OFFICE ACTION after ELECTION
This application has been assigned or remains assigned to Technology Center 1700, Art Unit 1774 and the following will apply for this application:
Please direct all written correspondence with the correct application serial number for this application to Art Unit 1774.
Telephone inquiries regarding this application should be directed to the Electronic Business Center (EBC) at http://www.uspto.gov/ebc/index.html or 1-866-217-9197 or to the Examiner at (571) 272-1139. All official facsimiles should be transmitted to the centralized fax receiving number (571)-273-8300.
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 .
Priority
Acknowledgment is made of applicant's claim for domestic priority under 35 U.S.C. § 119(e).
Information Disclosure Statement
Note the attached PTO-1449 form submitted with the Information Disclosure Statement filed 14 MAR 2024.
Election and Restriction Requirement
A requirement for restriction is made pursuant to 37 CFR §§1.141, 1.142 reproduced below:
§ 1.141 Different inventions in one national application.
(a) Two or more independent and distinct inventions may not be claimed in one national application, except that more than one species of an invention, not to exceed a reasonable number, may be specifically claimed in different claims in one national application, provided the application also includes an allowable claim generic to all the claimed species and all the claims to species in excess of one are written in dependent form (§ 1.75) or otherwise include all the limitations of the generic claim.
(b) Where claims to all three categories, product, process of making, and process of use, are included in a national application, a three-way requirement for restriction can only be made where the process of making is distinct from the product. If the process of making and the product are not distinct, the process of using may be joined with the claims directed to the product and the process of making the product even though a showing of distinctness between the product and process of using the product can be made.
§ 1.142 Requirement for restriction.
(a) If two or more independent and distinct inventions are claimed in a single application, the examiner in an Office action will require the applicant in the reply to that action to elect an invention to which the claims will be restricted, this official action being called a requirement for restriction (also known as a requirement for division). Such requirement will normally be made before any action on the merits; however, it may be made at any time before final action.
(b) Claims to the invention or inventions not elected, if not canceled, are nevertheless withdrawn from further consideration by the examiner by the election, subject however to reinstatement in the event the requirement for restriction is withdrawn or overruled.
Restriction to one of the following inventions is required under 35 U.S.C. 121:
I. Claims 1-16, drawn to an apparatus, classified in one or more of the CPC subgroups identified in the chart below.
II. Claims 17-21, drawn to a method, classified in one or more of the CPC subgroups identified in the chart below.
CPC classification chart of record:
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532
915
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The inventions are distinct, each from the other because of the following reasons:
Inventions II and I are related as process and apparatus for its practice. The inventions are distinct if it can be shown that either: (1) the process as claimed can be practiced by another and materially different apparatus or by hand, or (2) the apparatus as claimed can be used to practice another and materially different process. (MPEP § 806.05(e)). In this case, the apparatus as claimed can be used to practice another and materially different process such as by a process lacking a centrifuging step, e.g., the apparatus of Group I could be used for holding bioreactor vessels in preparation for further processing.
Restriction for examination purposes as indicated is proper because all these inventions listed in this action are independent or distinct for the reasons given above and there would be a serious search and examination burden if restriction were not required because one or more of the following reasons apply:
(a) the inventions have acquired a separate status in the art in view of their different classification;
(b) the inventions have acquired a separate status in the art due to their recognized divergent subject matter;
(c) the inventions require a different field of search (for example, searching different classes/subclasses or electronic resources, or employing different search queries);
(d) the prior art applicable to one invention would not likely be applicable to another invention;
(e) the inventions are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112, first paragraph.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of a invention to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected invention.
The election of an invention may be made with or without traverse. To reserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the restriction requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable on the elected invention.
If claims are added after the election, applicant must indicate which of these claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103(a) of the other invention.
Applicant’s election from representative MR. DOUG LIMBACH without traverse of GROUP II - claims 17-21 via a phone call on 18 JUNE 2026 is acknowledged with thanks. Accordingly, claims 1-16 are thereby withdrawn as being drawn to a nonelected invention (apparatus - kindly elected without traverse) whereas elected method claims 17-21 are treated on the merits below.
Drawings
The sheets of drawings filed on 2 FEB 2024 are approved by the examiner.
Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The Abstract of the Disclosure is objected to because:
a. the recitation of "Provided herein” in line 1 is an improper implied phrase.
Correction is required. See MPEP § 608.01(b).
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed (MPEP 606.01). The title should mention the centrifuging operation of the elected method.
Claim Rejections - 35 USC § 103
The terms used in this respect are given their broadest reasonable interpretation in their ordinary usage in context as they would be understood by one of ordinary skill in the art, in light of the written description in the specification, including the drawings, without reading into the claim any disclosed limitation or particular embodiment. See, e.g., In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004); In re Hyatt, 211 F.3d 1367, 1372 (Fed. Cir. 2000); In re Morris, 127 F.3d 1048, 1054-55 (Fed. Cir. 1997); In re Zletz, 893 F.2d 319, 321-22 (Fed. Cir. 1989). The Examiner interprets claims as broadly as reasonable in view of the specification, but does not read limitations from the specification into a claim. Elekta Instr. S.A.v.O.U.R. Sci. Int'l, Inc., 214 F.3d 1302, 1307 (Fed. Cir. 2000).
To determine whether subject matter would have been obvious, "the scope and content of the prior art are to be determined; differences between the prior art and the claims at issue are to be ascertained; and the level of ordinary skill in the pertinent art resolved .... Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented." Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18 (1966).
The Supreme Court has noted:
Often, it will be necessary for a court to look to interrelated teachings of multiple patents; the effects of demands known to the design community or present in the marketplace; and the background knowledge possessed by a person having ordinary skill in the art, all in order to determine whether there was an apparent reason to combine the known elements in the fashion claimed by the patent at issue.
KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1740-41 (2007). "Under the correct analysis, any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." (Id. at 1742).
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 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.
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.
The instant office action conforms to the policies articulated in the Federal Register notice titled “Updated Guidance for Making a Proper Determination of Obviousness” at 89 Fed. Reg. 14449, February 27, 2024, wherein the Supreme Court’s directive to employ a flexible approach to understanding the scope of prior art is reflected in the frequently quoted sentence, ‘‘A person of ordinary skill is also a person of ordinary creativity, not an automaton.’’ Id. at 421, 127 S. Ct. at 1742. In this section of the KSR decision, the Supreme Court instructed the Federal Circuit that persons having ordinary skill in the art (PHOSITAs) also have common sense, which may be used to glean suggestions from the prior art that go beyond the primary purpose for which that prior art was produced. Id. at 421–22, 127 S. Ct. at 1742. Thus, the Supreme Court taught that a proper understanding of the prior art extends to all that the art reasonably suggests, and is not limited to its articulated teachings regarding how to solve the particular technological problem with which the art was primarily concerned. Id. at 418, 127 S. Ct. at 1741 (‘‘As our precedents make clear, however, the analysis need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.’’). ‘‘The obviousness analysis cannot be confined . . . by overemphasis on the importance of published articles and the explicit content of issued patents.’’ Id. at 419, 127 S. Ct. at 1741. Federal Circuit case law since KSR follows the mandate of the Supreme Court to understand the prior art— including combinations of the prior art—in a flexible manner that credits the common sense and common knowledge of a PHOSITA. The Federal Circuit has made it clear that a narrow or rigid reading of prior art that does not recognize reasonable inferences that a PHOSITA would have drawn is inappropriate. An argument that the prior art lacks a specific teaching will not be sufficient to overcome an obviousness rejection when the allegedly missing teaching would have been understood by a PHOSITA—by way of common sense, common knowledge generally, or common knowledge in the relevant art. For example, in Randall Mfg. v. Rea, 733 F.3d 1355 (Fed. Cir. 2013), the Federal Circuit vacated a determination of nonobviousness by the Patent Trial and Appeal Board (PTAB or Board) because it had not properly considered a PHOSITA’s perspective on the prior art. Id. at 1364. The Randall court recalled KSR’s criticism of an overly rigid approach to obviousness that has ‘‘little recourse to the knowledge, creativity, and common sense that an ordinarily skilled artisan would have brought to bear when considering combinations or modifications.’’ Id. at 1362, citing KSR, 550 U.S. at 415–22, 127 S. Ct. at 1727. In reaching its decision to vacate, the Federal Circuit stated that by ignoring evidence showing ‘‘the knowledge and perspective of one of ordinary skill in the art, the Board failed to account for critical background information that could easily explain why an ordinarily skilled artisan would have been motivated to combine or modify the cited references to arrive at the claimed inventions.’’ Id.
From Norgren Inc. v. Int’l Trade Comm’n, 699 F.3d 1317, 1322 (Fed. Cir. 2012) (‘‘A flexible teaching, suggestion, or motivation test can be useful to prevent hindsight when determining whether a combination of elements known in the art would have been obvious.’’); Outdry Techs. Corp. v. Geox S.p.A., 859 F.3d 1364, 1370–71 (Fed. Cir. 2017) (‘‘Any motivation to combine references, whether articulated in the references themselves or supported by evidence of the knowledge of a skilled artisan, is sufficient to combine those references to arrive at the claimed process.’’). In keeping with this flexible approach to providing a rationale for obviousness, the Federal Circuit has echoed KSR in identifying numerous possible sources that may, either implicitly or explicitly, provide reasons to combine or modify the prior art to determine that a claimed invention would have been obvious. These include ‘‘market forces; design incentives; the ‘interrelated teachings of multiple patents’; ‘any need or problem known in the field of endeavor at the time of invention and addressed by the patent’; and the background knowledge, creativity, and common sense of the person of ordinary skill.’’ Plantronics, Inc. v. Aliph, Inc., 724 F.3d 1343, 1354 (Fed. Cir. 2013), quoting KSR, 550 U.S. at 418–21, 127 S. Ct. at 1741–42.
The Federal Circuit has also clarified that a proposed reason to combine the teachings of prior art disclosures may be proper, even when the problem addressed by the combination might have been more advantageously addressed in another way. PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1197–98 (Fed. Cir. 2014) (‘‘Our precedent, however, does not require that the motivation be the best option, only that it be a suitable option from which the prior art did not teach away.’’) (emphasis in original). One aspect of the flexible approach to explaining a reason to modify the prior art is demonstrated in the Federal Circuit’s decision in Intel Corp. v. Qualcomm Inc., 21 F.4th 784, 796 (Fed. Cir. 2021), which confirms that a proposed reason is not insufficient simply because it has broad applicability. Patent challenger Intel had argued in an inter partes review before the Board that some of Qualcomm’s claims were unpatentable because a PHOSITA would have been able to modify the prior art, with a reasonable expectation of success, for the purpose of increasing energy efficiency. Id. at 796–97. The Federal Circuit explained that ‘‘[s]uch a rationale is not inherently suspect merely because it’s generic in the sense of having broad applicability or appeal.’’ Id. The Federal Circuit further pointed out its pre-KSR holding ‘‘that because such improvements are ‘technology independent,’ ‘universal,’ and ‘even common-sensical,’ ‘there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves.’ ’’ Id., quoting DyStar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356, 1368 (Fed. Cir. 2006) (emphasis added by the Federal Circuit in Intel). When formulating an obviousness rejection, the PTO may use any clearly articulated line of reasoning that would have allowed a PHOSITA to draw the conclusion that a claimed invention would have been obvious in view of the facts. MPEP 2143, subsection I, and MPEP 2144. Acknowledging that, in view of KSR, there are ‘‘many potential rationales that could make a modification or combination of prior art references obvious to a skilled artisan,’’ the Federal Circuit has also pointed to MPEP 2143, which provides several examples of rationales gleaned from KSR. Unwired Planet, 841 F.3d at 1003.
When considering the prior art in its entirety, note Allied Erecting v. Genesis Attachments, 825 F.3d 1373, 1381, 119 USPQ2d 1132, 1138 (Fed. Cir. 2016) ("Although modification of the movable blades may impede the quick change functionality disclosed by Caterpillar, ‘[a] given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine.’" (quoting Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165, 77 USPQ2d 1865, 1870 (Fed Cir. 2006) (citation omitted))). However, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
In view of the guidance above, claims 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/003188 in view of EBERLE (US 3674198) or EBERLE (US 3674198) in view of WO 2021/003188.
WO 2021/003188 discloses the recited method of harvesting biological cells substantially as claimed including providing a plurality of 15 mL micro bioreactor vessels; adding biological material to the plurality of vessels; cultivating the biological material within the plurality of vessels; and removing the biological material from the vessels to harvest the cells as follows:
WO 2021/003188 relates to a method of cultivating adherent cells in a multiparallel bioreactor for the optimization of growth and production parameters of adherent cells. The invention also relates to a method for propagating viruses and vectors from adherent cells in a multiparallel bioreactor for production process optimization. Multiparallel bioreactors such as the AMBR® system (Sartorius) [as disclosed in the BACKGROUND section of the instant specification] are fully automated, single-use bioreactors that can be utilized for process development and process optimization of suspension cell growth parameters and conditions in a rapid timeframe. Multiparallel bioreactors have been historically used to perform multiple simultaneous Design of Experiments (DOEs) since they utilize low amounts of resources and reagents and have the ability to perform experiments with higher throughput than what can be performed in traditional reactors at a fraction of the cost. However, these systems can currently only be utilized for suspension cell platforms. Various biological agents such as viruses, viral vectors are better adapted to be propagated in adherent cells, and a procedure that makes these multiparallel bioreactors compatible to adherent cells for DOEs and production procedures and parameters optimization associated with adherent bioreactors is essential.
The procedure of the disclosure provides a novel method for using a solid attachment platform for adherent cells in a multiparallel bioreactors, for optimizing growth and production parameters of adherent cells. In the first aspect, the present invention provides a process for growing adherent cells in a containment box of a multiparallel bioreactor comprising: seeding the adherent cells on PET strips held in a culture dish; transferring the adherent cells on PET carrier strips to a containment box of the multiparallel bioreactor, and growing the adherent cells at a containment box impeller speed between 200 rpm to 1200 rpm. In another aspect, the process of the present invention further comprises, harvesting the adherent cells 3-10 days after the transfer of the adherent cells on to the PET carrier strips to the containment box of the multiparallel bioreactor. In another aspect of the invention, the process of the present invention further comprises infecting the adherent cells on PET carrier strips with at least one virus or virus particles, incubating the adherent cells on PET carrier strips with the virus, and harvesting the virus. In yet another aspect of the invention, the process of the present invention further comprises treating the cell with at least one vector that produces a biological agent, incubating the adherent cells on PET carrier strips with vector, and harvesting the biological agent.
FIG. 1 illustrates the PET carrier strips in a 6-well plate for seeding of cells. Three PET strips were placed in a well of a 6-well plate and covered with 1 mL of media. Cells are then added to the media well and incubated at 37°C overnight. FIG. 2 demonstrates the insertion of a PET carrier strips with adherent cells into the containment box of a multiparallel bioreactor. FIG. 3 illustrates a PET carrier strips with adherent cells in media within the containment box of the multiparallel bioreactor. The containment box includes an impeller. The settings of the impeller are set to the lowest possible impeller speed. A red circle demonstrates the impeller in the containment box. FIG. 4 illustrates a PET carrier strips with adherent cells within the AMBR containment box while in the bioreactor. Impeller speeds of about 300 and 1000 rpm were optimum for the growth of cells adhered to the PET strips. FIG. 8 is an illustration of a response contour of VCD proof-of-concept using the AMBR system. The data demonstrates optimal cell growth when cells are seeded between 10,000 and 12,500 cell/cm2, harvested at days 3, and agitated between 300 and 350 rpm at 37°C within the AMBR containment box.
The present invention involves a process for growing adherent cells in a containment box of a multiparallel bioreactor, comprising the steps of seeding of the adherent cells on PET carrier strips held in a culture dish, transferring the adherent cells on PET carrier strips to a containment box of the multiparallel bioreactor; and growing the adherent cells in the containment box at an impeller speed between 200 rpm and 1200 rpm.
As used here, the term “bioreactor” is a device that supports a biologically active environment in which a biological process such as propagation of virus and vectors under controlled conditions may be carried out. Bioreactors may be designed for small- scale cultures such as those used in research laboratories, as well as large-scale bioreactors comprising vessels or vats to produce and harvest biological macromolecules such as vaccine virus, antigens, and vectors on a pilot plant or commercial scale. A bioreactor may be used to propagate both suspended as well as adherent cells. The bioreactor is a controlled environment wherein the oxygen, nitrogen, carbon dioxide, and pH levels may be adjusted. Parameters such as oxygen, pH, temperature, and biomass are measured at periodic intervals.
As used herein, the term “multiparallel bioreactor” is a device in which at least two bioreactors vessels are run in parallel. As used herein, a “containment box” is a vessel of the multiparallel bioreactor. A multiparallel bioreactor may have 6-100 containment boxes. Preferably, the multiparallel bioreactor has 12 to 24 containment boxes. A multiparallel bioreactor may be fully automated, so that each containment box may be controlled for media fill, inoculation, sampling, and feeding. A containment box may be a one-use, disposable container. Each containment box may be individually controlled for temperature, pH, and impeller speed. Each containment box may include parts including but not limited to sensors ports for the continuous monitoring of pH and dissolved oxygen (DO), impeller for agitating/stirring, feed tube for media/reagent additions, gas delivery tube for the delivery of N2, O2.sub., and air, and sample port for sample removal.
Examples of commercially available multiparallel bioreactors that may be used for the process of the invention include but not limited to AMBR 15, AMBR 250, Solida Biotech parallel bioreactor, and xCubio bioreactor.
The Capacity of the bioreactor is the volume of media that may be held in the bioreactor. A multiparallel bioreactor capacity is the Capacity of each Containment Box. The multiparallel bioreactor capacity or “Capacity” as used herein may range from 5 mL to about 5 Litres. The Capacity may be about 2 mL to about 10 mL, from about 5 mL to about 50 mL, from about 25 mL to about 100 ML, from about 75 mL to about 500 mL, from about 250 mL to about 750 mL, from about 600 mL to about 1000 mL. Preferably, the Capacity maybe 15mL or 250 mL. More preferably, the containment box volume is 15 mL.
Adherent cells are cells that adhere to a surface in culture condition, anchorage may be required for their grown, and they may also be called anchorage- dependent cells. Adherent cells suitable for the procedure of the disclosure include but not limited to Madin-Darby Canine Kidney Epithelial Cells (MDCK), Madin-Darby Bovine Kidney Epithelial (MDBK) cells, chicken cells or quail cells, PerC6 cells, 3T3 cells, NTCT cells, CHO cells, PK15 cells, MDBK cells, LLC-MK2, MRC-5, 293, Hela cells, HEK293 cells, or a combination or modification thereof. The preferred adherent cell is an anchorage- dependent cell that may be grown on a carrier such as a PET strip, but suspension cells that may be adapted to grow as adherent cells may also be used. More preferably, the anchorage-dependent cells of the disclosure are Vero cells. It is within the knowledge of one skilled in the art to select an adherent host cell to use the process of the disclosure.
Specific metabolites may be evaluated in the cells-containing PET carrier strips in the AMBR Containment Box. For example, metabolites such as but not limited to glutamine, NEE, O.sub.2, CO.sub.2, glucose, and lactate may be evaluated in each containment box containing the adherent cells. Specific patterns of metabolite consumption and production can be used to evaluate cells-containing PET carrier strips in the AMBR system.
Conclusions for Experiments 1-5. Overall, these data demonstrate that cells bound to PET strips can be used in a multiparallel bioreactor such as AMBR suspension platform to perform DOE studies or small-scale bioreactor campaigns for production process optimization. This demonstrates a novel use of the system that has not been previously described and applications range from optimization of cell growth conditions to virus/vector infection or transfection procedures, to optimization of virus, protein, and/or antibody production parameters from adherent cells growing on PET strips. The resulting process optimization data can be utilized to establish the parameters used in adherent bioreactor systems. The PET- AMBR adherent strategy provides a means to obtain an abundance amount of data in a high-throughput and cost-effective manner using 24 or 48 small-scale bioreactors in parallel and can be used to replace multiple adherent bioreactor runs performed in parallel, which utilize high amounts of resources and time. This system allows for increased flexibility and enhanced decision-making processes, which aids in handling complex biotherapeutic, vaccine, and prophylactic development and production. Furthermore, multiple adherent bioreactor runs that are performed in parallel for process optimization lead to higher production costs; thus, incorporating the use of the novel PET-AMBR adherent optimization strategy leads to faster production timelines and lower overall production costs, two factors which are extremely critical in the medicinal market.
Thus, WO ‘188 discloses a process of growing adherent cells in a containment box of a multiparallel bioreactor comprising: seeding the adherent cells on a carrier held in a culture dish; transferring the adherent cells on the carrier to a containment box of the multiparallel bioreactor; growing the adherent cells at a containment box while agitating the media at an impeller speed between 200 rpm to a 1200 rpm; harvesting the adherent cells 3-10 days after the transfer of the adherent cells on the carrier to the containment box of the multiparallel bioreactor; wherein the multiparallel bioreactor is selected from a group including the AMBR 15, AMBR 250, Solida Biotech parallel bioreactor, and xCubio bioreactor; wherein the production processes optimized are cell propagation, virus production, antibody production.
[emphasis added]
WO ‘188 does not the recited centrifuging steps, namely inserting the plurality of vessels with their biological material remaining therein into a vessel holding apparatus; placing the vessel holding apparatus with the plurality of vessels into a centrifuge; spinning the vessel holding apparatus and vessels with the centrifuge.
EBERLE ‘198 discloses inserting a plurality of vessels 50 with their biological material therein into a vessel holding apparatus 6; placing the vessel holding apparatus 6 with the plurality of vessels into a centrifuge 57 (Figure 7); spinning the vessel holding apparatus 6 and vessels 50 with the centrifuge 57; wherein the vessel holding apparatus 6 comprises at least 12 receptacles 14, each of the receptacles 14 being configured to slidable receive one of the plurality of vessels 50; providing 24 vessels 50, wherein the inserting step comprises inserting the 24 vessels into two vessel holding apparatuses, each of the vessel holding apparatuses holding 12 vessels, wherein the placing step comprises placing both of the vessel holding apparatuses 6 into the centrifuge, and wherein the spinning step comprises spinning the two vessel holding apparatuses and the 24 vessels in the centrifuge simultaneously (Figure 7); and providing 48 vessels 50, wherein the inserting step comprises inserting the 48 vessels 50 into four vessel holding apparatuses 6, each of the vessel holding apparatuses 6 holding 12 vessels 50, wherein the placing step comprises placing all four of the vessel holding apparatuses 6 into the centrifuge 57, and wherein the spinning step comprises spinning the four vessel holding apparatuses 6 and the 48 vessels in the centrifuge 57 simultaneously (Figures 7-9 and 12).
EBERLE more specifically discloses a holder for centrifuges, for receiving specimen containers such as test tubes holding substances to be centrifuged, comprising three major parts which are connected in a form-fitting manner, namely a stirrup member, a cup member therein, and a frame in the latter, with bores in the frame for the test tubes. The invention relates to a receptacle holder for centrifuges, for receiving specimen containers such as test tubes and the like, to be pivotally supported in the centrifuge head by means of lateral journal pins and corresponding grooves in the centrifuge head.
It is also one of the objects of the invention to allow the inventive receptacle holder simultaneously to receive a plurality of specimen containers, such as test tubes, in the form of a battery or set, to be individually withdrawable from the holder. The stirrup is swingably supported in the head of the centrifuge and, while it has to withstand all the centrifugal inertial forces, is much simpler and cheaper to make and also much lighter in weight so that, as a result, the centrifugal forces to be endured by the pins are considerably lower, allowing substantially higher centrifuging speeds as well as a simpler construction of the centrifuge head itself.
It is known that for each centrifuging process simultaneously several receptacle holders are suspended in the centrifuge heads, in a manner symmetrical to the center axis, so as to insure a centrifuging process which is possibly free from unbalance. The receptacle support frame inserted in the cup and receiving a battery of individual specimen containers has the advantage that simultaneously, by a single movement, several specimen containers can be handled whereby a mix-up between individual containers is eliminated or at least considerably reduced. These support frames are furthermore very useful as stands for a number of specimen containers, and after the centrifuging they can be placed on a suitable surface (table, counter top, etc.).
As a further, optional feature of the inventive device, the stirrup and the bottom plate can be made from a single piece. This expedient results in a further reduction in costs and simplification of the manufacture.
In accordance with another recommended feature of the invention, the stirrup, made in different sizes, is designed to receive several cups and/or support frames. It is thus possible to lodge several receptacle supporting frames within the stirrup, thereby multiplying the capacity of the device, while using a standardized size of support frames and possibly also of matching cups. It is also possible to make the stirrup and the cup, or either of them, in various sizes, to receive different quantities of receptacle supporting frames. In this embodiment only a single cup is required, the size of which corresponds to that of the stirrup, and in which several smaller receptacle support frames of standard size can be inserted. A further reduction in costs and weight is achieved, in combination with an increase in specimen-container receptivity.
This allows not only the contents of the individual specimen containers to be observed from the outside through the cup walls and the lateral openings of the receptacle support frame but the possibility is also give continuously to observe during the centrifuging process any changes occurring in the condition of the material being centrifuged, and to photo-electrically to sense and use the changing transparency of the material. During sedimentation in the course of the centrifuging action a dense, opaque deposit develops, as a rule, in the lower portion of the specimen containers, while the upper portion clarifies and becomes transparent.
The receptacle supporting frame consists preferably of a substantially square-shaped hollow body with apertured side walls, a bottom and a massive top portion, the latter having perpendicular through bores, preferably arranged in rows, each for receiving a specimen container or test tube.
FIG. 7 is a somewhat oblique top view of a centrifuge head, on a reduced scale, adapted to be used with the inventive receptacle holder; FIG. 8 is a top view of a multiple assembly having several frames and cups therein; FIG. 9 is a top view similar to that of FIG. 8 of an assembly including a single frame with four cups therein, the bottom plate, shanks and journal pins having been omitted; FIG. 10 is a perspective view of another modified stirrup, large enough to accommodate optionally several cups and several frames; FIG. 12 is a somewhat schematic vertical sectional view showing the arrangement of the inventive receptacle holder, mounted in a centrifuge drum, with a photo-electric transducer and a stroboscope lamp flanking the flight path of the specimen containers.
As can be seen from FIGS. 1 and 6, the inventive receptacle holder, in its exemplary, preferred embodiment consists essentially of three major parts, namely a substantially U-shaped stirrup 1, with a bottom plate 2 and journal pins 3 at the ends of shanks 4, a cup 5 and a receptacle support frame 6. Specimen containers, for example test tubes 50, cam be inserted in the frame 6, as will be explained later in full detail.
The receptacle support frame 6 consists essentially of a square-shaped hollow member with windows or apertures 11 in its side walls, as shown in the upper section of FIG. 1. It has a bottom 12 and a sturdy head portion 13, the latter being provided with a plurality of perpendicular through bores 14, preferably arranged in several rows, adapted to receive and hold the above-mentioned test tubes 50 and the like. The latter have usually rounded bottom ends which rest on a soft insert 16 placed atop the bottom 12, inside the frame 6 (see FIG. 2, not shown in FIG. 1).
For the purpose of centrifuging sediments or other substances in the test tubes 50, the latter are placed into the frame 6 which is then inserted in the cup 5, both being subsequently placed into the stirrup 1. The inventive receptacle holder, in its assembled condition, thus consists of the major parts 1, 5 and 6 which can be pivotally inserted, by way of the journal pins 3, in a conventional centrifuge head 57, as schematically shown in FIG. 7. Further details of the head have been omitted since they are well known from centrifuges.
FIG. 7 shows that the rotatable centrifuge head 57 has a number of recesses 58, preferably arranged in a symmetrical manner, 3 or 4 in a circular arrangement, each recess being flanked by cut-outs 59 numbering four in total to receive four vessel holders 6 capable of receiving up to sixty specimen containers in each holder assembly 1” that is receivable in a respective cut-out 59.
Upon completion of the centrifuging process, the operator can remove from the centrifuge head 57 either the entire receptacle holder, that is stirrup 1, cup 5 and frame 6, or perhaps only the cut 5 with the frame 6 therein, or even the latter (frame) by itself, with the test tubes 50 therein. Another unit, assembled cup or frame can be inserted with test tubes containing substances that should be subjected to the next centrifuging operation.
FIGS. 8 and 9 show how four frames 6 can be simultaneously disposed in respective one or more cups which are inserted in the stirrup 1". As a first solution, reference should be had to FIG. 8 which shows four cups 5 each with its own frame of appropriate size, inserted together in the stirrup 1" and held therein by the girdle member 30.
The sectional detail view of FIG. 11 shows how to provide the bottom plate 2" of stirrup 1" with a trough or rim 31, releasably secured thereto by means of screws and the like. FIG. 10 illustrates ledges 32, extending partly or all along the peripheries of the plate 2", for safely holding the cup or cups in the stirrup.
Coming back to the afore-mentioned FIG. 9, another solution is illustrated for lodging several frames 6 in a stirrup, such as 1" as shown in FIG. 10, having four receptacle support frames 6 in a common cup 5" which is thus four times as large, as a matter of example, as the cup 5 of FIGS. 1, 6 and 8. It should be noted at this point that in the modified embodiment of FIGS. 8 to 10, there is no need for the locating means 8, 9 and 10, as described for the first exemplary embodiment, on account of the provision of the rectangular girdle member 30 although the sole or common cup 5" could have indentations or depressions which cooperate with the shanks 4" of stirrup 1", thus dispensing with the need for the number 30. The shanks and pins have been omitted from FIG 9 for the sake of clarity while they are shown in FIG. 8.
It is of course possible to design a support frame which fits snugly into the cup and contains four times as many test tubes as the frame 6 of the standard embodiment. Although measurements and proportions are not considered to be conclusive, for the sake of comparison it might be considered that stirrup 1" is about four times as large in its overall surface and receiving area as stirrups 1 and 1', with similar proportions prevailing between the respective cups and frames (e.g. 5" and 5).
The stirrup 1" of FIG. 10 having a larger space requirement, it should be suspended from a centrifuge head similar to head 57 as shown in FIG. 7, basically constructed for the stirrups 1 and 1'. In a larger centrifuge, an appropriately dimensioned and designed centrifuge head would be used to accommodate the fourfold capacity of stirrup 1", as will be understood by those skilled in the art.
There is nevertheless the advantage that the standard cups 5 and frames 6 can also be used in the larger stirrup 1", one each of the cups and frames fitting the stirrup 1 and 1" while four will be needed for 1". Similar structures could of course be designed for a smaller or larger number of elements (say three or six cups or frames, with a corresponding number of test tubes to be lodged therein for simultaneous processing).
FIG. 12 is a somewhat schematic partial, vertical sectional view through a centrifuge drum 55 which has a cover 56 closed during centrifuging. The inventive receptacle holder, consisting as it does of a stirrup 1 (1' or 1"), cup 5 (or 5") and frame 6 (or a modification of the latter), fitted with a number of test tubes 50, is shown in this figure in its flight path, assumed during high-speed centrifuging (the device swings outward on account of the centrifugal force, about the pins by which it is attached to the centrifuge head 57).
The above arrangement in Figure 12 allows it to determine the duration of the centrifuge process by the centrifuging effect itself, the signal derived from the photo-electric unit 17 serving to stop the centrifuge through conventional electrical circuit and switching means, schematically shown at 17c.
[emphasis added]
Accordingly, since EBERLE suggests the centrifuging of a variety of specimen containers with test tubes being but one example, it would have been obvious to one skilled in the art before the effective filing date of the invention to have employed any desired quantity of 15 mL micro bioreactor vessels with biological material therein as disclosed by WO ‘188 and to subject said quantity of bioreactor vessels to centrifugation as taught by EBERLE or to have substituted the generic specimen containers in the method of EBERLE with and desired quantity of the bioreactor vessels of WO ‘188 for the purpose of generating sedimentation within the biological material contained within the desired quantity of bioreactor vessels in the course of the centrifuging action provided by EBERLE such that a dense deposit develops in the lower portion of the bioreactor vessels, while the upper portion clarifies and becomes transparent (EBERLE at col. 3, lines 50-53).
Allowable Subject Matter
Claims 21-23 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is an Examiner's statement of reasons for the indication of allowable subject matter: The prior art of record does not teach or fairly suggest the recited details of the bioreactor vessel holders expressed in claims 21-23.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The cited prior art discloses centrifuges for centrifuging a plurality of specimen containers.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHARLES COOLEY whose telephone number is (571) 272-1139. The examiner can normally be reached M-F 9:30 AM - 6:00 PM.
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/CHARLES COOLEY/
Examiner, Art Unit 1774
DATED: 19 JUNE 2026
Prosecution Insights