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 .
Response to Amendment
The amendment filed 6/15/2026, amending claim(s) 1, 5, 6, and 20-22 and cancelling claim(s) 10 is acknowledged. Applicant’s amendments to the claims have overcome each and every claim objection, 112(a) written description rejection, and 112(b) rejection previously set forth in the Non-Final Office Action 01/13/2026.
The rejection of claims 1-4 under 35 U.S.C. 103 as obvious over Xiao, Weger, Nony, and Morris is withdrawn. The rejection of claims 5-10 and 20-22 under 35 U.S.C. 103 as obvious over Xiao, Weger, Nony, and Morris in further view of WO2019 is withdrawn. Applicant added the new limitations of “(a) a first nucleic acid molecule comprising the DNA molecule operably-linked to a CARE element, wherein the CARE element has the nucleotide sequence as given in SEQ ID NO: 5 or a variant thereof having at least 95% sequence identity to SEQ ID NO: 5 and which promotes the amplification of an operably-linked DNA molecule in the presence of a L4 22K polypeptide having the amino acid sequence of SEQ ID NO: 6 or 8;(b) a second nucleic acid molecule comprising a heterologous promoter operably- associated with a nucleotide sequence encoding a L4 22K polypeptide, wherein the nucleotide sequence encoding the L4 22K polypeptide is:(i) the nucleotide sequence as given in SEQ ID NO: 7 or a variant thereof which has a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 7 and which encodes a DNA-binding protein that promotes the amplification of a DNA molecule operably-linked to a CARE element; or (ii) a nucleotide sequence encoding the polypeptide of SEQ ID NO: 6 or 8, or a variant thereof having at least 95% nucleotide sequence identity to the nucleotide sequence encoding the polypeptide of SEQ ID NO: 6 or 8, and which encodes a DNA-binding protein that promotes the amplification of a DNA molecule operably-linked to a CARE element”, which are not taught in the cited prior art.
Claims 1-9 and 20-22 are pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed foreign application GB2001484.1 filed on 02/04/2020 and PCT/GB2021/050237 filed 02/03/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement – New, necessitated by amendment
Claims 1-9 and 20-22 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 amplifying a DNA molecule in a host cell, wherein the DNA molecule is operably-linked to a CARE element consisting of SEQ ID NO: 5, the method comprising the step of culturing a host cell which comprises:
(a) a first nucleic acid molecule comprising the DNA molecule operably-linked to a CARE element consisting of SEQ ID NO: 5;
(b) a second nucleic acid molecule comprising a heterologous promoter operably- associated with an amino acid sequence encoding a L4 22K polypeptide consisting of SEQ ID NO: 8, and
(c) a third nucleic acid molecule comprising a nucleotide sequence encoding an AAV Rep polypeptide, and
A process for producing virus particles, the process comprising the steps:
(a) introducing, into a host cell, an adenoviral vector comprising:
(i) a nucleic acid molecule comprising a heterologous promoter operably- associated with amino acid sequence encoding a L4 22K polypeptide consisting of SEQ ID NO: 8;
(ii) a Transfer Plasmid comprising 5'- and 3'-viral ITRs flanking a transgene;
(iii) helper genes for packaging a viral Transfer Plasmid,
the host cell comprising:
a CARE element consisting of SEQ ID NO: 5, operably-linked to
(i) an AAV cap gene; and
(ii) a nucleic acid molecule comprising a nucleotide sequence encoding a viral Rep polypeptide;
(b) culturing the host cell under conditions such that virus particles are assembled within the host cell; and
(c) harvesting packaged virus particles from the host cell or from the culture medium
does not reasonably provide enablement for
An L4 2KK polypeptide with a nucleotide sequence as given in SEQ ID NO: 7 or a variant thereof which has a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 7; or (ii) a nucleotide sequence encoding the polypeptide of SEQ ID NO: 6 or 8, or a variant thereof having at least 95% nucleotide sequence identity to the nucleotide sequence encoding the polypeptide of SEQ ID NO: 6 or 8,
The method of claim 6 (specifically, an adenoviral vector comprising a nucleic acid molecule comprising a heterologous promoter operably associated with a nucleotide sequence encoding a L4 22K polypeptide or variant thereof, and a nucleic acid molecule comprising a nucleotide sequence encoding a viral Rep polypeptide)
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
The Examiner incorporates herein the analysis discussed above in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
The Breadth of the Claims and The Nature of the Invention
The claims are directed toward methods of amplifying a DNA molecule in a host cell and processes for producing viral particles.
Claim 1, directed to a method of amplifying a DNA molecule in a host cell, only recites one method step: culturing the host cell (with no culturing conditions recited). The method steps of claims 5 and 6 are also generically recited.
Claims 5 and 6 generically recite the genus of a heterologous promoter operably-linked with the L4-22K polypeptide. A heterologous promoter is defined as “a promoter which is not an
adenoviral Major Late Promoter” in the specification (pg. 20).
The State of the Prior Art, The Level of One of Ordinary Skill and The Level of Predictability in the Art
The prior art teaches many methods for amplifying DNA molecules in a host cell/producing viral particles that comprise adenoviral vectors and AAV Rep-cap genes. See references cited in the 112(a) written description and scope of enablement rejections, as well as references cited under “Citation of Relevant Prior Art” in the Non-Final Office Action filed 01/13/2026.
However, the prior art fails to teach or suggest a L4 2KK polypeptide with a nucleotide sequence as given in SEQ ID NO: 7 or a variant thereof which has a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 7; or (ii) a nucleotide sequence encoding the polypeptide of SEQ ID NO: 6 or 8, or a variant thereof having at least 95% nucleotide sequence identity to the nucleotide sequence encoding the polypeptide of SEQ ID NO: 6 or 8 used in an AAV production system (e.g., the prior art fails to teach the importance of these specific sequences to amplify DNA operably-liked to a CARE element).
The Existence of Working Examples and The Amount of Direction Provided by the Inventor
The specification fails to provide any evidence that a L4 2KK polypeptide with a nucleotide sequence as given in SEQ ID NO: 7 or a variant thereof which has a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 7; or (ii) a nucleotide sequence encoding the polypeptide of SEQ ID NO: 6, or a variant thereof having at least 95% nucleotide sequence identity to the nucleotide sequence encoding the polypeptide of SEQ ID NO: 6 or 8 plays a critical role in the amplification of a DNA molecule operably-linked to a CARE element. Specifically, the specification fails to distinctly point out the criticality of these nucleotide sequences and why other L4-22K sequences would not result in the same functional outcome of amplifying a DNA molecule operably-linked to a CARE element The specification and working examples provide little guidance on the connection/relationship between L4 22K and a CARE element, and only provide CMV as an example of a heterologous promoter operably-associated with L4-22K.
The working examples (beginning pg. 37) describe generating control Ad5-E1 (which the Examiner concludes comprises a nucleotide sequence encoding SEQ ID NO:8, and this sequence represents an Ad5 L4-22K according to pg. 42 of the specification) and TERA-E1 (a recombinant replicating adenovirus wherein its modified major late promoter transcribes the repressor protein TetR, and wherein transcription from the modified major late promoter is repressed by the TetR) by molecular cloning methods and produced from HEK293. HELARC32 cells are transfected with plasmid pSF-AAV-EGFP and infected, in the presence of doxycycline or DMSO, with Ad5-E1 or TERA-E1. AAV2 particles are then harvested. Example 5 describes the same, except the HeLaRC32 cells were transfected with plasmids transcribing adenovirus L4 genes under control of the CMV promoter, and infected with TERA-E1. AAV Cap DNA was then quantified.
In summary, the plasmids and vectors of the working examples are described generically, with no specific sequences recited.
Additionally, the only heterologous promoter used in the working examples is CMV.
As such, the specification fails to make up for the deficiencies of the global scientific community.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
Thus, the quantity of necessary experimentation to make or use the invention as claimed, based upon what is known in the art and what has been disclosed in the specification, will create an undue burden for a person of ordinary skill in the art to necessarily and predictably use the claimed method with a L4 2KK polypeptide with a nucleotide sequence as given in SEQ ID NO: 7 or a variant thereof which has a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 7; or (ii) a nucleotide sequence encoding the polypeptide of SEQ ID NO: 6, or a variant thereof having at least 95% nucleotide sequence identity to the nucleotide sequence encoding the polypeptide of SEQ ID NO: 6 or 8, as well as successfully produce virus particles with a generic heterologous promoter operably-linked to the claimed L4-22K.
In conclusion, the specification fails to provide any guidance as to how an artisan would
have dealt with the art-recognized limitations of the claimed method commensurate with the
scope of the claimed invention.
Claim Rejections - 35 USC § 112(b) – New, necessitated by amendment
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 1-9 and 20-22 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 1 recites “(a) a first nucleic acid molecule comprising the DNA molecule operably-linked to a CARE element,… (c) a third nucleic acid molecule comprising a nucleotide sequence encoding an AAV Rep polypeptide”.
In the Applicant’s response filed 06/15/2026, the Applicant states “A CARE element has previously been identified within the AAV genome…It was also known that the CARE element is part of the rep gene sequence.” (pg. 5). In view of this, it is unclear whether the CARE element operably-linked to the DNA molecule recited in part (a) is the same as the AAV Rep polypeptide recited in part (c). For example, if a host cell comprises a nucleic acid molecule comprising a nucleotide sequence encoding an AAV Rep polypeptide, does this also fulfill the requirement of the CARE element (so long as at least 95% of SEQ ID NO: 5 is present in the nucleotide sequence encoding the Rep polypeptide)? If SEQ ID NO: 5 is present, does that fulfill the limitation of comprising a nucleotide sequence encoding an AAV Rep polypeptide? It would be remedial to clarify the relationship between the CARE element and the AAV Rep polypeptide in the claim language (e.g., does the nucleotide sequence encoding an AAV Rep polypeptide also read on the CARE element nucleotide sequence?). For examination purposes, embodiments where a nucleotide sequence encoding an AAV Rep polypeptide comprising at least 95% of SEQ ID NO: 5 is interpreted to read on the CARE molecule also being present.
Claim 1 recites “such that the second and third, and optionally additionally one or more of the further nucleic acid molecules, are expressed”. Claims 5 and 6 recite “culturing the host cell such that virus particles are assembled within the host cell”. The metes and bounds of the structure that results in these functional outcomes are not clearly and precisely defined. For example, what culturing conditions are required for the virus particles to be assembled within the host cell, vs. what culturing conditions would not result in the virus particles being assembled within the host cell? It is unclear how the recitations of “such that…” further limits the claimed invention.
Response to Arguments
Applicant's arguments filed 06/15/2026 have been fully considered but they are not persuasive.
The Examiner appreciates the Applicant’s explanations of and conclusions drawn from each of the working examples of the specification. However, the Applicant does not clearly address the enablement concerns regarding the nucleotide/amino acid sequences for L4-22K.
Instant claim 1 recites that the L4-22K polypeptide may be encoded by a nucleotide sequence sharing at least 95% identity with SEQ ID NO: 7, or share at least 95% identity with a nucleotide sequence encoding polypeptide sequences SEQ ID NO: 6 or 8. Specific nucleotide sequences that would share at least 95% identity with a nucleotide sequence encoding polypeptide sequences SEQ ID NO: 6 or 8 are not disclosed in the instant specification
The working examples only teach Ad5, which the Examiner concludes comprises SEQ ID NO:8, which corresponds to Ad5 L4-22K (see pg. 42 of specification). However, no working examples for SEQ ID NO: 7, a nucleotide sequence representing Ad5 L4-22K, or SEQ ID NO: 6, an amino acid sequence representing HAdV-9 are provided. Further, SEQ ID NOs: 6 and 8 vary greatly, only sharing 48.3% identity:
PNG
media_image1.png
314
626
media_image1.png
Greyscale
Due to the lack of guidance in the prior art on the role/function of SEQ ID NOs: 6-8 in DNA amplification and relationship with CARE elements, the specification fails to provide enough support for the enablement of SEQ ID NOs: 6 and 7 in the claimed method.
Additionally, the Applicant did not distinctly point out how the use of a CMV promoter in the working examples provides enablement for any heterologous promoter as recited in claims 5 and 6.
Conclusion
No claims are 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 ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
ALLISON M. JOHNSON
Examiner
Art Unit 1638
/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638
Prosecution Insights