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 .
Status of Claims
Claims 1-5, 7, 10-15, 17-18 and 25 are pending an under exam. Claims 6, 8-9, 16, 19-20, and 22 are cancelled. Claim 21 and 23-24 are withdrawn.
It is noted that the text of withdrawn claims 21 and 23-24 has been removed. However, 37 CFR 1.121(c) indicates that the claim listing should include the text of all pending and withdrawn claims.
WITHDRAWN REJECTIONS
Claim Rejections - 35 USC § 112(b)
Regarding claim 5: The rejection is withdrawn following claim amendments.
Regarding claim 8: The rejection is withdrawn following claim cancellation.
Regarding claim 12: the rejection is withdrawn for amendment of dependency.
Regarding claim 25: The rejection is withdrawn following claim amendments.
Claim Rejections - 35 USC § 112(d)
Claim 12 was rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The rejection is withdrawn following claim amendments.
Claim Rejections - 35 USC § 103
Claims 1-3, 5-6, 12-14 and 17-18 were rejected under 35 U.S.C. 103 as being unpatentable over Cawood et al (WO2019141993, published Jul. 25, 2019, hereinafter "Cawood;" See IDS of 11/27/2023) in view of Naso et al (BioDrugs.; Published 2017 Aug; hereinafter "Naso" See PTO-892) as further evidenced by Liao et al (Cell. 2017 Dec 14, hereinafter “Liao,” See PTO-892).
The rejection is withdrawn following claim amendments. New rejections are set forth below.
Claims 4, and 7-8 were rejected under 35 U.S.C. 103 as being unpatentable over Cawood et al (WO2019141993, published Jul. 25, 2019, hereinafter "Cawood;" See IDS of 11/27/2023) in view of Naso et al (BioDrugs.; Published 2017 Aug; hereinafter "Naso", See PTO-892), further in view of Weger et al (J Virol 90, published 2016; hereinafter "Weger" See IDS of 10/25/2022).
The rejection is withdrawn following claim amendments. New rejections are set forth below.
Claims 10-11 were rejected under 35 U.S.C. 103 as being unpatentable over Cawood et al (WO2019141993, published Jul. 25, 2019, hereinafter "Cawood;" See IDS of 11/27/2023) in view of Naso et al (BioDrugs.; Published 2017 Aug; hereinafter "Naso" See PTO-892), further in view of Small et al (Hum Gene Ther. 2014 Apr hereinafter "Small" See PTO-892).
The rejection is withdrawn following Applicant’s claim amendments.
Claim 15 was rejected under 35 U.S.C. 103 as being unpatentable over Cawood et al (WO2019141993, published Jul. 25, 2019, hereinafter "Cawood;" See IDS of 11/27/2023) in view of Naso et al (BioDrugs.; Published 2017 Aug; hereinafter "Naso"), further in view of (Cawood et al (WO2019020992A1; Published Jan 31, 2019; hereinafter "Cawood-II; See IDS of 11/27/2023").
The rejection is withdrawn following Applicant’s claim amendments.
NEW GROUND OF REJECTIONS NECESSITATED BY THE CLAIM AMENDMENTS
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 1-5, 7, 10-15, 17-18 and 25 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.
Regarding claim 1: Claim 1 encompasses any adenovirus which has no p5, functional p19, which has a mutation at the TATA box, and absence of adenovirus inhibitor sequence, where such sequences are either delivered in trans, meaning they are provided to the host cells on a separate plasmid from the recombinant AAV (rAAV) vector genome, and helper plasmid where, the E2A, E4 and VA are delivered in helper plasmid or inserted into an E1 locus, or when delivered using a separate virus or when rep and cap are delivered in totally different systems (such as rep in E1, cap in a helper plasmid) (See Qiao Abstract). The specification taught that the claimed AAV construct was applicable in TERA2.0 system, where TERA-AAV and TERA-RepCap are added to a cell. It is noted that the specification clearly states that in these vectors Cap genes are driven by minimal or full length CMV promoters. Specification also clearly stated that [t]he rep gene is inserted in the E1 region of the adenovirus. The Cap gene expression cassette is inserted into the E1 region of the adenovirus. The transcriptional orientation of the minimal CMV promoter or the full length CMV promoter does not drive towards the Rep coding sequence. (See specification at [0267]). The specification did not describe an adenovirus of the claimed construct in a AAV vector where rep and cap genes are not integrated in E1 locus, or where the cap genes are not driven by non-CMV promoters or if the rep/cap genes are integrated into a non-E1 locus such as E3.
As such it is clear that the Applicants did not have possession of the claimed invention.
Regarding claim 1: The claim recites that the TATA box of p19 is mutated, but the function of p19 is preserved. However, the specification fails to point out which TATA box is mutated. Further the specification the specification fails to describe how the TATA box is mutated. As such the claim encompasses any mutation (synonymous or otherwise) to the TATA box, and to any nucleotide or amino acid. The specification fails to provide support that any mutation to any and all TATA box of p19 is acceptable. For example, Hein et al (WO2019057691A1; Published 2019 Mar 28; hereinafter "Hein" See PTO-892) taught the mutation of “p19 promoter, preferably the SP1 -50 region (nucleotides 817 to 829), the TATA -20 region (nucleotides 843 to 849), or the TATA -35 region (nucleotides 830 to 835).“ (See Hein, p. 3, lines 20-35). Hein particularly pointed out that “3' motifs next to the promoter (SP1 -50; TATA -35, TATA -20) are important for the activation of the internal p19 promoter. Mutating only the TATA -20 motif led to a significant but not full reduction of expression of the short rep proteins suggesting that also SP1 -50 and TATA -35 are important for the activation of expression, supported further by the fact that mutating everything except the TATA -20 also resulted in a clear decrease of expression of the short rep proteins.” Hein also taught that “inactivation of the internal AAV p19 promoter by mutations [[which]] prevent constitutive Rep52 and Rep40 expression while at the same time maintaining the functionality of said Rep78 and Rep68 proteins.” (See Hein, p. 3, lines 5-10). It is noted that instant specification taught only SEQ ID NO: 12 as the p19 promoter ablated sequence. As such it is submitted that the specification did not describe any mutation to any TATA box of p19, to retain it’s function.
It is submitted that the full scope of the claim is not adequately disclosed in the specification.
Claims 2-5, 7, 10-15, 17-18 and 25 depend from the rejected claim and inherit the deficiency and rejection.
Claims 1-5, 7, 10-15, 17-18 and 25 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant's specification is found enabling for adenovirus which has no p5, functional p19, which has a mutation at the TATA box, and absence of adenovirus inhibitor sequence, wherein the ablated p19 has SEQ ID NO: 12 and wherein rep and cap genes are inserted in the E1 region of the adenovirus and where the cap genes are driven by minimal or full length CMV promoters.
Applicant's specification is not found to be enabling for any adenovirus which has no p5, functional p19, which has a mutation at the TATA box, and absence of adenovirus inhibitor sequence, where such sequences are either delivered in trans, meaning they are provided to the host cells on a separate plasmid from the recombinant AAV (rAAV) vector genome, and helper plasmid where, the E2A, E4 and VA are delivered in helper plasmid or inserted into an E1 locus, or when delivered using a separate virus or when rep and cap are delivered in totally different systems (such as rep in E1, cap in a helper plasmid) (See Qiao Abstract). The specification is also not enabling for all mutations of the one or both of the TATA boxes in p19 promoter region. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to carry out the method of the invention commensurate in scope with the current claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Applicants' claims are directed to rep gene construct in the adenovirus vector. The breadth of the claims includes any and all constructs of rep and cap genes in adenovirus and any and all mutations of the TATA boxes in p19.
The specification provides rep gene is inserted in the E1 region of the adenovirus. The Cap gene expression cassette is inserted into the E1 region of the adenovirus. The transcriptional orientation of the minimal CMV promoter or the full length CMV promoter does not drive towards the Rep coding sequence. (See specification at [0267]). (Example 1). The specification taught stably integrating and replicating AAV rep DNA with the adenovirus genome by scrambling p5, p19 promoters and the p40 adenovirus inhibitor sequence (whilst maintaining the AAV Rep78 and Rep68 polypeptide) and inserted into the E1-deleted region of an adenoviral vector and co infection with TERA vectors. (Examples 2-3). The specification further taught that co-infection with tera vectors encoding the aav transfer genome and aav2 cap with tera encoding aav rep78-68 significantly increases the production of aav in hek293 cells compared to helper-free plasmid transfection method. The specification also taught AAV2, AAV9, AAV6 and AAV5 production using their construct described above. Further the specification taught a rep polypeptide comprising a rep polypeptide encoding sequence of SEQ ID NO: 12 (See specification [0143]).
At the time the invention was filed several ways to deliver rep and cap genes to a production cell line were known. For example, delivery of AAV in trans or cis or delivery in a baculovirus or in separate systems. It is known in the art that careful control of rep and cap genes are necessary to avoid cytotoxicity (See Qiao p. 1901, col. 2, para 1; p. 1911, col. 2, last para). Further as pointed out above, Hein taught the presence of two TATA boxes, which partially attenuate the p19 promoter. Hein also taught that “mutating only the TATA -20 motif led to a significant but not full reduction of expression of the short rep proteins suggesting that also SP1 -50 and TATA -35 are important for the activation of expression, supported further by the fact that mutating everything except the TATA -20 also resulted in a clear decrease of expression of the short rep proteins.” Hein also taught that “inactivation of the internal AAV p19 promoter by mutations [[which]] prevent constitutive Rep52 and Rep40 expression while at the same time maintaining the functionality of said Rep78 and Rep68 proteins.” (See Hein, p. 3, lines 5-10). Further Hein taught specific TATA mutations, such as those “that maintain the functionality of said Rep78 and Rep68 proteins” (See Hein Abstract) but “prevent constitutive Rep52 and Rep40 expression”. (Hein, p. 3, lines 5-10). The prior art did not teach that any mutation of TATA region of p19 would result in functional p19. Therefore, there was a recognized level of unpredictability with regards to the general construct and sequence of TATA box mutation of p19 promoter.
Due to the lack of teachings in the art regarding an appropriate sequence of TATA box for maintaining p19 functionality and adenovirus delivery methods, and the recognized unpredictability in the area of adenovirus production, a large amount of guidance and teachings would be necessary in order to be enabling for arriving at the claimed composition.
Guidance and teachings provided by Applicants in the instant specification is limited to SEQ ID NO: 12 for rep proteins encoding nucleic acid and insertion of rep and cap in E1 region, where cap is driven by CMV promoter. The Examiner acknowledges that the Office does not require the presence of working examples to be present in the disclosure of the invention (see MPEP §2164.02). However, in light of the state of the art, discussed above, which recognizes a high level of unpredictability in the field of AAV production, and limited teachings with regards to rep polypeptides and AAV production constructs, the Office would require appropriate disclosure to support the claimed construct. The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Thus, due to the high level of unpredictability in the art, the current specification would have to provide greater amounts of teachings and guidance directed to methods of carrying out the claimed invention.
Therefore, due to the sum of all the aforementioned factors, one of ordinary skill in the art, at the time the invention was made, would not expect success arriving at the claimed composition. It is recognized that the skilled artisan would be faced with the impermissible burden of undue experimentation in order to practice the claimed invention using any species of stem cell. Accordingly, claims 1-5, 7, 10-15, 17-18 and 25. are deemed properly rejected.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633