DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
This action is written in response to applicant’s correspondence received on 02/29/2024. Claims 1-4, 7, 20-21, 30-33, 35, 37-40 and 43-46 are currently pending.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The FIGs. 1-12 are objected to.
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."”
In the current case, the view numbers for FIGs. 1-12 are preceded by the word "Figure" instead of the abbreviation "FIG.".
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claims 21, 35, 38 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 21 recites the limitation “…the AAV1” in the second line of the claim. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 35, the term “a reference method” is not defined in the claims and the limitation “in which the culture of a) does not comprises [sic] dextran sulfate” is open to multiple interpretations as “a)” is not a defined component of “a reference method” in the claims, nor in the specification. Furthermore, it is not clear what other component(s) might be included in the “reference method” other than “…does not comprises [sic] dextran sulfate”. On pages 36-38 of the specification, ¶[00100] and ¶[00101] refer to the “reference method” multiple times, but the details regarding the components therein remain unexplained. In other sections of the specification, ¶[0066] and ¶[00194] recite a “control method” and ¶[002030] recites a “control production culture” with similar description regarding dextran sulfate such as “in the absence of dextran sulfate” or “…that does not comprise dextran sulfate”, without clarifying what other components are included. The phrase “reference method” renders the claim indefinite.
Claim 38 contains the trademark/trade name “PerC6”, which refers to the PER.C6® cell line trademark, used for vaccine and protein production, belongs to Janssen Vaccines & Prevention B.V. (formerly Crucell Holland B.V.), a Johnson & Johnson company, and is licensed for use in biotech and pharma, notably in adenovirus vector technologies for gene therapy and vaccines. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe Immortalized human embryonic retinal cells used for vaccines, recombinant proteins and viral vector/particle production and, accordingly, the identification/description is indefinite.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 7, 20-21, 35, 37-39 and 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (Scalable production of adeno-associated virus type 2 vectors via suspension transfection. Biotechnol Bioeng. 2006 Jun 20;94(3):416-30; Cited on IDS submitted on 07/14/2023; Hereinafter, Park) in view of Gribble et al. (WO 2020/219897 A1, published on 10/29/2020; Cited on IDS submitted on 07/14/2023; Hereinafter, Gribble).
Park (2006) teaches a method of producing a recombinant virus particle, i.e. a rAAV particle, which inherently incorporates a method of transiently transfecting cells suitable for producing recombinant virus particles and a method of producing a recombinant polypeptide, i.e. the capsid protein, in a suspension cell culture system comprising one or more necessary polynucleotides and a transfection reagent that is a polymer (page, 416, Abstract, left column, first paragraph; Page 417, Material and Methods, left column, 4th & 5th ¶, right column, 1st and 2nd ¶; Page 418, left column, 3rd ¶).
Park does not teach using dextran sulfate in the cell culture medium to enhance the production of recombinant products (peptides and/or virus particles).
However, Gribble (2020) teaches a method of using dextran sulfate to boost the production of recombinant virus particles, i.e. a rHSV particle. Gribble teaches that providing dextran sulfate at a dose range of 0.5mg/L-50mg/L (Page 2, ¶[007]), which covers the range of “between about 1mg/L and about 3mg/L…” claimed by the instant application, dose-dependently improves the transfection of rHSV producing cells resulting in higher quantity and potency in rHSV virus particle production in a bimodal fashion (Figure 2), similar to the instant application. Furthermore, the rHSV particles produced at the presence of dextran sulfate encode essential genes required for the packaging of rAAV particles, and they further improve the rAAV production over rHSV particles produced in the absence of dextran sulfate (Figure. 3).
Gribble does not teach directly providing dextran sulfate at the claimed concentration ranges to the rAAV production cell culture medium.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the known elements taught by Park and Gribble to yield predictable results because the benefits of Park’s disclosure can be further enhanced by combining the element of using dextran sulfate to boost the production of a recombinant virus particle in Gribble’s disclosure. Adding the element of dextran sulfate at the predicted concentrations to the element of suspension-based transfection culture medium in the presence of a polymer-based transfection reagent would have been predicted to provide the same function as they do individually, i.e. promote transfection/infection, enhance the production of recombinant polypeptide, and improve the production of recombinant viral particles. Routine optimization of the dextran sulfate would have allowed persons with ordinary skill in the art to identify the narrow range of effective concentration from the broad range of concentration taught by the prior art. See MPEP § 2144.05 II.A, Optimization Within Prior Art Conditions or Through Routine Experimentation: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical”.
Regarding claim 2, Park further teaches the inherent method of recombinant polypeptide production in the form of rAAV capsid proteins.
Regarding claim 4, 7, 20-21, the rationale of simple combination of known elements with predictable results continue to apply.
Regarding claim 35, Gribble further teaches that the inclusion of dextran sulfate, at the claimed concentration range in the recombinant product culture medium, significantly increased the production of recombinant viral particles to at least 1.1 times or more over the control culture medium in the absence of dextran sulfate (Figure 3), although for clarity, the graph shows the increase in rAAV productivity, which it is a direct reflection of the impact of dextran sulfate on the production of rHSVs that were produced with or without dextran sulfate in the culture medium.
Regarding claim 37, Park further teaches suspension adapted cells (Page 417, left column, the last ¶ under Adaptation of HEK 293 Cells to Suspension Culture).
Regarding claim 38-39, Park further teaches HEK293 cells (Page 417, left column, 4th ¶ under Cell Cultures and Viruses).
Regarding claims 43-44, Park further teaches that the polymer-based transfection reagent is a linear polyethylenimine (PEI; page, 416, Abstract, left column, first paragraph).
Claims 30-33 are rejected under 35 U.S.C. 103 as being unpatentable over Park in view of Gribble as applied to claims 1 & 2 above, and further in view of Agilent (Agilent AAV Helper-Free System manual; Published 2015 on Agilent product website).
Park further teaches the method of producing a recombinant virus particle comprising one or more polynucleotides such as pAAV-hrGFP, pAAV-LacZ, pAAV-RC, and pHelper obtained from Stratagene (Page 417, right column, under Plasmids, first ¶), which is now part of Agilent Technologies.
Park does not teach that these plasmids encode a) an rAAV genome to be packaged, b) adenovirus helper functions necessary for packaging, c) an AAV rep protein sufficient for packaging, and d) an AAV cap proteins sufficient for packaging.
However, Agilent teaches that the Agilent AAV Helper Free system does incorporate all of the above claimed elements (manual attached in PTO-892; Page 4-5 under Introduction; Page 8, FIGURE 1).
Regarding claim 32, Agilent further teaches that the aforementioned pHelper plasmid contains an adenovirus E2A gene, E4 gene, and adeno VA gene (Page 17, pHelper plasmid map).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the known elements taught by Park and Gribble in view of the reagent kit reagents and user manual from Agilent to yield predictable results taught by the current disclosure because all essential components and optimized workflow of the recombinant rAAV packaging system are provided by these prior arts, which serve as highly reproducible, tried and true, standard operation procedures to guide persons of ordinary skill in the art to predictable success.
Claims 3 & 40 are rejected under 35 U.S.C. 103 as being unpatentable over Park in view of Gribble as applied to claims 1 & 2 above, and further in view of Hyoung et al. (The molecular weight and concentration of dextran sulfate affect cell growth and antibody production in CHO cell cultures. Biotechnol Prog. 2016 Sep;32(5):1113-1122; Hereinafter, Hyoung; Cited in IDS submitted on 07/14/2023).
The teachings of Park and Gribble are discussed above.
Neither Park nor Gribble discloses the production of recombinant antibody or antigen- binding fragment thereof, bispecific antibody, enzyme, fusion protein or Fc fusion protein.
However, Hyoung teaches that recombinant monoclonal antibody (mAB) production using a suspension-adapted CHO cell culture medium can be boosted by dextran sulfate.
Regarding claim 40, Neither Park nor Gribble discloses the production of recombinant peptides or virus particles using CHO cells.
Hyoung further teaches using CHO cells (Page 1113, Abstract, lines 4-5; Introduction, left column, first ¶; Page 1114, left column, third ¶ under Cell line and culture maintenance).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the known elements disclosed by Park, Gribble, and apply the techniques and expand the recombinant applications disclosed by Hyoung to arrive at the same invention as a predictable result using suspension CHO cell cultures to produce immunology related recombinant polypeptides for antibody related applications
Claims 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over Park in view of Gribble as applied to claims 1 & 2 above, and further in view of Merten et al. (Virus Production Under Suspension Conditions" In: "Industrial Scale Suspension Culture of Living Cells, Wiley- VCH Verlag GmbH & Co. KGaA, June 18, 2014, pages 503-554.; Hereinafter, Merten).
The teachings of Park and Gribble are discussed above.
Neither Park nor Gribble discloses the production of recombinant virus particles in cell culture with a volume of between about 50 liters and about 20,000 liters, or between about 50 liters and about 5,000 liters.
However, Merten teaches “However, the real technological breakthrough is the use of suspension cells for virus production, which allows production scales beyond several 10 000s of liters.” (Page, 503, Abstract, lines 7-9).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the known elements disclosed by Park, Gribble, and adopt the visions and guidance of Merten to arrive at the same scaled up invention as a predictable result with reasonable expectation of success in achieving scalable volume production of recombinant virus particles suitable for different scales of demands from mid-range volume bench research or early stage clinical testing to large scale industrial productions.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636