DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-8 and 10-20 are pending following the Reply filed 11/10/2025. Claims 1, 3-4, 10, 13-15 and 17 have been amended, and new claims 18-20 have been added, without introducing new matter.
Withdrawn
The rejection of claims 1-7 under 35 U.S.C. 102 as being anticipated by Rajendran has been withdrawn in light of the amendments. However, the rejection under 35 U.S.C. 103 has been maintained. See Claim Rejections - 35 U.S.C. 103 and Response to Arguments below for further discussion.
Maintained Rejections and New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Rajendran (US 20160176921 A1; previously cited).
Regarding instant claim 1, Rajendran teaches a method for purifying a recombinant protein (see claim 1) which meets the limitation of a “biomolecule of interest” as relevant to the instant claim. Rajendran’s method comprises obtaining the recombinant protein from a bioreactor containing a culture of mammalian cells that secrete the recombinant protein (see pg. 9, ¶[0080]). Examiner notes that in order to secrete the protein, the cells must be “expressing” the protein when in the bioreactor. Rajendran’s method further comprises clarifying the cell culture by filtration to obtain a liquid culture medium that is substantially free of cells (see pg. 9, ¶[0081]) and to remove other contaminants and impurities from the solution (see pg. 3, ¶[0026]); capturing the recombinant protein from the liquid culture medium (see claim 1(a)) using an affinity chromatography resin (see claim 2) to concentrate the product and further remove impurities (see pg. 23, ¶[0138]); and performing one or more unit operations following capturing (see claim 1(b)) that may include ultrafiltration/diafiltration, viral inactivation, polishing, and viral filtration (see claim 4). Rajendran’s Examples on pgs. 19-32 disclose that the steps of culture medium clarification (i.e., filtration), protein A affinity chromatography, viral inactivation, polishing of the recombinant protein, ultrafiltration/diafiltration, viral filtration, and formulation are all performed in sequence (See, e.g., pg. 20, ¶[0126]; “Example 4” on pgs. 22-28; and Fig. 5). Furthermore, Rajendran’s experiments demonstrate that purification systems with reduced soluble protein aggregates and flow decay at the virus filter during viral filtration include ultrafiltration/diafiltration prior to viral filtration (see, e.g., pg. 20, ¶[0126]; Figs. 3 & 4) which Rajendran teaches to increase product yield and enhance the safety of the final product (see pg. 5, ¶[0050], lines 31-41).
Regarding the limitation of “subsequently subjecting said filtered product sample to an initial diafiltration step occurring immediately prior to virus filtration”, there is no description in Rajendran’s disclosure to the effect that multiple diafiltration steps are required, and therefore it is understood that the ultrafiltration/diafiltration step prior to virus filtration may be the initial diafiltration step. Rajendran states:
Some embodiments further include, for example, performing at least one ( such as two, three, or four) unit operation before the capturing step (e.g., selected from the group of clarifying a culture medium, ultrafiltration/diafiltration to concentrate the recombinant protein in a solution… In some embodiments, [following capturing] step (b) includes performing one or more (such as two, three, or four) unit operations on the solution, e.g., selected from the group of ultrafiltration/diafiltration… (pg. 17, para. [0052], Emphasis added)
Therefore, Rajendran teaches that the initial ultrafiltration/diafiltration step prior to the capturing step is an optional step, which effectively means that there are embodiments within the scope of the disclosure where the diafiltration step prior to virus filtration is the “initial” diafiltration step.
Regarding the limitation of “wherein said filtered product sample is in the same diafiltration buffer when subjected to the virus filtration, and wherein the same diafiltration buffer is used in a final formulation of the filtered product sample”, there is no description in Rajendran’s disclosure to the effect that buffer solutions must be changed between the ultrafiltration/diafiltration and viral filtration steps, and therefore it is understood that a diafiltration buffer agent may be present during the viral filtration process and in the final formulation. Rajendran states:
Some methods described herein can include a step of adjusting the pH and/or ionic concentration of a solution comprising the recombinant protein. As described herein, the pH and/or ionic concentration of a solution comprising the recombinant protein can be adjusted (before and/or after it is fed into a depth filter) by adding a buffer to the solution (e.g., through the use of an in-line buffer adjustment reservoir). (pg. 19, para. [0120], Emphasis added)
The examiner also notes that Experiment 1 of Rajendran does not include the use of a depth filter, and Experiment 3 uses a depth filter before the ultrafiltration/ diafiltration (UF/DF) step (see Fig. 3).
Therefore, Rajendran clearly teaches the step of adding/changing buffer solution as being optional, which effectively means that Rajendran includes embodiments that do not include this step. See Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005), wherein the reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component.
Therefore, it would have been prima facie obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention in view of Rajendran, by performing the initial diafiltration step immediately prior to virus filtration and by not changing the diafiltration buffer before formulation. While the examiner acknowledges that Rajendran teaches embodiments which may include these steps, Rajendran clearly teaches these to be optional steps, which is an implicit disclosure of embodiments which do not include these steps. In considering the disclosure of Rajendran, one skilled in the art would reasonably recognize the inferences made by the specific teachings of the disclosure to arrive at the claimed invention. See MPEP 2144.01 which states:
"[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968)
In this case, Rajendran teaches the purpose of adding buffer to the solution comprising the recombinant protein is to adjust the pH and/or ionic concentration of said solution. A person of ordinary skill would have recognized that if the solution subjected to an initial diafiltration step prior to virus filtration results in a solution that already has the desired pH and/or ionic concentration for final formulation, there would be no need to add buffer to the solution. See MPEP 2144.04(II)(A) which states that the omission of an element and its function is obvious if the function of the element is not desired. Hence, it would have been obvious for one of ordinary skill to apply the methods taught by Rajendran to purify a sample comprising a biomolecule of interest, wherein the selection of diafiltration buffer results in the pH and/or ionic concentration desired for final formulation. A skilled artisan would have recognized that this can be accomplished without requiring any intervening step of adding and/or changing said buffer prior to virus filtration or final formulation.
Furthermore, it is well within the ordinary skill in the art to select, add, and/or change buffer solutions or diafiltration mediums in accordance with the characteristics of the biomolecule of interest and desired product. It would have been known at the time of filing to a person of ordinary skill how and when to use buffers to alter and/or maintain the pH and/or ionic concentration of a solution, and there are a finite number of solutions for one to attempt (i.e., to change the buffer or maintain the same buffer; to perform multiple diafiltrations or only one diafiltration) which are also within the scope of the prior art reference. Hence, the optimization required to have arrived at the claimed invention is within prior art conditions and can be accomplished through routine experimentation. See MPEP 2144.05(II)(A)-(B). See also KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007), wherein the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions (Emphasis added).
Moreover, Applicant’s disclosure provides no evidence of unexpected results when omitting or rearranging the steps taught by Rajendran. “[S]election of any order of performing process steps is prima facie obvious in the absence of new or unexpected results”. In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946). Accordingly, the claimed invention as a whole was prima facie obvious, especially in the absence of evidence to the contrary. Therefore, per MPEP § 2112 (III), the burden has been shifted to the applicant to show an unobvious difference (MPEP §2112(v); In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977)).
Regarding claim 2, Rajendran teaches the affinity chromatography resin may utilize a protein A-binding capture mechanism (see claim 3).
Regarding claim 3, Rajendran teaches a viral inactivation step (see claim 4) that is performed prior to an ultrafiltration/diafiltration step (see, e.g., “Schematic 3” in Figs. 5 & 6).
Regarding claim 4, Rajendran teaches a polishing step using hydrophobic interaction chromatography (see claim 6) which is performed after the viral inactivation step and before an ultrafiltration/diafiltration step (see, e.g., pg. 4, ¶[0038]).
Regarding claim 5, Rajendran teaches that the polishing step may use hydrophobic interaction chromatography (see claim 6) or ion-exchange chromatography (see pg. 2, col. 1, lines 1-3), such as anion exchange chromatography (see pg. 6, col. 1, lines 6-7).
Regarding claim 6, Rajendran teaches that the recombinant protein may be a monoclonal antibody (see pg. 5, ¶[0050], lines 1-3).
Regarding claim 7, Rajendran discloses methods for the purification of a recombinant protein, as discussed above.
Claims 8 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Rajendran as applied to claims 1-7 above, and further in view of Fiedler (US 2019/0365835 A1; previously cited).
Regarding claim 8, Rajendran, as discussed above, teaches a method for purifying a biomolecule of interest comprising subjecting a sample from a bioreactor to filtration and clarification, affinity chromatography, virus inactivation, polishing, ultrafiltration/diafiltration, viral filtration, and final formulation.
Rajendran does not teach the method wherein the biomolecule of interest is a virus.
Fiedler teaches a method of purifying full adeno-associated virus (AAV) capsids comprising harvesting a supernatant from a cell culture (see claims 1 and 41); filtering the harvested supernatant via depth filtration (see claim 43); applying an AAV fraction to an anion exchange chromatography column (see claim 46); inactivating lipid enveloped viruses with a solvent and/or detergent (see claim 53); concentrating an AAV fraction using an ultra/diafiltration system after anion exchange chromatography (see claim 50); and performing nanofiltration of an AAV fraction to remove viruses greater than 35 nm (claim 54). Note that the dependency of Fiedler’s claims encompass embodiments having the same order of steps as the instant claims. Figure 2 of Fiedler’s disclosure also shows an example wherein the harvesting, clarification, purification by chromatography, viral inactivation, polishing by anion exchange chromatography and virus filtration (targeting unwanted viruses based on their size) are all performed in sequence, as shown below:
PNG
media_image1.png
603
451
media_image1.png
Greyscale
Fiedler also suggests rearranging and modifying the method steps of the disclosure. For example, “[a]ll methods described herein can be performed in any suitable order unless otherwise indicated” (see pg. 29, para. [0231]). Further, “[t]he inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than as specifically described herein” and “any combination of the above-described elements in all possible variations thereof are encompassed by the disclosure unless otherwise indicated” (see pg. 29, para. [0232]).
The examiner also notes that the instant specification does not provide any specific guidance regarding the purification of a virus compared to other biomolecules of interest, and therefore provides the same disclosure for purifying a virus as it does for proteins and antibodies.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have combined the teachings of Rajendran and Fiedler to arrive at the claimed invention because both references teach processes to purify a protein-based biomolecule of interest and Fiedler further teaches a purification method for viruses which employs many of the same unit operations as Rajendran’s disclosure. A person of skill would have recognized from Fiedler’s disclosure that Rajendran’s methods included steps that served the same functional purpose as those in Fiedler and that the results of applying these common steps, aided by the teachings of both disclosures, would have yielded predictable results. Furthermore, it is well within the ordinary skill in the art to modify a sequence of known unit operation steps based on prior art teachings. Moreover, one of ordinary skill in the art would have had as reasonable expectation of success at modifying Rajendran’s teachings to purify a virus as they would have had at modifying the teachings of the present disclosure to achieve the same. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 18, Fiedler teaches the use of tangential flow filtration to perform ultra/diafiltration (see pg. 15, para. [0127]).
Claim(s) 10-12, 14-16 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rajendran as applied to claims 1-7 above, and further in view of Xenopoulos (US 2017/0320909 A1; previously cited).
Regarding claim 10, and as discussed above, Rajendran teaches a process for purifying a biomolecule of interest comprising subjecting a sample from (a) a bioreactor to (b) filtration and clarification, (c) affinity chromatography, (d) virus inactivation, (e) hydrophobic interaction chromatography, (f) ultrafiltration/diafiltration and (g) viral filtration. Rajendran also teaches the method can be applied as a system to perform the same (see pg. 5, ¶[0051]) and the use of a (d) Zeta Plus Delipid depth filter during the viral inactivation step downstream of (c) protein A affinity chromatography (see pg. 29, ¶[0157]). Furthermore, Rajendran’s experiments demonstrate that purification systems with reduced soluble protein aggregates and flow decay at the virus filter during viral filtration include ultrafiltration/diafiltration prior to viral filtration (see, e.g., pg. 20, ¶[0126]; Figs. 3 & 4) which Rajendran teaches to increase product yield and enhance the safety of the final product (see pg. 5, ¶[0050], lines 31-41). Rajendran’s Examples on pgs. 19-32 disclose that the steps of (b) culture medium clarification (i.e., filtration), (c) protein A affinity chromatography, (d) viral inactivation, (e) polishing of the recombinant protein, (f) ultrafiltration/ diafiltration, (g) viral filtration, and formulation are all performed in sequence (See, e.g., pg. 20, ¶[0126]; “Example 4” on pgs. 22-28; and Fig. 5). Regarding limitations “f” and “g”, it would have been obvious to have performed the initial diafiltration prior to virus filtration without changing the diafiltration buffer, as discussed regarding claim 1.
Rajendran does not teach a system wherein (c) “at least two” affinity chromatography columns are configured in series downstream of the filtration unit.
Xenopoulos teaches a process and a system for the purification of a target molecule from a sample provided from a bioreactor (see claim 19) comprising providing the sample comprising the target molecule and one or more impurities (see claim 1(a)); subjecting the sample to clarification (see claim 1(b)); bind and elute chromatography comprising at least two separation units (see claim 1(c)) that employs continuous multi-column chromatography (see claim 14) selected from the group that includes affinity chromatography (see claim 15); a virus inactivation step between steps (c) and (d) (see claim 3); flow-through purification comprising the use of two or more media (see claim 1(d)) selected from anion exchange chromatography and cation exchange chromatography (see claim 25); flow-through purification using a virus filtration membrane (see claim 26); and a formulation step (see claim 29) comprising diafiltration, concentration and sterile filtration (see claim 30). Xenopoulos teaches that in continuous chromatography several identical columns are typically connected in an arrangement that allows them to be operated in series and for continuous operation, resulting in a better utilization of chromatography resin and reduced buffer requirements which benefits process economy (see pg. 16, ¶[0203]). Xenopoulos also teaches that diafiltration results in the replacement of the fluid which contains the target molecule with the desired buffer for formulation of the target molecule (see pg. 20, para. [0268]). Hence, Xenopoulos teaches the diafiltrate buffer is used in final formulation of the product sample.
It would have been obvious at the time of filing for a person of ordinary skill in the art to have combined the teachings of Rajendran and Xenopoulos to have arrived at the claimed invention because both references teach systems for the purification of a biomolecule utilizing a combination of known unit operations. A person of skill would have recognized from Xenopoulos the advantage of using multiple affinity chromatography columns in series, and they would have also recognized from Rajendran the advantage of a having a diafiltration unit upstream from the virus filtration unit. The results of the combination would have been predictable, because each element (i.e., affinity chromatography column) merely performs the same function while in combination as it does separately. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103). Furthermore, it is well within the ordinary skill in the art to have made modifications to a system comprised of known unit operation devices connected in sequence by merely adding an additional affinity column.
Regarding claim 11, Xenopoulos teaches that in preferred embodiments the bind and elute chromatography step uses affinity chromatography using a Protein A ligand (see, e.g., pg. 2, ¶[0023]).
Regarding claim 12, Xenopoulos discusses the ability to run unit operations of the system in a batch mode (see, e.g., pg. 1, ¶[0060]; pg. 4, ¶[0065]; pg. 5, ¶[0081]; pg. 8, ¶[0110]).
Regarding claim 14, Xenopoulos teaches that the bind and elude step using at least two affinity chromatography columns may alternatively use chromatography membranes instead of columns (see pg. 10, ¶[0088]). Otherwise, claim 14 is obvious for the same reasons discussed regarding claim 10.
Regarding claim 15, Xenopoulos teaches that in preferred embodiments the bind and elute chromatography step utilizes affinity chromatography using a Protein A ligand (see, e.g., pg. 2, ¶[0023].
Regarding claim 16, Xenopoulos discusses the ability to run unit operations of the system in a batch mode (see, e.g., pg. 1, ¶[0060]; pg. 4, ¶[0065]; pg. 5, ¶[0081]; pg. 8, ¶[0110]).
Regarding claim 19, Xenopoulos teaches that diafiltration “typically employs the use of an ultrafiltration membrane in a Tangential Flow Filtration (TFF) mode” (see pg. 20, para. [0267]).
Regarding claim 20, Xenopoulos teaches that diafiltration “typically employs the use of an ultrafiltration membrane in a Tangential Flow Filtration (TFF) mode” (see pg. 20, para. [0267]).
Claim(s) 13 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rajendran and Xenopoulos as applied to claims 10-12, 14-16 and 19-20 above, and further in view of Millipore 2003 (“Protein Concentration and Diafiltration by Tangential Flow Filtration”; cited on Form 892).
Regarding claim 13, Xenopoulos teaches the system to be capable of continuous operation with all unit operation devices connected and in fluid communication with each other (see claims 45 and 46). Xenopoulos teaches that diafiltration “typically employs the use of an ultrafiltration membrane in a Tangential Flow Filtration (TFF) mode” (see pg. 20, para. [0267]).
Xenopoulos does not explicitly teach the diafiltrate buffer is added at a same rate that a filtrate is generated by the initial diafiltration unit.
Millipore discloses protein processing methods using membrane-based tangential flow filtration unit operations for the clarifying, concentrating, and purifying of proteins (see pg. 1, col. 1, para. 1). Millipore teaches that diafiltration is a tangential flow filtration (TFF) process that can be performed in combination with any of the other categories of separation to enhance either product yield or purity (see pg. 2, col. 3, para. 3). Millipore teaches that of the two most common modes of diafiltration, batch mode and constant-volume mode, constant-volume diafiltration is the more efficient and commonly used control mode (see pg. 11, para. 2). Millipore teaches that to perform a constant-volume diafiltration, buffer is added to the recycle tank at the same rate that filtrate is removed (see pg. 11, para. 2).
Therefore, it would have been obvious to have used constant-volume diafiltration during the diafiltration step taught by Rajendran and Xenopoulos, because Millipore teaches that constant-volume diafiltration is the more commonly used and efficient option when using TFF to perform diafiltration. Hence, one would have been motivated to use the constant-volume mode taught by Millipore for the diafiltration system used in the system configured to operate in a continuous mode as taught by Xenopoulos. As both Xenopoulos and Millipore teach diafiltration using tangential flow filtration to be commonly used during protein purification methods, a person of ordinary skill would have recognized that the results of the combination would have been predictable with a reasonable expectation of success. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 17, the claim is obvious for the same reasons discussed regarding claim 13.
Response to Arguments
Regarding the previous rejection of claims 1-7 under 35 USC § 102(a)(1), Applicant argues that Rajendran fails to disclose or teach all of the features of amended independent claim 1.
Applicant’s arguments with respect to the claims rejected as being anticipated by Rajendran have been fully considered and are persuasive. Accordingly, the rejection of claims 1-7 under 35 U.S.C. 102 has been withdrawn. However, the rejection under 35 U.S.C. 103 has been maintained. See the present rejection for further discussion.
Regarding the rejections of claims 1-7 under 35 USC § 103, Applicant argues that Rajendran fails to disclose, teach, or suggest the features of “subsequently subjecting said filtered product sample to an initial diafiltration step occurring immediately prior to virus filtration” as recited in amended independent claim 1. Applicant argues that Rajendran clearly discloses a process that contains multiple diafiltration steps, the first one occurring prior to an affinity chromatography step. Applicant recites portions of Rajendran’s Examples from paras. [0126]-[0127] and paras. [0128], [0130], [0132], and FIGS. 1 and 3, wherein the initial diafiltration step occurs earlier in the process of Rajendran than recited in the instant claims.
Applicant’s arguments have been fully considered but are not persuasive, because as discussed under the present rejection, Rajendran teaches embodiments wherein each diafiltration step is described as being optional. When the prior art reference teaches the inclusion of an element as being optional, the reference in effect teaches embodiments that both do and do not contain that element. See MPEP 2123 which states:
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component) (Emphasis added)
In the instant case, Rajendran teaches embodiments which “may” include additional diafiltration steps, which is an implicit disclosure of embodiments which do not include these steps. Furthermore, it was well within the ordinary skill in the art at the time of filing to have omitted or rearranged certain steps taught in Rajendran’s Examples or preferred embodiments to have arrived at the claimed invention through no more than routine optimization. Moreover, Applicant has not provided any evidence of unexpected results to support a case of nonobviousness, where the “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results”. In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946). See the present rejection of claim 1 for further discussion.
Regarding the rejection of claim 8 under 35 USC § 103, Applicant argues that Fiedler fails to remedy the fundamental deficiencies of Rajendran as set forth above with respect to amended independent claim 1, from which claim 8 depends, because Fiedler also fails to disclose, teach, or suggest performing a first or initial diafiltration step downstream from a chromatography step and immediately upstream of the virus filtration step.
Applicant’s arguments have been fully considered but are not persuasive, because, as discussed in the present rejection, Fiedler teaches concentrating an AAV fraction using an ultra/diafiltration system after anion exchange chromatography (see claim 50); and further performing nanofiltration of the AAV fraction to remove viruses greater than 35 nm (claim 54). Furthermore, it was well within the ordinary skill in the art to have omitted or rearranged certain steps disclosed in the references. Fiedler even suggests “[a]ll methods described herein can be performed in any suitable order unless otherwise indicated” (see pg. 29, para. [0231]), and further, “[t]he inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than as specifically described herein” (see pg. 29, para. [0232]). Furthermore, “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results”. In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946). In the instant case, Applicant’s disclosure provides no evidence of unexpected results when omitting or rearranging the steps taught by Rajendran or Fiedler, and it would have been prima facie obvious to have performed the initial diafiltration step immediately prior to virus filtration. See the present rejection of claims 1 and 8 for further discussion.
Regarding the rejections of claims 10-17 under 35 USC § 103, Applicant argues that Rajendran and Xenopoulos, alone or in combination, fail to disclose, teach, or suggest all of the features of amended independent claims 10 and 14, specifically, the features of “an initial diafiltration unit positioned downstream of said one or more anion exchange, cation exchange or hydrophobic interaction exchange chromatography membrane unit(s), wherein the initial diafiltration unit is configured to subject the product sample in a diafiltrate buffer to a first diafiltration process" and "a virus filtration unit positioned immediately downstream of said initial diafiltration unit," as recited in amended independent claim 10, and similarly recited in amended independent claim 14.
Applicant’s arguments have been fully considered but are not persuasive for the same reasons discussed regarding claims 1-8 above. Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Xenopoulos is relied upon in the rejection for the disclosure of multi-column affinity chromatography units, while the alleged “deficiencies” of Rajendran, as they are relevant to Applicant’s argument, are fully addressed above.
Regarding new claims 18-20, Applicant argues that none of Rajendran, Fielder, or Xenopoulos disclose, teach, or suggest an initial diafiltration step/unit immediately prior to a virus filtration step/unit, where the initial diafiltration step/unit utilizes tangential flow filtration.
Applicant’s arguments has been fully considered but are not persuasive for the following reasons. First, the limitation of “an initial diafiltration step/unit immediately prior to a virus filtration step/unit” is fully addressed in the response to arguments above. Second, Fiedler teaches the use of tangential flow filtration to perform ultra/diafiltration (see pg. 15, para. [0127]), and Xenopoulos teaches that diafiltration “typically employs the use of an ultrafiltration membrane in a Tangential Flow Filtration (TFF) mode” (see pg. 20, para. [0267]), as discussed in the present rejections of claims 18-20.
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 DENNIS ARMATO whose telephone number is (703)756-5348. The examiner can normally be reached Mon-Fri 11:00am-7:30pm EST.
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, Melenie Gordon can be reached at (571) 272-8037. 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.
/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651