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 .
Withdrawn Rejections
The rejection of claims 78 and 83-85 under 35 U.S.C. 103 as being unpatentable over Reid et al. (Journal of Virological Methods, 2003, 108:91-96) and Kessler et al. (BMC Research Notes, 2014, 7:159) has been withdrawn in view of applicant’s amendments to the claims. Reid et al. does not teach that the RLPs are non-infectious.
The rejection of claims 78-85 under 35 U.S.C. 103 as being unpatentable over Wang-Johanning et al. (Int. J. Cance, 2014, 134:587-595) and further in view of Brudek et al. (Retrovirology, 2009, 6:104) and Kessler et al. (BMC Research Notes, 2014, 7:159) has been withdrawn in view of applicant’s amendments to the claims. Wang-Johanning et al. does not teach that the RLPs are from CHO cells and are non-infectious.
The rejection of claims 78, 80-81 and 83-85 under 35 U.S.C. 103 as being unpatentable over Muster et al. (Cancer Research, 2003, 63:8735-8741) has been withdrawn in view of applicant’s amendments to the claims. Muster et al. does not teach that the RLPs are from CHO cells and are non-infectious.
The rejection of claims 79 and 82 under 35 U.S.C. 103 as being unpatentable over Muster et al. (Cancer Research, 2003, 63:8735-8741) as applied to claims 78, 80-81 and 83-85 and further in view of Wang-Johanning et al. (Int. J. Cance, 2014, 134:587-595) has been withdrawn in view of applicant’s amendments to the claims. Muster et al. does not teach that the RLPs are from CHO cells and are non-infectious.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 78, 80-81 and 83-87 are rejected under 35 U.S.C. 103 as being unpatentable over Strauss et al. (Biotechnol. Prog., 2009, 25(4):1194-1197) and further in view of Anderson et al. (Virology, 1991, 181:305-311).
The instant claims are directed to a kit comprising at least one container comprising:
a stock solution comprising (i) at least 1010 mammalian cell-endogenous retrovirus like particles (RLP)/ml of solution, wherein the RLPs are Chinese Hampster Ovary (CHO)-derived and non-infectious, (ii) less than 1 part per million therapeutic of interest, (iii) less than 1 mg/ml of endogenous mammalian host cell protein, and (iv) less than 500 ng/mL endogenous mammalian cell DNA; and
at least one container comprising one or more of the following:
a) a PCR primer capable of binding to a nucleic acid sequence contained within the mammalian cell-endogenous retrovirus like particles;
b) a segment of nucleic acid bound to a molecule which can be bound to the mammalian cell-endogenous retrovirus like particles;
c) an antibody capable of binding to the mammalian cell-endogenous retrovirus like particles; and/or
d) a molecule which can bind to the mammalian cell-endogenous retrovirus like particles.
Strauss et al. states that:
The ability of a monoclonal antibody (mAb) purification process to remove viruses is determined through viral clearance experiments. For each unit operation, a high-titer virus stock is spiked into a representative load pool, which is then processed using a small scale version of the recovery process, and a logarithmic viral reduction value (LRV) is calculated. This strategy, however, has not been used for the endogenous RVLPs found in CHO cell cultures since high titer RVLP stocks are not commercially available and, until recently, appropriate assays have not been available. Rather, small scale viral clearance studies are generally performed using model viruses such as the retrovirus xenotropic murine leukemia virus (X-MuLV). However, extrapolating such data to the removal of RVLPs during manufacturing comes with certain caveats. For example, little data exists on how well X-MuLV stocks, which are produced using cell lines and culturing processes optimized for virus production, represent the RVLPs produced endogenously by mAb-producing cell lines and culturing processes.
Strauss et al. teaches an assay where mAb-containing feedstocks were obtained from manufacturing operations and adjusted to pH 8.0 with 1 M Tris base. For spiking experiments, concentrated RVLP stocks were prepared by centrifuging harvested cell culture fluid (HCCF) pools, and the pellet was resuspended in buffer. Chromatography runs were performed on an AKTA purifier. Small scale chromatography columns were each packed to 20 cm bed height with naive QSFF and equilibrated with equilibration buffer. The feedstock was loaded onto the column, and collection was started. Protein was loaded to 50 g mAb/L resin and the column was then washed with equilibration buffer before product collection ended. Aliquots of the product pool and the remaining feedstock pool were collected and stored at -80°C. The large-scale manufacturing process for mAb3 utilizes comparable running conditions to these small-scale experiments regarding all parameters relevant to viral clearance (see Materials and Methods).
Anderson et al. states that “[b]ecause of the low numbers of retrovirus-like particles present in CHO cells, characterization has been difficult. However, continuous-flow ultracentrifugation of large volumes of culture fluid from a recombinant CHO cell line has yielded sufficient quantities of extracellular particles for molecular and biochemical characterization” (see page 305, left column). Thus, Anderson et al. teaches a need for large quantities of the RLPs for molecular and biochemical characterization.
Anderson et al. solves this problem by isolating and purifying defective retrovirus-like particles from large volumes of supernatant of CHO cells. Anderson et al. purified retrovirus-like particles from CHO cells which involved centrifugal concentration of large volumes of culture fluid, followed by fractionation on two sequential sucrose density gradients. Cell culture fluid, which had been concentrated 4000- to 6000-fold by ultracentrifugation, was initially fractionated by centrifugation to equilibrium in a sucrose step gradient (see Materials and Methods and page 307, left column). DNA sequence analysis of a cDNA clone isolated from purified particles revealed multiple interruptions of the endonuclease reading frame, providing one possible explanation for the noninfectious nature of the observed particles (see, for example, the abstract). Anderson et al. reports that the “use of continuous-flow ultracentrifugation to concentrate extracellular, retrovirus-like particles from large volumes of culture fluid of a recombinant CHO cell line has facilitated purification and biochemical characterization of these particles” (see page 309, right column).
As outlined above, Strauss et al. teaches purifying and concentrating CHO-derived RVLPs and using the purified RVLPs in spiking assays and in qPCR assays for small scale validation studies. Strauss et al. is silent as to the amount of RVLPs per mL of stock solution [at least 1010 mammalian cell-endogenous RLPs/ml of solution] and is silent as to the level of purity of the RVLPs [less than 1 part per million therapeutic of interest, less than 1 mg/ml of endogenous mammalian host cell protein, and less than 500 ng/mL endogenous mammalian cell DNA]. Because the purpose of the RVLP stock solution of Strauss et al. is for validation (spiking) studies, it is obvious and well within the purview of one of ordinary skill in the art to perform additional purification and concentration steps to achieve a higher level of purity and a higher concentration of RVLP per mL, e.g., for large scale validation studies. One of ordinary skill in the art can use the methods of Anderson et al. to achieve higher volumes of concentrated and purified RVLPs from large volumes of CHO culture fluid.
Because Anderson et al. used supernatants from CHO cells, there was no therapeutic of interest present in the stock solution.
Regarding at least one container comprising a) a PCR primer, b) a segment of nucleic acid, c) an antibody and/or d) a molecule, Strauss et al. teaches the use of qPCR assays to detect and quantify the spiked RVLP titers (see page 1195, left column). Additionally, Anderson et al. teaches using the purified RVLPs in RT assays and in core detection assays using anti-p27 sera (see page 306, right column).
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the RVLPs, purified by the method of Anderson et al., as a source of viral particles in various validation assays (e.g., qPCR assays with PCR primers to detect spiked RVLPs as taught by Strauss et al. or immunoassay with anti-p27 sera to detect the capsid as taught by Anderson et al.). As for a kit, the concept of packaging components into a kit is well known and routine in the art. For example, immunoassay kits, RT-PCR kits and qPCR kits are well known in the art. It would have been obvious to one of ordinary skill in the art at the time the invention was made to package components (e.g., purified RVLPs along with the necessary immunoassay or qPCR reagents) into a kit for detecting RVLP capsid protein or nucleic acids. One would be motivated to do this for commercial exploitation of the invention by providing convenience for the end user. Thus, the claimed kit is obvious.
It appears applicant’s invention is primarily focused on the stock solution of at least 1010 endogenous retroviral particles per ml with a certain level of purity. As outlined above, Strauss et al. and Anderson et al. render the claimed stock solution obvious. As stated above, Anderson et al. discloses a method of purifying and concentrating noninfectious RLPs from large volumes of CHO supernatants. It is obvious and well within the purview of one of ordinary skill in the art to perform additional purification and concentration steps to achieve a higher level of purity and a higher concentration.
The claimed stock solution is not patentably distinct from the purified and concentrated RVLP stock solution produced by the method of Anderson et al. The claimed stock solution and the stock solution of the prior art contains RLPs isolated from CHO supernatants. The only difference, if any, is the level of purity and the number of particles per mL. There is no structural difference between the two stock solutions. Further, packaging the stock solution in a kit with other components such as an antibody or a primer does not render the stock solution patentable.
For claim 80, Anderson et al. does not teach that the anti-p27 sera is conjugated to a nucleic acid or an enzyme.
For claim 81, Anderson et al. teaches that a secondary antibody is used. For the kit, the concept of packaging components into a kit is well known and routine in the art. For example, immunoassay kits, RT-PCR kits and PCR kits are well known in the art. It would have been obvious to one of ordinary skill in the art at the time the invention was made to package components (e.g., purified RLP along with the necessary immunoassay reagents such as the p27 anti sera and the secondary antibody) into a kit for detecting RLP capsid protein. One would be motivated to do this for commercial exploitation of the invention by providing convenience for the end user. Thus, the claimed kit is obvious.
For claims 83-85, Strauss et al. teaches qPCR assays with PCR primers to detect spiked RVLPs. As outlined above, it would have been obvious to one of ordinary skill in the art at the time the invention was made to package components (e.g., purified RVLPs along with the necessary immunoassay or qPCR reagents) into a kit for detecting RVLP capsid protein or nucleic acids.
For claims 86-87, the RVLPs produced by the method of Anderson et al. are produced in vitro and are non-infectious.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 79 and 82 are rejected under 35 U.S.C. 103 as being unpatentable over Strauss et al. (Biotechnol. Prog., 2009, 25(4):1194-1197) and Anderson et al. (Virology, 1991, 181:305-311) as applied to claims 78, 80-81 and 83-87 above and further in view of Wang-Johanning et al. (Int. J. Cance, 2014, 134:587-595).
The instant claims are directed to the kit of claim 78 where the antibody that binds to the endogenous retrovirus is conjugated to a nucleic acid or an enzyme (claim 79) and the kit further comprises an ELISA plate pre-coated with the antibody.
The teachings of Strauss et al. and Anderson et al. are outline above and incorporated herein. While Strauss et al. and Anderson et al. teach detecting the purified RVLPs using p27 antibodies, Strauss et al. and Anderson et al. do not teach using an ELISA to detect the purified RVLPs. However, Wang-Johanning et al. discloses an ELISA assay for detecting endogenous retrovirus proteins (see page 588).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use known immunoassays (e.g., an ELISA of Wang-Johanning et al.) to detect the RVLP of Strauss et al. and Anderson et al. via capsid proteins and the results would be predictable (detection of the proteins, if present, in a sample by the anti-p27 antibodies).
As for the type of ELISA, one of ordinary skill in the art would readily understand that the ELISA assay would include antibodies to detect the endogenous retrovirus. Such antibodies can be coated on an ELISA plate (e.g., as in a sandwich-type ELISA) where the immobilized antibodies capture virus present in a sample (or positive control) and a secondary antibody that may be optionally labeled with a fluorophore or an enzyme is used to detect the presence of the captured virus. Such assays are well known in the art. See the images below. The first image demonstrates the steps for a sandwich ELISA where the capture antibody, which is immobilized on the ELISA plate, is not labeled and the detecting secondary antibody is labeled with an enzyme [claims 79 and 82]. Both antibodies bind to the antigen. The second image demonstrates other types of known sandwich ELISA assays that may involve secondary antibodies.
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It is well within the purview of one of ordinary skill in the art to determine the type of ELISA and any additional components necessary to detect the target antigen/virus.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
In the reply dated 7/15/2025, applicant argues that secondary considerations such as commercial success and a long felt need should render the claims nonobvious. Applicant submits a Declaration under 37 C.F.R. §132 and Exhibits to support these arguments. Applicant’s arguments, Declaration under 37 C.F.R. §132 and Exhibits have been considered and not found persuasive.
It appears applicant’s invention is primarily a stock solution of 1010 endogenous retroviral particles per ml with a certain level of purity [less than 1 part per million therapeutic of interest, less than 1 mg/ml of endogenous mammalian host cell protein, and less than 500 ng/mL endogenous mammalian cell DNA]. As outlined above, the prior art reference Strauss et al. isolated RVLPs from CHO cell culture supernatants that were successfully used in spiking assays. The isolated and purified and concentrated RVLPs are non-infectious. Anderson et al. teaches a method of isolating non-infectious RVLPs from large quantities of CHO culture supernatant. Applicant has merely performed additional purification and/or concentration steps on an art recognized product to obtain a higher concentration.
However, as stated in the rejection above, it is obvious and well within the purview of one of ordinary skill in the art to perform additional purification and concentration steps to achieve a higher level of purity and a higher concentration, particularly in view of the teaches of Strauss et al. and Anderson et al. Applicant has not provided any evidence that the claimed stock solution is patentably distinct from the stock solution of Strauss et al. or Anderson et al. Further, packaging the stock solution in a kit with other components such as an antibody or a primer does not render the stock solution patentable.
Applicant’s supporting documents
Supporting Emails
It is noted that one supporting document (email from Shawkat Hussain) discusses Cygnus Technology’s “innovative method to harvest, concentrate and purify native retrovirus like particle (RVLP) stocks”. It appears this statement is referring to the innovative method that was used to obtain the concentrated RVLPs. In two other supporting documents (emails from Amanda Mak and Jukka Kervinen) it is stated that “The method employed by Cygnus Technologies to produce a retrovirus like particle stock solution results in the only known commercial source of retrovirus like particles . . .” Again, it appears the supporting documents are recognizing a potentially innovative method. While the method may be innovative, the resulting stock solution is rendered obvious by the prior art.
Product Description
The MockV product is described as a “BSL-1 compatible stock solution of non-infectious Retrovirus-like Particles (RVLP), derived endogenously from CHO cell culture, as a spiking agent for viral clearance testing”. This is the same description as the prior art stock solutions of Strauss et al. and Anderson et al. For example, Anderson et al. states: “[b]ecause of the low numbers of retrovirus-like particles present in CHO cells, characterization has been difficult. However, continuous-flow ultracentrifugation of large volumes of culture fluid from a recombinant CHO cell line has yielded sufficient quantities of extracellular particles for molecular and biochemical characterization” (see page 305, left column). Thus, Anderson et al. teaches a need for large quantities of the RLPs for molecular and biochemical characterization.
Anderson et al. solves this problem by isolating and purifying defective retrovirus-like particles from large volumes of supernatant of CHO cells. Cell culture fluid, which had been concentrated 4000- to 6000-fold by ultracentrifugation, was initially fractionated by centrifugation to equilibrium in a sucrose step gradient (see Materials and Methods and page 307, left column). Anderson et al. reports that the “use of continuous-flow ultracentrifugation to concentrate extracellular, retrovirus-like particles from large volumes of culture fluid of a recombinant CHO cell line has facilitated purification and biochemical characterization of these particles”.
The MockV product description also makes note of the limitations using model retroviruses (XMuLV) for validation (spike) studies. Strauss et al. also discussed these limitations. Strauss et al. states:
small scale viral clearance studies are generally performed using model viruses such as the retrovirus xenotropic murine leukemia virus (X-MuLV). However, extrapolating such data to the removal of RVLPs during manufacturing comes with certain caveats.9 For example, little data exists on how well X-MuLV stocks, which are produced using cell lines and culturing processes optimized for virus production, represent the RVLPs produced endogenously by mAb-producing cell lines and culturing processes. Furthermore, virus stocks undergo only minimal purification while RVLPs may undergo multiple upstream purification steps which differ considerably from those used to purify virus stocks.
Sales
Applicant has provided sales data for the “RVLP Kit”. It is not clear if the sales data are for a kit comprising:
The claimed stock solution and a PCR primer capable of binding to a nucleic acid sequence contained within the mammalian cell-endogenous retrovirus like particles,
OR
the claimed stock solution and a segment of nucleic acid bound to a molecule which can be bound to the mammalian cell-endogenous retrovirus like particles,
OR
the claimed stock solution and an antibody capable of binding to the mammalian cell-endogenous retrovirus like particles,
OR
the claimed stock solution and a molecule which can bind to the mammalian cell-endogenous retrovirus like particles,
OR
a combination of any of the above.
It is not clear if the alleged commercial success is commensurate with the scope of the claims.
Applicant next argues that the previously provided Declaration and supporting Exhibits focus on CHO-derived, non-infectious RVLPs instead of the mock viral particles (MVPs). It is noted that applicant has amended the claims to recite that the RLPs are CHO-derived and non-infectious.
As outlined in the rejection above, the cited prior art Strauss et al. teaches purified and concentrated RVLPs that were isolated from CHO cell cultures and that are non-infectious. Strauss et al. also recognized the need for larger quantities of the CHO-derived RVLPs, and Anderson et al. solves the problem by providing a method to obtain larger quantities of CHO-derived RVLPs.
Applicant next argues that prior to the filing of the present application, those of skill in the art had failed to develop a RVLP stock solution that could be used in viral clearance spiking studies. Applicant’s arguments have been considered and not found persuasive.
Strauss et al. and Anderson et al. teach concentrated and purified stock solutions of CHO-derived, non-infectious RVLPs that were used in viral clearance spiking studies. Thus, such RVLP stock solutions were known in the art. Again, applicant merely further concentrated the art recognized stock solutions to achieve a higher concentration.
Applicant’s Declaration under 37 C.F.R. §132 does not provide evidence that the claimed stock solution of virus is patentably distinct from the stock solution prepared by the method of Anderson et al.
It is noted that the specification contains 22 examples, which are all prophetic. None of the examples describe the process where mammalian-cell endogenous retrovirus were actually purified1 and concentrated to at least 1010 RVLP/ml of solution.
Conclusion
No claim is 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 Nicole Kinsey White whose telephone number is (571)272-9943. The examiner can normally be reached M to Th 6:30 am to 6:00 pm.
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/NICOLE KINSEY WHITE/Primary Examiner, Art Unit 1672
1 Purified to less than 1 part per million therapeutic of interest, less than 1 mg/ml of endogenous mammalian host cell protein, and less than 500 ng/mL endogenous mammalian cell DNA.