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 .
Response to /Amendment
Applicant’s amendment and remark filed on 01/08/26 have been entered. Claims 1-2, 8, 11, 14, 17, 23, 36, 42-43, 46-52, 58, 67, 71, 73, 92-93, and 96-99 remain pending. Applicant’s remark and amendment have overcome each and every objection and rejection set forth in the previous Office Action.
Status of Objection and Rejection
The objection of claim 51 is withdrawn in view of Applicant’s amendment.
The rejection of claim 100 is obviated by Applicant’s cancellation.
The rejection of claims 8, 11, 14, 86 under 112(b) is withdrawn in view of Applicant’s amendment.
The amendment necessitated new ground of rejection.
Claim Rejections - 35 USC § 112
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 following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 23, 36, and 50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 23 and 50, claim 50 recites the third wash solution with a pH of about 7.2, 9wherein the first component is acetate and the second component is NaCl; while claim 23 recites the third wash solution have a pH of about 7-9. The specification does not provide support for this embodiment, at best the specification provide support for a pH of 6.5 (para. [0046]) of the specification. The disclosed embodiment of 6.5 is in the acidic range, yet the claimed 7-7.2 is neutral/basic neutral range. Thus, the claimed invention is not described in the specification in such a way as to reasonably convey to one skilled in the art to utilize a solution at neutral instead of acidic 6.5 of the specification. Though the numerical difference may appear minor (6.5 vs 7.2), it is noted that a one-unit change in pH signals a 10-fold shift in hydrogen ions in the solution.
Claim 36 is also rejected for being dependent on claim 23 and unable to cure the deficiency.
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 67 and 71 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.
The claims recite “the second wash solution” without properly establish antecedent basis in the parent claim. Claim 51 simply recites performing three washing without explicitly using three washing solutions (in other word, some solution can be used repeatedly). Examiner recommends amending the claim language to include “the second wash comprises a second wash solution, wherein the second component…” to cure the deficiency.
Claim Rejections - 35 USC § 102
Claim(s) 1, 8, 42, 43, and 46-49 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sun (US 20080064861 A1).
Regarding claim 1, Sun discloses a method for purifying an antibody comprising loading a composition comprising an antibody on a Protein A Chromatography column (A MabSelect™ Protein A column was initially loaded with conditioned culture media from a Chinese Hamster Ovary (“CHO”) cell culture process; para [0088]) and washing the column (Table 1, para. [0089]) comprising three washes (Equilibration, Post Load Flush, Wash 1, Pre-Elution Flush, Post Strip Flush, Table 1) comprising:
a first component selected from TRIS (Equilibration and Post Load Flush (10 mM Tris), Wash 1 (20 mM Tris; See No. 1 of Table 2 of para. [0090]), Pre-Elution Flush (10 mM Tris), Post Strip Flush (10 mM Tris); Table 1 and Table 2; para. [0089]-[0090]);
and a second component selected from the group consisting of sodium chloride (Equilibration, Post Load Flush, Pre-Elution Flush, Post Strip Flush (100 mM NaCl; Table 1); Wash 1 (1 M NaCl, No. 1, Table 2).
Regarding claim 8, Sun discloses the claimed invention as discussed above in claim 1. Sun discloses the concentration of the first component is from about 1 mM to about 50 mM (10 mM TRIS for Equilibration, Post Load Flush, Pre-Elution Flush, and Post Strip Flush; Table 1; 20 mM TRIS for Wash 1, Table 2).
Regarding claim 42, Sun discloses the claimed invention as discussed above in claim 1. Sun discloses the wash are conducted at room temperature (which is between 0 and 50 C).
Regarding claim 43, Sun discloses the claimed invention as discussed above in claim 1. Sun discloses the antibody is monoclonal, recombinant, humanized, and chimeric (para. [0041]).
Regarding claim 46, Sun discloses the claimed invention as discussed above in claim 1. Sun discloses further comprises purifying the antibody (elution step, In certain embodiments of the invention, the product may be eluted from a washed medium…In another embodiment, the eluate includes an isolated product; para. [0072]-[0076]).
Regarding claim 47, Sun discloses the claimed invention as discussed above in claim 46. Sun discloses the method further comprises formulating the antibody (…it will typically be desirable to further isolate and/or purify products isolated according to the present invention and formulate them for pharmaceutical use according to standard methods. Para. [0083]).
Regarding claim 48, Sun discloses the claimed invention as discussed above in claim 46. Sun discloses that the purified antibody is substantially free of contaminants (In other embodiments, the method results in reduced turbidity as well as reduced impurities in the eluate that contains the product… In some cases, one or more processes are used to process the eluate, e.g., to remove contaminants or impurities that are in the eluate. Para. [0081]-[0082]). Furthermore, in method claims, it is the overall method steps that are given patentable weight not the intended result thereof because the intended result does not materially alter the overall method. In method claims, the intended result is not given patentable weight when it simply expresses the intended result of a process step positively recited (MPEP § 2111.04).
Regarding claim 49, Sun discloses the claimed invention as discussed above in claim 48. Sun discloses the contaminant is host cell protein (In certain embodiments of this aspect, one or more of the impurities is a host cell protein; para. [0013].)
Claim Rejections - 35 USC § 103
Claim(s) 2, 11, and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Bian (US 20160193633 A1) and FDA (BAM R60: 0.01 M Phosphate-Buffered Saline (pH 7.5), 2001).
Regarding claim 2, Sun discloses the claimed invention as discussed above in claim 1. Sun discloses the second wash comprises a second wash solution wherein the first component is TRIS (Post Load Flush; Table 1) and third wash comprises a third wash solution wherein the first component is acetate (1 M arginine, 20 mM sodium acetate, No. 6, Table 2). Sun does not explicitly disclose the first wash comprises a first wash solution wherein the first component is phosphate. Instead, Sun discloses first wash solution comprises TRIS.
In analogous art Bian also discloses a Protein A chromatography for CHO or NS0 cells (Abstract and para. [0043]). Bian discloses that for equilibration step a neutral buffer at pH 7-7.5 such as phosphate saline or a TRIS buffer are both comparable and applicable for such purpose (The column may first be equilibrated with a suitable equilibration buffer. This is usually achieved by flowing 3-10 column volumes (CVs) of a neutral pH buffer, such as, phosphate saline buffer, or a Tris buffer, at pH 7-7.5, through the Protein A resin. Para. [0058]).
In another analogous art such as FDA, FDA discloses preparation of 0.01 phosphate-buffered saline from a 0.1 M stock solution, the final concentration of would be 130 mM NaCl and 12 mM phosphate (converted from grams to mole based on molecular weight and divide by the volume of the solution).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have make a substitution of TRIS buffer of Sun with phosphate saline buffer of FDA to derive the claimed invention. It would have been obvious to one of ordinary skill in the art to have utilized a 7.5 pH PBS such as the one disclosed by the FDA as substitution for the TRIS buffer of Sun to derive the claimed invention. One of ordinary skill in the art would have a reasonable expectation of success as both the TRIS buffer of Sun and phosphate saline buffer of Bian are both at neutral pH of 7-7.5, and Bian discloses that both buffers are applicable for equilibration (Bian, para. [0058]), suggesting the choice of the two buffers may be a matter of availability.
Regarding claim 11, Modified Sun discloses the claimed invention as discussed above in claim 2. Sun discloses the second component is about 1M for arginine (No. 6 Table 2) and 100 mM for NaCl in first and second wash solution (Table 1), and FDA discloses the final concentration of would be 130 mM NaCl (converted from grams to mole based on molecular weight and divide by the volume of the solution).
Regarding claim 14, Modified Sun discloses the claimed invention as discussed above in claim 2. Sun discloses the concentration of the second component is 0.8% for NaCl for the first and second solutions (divide grams of NaCl used in FDA by 1000 grams, the approximate weight of the distilled water used to make 1 L of solution) and 15% for arginine (divide 1 mole of arginine in grams (174) by weight of the solution, which is the sum of 1000 grams of distilled water used to prepare 1L of the solution and 174 grams of arginine) for the third solution.
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Bian and FDA as discussed above in claim 2, and further in view of Holstein (Protein A Intermediate Wash Strategies, 2015) and Han (The adequate amount of sodium chloride in Protein A wash buffer for effective host cell protein clearance ,2019).
Regarding claim 17, Modified Sun discloses the claimed invention as discussed above in claim 2. Bian and FDA disclose the second component of the first wash is NaCl. Neither Sun, Bian, nor FDA discloses the second component of the third wash is NaCl. At best, Sun discloses the third wash solution comprises sodium acetate and arginine at pH 5.0. In an analogous art, Holstein discloses Protein A chromatography intermediate Wash Strategies (Table 1) using a solution of 100 mM sodium acetate and 500 mM NaCl at pH 5 (Figure 5-8).
In another analogous art, Han discloses adding salt to Protein A wash buffer in an acetate wash solution (Table 1) can effectively improve HCP removal (Abstract). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have make a substitution of the wash solution acetate and arginine of Sun with wash solution of acetate and NaCl of Holstein to derive the claimed invention. One of ordinary skill in the art would have a reasonable expectation of success and expect the solution disclosed by Holstein as an acceptable alternative since both solutions comprises acetate and at acidic pH of 5-5.5 and are used as intermediate wash buffer, and Han discloses adding adequate amount of NaCl to wash buffer generally improves host cell protein removal.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Bian and FDA as applied to claim 2 above, and further in view of Han.
Regarding claim 23, Modified Sun discloses the claimed invention as discussed above in claim 2. Sun discloses the first and second solution have a pH of about 7.5 (Table 1), but neither Sun, Bian nor FDA discloses a third solution have a pH of about 7 to 9. The acetate solution Sun disclosed is 5.0. Sun discloses an alternative to the wash to the acetate solution is 1 M NaCl, 20 mM Tris, pH 7.5 (No. 1, Table 1).
In an analogous art, Han discloses adding salt to Protein A wash buffer in an acetate wash solution (Table 1) can effectively improve HCP removal (Abstract), wherein the intermediate wash comprises 50 mM Tris-Acetate and 150 mM NaCl, pH 7.4 (Table 1, Wash 1). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have make a substitution of the wash solution No. 1 of Sun with wash solution of Tris-acetate and NaCl of Han to derive the claimed invention. One of ordinary skill in the art would have a reasonable expectation of success and expect the solution disclosed by Han as an acceptable alternative since both solutions comprises TRIS and NaCl at slightly basic pH and are used as intermediate wash buffer.
Claim(s) 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Bian, Han, and FDA as applied to claim 23 above, and further in view of Shukla (Host cell protein clearance during protein a chromatography: Development of an improved column wash step, 2008).
Regarding claim 36, Modified Sun discloses the claimed invention as discussed above in claim 23. Sun discloses the first wash solution has a pH of about 7.2 (applicant defines about as within 10%; 7.5, Table 1), and Han discloses the third wash solution has a pH of about 7.2 (7.4, Table 1), but neither Sun, Bian, Han nor FDA discloses a second solution have a pH of about 9. The solution Sun disclosed is 7.5. Sun discloses an alternative to the wash to the acetate solution is 1 M NaCl, 20 mM Tris, pH 7.5 (No. 1, Table 1).
In an analogous art, Shukla discloses a list of Protein A wash buffer for washing the column between loading and elution to minimize HCP levels (Abstract) using a list of basic solution/buffer with pH 9 such as 25 mM Tris, 100 mM NaCl, pH 9.0 (Table 1). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have make a substitution of the wash solution No. 1 of Sun with wash solution of Tris and NaCl at pH of 9 of Shukla to derive the claimed invention. One of ordinary skill in the art would have a reasonable expectation of success and expect the solution disclosed by Shukla as an acceptable alternative since both solutions comprises TRIS and NaCl at slightly and use as a second wash after loading but before elution. Furthermore, Shukla discloses moving to a higher pH for wash buffer allow for greater improve of yield and purity since at high pH the electrostatic repulsion between the antibody and Protein A is minimized (One means of accomplishing this was investigated by performing the wash under high pH conditions (>7.0). At this pH range, the electrostatic repulsion between the antibody and Protein A can be considered to be minimal. Results and Discussion, para. 7).
Claim(s) 50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Bian, FDA, Shukla, and Han.
Regarding claim 50, Sun discloses the claimed invention as discussed above in claim 1. Sun discloses the first wash solution comprises NaCl at a pH of about 7.2 (7.5 is within the 10% range, Table 1), the second wash comprises a second wash solution wherein the first component is TRIS (Post Load Flush; Table 1) and third wash comprises a third wash solution wherein the first component is acetate (1 M arginine, 20 mM sodium acetate, No. 6, Table 2) or another TRIS-NaCl solution (no. 1, Table 2). Sun does not explicitly disclose the first wash comprises a first wash solution wherein the first component is phosphate, the second wash is at a pH of about 9, and the third wash is at a pH of about 7.2 and comprises acetate and NaCl.
Regarding the deficiency of the first wash solution, at best, Sun discloses first wash solution comprises TRIS. In analogous art Bian also discloses a Protein A chromatography for CHO or NS0 cells (Abstract and para. [0043]). Bian discloses that for equilibration step a neutral buffer at pH 7-7.5 such as phosphate saline or a TRIS buffer are both comparable and applicable for such purpose (The column may first be equilibrated with a suitable equilibration buffer. This is usually achieved by flowing 3-10 column volumes (CVs) of a neutral pH buffer, such as, phosphate saline buffer, or a Tris buffer, at pH 7-7.5, through the Protein A resin. Para. [0058]).
In another analogous art such as FDA, FDA discloses preparation of 0.01 phosphate-buffered saline from a 0.1 M stock solution, the final concentration of would be 130 mM NaCl and 12 mM phosphate (converted from grams to mole based on molecular weight and divide by the volume of the solution).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have make a substitution of TRIS buffer of Sun with phosphate saline buffer of FDA to derive the claimed invention. It would have been obvious to one of ordinary skill in the art to have utilized a 7.5 pH PBS such as the one disclosed by the FDA as substitution for the TRIS buffer of Sun to derive the claimed invention. One of ordinary skill in the art would have a reasonable expectation of success as both the TRIS buffer of Sun and phosphate saline buffer of Bian are both at neutral pH of 7-7.5, and Bian discloses that both buffers are applicable for equilibration (Bian, para. [0058]), suggesting the choice of the two buffers may be a matter of availability.
Regarding the deficiency of the second wash solution, Sun discloses the wash solution comprises Tris and NaCl at a pH of 7.5 (Table 1). In an analogous art, Shukla discloses a list of Protein A wash buffer for washing the column between loading and elution to minimize HCP levels (Abstract) using a list of basic solution/buffer with pH 9 such as 25 mM Tris, 100 mM NaCl, pH 9.0 (Table 1). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have make a substitution of the wash solution No. 1 of Sun with wash solution of Tris and NaCl at pH of 9 of Shukla to derive the claimed invention. One of ordinary skill in the art would have a reasonable expectation of success and expect the solution disclosed by Shukla as an acceptable alternative since both solutions comprises TRIS and NaCl at slightly and use as a second wash after loading but before elution. Furthermore, Shukla discloses moving to a higher pH for wash buffer allow for greater improve of yield and purity since at high pH the electrostatic repulsion between the antibody and Protein A is minimized (One means of accomplishing this was investigated by performing the wash under high pH conditions (>7.0). At this pH range, the electrostatic repulsion between the antibody and Protein A can be considered to be minimal. Results and Discussion, para. 7).
Regarding the deficiency of the third wash solution, Sun disclosed an acetate and arginine solution at pH 5.0 and a 1 M NaCl, 20 mM Tris, pH 7.5 for intermediate wash (No. 6 and No. 1, Table 1). Neither Sun, Bian, Shukla nor FDA discloses a third solution have a pH of about 7.2
In an analogous art, Han discloses adding salt to Protein A wash buffer in an acetate wash solution (Table 1) can effectively improve HCP removal (Abstract), wherein the intermediate wash comprises 50 mM Tris-Acetate and 150 mM NaCl, pH 7.4 (7.4 within the 10% range of “about” as defined by the spec; Table 1, Wash 1). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have make a substitution of the wash solution No. 1 of Sun with wash solution of Tris-acetate and NaCl of Han to derive the claimed invention. One of ordinary skill in the art would have a reasonable expectation of success and expect the solution disclosed by Han as an acceptable alternative since both solutions comprises TRIS and NaCl at slightly basic pH and are used as intermediate wash buffer.
Claim(s) 51, 58, 67, 71, 73, 92, 93, 96-99 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Liu (Recovery and purification process development for monoclonal antibody production, 2010) and Li (Cell culture processes for monoclonal antibody production, 2010) as cited in previous Office Action.
Regarding claims 51, Sun discloses a method for purifying an antibody comprising
Pre-culture to produce antibody expressing cells (The antibody preparations used with methods described herein can be from a number of sources including…conditioned culture medium derived from culturing a recombinant cell line that expresses the antibody molecule; para. [0065]);
Harvesting the antibody by filtration (The term “conditioned culture medium” as used herein refers to the supernatant that is generated from the removal of cells and cellular debris by a separation method, such as centrifugation and/or microfiltration, from cell culture medium that has been exposed to host cells, which may secrete desired recombinant polypeptide(s) of interest…The term conditioned culture medium includes clarified conditioned medium, filtered conditioned medium, and conditioned cell culture medium, para. [0034]; also see para. [0065]);
Performing Protein A affinity chromatography (The invention relates to methods, in part, for isolating a product from a load fluid that contains a product, such as an antibody, and one or more impurities by passing the load fluid through a medium that binds the product; para [0006]; In specific embodiments, the medium is a Protein A chromatography column, e.g., a recombinant Protein A column; para. [0009]), comprising three washes (Wash 1, Post Strip Flush, Pre-Elution Flush, Post Load Flush, Table 1 and para. [0089]; also see rejection of claim 1) with wash solutions comprising:
a first component selected from the group consisting of TRIS (Table 1 and 2; para. [0089]-[0090]); and
a second component selected from the group consisting of NaCl and arginine(Table 1; No. 1 and 2 of Table 2; para. [0089]-[0090]);
Final formulation and final filtration (The method further comprises contacting the washed medium with an elution solution under conditions suitable for eluting the product. The eluate comprising the product may then be collected. The product may also be further purified and/or formulated for therapeutic use. Para. [0007]).
Sun does not explicitly disclose nor suggest growing antibody expressing cells in a bioreactor; and steps (e) to (i).
Regarding the limitation of growing antibody expressing cells in a bioreactor, Li discloses study of optimizing the scale-up of the monoclonal antibody production (Abstract). In one embodiment, Li discloses that cell cultures can be grow in small-scale bioreactors in order to evaluate the quality, manufacturability, and volumetric productivity by predicting performances in scale-up operation (The cell culture platform often consists of common host cell, expression vector, transfection and selection methods during cell line generation, and standard cell culture media, process control and scale up methodologies during process optimization. This approach not only enables fast process development, but also provides predictable performances in scale up, Introduction, paragraph 4; At this stage, in order to predict clone performance in large-scale production bioreactors, an enriched medium that is similar to the final production medium formulation and a similar feeding regime can be tested in shake flasks or in small-scale bioreactors. Several clone attributes should be considered and evaluated for features such as product quality, manufacturability, and volumetric productivity. Clone Selection, paragraph 2). It would have been obvious to one of ordinary skill in the art to have incorporate a step of growing the cells preculture in a microbioreactor as suggested by Li to derive the claimed invention. Growing cells in a bioreactor allows one of ordinary skill in the art to better control and optimize parameters such as temperature, gas flow rate, agitation speed for achieving high expression of culture products (Culture operating parameter optimization is required to achieve high expression of product with acceptable product quality profiles. Bioreactor Optimization and Scale Up, paragraph 1).
Regarding the limitation of step (e) to step (i), in an analogous art, Liu discloses the typical monoclonal antibody recovery process for deriving formulated bulk drug substance comprising (See Introduction, paragraph 4 and Figure 1 of Sun below):
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Furthermore, Li discloses the need for two or three subsequent chromatographic polishing steps after Protein A chromatography (Protein A chromatography follows harvest, and yields a relatively pure product that only requires removal of a small proportion of process and product related impurities. One or two additional chromatography steps are employed as polishing steps, generally incorporating cation and anion exchange chromatography. Introduction, paragraph 4). For reducing host cell proteins, Li recommends using ion exchange chromatography (both anionic and cationic depending on the charge of residual impurities) (For an antibody having a basic isoelectric point (pI), cation exchange chromatography can even be used as an initial capture step,43 but most frequently ion exchange chromatography is applied as a polishing step(s) after the Protein A step. Ion exchange chromatography is ideal for reducing high molecular weight aggregate, charge-variants, residual DNA and host cell protein, leached Protein A and viral particles. Ion exchange chromatography, paragraph 1).
Both Modified Sun (after incorporation with Liu) and Li are concerned with purifying antibodies for potential drug formulation application. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have incorporated the additional purification steps as disclosed by Li to the A chromatography step as disclosed by Sun to derive the claimed invention. One would have adhered to the common biopharmaceutical industrial standard of purifying a mAbs product and incorporate the final purified products into the formulation as taught by Li. Furthermore, it is noted that known work (the biopharmaceutical industrial standard for purification methodology taught by Li) in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable (deriving the final formulation buffer) to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, F.).
Regarding claim 58, Modified Sun discloses the claimed invention as discussed above in claim 51. Sun discloses the concentration of the first component is from about 1 mM to about 50 mM (10 mM TRIS for Post Load Flush, Pre-Elution Flush, and Post Strip Flush; Table 1; 20 mM TRIS for Wash 1, Table 2).
Regarding claim 67 and 71, Modified Sun discloses the claimed invention as discussed above in claim 51. Sun discloses the second component of the second wash solution comprises arginine (Wash 1, para. [0089] and Table 1; and No. 2 of Table 2, para. [0090]).
Regarding claim 73, Modified Sun discloses the claimed invention as discussed above in claim 51. Sun discloses the wash solution has a pH of about pH 7.5 (Table 1 and 2).
Regarding claim 92, Modified Sun discloses the claimed invention as discussed above in claim 51. Sun discloses the wash are conducted at room temperature (which is between 0 and 50 C).
Regarding claim 93, Sun discloses the claimed invention as discussed above in claim 51. Sun discloses the antibody is monoclonal, recombinant, humanized, and chimeric (para. [0041]).
Regarding claim 96, Modified Sun discloses the claimed invention as discussed above in claim 51. Sun discloses further comprises purifying the antibody (elution step, In certain embodiments of the invention, the product may be eluted from a washed medium…In another embodiment, the eluate includes an isolated product; para. [0072]-[0076]).
Regarding claim 97, Modified Sun discloses the claimed invention as discussed above in claim 96. Sun discloses the method further comprises formulating the antibody (…it will typically be desirable to further isolate and/or purify products isolated according to the present invention and formulate them for pharmaceutical use according to standard methods. Para. [0083]).
Regarding claim 98, Modified Sun discloses the claimed invention as discussed above in claim 96. Sun discloses that the purified antibody is substantially free of contaminants (In other embodiments, the method results in reduced turbidity as well as reduced impurities in the eluate that contains the product… In some cases, one or more processes are used to process the eluate, e.g., to remove contaminants or impurities that are in the eluate. Para. [0081]-[0082]). Furthermore, in method claims, it is the overall method steps that are given patentable weight not the intended result thereof because the intended result does not materially alter the overall method. In method claims, the intended result is not given patentable weight when it simply expresses the intended result of a process step positively recited (MPEP § 2111.04).
Regarding claim 99, Modified Sun discloses the claimed invention as discussed above in claim 98. Sun discloses the contaminant is host cell protein (In certain embodiments of this aspect, one or more of the impurities is a host cell protein; para. [0013].)
Claim(s) 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Liu and Li as discussed above in claim 51, and further in view of Holstein (Protein A Intermediate Wash Strategies, 2015) and Han (The adequate amount of sodium chloride in Protein A wash buffer for effective host cell protein clearance ,2019).
Regarding claim 52, Modified Sun discloses the claimed invention as discussed above in claim 51. Furthermore, Sun discloses the second wash comprises a second wash solution wherein the first component is TRIS (Post Load Flush; Table 1) and third wash comprises a third wash solution wherein the first component is acetate (1 M arginine, 20 mM sodium acetate, No. 6, Table 2). Sun does not explicitly disclose the first wash comprises a first wash solution wherein the first component is phosphate. Instead, Sun discloses first wash solution comprises TRIS.
In analogous art Bian also discloses a Protein A chromatography for CHO or NS0 cells (Abstract and para. [0043]). Bian discloses that for equilibration step a neutral buffer at pH 7-7.5 such as phosphate saline or a TRIS buffer are both comparable and applicable for such purpose (The column may first be equilibrated with a suitable equilibration buffer. This is usually achieved by flowing 3-10 column volumes (CVs) of a neutral pH buffer, such as, phosphate saline buffer, or a Tris buffer, at pH 7-7.5, through the Protein A resin. Para. [0058]).
In another analogous art such as FDA, FDA discloses preparation of 0.01 phosphate-buffered saline from a 0.1 M stock solution, the final concentration of would be 130 mM NaCl and 12 mM phosphate (converted from grams to mole based on molecular weight and divide by the volume of the solution).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have make a substitution of TRIS buffer of Sun with phosphate saline buffer of FDA to derive the claimed invention. It would have been obvious to one of ordinary skill in the art to have utilized a 7.5 pH PBS such as the one disclosed by the FDA as substitution for the TRIS buffer of Sun to derive the claimed invention. One of ordinary skill in the art would have a reasonable expectation of success as both the TRIS buffer of Sun and phosphate saline buffer of Bian are both at neutral pH of 7-7.5, and Bian discloses that both buffers are applicable for equilibration (Bian, para. [0058]), suggesting the choice of the two buffers may be a matter of availability.
Claim(s) 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Liu, Bian, FDA, and Li as discussed above in claim 52, and further in view of Holstein and Han.
Regarding claim 53, Modified Sun discloses the claimed invention as discussed above in claim 52. Bian and FDA disclose the second component of the first wash is NaCl. Neither Sun, Bian, Liu, Li, nor FDA discloses the second component of the third wash is NaCl. At best, Sun discloses the third wash solution comprises sodium acetate and arginine at pH 5.0. In an analogous art, Holstein discloses Protein A chromatography intermediate Wash Strategies (Table 1) using a solution of 100 mM sodium acetate and 500 mM NaCl at pH 5 (Figure 5-8).
In another analogous art, Han discloses adding salt to Protein A wash buffer in an acetate wash solution (Table 1) can effectively improve HCP removal (Abstract). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have make a substitution of the wash solution acetate and arginine of Sun with wash solution of acetate and NaCl of Holstein to derive the claimed invention. One of ordinary skill in the art would have a reasonable expectation of success and expect the solution disclosed by Holstein as an acceptable alternative since both solutions comprises acetate and at acidic pH of 5-5.5 and are used as intermediate wash buffer, and Han discloses adding adequate amount of NaCl to wash buffer generally improves host cell protein removal.
Claim(s) 86 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sun in view of Liu and Li as discussed above in claim 51, and further in view of Shukla.
Regarding claim 86, Modified Sun discloses the claimed invention as discussed above in claim 51. Sun discloses the first and third wash solution has a pH of about 7.2 (applicant defines about as within 10%; 7.5, Table 1), but neither Sun, Liu, nor Li discloses a second solution have a pH of about 9. Sun discloses one embodiment of the composition of the second solution is 1 M NaCl, 20 mM Tris, pH 7.5 (No. 1, Table 2).
In an analogous art, Shukla discloses a list of Protein A wash buffer for washing the column between loading and elution to minimize HCP levels (Abstract) using a list of basic solution/buffer with pH 9 such as 25 mM Tris, 100 mM NaCl, pH 9.0 (Table 1). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to have make a substitution of the wash solution No. 1 of Sun with wash solution of Tris and NaCl at pH of 9 of Shukla to derive the claimed invention. One of ordinary skill in the art would have a reasonable expectation of success and expect the solution disclosed by Shukla as an acceptable alternative since both solutions comprises TRIS and NaCl at slightly and use as a second wash after loading but before elution. Furthermore, Shukla discloses moving to a higher pH for wash buffer allow for greater improve of yield and purity since at high pH the electrostatic repulsion between the antibody and Protein A is minimized (One means of accomplishing this was investigated by performing the wash under high pH conditions (>7.0). At this pH range, the electrostatic repulsion between the antibody and Protein A can be considered to be minimal. Results and Discussion, para. 7).
Response to Arguments
Applicant’s arguments, see pages 10-14, filed 01/08/26, with respect to the rejection(s) of claim(s) 1-2, 8, 11, 14, 17, 23, 36, 42-43, 46-52, 58, 67, 71, 73, 92-93, and 96-99 under 102 and 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of an alternative embodiment of Sun.
Conclusion
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/M.H./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758