DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8-20-26 has been entered.
Claims 1-12, 14, 15, 17, 20, 23, 26 have been canceled. Claims 13, 16, 18, 19, 21, 22, 24, 25 remain pending.
Applicant's arguments filed 8-20-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The concept of AAV9 vectors with AAV2 ITRs in Example 1 of the specification was not disclosed in provisional application 62/280269 filed 1-9-19. The concept was first introduced in PCT/US2017/014164 filed 1-19-17. Chandler (Human Mol. Genetics, 2017, available online 10-25016, Vol. 27, No. 1, pg 52-64) used such a vector to treat Niemann-Pick disease, a lysosomal storage disease. The provisional application generically states AAV ITRs can be from any of several serotypes (paragraph 42); however, it does not specifically contemplate AAV9 with AAV2 ITRs. Applicants’ disclosure mentions the source of the AAV9/AAV2 hybrid vector (para 99), but applicants fail to disclose what was known about the vector, disclose any literature about the vector, or provide any indication whether it was available to the public. If patentability hinges on the structure of the AAV vector required for therapeutic results, clarification may be required.
Claim Rejections - 35 USC § 112
Enablement
Claims 13, 16, 18, 19, 21, 22, 24, 25 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method reducing autophagy in myocardial tissue of a mammal that has Danon disease, the method comprising:
administering an adenoassociated viral (AAV) vector comprising a nucleic acid sequence encoding lysosome-associated membrane protein 2B (LAMP-2B) operably linked to a hybrid promoter comprising a chicken beta-actin promoter and a CMV enhancer (CAG) promoter into a mammal that has autophagy in myocardial tissue and Danon disease via intravenous, intraarterial, intracardiac, intracoronary, or intramyocardial administration, or direct injection to the heart such that fusion of autophagosomes and lysosomes increase (i.e. autophagy is reduced) in myocardial tissue of the mammal,
does not reasonably provide enablement for
treating any additional autophagy disorder as required in claim 18 other than Danon disease, or treating heart failure, myocardial infarction, drug toxicities, diabetes, or renal failure as required in claim 25.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
A) The specification does not enable using AAV encoding LAMP2B to increase “fusion of autophagosomes and lysosomes” in any “mammal having Danon disease and [ ] reduced or non-detectable LAMP2B gene expression” by delivering the AAV to the mammal’s myocardium cells wherein the mammal has an additional autophagy disorder and treating that additional autophagy disorder as encompassed by claim 18.
Claim 18 encompasses treating a mammal that has Danon disease and another autophagy disease with any decreased LAMP2B expression such that symptoms of the Danon disease and the other autophagy disease are ameliorated.
“Autophagy” is the consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases.
Danon disease causes myocardial tissue to be destroyed by the body. The purpose of the invention is to prevent the mammal with Danon disease from destroying its own myocardial tissue. Therefore, mammals with Danon disease exhibit increased autophagy (decreased fusion of autophagosomes with lysosomes) of myocardial tissue; the treatment must decrease autophagy (increase fusion of autophagosomes with lysosomes) of the tissue.
The ”additional autophagy disorder” encompasses anything with increased OR decreased autophagy.
Pg 16, para 59, contemplates treating a mammal with Danon disease, heart failure, myocardial infarction, drug toxicity, renal failure or aging. The specification is limited to decreasing autophagy (increasing fusion of autolysosomes and lysosomes) in myocardial tissue of mice with an inactivated LAMP2 gene using an AAV9 vector encoding LAMP2 administered intravenously (pg 30, Example 7). Administration of the vector occurs in the mice only once “there has been sufficient accumulation of pathology” (pg 17, lines 3-5).
The specification and the art at the time of filing are limited to intravenously administering AAV encoding LAMP2B operably linked to a CAG promoter to a mammal that has a mutant LAMP2B gene, Danon disease, and increased autophagy in myocardial tissue (Examples 6 and 7) such that autophagy is decreased in the mammal.
Example 6, pg 29, para 107, says “The CAG-RFP-EGFP-LC3B Autophagy Reporter System allows assessment of macroautophagic flux”, but does not teach the meaning of “autophagic flux” or how to perform any analysis other than determine the amount of autophagy. The last line of Example 6 says “The accumulation of autophagosomes and near absence of autolysosomes, along with an overall greater number of autophagic vacuoles (AVs), reflects a defect in autophagic flux due to the absence of Lamp-2 (see Figure 9H)”, but it does not teach whether the “defect” is an increase or decrease in “autophagic flux”.
Example 7, para 110, describes treatment with AAV encoding LAMP2 and concludes “such expression leads to the reversal of defects in autophagic flux and cardiomyocyte ultrastructure” , but it does not define “autophagic flux” or teach whether the “defect” was increased or decreased in “autophagic flux” or whether the reversal was a decrease or increase in in “autophagic flux”.
The specification does not correlate administering the AAV to a mammal with a mutant LAMP2B gene and Danon disease to treating a subject with Danon disease and “an additional autophagy disorder” as required in claim 18. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to treat a mammal with Danon disease and any additional increased or decreased autophagy disorder.
B) The specification does not enable using AAV encoding LAMP2B to increase “fusion of autophagosomes and lysosomes” in any “mammal having Danon disease and [ ] reduced or non-detectable LAMP2B gene expression” by delivering the AAV to the mammal’s myocardium cells wherein the mammal has heart failure, myocardial infarction, drug toxicity, renal failure and treating the heart failure, myocardial infarction, drug toxicity, renal failure as encompassed by claim 25.
Claim 25 encompasses treating a mammal that has Danon disease and heart failure, myocardial infarction, drug toxicity, renal failure with any decreased LAMP2B expression such that symptoms of the Danon disease and the heart failure, myocardial infarction, drug toxicity, renal failure are ameliorated.
“Autophagy” is the consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases.
Danon disease causes myocardial tissue to be destroyed by the body. The purpose of the invention is to prevent the mammal with Danon disease from destroying its own myocardial tissue. Therefore, mammals with Danon disease exhibit increased autophagy (decreased fusion of autophagosomes with lysosomes) of myocardial tissue; the treatment must decrease autophagy (increase fusion of autophagosomes with lysosomes) of the tissue.
The heart failure, myocardial infarction, drug toxicity, renal failure have nothing to do with increased OR decreased autophagy.
Pg 16, para 59, contemplates treating a mammal with Danon disease, heart failure, myocardial infarction, drug toxicity, renal failure or aging. The specification is limited to decreasing autophagy (increasing fusion of autolysosomes and lysosomes) in myocardial tissue of mice with an inactivated LAMP2 gene using an AAV9 vector encoding LAMP2 administered intravenously (pg 30, Example 7). Administration of the vector occurs in the mice only once “there has been sufficient accumulation of pathology” (pg 17, lines 3-5).
The specification and the art at the time of filing are limited to intravenously administering AAV encoding LAMP2B operably linked to a CAG promoter to a mammal that has a mutant LAMP2B gene, Danon disease, and increased autophagy in myocardial tissue (Examples 6 and 7) such that autophagy is decreased in the mammal for reasons set forth above.
The specification does not correlate administering the AAV to a mammal with a mutant LAMP2B gene and Danon disease to treating a subject with Danon disease and heart failure, myocardial infarction, drug toxicity, renal failure as required in claim 25. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to treat Danon disease and heart failure, myocardial infarction, drug toxicity, or renal failure in a mammal using the AAV claimed.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Written Description
Claims 13, 16, 18, 19, 21, 22, 24, 25 remain rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
A) The specification lacks written description for using AAV encoding LAMP2B to increase “fusion of autophagosomes and lysosomes” in any “mammal having Danon disease and [ ] reduced or non-detectable LAMP2B gene expression” by delivering the AAV to the mammal’s myocardium cells wherein the mammal has an additional autophagy disorder and treating that additional autophagy disorder as encompassed by claim 18.
Claim 18 encompasses treating a mammal that has Danon disease and another autophagy disease with any decreased LAMP2B expression such that symptoms of the Danon disease and the other autophagy disease are ameliorated.
“Autophagy” is the consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases.
Danon disease causes myocardial tissue to be destroyed by the body. The purpose of the invention is to prevent the mammal with Danon disease from destroying its own myocardial tissue. Therefore, mammals with Danon disease exhibit increased autophagy (decreased fusion of autophagosomes with lysosomes) of myocardial tissue; the treatment must decrease autophagy (increase fusion of autophagosomes with lysosomes) of the tissue.
The ”additional autophagy disorder” encompasses anything with increased OR decreased autophagy.
Pg 16, para 59, contemplates treating a mammal with Danon disease, heart failure, myocardial infarction, drug toxicity, renal failure or aging. The specification is limited to decreasing autophagy (increasing fusion of autolysosomes and lysosomes) in myocardial tissue of mice with an inactivated LAMP2 gene using an AAV9 vector encoding LAMP2 administered intravenously (pg 30, Example 7). Administration of the vector occurs in the mice only once “there has been sufficient accumulation of pathology” (pg 17, lines 3-5).
The specification and the art at the time of filing are limited to intravenously administering AAV encoding LAMP2B operably linked to a CAG promoter to a mammal that has a mutant LAMP2B gene, Danon disease, and increased autophagy in myocardial tissue (Examples 6 and 7) such that autophagy is decreased in the mammal.
Example 6, pg 29, para 107, says “The CAG-RFP-EGFP-LC3B Autophagy Reporter System allows assessment of macroautophagic flux”, but does not teach the meaning of “autophagic flux” or how to perform any analysis other than determine the amount of autophagy. The last line of Example 6 says “The accumulation of autophagosomes and near absence of autolysosomes, along with an overall greater number of autophagic vacuoles (AVs), reflects a defect in autophagic flux due to the absence of Lamp-2 (see Figure 9H)”, but it does not teach whether the “defect” is an increase or decrease in “autophagic flux”.
Example 7, para 110, describes treatment with AAV encoding LAMP2 and concludes “such expression leads to the reversal of defects in autophagic flux and cardiomyocyte ultrastructure” , but it does not define “autophagic flux” or teach whether the “defect” was increased or decreased in “autophagic flux” or whether the reversal was a decrease or increase in in “autophagic flux”.
The specification does not correlate administering the AAV to a mammal with a mutant LAMP2B gene and Danon disease to treating a subject with Danon disease and “an additional autophagy disorder” as required in claim 18. Accordingly, the specification lacks written description for treating a mammal with Danon disease and any additional increased or decreased autophagy disorder.
B) The specification lacks written description for using AAV encoding LAMP2B to increase “fusion of autophagosomes and lysosomes” in any “mammal having Danon disease and [ ] reduced or non-detectable LAMP2B gene expression” by delivering the AAV to the mammal’s myocardium cells wherein the mammal has heart failure, myocardial infarction, drug toxicity, renal failure and treating the heart failure, myocardial infarction, drug toxicity, renal failure as encompassed by claim 25.
Claim 25 encompasses treating a mammal that has Danon disease and heart failure, myocardial infarction, drug toxicity, renal failure with any decreased LAMP2B expression such that symptoms of the Danon disease and the heart failure, myocardial infarction, drug toxicity, renal failure are ameliorated.
“Autophagy” is the consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases.
Danon disease causes myocardial tissue to be destroyed by the body. The purpose of the invention is to prevent the mammal with Danon disease from destroying its own myocardial tissue. Therefore, mammals with Danon disease exhibit increased autophagy (decreased fusion of autophagosomes with lysosomes) of myocardial tissue; the treatment must decrease autophagy (increase fusion of autophagosomes with lysosomes) of the tissue.
The heart failure, myocardial infarction, drug toxicity, renal failure have nothing to do with increased OR decreased autophagy.
Pg 16, para 59, contemplates treating a mammal with Danon disease, heart failure, myocardial infarction, drug toxicity, renal failure or aging. The specification is limited to decreasing autophagy (increasing fusion of autolysosomes and lysosomes) in myocardial tissue of mice with an inactivated LAMP2 gene using an AAV9 vector encoding LAMP2 administered intravenously (pg 30, Example 7). Administration of the vector occurs in the mice only once “there has been sufficient accumulation of pathology” (pg 17, lines 3-5).
The specification and the art at the time of filing are limited to intravenously administering AAV encoding LAMP2B operably linked to a CAG promoter to a mammal that has a mutant LAMP2B gene, Danon disease, and increased autophagy in myocardial tissue (Examples 6 and 7) such that autophagy is decreased in the mammal for reasons set forth above.
The specification does not correlate administering the AAV to a mammal with a mutant LAMP2B gene and Danon disease to treating a subject with Danon disease and heart failure, myocardial infarction, drug toxicity, renal failure as required in claim 25. Accordingly, the specification lacks written description for treating Danon disease and heart failure, myocardial infarction, drug toxicity, or renal failure in a mammal using the AAV claimed.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Indefiniteness
The rejection regarding the metes and bounds of “increasing autophagic flux” and “decreasing” it in claim 13 have been withdrawn in view of the amendment.
The rejection regarding the phrase “wherein the subject is exhibiting symptoms of Danon disease and an additional autophagy disorder” in claim 18 has been withdrawn in view of the amendment.
The rejection regarding the metes and bounds of the phrase “minithoracotomy” in claim 24 has been withdrawn in view of the amendment.
The rejection regarding the metes and bounds of “end-stage heart failure” and “end-stage renal failure” in claim 25 has been withdrawn in view of the amendment.
The rejection regarding the phrase “the autophagy disorder is end-stage heart failure,…” in claim 25 further limits the “an additional autophagy disorder” in claim 18 or if it further limits the Danon disease or the “additional autophagy disorder” in claim 18 has been withdrawn in view of the amendment.
Claim Rejections - 35 USC § 103
Claims 13, 18, 19, 21, 22 remain rejected under 35 U.S.C. 103 as being unpatentable over Rebar (2014/0112896) in view of Sun (Mol. Ther. 2003, Vol. 7, pg 193-201) and Nishino (Nature, 2000, Vol. 406, pg 906-910).
Rebar taught a donor sequence comprising a nucleic acid sequence encoding LAMP2 (pg 16, paragraph 161) and that “[t]he donor molecules described herein can include sequences coding for one or more enzymes lacking or deficient in subjects with lysosomal storage diseases, including but not limited to the proteins shown in Table 2” (pg 18, Table 2, under “5. Defects in lysosomal trafficking proteins”). The donor can be DNA or RNA (pg 16, paragraph 154) and introduced as part of a vector “e.g. adenovirus, AAV, herpesvirus, retrovirus, lentivirus and integrase defective lentivirus” (paragraph 155), specifically AAV serotypes 1-9 (pg 20, paragraph 178), most specifically AAV2/8 (paragraph 204). Danon disease inherently MUST be caused by a mutant LAMP2B gene as required in claim 13 (paragraph 3 of the instant application). Danon disease inherently MUST cause decreased fusion of autophagosomes and lysosomes in the myocardium of the patient as required in claim 13 because applicants described it as being part of the invention.
Rebar taught intravenous injection as required in claim 23 (para 25, 35, Fig. 3, 183, 187, 189, 203, 212, 218). Specifically, injection of gene therapy vectors, such as AAV, is intravenous (paragraph 183, 187). The starting materials, subject, route of administration described by Rebar inherently MUST increase fusion of autophagosomes and lysosomes in the myocardium of the patient because it is the same combination of elements described by applicants as being part of the invention. Overall, Rebar enabled intravenous injection of an AAV vector encoding LAMP2 to a mammal with Danon disease, a mutant LAMP2 gene, and increased fusion of autophagosomes and lysosomes in the myocardium of the patient as required in claim 13.
Rebar did not teach the AAV encoding LAMP2 was under the control of a CAG promoter as required in claim 13.
However, Sun administered AAV8 encoding human acid α glucosidase (GAA) to GAA-knockout mice such that glycogen levels were corrected (pg 194, “Neonatal muscle-targeted Ad-AAV administration…)” for treating a lysosomal storage disease in vivo. Sun specifically described using a CMV/chicken beta actin promoter (CAG promoter) to drive expression of GAA (pg 200, col. 1, “construction of an AAV vector plasmid encoding hGAA”) for treating a lysosomal storage disease in vivo.
Thus it would have been obvious to those of ordinary skill in the art at the time of filing to administer an AAV vector encoding LAMP2 to a subject with a defect in LAMP2 (Danon disease) as described by Rebar using AAV8 and the hybrid CAG promoter described by Sun. Those of ordinary skill in the art at the time of filing would have been motivated to use an AAV8 vector because Sun taught AAV8 had tropism for the heart. A promoter was well-known to be essential for expression, and the CAG promoter was well-known at the time of filing for constitutive expression in vivo for treating lysosomal disease as described by Sun; therefore, those of skill would have been motivated to use the CAG promoter for constitutive expression in vivo for treating lysosomal storage disease.
The combined teachings of Rebar and Sun did not teach the LAMP-2 in the vector was “LAMP-2B” as required in claim 13.
However, it was well-known that Danon disease was primarily caused by a defective LAMP-2B gene as evidenced by Nishino who taught the structure of the wild-type human LAMP-2B coding sequence and the mutant human LAMP-2 coding sequence that caused Danon disease (pg 906, Fig. 1; pg 907, Fig. 2).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to administer an AAV vector encoding LAMP2 to a subject with a defect in LAMP2 (Danon disease) as described by Rebar using LAMP-2B described by Nishino. Those of ordinary skill in the art at the time of filing would have been motivated to do so because a defective LAMP-2B gene was the primary cause of Danon disease (sentence bridging pg 907-908).
Claim 18 has been included because Rebar taught treating patients with Danon disease in Table 2.
Claim 19 has been included because taught Danon disease was primarily caused by a mutant LAMP2B gene that caused reduced LAMP2B expression.
AAV9 described by Rebar inherently MUST have tropism for cardiomyocytes and their progenitors as required in claim 21 because applicants say AAV9 has tropism for cardiomyocytes and their progenitors on pg 27, para 99-100.
Rebar taught AAV9 as required in claim 22 (see above).
Response to arguments
Applicants argue the rejection relies on hindsight reasoning (pg 6). Applicants’ argument is not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, 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). The combined teachings taught the exact same method steps in the exact same mammal; therefore, they inherently MUST increase fusion of autophagosomes and lysosomes in the myocardium of the patient.
Applicants argue Rebar and Sun did not teach using LAMP2B (pg 7). Applicants’ argument is not persuasive. The combined teachings of Rebar and Sun did not teach the LAMP-2 in the vector was “LAMP-2B” as required in claim 13. However, Rebar taught treating Danon disease using LAMP2B and it was well-known that Danon disease was primarily caused by a defective LAMP-2B gene as evidenced by Nishino who taught the structure of the wild-type human LAMP-2B coding sequence and the mutant human LAMP-2 coding sequence that caused Danon disease (pg 906, Fig. 1; pg 907, Fig. 2).
Applicants argue Rebar does not cure these deficiencies (pg 8). Applicants’ argument is not persuasive. The basis of the rejection is that Rebar taught everything in claim 13 except for the promoter and the “B” in LAMP-2B.
Applicants argue the examiner’s rejection relies on functional equivalents (pg 8-9). Applicants’ argument is not persuasive. The examiner’s response to applicants’ arguments discussed equivalents. The rejection does not. The obviousness rejection is based any of the diseases listed by Rebar being treatable, i.e. Rebar is enabled for treating Danon disease because they say it is so. The rejection is not based on choosing only one of the functionally equivalent vectors described by Rebar; they are all enabled.
Applicants discuss Sun on pg 9 and say the only connection between Rebar and Sun is the general use of AAV for treating lysosomal storage disease, “neither of which are related to the specific limitations of claim 13”. If applicants are attempting to argue the references are non-analogous art, Applicants’ argument is not persuasive because they both relate to using AAV for treating lysosomal storage disease.
Claim 16 remains rejected under 35 U.S.C. 103 as being unpatentable over Rebar (2014/0112896) in view of Sun (Mol. Ther. 2003, Vol. 7, pg 193-201) and Nishino (Nature, 2000, Vol. 406, pg 906-910) as applied to claims 13, 18, 19, 21, 22 and further in view of Dodge (8796236).
The combined teachings of Rebar, Sun, and Nishino taught intravenous injection of an AAV vector encoding LAMP2B operably linked to a CAG promoter to a mammal with Danon disease, a mutant LAMP2 gene, and decreased “autophagic flux” such that “autophagic flux” increases as required in claim 13.
The combined teachings of Rebar, Sun, and Nishino did not teach administering the AAV multiple times as required in claim 16.
However, multiple injections of an AAV vector for treating lysosomal storage disorders was well known in the art as described by Dodge (col. 15, lines 55-63).
Thus it would have been obvious to those of ordinary skill in the art at the time of filing to administering an AAV vector encoding LAMP2B operably linked to a CAG promoter to a mammal with Danon disease as described by the combined teachings of Rebar, Sun, and Nishino using multiple injections as described by Dodge. Those of ordinary skill in the art at the time of filing would have been motivated to repeat the injection to administer more viral particles and increase LAMP2 expression or to target multiple tissues or to repeat injection after a period of time to sustain LAMP2 expression.
Response to arguments
Applicants do not specifically address this rejection.
Claim 24 remains rejected under 35 U.S.C. 103 as being unpatentable over Rebar (2014/0112896) in view of Sun (Mol. Ther. 2003, Vol. 7, pg 193-201) and Nishino (Nature, 2000, Vol. 406, pg 906-910) as applied to claims 13, 18, 19, 21, 22 and further in view of Kaplitt (6162796).
The combined teachings of Rebar, Sun, and Nishino taught intravenous injection of an AAV vector encoding LAMP2B operably linked to a CAG promoter to a mammal with Danon disease, a mutant LAMP2 gene, and decreased “autophagic flux” such that “autophagic flux” increases as required in claim 13.
The combined teachings of Rebar, Sun, and Nishino did not teach administering the AAV into the coronary artery as encompassed by claim 24.
However, administering an AAV into the coronary artery for heart therapy was well known in the art as described by Kaplitt (background paragraph 19, 26, 27; Description para of Fig. 2, para 71).
Thus it would have been obvious to those of ordinary skill in the art at the time of filing to administering an AAV vector encoding LAMP2B operably linked to a CAG promoter to a mammal with Danon disease as described by the combined teachings of Rebar, Sun, and Nishino using intracoronary injection as described by Kaplitt. Those of ordinary skill in the art at the time of filing would have been motivated to administer AAV into the coronary artery to more-directly target LAMP2 expression to the heart.
Response to arguments
Applicants do not specifically address this rejection.
Claim 25 remains rejected under 35 U.S.C. 103 as being unpatentable over Rebar (2014/0112896) in view of Sun (Mol. Ther. 2003, Vol. 7, pg 193-201) and Nishino (Nature, 2000, Vol. 406, pg 906-910) as applied to claims 13, 18, 19, 21, 22 and further in view of Kanamori (Cardiovascular Res., 2011, Vol. 91, pg 33-339) and MacKeigan (20120045459).
The combined teachings of Rebar, Sun, and Nishino taught intravenous injection of an AAV vector encoding LAMP2B operably linked to a CAG promoter to a mammal with Danon disease, a mutant LAMP2 gene, and decreased “autophagic flux” such that “autophagic flux” increases as required in claim 13.
The combined teachings of Rebar, Sun, and Nishino did not teach administering the AAV to treat myocardial infarction as encompassed by claim 25.
However, Kanamori taught autophagy is activated after myocardial infarction (abstract), and MacKeigan taught “autophagy is a critical step in the pathogenesis of several cardiovascular diseases, including, but not limited to myocardial infarction” (Description para 411).
Thus it would have been obvious to those of ordinary skill in the art at the time of filing to administering an AAV vector encoding LAMP2B operably linked to a CAG promoter to a mammal with autophagy of the heart as described by the combined teachings of Rebar, Sun, and Nishino wherein the autophagy of the heart was a result of myocardial infarction as described by Kanamori and MacKeigan. Those of ordinary skill in the art at the time of filing would have been motivated to treat autophagy associated with myocardial infarction because myocardial infarction is one of the leading causes of cardiac disease in the world.
Response to arguments
Applicants do not specifically address this rejection.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
D’Souza (Circ. Heart Failure, 2014, Vol. 7, pg 843-849) reviewed Danon disease.
Franco (Mol. Therapy, 2005, Vol. 12, No. 5, pg 876-884) administered AAV8 encoding human acid α glucosidase (GAA) to GAA-knockout mice intravenously such that normal glycogen levels were obtained in the her and skeletal muscle. Franco specifically described using a CMV/chicken beta actin promoter to drive expression of GAA (pg 877, col. 2).
Adler (JACC, March 12, 2019, Vol. 73, No. 9, 1 page) AAV9.LAMP-2B IMPROVES METABOLIC AND PHYSIOLOGIC FUNCTION IN MURINE AND HUMAN IN-VITRO MODELS OF DANON DISEASE.
No claim is allowed.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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