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 2, 5, 6, 11-16 have been canceled. Claims 18-24 have been added. Claims 1, 3, 4, 7-10, 17-24 are pending and under consideration.
Applicant's arguments filed 6-30-25 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.
Claim Objections
The preamble of claim 1 uses inverse copular construction with the verb and noun. The mutation and its function (causes a reduction but does not eliminate PKP2 expression) should be with the mammal and the mutation. SEQ ID NO: 2 should be with PKP2 in the vector. Extraneous wording should be eliminated in claim 1. The body of claim 1 does not contain clear, positive functional language indicating the “administering” step ameliorates symptoms of ARVC or treats ARVC in the mammal.
Claim 1 can be written more clearly as ---A method of treating arrhythmogenic right ventricular cardiomyopathy (ARVC) in a mammal, the method comprising intravenously, intracardially, pericardially, or intraarterially administering an adeno-associated viral (AAV) vector comprising a nucleic acid sequence encoding plakophilin 2 (PKP2) that is at least 85% identical to the nucleotide sequence of SEQ ID NO: 2 operably linked to a cardiac specific promoter to a mammal that has ARVC and a mutation in a PKP2 gene that causes a reduction but not elimination of PKP2 expression such that symptoms of ARVC are treated in the mammal ---.
SEQ ID NO: 2 is a nucleic acid, so claim 22 is scientifically inaccurate because it says the PKP2 protein comprises SEQ ID NO: 2. PKP2 protein comprises amino acids and cannot comprise a nucleic acid sequence as claimed. If applicants are attempting to say the PKP2 is encoded by a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 2, then say ---The method of claim 1, wherein the nucleic acid sequence encoding plakophilin 2 (PKP2) is at least 90% identical to the nucleotide sequence of SEQ ID NO: 2---.
SEQ ID NO: 2 is a nucleic acid, so claim 23 is scientifically inaccurate because it says the PKP2 protein comprises SEQ ID NO: 2. PKP2 protein comprises amino acids and cannot comprise a nucleic acid sequence as claimed. If applicants are attempting to say the PKP2 is encoded by a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 2, then say ---The method of claim 1, wherein the nucleic acid sequence encoding plakophilin 2 (PKP2) is at least 95% identical to the nucleotide sequence of SEQ ID NO: 2---.
SEQ ID NO: 2 is a nucleic acid, so claim 24 is scientifically inaccurate because it says the PKP2 protein comprises SEQ ID NO: 2. PKP2 protein comprises amino acids and cannot comprise a nucleic acid sequence as claimed. If applicants are attempting to say the PKP2 is encoded by a nucleic acid sequence that is 100% identical to SEQ ID NO: 2, then say ---The method of claim 1, wherein the nucleic acid sequence encoding plakophilin 2 (PKP2) is the nucleotide sequence of SEQ ID NO: 2---.
Claim Rejections - 35 USC § 112
Enablement
Claims 1, 3, 4, 7-10, 17 remain and claims 18-24 are 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 of treating arrhythmogenic right ventricular cardiomyopathy (ARVC), the method comprising administering an AAV vector encoding PKP2 operably linked to a cardiac-specific promoter intravenously, intracardially, pericardially, or intraarterially to a mammal that has ARVC and whose genome comprises a mutant PKP2 gene such that the ARVC is treated---, does not reasonably provide enablement for treating any ACM other than ARVC or preventing ARVC or ACM. 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/use the invention commensurate in scope with these claims.
The specification does not enable administering an AAV vector encoding PKP2 to treat a mammal with ARVC, a mutant PKP2 gene, and reduced but not eliminated PKP2 expression as broadly encompassed by claim 1 or doing so without obtaining a therapeutic effect.
Claim 1 is drawn to a method of treating a mammal that has ARVC, a mutant PKP2 gene, and reduced but not eliminated PKP2 expression.
Example 3 (pg 44) describes administering an AAV vector encoding PKP2 operably linked to a cardiac-specific promoter into mammalian cardiomyocytes (para 141-142; Fig. 8). Para 143-144 describes administering AAV-TNT-PKP2 into a wild-type mammal with no adverse effects. Example 4 (pg 45) describes a mouse model that has a mutant PKP2 gene that causes reduced but not eliminated PKP2 expression and ARVC. Example 5 (pg 47) describes administering an AAV vector encoding PKP2 operably linked to a cardiac-specific promoter into the mouse model of ARVC (para 152-156). The vector was administered retro-orbitally (para 143 & 154) which is intravenous, i.e. systemic administration.
The specification is limited to a PKP2 knockout mouse model of ARVC that lacks PKP2 expression (example 5). Support cannot be found of a mammal that has a mutant PKP2 gene with reduced but not eliminated PKP2. The PKP2-KO mouse in the specification and the art at the time of filing lacks expression of PKP2 which is different than a mouse with reduced but not eliminated PKP2 expression as claimed.
The specification is limited to administering the AAV to the PKP2-KO mouse model of ARVC such that a therapeutic effect. This is missing from the body of the claim. The sole disclosed purpose for doing so is therapy. The preamble requires treating the mammal with ARVC, but that is an intended use does not necessarily have to occur. The body of claim 1 does not contain clear, positive functional language indicating the “administering” step ameliorates symptoms of ARVC or treats ARVC in the mammal. 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 administer an AAV vector encoding PKP2 to treat any mammal with ARVC, a mutant PKP2, and reduced but not eliminated PKP2 expression or to do so without treating symptoms of ARVC as broadly encompassed by claim 1.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Applicants point to para 5, 33, 34, 44, 102, 131, 141, 145, Fig. 20A. When referencing the specification, please use page and paragraph number (and line number as necessary) of the original specification. Do not simply use paragraph numbers or refer to the US Patent Application Publication. In the future, please provide a detailed explanation for how each new phrase in claim 1 is supported in the specification using page and paragraph [and line number within if necessary], e.g. ---Support for the PKP2 being encoded by a nucleic acid sequence that is at least 85% identical to the nucleotide sequence of SEQ ID NO: 2 is found on pg X, paragraph Y---. Each new concept in each new claim should be pointed to specifically by page and paragraph or line number within as necessary. Where support is implicit please provide a reasoned explanation.
The citations provided on pg 5 of the response filed 6-30-25 are not persuasive because they do not teach a mammal with a mutant PKP2 gene that has reduced but not eliminated PKP2 expression as claimed.
Written Description
Claims 1, 3, 4, 7-10, 17-24 are 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 rejection modified
The specification lacks written description for administering an AAV vector encoding PKP2 to treat a mammal with ARVC, a mutant PKP2 gene, and reduced but not eliminated PKP2 expression as broadly encompassed by claim 1.
Claim 1 is drawn to a method of treating a mammal that has ARVC, a mutant PKP2 gene, and reduced but not eliminated PKP2 expression.
Example 3 (pg 44) describes administering an AAV vector encoding PKP2 operably linked to a cardiac-specific promoter into mammalian cardiomyocytes (para 141-142; Fig. 8). Para 143-144 describes administering AAV-TNT-PKP2 into a wild-type mammal with no adverse effects. Example 4 (pg 45) describes a mouse model that has a mutant PKP2 gene that causes reduced but not eliminated PKP2 expression and ARVC. Example 5 (pg 47) describes administering an AAV vector encoding PKP2 operably linked to a cardiac-specific promoter into the mouse model of ARVC (para 152-156). The vector was administered retro-orbitally (para 143 & 154) which is intravenous, i.e. systemic administration.
The specification is limited to a PKP2 knockout mouse model of ARVC that lacks PKP2 expression (example 5). Support cannot be found of a mammal that has a mutant PKP2 gene with reduced but not eliminated PKP2. The PKP2-KO mouse in the specification and the art at the time of filing lacks expression of PKP2 which is different than a mouse with reduced but not eliminated PKP2 expression as claimed.
Accordingly, the specification lacks written description for administering an AAV vector encoding PKP2 to treat any mammal with ARVC, a mutant PKP2, and reduced but not eliminated PKP2 expression as broadly encompassed by claim 1.
New rejection
The specification lacks written description for using a nucleic acid encoding PKP2 that is at least 85% identical to the nucleotide sequence of SEQ ID NO: 2 as required in claim 1 other than a sequence that is 100% identical to SEQ ID NO: 2. The claim requires administering an AAV vector comprising a nucleic acid sequence encoding PKP2 that is at least 85% identical to the nucleotide sequence of SEQ ID NO: 2 to a mammal that has ARVC, a mutation in a PKP2 gene, and reduced but not eliminated PKP2 expression. The claim encompasses doing so such that symptoms of ARVC are treated in the mammal. The PKP2 coding sequence that is at least 85% identical to SEQ ID NO: 2 may be completely functional, partially function, or inactive. The specification is limited to a nucleic acid sequence encoding PKP2 that is at least 100% identical to the nucleotide sequence of SEQ ID NO: 2 to a mammal that has ARVC and a mutation in a PKP2 gene such that symptoms of ARVC are treated in the mammal. The specification does not correlate SEQ ID NO: 2 to any sequence that is partially functional as broadly encompassed by claim 1. The specification does not teach any sequence that is less than 100% identical to SEQ ID NO: 2 that has complete PKP2 function. Accordingly, the specification lacks written description for using a nucleic acid encoding PKP2 that is at least 85% identical to the nucleotide sequence of SEQ ID NO: 2 as required in claim 1 other than a sequence that is 100% identical to SEQ ID NO: 2
Claims 22, 23 have been included in this rejection for reasons set forth above in context of a sequence that is 90% or 95% identical to SEQ ID NO: 2.
Indefiniteness
Claims 1, 3, 4, 7-10, 17 remain and claims 18-24 are 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Withdrawn rejections
The rejection regarding “the gene therapy vector” in claims 8, 10, 17 lacking antecedent basis has been withdrawn.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 3, 4, 7-10, 17 under 35 U.S.C. 102(a)(2) as being anticipated by Herzog (2022/0168447) has been withdrawn because Herzog did not teach a nucleotide sequence encoding PKP2 that is at least 85% identical to SEQ ID NO: 2 as required in claim 1.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 3, 4, 7-10, 17 under 35 U.S.C. 103 as being unpatentable over Herzog (2022/0168447) in view of Voit (WO 2021053222), Marcus (European Heart Journal, 2010, Vol. 31, pg 806-814), Huang (CN 107828879), van Opbergen (International J. Mol. Sci., 2019, Vol. 20, Article 4076, pg 1-21), and Voit (WO 2021053222; EFD = 9-21-20) has been withdrawn because Herzog did not teach a nucleotide sequence encoding PKP2 that is at least 85% identical to SEQ ID NO: 2 as required in claim 1.
Double Patenting
Pending rejections
A) Claims 1, 3, 4, 7-10, 17 remain and claims 18-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent Application 17390395, now US Patent 11781156. Although the claims at issue are not identical, they are not patentably distinct from each other because they all require treating heart disease using an AAV vector encoding PKP2 operably linked to a promoter. SEQ ID NO: 2 was disclosed in ‘156 and could have been claimed. The variations between the claim language are obvious variants
Response to arguments
Applicants argue the claims of ‘156 requires the mammal has ARVC or ACM and administering a nucleic acid sequence encoding PKP2 while the instant claims are limited to treating a mammal with a mutation in a PKP2 that causes reduced but not eliminated PKP2 expression. Applicants’ argument is not persuasive because the claims are obvious variants in both ways. The mammal with ARVC in ‘156has mutant PKP2 gene as claimed (Example 5 of ‘156). SEQ ID NO: 2 was disclosed in ‘156 and could have been claimed.
B) Claims 1, 3, 4, 7-10, 17 remain and claims 18-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent Application No. 17882395. Although the claims at issue are not identical, they are not patentably distinct from each other because they all require treating heart disease using an AAV vector encoding PKP2 operably linked to a promoter. SEQ ID NO: 2 was disclosed in ‘156 and could have been claimed. The variations between the claim language are obvious variants
Response to arguments
Applicants argue the claims of ‘395 requires the mammal has a certain parameter of ventricular contractions and administering a nucleic acid sequence encoding PKP2 while the instant claims are limited to treating a mammal with a mutation in a PKP2 that causes reduced but not eliminated PKP2 expression. Applicants’ argument is not persuasive because the claims are obvious variants in both ways. The mammal with ARVC in ‘395 has mutant PKP2 gene as claimed (Example 5 of ‘395).
New rejection
Claims 1, 3, 4, 7-10, 17-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent Application No. 17882314. Although the claims at issue are not identical, they are not patentably distinct from each other because they all require treating heart disease using an AAV vector encoding PKP2 operably linked to a promoter. SEQ ID NO: 2 was disclosed in ‘156 and could have been claimed. The variations between the claim language are obvious variants
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Sheikh (20210024956) AAV9-TNT-GFP to patients with arrhythmia.
Hertzog (2022/0168446; EFD = 8-9-21; 17670389) same as 20220168447
Hertzog (WO 2022032226; EFD 9-8-21) AAV9-HTNNT2-PKP2
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.
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