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 .
Claims Status
Claims 1-32, 35, and 37-38.
Claims 33-34 and 36 are canceled.
Election/Restrictions
Applicant’s election of:
Species Group 1: adsorptive depth prefilters
Species Group 2: alkyl group
Species Group 3: butyl group
Species Group 4: Applicant did not elect a species
Species Group 5: Applicant did not elect a species
Species Group 6: sodium chloride
Species Group 7: sodium phosphate
Species Group 8: polyethersulfone (PES) membrane
Species Group 9: high capacity diatomaceous earth metals and cellulose
Species Group 10: Applicant did not elect a species.
Species Group 11: viral inactivation
in the reply filed on 06/12/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 32 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/12/2026.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/30/2024 is acknowledged. The submission is in compliance with the provision of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered.
Claim Objections
Claim 26 objected to because of the following informalities:
Claim 26 recites b) that is that is subjected. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 25-26 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 25 recites 1 wt% of the HIC Peak 3. There is lack of antecedent basis in the claim or previous claims for the HIC Peak 3 thus the claim is rendered indefinite.
Claim 26 recites 1 wt% of the HIC Peak 1. There is lack of antecedent basis in the claim or previous claims for the HIC Peak 1 thus the claim is rendered indefinite.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7, 12-14, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm,, pg. 43-50, published September 2002).
With regards to claim 1, Sandoz teaches a method for purifying a TNFR:Fc fusion protein by subjecting a solution comprising TNFR:Fc to hydrophobic interaction chromatography (HIC) (see Abstract). Sandoz teaches that hydrophobic interaction chromatography was used for separating TNFR:Fc degradation products, aggregation products, and other impurities having no or reduced TNFR:Fc bioactivity (see lines 30-32, pg. 21 and lines 1-2, pg. 22). Sandoz further teaches that TNFR:Fc binds to the HIC resin (see line 16, pg. 10).
Sandoz further teaches subjecting a solution comprising TNFR:Fc to hydrophobic interaction chromatography, and collecting the eluate to obtain purified TNFR:Fc (see lines 31-38, pg. 13). Sandoz teaches the hydrophobic interaction chromatography (HIC) has hydrophobic groups such as octyl or phenyl groups and useful HIC columns are Phenyl sepharose, for example (see lines 5-8, pg. 10).
Sandoz also teaches that the method may further include subjecting the eluate to nanofiltration, ultrafiltration, and/or diafiltration in order to separate any inactivated virisu or other contaminants from the purified solution (see lines 10-15, pg. 13).
With regards to claim 2, Sandoz teaches that the TNFR:Fc fusion protein is etanercept (see line 19, pg. 16).
With regards to claim 4, Sandoz teaches that the TNFR:Fc fractions are subjected to hydrophobic interaction chromatography (HIC) where nonpolar groups on the protein surface interact with the hydrophobic groups, e.g. octyl group (alkyl group) of the HIC resin (see lines 5-7, pg. 10).
With regards to claim 12, Sandoz teaches that the TNFR:Fc containing fraction to be applied to the hydrophobic interaction chromatography is diluted with a buffer comprising sodium citrate, sodium phosphate, and/or sodium acetate and sodium sulphate at a concentration of 1.0 M.
With regards to claim 13, Sandoz teaches that TNFR:Fc is subjected to hydrophobic interaction chromatography and that it is carried out in a buffer having a pH ranging from 5.5-6.5 (see lines 5-15, pg. 10).
With regards to claim 14, Sandoz teaches that the TNFR:Fc is eluted by applying a 0-100% gradient from said washing buffer to an elution buffer having a lower concentration of ions (see lines 31-32, pg. 10).
Sandoz does not teach filtering the eluant from step b through one or more charged surface modified microporous membranes or one or more adsorptive depth prefilters, nor does Sandoz teach that the eluate from step c is filtered through one or more viral filtration membranes.
Sandoz also does not teach that the ligand of the HIC medium alkyl group selected from a butyl group or that the HIC medium is composed of hydroxylated methacrylic polymer resins functionalized with a butyl ligand group.
Sandoz teaches that nanofiltration may be used to remove inactivated viruses from the purified solution to render the TNFR:Fc ready for downstream processing such as preparation into a pharmaceutical composition (see lines 10-14, pg. 13) but does not teach a specific viral filtration or viral inactivation step.
However, Banerjee teaches a method of reducing HCP (contaminant) from TNFR:Fc fusion protein by hydrophobic interaction HPLC (see paragraph 0013-0014).
Banerjee teaches that the hydrophobic interaction chromatography uses a Butyl Toyopearl 650 M resin (see paragraph 0094).
Banerjee also teaches that eluate from the mixed-mode chromatography was subjected to virus filtration and that virus filtration was performed with PALL DV20 filter. (see paragraph 0109).
Banerjee does not teach filtering through one or more absorptive depth prefilters.
However, Tipton teaches that adsorptive depth filters have been reported to effectively remove virus during Chon fractionation of human immunoglobin (see pg. 43). Tipton also teaches that a depth filter was used to provide both viral reduction and clarification of the affinity column eluate before further downstream processing (see pg. 43).Tipton teaches that such filters are relatively economical and easy to use (see Abstract, pg. 43).
It would have been obvious to one of ordinary skill in the art of protein purification before the effective filing date of the current instant application to modify the purification method taught by Sandoz by incorporating an adsorptive depth filter step taught by Tipton in which the eluate collected from the chromatography medium is passed through an adsorptive depth filter. One of ordinary skill in the art would be motivated to do so since Tipton teaches that addition of adsorptive depth filter steps can remove host cell proteins and thus improve the purification process. One of ordinary skill in the art of protein purification would also be further motived by the teaching of Banerjee to incorporate a viral filtration step to the eluate collected from the adsorptive depth prefilter since Banerjee teaches that viral filtration membranes such as PALL DV20 can be used for virus removal. One of ordinary skill in the art would be motivated to do so as a means to remove viral contaminates from the TNFR:Fc fusion protein purified product. One of ordinary skill in the art of protein purification would have expectation of success in doing so since the combined teachings of Sandoz, Banerjee, and Tipton provide all the necessary teachings and methods to do so.
With regards to claim 5-7, it would have been obvious to one of ordinary skill in the art of protein purification before the effective date of the current instant application to modify the HIC medium in purification method taught by Sandoz by using a Butyl Toyopearl 650 M resin as the hydrophobic interaction chromatography medium. One of ordinary skill in the art would be motivated to do so as Banerjee teaches that Butyl Toyopearl 650 M resin can be used in hydrophobic interaction chromatography for the purification of TNFR:Fc fusion proteins (see paragraph 0094). As evidenced by Tosoh Bioscience (product specification information, attached to Form 892), Toyopearl Butyl-650M is a hydrophobic interaction chromatography (HIC) resin for biomolecule purification. The resin is composed of a base material of hydroxylated methacrylic polymer beads that have been functionalized with a butyl ligand group (see Toso Bioscience specification sheet). The combination of familiar elements according to known methods is obvious when it does no more than yield predictable results (see KSR Int’l v. Teleflex, Inc., 127 s. Ct. 1727, 1739 (2007). One of ordinary skill in the art would have expectations in being successful in doing so since the combined teachings of Sandoz, Banerjee (as evidenced by Tosoh Bioscience), and Tipton provide all the teachings necessary to do so.
With regards to claim 38, Sandoz teaches that nanofiltration may be used to remove inactivated viruses from the purified solution to render the TNFR:Fc ready for downstream processing such as preparation into a pharmaceutical composition (see lines 10-14, pg. 13). Sandoz does not teach a specific viral inactivation step.
However, Banerjee teaches that a viral inactivation step can be applied to eluted TNFR:Fc at low pH in order to inactivate viruses (see Paragraph 0091).
It would have been obvious to one of ordinary skill in the art of protein purification prior to the effective filing date of the current instant application to apply a viral inactivation step as taught by Banerjee to the TNFR:FC sample obtained after the purification method of TNFN:Fc as taught by the combined teachings of Sandoz, Banerjee, and Tipton in order to inactivate any lingering viral contaminants and prepare the TNFR:Fc for any downstream processing such as incorporation into a pharmaceutical composition. One of ordinary skill in the art of protein purification would be motivated to do so in order to remove any remaining live virus particles from the purified etanercept composition and to ensure safety of the purified composition for use in further downstream processing. One of ordinary skill in the art of protein purification would have expectations of success in doing so as the combined teachings of Sandoz, Banerjee, and Tipton provide all the necessary teachings and guidance to do so.
Therefore, claims 1-7, 12-14 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm,, pg. 43-50, published September 2002), hereinafter referred to as Tipton.
Claims 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002) as applied to claim 1 above, and further in view of Hassett et al. (MABS, Vol. 10, pg. 159-165; published online November 29, 2017), hereinafter referred to as Hassett.
The teaching of Sandoz, Banerjee, and Tipton as applied to claim 1 is summarize above.
Neither Sandoz, Banerjee or Tipton teach that in the method of claim 1, the eluate from step b that is subjected to the filtration in step c further comprises less than about 1 wt% of the HIC peak 3 or less than 1wt% HIC peak 1. Furthermore, neither Sandoz, Banerjee, or Tipton teach that the eluate being filtered in step c has a protein concentration of from about 2 mg/mL to about 10 mg/mL.
However, Hassett teaches a method in which hydrophobic interaction chromatography is used to assess the purity of etanercept (ETN). Hassett teaches that the method is used to resolve three variants of ETN which differ in biological activity, Hassett teaches that peak 1 is predominantly clipped species, peak 2 is homogenous ETN, and peak 3 consists of misfolded species, aggregates and ETN fragments (see pg. 163).
Hassett teaches that 2 mg/mL of etanercept was loaded onto a TSKgel Butyl-NPR analytical column and the sample was separated into HIC Peak 1, Peak 2, and Peak 3 (see pg. 163).
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the eluant to be filtered through an adsorptive depth filter as taught by the combined teachings of Sandoz, Banerjee, and Tipton by selecting the homogenous peak 2 which contains homogenous ETN as taught by Hassett. One of ordinary skill in the art would recognize that since peak 2 is separate from peak 1 and peak 3, the eluant would comprise less than 1%wt of Peak 1 and Peak 2. One of ordinary skill of the art in protein purification would be also skilled in adjusting the concentration back to around 2 mg/mL by concentration of the eluted protein as this is within the working range of the loaded sample prior to filtration. One of ordinary skill in the art would be motivated to select peak 2 for filtration as Hassett teaches that peak 2 contains homogenous ETN and would be the sample of the highest purity of ETN. It is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) and where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454, 456, 105 USPQ 233; 235 (CCPA 1955). One of ordinary skill in the art would have expectations in doing so as Sandoz, Banerjee, Tipton, and Hassett provide all the teachings and guidance necessary to do so.
Therefore, claims 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002) as applied to claim 1 above, and further in view of Hassett et al. (MABS, Vol. 10, pg. 159-165; published online November 29, 2017), hereinafter referred to as Hassett.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002). as applied to claim 1 above, and further in view of Minow et al. (Bioprocess International 12(4)s, pg. 36-46; published April 2014), hereinafter referred to as Minow.
The teachings of Sandoz, Banerjee, and Tipton as applied to claim 1 are summarized above.
Neither Sandoz, Banerjee, or Tipton teach that the eluate from the HIC is filtered through a high capacity diatomaceous earth metals and cellulose adsorptive prefilter.
However, Minow teaches a single-use depth filter that consists of a double-layer material that combined two diatomaceous earth metal containing cellulose layers (see pg. 40). Minow teaches that filtration is effective in removal of host cell proteins and to remove or reduce bioburden (see pg. 36).
It would have been obvious to one of ordinary skill in the art of protein purification before the effective filing date of the current instant application to select an adsorptive depth prefilter composed of diatomaceous earth metals and cellulose taught by Minow as the prefilter for use in the viral filtration of the TNFR:Fc eluant as taught by the combined teachings of Sandoz, Banerjee, and Tipton as a means of removing contaminants such as host cell proteins or other particles. One of ordinary skill in the art of protein purification would be motivated to do so as Minow teaches that the filters help removal typical contaminants during biopharmaceutical processes. One of ordinary skill in the art of protein purification would have expectations of success in doing so as Sandoz, Banerjee, Tipton, and Minow provide all the necessary teachings and guidance to do so.
Therefore, claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002). as applied to claim 1 above, and further in view of Minow et al. (Bioprocess International 12(4)s, pg. 36-46; published April 2014), hereinafter referred to as Minow.
Claims 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton as applied to claim 1 above, and further in view of Liu et al. (mAbs 2:5, pg. 480-499, published Epub September 1, 2010), hereinafter referred to as Liu.
The teachings of Sandoz, Banerjee, and Tipton as applied to claim 1 are summarized above.
With regards to claims 28-29, neither Sandoz, Banerjee, or Tipton specifically disclose the viral filtration membranes have a pore size from about 20 nm to about 100 nm.
With regards to claim 30, Sandoz, Banerjee, and Tipton are silent on whether the viral filtration membranes are polyethersulfone (PES).
However, Liu teaches that current virus-retention filters are ultrafilters or microfilters with very small pores. Liu teaches that according to the size distribution of viruses that are removed, virus filters can be categorized into retrovirus and parovirus filters. (see Paragraph 1, left column, pg. 492). Liu further teaches a list of commercially available virus filters, their construction materials, and virus retention in Table 1 of pg. 492. Liu teaches that Viresolve Pro (made of PES) can be used to filter viruses such as size 18-24 nm, Viresolve NFR (made of PES) can filter viruses of size 80-130 nm, or Sartoriu Virosart CPV (made of PES) which can filter virus sizes of 80-130 nm.
It would have been obvious to one of ordinary skill in the art of protein purification before the effective filing date of the current instant application to select a Sartorius Virosart CPV or Viresolve Pro filter taught by Liu as the viral filtration membrane for the viral filtration of the TNFR:FC eluant taught by the combined teachings of Sandoz, Banerjee, and Tipton.. One of ordinary skill in the art of protein purification would be motivated to so since Liu teaches that these filters are well known in the art and provide the necessary material (PES) and pore size for viral filtration. The combination of familiar elements according to known methods is obvious when it does no more than yield predictable results (see KSR Int’l v. Teleflex, Inc., 127 s. Ct. 1727, 1739 (2007). One of ordinary skill in the art of protein purification would have expectations in success of doing so since Sandoz, Banerjee, Tipton, and Liu provide all the necessary teachings and guidance to do so.
Therefore, claims 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton as applied to claim 1 above, and further in view of Liu et al. (mAbs 2:5, pg. 480-499, published Epub September 1, 2010), hereinafter referred to as Liu.
Claims 31 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton as applied to claim 30 above, and further in view of Liu et al. (mAbs 2:5, pg. 480-499, published Epub September 1, 2010) as applied to claim 30 above, and further in view of Otitoju et al. (RSC Advances, Vol. 8, 22710; published June 19, 2018), hereinafter referred to as Otitoju.
The teachings of Sandoz, Banerjee, Tipton, and Liu as applied to claim 30 are summarized above.
Neither Sandoz, Banerjee, Tipton, or Liu teach that the PES membrane is a hydrophilic asymmetric surface modified PES membrane.
However, Otitoju teaches that the blending of additives in PES matrix is an important approach in the membrane industry to reduce membrane hydrophobicity and improve performance. Otitoju teaches that PES possess a high mechanical and hydrolytic stability, thermal and chemical resistance, and outstanding oxidative characteristic making it ideal for preparation of asymmetric membranes with different surfaces and pore sizes (see. pg. 22710). Otitoju teaches that PES chains are first activated by chemical reaction followed by grafting with hydrophilic additives. Otitoju teaches that since most of the additives are hydrophilic in nature, they are able to increase the hydrophilicity of the resulting membranes and thus can reduce fouling effects (see pg. 22711).
It would have been obvious to one of ordinary skill in the art of protein purification before the effective filing date of the current instant application to use a PES membrane with hydrophilic asymmetric surface modified PES membrane taught by Otitoju in the viral filtration step of the TNFR:Fc eluant taught by the combined teachings of Sandoz, Banerjee, Tipton, and Liu in order to reduce fouling effects (substance accumulation). One of ordinary skill in the art of protein purification would be motivated to do so since Otitoju teaches that the hydrophilic asymmetric surface modified PES membrane has enhanced hydrophilicity and performance. One of ordinary skill in the art of protein purification would have expectations of success in doing so as Sandoz, Banerjee, Tipton, Liu, and Otitoju provide all the teachings and guidance needed to do so.
Therefore, claims 31 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton as applied to claim 30 above, and further in view of Liu et al. (mAbs 2:5, pg. 480-499, published Epub September 1, 2010) as applied to claim 30 above, and further in view of Otitoju et al. (RSC Advances, Vol. 8, 22710; published June 19, 2018), hereinafter referred to as Otitoju.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton as applied to claim 1 above, and further in view of Gagnon et al (US Patent No. US 8,188,242 B2; published May 29, 2012), hereinafter referred to as Gagnon.
The combined teachings of Sandoz, Banerjee, and Tipton as applied to claim 1 are summarized above.
Neither Sandoz, Banerjee, or Tipton teach that the chromatography medium of claim 1 comprises a ligand comprising a hydrophobic group and an ionic group or that the hydrophobic group is a phenyl group or benzyl group, and the ionic group is a strong cation group, a weak cation group, or a combination thereof.
With regards to claim 8-9, Sandoz teaches that after affinity chromatography, the TNFR:Fc is subjected to anion exchange chromatography which allows separation and purification of molecules based on their charge (see lines 35-27, pg. 7) and that the anion chromatography may also use a multimodal chromatography (MMC) matrix in which more than one form of interactions between the resin and TNFR:Fc is utilized to achieve separation and purification (see lines 21-23, pg. 8). Sandoz teaches that multimodal anion exchange chromatography combines principles of anion exchange chromatography with those of hydrophobic interaction chromatography (see lines 25-28, pg. 19). Sandoz teaches that loading of an eluate onto a Capto adhere resin (see line 30, pg. 19). As evidenced by the Cytiva product specification sheet for the Capto adhere resin (attached to form 892), the Capto adhere ligand exhibits many functionalities for interaction. The most pronounced are ionic interaction, hydrogen bonding, and hydrophobic interaction (see Cytiva specification sheet, pg. 1). As shown in the product specification sheet, according to the multimodal ligand structure for Capto adhere, the hydrophobic group is a phenyl group and also contains an ionic group that is a weak cation (see structure below from product specification).
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Neither Sandoz, Banerjee, or Tipton specifically teach that the TNFR:Fc fusion protein binds and elutes from a mixed mode chromatography column.
However, Gagnon teaches a method for purifying antibodies from a solution containing antibodies in which the method involves contacting the solution with a mixed mode chromatography matrix, separating the matrix with the bound antibodies from the solution and eluting the bound antibodies (see Column 18, claim 1). Gagnon teaches that the mixed-mode chromatography support exploits a combination of anion exchange and hydrophobic interaction functionalities and that an example resin is Capto Adhere (see Column 6, lines 15-16).
It would have been obvious to one of ordinary skill in the art of protein purification to modify the HIC medium in the purification method of TNFR:Fc from combined teachings of Sandoz, Banerjee, and Tipton, by using a mixed mode chromatography medium comprising a ligand comprising a hydrophobic group and an ionic group as the HIC medium. One of ordinary skill in the art would be motivated to do so since Gagnon teaches that mixed mode chromatography can be used to bind and elute antibodies during purification. The combination of familiar elements according to known methods is obvious when it does no more than yield predictable results (see KSR Int’l v. Teleflex, Inc., 127 s. Ct. 1727, 1739 (2007). One of ordinary skill in the art would have expectations of success in doing so since Sandoz, Banerjee, Tipton, and Gagnon provide all the teachings and guidance to do so.
Therefore, claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton as applied to claim 1 above, and further in view of Gagnon et al (US Patent No. US 8,188,242 B2; published May 29, 2012), hereinafter referred to as Gagnon.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton as applied to claim 8 above, and further in view of Gagnon et al (US Patent No. US 8,188,242 B2; published May 29, 2012), hereinafter referred to as Gagnon. and further in view of Arakawa et al. (Protein Expression and Purification, Vol. 116, pg. 144-151; published December 2015), hereinafter referred to as Arakawa.
The combined teachings of Sandoz, Banerjee, Tipton, and Gagnon as applied to claim 8 is summarized above.
Neither Sandoz, Banerjee, Tipton or Gagnon specifically teach a chromatography medium wherein the hydrophobic group is a benzyl group and the ionic group is a weak anion group.
However, Arakawa teaches that two mixed-mode chromatography resins, Capto MMC and Capto adhere were used to separate misfolded etanercept and BSA oligomers. Arakawa teaches that simultaneous gradient of pH and salt concentration on Capto MMC resulted in separation of native etanercept (see Abstract, pg. 144). Capto MMC contains a hydrophobic group that is a benzyl group and the ionic group is a weak anion group as evidenced by Hirano et al (see Figure 1, Journal of Chromatography A, Vol. 1338, pg. 58-66; published 2014) (chemical structure of the ligand shown below).
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Greyscale
It would have been obvious to one of ordinary skill in the art of protein purification before the effective filing date of the current instant application to modify the hydrophobic interaction chromatography media taught the combined teachings of Sandoz, Banerjee, Tipton and Gagnon by selecting a mixed-mode chromatography resin, Capto MMC, as the HIC medium in the purification procedure. One of ordinary skill in the art of protein purification would be motivated to do so since Arakawa teaches that Capto MMC is effective in achieving separation of native etanercept. One of ordinary skill in the art would have expectations of success in doing so since Sandoz, Banerjee, Tipton, Gagnon and Arakawa provide all the necessary teachings and guidance to do so.
Therefore, claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton as applied to claim 8 above, and further in view of Gagnon et al (US Patent No. US 8,188,242 B2; published May 29, 2012), hereinafter referred to as Gagnon. and further in view of Arakawa et al. (Protein Expression and Purification, Vol. 116, pg. 144-151; published December 2015), hereinafter referred to as Arakawa.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton, and further in view of Gagnon et al (US Patent No. US 8,188,242 B2; published May 29, 2012), hereinafter referred to as Gagnon, as applied to claim 8 above, and further in view of Wang et al. (Journal of Chromatography B, Vol. 936, pg. 33-41; published October 1, 2013), hearinafter referred to as Wang.
The combined teachings of Sandoz, Banerjee, Tipton and Gagnon as applied to claim 8 is summarized above.
Neither Sandoz, Banerjee, Tipton, or Gagnon teach that the ligand of the chromatography medium comprises a benzyl group and an amine group, a phenyl group and a carboxylic group or a benzyl group, as sulfonic group and a carboxylic group.
With regards to claim 11, Wang teaches that mixed-mode chromatography has been focused as a cost-effective new technique for antibody purification. Wang teaches that the mixed mode-resin with N-benzyl-N-methyl ethanol amine as the ligand had the best ability to separate IgG and BSA. Wang teaches that high purity and high recovery of IgG were obtained and that the results indicate that mixed-mode chromatography would be a potential option for antibody purification (see Abstract, pg. 33).
Therefore, it would have been obvious to one of ordinary skill in the art of protein purification before the effective filing date of the current instant application to select a mixed-mode resin with N-benzyl-N-methyl-amine taught by Wang as a ligand for the chromatography medium and apply it to the HIC purification of TNFR:Fc as taught by the combined teachings of Sandoz, Banerjee, Tipton, and Gagnon. One of ordinary skill in the art of protein purification would be motivated to do so since Wang teaches that the ligand has the best ability to separate IgG and BSA and would be a potential option for antibody purification. One of ordinary skill in the art would have expectations of success in doing so from the combined teachings of Sandoz, Banerjee, Tipton, Gagon and Wang who provide all the necessary teachings and guidance to do so.
Therefore, claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton, and further in view of Gagnon et al (US Patent No. US 8,188,242 B2; published May 29, 2012), hereinafter referred to as Gagnon as applied to claim 8 above, and further in view of Wang et al. (Journal of Chromatography B, Vol. 936, pg. 33-41; published October 1, 2013), hearinafter referred to as Wang.
Claims 15-24 are rejected under 35 U.S.C. 103 as being unpatentable over over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton as applied to claim 14 above, and further in view of Won et al. (US Patent Application Publication No. US 2014/0316114 A1; published October 23, 2014), hereinafter referred to as Won.
The teachings of Sandoz, Banerjee, and Tipton as applied to claim 14 are summarized above.
With regards to claim 15, neither Sandoz, Banerjee, or Tipton specifically state that the TNFR:Fc fusion protein is eluted in step b using a gradient from 100% of a fist solution having a salt concentration of from about 0.4M to about 2M, to 100% of a second solution having a salt concentration of from 0 mM to about 100 mM.
With regards to claim 17, neither Sandoz, Banerjee, or Tipton specifically state that the first solution comprises a salt selected from sodium chloride.
With regards to claim 18, neither Sandoz, Banerjee, or Tipton specifically state that the second solution comprises a salt selected from sodium phosphate.
With regards to claim 19, neither Sandoz, Banerjee, or Tipton specifically state that the first and second solutions each has a pH of from about 5.0 to 8.5.
With regards to claim 20, , neither Sandoz, Banerjee, or Tipton specifically state that the first and second solutions have the same pH.
With regards to claim 21, neither Sandoz, Banerjee, or Tipton specifically state that the first and second solutions have the same buffer.
With regards to claim 22, neither Sandoz, Banerjee, or Tipton specifically state that the first and second solutions each comprises a phosphate buffer, an acetate buffer, or a citrate buffer.
With regards to claim 23, neither Sandoz, Banerjee, or Tipton specifically state that the first and second solutions each comprise a buffering agent at a concentration of from about 10 mM to about 200 mM.
With regards to claim 15 and 17-23, Won teaches a method for separating a TNFR:Fc fusion protein using hydrophobic interaction chromatography (see abstract). Won teaches that TNFR:Fc samples were subjected to hydrophobic-HPLC using a Butyl NPR column (See paragraphs 0092-0093, Column 8). Won teaches that mobile phase A (first solution) was a solution of 1.8 M ammonium sulfate and 100 mM sodium phosphate (pH 7.0) and mobile phase B (second solution) was a solution (pH 7.0) of 100 mM sodium phosphate. Won teaches that for the initial 5 minutes, the mobile phase A composition was maintained at 100% followed by a linear gradient of the mobile phase A from 100% to 0%(see paragraph 0092, Column 8). Figure 6 shows the elution profile resulting in a Peak 1, Peak 2, and Peak 3 and that peak 2 was found to include a single fraction of the active form (see paragraph 0093, column 8).
With regards to claim 17, Won teaches an embodiment of hydrophobic interaction chromatography using a column packed with butyl sepharose 4 Fast Flow. A buffer solution of 0.75M sodium chloride and 50 mM Tris-HCl (Buffer X, first solution was used to equilibrate the column (see paragraph 088)..
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application to apply the chromatographic gradient conditions taught by Won to the HIC purification of TNFR:Fc taught by the combined teachings of Sandoz, Banerjee, and Tipton. One of ordinary skill in the art would be motivated to do so since Won teaches that gradient elution assists in purification of TNFR:Fc fusion proteins in hydrophobic interaction chromatography and is able to achieve separation of a single fraction of the active form of TNFR:Fc. One of ordinary skill in the art of protein purification would have expectations of success in doing so since Sandoz, Banerjee, Tipton, and Won provide all the teachings and guidance needed to do so.
With regards to claims 16 and 24, Won teaches a method for separating a TNFR:Fc fusion protein using hydrophobic interaction chromatography (see abstract). Won teaches that in hydrophobic interaction chromatography, the more hydrophobic the molecule, the less salt is needed to promote binding to the column (see paragraph 0056). Won teaches that active TNFR-Fc fusion proteins can be separated from the inactive TNFR-Fc fusion proteins or aggregates by adjusting the salt concentration (see paragraph 0056). Won teaches that the elution buffer is a buffer having a lower salt concentration than the equilibration buffer and the wash buffer (see paragraph 0057). Won teaches that an elution buffer comprises 50-100 mM sodium phosphate but is not limited thereto (see paragraph 0057). Won teaches that in one embodiment, an elution buffer comprising 0.4M sodium citrate and 50 mM sodium phosphate at pH 6.8 (first solution) and an elution buffer comprising 0.4 M sodium sulfate and 50 mM sodium phosphate at pH 6.8 were used (second solution) (see paragraph 0057). This buffer is very similar to the applicant’s current claimed first solution comprises 0.42 M sodium citrate, 0.05 M sodium phosphate, and a pH of about 6.5 and the second solution comprises 0.05 M sodium phosphate and pH of about 6.5 in claim 24.
Won also teaches that in one embodiment, hydrophobic interaction chromatography was performed using a column packed with Butyl Sepharose 4 Fast Flow resin. A buffer solution (pH 6.8) of 0.5 M sodium citrate and 50 mM sodium phosphate (Buffer I) (first solution) and a buffer solution (pH 6.8) of 50 mM sodium phosphate (Buffer J) (second solution) were prepared. The elution buffer was made to have a composition of 80% buffer I and 20% buffer J and as a result elution profile of separated peaks 1, 2, and 3 were obtained (see paragraphs 0081-0083).
It would have therefore been obvious to one of ordinary skill in the art of protein purification to apply the gradient elution conditions taught Won to the hydrophobic interaction chromatography taught by the combined teachings of Sandoz, Banerjee, and Tipton in order to achieve a gradient elution of TNFR:Fc from the hydrophobic interaction chromatography medium. It is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) and where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art . In re Aller, 220 F2d 454, 456, 105 USPQ 233; 235 (CCPA 1955).
One of ordinary skill in the art would be motivated to so since Won teaches that active TNFR:Fc fusion proteins can be separated from inactive TNFR:Fc fusion proteins by adjusting the salt concentration during elution during hydrophobic interaction chromatography. One of ordinary skill in the art of protein purification would have expectations in successfully doing so since Sandoz, Banerjee, Tipton, and Won provide all the teachings and guidance necessary to do so.
Therefore, claims 15-24 are rejected under 35 U.S.C. 103 as being unpatentable over Sandoz AG (WIPO International Publication Number WO 2016/009049 A1; published January 21, 2016), hereinafter referred to as Sandoz, in view of Banerjee et al. (US Patent Application Publication No. US 2017/0152298 A1; published June 1, 2017), hereinafter referred to as Banerjee, and further in view of Tipton et al. (BioPharm, pg. 43-50, published September 2002), hereinafter referred to as Tipton as applied to claim 14 above, and further in view of Won et al. (US Patent Application Publication No. US 2014/0316114 A1; published October 23, 2014), hereinafter referred to as Won.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1 and 8-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-7 of U.S. Patent No. US 11,952,399 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1 and 6-7 of US 11,952,399 B2 are directed to a method for purifying a tumor necrosis factor receptor (TNFR):Fc fusion protein comprising (a) subjecting a sample to at least one contaminant to a chromatographic medium under conditions whereby the TNFR:Fc fusion protein binds to the chromatography medium, (b) eluting the TNFR:Fc fusion protein form the chromatography medium and, (c) filtering the eluate from (b) through (i) one or more adsorptive prefilters; or (ii) one or more charged or surface modified microporous membranes; and (d) filtering the eluate from (c) through one or more viral filtration membranes to obtain the purified TNFR:Fc fusion protein, wherein the chromatography medium (i) is a hydrophobic interaction chromatography (HIC) medium or (ii) comprises a ligand comprising a hydrophobic group and an ionic group; a method of claim 1 wherein the chromatography medium comprises a ligand comprising a hydrophobic group and an ionic group and a) the hydrophobic group is a phenyl group or benzyl group, and the ionic group is a strong cation group , a weak cation group, or a combination thereof; or b) the hydrophobic group is a phenyl group or a benzyl group, and the ionic group is a strong anion group, a weak anion group, or a combination thereof; and the method of claim 1 wherein the chromatography medium comprises a hydrophobic group and an ionic group and the ligand comprises 1) a benzyl group and an amine group, 2) a phenyl group and a carboxylic group, or 3) a benzyl group, a sulfonic group and a carboxylic group anticipate and make obvious instant claims 1 and 8-11 drawn to (instant claim 1) a method for purifying a tumor necrosis factor receptor (TNFR):Fc fusion protein, comprising: (a) subjecting a sample comprising the TNFR:Fc fusion protein and at least one contaminant to a chromatography medium under conditions whereby the TNFR:Fc fusion protein binds to the chromatography medium, (b) eluting the TNFR:Fc fusion protein from the chromatography medium, (c) filtering the eluate from (b) through (i) one or more charged or surface modified microporous membranes or (ii) one or more adsorptive depth prefilters; and (d) filtering the eluate from (c) through one or more viral filtration membranes to obtain the purified TNFR:Fc fusion protein, wherein the chromatography medium comprises a ligand comprising a hydrophobic group (instant claim 8 dependent from instant claim 1) wherein the chromatography medium comprises a ligand comprising a hydrophobic group and an ionic group; (instant claim 9, dependent from instant claim 8) wherein the hydrophobic group is a phenyl group or a benzyl group, and the ionic group is a strong cation group, a weak cation group, or a combination thereof; (instant claim 10 dependent from instant claim 8) wherein the hydrophobic group is a phenyl group or a benzyl group, and the ionic group is a strong anion group, a weak anion group, or a combination thereof; and (instant claim 11 dependent from instant claim 8) wherein the ligand of chromatography medium comprising 1) a benzyl group and an amine group, 2) a phenyl group and a carboxylic group, or 3) a benzyl group, a sulfonic group and a carboxylic group.
Conclusion
No claims are allowed.
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/GEORGE THEMISTOCLIS LOUNTOS/ Examiner, Art Unit 1652
/ROBERT B MONDESI/ Supervisory Patent Examiner, Art Unit 1652
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