na+ channel blocker that inhibits RyR2, verapamil, which may also inhibit RyR2, small molecules thought to inhibit RyR2, and a CaMKII inhibitor. Conspicuously absent from this list is any mention of a Ca2+ buffering agent, much less CASQ2 (Remarks, p. 10, para 1).
Applicant is reminded that a 35 U.S.C. § 103 based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, as cited by Applicant, Priori proposes two approaches to suppress CPVT: (1) the prevention of SR Ca2+ overload and (2) the resolution of the defect in SOICR by RyR2 modulation, both aiming at the common mechanism of SOICR in both RyR2-mut CPVT (in the instant invention) and CASQ2-mut CPVT (treated by Denegri). Thus, one of ordinary skill in the art would have understood that Priori teaches a common mechanism of CPVTs and suggests common approaches to suppress the CPVTs. In regard to Priori being silent on a Ca2+ buffering agent, much less CASQ2, on the contrary, Priori teaches “The level of CASQ2 has also been suggested to be important in modulating the activity of RyR2” and refers to Kubalova et al demonstrating that changing the level of CASQ2 protein markedly alter the dynamics of SR Ca2+ recovery after SR Ca2+ release and the frequency of SOICR (p. 879, right col, 2nd full para. Underlined by examiner). Thus, Priori clearly mentions CASQ2 may be a resolution of the defect in SOICR by RyR2 modulation when considering the reference as a whole.
Applicant additionally argues that there is no teaching or suggestion in Kubalova or Priori of using CASQ2 as a therapeutic for any form of CPVT. Instead, Kubalova teaches an in vitro model derived from Sprague-Hawley rats. The myocytes were transfected with an adenoviral vector carrying a CASQ2 transgene, an antisense CASQ2 transgene, or a truncated CASQ2 coding sequence, with the truncated CASQ2 coding sequence being used as the control. There is no data from untransfected cells or any other data related to endogenous CASQ2 in these myocytes, nor is there any teaching or suggestion of a RyR2 mutation in the myocytes. Kubalova does not teach or suggest any method of treatment of either dominant or recessive CPVT. Moreover, Priori only discusses Kubalova in the context of the functional and structural consequences of CASQ2 mutations and not as relevant to any therapeutic approach. Priori also does not teach or suggest CASQ2 as a therapeutic agent (Remarks, p. 10-11).
Applicant is reminded, 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). In the instant case, as discussed above, Denegri teaches the use of CASQ2 as a therapeutic agent for treating recessive CPVT. Priori, as a whole, teaches a common mechanism (SOICR) and suggests common approaches to suppress the CPVTs of both RyR2-mut CPVT (in the instant invention) and CASQ2-mut CPVT (treated by Denegri). Kubalova, referred to by Priori, teaches overexpressing CASQ2 by a virus vector (a similar approach used by Denegri) in ventricular myocytes slows down the SR free Ca2+ recovery.
Accordingly, one of ordinary skill in the art would have expected that slowing down the SR Ca2+ recovery thus reducing the SOICR (by overexpressing CASQ2 as suggested by Denegri and Kubalova) would have suppressed CPVTs caused by SOICR, which is a common mechanism for both RyR2-mut CPVT and CASQ2-mut CPVT suggested by Priori.
Applicant further argues that one of ordinary skill in the art would not be motivated to combine, and would not have had a reasonable expectation of success (Remarks, p. 11-12).
As discussed above, one of ordinary skill in the art would have had a reason to substitute the recessive CASQ2-mut CPVT subject with the dominant CPVT caused by RYR2 mutations in Denegri’s method of CASQ2 gene therapy in order to prolong the period for SR free Ca2+ recovery after SR Ca2+ release and thus to reduce the frequency of SOICR and suppress CPVT as suggested by Kubalova and Priori. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success because: (1) the reference of Denegri et al. contained a detailed enabling methodology for CASQ2 gene therapy on recessive CPVT that could easily be applied to other CPVTs (i.e., a dominant CPVT caused by RYR2 mutations), (2) Priori provides suggestions that both recessive and dominant CPVTs share a unifying mechanism of SR Ca2+ overload and refers to Kubalova demonstrating that changing the level of CASQ2 protein markedly alter the dynamics of SR Ca2+ recovery after SR Ca2+ release and the frequency of SOICR (p. 879, right col, 2nd full para), and (3) the success of making and using CASQ2 overexpression in cardiomyocytes prolongs the period for SR free Ca2+ recovery after SR Ca2+ release as taught by Kubalova suggest modification of the method of CASQ2 gene therapy of Denegri to treat dominant CPVT caused by RYR2 mutations would be successful.
In regard to the argument that Kubalova's artificial in vitro system would not be sufficient to convince the skilled person that such a therapeutic has a reasonable expectation of success, one of the ordinary skill in the art would have understood that a clinical therapy is being developed by a bench-to-bedside approach, starting from an artificial in vitro system. For example, Priori teaches in vitro studies and development of knock-in mice have provided important information that have advanced the field, and the field has been particularly productive in bringing advancements to the clinics where new therapies have already been introduced. Advances in our understanding of the regulation of intracellular Ca2+ in health and disease will facilitate the development of novel risk stratification and management scheme to improve survival and quality of life of CPVT patients. (p. 880, last section “Summary”).
Applicant finally argues that the obviousness rejection is predicated on unsupported conclusions and improper hindsight analysis of the cited references. Without the benefit of improper hindsight gleaned from the benefit of Applicant's disclosure, one of ordinary skill in the art armed with the combined teachings of Denegri, Priori, Kubalova, and Sequence Alignment would fail to arrive at Applicant's claimed invention (Remarks, p. 12).
In response to applicant's argument, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, as discussed above, Denegri teaches the use of CASQ2 as a therapeutic agent for treating recessive CPVT. Priori teaches a common mechanism (SOICR) and suggests common approaches to suppress the CPVTs of both RyR2-mut CPVT (in the instant invention) and CASQ2-mut CPVT (treated by Denegri). Kubalova, referred to by Priori, teaches overexpressing CASQ2 by a virus vector (a similar approach used by Denegri) in ventricular myocytes slows down the SR free Ca2+ recovery thus reduces SOICR. Accordingly, one of ordinary skill in the art would have combined the teachings of Denegri, Priori and Kubalova to arrive at a method of CASQ2 gene therapy for dominant CPVT patients having a gain-of-function RYR2 mutation.
In summary, Applicant’s arguments are not persuasive, thus the prior rejection over Denegri in view of Priori, Kubalova and Sequence Alignment has been maintained.
Maintained Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 10-11, 22, 30-31, 34-35, 39, 51 and 66 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims of US Patent Nos. 11,173,215, 10,195,292, 9,700,636, or 8,859,517, in view of Priori et al., (Circ Res. 2011;108:871-883) and Kubalova et al., (J Physiol. 2004; 561(2): 515-524). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patented claims recite a method of treating recessive CPVT in a human patient, the method comprising introducing an AAV vector, such as an AAV2/9, comprising a nucleic acid encoding a wild-type human CASQ2 protein into a cardiomyocyte in the patient, wherein physiological levels of expression of CASQ2 are restored following administration of the AAV vector to the patient, wherein triadin and junctin are restored. It is noted that it is obvious to use a wild-type human CASQ2 cDNA to express the wild-type human CASQ2 protein to treat a human patient.
However, patented claims do not recite the patient having a dominant CPVT caused by a gain-of-function mutation in endogenous gene encoding RYR2 selected from a list of mutations, nor teach the mutation results in an increase in cytosolic calcium release in a cardiac myocyte.
Priori summarizes the molecular basis and the pathophysiological mechanisms of CPVT caused by RyR2 and CASQ2 mutations (e.g., abstract). Priori teaches a unifying theory for dominant CPVT caused by mutant RyR2 and recessive CPVT caused by mutant CASQ2 (see Fig 6). Priori teaches mutations in RyR2 lower the Store Overload Induced Ca2+ Release (SOICR) threshold (Fig 6C), whereas mutations in CASQ2 reduce Ca2+ buffering capability (Fig 6A). During SR Ca2+ overload, the free luminal Ca2+ level is more likely to exceed the RyR2 mutation-lowered SOICR threshold (Fig 6C, bottom) or the threshold lack of SR Ca2+ buffering by CASQ2 mutations resulting in a fast recovery of SR free Ca2+ after each Ca2+ release (Fig 6A, bottom), leading to arrhythmias (see Fig 6 legend and p. 879, left col, last para). Priori summarizes the human mutations in the RYR2 protein (see Figs 3-4), including, e.g., L433P and R176Q/T2504M located in the N-terminal region of the channel; mutations S2246L and R2474S located in the central region; and Q4201R, N4104K, R4496C, I4867M, N4895D, and V4653F located in the C-terminal region (p. 876, right col, para 1). Priori teaches mutations in RyR2 lower the SOICR threshold (Fig 6C) thus during SR Ca2+ overload, lead to severe Ca2+ spillover into cytosol (i.e., resulting in an increase in cytosolic calcium release, see Fig 6 and legend). Priori teaches this enhanced SOICR has been observed in cardiomyocytes isolated from various knock-in mice harboring CPVT RyR2 mutations (p. 876, last para).
Priori teaches a promising approach for suppressing CPVT is the prevention of SR Ca2+ overload (p. 880, left col, 1st full para), and refers to Kubalova et al (Reference #91) demonstrating that changing the level of CASQ2 protein markedly alter the dynamics of SR Ca2+ recovery after SR Ca2+ release and the frequency of SOICR (p. 879, right col, 2nd full para).
Kubalova, being the Reference #91 of Priori, teaches overexpressing CASQ2 by an adenovirus vector in ventricular myocytes results in a significant increase in the Ca2+ interwave intervals, and the rate of [Ca2+]SR recovery following Ca2+ release increases ∼3-fold in CASQ2-overexpressing myocytes (e.g., abstract; p. 519, left col, bottom half, also see Fig 4D), suggesting overexpressing CASQ2 prolongs the period for SR free Ca2+ recovery after SR Ca2+ release.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating recessive CPVT patients recited in patented claims, by substituting with a dominant CPVT patient having a gain-of-function mutation in endogenous gene encoding RYR2 as suggested by Priori and Kubalova with a reasonable expectation of success. Since Priori teaches a unifying theory for dominant CPVT caused by mutant RyR2 and recessive CPVT caused by mutant CASQ2 (see Fig 6) and suggests a promising approach for suppressing CPVT by the prevention of SR Ca2+ overload (p. 880, left col, 1st full para) and refers to Kubalova et al demonstrating changing the level of CASQ2 protein markedly alter the dynamics of SR Ca2+ recovery after SR Ca2+ release and the frequency of SOICR (p. 879, right col, 2nd full para), and since Kubalova teaches overexpressing CASQ2 in ventricular myocytes results in a significant increase in the Ca2+ interwave intervals and a 3-fold increase in the rate of [Ca2+]SR recovery following Ca2+ release (e.g., abstract; p. 519, left col, bottom half, also see Fig 4D), one of ordinary skill in the art would have had a reason to substitute the subject with the dominant CPVT caused by RYR2 mutations in the claimed CASQ2 gene therapy method in order to prolong the period for SR free Ca2+ recovery after SR Ca2+ release and thus to reduce the frequency of SOICR and suppress CPVT as suggested by Kubalova and Priori.
Since the instant application claims obvious over cited patent claims, in view of Priori and Kubalova, said claims are not patentably distinct.
Response to Traversal:
Applicant' s arguments filed on 02/11/2026 (p. 13 of Remarks) are acknowledged and have been discussed above.
Conclusion
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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