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 . References not included with this Office action can be found in a prior action.
Election/Restrictions
Applicant’s election of Group I, presently claims 1-6, 8, 9, 13, 15-17, 19, 21, 22, 24, 26-28, and 32-34, in the reply filed on 7/21/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 37-40, 42, 43, 48, 50, and 51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/21/2026.
Claims 1-6, 8, 9, 13, 15-17, 19, 21, 22, 24, 26-28, and 32-34 are under consideration on the merits.
Claim Rejections - 35 USC § 103
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, 3-6, 15-17, 19, 21, 22, 24, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Kasper et al. (European Journal of Pharmaceutics and Biopharmaceutics 77 (2011) 182–185).
Kasper teaches an in-line complexer mixing device comprising
(a) a first input tubing in communication at a proximal end to a source that comprises nucleic acids,
(b) a second input tubing in communication at a proximal end to a source that comprises linear polyethyleneimine (LPEI), and
(c) an output tubing that is in communication (i) at a proximal end to a distal end of the first input tubing and a distal end of the second input tubing and (ii) at a distal end to the vessel that comprises host cells (Figure 1),
wherein the first input tubing and the second input tubing are each in communication with a pump that has a linear flow rates of 0.1, 0.2, 0.5, or 1.0 cm/min and being effective to generate average transfection polyplexes with a diameter of about 60-200 nm (subheading 2.3 and Fig. 2), and the output tubing is about 60mm to 100,000mm in length and about 0.3mm to 250mm in inner diameter (subheading 2.3, i.e. 0.5mm inner diameter and 5cm length), reading in-part on claims 1, 22, and 24, reading on the embodiment of a polymer for claim 16 and PEI for claim 17. Kasper teaches the input and output tubing connected to a T-junction (Fig. 1, element 5), reading on the embodiment of a 90° angle for claim 3, reading on the embodiment of a T-junction mixer for claim 26, and reading on the embodiment of dual syringe injectors as species of a static mixer for claim 27 when read in-light of the specification at [0326]-[0327]. Kasper teaches mixing equal volumes of 2.5 ml each the plasmid solution and LPEI solution (subheading 2.3), reading in-part on claims 4-6. Kasper teaches that the DNA-LPEI polyplexes are diluted in culture media immediately before transfection (subheading 2.5), reading on claim 15. Kasper teaches an average diameter range of DNA-LPEI complexes of 60-170 nm (Figure 4, “upscaled”), reading on claims 19 and 21. Kasper teaches a vessel comprising 96-well plates (subheading 2.5), reading on that embodiment of the bioreactor of claim 28 when read in-light of Applicant’s broad definition of bioreactor at [069] of the specification.
Regarding claims 1 and 4-6, Kasper is silent on a pump capable of a flow rate of about 1-5000 mL/min. However, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. Regarding claim 1, Kasper clearly teaches that the linear flow rate is effective to generate average transfection polyplexes with a diameter of about 60-200 nm. Regarding claims 4-6, Kasper clearly teaches that equal volumes of the plasmid solution and LPEI solution are effective to generate average transfection polyplexes with a diameter of about 60-200 nm, and the mere scaling up of a prior art process capable of being scaled up is not sufficient to establish patentability in a claim to an old process so claimed absent any persuasive showing the contrary (see M.P.E.P. § 2144.04(IV)). Thus, the burden is shifted back to establish criticality of the claimed flow rate range of claim 1 and the volume ranges of claims 4-6 by objective evidence.
Regarding claims 22 and 24, claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure; see M.P.E.P. § 2111.02 and 2111.04. In this case, the wherein clauses only recite the intended outcome/result of the process steps of claim 1 and so the methods of Kasper are reasonably presumed capable of meeting the wherein clause of claim 22 towards the residence time range in the output tubing and the wherein clause of claim 24 towards the shear rate range in the absence of any showing to the contrary.
Alternatively, the limitations of claims 22 towards residence time in the output tubing and claim 24 towards shear rates are simply an extension of the optimization within prior art conditions or through routine experimentation of the flow rate range of Kasper, absent any showing of criticality of the claimed ranges to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case, Kasper clearly teaches that the linear flow rate is effective to generate average transfection polyplexes with a diameter of about 60-200 nm, and residence time of claim 22 and the shear rate in Kasper’s methods would be in-part mathematically dependent on the flow rate. Thus, the burden is alternatively shifted back to establish criticality of the claimed residence time range of claim 22 and shear rate range of claim 24 by objective evidence.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Kasper as applied to claim 1 above, and further in view of Draghia-Akli et al. (WO 2008/148010; Reference N).
The teachings of Kasper are relied upon as set forth above.
Regarding claim 2, Kasper does not teach wherein the output tubing is in a coil configuration.
Draghia-Akli teaches methods and devices for purifying samples of biologically active molecules of interest such as plasmid DNA from bacterial cells (Abstract, and the paragraph spanning pages 27-28), reading on claim 2. Draghia-Akli teaches a system for isolating and purifying biologically active molecules of interest from bacterial cells in a continuous flow process comprising an in-line mixer and holding coil (see elements 107 and 108 of Figure 1, and the 1st paragraph on page 28), reading on claim 2. Draghia-Akli teaches a holding coil comprises a length of tubing sufficient to provide that the fluid passes through the coil for a determined time (page 14, lines 14-16), reading on claim 2.
Regarding claim 2, it would have been obvious to a person of ordinary skill in the art before the invention was filed to further configure the output tubing of Kasper to a coil configuration in view of Draghia-Akli. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Kasper and Draghia-Akli are in-part directed towards methods of purifying DNA after passage through an in-line mixer, and because Draghia-Akli is reasonably pertinent to the problem faced by the inventor. The skilled artisan would have been motivated to do so because Draghia-Akli teaches that holding coils are predictably advantageous to provide for a sufficient and pre-determined time in methods of DNA purification, thus improving upon the methods of Kasper.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claims 8, 9, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Kasper as applied to claim 1 above, and further in view of Panteli et al. (WO 2018/208960; Reference O).
The teachings of Kasper are relied upon as set forth above. Kasper further teaches that the micro-mixer method is advantageous to allow highly reproducible preparation of large, standardized batches of homogenous, well-defined and transfection-competent polyplexes, banishes the risk of batch-to-batch variations and prevents handling inconsistencies among different operators, resulting in an increased polyplex quality (page 184, the first and only paragraph of the Conclusion), reading in-part on claims 8, 9, and 13.
Regarding claim 8, Kasper does not teach wherein the nucleic acids comprise one or more vectors encoding: (i) at least one payload flanked by an AAV inverted terminal repeat (ITR) on either side of the at least one payload; (ii) at least one AAV Rep polypeptide; (iii) at least one AAV Cap polypeptide; (iv) at least one Adenoviral helper polypeptide; or (v) any combination thereof. Regarding claim , Kasper does not teach wherein the one or more vectors comprise: (i) a first vector encoding at least one payload flanked by an AAV ITR on either side of the at least one payload, (ii) a second vector encoding at least one AAV Rep polypeptide and at least one AAV Cap polypeptide; (iii) a third vector encoding at least one Adenoviral helper polypeptide; or (iv) any combination thereof. Regarding claim 13, Kasper does not teach further comprising collecting rAAV particles from the vessel.
Panteli teaches easy-to-scale methods of creating DNA/transfection reagent master mixes for transfecting cells in culture (Abstract). Panteli teaches a method of transfecting cells, the method comprising 1) providing a first recombinant adeno-associated virus (rAAV) plasmid comprising a gene of interest (e.g. at least one payload) flanked by inverted terminal repeats (ITR), a second rAAV plasmid comprising AAV replication genes and AAV capsid genes, and a third rAAV plasmid comprising helper virus genes that facilitate rAAV viral replication, 2) combining the rAAV plasmids with a transfection reagent comprising polyethyleneimine (PEI), and 3) transfecting cells with the rAAV plasmid and PEI mixture such that the cells can operably generate rAAV (Figure 1 and [0016], and Example 2), reading on claims 8 and 9. Panteli teaches culturing the transfected cells for 3-5 days and they collecting/harvesting the rAAV particles by lysing the packaging cells ([0033]), reading on claim 13. Panteli teaches that the successful use of rAAV in clinical trials has underscored the need for production and purification systems capable of generating large amounts of highly pure rAAV particles ([0004]), reading on claims 8, 9, and 13
It would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the non-viral plasmid of Kasper with the rAAV plasmids and rAAV harvesting methods of Panteli to the cellular transfection methods of Kasper. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Kasper and Panteli are in-part directed towards methods of transfecting cells with DNA and PEI. The skilled artisan would have been motivated to do so because Panteli teaches that there is a need to produce large quantities of rAAV particles for clinical trials and because Kasper teaches that the micro-mixer method is advantageous to allow highly reproducible preparation of large, standardized batches of homogenous, well-defined and transfection-competent polyplexes, banishes the risk of batch-to-batch variations and prevents handling inconsistencies among different operators, resulting in an increased polyplex quality, and so the substitution would be predictably advantageous to combine the Panteli’s rAAV plasmids with the large scale and homogenous transfection-competent DNA/PEI polyplex composition of Kasper.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claims 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Kasper as applied to claims 1 and 28 above, and further in view of Lesch et al. (WO 2016/048556; Reference P).
The teachings of Kasper are relied upon as set forth above.
Regarding claim 32, Kasper does not teach wherein the bioreactor is a
continuous flow bioreactor, a batch process bioreactor, a perfusion bioreactor, or a fed
batch bioreactor. Regarding claim 33, Kasper does not teach wherein the bioreactor comprises one or more probes. Regarding claim 34, Kasper does not teach wherein the host cells are suspension adapted host cells.
Lesch teaches that inoculating an adherent culture bioreactor with suspension-adapter producer cells counter-intuitively improves commercial-scale production of recombinant biological products in the adherent-cell bioreactors (Abstract and subheading 3 on pages 13-15), reading on claim 34. Lesch teaches that the bioreactor can be any available in the art in which cells are expanded in suspension, for example any of a batch, fed-batch or continuous bioreactor types, single-use or multiuse, stirred tank or wave type bioreactor, perfusion or recirculation type bioreactor; or combinations thereof (page 7, lines 10-13), reading on claim 32. Lesch teaches installing calibrated probes into the bioreactor to monitor pH, glucose, and lactate (page 13, lines 1-7), reading on claim 33. Lesch teaches a preferred biological product comprising viral vectors, and their production by transduction, transfection of plasmid DNA, or infection, of expanded cells inside the bioreactor (page 8, lines 35 through page 9, line 14), reading on claims 32-34.
Regarding claim 32, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the 96-well plates of Kasper with the continuous flow bioreactor, a batch process bioreactor, a perfusion bioreactor, or fed
batch bioreactors of Lesch in Kasper’s transfection methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Kasper and Lesch are in-part directed towards methods of transfecting cells cultured in bioreactors with plasmid DNA. The skilled artisan would have been motivated to do so because the substitution would be predictably advantageous to scale up the methods of Kasper.
Regarding claim 33, it would have been obvious to a person of ordinary skill in the art before the invention was filed to further add the pH and glucose/lactate probes of Lesch with Lesch’s bioreactor to the transfection methods of Kasper. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Kasper and Lesch are in-part directed towards methods of transfecting cells cultured in bioreactors with plasmid DNA. The skilled artisan would have been motivated to do so because the further addition of sensor probes would be predictably advantageous to monitor the pH and glucose/lacate and accordingly adjust the pH and cell density in Kasper’s methods.
Regarding claim 34, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the suspension-adapted cells of Lesch to the transfection methods of Kasper. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Kasper and Lesch are in-part directed towards methods of transfecting cells cultured in bioreactors with plasmid DNA. The skilled artisan would have been motivated to do so because Lesch teaches that the addition is predictably advantageous to improve commercial-scale production of recombinant biological products in the adherent-cell bioreactors, thus scaling up and improving upon the methods of Kasper.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Conclusion
No claims are allowed. No claims are free of the art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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