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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 February 19, 2026 has been entered.
Status of Claims/Rejections
Claims 29-31, 33-34, 37-38, and 40-43 are currently pending and under examination on the merits in the instant application.
Any rejections not repeated in this Office action are withdrawn, and the following rejections are the only rejections applied in this application.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. 61/874,118, 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. The ‘118 provisional application is completely silent regarding SEQ ID NO:1, SEQ ID NO:3, and SEQ ID NO:5 recited in the instant claims. Hence, the ‘118 application fails to describe the method of claims 29-31, 33-34, 37-38, and 40-43 in the manner provided by 35 U.S.C. 112(a).
Accordingly, claims 29-31, 33-34, 37-38, and 40-43 are not entitled to the ‘118 application filing date and the effective filing date of claims 29-31, 33-34, 37-38, and 40-43 will be the PCT application filing date.
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 29-31, 33-34, 37-38, and 40-42 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.
The instant claims are drawn to a method of decreasing/inhibiting pathological tau in the brain of a mammal including a human having AD comprising administering an rAAVrh10 encoding an antibody comprising the heavy Ig chain and the light Ig chain of SEQ ID NO:3, wherein claim 29 and dependent claims thereof do not explicitly require codon-optimized sequence encoding SEQ ID NO:3, whereas claims 40-41 require that the nucleotide sequence be “modified relative to SEQ ID NO:1.”
It is found that the instant specification expressly discloses the following in paragraph 0093: “Antibody light and heavy chains are expressed in a 1:1 ratio under the CAG promoter by use of a 2A cis-acting hydrolase element downstream of a furin cleavage recognition site, Furin 2A (see Figure 1 and Figure 5). These pAAV constructs were used to test expression in vitro and in vivo in a mouse model. Nucleotide sequences were further optimized for expression in mammalian cells by use[ing] replacement of at least some codons with those preferred (usage) in mammalian cells, removal of potential splicing signals, mRNA instability elements and high GC content regions (Sequences 5, 6 in Figure 5).” (emphasis added).
The aforementioned disclosure of paragraph 0093 makes it clear on the record that the “AAV.rh10 PHF-1 vector” injected into the brain of the mice is SEQ ID NO:5, which is codon-optimized and actually administered to mice in the instant specification’s working example. It is found that the codon-optimized sequence of SEQ ID NO:5 shares about 80% sequence identity with the non-optimized, unmodified wild-type nucleotide sequence of SEQ ID NO:1. In the instant case, there is no adequate written description support in the specification that the non-optimized nucleotide sequence of SEQ ID NO:1 encoding the light and heavy chains of SEQ ID NO:3 in the PHF-1 antibody has the required function of “inhibiting pathological tau levels in a mammal with Alzheimer’s disease”, wherein the effective amount of SEQ ID NO:1 “decreases tangle development, decreases insoluble tau in the brain, or improves motor performance.” It is only the codon-optimized sequence of SEQ ID NO:5, which has been described to result in a better rotarod test performance and a decrease in the amount of the pathological tau in the brain of the P301S mice. This single, codon-optimized nucleotide sequence of SEQ ID NO:5 having about 80% sequence identity with the unmodified nucleotide sequence of SEQ ID NO:1 is not a representative number of numerous nucleic acid sequences that encode SEQ ID NO:3 having the required functions in the claimed treatment method. That is, one of ordinary skill in the art would not have been able to extrapolate that the non-codon-optimized sequence of SEQ ID NO:1 would have the in vivo effects based on the results provided by SEQ ID NO:5 as the two nucleotide sequences share only about 80%. As such, any of the “numerous” nucleotide sequences capable of encoding the heavy and light chains of SEQ ID NO:3 cannot be reasonably expected to perform as the codon-optimized SEQ ID NO:5, unless there is a sufficient showing that all and any nucleotide sequence variants would perform similarly, wherein such showing is not provided in the instant specification or in the relevant prior art. Indeed, it was art-recognized knowledge in the relevant art that the actual antibody’s in vivo function is unpredictable and highly depends on the actual nucleotide sequence (e.g., codon-optimized vs. wild-type) encoding the antibody’s amino acid sequence. See for instance Hooper et al. (US 2009/0074792 A1), who report that although “both the codon optimized version and the non-codon optimized tPA-L1R were effective in raising potent neutralizing antibodies”, “the codon optimized version showed enhanced protection in a side-by-side comparison- i.e. more animals survived being vaccinated by tPA-L1R codon optimized than tPA-L1R that was not codon optimized.” See paragraph 0027. See also Figure 14 reproduced below, which shows about 70% survival rate on day 21 in mice treated with a DNA comprising the codon-optimized antibody encoding sequence (“COD L1R”) as opposed to about 15% survival rate on day 21 in mice treated with a DNA comprising the non-codon-optimized antibody encoding sequence (“L1R”), wherein the mice were challenged with VACV (vaccina virus) strain IHD-J.
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Hence, the actual in vivo function of a non-codon-optimized antibody-encoding DNA sequence was not known to be similar or better than that of a codon-optimized antibody-encoding DNA sequence, and even better, the in vivo function of the non-codon-optimized antibody-encoding DNA sequence was known to be significantly lower that that of the codon-optimized sequence as shown above.
Moreover, not all codon-optimized heavy chain and light chain sequences were known to provide the same or similar antibody-producing activity levels when combined in vitro as reflected by the post-filing reference of Mauro (BioDrugs, 2018, 32:69-81), who discloses the following at page 77: “In unpublished studies, we ordered codon optimized light and heavy chain genes for a mAb. Three light chain genes and three heavy chain genes were ordered from the same commercial provider. Comparison of the codon-optimized nucleotide sequences revealed that they were all different, i.e., different synonymous codon mutations were used for each gene. Strikingly, when combinations of these light and heavy chain genes (t = 9) were expressed in transiently transfected CHO cells and mAb expression levels were compared, the results showed that expression varied by > 5-fold. The magnitude of the difference in mAb expression between different light and heavy chain combinations is difficult to reconcile with the proposed mechanism of increased elongation rates and does not inspire confidence regarding the expected expression properties of codon optimized genes.” (emphasis added). As evidenced by the post-filing reference, it is deemed that it was not expected or predicted in the relevant prior art that any given codon-optimized or modified nucleotide sequences encoding the heavy chain and light chain sequences of the same antibody would be successful in producing the intended antibody at the intended expression levels for in vivo treatment purpose.
In view of the foregoing, there is no adequate written description support in the instant specification or in the relevant prior art that the unmodified nucleotide sequence as encompassed by claims 29-31, 33-34, 34-38, and 42 and any modified sequences other than SEQ ID NO:5 as encompassed by claims 29-31, 33-34, 34-38, and 40-42 would have the AD treatment function/effects as required by the claimed method.
Note that “when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”).” (emphasis added). See MPEP §2163.
In view of the foregoing, the codon-optimized nucleotide sequence of SEQ ID NO:5 included in “AAV.rh10 PHF-1 vector” is not considered to be a representative number of species reflecting the substantial variation of numerous nucleotide sequence species. Therefore, it is concluded that the instant specification fails to adequately describe and support the instantly claimed method comprising administering the genus of any nucleotide sequence encoding the heavy and light chains of SEQ ID NO:3 in such a way to reasonably convey that the instant co-inventors had possession of the entire genus as of the filing date sought (year 2013) or granted (year 2014) in the instant case.
Response to Arguments
Applicant's arguments filed on February 19, 2026 have been fully considered but they are not persuasive. Applicant argues applicant “need only describe in detail that which is new and not conventional.” In response, it is noted that SEQ ID NO:3 itself was created by the instant co-inventors hence it is deemed “new and not conventional.” Is applicant admitting on the record that the instantly claimed amino acid sequence of SEQ ID NO:3 was not “new”? If so, applicant is advised to submit an IDS citing a prior art reference that teaches SEQ ID NO:3 as there is no such art of record in any of IDS filed by applicant in this application. It is applicant’s duty to disclose relevant art in an IDS for examiner’s consideration.
Since the amino acid sequence of SEQ ID NO:3 per se was not known in the prior art absent objective evidence to the contrary, a codon-optimized nucleotide sequence encoding the therapeutic agent of SEQ ID NO:3, which is required and claimed to reduce pathological tau levels in an AD patient in the claimed therapeutic method is also deemed “new and not conventional.” Applicant did not provide any persuasive arguments or objective, factual evidence that SEQ ID NO:1 itself or any nucleotide sequence that “is modified relative to SEQ ID NO:1” was known to provide the claimed function/effects “in a mammal with Alzheimer’s disease”.
Applicant argues that the antibody’s function is related to the amino acid sequence and any “nucleic acid sequences are readily envisioned by the art worker.” In response, it is noted that the actual antibody’s function, especially a therapeutic function, and more particularly AD treatment function in an AD patient, was not known to be predictable unless actually tested as set forth in the rejection above. See the teachings of Hooper et al. (US 2009/0074792 A1) and Mauro (BioDrugs, 2018, 32:69-81). That is, the mere fact that one could envision various nucleotide sequences encoding SEQ ID NO:3 is insufficient to support the instantly claimed AD treatment method claims, especially when the instant specification discloses only a single species within the claimed genus encompassing substantial variation of nucleotide sequences for each of the heavy chain and the light chain, further especially in light of the fact that it was more than reasonably suggested in the relevant prior art that there is “unpredictability in the results obtained from species other than those specifically enumerated.” Again, see Hooper and Mauro.
Applicant argues that it was within the skills of a person of ordinary skill in the art “to test whether nucleic acid sequences other than SEQ ID NO:5” “are effective to inhibit pathological tau levels.” In response, applicant’s attention is directed to the fact that the instant rejection is not an enablement rejection as such, whether or not one skilled in the art can test various sequences for their function in inhibiting pathological tau levels is irrelevant. Furthermore, the mere possibility for a ordinarily skilled artisan to test various nucleotide sequences is not sufficient to comply with the written description requirement, whose inquiry occurs as of the filing date sought, because of the art-recognized unpredictability as evidenced by Hooper and as reflected in the post-filing reference by Mauro, who specifically tested nine different combinations of codon-optimized heavy chain and light chain sequences for the same antibody amino acid sequence and observed “expression varied by > 5-fold” among the nine different combinations, wherein “the magnitude of the difference in mAb expression between different light and heavy chain combinations is difficult to reconcile”. In the instant case, there is no teaching in the instant specification that which nucleotide sequences for the light chain and which nucleotide sequences for the heavy chain encoding SEQ ID NO:3 are expected to provide reduced pathological tau levels in the brain of an AD patient to the extent that the AD patient has improved functions as required by the claims. Again, neither the relevant prior art nor the instant specification provides the required structure-function correlation for a representative number of various nucleotide sequences encoding each of the heavy chain and light chain in SEQ ID NO:3 within the claimed genus. Furthermore, there is no evidence of record that the activity of SEQ ID NO:5 encoding SEQ ID NO:3 is predictive or indicative of the in vivo AD patient treatment function/activity of various other nucleotide sequences including the non-codon-optimized sequence of SEQ ID NO:1 that was not used/tested by the instant co-inventors. Hence there was no “known or disclosed correlation between function and structure”, wherein the claimed structure, the very active agent administered to the “mammal with Alzheimer’s disease” in the claimed method, is a “nucleic acid sequence”, not the “amino acid sequence” of SEQ ID NO:3 per se. Again, note that the instant claims are not directed to a nucleotide sequence product encoding SEQ ID NO:3; they are directed to a method of treating a “mammal with Alzheimer’s disease” using any nucleotide sequence encoding SEQ ID NO:3. Hence, applicant has misrelied on and misapplied MPEP §2163 cited at pages 7-8 of the remarks as there is no objective, factual evidence showing that the correlation between any and all nucleotide sequence variants and the antibody-producing function in vivo and AD patient treatment function in vivo was “known or disclosed”. Again, see the teachings of Hooper and Mauro for the lack of a reasonable correlation between nucleotide sequences encoding the same antibody and their function of producing antibody and/or in vivo biological function.
Since there is no objective evidence showing that the instant specification itself conveys that the instant co-inventors had possession of the entire genus of various nucleotide sequences encoding SEQ ID NO:3 that must result in the functions recited in the claimed AD treatment method, and since there is no objective, factual evidence that any given nucleotide sequence encoding SEQ ID NO:3 was predicted and expected to result in the same or similar effects as SEQ ID NO:5, which is the only species actually used by the instant co-inventors, this rejection is hereby reiterated.
Claim Objections/Allowable Subject Matter
Claim 43 is objected to because of the following informalities: “the modified” should be “the codon modified”. Appropriate correction is required.
Claim 43 would be allowable if rewritten in independent form including all of the limitations of the base claim.
Conclusion
No claim is allowed.
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/DANA H SHIN/Primary Examiner, Art Unit 1635