DETAILED ACTION
This action is in reply to papers filed 7/28/2026. Claims 1-9,11-12, 14-15, 19-23, 25-26, 28-30, 33-34. 36-37, 39-40, 42 and 58-60 are pending and examined herein.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230241249A1, Published 8/3/2023.
Withdrawn Rejection
The U.S.C. 112(a) rejection of claims 1-2, 5-9, 11-12, 14-15, 19-23, 25-26, 28-30, 33-34. 36-37, 39-40, 42 and 58-60 as being not enabled is withdrawn. The rejection is withdrawn in view of the cancellation of the limitation of ‘preventing heart disease’.
Maintained Rejection(s)
The 103 (a) rejection of claims 1-4, 6, 42 and 58-59 as being unpatentable over The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’, is maintained. Applicant’s arguments will be addressed following maintained rejection.
The 103 (a) rejection of claims 5, 7-9, 11-12, 14-15, 23, 29 and 37 as being unpatentable over The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’ as applied to claims 1-4, 6, 42 and 58-59 above, and further in view of Reid (PgPub US20220154217A1, Filed 3/31/2020) and Giordano et al. (PgPub US20090082293A1, Published 3/26/2009) is maintained. Applicant’s arguments will be addressed following maintained rejection.
The 103 (a) rejection of claims 19-22 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’ as applied to claim 1-4, 6, 42 and 58-59 above, and further in view of Makarewich et al. (eLife. 2018 Oct 9;7:e38319.; Ref. C4 in IDS filed 10/11/2023) is maintained. Applicant’s arguments will be addressed following maintained rejection.
The 103 (a) rejection of claims 25-26 and 28 rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System. (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’ as applied to claim 1-4, 6, 42 and 58-59 above, and further in view of Wilson (PgPub US US20070036760A1, Published 2/15/2007; Ref. A1 in IDS filed 10/11/2023) is maintained. Applicant’s arguments will be addressed following maintained rejection.
The 103 (a) rejection of Claim 30 as being unpatentable The Board of Regents of the University of Texas System in view of The Board of Regents of the University of Texas System. (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’, Reid (PgPub US20220154217A1, Filed 3/31/2020) and Giordano et al. (PgPub US20090082293A1, Published 3/26/2009) as applied to 1-9, 11-12, 14-15, 23, 29, 37, 42 and 58-59 (Prior Art Rejection 2) above, and further in view of Sheikh et al. (PgPub US20200215155A1, Filed 9/20/2018) is maintained. Applicant’s arguments will be addressed following maintained rejection.
The 103 (a) rejection of claim(s) 33-36 rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’ as applied to claim 1-4, 6, 42 and 58-59 above, and further in view of Olson et al. (PgPub US20170298107A11, Published 10/19/2017; Ref. A8 in IDS filed 4/24/2024) is maintained. Applicant’s arguments will be addressed following maintained rejection.
The 103 (a) rejection of Claim 39 as being unpatentable over The Board of Regents of the University of Texas System in view of The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’, Reid (PgPub US20220154217A1, Filed 3/31/2020) and Giordano et al. (PgPub US20090082293A1, Published 3/26/2009) as applied to 1-9, 11-12, 14-15, 23, 29, 37, 42 and 58-59 (Prior Art Rejection 2) above, and further in view of Choi et al. (WO2020086881A1, Published 4/30/2020) is maintained. Applicant’s arguments will be addressed following maintained rejection.
The 103 (a) rejection of claim 60 is rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), Reid (PgPub US20220154217A1, Filed 3/31/2020) and Wilson (PgPub US US20070036760A1, Published 2/15/2007; Ref. A1 in IDS filed 10/11/2023) is maintained. Applicant’s arguments will be addressed following maintained rejection.
The rejections are copied below for Applicant’s convenience. Applicant’s arguments will be addressed following maintained rejections. Arguments presented in the ‘Ivey Declaration’ will also be addressed.
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 (i.e., changing from AIA to pre-AIA ) 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.
Prior Art Rejection 1
Claim(s) 1-4, 6, 42 and 58-59 remain rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’.
Regarding claim 1 and claim 42, Univ of Texas teach a method of correcting a genetic defect (i.e. treating (Pg. 21, lines 20-22)) in a cell in a subject comprising: (a) providing a non-muscle cell from said subject; (b) administering an effective amount of a recombinant adeno-associated virus (rAAV) virion (Pg. 32, line 15+), the rAAV virion comprising an AAV capsid (paragraph bridging Pgs. 35- 36, line 17) and an expression cassette comprising a polynucleotide into said non-muscle cell expressing (i) exogenous therapeutic genes operably linked to a promoter (Pg. 17, lines 11-28); and contacting said non-muscle cell with a muscle cell having a genetic defect, wherein said non-muscle cell expressing the therapeutic gene will fuse with said muscle cell and deliver said therapeutic gene or genes to said muscle cell, thereby correcting said genetic defect (paragraph bridging Pg. 4 and Pg. 5). Although Univ of Texas teaches the exogenous therapeutic gene to be Myoximer, Univ of Texas also notes that heart-specific DWORF (as further in claim 1 and claim 42) is similar to Myoximer (Pg. 12, lines 14-19). In fact, Univ of Texas teaches DWORF localizes to the sarcoplasmic reticulum of cardiomyocytes where it associates with the SERCA calcium ATPase and stimulates its activity. Thus, there is a reasonable expectancy in the similarities in function of the two therapeutic genes~ DWORF and Myoximer.
In one embodiment, Univ of Texas teaches the genetic disease is Pompe disease. Univ of Texas notes that the disease is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. This build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly the heart, skeletal muscles, liver and nervous system. Univ of Texas teaches as the disease progresses heart muscles thicken and progressively fail. Without treatment, death usually occurs due to heart failure and respiratory weakness. This teaching by Univ of Texas establishes the treatment method of Univ of Texas prevents heart failure (as further in claim 1). Univ of Texas teaches the usual presenting features of Pompe disease include cardiomyopathy (as in claim 2, claim 3, claim 4 and claim 6) (Pg. 25, line 11+). Univ of Texas teaches Pompe disease, an autosomal recessive disease, is caused by a mutation in a gene on long arm of chromosome 17 at l 7q25.2-q25.3 and most cases appear to be due to three mutations (as further in claim 6) (last paragraph Pg. 26-27, first paragraph).
Univ of Texas teaches where therapeutic applications are contemplated, it will be necessary to prepare pharmaceutical compositions, comprising a pharmaceutically acceptable carrier, in a form appropriate for the intended application (as in claim 58) (Pg. 45). Univ of Texas also teaches kits (as in claim 59), which includes directions and or other information on an insert (Pg. 48).
When taken with Univ of Texas’ teachings regarding the equivalency of Myoximer and DWORF, one of ordinary skill in the art would have found it prima facie obvious to use the heart-specific DWORF in the method of treating Pompe disease, as set forth in Univ of Texas. The skilled artisan would have found it prima facie obvious to do so because Univ of Texas teaches localizes to the sarcoplasmic reticulum of cardiomyocytes where it associates with the SERCA calcium ATPase and stimulates its activity.
Prior Art Rejection 2
Claim(s) 5, 7-9, 11-12, 14-15, 23, 29 and 37 remain rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’ as applied to claims 1-4, 6, 42 and 58-59 above, and further in view of Reid (PgPub US20220154217A1, Filed 3/31/2020) and Giordano et al. (PgPub US20090082293A1, Published 3/26/2009).
The teachings of Univ of Texas are relied upon as detailed above. However, Univ of Texas fails to teach the subject suffers from or is at risk for dilated cardiomyopathy (as in claim 5), the heart failure is myocardial infarction (as in claim 7), with reduced ejection fraction (as in claim 8) or with preserved ejection fraction (as in claim 9).
Before the effective filing date of the claimed invention, Reid taught methods of treating a cardiac pathology in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an rAAV virion to the subject, wherein the rAAV virion comprises a nucleotide sequence encoding a heterologous therapeutic gene product and transduces cardiac tissue (Abstract; Pg. 1, para. 14). Reid teaches subjects in need of treatment using compositions and methods of the present disclosure include, but are not limited to, individuals having a degenerative muscle disease or condition such as dilated cardiomyopathy (as in claim 5) (Pg. 13, para. 163) or myocardial infarction (as in claim 7) (Pg. 24, para. 268). Reid further teaches heart failure includes heart failure with reduced ejection fraction (HFrEF) (as in claim 8) and heart failure with preserved ejection fraction (HFpEF) (as in claim 9) (Pg. 13, para. 164). Reid teaches a nucleotide sequence encoding a heterologous gene product in an rAAV virion of the present disclosure can be operably linked to a cardiac-specific promoter, such as the cardiac troponin (cTnC) promoter (as in claim 29) (Pg. 18, para. 226). In one embodiment, Reid teaches an AAV genome flanked by AAV2 ITRs (as in claim 37) (Pg. 32, para. 430). Reid adds that infecting or transducing a cardiac cell (e.g., cardiac fibroblast) is carried out in vitro. In some embodiments, infecting or transducing a cardiac cell (e.g., cardiac fibroblast) is carried out in vitro; and the infected/transduced cardiac cell (e.g., cardiac fibroblast) is introduced into (e.g., transfused into or implanted into) an individual in need thereof, e.g., directly into cardiac tissue (as in claim 14 and claim 15) of an individual in need thereof (Pg. 21, para. 250). Reid teaches an antegrade intracoronary injection (as in claim 23) (Pg. 24-25, para. 276).
And although Reid teaches myocardial infarction, Reid fails to teach wherein the myocardial infarction is chronic myocardial infarction (as in claim 11) or acute myocardial infarction (as in claim 12).
Before the effective filing date of the claimed invention, Giordano et al. taught methods for treating patients with cardiovascular disease, including heart disease via an in vivo delivery of therapeutic genes the myocardium (Abstract). Giordano et al. teach by heart disease they mean heart disease” refers to acute and/or chronic cardiac dysfunctions (as in claim 11 and claim 12) (Pg. 5,para 43).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Univ of Texas, wherein Univ of Texas teaches a method of treating heart failure by administering an rAAV virion comprising a polynucleotide encoding a DWORF polypeptide, with the teachings of Reid, wherein Reid teaches a nucleotide sequence encoding a heterologous gene product operably linked to a cTnC promoter in an rAAV vector flanked by two AAV2 ITRs for the same purpose. That is, one of ordinary skill in the art would have found it prima facie obvious to use the ITRs and promoter of Reid as Reid teaches
their rAAV virion was able to transduce heart tissue. Moreover, the skilled artisan would have had a reasonable expectation of treating acute or chronic heart disease, as set forth in Giordano et al., because Giordano teaches the phrase “heart disease” embraces both acute and chronic heart disease.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 3
Claim(s) 19-22 and 40 remain rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’ as applied to claim 1-4, 6, 42 and 58-59 above, and further in view of Makarewich et al. (eLife. 2018 Oct 9;7:e38319.; Ref. C4 in IDS filed 10/11/2023).
The teachings of Univ of Texas are relied upon as detailed above. However, Univ of Texas fails to teach the method improves cardiac function (as in claim 19 ), the method improves fractional shortening and/or left ventricular internal dimension (LVID), and wherein the improvement in cardiac function is observed at weeks 2 through 12 (as in claim 20), the method reduces adverse cardiac remodeling (as in claim 21) and wherein the method prevents a decrease in DWORF expression (as in claim 22).
Before the effective filing of the claimed invention, Makarewich et al. teach they previously generated DWORF transgenic (Tg) mice using the α-myosin heavy chain (αMHC) promoter to overexpress DWORF specifically in the heart. Makarewich teaches cardiomyocytes from DWORF Tg mice have a cellular phenotype that mimics that observed in PLN null mice, including an increase in peak Ca2+ transient amplitude, faster cytosolic Ca2+ decay rates, higher SR Ca2+ load and enhanced cardiomyocyte contractility. Makarewich teaches their previous work indicates that DWORF activates SERCA by displacing its negative regulator, PLN, and suggests that the profile of enhanced contractility in DWORF Tg animals is due to the ability of DWORF to compete PLN off of SERCA and relieve its inhibitory effects. To investigate this in vivo, Makarewich and colleagues crossed DWORF Tg mice with the well-characterized αMHC-PLN transgenic mice (PLN Tg) to generate double transgenic (PLN/DWORF Tg) animals. Cardiomyocytes from PLN Tg animals exhibit a cellular phenotype opposite that of DWORF Tg mice, with reduced peak Ca2+ transient amplitude, slower transient decay rates, and reduced fractional shortening due to super-inhibition of SERCA. Makarewich hypothesized that overexpression of DWORF in PLN Tg mice would lead to displacement of the excess PLN from SERCA and relieve its inhibitory effects (paragraph bridging Pg. 4 and Pg. 5).
Towards this end, Makarewich observed that baseline cardiac phenotyping of wild-type (WT), PLN Tg, DWORF Tg, or PLN/DWORF Tg mice by echocardiography (ECHO) indicated that all genotypes had similar cardiac function at 8 weeks (Fig. 3) (as in claim 19) as measured by ejection fraction or fractional shortening (Figure 2—figure supplement 1A,B). Additionally, all genotypes analyzed had comparable cardiac dimensions as assessed by ECHO (Figure 2—figure supplement 1C,D), normal heart weight to tibia length measurements (Figure 2—figure supplement 1E), and similar histological appearances (Figure 2—figure supplement 1F), indicating that overexpression of PLN, DWORF (as in claim 22), or a combination of the two did not lead to adverse remodeling (as in claim 21). They found that DWORF Tg animals had enhanced Ca2+ cycling with increased peak Ca2+ transient amplitude and faster transient decay rates (Figure 2A–C) accompanied by increased fractional shortening (Figure 2D,E) (as in claim 20) (Pg. 5, par. 1).
Also, Makarewich evaluated LV diastolic function in mice by pulse-wave Doppler echocardiography of transmitral valve blood flow and by mitral annular tissue Doppler. Makarewich teaches that in MLP KO/DWORF Tg mice, both the E/A ratio (Figure 3H) and E/E’ ratio (Figure 3I), where E/A ratio is ratio of the early [E] to late [A] ventricular filling velocities and E/E’ ratio is ratio of early filling [E] to early diastolic mitral annular velocity, were indistinguishable from those of WT mice, indicating that DWORF overexpression ameliorates the diastolic dysfunction (~ heart valve function) (as in claim 40) observed in MLP KO mice (Pg. 7, last full paragraph).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Univ of Texas, wherein Univ of Texas teaches a method of treating heart failure by administering an rAAV virion comprising a polynucleotide encoding a DWORF polypeptide, with the teachings of Makarewich et al., wherein Makarewich teaches overexpression of DWORF in an animal in need thereof led to an increase in cardiac function and amelioration of the diastolic dysfunction. That is, one of ordinary skill in the art would have found it prima facie overexpress DWORF in a subject having heart disease because Makarewich provides evidence of DWORF’s therapeutic ability.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 4
Claim(s) 25-26 and 28 remain rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System. (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’ as applied to claim 1-4, 6, 42 and 58-59 above, and further in view of Wilson (PgPub US US20070036760A1, Published 2/15/2007; Ref. A1 in IDS filed 10/11/2023).
The teachings of Univ of Texas are relied upon as detailed above. However, Univ of Texas fails to teach the rAAV virion is an rAAV virion of serotype AAV9, and the AAV capsid comprises a capsid protein that shares at least 90% identity to SEO ID NO: 14 (as in claim 25),
the AAV capsid comprises a capsid protein that shares at least 98% identity to SEQ ID NO: 14 (as in claim 26) or that the AAV capsid comprises a capsid protein comprising the polypeptide sequence of SEQ ID NO: 14 (as in claim 28).
Before the effective filing date of the claimed invention, Wilson et al. taught AAV-mediated delivery of therapeutic and immunogenic genes using sequences of novel adeno-associated virus capsids and vector (Abstract). In one embodiment, Wilson teaches a novel AAV serotype identified herein as hu.14/AAV9 [SEQ ID Nos: 3 and 123] (Pg. 6, para. 59).
The alignment between SEQ ID NO: 14 (Qy, query) and the AAV serotype identified herein as hu.14/AAV9 taught by Wilson et al. (Db, database) is provided below.
RESULT 1
US-10-573-600A-123
(NOTE: this sequence has 291 duplicates in the database searched.
See complete list at the end of this report)
Sequence 123, US/10573600A
Patent No. 7906111
GENERAL INFORMATION
APPLICANT: The Trustees of the University of Pennsylvania
APPLICANT: Wilson, James M.
APPLICANT: Gao, Guangping
APPLICANT: Alvira, Mauricio R.
APPLICANT: Vandenberghe, Luk H.
TITLE OF INVENTION: Adeno-Associated Virus (AAV) Clades, Sequences, Vectors
TITLE OF INVENTION: Containing Same, and Uses Therefor
FILE REFERENCE: UPN-P3230PCT
CURRENT APPLICATION NUMBER: US/10/573,600A
CURRENT FILING DATE: 2006-03-24
PRIOR APPLICATION NUMBER: US 60/508,226
PRIOR FILING DATE: 2003-09-30
PRIOR APPLICATION NUMBER: US 60/566,546
PRIOR FILING DATE: 2004-04-29
NUMBER OF SEQ ID NOS: 236
SEQ ID NO 123
LENGTH: 736
TYPE: PRT
ORGANISM: Unknown
FEATURE:
OTHER INFORMATION: capsid of hu.14/AAV9
Query Match 100.0%; Score 3986; Length 736;
Best Local Similarity 100.0%;
Matches 736; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLD 60
Qy 61 KGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQ 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 KGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQ 120
Qy 121 AKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTE 180
Qy 181 SVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVI 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVI 240
Qy 241 TTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQR 300
Qy 301 LINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAH 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 LINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAH 360
Qy 361 EGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENV 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 EGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENV 420
Qy 421 PFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLKFSVAGPSNMAVQGRNYIP 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 PFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLKFSVAGPSNMAVQGRNYIP 480
Qy 481 GPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGS 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGS 540
Qy 541 LIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 LIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQG 600
Qy 601 ILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 ILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPT 660
Qy 661 AFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGV 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 AFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGV 720
Qy 721 YSEPRPIGTRYLTRNL 736
||||||||||||||||
Db 721 YSEPRPIGTRYLTRNL 736
Note that SEQ ID NO: 123, taught by Wilson et al., is 100% identical to SEQ ID NO: 14 (as in claim 25, claim 26 and claim 28). Wilson at para. 63 (Pg. 6) teaches this sequence is useful for constructing vectors that are highly efficient in muscle.
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Univ of Texas, wherein Univ of Texas teaches a method of treating heart failure by administering an rAAV virion comprising a polynucleotide encoding a DWORF polypeptide, with the teachings of Wilson et al., wherein Wilson teaches a nucleotide sequence that is 100% identical to SEQ ID NO: 14. That is, one of ordinary skill in the art would have found it prima facie use the AAV9 capsid of Wilson, as set forth in Wilson, in the AAV vector of Univ of Texas because Wilson notes that this capsid is useful for constructing vectors that are highly efficient in muscle.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 5
Claim 30 remains rejected under 35 U.S.C. 103 as being unpatentable The Board of Regents of the University of Texas System in view of The Board of Regents of the University of Texas System. (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’, Reid (PgPub US20220154217A1, Filed 3/31/2020) and Giordano et al. (PgPub US20090082293A1, Published 3/26/2009) as applied to 1-9, 11-12, 14-15, 23, 29, 37, 42 and 58-59 (Prior Art Rejection 2) above, and further in view of Sheikh et al. (PgPub US20200215155A1, Filed 9/20/2018).
The teachings of Univ of Texas are relied upon as detailed above. And although Reid teaches a cTnT promoter, none of Univ of Texas, Reid nor Giordano teach the cTnT promoter comprises a polynucleotide sequence that shares at least 95% identity to SEQ ID NO: 11 (as in claim 30).
Before the effective filing date of the claimed invention, Sheik teaches methods of administering a gene therapy construct comprising a therapeutic gene, wherein as a result of the administration, the therapeutic gene levels in at least a portion of the heart are increased (Abstract). In one embodiment, Sheik teaches the therapeutic gene is targeted for clinical therapies in patients by generating a cardiac troponin T promoter-driven AAV9 vector (Pg. 5, para. 37).
The alignment between SEQ ID NO: 11 (Qy, query) and the cardiac troponin T promoter taught by Sheikh et al. (Db, database) is provided below.
RESULT 14
US-16-648-922-8
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
Sequence 8, US/16648922
Patent No. 12186369
GENERAL INFORMATION
APPLICANT: The Regents of the University of California
TITLE OF INVENTION: A Gene Therapy Strategy to Restore Electrical and Cardiac
TITLE OF INVENTION: Function in Arrhythmic Right Ventricular Cardiomyopathy
FILE REFERENCE: 1959169.00030
CURRENT APPLICATION NUMBER: US/16/648,922
CURRENT FILING DATE: 2020-03-19
PRIOR APPLICATION NUMBER: US62560989
PRIOR FILING DATE: 2017-09-20
NUMBER OF SEQ ID NOS: 12
SEQ ID NO 8
LENGTH: 6146
TYPE: DNA
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: pAAV-tnt-GFP-CX43 vector sequence
Query Match 100.0%; Score 413; Length 6146;
Best Local Similarity 100.0%;
Matches 413; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGGATAAAAGCAGTCTGGGCTTTCACATGACAGCATCTGGGGCTGCGGCAGAGGGTCGGG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 233 GGGATAAAAGCAGTCTGGGCTTTCACATGACAGCATCTGGGGCTGCGGCAGAGGGTCGGG 292
Qy 61 TCCGAAGCGCTGCCTTATCAGCGTCCCCAGCCCTGGGAGGTGACAGCTGGCTGGCTTGTG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 293 TCCGAAGCGCTGCCTTATCAGCGTCCCCAGCCCTGGGAGGTGACAGCTGGCTGGCTTGTG 352
Qy 121 TCAGCCCCTCGGGCACTCACGTATCTCCGTCCGACGGGTTTAAAATAGCAAAACTCTGAG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 353 TCAGCCCCTCGGGCACTCACGTATCTCCGTCCGACGGGTTTAAAATAGCAAAACTCTGAG 412
Qy 181 GCCACACAATAGCTTGGGCTTATATGGGCTCCTGTGGGGGAAGGGGGAGCACGGAGGGGG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 413 GCCACACAATAGCTTGGGCTTATATGGGCTCCTGTGGGGGAAGGGGGAGCACGGAGGGGG 472
Qy 241 CCGGGGCCGCTGCTGCCAAAATAGCAGCTCACAAGTGTTGCATTCCTCTCTGGGCGCCGG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 473 CCGGGGCCGCTGCTGCCAAAATAGCAGCTCACAAGTGTTGCATTCCTCTCTGGGCGCCGG 532
Qy 301 GCACATTCCTGCTGGCTCTGCCCGCCCCGGGGTGGGCGCCGGGGGGACCTTAAAGCCTCT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 533 GCACATTCCTGCTGGCTCTGCCCGCCCCGGGGTGGGCGCCGGGGGGACCTTAAAGCCTCT 592
Qy 361 GCCCCCCAAGGAGCCCTTCCCAGACAGCCGCCGGCACCCACCGCTCCGTGGGA 413
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 593 GCCCCCCAAGGAGCCCTTCCCAGACAGCCGCCGGCACCCACCGCTCCGTGGGA 645
Note that SEQ ID NO: 8, taught by Sheikh et al. is 100% identical to SEQ ID NO: 11 (as in claim 30).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Univ of Texas, wherein Univ of Texas teaches a method of treating heart failure by administering an rAAV virion comprising a polynucleotide encoding a DWORF polypeptide, with the teachings of Sheik et al., wherein a cTnT promoter operably linked to a nucleotide encoding a therapeutic protein. That is, one of ordinary skill in the art would have found it prima facie use the cTnT promoter of Sheik, as set forth in Sheik, in the AAV vector of Univ of Texas because Sheik teaches use of the promoter results in an increase in the level of therapeutic gene in the heart.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 6
Claim(s) 33-36 remain rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’ as applied to claim 1-4, 6, 42 and 58-59 above, and further in view of Olson et al. (PgPub US20170298107A11, Published 10/19/2017; Ref. A8 in IDS filed 4/24/2024).
The teachings of Univ of Texas are relied upon as detailed above. However, Univ of Texas fails to teach the DWORF polypeptide is human (as in claim 33) and the DWORF polypeptide comprises a polypeptide sequence that shares at least 95% identity to SEQ ID NO: 3 (as in claim 34) or comprises the polypeptide sequence of SEQ ID NO: 3 (as in claim 36).
Before the effective filing date of the claimed invention, Olson et al. taught Dwarf Open Reading Frame ( DWORF), a native peptide. Olson teaches this peptide enhances the apparent activity of the SERCA pump, is positively inotropic and lusitropic, and therefore is provided as a therapeutic agent for disorders characterized by cytosolic calcium overload (Abstract). In one embodiment, Olson teaches such a disorder is heart failure (Pg. 1, para. 7).
The alignment between SEQ ID NO: 3 (Qy, query) and the DWORF peptide by Olson et al. (Db, database) is provided below.
BEM79202
(NOTE: this sequence has 8 duplicates in the database searched.
See complete list at the end of this report)
ID BEM79202 standard; peptide; 35 AA.
XX
AC BEM79202;
XX
DT 14-DEC-2017 (first entry)
XX
DE Human DWORF polypeptide, SEQ ID 3.
XX
KW DWORF protein; dwarf open reading frame; enzyme activity;
KW voltage-gated calcium channel.
XX
OS Homo sapiens.
XX
CC PN US2017298107-A1.
XX
CC PD 19-OCT-2017.
XX
CC PF 19-APR-2017; 2017US-00491057.
XX
PR 19-APR-2016; 2016US-0324706P.
XX
CC PA (TEXA ) UNIV TEXAS SYSTEM.
XX
CC PI Bassel-Duby RS, Makarewich CA, Nelson BR, Olson EN;
XX
DR WPI; 2017-71499N/73.
DR N-PSDB; BEM79203.
XX
CC PT Promoting activity of sarco/endoplasmic reticulum calcium ATPase calcium
CC PT pump in cell involves contacting sarco/endoplasmic reticulum calcium
CC PT ATPase pump with DWORF and enhances activity of SERCA pump, where DWORF
CC PT has defined amino acids.
XX
CC PS Claim 2; SEQ ID NO 3; 48pp; English.
XX
CC The present invention relates to a novel method for promoting the
CC activity of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) calcium
CC pump in a cell. The method involves contacting the SERCA pump with DWORF.
CC The invention also provides: an isolated polypeptide comprising the
CC sequence of SEQ ID NOs: 1-9 (see BEM79200-BEM79208 (odd numbers)); and an
CC isolated nucleic acid molecule encoding the polypeptide. The present
CC sequence represents a human DWORF polypeptide, which can be used in
CC performing the above mentioned method for promoting the activity of the
CC SERCA calcium pump in a cell.
XX
SQ Sequence 35 AA;
Query Match 100.0%; Score 177; Length 35;
Best Local Similarity 100.0%;
Matches 35; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAEKAGSTFSHLLVPILLLIGWIVGCIIMIYVVFS 35
|||||||||||||||||||||||||||||||||||
Db 1 MAEKAGSTFSHLLVPILLLIGWIVGCIIMIYVVFS 35
Note that SEQ ID NO: 3, taught by Olson et al., is 100% identical to SEQ ID NO: 14 (as in claim 33, claim 34 and claim 36).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationale B is applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to substitute the generic DWORF peptide of Univ of Texas with the human DWORF peptide of Olson et al., with a reasonable expectation of arriving at the claimed invention. The skilled artisan would have found it prima facie obvious to make such a substitution for the purposes of treating human subjects.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 7
Claim 39 remains rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System in view of The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), herein referred to as ‘Univ of Texas’, Reid (PgPub US20220154217A1, Filed 3/31/2020) and Giordano et al. (PgPub US20090082293A1, Published 3/26/2009) as applied to 1-9, 11-12, 14-15, 23, 29, 37, 42 and 58-59 (Prior Art Rejection 2) above, and further in view of Choi et al. (WO2020086881A1, Published 4/30/2020).
The teachings of Univ of Texas are relied upon as detailed above. And although Reid teaches the ITRS are AAV2 ITRs, none of Univ of Texas, Reid nor Giordano teach the ITRs comprise the polynucleotide sequence of SEQ ID NO: 12 or SEQ ID NO: 13 (as in claim 39).
Before the effective filing date of the claimed invention, Choi et al. taught a plasmid system for recombinant Adeno-Associated Viral Vector (rAAV) production comprising: (i) a transgene-containing plasmid comprising at least one heterologous nucleic acid sequence flanked by a 5' and 3' AAV inverted terminal repeat (ITR) (Abstract). In one embodiment, Choi teaches the ITRS comprise SEQ ID NO: 3 (Pg. 5, para. 20).
The alignment between SEQ ID NO: 13 (Qy, query) and the AAV ITRS taught by Choi et al. (Db, database) is provided below.
RESULT 9
BHS95962
(NOTE: this sequence has 7 duplicates in the database searched.
See complete list at the end of this report)
ID BHS95962 standard; DNA; 133 BP.
XX
AC BHS95962;
XX
DT 25-JUN-2020 (first entry)
XX
DE Recombinant 3' inverted terminal repeat (ITR) sequence, SEQ ID 3.
XX
KW drug delivery; ds; plasmid; prophylactic to disease; therapeutic; vector.
XX
OS Unidentified.
XX
CC PN WO2020086881-A1.
XX
CC PD 30-APR-2020.
XX
CC PF 24-OCT-2019; 2019WO-US057916.
XX
PR 25-OCT-2018; 2018US-0750603P.
XX
CC PA (BAXA ) BAXALTA INC.
CC PA (BAXA ) BAXALTA GMBH.
XX
CC PI Choi V, Li X;
XX
DR WPI; 2020-35899B/038.
XX
CC PT Plasmid system for Recombinant Adeno-Associated Viral Vector production
CC PT and composition, comprises a transgene-containing plasmid comprising at
CC PT least one heterologous nucleic acid flanked by AAV inverted terminal
CC PT repeat.
XX
CC PS Claim 18; SEQ ID NO 3; 75pp; English.
XX
CC The present invention relates to a novel plasmid system for recombinant
CC adeno-associated viral vector (rAAV) production and composition. The
CC plasmid system comprises (a) a transgene-containing plasmid comprising at
CC least one heterologous nucleic acid flanked by a 5' and 3' AAV inverted
CC terminal repeat (ITR) and a stuffer sequence outside of the ITRs, (b) a
CC plasmid comprising AAV replication (Rep) and capsid (Cap) gene sequences,
CC and (c) an adenovirus (Ad) helper plasmid. The invention also provides: a
CC host cell comprising the plasmid system; the recombinant AAV produced by
CC the cell; a DNA titer tag allowing for universal vector titering; a
CC method for producing the rAAV, by transducing a cell with the plasmid
CC system and isolating the rAAV; a pharmaceutical composition comprising
CC the rAAV; a method for delivering or transferring a nucleic acid sequence
CC into a subject's cell; a method for treating or preventing a disease or
CC disorder in a subject; and a method for transducing the host cell. The
CC disease or disorder can be inflammatory and immune disorders, cancer,
CC blood disorder (e.g., hemophilia), and metabolic disorder.
XX
SQ Sequence 133 BP; 21 A; 47 C; 46 G; 19 T; 0 U; 0 Other;
Query Match 100.0%; Score 129; Length 133;
Best Local Similarity 100.0%;
Matches 129; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 GGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGC 61
Qy 61 CGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 62 CGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCG 121
Qy 121 AGCGCGCAG 129
|||||||||
Db 122 AGCGCGCAG 130
Note that SEQ ID NO: 3, taught by Choi et al., is 100% identical to SEQ ID NO: 13 (as in claim 39).
When taken with the teachings of Univ of Texas’, Reid and Giordano et al., wherein the combination teaches a method of treating heart failure by administering an rAAV virion comprising a polynucleotide encoding a DWORF polypeptide operably linked to a cTnC promoter in an rAAV vector flanked by two AAV ITRs, one of ordinary skill in the art would have found it prima facie obvious to substitute the ITRs of Reid et al. for the ITRs of Choi et al. with a reasonable expectation of arriving at the claimed invention. The skilled artisan would have found it obvious to make such a substitution in order to compare the efficacy of Choi’s ITRs to Reid’s ITRs in transducing muscle.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 8
Claim 60 remains rejected under 35 U.S.C. 103 as being unpatentable over The Board of Regents of the University of Texas System (WO2018156397A1, Published 8/30/2018; Ref. B1 in IDS filed 10/11/2023), Reid (PgPub US20220154217A1, Filed 3/31/2020) and Wilson (PgPub US US20070036760A1, Published 2/15/2007; Ref. A1 in IDS filed 10/11/2023).
Regarding 60, Univ of Texas teach a method of correcting a genetic defect (i.e. treating (Pg. 21, lines 20-22)) in a cell in a subject comprising: (a) providing a non-muscle cell from said subject; (b) administering an effective amount of a recombinant adeno-associated virus (rAAV) virion (Pg. 32, line 15+), the rAAV virion comprising an AAV capsid (paragraph bridging Pgs. 35- 36, line 17) and an expression cassette comprising a polynucleotide into said non-muscle cell expressing (i) exogenous therapeutic genes operably linked to a promoter (Pg. 17, lines 11-28); and contacting said non-muscle cell with a muscle cell having a genetic defect, wherein said non-muscle cell expressing the therapeutic gene will fuse with said muscle cell and deliver said therapeutic gene or genes to said muscle cell, thereby correcting said genetic defect (paragraph bridging Pg. 4 and Pg. 5). Although Univ of Texas teaches the exogenous therapeutic gene to be Myoximer, Univ of Texas also notes that heart-specific DWORF (as further in claim 1 and claim 42) is similar to Myoximer (Pg. 12, lines 14-19). In fact, Univ of Texas teaches DWORF localizes to the sarcoplasmic reticulum of cardiomyocytes where it associates with the SERCA calcium ATPase and stimulates its activity. Thus, there is a reasonable expectancy in the similarities in function of the two therapeutic genes~ DWORF and Myoximer.
In one embodiment, Univ of Texas teaches the genetic disease is Pompe disease. Univ of Texas notes that the disease is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. This build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly the heart, skeletal muscles, liver and nervous system. Univ of Texas teaches as the disease progresses heart muscles thicken and progressively fail. Without treatment, death usually occurs due to heart failure and respiratory weakness (Pg. 25, line 10+). This teaching by Univ of Texas establishes the treatment method of Univ of Texas prevents heart failure (as further in claim 60).
However, Univ of Texas fails to teach the AAV virion is serotype 9 (as further in claim 60).
Before the effective filing date of the claimed invention, Reid taught methods of treating a cardiac pathology in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an rAAV virion to the subject, wherein the rAAV virion comprises a nucleotide sequence encoding a heterologous therapeutic gene product (Abstract; Pg. 18, para. 226; Pg. 21, para. 249) and transduces cardiac tissue (Pg. 24, para. 270). Reid teaches the AAV capsid is serotype 9 (as further in claim 60) (Pg. 16, para. 206) and that said vector comprises a nucleotide sequence encoding a heterologous gene product in operably linked to a cardiac-specific promoter, such as the cardiac troponin (cTnC) promoter (as further in claim 60) (Pg. 18, para. 226).
However, neither Univ of Texas nor Reid teach the AAV capsid protein shares at least 98% or 100% identity to SEQ ID NO: 14 (as further in claim 60).
Before the effective filing date of the claimed invention, Wilson et al. taught AAV-mediated delivery of therapeutic and immunogenic genes using sequences of novel adeno-associated virus capsids and vector (Abstract). In one embodiment, Wilson teaches a novel AAV serotype identified herein as hu.14/AAV9 [SEQ ID Nos: 3 and 123] (Pg. 6, para. 59).
The alignment between SEQ ID NO: 14 (Qy, query) and the AAV serotype identified herein as hu.14/AAV9 taught by Wilson et al. (Db, database) is provided below.
RESULT 1
US-10-573-600A-123
(NOTE: this sequence has 291 duplicates in the database searched.
See complete list at the end of this report)
Sequence 123, US/10573600A
Patent No. 7906111
GENERAL INFORMATION
APPLICANT: The Trustees of the University of Pennsylvania
APPLICANT: Wilson, James M.
APPLICANT: Gao, Guangping
APPLICANT: Alvira, Mauricio R.
APPLICANT: Vandenberghe, Luk H.
TITLE OF INVENTION: Adeno-Associated Virus (AAV) Clades, Sequences, Vectors
TITLE OF INVENTION: Containing Same, and Uses Therefor
FILE REFERENCE: UPN-P3230PCT
CURRENT APPLICATION NUMBER: US/10/573,600A
CURRENT FILING DATE: 2006-03-24
PRIOR APPLICATION NUMBER: US 60/508,226
PRIOR FILING DATE: 2003-09-30
PRIOR APPLICATION NUMBER: US 60/566,546
PRIOR FILING DATE: 2004-04-29
NUMBER OF SEQ ID NOS: 236
SEQ ID NO 123
LENGTH: 736
TYPE: PRT
ORGANISM: Unknown
FEATURE:
OTHER INFORMATION: capsid of hu.14/AAV9
Query Match 100.0%; Score 3986; Length 736;
Best Local Similarity 100.0%;
Matches 736; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLD 60
Qy 61 KGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQ 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 KGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQ 120
Qy 121 AKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPAKKRLNFGQTGDTE 180
Qy 181 SVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVI 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCDSQWLGDRVI 240
Qy 241 TTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQR 300
Qy 301 LINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAH 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 LINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAH 360
Qy 361 EGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENV 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 EGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENV 420
Qy 421 PFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLKFSVAGPSNMAVQGRNYIP 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 PFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLKFSVAGPSNMAVQGRNYIP 480
Qy 481 GPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGS 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGS 540
Qy 541 LIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 LIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQG 600
Qy 601 ILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPT 660
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Db 601 ILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPT 660
Qy 661 AFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGV 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 AFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGV 720
Qy 721 YSEPRPIGTRYLTRNL 736
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Db 721 YSEPRPIGTRYLTRNL 736
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Univ of Texas, wherein Univ of Texas teaches a method of treating heart failure by administering an rAAV virion comprising a polynucleotide encoding a DWORF polypeptide, with the teachings of Reid et al. and Wilson et al., wherein Reid teaches an AAV9 capsid for use in Reid treating a cardiac pathology in a subject in need thereof and Wilson teaches an AAV capsid protein that is 100% identical to SEQ ID NO: 14. That is, one of ordinary skill in the art would have found it prima facie use the AAV9 capsid of Wilson, as set forth in Wilson, in the AAV vector of Univ of Texas because Wilson notes that this capsid is useful for constructing vectors that are highly efficient in muscle and Reid provides evidence of its use in treating a cardiac pathology.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Applicant’s Arguments/Response to Arguments
Applicant argues: On Pg. 8, Applicant argues that the Action misrepresents the ‘397 Application and, when read properly, it provides no basis for the rejections.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. There are two recitations of the term ‘DWORF’ in the ‘397 Application. They are copied below, with full context.
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Since the language of Pg. 12 is similar to Pg. 59 of the ‘397 Application, the context of Pg. 12 is elaborated upon. Critically, the title of the Pg. 12 recitation is ‘Myoximer’. It is reasonable to assume that the recitation of one peptide ‘DWORF’ under the title of another peptide ‘Myoximer’ implies a relationship between the two. Moreso, in the paragraph immediately preceding the recitation of ‘DWORF’, the ‘397 Application teaches:
“The inventors have not found Myomixer-related genes in Drosophila, which also lacks an obvious Myomaker ortholog, suggesting that the Myomixer-Myomaker protein partnership is an invention of higher vertebrates. Perhaps the formation of the large muscles of vertebrates requires this robust fusogenic machinery superimposed upon the basic cell-cell fusion events of simpler organisms such as Drosophila.”
When read in this context, the supposition is then that ‘DWORF’- which is the only peptide specifically mentioned in the subsequent paragraph- is related to DWORF. Note the following terms “Myomixer-related genes” and “ortholog”. After the paragraph cited above, the ‘397 Application states “The inventors note some striking similarities between Myomixer and the heart-specific micropeptide, DWORF (Dwarf open reading frame)…”Similarity refers to a general state of being alike. Similarities mean multiple specific traits or features are alike. Therefore, Examiner disagrees that Examiner has misread the ’397 Application because at Pg. 8 of the Action, Examiner plainly states:
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Applicant argues: The Action's statements regarding the alleged similarities between Myomixer and DWORF lack supporting objective evidence as explained below and in the attached declaration under 37 C.F.R. §1.132 from Dr. Kathryn N. Ivey. Although Myomixer and DWORF are both classified as micropeptides (that is, in fact, the extent of their similarities), the proteins differ fundamentally in their tissue expression, cellular localization, interaction partners, and biological function. Myomixer is expressed in skeletal muscle but not cardiac muscle ('397 application paragraph bridging pages 56-57), localizes to the plasma membrane ('397 application, second full paragraph, page 10), and functions together with Myomaker to mediate the fusion of developing myoblasts into multinucleated myofibers ('397 application, second full paragraph, page 10). That is why the '397 application is directed to expression of the Myomixer protein in non-muscle cells (e.g., published claims 3, 11, 21, 31, and 62), i.e., to promote fusion with muscle cells and delivery of genetic materials to the muscle cells to treat genetic diseases. By contrast, DWORF is expressed primarily in cardiac muscle and slow-twitch skeletal muscle, localizes to the sarcoplasmic reticulum, and regulates SERCA activity through competition with phospholamban, sarcolipin, and myoregulin (see Nelson et al., Science, 351:271-275. 2016) and thus used in the presently claimed AAV-based gene therapy method of treating, e.g., heart failure or cardiomyopathy in a subject.
In Response: As noted above, the ‘397 does not state that the only similarity between Myoximer and DWORF is that they are both micropeptides. Indeed, the use of the phrase “some striking similarities” clearly indicates a plurality of similarities.
Regarding cell type expression, this argument is moot in view of the rejection made by the Examiner. Note that the Examiner specifically stated that “When taken with Univ of Texas’ teachings regarding the equivalency of Myoximer and DWORF, one of ordinary skill in the art would have found it prima facie obvious to use the heart-specific DWORF in the method of treating Pompe disease, as set forth in Univ of Texas. The skilled artisan would have found it prima facie obvious to do so because Univ of Texas teaches DWORF localizes to the sarcoplasmic reticulum of cardiomyocytes where it associates with the SERCA calcium ATPase and stimulates its activity.”
It has been consistently held that the reason or motivation to modify a reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. >See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.");< In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below). Although Ex parte Levengood, 28 USPQ2d 1300, 1302 (Bd. Pat. App. & Inter. 1993) states that obviousness cannot be established by combining references "without also providing evidence of the motivating force which would impel one skilled in the art to do what the patent applicant has done" (emphasis added), reading the quotation in context it is clear that while there must be motivation to make the claimed invention, there is no requirement that the prior art provide the same reason as the applicant to make the claimed invention.
In the instant case, the teachings of the ‘397 Application provide a reasonable expectation that the administration of the heart-specific DWORF would treat Pompe disease in a subject. Note the ‘397 Application’s teaching that the accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme in Pompe disease causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system (Pg. 25). The ‘397 Application also teaches that as the disease progresses heart muscles thicken and progressively fail (Pg. 25). Therefore, there exists a reasonable expectation that enhancing SERCA activity (via expression of DWORF) would counteract cardiac thickening and dysfunction in Pompe disease. It is well established in patent law that obviousness does not require absolute predictability, only some degree of predictability is required.
Because Applicant’s arguments were not found persuasive, the rejection is maintained.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 mailing date of this final action.
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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632
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