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 1-2, 5, 7, 11-12, 14-15, 17, and 18 are pending and under exam. Claims 3-4, 6, 8-10, 13, 16, 19-20, 22, and 25 are cancelled. Claims 21, 23 and 24 are withdrawn.
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 1-2, 5, 7, 11-12, 14-15, 17, and 18 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.
Regarding Claim 1: The claim requires a vector with a Rep polypeptide-encoding sequence given in SEQ ID NO: 12 or variants having 90% nucleotide identity thereto.
This claimed composition encompasses all vectors polynucleotides comprising >90% identity to SEQ ID NO: 12.
Applicant’s claims do not provide support for all nucleic acids comprising 90% identity to SEQ ID NO: 12. The specification as filed does not provide sufficient evidence that Applicants were in possession of the full scope of the claimed invention at the time of filing of the instant invention. As such, >90% identity to a 1932 base pair polynucleotide, encompasses
1932
C
1739
×
3
1739
= more than
1
×
10
1151
nucleotide molecules if only substitutions are considered. It is noted that language support insertions and deletion mutations as well. This amounts to enormous number of polynucleotides which do not have support in the specification. It is noted that the Applicants imposed some structural and functional limitations on the variants, such as “p 19 and p 40 are ablated rep gene construct in the adenovirus vector, the adenoviral inhibitor sequence is non-functional and the Rep78 and Rep68 coding sequences are maintained, the nucleic acid molecule does not comprise a p5 promoter, and wherein the adenoviral vector additionally comprises an AAV cap gene operably-associated with a minimal or full length CMV promoter, and wherein the nucleic acid molecule and AAV cap gene are located in the adenoviral E1 region.” The specification also does not provide any guidance on how what change where, exerts the claimed functional limitations. It is clear that the vector of the invention was restricted to SEQ ID NO: 12. For example, see instant specification at [0143].
Thus, Applicants were not in possession of the full scope of the claimed invention at the time of filing of the instant invention.
It is further noted that the claim requires ablated p19/p40 promoters. As noted above the specification provided limited set of promoter-modified sequences (i.e. SEQ ID NO: 12). The specification did not define or establish structural details of all possible promoter alterations that result in complete functional ablation of p19 and p40 while preserving Rep 78 and Rep 68 sequences. “An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.” (MPEP 2613. II.A. 3.(a)) The specification did not disclose any structural features that are necessary for a person of ordinary skill in the art to determine which sequences contribute to ablated p40 and p90 are encompassed under “p19 and p40 are ablated.” As such the claim lacks written description.
Claims 2, 5, 7, 11-12, 14-15, 17, and 18 inherit the rejection due to their dependency on claim 1.
Regarding claim 2: The claim requires a functional Rep 78/Rep68 polypeptide, without sufficient disclosure of a complete set of structures corresponding to the full claimed functional scope. “An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.” (MPEP 2613. II.A. 3.(a)) The specification did not disclose any structural features that are necessary for a person of ordinary skill in the art to determine which Rep78/68 peptides are encompassed under “functional Rep78/68). As such the claim lacks written description.
Regarding claim 14: The claim recites an adenoviral vector encoding “a polypeptide that is capable of transcriptionally-activating a promoter that is not present in the adenoviral vector”. The breadth of the claim encompasses any polypeptide that can transcriptionally activate an promoter not present in the vector. The breadth of the promoter includes Gal4-based activators, synthetic transcription factors, CRISPR systems bacterial activators and any known/unknown future activator proteins. The disclosed examples in the specification only focus on Rep/Cap expression systems, MLP repression and TERA system constructs. The specification did not disclose additional activator proteins or specific target promoter systems, or functional pairing of activators to a target promoter. As such there is no representative sampling of the claimed functional genus. As such Applicant has not shown possession of the full scope of the claimed invention as the specification did not show examples or embodiments of any promoter not present in the vector and use of any polypeptide capable of activation. The claim discloses a separate regulatory module that is not described in the specification.
Regarding claim 15: The claim requires “a repressible Major Late Promoter (MLP) wherein the MLP comprises one or more repressor elements that are capable of regulating or controlling transcription of the adenoviral late genes, and wherein one or more of the repressor elements are located downstream of the MLP TATA box.” The claim encompasses a broad genus of DNA elements that are characterized as functionally repressible. (See Song, Fessler (PTO-892)) However, the specification fails to identify representative species of all the motifs that fall within the claimed functional limitation. Further, the specification fails to provide a general rule or structural framework that would allow a skilled artisan to design repressible MLP systems across full scope of the claim without undue experimentation, or demonstrate promoter architectures that broadly define repression, rather than the specifically disclosed embodiments. For at least these reasons, the specification does not reasonably convey to a person of ordinary skill in the art that the inventors had possession of the claimed invention. It is further noted that generic positions like “downstream of TATA box” do not provide precise structural elements necessary for ascertaining scope of the claimed invention.
Claims 1-2, 5, 7, 11-12, 14-15, 17, and 18 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 not found to be enabling for
all polynucleotides encompassing 90% identity to SEQ ID NO: 12 in claim 1,
all possible repressor elements that are located
any place downstream of the MLP TATA box in claim 15.
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 all variants of SEQ ID NO: 12 where, p 19 and p 40 are ablated rep gene construct in the adenovirus vector, the adenoviral inhibitor sequence is non-functional and the Rep78 and Rep68 coding sequences are maintained, the nucleic acid molecule does not comprise a p5 promoter, and wherein the adenoviral vector additionally comprises an AAV cap gene operably-associated with a minimal or full length CMV promoter, and wherein the nucleic acid molecule and AAV cap gene are located in the adenoviral E1 region (claim 1). The breadth of the claim includes an enormous amount of polynucleotides, in which there are certain structural and functional limitations. The breadth of the claim includes multitude of different positions for CMV promoter, any orientation of the genes in E1 region and any mutation that ablates the activity of p19 and p40 promoters. Further, Applicant’s claim 15 requires any repressor element present at any position downstream of TATA box.
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, PTO-892 of 10/27/2025). 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; See PTO-892 of 10/27/2025). 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.
Additionally, Song and Fesser described several repressor elements; downstream by definition is not indicative of any particular position, just 3’ of the TATA box.
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. Further the specification did not describe any particular resign of MLPs.
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.
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.
Claims 2 and 15 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Regarding claim 2: The claim requires “functional AAV Rep78 and Rep68 polypeptides”. However the specification or the claim does not define how the function is measured or indicate what percentage of the optimal activity will fall under the scope of the claimed invention.
Regarding claim 15: The claim requires “repressible” elements “downstream of TATA box”. Such relative terms render the claim do not define the scope of the invention. Also the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Conclusion
No claim is allowed.
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
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