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 .
Election/Restrictions
Applicant’s election without traverse of claims 1-19 and 30 in the reply filed on May 18, 2026 is acknowledged.
Status of Claims
Claims 1, 19-29, and 35 are currently pending in the instant application.
Upon further consideration, claims 20-29 and 35, directed to the process of using applicant’s elected claim 1, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all process claims have been rejoined, the restriction requirement as set forth in the Office action mailed on March 17, 2026 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Accordingly, claims 1, 19-29, and 35 are under examination on the merits in the instant application.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/173,527, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. It is noted that the ‘527 provisional application is completely silent regarding SEQ ID NO:9 that is claimed in the instant case.
Accordingly, claims 1, 19-29, and 35 are not entitled to the benefit of the ‘527 filing date.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 20-29 and 35 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.
Claim 20 recites “administering to the subject at least one therapeutically effective amount”. The phrase “at least one” reads on a plurality. As such, the aforementioned limitation reads on administering a plurality of therapeutically effective amounts of the rAAV vector of claim 1. It is unclear whether the plurality of therapeutically effective amounts are the same amount that is administered multiple times or whether the limitation pertains to simultaneously co-administration of various amounts of the rAAV vector of claim 1. Hence, the metes and bounds pertaining to the “administering” method step are unclear. Since claims 21-29 and 35 depend from claim 20, all dependent claims are deemed indefinite for the same reasons.
Claim 26 recites “preserves electrical and structural integrity to prevent ARVC”. The claim fails to particularly point out and distinctly claim which “electrical and structural integrity” should be preserved.
Claim 29 recites “intranervally” and “intranerve”. It is unclear how the two limitations differ from each other.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 19-29, and 35 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.
Claims 1 and 19 are drawn to an rAAV vector comprising “a nucleic acid sequence that is at least 99% identical to SEQ ID NO:9”, which is formulated as a “pharmaceutical composition”, and all method claims, claims 20-29 and 35 require claim 1. It is found that the instant specification discloses a single nucleotide sequence species satisfying the instantly claimed “nucleic acid sequence”: SEQ ID NO:9 itself. There is no nucleotide sequence variant having at least 99% sequence identity to SEQ ID NO:9, nor is there a nucleotide sequence species having the recited “pharmaceutical” function when the nucleotide sequence species is less than 100% identical to SEQ ID NO:9. The instant specification is completely silent regarding which nucleotide position within the 4,498 nucleotides in length of SEQ ID NO:9 can be altered or which nucleotide sequences can be deleted and/or added so as to provide the “pharmaceutical” function. Accordingly, the specification fails to provide a representative number of species having the requisite structure-function correlation for the genus of “nucleic acid sequence” species thus fails to reasonably convey that the instant co-inventors had possession of the entire nucleic acid sequence variants as of the filing date sought or granted in the instant case.
Claims 20-29 and 35 are drawn to a therapeutic method comprising administering an rAAV rh10 vector comprising SEQ ID NO:9. The instant specification is completely silent regarding the structure-function correlation for the rAAV rh10 vector comprising SEQ ID NO:9 as there is no implicit or explicit disclosure/identification of the exact AAV construct that was actually administered to mice. That is, the instant specification is so deficient in adequately describing whether the vector comprising SEQ ID NO:9 or 99% sequence identity thereof is the vector “AAVrh10-PKP2” that provided a therapeutic effect in mice because “AAVrh10-PKP2” is not clearly identified with any nucleotide sequence identifier. In other words, the identity (the exact nucleotide sequence) of the “AAVrh10-PKP2” is concealed thus, it remains unknown whether the claimed therapeutic method that administers the vector of claim 1 actually provides the required function of treating any disease involving a PKP2 gene or ARVC in a subject.
As of the filing date sought in the instant case, it was known and demonstrated in the art that the actual PKP2 upregulation is highly nucleotide sequence-dependent as evidenced by
Herzog et al. (US 2022/0168446 A1, applicant’s citation), who experimentally demonstrate significantly different levels of PKP2 expression provided by different vectors having different nucleotide sequences. See Figure 5B reproduced below.
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Even better, Herzog demonstrates that the in vitro protein expression results in human myocardial cells in Figure 5B do not translate into in vivo therapeutic results pertaining to the LVEF % as shown in Figures 6A-D reproduced below.
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As shown above, “AAV9-hTnT”, which upregulated PKP2 protein expression by only about 1.5-fold (see Figure 5B), provided the highest level (consistently about 60%) of LVEF % at days 21 and 28 post tamoxifen treatment corresponding to 25 and 32 weeks after the AAV treatment (see Figure 6C), whereas “AAVrh.74-MHCK7”, which upregulated PKP2 protein expression by about 9.3-fold, provided about 40% and 30% of LVEF after 25 and 32 weeks after the AAV treatment (see Figure 6B). Taken together, a high level of nucleotide sequence-dependent unpredictability pertaining to the claimed subject matter was art-recognized. As such, the nondisclosure and concealment of the actual nucleotide sequence pertaining to “AAVrh10-PKP2” that was tested in mice in the instant application cannot describe that the very same vector fully satisfies the vector claimed in the instant treatment methods.
In addition, claims 20-21, 23-29, and 35 are broadly drawn to a method for treating “a disease and/or disorder involving a PKP2 gene”. As broadly written, “involving a PKP2 gene” reads on involving a wild-type PKP2 gene as well as a PKP2 gene having any mutated/altered bases, and furthermore, a “disorder involving a PKP2 gene” also reads on a disorder having overexpression of any PKP2 gene and underexpression of any PKP2 gene. Neither the instant specification nor the relevant prior art teaches that PKP2 protein overexpression treats any and all disorders involving any PKP2 gene sequence. The specification at best appears to teach PKP2 overexpression “could” be “a means to restore PKP2 levels” or “a means to restore PKP2 function” or a means “to restore cell-cell junction complex reassembly” in “ARVC patients.” See paragraph 0248. The single disease/disorder of “ARVC”, which is an autosomal dominant PKP2 cardiomyopathy (see paragraph 0004 of Herzog), is not a representative number of species within the broadly claimed genus of diseases/disorders involving any PKP2 nucleotide sequence.
Regarding the “therapeutically effective amount”, which “improves electrical and structural cardiac integrity”, “rescues and reassembles cell-cell junction proteins”, “improves cardiac function”, and “preserves electrical and structural integrity to prevent ARVC”, the instant specification does not identify the “AAVrh10-PKP2” administered to mice satisfies the structural limitation of the vector claimed in the instant method claims as explained above. As such, the specification fails to describe that the dose of “5e13 vg/kg” administered to mice is the dose pertaining to the claimed vector. Now, even if the instant specification provides adequate written description support that “AAVrh10-PKP2” is the claimed vector, the dose of “5e13 vg/kg” is not adequately described to provide the required effects in the treated subject, nor is the single dose representative of the entire range of “from about 1.0x1012 vg/kg to about 2.5x1014 vg/kg.” Hence, the “therapeutically effective amount” is not adequately described by the instant specification.
In addition, the instant specification does not describe that any and all administration routes including those recited in claim 29 provide the treatment effect in a subject. For instance, neither the instant specification nor the relevant prior art teaches that administration to the brain via the intracerebral or intranasal or intrathecal route delivers the claimed vector to the heart of the subject for providing the intended treatment effects in the subject having ARVC.
In view of the foregoing, it is concluded that the instant specification fails to describe that the “AAVrh10-PKP2” is indeed the claimed vector comprising SEQ ID NO:9 or at least 99% sequence identity thereof, which is claimed in the rejected therapeutic method claims thus, fails to reasonably convey that the instant co-inventors completed and had possession of the claimed subject matter as a whole or the genus as of the filing date sought in the instant case.
Relevant Prior Art
The following prior art are considered pertinent to applicant's disclosure:
1. Xu (US 2022/0098617 A1) discloses a 581-nt SEQ ID NO:15 as an “optimized version of WPRE” (oPRE), which is 100% identical to a 581-nt sequence at positions 3156-3736 of SEQ ID NO:9. See paragraph 0044; Table 1.
2. Mertins et al. (US 2024/0141373 A1) disclose linker sequences included in SEQ ID NO:9 claimed in the instant case such as SEQ ID NO:218, which corresponds to nucleotide positions 142-168 of SEQ ID NO:9, and SEQ ID NO:220, which corresponds to nucleotide positions 582-611 of SEQ ID NO:9.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, RAM SHUKLA can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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