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 .
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 11-25-25 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 Objections
The final result of delivering the AAV remains unclear in claim 13 because the concept of “increasing autophagic flux” “as compared to a baseline before delivering the AAV” is confusing. The term “flux” infers an oscillating state of amounts, and the term “autophagic” is defined as the consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases, but it is unclear what applicants consider the “flux” of autophagy or when that “flux” of autophagy is “increased” “as compared to a baseline before delivering the AAV”. See 112/2nd.
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 autophagy is reduced in myocardial tissue of the mammal,
does not reasonably provide enablement for
A) using AAV encoding LAMP2B to increase “autophagic flux” in a mammal that has Danon disease and reduced or non-detectable LAMP-2B as broadly encompassed by claim 13 or “an additional autophagy disorder” (claim 18), heart failure, myocardial infarction, drug toxicity, renal failure or aging (claim 25) other than administering the AAV encoding LAMP2B to a mammal that has a mutant LAMP2B gene, autophagy in myocardial tissue, and Danon disease or B) obtaining any therapeutic effect as broadly encompassed by claim 13 other than reducing autophagy in myocardial tissue of a mammal that has Danon disease,
B) any mammal with reduced or non-detectable LAMP2 expression other than a human with a mutant LAMP2 that expresses mutant LAMP2.
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.
Pending rejections
The specification does not enable using AAV encoding LAMP2B to increase “autophagic flux” in any “mammal having Danon disease and [ ] reduced or non-detectable LAMP2B gene expression” by delivering the AAV to the mammal’s myocardium cells as broadly encompassed by claim 13 other than administering the AAV encoding LAMP2B to a mammal that has a mutant LAMP2B gene, increased autophagy in myocardial tissue, and Danon disease such that autophagy in myocardial tissue decreases.
Claim 13 encompasses treating any mammal with Danon disease with any decreased LAMP2B expression. The mammal does not necessarily have to have a mutant LAMP2B gene. The mammal may have impaired or normal “autophagic flux”. The mammal may have increased, decreased, or normal autophagy in myocardial tissue.
“Autophagy” is the consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases.
The metes and bounds of “autophagic flux” in claim 13 cannot be determined (see 112/2nd). The specification states Danon disease causes “impaired autophagic flux” and increased autophagy (paragraph 3). In other words, 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, the mammal with Danon disease must exhibit increased autophagy of myocardial tissue, and the treatment must result in decreased autophagy of the tissue. It is unclear whether the mammal with Danon disease in claim 13 has increased, normal, or decreased “autophagic flux” because it is unclear when “autophagic flux” is “impaired” as described in paragraph 3. Claim 13 requires that administration of AAV increases “autophagic flux”, but increasing “autophagic flux” increases autophagy of myocardial tissue – this does not make sense because it would kill additional myocardial tissue in the mammal.
Rebar (2014/0112896) 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 is caused by a mutant LAMP2 gene as required in claim 13 (paragraph 3 of the instant application). Rebar taught intravenous injection (para 25, 35, Fig. 3, 183, 187, 189, 203, 212, 218) of gene therapy vectors, such as AAV (paragraph 183, 187). The method of Rebar inherently MUST increase “autophagic flux” in the subject with Danon disease because the starting materials, subject, route of administration described by Rebar are disclosed by applicants as being part of the invention and are encompassed by claim 13.
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 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.
The specification does not correlate administering the AAV to a mammal with a mutant LAMP2B gene, autophagy in myocardial tissue, and Danon disease to treating heart failure, myocardial infarction, drug toxicity, renal failure or aging as encompassed by claim 25. The specification and the art at the time of filing do not teach overexpression of LAMP2 in myocardial tissue of any mammal with heart failure, myocardial infarction, drug toxicity, renal failure or aging will improve autophagy or any other disease condition in the myocardium.
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 target expression of LAMP2B via a gene therapy vector to myocardial tissue in a mammal with Danon disease and decreased/non-detectable LAMP2B expression as required in claim 13 other than intravenously administering AAV encoding LAMP2B to a mammal that has a mutant LAMP2B gene, Danon disease, and increased autophagy in myocardial tissue such that autophagy decreases.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive because mammals with Danon disease do not have decreased “autophagic flux” or decreased “autophagy” as claimed. Danon disease causes apoptosis, i.e. increased autophagy, of myocardial disease.
Applicants argue that “impaired autophagic flux” means decreased “autophagic flux” (pg 7, line 6-9, of the response filed 11-25-25). Applicants’ argument is not persuasive because there is no definition in the specification or the art at the time of filing for “autophagic flux” or any indication that “impaired” “autophagic flux” means “autophagic flux” is decreased. A wider oscillation, i.e. an increase in autophagy fluctuation, seems more apropos as a disease condition associated with Danon disease.
Applicants argue “autophagic flux” is a widely used and understood term (pg 7, line 9-10). Applicants’ argument is not persuasive because it is unfounded.
Applicants argue apoptosis and autophagy are not the same (pg 7, line 16). Applicants’ argument is not persuasive because claim 13 is not limited to apoptosis or autophagy, because claim 13 invokes language about “autophagic flux”, because the metes and bounds of “autophagic flux” are not defined, because there is nothing in the specification or art that defines when a mammal with Danon disease has “impaired autophagic flux”, and because there is nothing in the specification or that art that teaches increasing “autophagic flux” in a mammal with Danon disease will treat any symptom of autophagy (or apoptosis).
Applicants point to Example 6 and Fig. 9H and Example 7 and Fig. 10A-D and argue they show “autophagic flux” was decreased in mammals that did not express LAMP2 (pg 8 of the response filed 11-25-25). Applicants’ argument is not persuasive. 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 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.
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.
Pending rejections
The specification lacks written description for delivering an AAV encoding LAMP2B to increase “autophagic flux” in any “mammal having Danon disease and [ ] reduced or non-detectable LAMP2B gene expression” by delivering the AAV to the mammal’s myocardium cells as broadly encompassed by claim 13 other than administering the AAV encoding LAMP2B to a mammal that has a mutant LAMP2B gene, increased autophagy in myocardial tissue, and Danon disease such that autophagy in myocardial tissue decreases.
Claim 13 encompasses treating any mammal with Danon disease with any decreased LAMP2B expression. The mammal does not necessarily have to have a mutant LAMP2B gene. The mammal may have impaired or normal “autophagic flux”. The mammal may have increased, decreased, or normal autophagy in myocardial tissue.
“Autophagy” is the consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases.
The metes and bounds of “autophagic flux” in claim 13 cannot be determined (see 112/2nd). The specification states Danon disease causes “impaired autophagic flux” and increased autophagy (paragraph 3). In other words, 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, the mammal with Danon disease must exhibit increased autophagy of myocardial tissue, and the treatment must result in decreased autophagy of the tissue. It is unclear whether the mammal with Danon disease in claim 13 has increased, normal, or decreased “autophagic flux” because it is unclear when “autophagic flux” is “impaired” as described in paragraph 3. Claim 13 requires that administration of AAV increases “autophagic flux”, but increasing “autophagic flux” increases autophagy of myocardial tissue – this does not make sense because it would kill additional myocardial tissue in the mammal.
Rebar (2014/0112896) 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 is caused by a mutant LAMP2 gene as required in claim 13 (paragraph 3 of the instant application). Rebar taught intravenous injection (para 25, 35, Fig. 3, 183, 187, 189, 203, 212, 218) of gene therapy vectors, such as AAV (paragraph 183, 187). The method of Rebar inherently MUST increase “autophagic flux” in the subject with Danon disease because the starting materials, subject, route of administration described by Rebar are disclosed by applicants as being part of the invention and are encompassed by claim 13.
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 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.
The specification does not correlate administering the AAV to a mammal with a mutant LAMP2B gene, autophagy in myocardial tissue, and Danon disease to treating heart failure, myocardial infarction, drug toxicity, renal failure or aging as encompassed by claim 25. The specification and the art at the time of filing do not teach overexpression of LAMP2 in myocardial tissue of any mammal with heart failure, myocardial infarction, drug toxicity, renal failure or aging will improve autophagy or any other disease condition in the myocardium.
Accordingly, the concept of delivering AAV encoding LAMP2B to myocardial tissue in a mammal with Danon disease and decreased/non-detectable LAMP2B expression as required in claim 13 lacks written description other than intravenously administering AAV encoding LAMP2B to a mammal that has a mutant LAMP2B gene, Danon disease, and increased autophagy in myocardial tissue such that autophagy decreases.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive because mammals with Danon disease do not have decreased “autophagic flux” or decreased “autophagy” as claimed. Danon disease causes apoptosis, i.e. increased autophagy, of myocardial disease.
Applicants arguments appear the same as those above for enablement which are not persuasive for reasons set forth above.
Indefiniteness
Claims 13, 16, 18, 19, 21, 22, 24, 25 remain rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Pending rejections
A) The metes and bounds of “increasing autophagic flux” and “decreasing” it in claim 13 remain indefinite because mammals with Danon disease have increased “autophagic flux” or increased “autophagy” (paragraph 3 of the specification). Danon disease causes apoptosis, i.e. increased autophagy or “autophagic flux”, of myocardial disease which is the opposite of mammals with decreased autophagy as required in claim 13. Increasing “autophagy” or “autophagic flux” in the mammal with Danon disease would kill MORE myocardial cells and potentially the mammal.
Furthermore, the term “flux” infers an oscillating state of amounts, and the term “autophagic” infers self-consumption, but the metes and bounds of “autophagic flux” are not defined in the specification or the art at the time of filing. While autophagy is defined as the consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases, it is unclear how the state of autophagy correlates to “autophagic flux” or an oscillating state of autophagy/non-autophagy. It is also unclear how the state of autophagy correlates to increasing autophagy or increasing the oscillation between autophagy and non-autophagy. To compound the confusion, the claim requires the subject has a mutant LAMP2 gene without ever requiring the subject has impaired autophagy or “autophagic flux”. Therefore, it is unclear whether the claim encompasses treating a subject that has a mutant LAMP2 with or without impaired autophagy or impaired “autophagic flux”. It is unclear whether the claim encompasses increasing autophagy or “autophagic flux” in a subject having wild-type autophagy or “autophagic flux” or whether it is limited to increasing autophagy or “autophagic flux” in a subject having impaired autophagy or “autophagic flux”. Accordingly, those of skill would not be able to determine they were “increasing autophagic flux” as required in claim 13.
Response to arguments
Applicants argue that “impaired autophagic flux” means decreased “autophagic flux” (pg 10, 3rd full paragraph, of the response filed 11-25-25). Applicants’ argument is not persuasive because there is no definition in the specification or the art at the time of filing for “autophagic flux” or any indication that “impaired” “autophagic flux” means “autophagic flux” is decreased. A wider oscillation, i.e. an increase in autophagy fluctuation, seems more apropos as a disease condition associated with Danon disease.
Applicants argue “autophagic flux” is a widely used and understood term (pg 7, line 9-10). Applicants’ argument is not persuasive because it is unfounded.
Applicants argue apoptosis and autophagy are not the same (pg 7, line 16). Applicants’ argument is not persuasive because claim 13 is not limited to apoptosis or autophagy, because claim 13 invokes language about “autophagic flux”, because the metes and bounds of “autophagic flux” are not defined, because there is nothing in the specification or art that defines when a mammal with Danon disease has “impaired autophagic flux”, and because there is nothing in the specification or that art that teaches increasing “autophagic flux” in a mammal with Danon disease will treat any symptom of autophagy (or apoptosis).
Applicants point to Example 6 and Fig. 9H and Example 7 and Fig. 10A-D and argue they show “autophagic flux” was decreased in mammals that did not express LAMP2 (pg 8 of the response filed 11-25-25). Applicants’ argument is not persuasive. 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 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.
B) The phrase “wherein the subject is exhibiting symptoms of Danon disease and an additional autophagy disorder” make claim 18 are indefinite. The phrase in claim 18 does not further limit the subject with a mutant LAMP2B gene in claim 13 because the phrase is broader than the concept of a subject with a mutant LAMP2B gene in claim 13. It is unclear whether applicants are attempting claim treatment of any mammal undergoing autophagy in myocardial tissue or autophagy anywhere. It is unclear whether applicants are attempting to claim “other” autophagy disorders associated with LAMP2 insufficiencies or if applicants are attempting to claim “other” autophagy disorders associated with any cause (i.e. gene mutations, disease states, or aging). If applicants are indeed attempting to claim any autophagy disorder associated with any cause (i.e. gene mutations, disease states, or aging), then claim 18 is broader than claim 13.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
C) The metes and bounds of the phrase “minithoracotomy” in claim 24 are indefinite. It is unclear what is being included/excluded by use of the term “mini” because size is relative and at the discretion of the investigator. If the phrase is intended to excluded certain sizes of Thoracotomies, then it is unclear what size is included. The specification and the art at time of filing do not teach the metes and bounds of the sizes associated with minithoracotomies. Those of skill would not be able to determine when/if they were infringing on the claim.
Response to arguments
Applicants argue “mini” does not refer to the size of the thoracotomy but rather to “a minimally-invasive” thoracotomy. Applicants’ argument is not persuasive because the specification and the art at the time of filing do not say that and because it is unclear when a thoracotomy is “minimally-invasive”.
D) The metes and bounds of “end-stage heart failure” and “end-stage renal failure” in claim 25 cannot be determined. The symptoms, structures, and functions that define “end-stage” heart or kidney failure are not disclosed in the specification or the art at the time of filing. It is unclear whether “end-stage” refers to certain death, a likelihood of death, or if death is not a consideration. Those of skill would not be able to determine when/if they were infringing on the claim.
Response to arguments
Applicants argue the terms are well-known in the art. Applicants’ argument is not persuasive because there is no definition of the metes and bounds of the term in the specification or any of the references provided by applicants, and no definition of the metes and bounds of the terms can be found.
E) It is unclear whether 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. If the phrase further limits the Danon disease, it is unclear how. If applicants are attempting to treat “end-stage heart failure, myocardial infarction,…”, then it is unclear what/when such conditions are caused by “autophagy”. If applicants are attempting to say the mammal with Danon disease also has “end-stage heart failure, myocardial infarction,…”, then that has not been established in the claim. If applicants are attempting to say “end-stage heart failure, myocardial infarction,…” is treated in the mammal, then that is missing from the claim.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
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 “autophagic flux” 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 “autophagic flux” in the subject with Danon disease described by Rebar because they are disclosed 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 decreased “autophagic flux” such that “autophagic flux” increases 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 14). 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 decrease autophagy (not claimed) and “increase autophagic flux (claimed and indefinite).
Applicants argue Rebar is limited to targeting red blood cells, liver cells, skeletal cells or stem cells in paragraph 9 or 44. Applicants’ argument is not persuasive. Rebar teaches treating Danon disease which inherently MUST be caused by a mutant LAMP2 gene and inherently MUST cause impaired “autophagic flux” (paragraph 3 of the instant application).
Applicants argue Rebar does not provide motivation to specifically choose treating Danon disease out of the 49 possible protein targets. Applicants’ argument is not persuasive. The fact IS that Rebar taught using any of a number of functionally equivalent vectors including AAV to deliver LAMP2 protein to any of a number of functionally equivalent patients including those with Danon disease caused by a mutant LAMP2 gene. The obviousness rejection is not based on choosing one of the functionally equivalent diseases described by Rebar; they are all enabled because they are functional equivalents. Nor is it based on choosing one of the functionally equivalent vectors described by Rebar; they are all enabled because they are functional equivalents. The obviousness rejection is based on using the teachings of Rebar for treating Danon disease using an AAV vector encoding LAMP2B in combination with a CAG promoter.
Applicants argue those of skill would not express all AAV serotypes are functionally equivalent and point to Naso and Munis. Applicants’ argument is not persuasive. The claims (and the specification) do not require the AAV in and of itself has any specific function. The intravenous route of delivery taught by Rebar would allow ANY AAV to reach the heart.
Applicants discuss Sun on pg 17-18 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.
Applicants argue Nishino has nothing to do with treating Danon disease using AAV encoding LAMP2 (pg 13). Applicants’ argument is not persuasive. Nishino has been relied upon as evidence that was well-known that Danon disease was primarily caused by a defective LAMP-2B gene. Nishino need not teach all the limitations of claim 13.
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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638