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 .
Claim Status
Claims 1, 6, 8, 12-15,17-33, 40-45, 48-49, 50-51, 54, 56-59, 68-70, 78, 82-89 are pending.
Claim 89 is amended.
Claims 2-5,7, 9-11, 16, 34-39, 46-47, 52-53, 71-77, 79-81 are canceled.
Claim 50 is withdrawn.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1,6,8,12-15, 17-33, 40-45, 48-49, 51, 54, 56-59, 68-70, 78, 82-89 in the reply filed on 03/05/2026 is acknowledged.
Applicant’s election without traverse of the following species:
Species Group 1: low pH inactivation
Species Group 2: --H
Species Group 3: SEQ ID NO: 91
Species Group 4: SEQ ID NO. 256
Species Group 5: guanidinium
Species Group 6: ion exchange chromatography
Species Group 7: sodium phosphate
in the reply filed on 03/05/2026 is acknowledged.
Claim 50 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.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 03/05/2026.
Claim Objections
Claim 8 is objected to because of the following informalities:
Claim 8 recites “a conjugate polymer loading the conjugate protein…”. This is a run on sentence and should be separated by a punction mark. Appropriate correction is required.
Claim 70 is dependent on the rejected claim 69.
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 26, 28, 45 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 26 is dependent on claim 24 and recites “the method of claim 24, wherein the antibody conjugate has the structure of Formula (I)..”. However, the preceding claim 24 does not recite “the antibody conjugate”. Therefore, the claim is indefinite. For the purpose of advancing prosecution, the Examiner is interpreting the claim as being dependent on claim 25, which recites “an antibody conjugate”.
Claim 28 is dependent on claim 24 and recites “wherein the bispecific antibody comprises anti-VEGF and anti IL-6 binding moieties”. The preceding claim 24 does not recite “the bispecific antibody”. Therefore, the claim is rendered indefinite. For the purpose of advancing prosecution, the Examiner is interpreting the claim as being dependent on claim 27, which recites “a bispecific antibody”.
Claim 45 recites “wherein the intermediate tris wash buffer comprises..”. There is a lack of antecedent basis for “the intermediate tris wash buffer” thus the claim is rendered indefinite.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
(g)(1) during the course of an interference conducted under section 135 or section 291, another inventor involved therein establishes, to the extent permitted in section 104, that before such person’s invention thereof the invention was made by such other inventor and not abandoned, suppressed, or concealed, or (2) before such person’s invention thereof, the invention was made in this country by another inventor who had not abandoned, suppressed, or concealed it. In determining priority of invention under this subsection, there shall be considered not only the respective dates of conception and reduction to practice of the invention, but also the reasonable diligence of one who was first to conceive and last to reduce to practice, from a time prior to conception by the other.
A rejection on this statutory basis (35 U.S.C. 102(g) as in force on March 15, 2013) is appropriate in an application or patent that is examined under the first to file provisions of the AIA if it also contains or contained at any time (1) a claim to an invention having an effective filing date as defined in 35 U.S.C. 100(i) that is before March 16, 2013 or (2) a specific reference under 35 U.S.C. 120, 121, or 365(c) to any patent or application that contains or contained at any time such a claim.
Claims 1, 6, 12-14, 56-59, 78, and 89 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth.
With respect to claim 1, Wyeth discloses a method of purifying a product, SMIP protein, using affinity chromatography (Protein A affinity column), (see Paragraphs 0162-0163, pg. 43). Wyeth discloses that a Protein A affinity chromatography column was equilibrated with Hepes buffered-saline and loaded with clarified conditioned media (which contains the product protein, SMIP [see paragraph 0148, pg. 39]). Wyeth discloses that the primary objectives of the Protein A affinity chromatography step is to include product capture from cell free clarified conditioned medium (see paragraph 0150, pg. 40). Wyeth discloses that the loaded resin was washed with Hepes buffer containing calcium chloride (chaotropic agent) (see paragraph 163, pg. 43). Note that the current instant application lists calcium salts as a chaotropic agent (see instant application specification, paragraph 0007).
With respect to claim 6, Wyeth discloses a method of producing a product (an anti-CD20 SMIP protein TRU-105 using a recombinant CHO cell line grown in suspension culture (see paragraph 0139, pg. 37). Wyeth discloses that various protein preparations may be used as load materials (see paragraph 0120, pg. 32) and further discloses an example where clarified cell-free conditioned medium containing TRU-015 was harvested through a disc-stacked centrifuge to yield clarified conditioned medium containing the SMIP protein (collected load fluid, protein of interest) (see paragraphs -146-0148, pg. 39) . The conditioned medium was subjected to Protein A affinity chromatography (see paragraph 0163, pg. 43). Wyeth discloses that affinity chromatography uses an absorbent such as Protein A affixed to a solid support (matrix) to chromatographically separate molecules that bind more or less tightly to the absorbent (see Paragraph 0047, pg. 11). Wyeth discloses that the loaded resin was washed with a Hepes Buffer containing calcium chloride (chaotropic agent, noet that the instant application specification, paragraph 0007 defines calcium salts as a chaotropic agent) and was followed by a wash containing low concentration of Hepes buffer and sodium chloride after which the bound product was eluted from the column with a low pH acetic acid buffer. The product pool (collected eluant) was held at low pH (see paragraph 0164, pg. 43).
With respect to claim 12-14, in addition to the disclosures of Wyeth as applied to claim 6 above, Wyeth further discloses that to minimize eluate precipitations different combinations of excipient wash (pharmaceutical excipient), elution, and neutralization conditions were screened (see paragraph 0151, pg. 40 and Figure 7 ). Wyeth discloses that a pharmaceutical composition is formulated to be compatible with the intended route of administration and can include components such as buffers and antibacterial agents (pharmaceutical excipient) (see Paragraphs 0134-0135, pg. 35-36).
With respect to claim 56-57, in addition to the disclosure of Wyeth as applied to claim 1 above, Wyeth discloses that in some embodiments, a suitable wash solution may contain a chaotropic agent (guanidinium hydrochloride). Wyeth also teaches that a suitable salt concentration may range from 0 mM to 1M (see paragraph 0096, pg. 25). Guanidinium is the free ion of guanidinium hydrochloride as evidenced by BenchChem Technical Report (published 2025, listed in Form 892).
With respect to claim 58, in addition to the disclosure of Wyeth as applied to claim 1, Wyeth discloses that the step of affinity chromatography comprises washing an affinity chromatography using a washing buffer comprising Tris (see paragraph 0010, pg. 3).
With respect to claim 59, in addition to the disclosure of Wyeth as applied to claim 58 above, Wyeth discloses that after a protein preparation is loaded, the bound column may be washed with a wash solution and the wash solution may contain 20 mM to 50 mM Tris (see Paragraphs 0094-0095, pg. 24-25).
With respect to claim 78, in addition to the disclosure of Wyeth as applied to claim 1, Wyeth discloses that in some embodiments, ion exchange chromatography is used in combination with affinity chromatography (see Paragraph 0101, pg. 26).
With respect to claim 89, Wyeth discloses that chromatography and loading can occur in a variety of buffers and that an example is sodium phosphate (see Paragraph 0130, pg. 34).
Therefore, claims 1, 6, 12-14, 56-59, 78, and 89 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010).
Claims 85-86 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Blake et al., (US Patent Application Publication US 2006/0216789 A1; published September 28, 2006), hereinafter referred to as Blake et al..
With respect to claim 85, Blake et al. disclose a method for processing a product in which a PT toxin is purified. Blake et al. disclose that PT may be purified using a peptide affinity column (the column consisting of a gel matrix (see paragraph 0070, pg. 9). The PT is absorbed onto the column, washed with buffer containing 50 mM Tris HCl pH 6.2 and the PT is eluted with 4M MgCl2 (see paragraph 0050, pg. 6). Note that in the instant application specification, paragraph 0007, magnesium salts are listed as chaotropic agents. The chaotropic salt, MgCl2, is increased from a first concentration of 0 M to a second concentration of 4M during the wash buffer step (see paragraph 0050, pg. 6). Blake et al. also disclose that the eluted PT (in 4M MgCl2) is subjected to dialysis to remove MgCl2 to give substantially pure PT (fraction comprising product of interest) (see Paragraph 0050, pg. 6).
With respect to claim 86, in addition to the disclosure of Blake et al. as applied to claim 85 above, Blake et al. disclose the concentration of the chaotropic salt (MgCl2) is 0 M at the first wash (first concentration) and then the concentration is 4M (second concentration) during elution of PT (see paragraph 0050, pg. 6).
Therefore, claims 85-86 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Blake et al., (US Patent Application Publication US 2006/0216789 A1; published September 28, 2006), hereinafter referred to as Blake et al..
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.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth, in view of Kodiak Sciences (WIPO International Publication Number WO 2017/117464 A1; published July 6, 2017), hereinafter referred to as Kodiak et al..
With respect to claim 8, Wyeth teaches a method of producing a product (an anti-CD20 SMIP protein TRU-105 using a recombinant CHO cell line grown in suspension culture (see paragraph 0139, pg. 37). Wyeth teaches that various protein (of interest) preparations may be used as load materials (see paragraph 0120, pg. 32) and further discloses an example where clarified cell-free conditioned medium containing TRU-015 was harvested through a disc-stacked centrifuge to yield clarified conditioned medium containing the SMIP protein (collected load fluid, protein of interest) (see paragraphs -146-0148, pg. 39) . The conditioned medium was subjected to Protein A affinity chromatography (see paragraph 0163, pg. 43). Wyeth teaches that affinity chromatography uses an absorbent such as Protein A affixed to a solid support (matrix) to chromatographically separate molecules that bind more or less tightly to the absorbent (see Paragraph 0047, pg. 11). Wyeth teaches that the loaded resin was washed with a Hepes Buffer containing calcium chloride (chaotropic agent, note that in the instant application specification, paragraph 0007 defines calcium salts as a chaotropic agent) and was followed by a wash containing low concentration of Hepes buffer and sodium chloride after which the bound product was eluted from the column with a low pH acetic acid buffer. The product pool (collected eluant) was held at low pH (see paragraph 0164, pg. 43).
Wyeth does not teach a conjugate protein, wherein the conjugate protein comprises an antibody bound to a conjugate polymer.
Kodiak, however, teaches a conjugate protein, wherein the conjugate protein comprises an antibody bound to a conjugate polymer (see Paragraph 0209, pg. 54). Kodiak also teaches that the conjugated protein (conjugate protein comprising an antibody bound to a conjugate polymer (paragraph 209, pg. 54), can be contacted to an affinity chromatography column for purification (to remove the conjugated protein from the unconjugated). Kodiak teaches that the affinity chromatography medium separates the conjugated protein from the free polymer and decapped protein (see Paragraph 0247, pg. 66). Furthermore, Kodiak teaches that the affinity chromatography resin comprises a recombinant Protein A (Protein A chromatography) (affinity chromatography matrix) (see Paragraph 00332, pg. 89).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application to take the conjugate protein comprising an antibody bound to a conjugate polymer taught by Kodiak and substitute it for the SMIP protein in the chromatography purification protocol taught by Wyeth. One of ordinary skill in the art would be motivated to do so because both Wyeth and Kodiak teach a protein purification protocol using Protein A affinity chromatography to purify a protein of interest. Since Kodiak teaches purification of the conjugate protein by Protein A chromatography, it would be obvious to purify the conjugate protein taught by Kodiak using the Protein A affinity chromatography protocol taught by Wyeth in order to obtain a purified protein product. One of ordinary skill in the art in protein biochemistry and protein purification would have high expectations of success since both Wyeth and Kodiak teach all the methods of the affinity chromatography protocol needed to purify the conjugate protein.
Therefore, claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010) in view of Kodiak Sciences (WIPO International Publication Number WO 2017/117464 A1; published July 6, 2017).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth, as applied to claim 12 above, and further in view of Kodiak Sciences (WIPO International Publication Number WO 2017/117464 A1; published July 6, 2017), hereinafter referred to as Kodiak et al..
The teachings of Wyeth as applied to claim 12 are taught above.
Wyeth does not teach the pharmaceutical composition is further refined for intravitreal injection.
Kodiak, however, teaches methods for preparing conjugate compositions of antibodies (see Paragraph 0091, pg. 23) that are purified by affinity chromatography (see Paragraph 0247, pg. 66) in which the chromatography resin comprises a recombinant Protein A (Protein A chromatography, affinity chromatography) (see Paragraph 0332, pg. 89). Kodiak further teaches that the antibody conjugates are used to treat patients and that the patients are treated via intravitreal injection (see paragraph 0289, pg. 78).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application, to further refine the pharmaceutical composition taught by Wyeth in order to prepare a composition for intravitreal injection as taught by Kodiak. One of ordinary skill in the art would be motivated to do so because Kodiak teaches an example of preparing a pharmaceutical composition after affinity chromatography purification and further refining it for intravitreal injection. One of ordinary skill in the art of biochemistry and protein purification would have high expectations as Wyeth and Kodiak teach all the methods needed to take the pharmaceutical composition and refine it further for intravitreal injection.
Therefore, claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth, as applied to claim 12 above, and further in view of Kodiak Sciences (WIPO International Publication Number WO 2017/117464 A1; published July 6, 2017), hereinafter referred to as Kodiak et al..
Claims 17-24 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth.
With respect to claim 17 (and claims 21-23 dependent on), Wyeth discloses a method of producing a product (an anti-CD20 SMIP protein TRU-105) using a recombinant CHO cell line grown in suspension culture (see paragraph 0139, pg. 37). Wyeth discloses that various protein preparations may be used as load materials (see paragraph 0120, pg. 32) and further discloses an example where clarified cell-free conditioned medium containing TRU-015 was harvested through a disc-stacked centrifuge to yield clarified conditioned medium containing the SMIP protein (collected load fluid, protein of interest) (see paragraphs -146-0148, pg. 39) . The conditioned medium was subjected to Protein A affinity chromatography (see paragraph 0163, pg. 43). Wyeth discloses that affinity chromatography uses an absorbent such as Protein A affixed to a solid support (matrix) to chromatographically separate molecules that bind more or less tightly to the absorbent (see Paragraph 0047, pg. 11). Wyeth teaches that the Protein A column was equilibrated with Hepes-buffered saline and loaded clarified medium. The loaded column was washed with Hepes buffer containing calcium chloride (wash containing a chaotropic salt) followed by a wash containing a low concentration of Hepes (removal of chaotropic agents). The bound product (protein of interest) was eluted from the column with a low pH acetic acid buffer) (see Paragraph 0047, pg. 11). Wyeth also teaches that the bound product was eluted from the column with a low pH acetic acid buffer and that the low pH hold was designed to inactivate enveloped virus (see Paragraph 0163, pg. 43)
Wyeth does not teach three washes after loading of the protein sample in the above example. However, in a separate embodiment , Wyeth teaches a first wash with an equilibration buffer to remove unbound product (see Paragraph 0165, pg. 43). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application, to add a first wash to the protocol of Wyeth as taught above in order to remove and collect and unbound protein of interest that did not initially bind to the affinity column. One of ordinary skill in the art would be motivated to do so, as it would be beneficial to add a first wash with equilibration buffer after loading the protein sample on the column in order to recover any unbound protein of interest after loading. One of ordinary skill in the art of protein purification, would have expectation of success as Wyeth teaches all the methods and protocols.
With respect to claim 18, in addition to the teaching of Wyeth as applied to claim 17 above, in another embodiment, Wyeth teaches the use of a first wash buffer (see Paragraph 0165, pg. 43) and that an elution buffer may contain contain 1-100 mM sodium phosphatate (see Paragraph 0123, pg. 33).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application, to have modified the Protein A affinity method of Wyeth by replacing the first wash buffer with sodium phosphate (1-100 mM) since Wyeth teaches in another embodiment that this would be a suitable wash buffer.
With respect to claim 19, in addition to the teachings of Wyeth as applied to claim 17 above, although Wyeth teaches that the first wash buffer above contains Hepes-buffered saline (NaCl), Wyeth does not specify a concentration of NaCl.
However, in another embodiment, Wyeth teaches that a suitable phosphate buffer further contains sodium chloride at a concentration of 100 mM to 2.5 M.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application, to have modified the Protein A affinity method of Wyeth by further adjusting first wash buffer with NaCl ( 100 mM -250 mM) since Wyeth teaches in another embodiment that this would be a suitable concentration range.
With respect to claim 20, in addition to the teachings above as applied to claim 19, Wyeth teaches that a suitable wash solution may contain a buffer such as 20-50 mM Tris (see Paragraph 0093, pg. 24). It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application, to have modified the Protein A affinity method of Wyeth by further adjusting the first wash buffer to comprise Tris (20-50 mM) since Wyeth teaches in another embodiment that this would be a suitable buffer and concentration range.
With respect to claim 24, in addition to the teachings of Wyeth as applied to claim 23 above, Wyeth also teaches that Protein A (affinity chromatography resin) binds to an IgG antibody (another protein of interest) (see Paragraph 0047, pg. 11). It would be obvious to one of ordinary skill in the art, to substitute an IgG-antibody for SMIP protein in the Protein A affinity chromatography protocol, since Wyeth discloses that the chromatography resin containing Protein A can bind to an IgG-antibody. One of ordinary skill in the art would be motivated to do so since Wyeth teaches the Protein A affinity chromatography resin has affinity for an IgG-antibody, and therefore would be a suitable chromatographic method for purification of an IgG-antibody using the protocol taught by Wyeth. One of ordinary skill in the art in protein purification would have high expectations of success in doing so as Wyeth teaches all the necessary methods.
Therefore, claims 17-24 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010).
Claims 29-33, 40-42, 44-45, and 82-84 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth.
With respect to claim 29, Wyeth teaches a method of producing a product. Wyeth teaches that an anti-CD20 SMIP protein TRU-105 was produced using a recombinant CHO cell line grown in suspension culture (see Paragraph 0139, pg. 37). Wyeth teaches that conditioned medium containing TRU-015 was generated in a bioreactor and that the conditioned medium from the production bioreactor was harvested through a disc-stacked centrifuge to yield a clarified conditioned medium (recovering cell culture supernatant with protein of interest) (see Paragraphs 0146-0148). Wyeth teaches a Protein A chromatography with the primary objectives being to include product capture from cell-free clarified conditioned medium and separation of TRU-015 (SMIP protein). Wyeth further teaches that the clarified cell-free conditioned medium was subjected to Protein A affinity chromatography (loading eluent onto chromatography column matrix). Wyeth teaches that the loaded resion was washed with Hepes buffer contaiing calcium chloride (chaotropic salt), followed by a wash containing a low concentration of Hepes buffer and sodium chloride. Wyeth teaches that the bound product was eluted with a low pH acetic acid buffer and that the product pool was held at low pH to inactivate enveloped viruses (see Paragraph 0163-0164).
Wyeth teaches a filter step of the protein preparation before anion exchange chromatography (see claim 36, pg. 72).
Wyeth further teaches that a TMAE HiCap (M) column (ion exchange chromatography), was loaded with the Protein A chromatography peak (containing protein of interest) to remove impurities and collect the product protein (see Paragraph 0165, pg. 43). Wyeth further teaches that a Planova 20N virus retaining filtration (VRF) step provides a significant level of viral clearance for assurance of product safety by removal of particles that may be potential viral contaminants. Wyeth teaches that a single-use Planova 20N VRF device was equilibrated with loaded with a product pool and the TRU-015 protein of interest was collected (filtration, retentate) (see paragraph 0167, pg. 44).
In the example described above, Wyeth does not teach a first wash buffer containing Tris or Sodium before running a wash buffer comprising a chaotropic salt. However, in a separate embodiment , Wyeth teaches a first wash with an equilibration buffer to remove unbound product (see Paragraph 0165, pg. 43). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application, to add a first wash to the protocol of Wyeth as taught above in order to remove and collect and unbound protein of interest that did not initially bind to the affinity column. One of ordinary skill in the art would be motivated to do so, as it would be beneficial to add a first wash with equilibration buffer after loading the protein sample on the column in order to recover any unbound protein of interest after loading. One of ordinary skill in the art of protein purification, would have expectation of success as Wyeth teaches all the methods and protocols.
With respect to claim 30, in addition to the teaching of Wyeth as applied to claim 29 above, Wyeth teaches that exemplary sources for protein preparation that are suitable for the method include bacterial cells such as Escherichia coli (animal component free cell culture) and further discloses the use of a bioreactor (see Paragraph 0143, pg. 38).
With respect to claim 31, in addition to the teaching of Wyeth as applied to claim 29 above, Wyeth teaches the harvesting of cell products from a cell culture. Wyeth teaches that the medium from the production bioreactor is harvested through a disc-stacked centrifuge to yield clarified conditioned medium (see Paragraph 0148, pg. 39).
With respect to claim 32, in addition to the teaching of Wyeth as applied to claim 31 above, Wyeth teaches that the conditioned medium (cell culture) from the production bioreactor was harvested through a disc-stacked centrifuge to yield a clarified conditioned medium to separate CHO cells and cell debris from the conditioned medium containing the SMIP protein (see Paragraph 0148, pg. 39).
With respect to claim 33, in addition to the teaching of Wyeth as applied to claim 29, Wyeth teaches that the primary objectives of the Protein A affinity chromatography step include product capture from cell-free clarified conditioned medium (eluent) (see Paragraph 0150, pg. 40).
With respect to claim 40-42, in addition to the teaching of Wyeth as applied to claim 29 above, Wyeth teaches that in some embodiments, after the protein preparation is loaded, the affinity column is washed using a wash solution ( e.g. phosphate buffer) see Paragraph 0122, pg. 33) (first wash). Wyeth also teaches that in another embodiment, the affinity column may be equilibrated with a solution containing sodium phosphate at a pH of 6.0-8.0 and also contain NaCl (see Paragraph 0093, pg. 24). Wyeth also teaches that in some embodiments, a suitable phosphate buffer contains sodium phosphate at a concentration ranging from 1 mM to 50 mM (see Paragraph 0019, pg. 6). Wyeth also teaches that in some embodiments, a suitable phosphate buffer further contains 100 mM to 2.5 M sodium chloride (See Paragraph 0019, pg. 6). One of ordinary skill in the art would find it would find this combination obvious as an alternative buffer solution as taught by Wyeth that could be applied as a first wash solution.
With respect to claim 43, in addition to the teaching of Wyeth as applied to claim 29 above, Wyeth also teaches that after a protein preparation is loaded, the bound column may be washed with a wash solution (first wash) and that suitable wash solution may contain Tris (see Paragraph 0094, pg. 24) and that a wash solution may contain 20-50 mM Tris (see Paragraph 0095, pg. 25).
With respect to claim 44, in addition to the teaching of Wyeth as applied to claim 29 above, Wyeth teaches that in some embodiments, after a protein preparation is loaded, the bound column may be washed with a wash solution (first wash). Wyeth teaches that suitable wash conditions may contain a salt (i.e. sodium chloride) and Tris. Wyeth also teaches that a suitable salt concentration (e.g. sodium chloride) may range from 0 mM to 1M (see Paragraph 96, pg. 25).
With respect to claim 45, in addition to the teaching of Wyeth as applied to claim 29 above, Wyeth teaches that a wash solution may contain 20 mM to 50 mM Tris (see Paragraph 0095, pg. 25).
With respect to claims 82-84, in addition to the teaching of Wyeth to claim 17 above, Wyeth teaches in a separate embodiment a first wash buffer after loading a protein sample onto an affinity chromatography column (see Paragraph 0165, pg. 43) and that a suitable phosphate buffer contains sodium phosphate at a concentration ranging from 1-50 mM (see Paragraph 0006, pg. 2). Wyeth also teaches that an equilibration buffer can contain 0.05 to 0.2M sodium chloride (see Paragraph 0119, pg. 32).
Therefore, 29-33, 40-42, 44-45, and 82-84 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth.
Claim 48 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth as applied to claim 29 above, and further in view of Novartis (US Patent Application Publication No: US 2012/0283416 A1; published November 8, 2012), hereinafter referred to as Novartis.
The teachings of Wyeth as applied to claim 29 are taught above.
Wyeth does not teach that the concentration of magnesium chloride in the second wash buffer is 2.8 M.
However, Wyeth teaches that the step of affinity chromatography comprises washing an affinity chromatography column with a wash buffer that contains magnesium chloride but does not specify a concentration of 2.8 M (see claim 26, pg. 71).
Novartis teaches a Protein A chromatography (affinity chromatography) washing method and teaches that the wash solutions contain a nonbuffering salt such as magnesium chloride and that the concentration of the nonbuffering can be greater than 1M (see Paragraph 0037, pg. 4).
It would have been obvious to one of ordinary skill in the art to modify the concentration of the magnesium chloride buffer in the Wyeth method to include a concentration of greater than 1M (such as 2.8 M) as Novartis teaches that the nonbuffering salt concentration can be greater than 1M. One of ordinary skill in the art would be motivated to do so as a way of optimizing the magnesium chloride concentration in the washing buffer step. One of ordinary skill in the art of protein purification would have high expectation of success in doing so as both Wyeth and Novartis teach all the necessary methods.
Therefore, claim 48 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010) as applied to claim 29 above, and further in view of Novartis (US Patent Application Publication No: US 2012/0283416 A1; published November 8, 2012).
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth, as applied to claim 29 above, in view of Lund et al. (Journal of Chromatography A, Vol. 1225, pg. 158-167, published 2012), hereinafter referred to as Lund et al..
The teachings of Wyeth as applied to claim 29 are taught above.
With respect to claim 49, Wyeth does not teach that the elution buffer contains sodium formate.
However, Lund et al. teaches that a Protein A resin affinity column that was eluted with 10 mM sodium formate (see 1st column, Paragraph 2, pg. 160). It would have been obvious to one of ordinary skill of the art before the effective filing date of the current instant application, to modify the elution buffer taught by Wyeth by incorporating 10 mM sodium formate. It would have been obvious to one of ordinary skill in the art to do so, as Lund et al. teaches a Protein A chromatography method where incorporating 10 mM sodium formate into an elution buffer served as an effective elution buffer component. One of ordinary skill in the art of protein purification would have expectations of success in doing so as both Wyeth and Lund et al. teach all the necessary methods and protocols.
Therefore, claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), as applied to claim 29 above, in view of Lund et al. (Journal of Chromatography A, Vol. 1225, pg. 158-167, published 2012).
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth, as applied to claim 1 above, and further in view of Kodiak Sciences (WIPO International Publication Number WO 2017/117464 A1; published July 6, 2017), hereinafter referred to as Kodiak et al..
The teachings of Wyeth as applied to claim 1 are taught above.
Wyeth further teaches that an antibody can be a protein of interest for purification by affinity chromatography (see Paragraph 0047, pg. 11) but does not teach that the antibody is an antibody conjugate.
However, Kodiak teaches an antibody that is an antibody conjugate (see Paragraph 0209, pg. 54) and that conjugated proteins can be purified by affinity chromatography (see Paragraph 0247, pg. 66)..
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application, to modify the method of Wyeth as taught above by substituting the antibody conjugate taught by Kodiak for the protein of interest in the Wyeth method since Wyeth teaches that the Protein A affinity chromatography can be used to purify antibodies and that Kodiak teaches that conjugated proteins such as antibodies can be purified by affinity chroamtography. One of ordinary skill in the art would be motivated to do so as the Wyeth method is a viable option for antibody purification. One of ordinary skill in the art would have high expectation of success in carrying out the substitution as Wyeth and Kodiak teach all the necessary methods and protocols.
Therefore, claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010) as applied to claim 1 above, and further in view of Kodiak Sciences (WIPO International Publication Number WO 2017/117464 A1; published July 6, 2017).
Claims 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth, as applied to claims 17-24 above, and further in view of Kodiak Sciences (WIPO International Publication Number WO 2017/117464 A1; published July 6, 2017), hereinafter referred to as Kodiak et al..
The teachings of Wyeth as applied to claims 17-24 are taught above.
With regards to claim 25, Wyeth does not teach that the antibody is further conjugated to a polymer to form an antibody conjugate. However, Kodiak teaches an antibody that is further conjugated to a polymer to form an antibody conjugate (see Paragraph 0206, pg. 53). Kodiak further teaches that conjugated proteins can be purified by affinity chromatography (see Paragraph 0247, pg. 86).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application, the substitute the antibody that is conjugated to a polymer in the method of Wyeth, since Kodiak teaches that the antibody conjugated to a polymer can be purified by affinity chromatography. One of ordinary skill in the art would be motivated to do so because of the combined teaching of Wyeth and Kodiak which teach that the antibody conjugated to a polymer can be purified by affinity chromatography and that Wyeth also teaches that Protein A affinity chromatography has affinity the Fc domain of antibodies. One of ordinary skill in the art in protein purification would have high expectation of success as Wyeth and Kodiak teach all the methods and protocols needed.
With regards to claim 26, in addition to the combined teachings of Wyeth and Kodiak as applied to claim 25, Wyeth does not teach that the antibody conjugate has the structure of formula (I):
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818
722
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wherein the curvy line indicates the point of attachment to the rest of the polymer, where X is a) -OR where R is -H, methyl, ethyl, propyl, isopropyl, b) -H, c) any halogen, including -Br, -Cl, or -I, d) -SCN, or e) -NCS; and either i) wherein n1, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different and are integers from 0 to 3000; or ii) wherein n1, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different such that the sum of n1, n2, n3, n4, n5, n6, n7, n8 and n9 is 2500 plus or minus 15%.
However, Kodiak teaches an antibody conjugate having the following structure (see Paragraph 0209, pg. 54):
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489
604
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76
208
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Wherein : each heavy chain of the ant-VEGF-A antibody is denoted by the letter H, and each light chain of the anti-VEGF-A antibody is denoted by the letter L. The polymer is bonded to the anti-VEG-A antibody through the sulfhydryl of C443 (EU numbering) which bond is depicted in one of the heavy chains; PC is: where the curvey line indicates that the point of attachment to the rest of the polymer where X=a) OR R=H, methyl, ethyl, propyl, isopropyl, b) H or c) any halide, including Br, and n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different such that the sum of n1, n2, n3, n4, n5, n6, n7, n8, and n9 is 2500 plus or minus 15%.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application, to substitute the antibody that is conjugated to a polymer and having the structure as just described above by the teachings of Kodiak in the method of Wyeth, since Kodiak teaches that the antibody conjugated to a polymer can be purified by affinity chromatography (see Paragraph 0247, pg. 66). One of ordinary skill in the art would be motivated to do so because of the combined teaching of Wyeth and Kodiak which teach that the antibody conjugated to a polymer can be purified by affinity chromatography and that Wyeth also teaches that Protein A affinity chromatography has affinity the Fc domain of antibodies. One of ordinary skill in the art in protein purification would have high expectation of success as Wyeth and Kodiak teach all the methods and protocols needed.
Therefore, claims 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010) as applied to claims 17-24 above, and further in view of Kodiak Sciences (WIPO International Publication Number WO 2017/117464 A1; published July 6, 2017).
Claim 25, and 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth, as applied to claim 17-24 above, and further in view Genentech (US Patent Application Publication No: US 2019/0100581 A1; published April 4, 2019), hereinafter referred to as Genentech.
The teachings of Wyeth as applied to claim 17-24 are taught above.
With respect to claim 25, Wyeth also does not teach that the antibody is further conjugated to a polymer to form an antibody conjugate. However, Genentech teaches an antibody that is further conjugated to a polymer to form an antibody conjugate (an antibody conjugate comprising a hydrophilic polymer covalently attached to the antibody (see Paragraph 0045, pg. 6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application, the substitute the antibody that is conjugated to a polymer in the method of Wyeth, since Genentech teaches that the antibody conjugated to a polymer can be purified by affinity chromatography. One of ordinary skill in the art would be motivated to do so because of the combined teaching of Wyeth and Genentech which teach that the antibody conjugated to a polymer can be purified by affinity chromatography and that Wyeth also teaches that Protein A affinity chromatography has affinity the Fc domain of antibodies. One of ordinary skill in the art in protein purification would have high expectation of success as Wyeth and Genentech teach all the methods and protocols needed.
With respect to claim 27, in addition to the teachings of Wyeth and Genentech as applied to claim 25, Wyeth does not teach an antibody conjugate comprises a bispecific antibody.
However, Genentech teaches that the antibody conjugate (an antibody conjugate comprising a hydrophilic polymer covalently bound to the antibody) (see Paragraph 0045, pg. ) is a bispecific anti-VEGF/anti-IL-6 bispecific antibody (see Paragraph 303, pg. 34).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application to have modified the Wyeth method by substituting the antibody with the bispecific antibody taught by Genentech. One of ordinary skill in the art would be motivated to do so because both Wyeth and Genentech teach methods of purifying antibodies by affinity chromatography. The modification of Wyeth’s method by substituting the bispecific antibody taught by Genentech would simply be a substitution of the protein of interest as Wyeth teaches that Protein A affinity chromatography can be used to purify antibodies by binding to an Fc portion of an IgG antibody, rather than the general properties of the molecule (see paragraph 0047, pg. 11). One of ordinary skill in the art of protein purification would have high expectation of success as both Wyeth and Genentech teach all the necessary methods and protocols needed to perform the purification.
With respect to claim 28, in addition to the teachings of Wyeth and Genentech as applied to claim 27 above, Wyeth does not teach a bispecific antibody that comprises anti-VEGF and IL-6 binding moieties.
However, Genentech teaches a bispecific antibody that comprises anti-VEGF and anti-IL-6 binding moieties (see Paragraph 0303, pg. 34).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application to have modified the Wyeth method by substituting the antibody with the bispecific antibody taught by Genentech. One of ordinary skill in the art would be motivated to do so because both Wyeth and Genentech teach methods of purifying antibodies by affinity chromatography. The modification of Wyeth’s method by substituting the bispecific antibody taught by Genentech would simply be a substitution of the protein of interest as Wyeth teaches that Protein A affinity chromatography can be used to purify antibodies by binding to an Fc portion of an IgG antibody, rather than the general properties of the molecule (see paragraph 0047, pg. 11). One of ordinary skill in the art of protein purification would have high expectation of success as both Wyeth and Genentech teach all the necessary methods and protocols needed to perform the purification.
Therefore, claims 25 and 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010) as applied to claim 17-24 above, and further in view Genentech (US Patent Application Publication No: US 2019/0100581 A1; published April 4, 2019).
Claim 51 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth, as applied to claim 1 above, and further in view Genentech (US Patent Application Publication No: US 2019/0100581 A1; published April 4, 2019), hereinafter referred to as Genentech.
The teachings of Wyeth as applied to claim 1 are taught above.
Wyeth does not teach a bispecific antibody but does teach that the Protein A affinity chromatography column binds to an IgG antibody, therefore an antibody can be a protein of interest for purification by affinity chromatography (see Paragraph 047, pg. 11 and Paragraph 0163, pg. 43).
Genentech teaches a bispecific antibody that is a bispecific anti-VEGF/anti-IL-6 antibody (see Paragraph 0303, pg. 34).
It would have been obvious to one of ordinary skill in the art to modify the method of Wyeth by substituting the protein of interest (antibody) for purification with the bispecific antibody taught by Genentech. One of ordinary skill in the art would be motivated to do so because Wyeth teaches that the affinity chromatography method can be used to purify antibodies. One of ordinary skill in the art of protein purification would have high expectations carrying out the substitution as Wyeth and Genentech teach all the necessary methods and protocols.
Therefore, claim 51 is rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010) as applied to claim 1 above, and further in view Genentech (US Patent Application Publication No: US 2019/0100581 A1; published April 4, 2019).
Claims 68-69 are rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth, as applied to claims 17-24 above, and further in view of Wyeth and Kodiak Sciences (WIPO International Publication Number WO 2017/117464A1, hereinafter referred to as (Wyeth/Kodiak) as applied to claim 25 above and further in view of Kodiak (US Patent Application Publication No: US 2019/0270806 A1; published Sep. 5, 2019), hereinafter referred to as Kodiak 2019.
The teachings of Wyeth as applied to claims 17-24 and Wyeth and Kodiak as applied to claim 25 are taught above.
With regards to claim 68, the combined teachings of Wyeth/Kodiak do not teach wherein the antibody conjugated to a polymer has the structure of Formula (I).
However, Kodiak 2019 teaches wherein the antibody has the structure of Formula (I) (meets limitations of Formula I as recited in instant application claim), as shown: an antibody conjugate formula in paragraph 0335, pg. 36. (see Figure 2K below from Kodiak 2019).
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991
1282
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415
1294
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Kodiak 2019 further teaches that the meleimido group having the structure of (see paragraph 0204, pg. 15) :
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144
272
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which upon reaction with a sulfhydryl (e.g. a thio alkyl group) froms an -S-meleimod group having the structure (see paragraph 0205, pg. 15):
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194
317
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Kodiak 2019 also teaches that in some embodiments, the heavy chain constant domain further comprises a cysteine residue introduced by recombinant DNA technology and that in some embodiments, the cysteine residue is selected from the group of L443C (EU numbering). Kodiak 2019 teaches that in some embodiments, the cysteine added by direct mutagenesis for subsequent polymer attachment is L443C and that a conjugate consists essentially of molecules each comprising one molecule of IL-6 antagonist antibody and/or IL-6 Ab VEGF Trap conjugated to one molecule of polymer (see paragraph 0288, pg. 30).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application to have modified the teachings of Wyeth/Kodiak by substituting the protein of interest that is purified by Protein A affinity chromatography with the antibody that is further conjugated to a polymer to form an antibody conjugate having the structure of Formula I as taught by Kodiak 2019. One of ordinary skill in the art would be motivated to do so because both Wyeth/Kodiak and Kodiak 2019 teach methods of purifying antibodies by affinity chromatography. The modification of the Wyeth/Kodiak teachings by substituting the antibody conjugated to a polymer with Formula I taught by Kodiak 2019 would simply be a substitution of the protein of interest as Wyeth teaches that Protein A affinity chromatography can be used to purify antibodies by binding to an Fc portion of an IgG antibody, rather than the general properties of the molecule (see paragraph 0047, pg. 11). One of ordinary skill in the art of protein purification would have high expectation of success as both Wyeth/Kodiak and Kodiak 2019 teach all the necessary methods and protocols needed to perform the purification.
With regards to claim 69, in addition to the combined teachings of Wyeth/Kodiak and Kodiak 2019 as applied to claim 68 above, Wyeth/Kodiak do not teach that wherein the antibody conjugate comprises an anti-VEGF antibody conjugate comprising an anti-VEGF-A light chain and an anti-VEGF-A heavy chain, wherein the anti-VEGF-A antibody heavy chain comprises CDRH1: that is a CDRH1 in SEQ ID NO: 172 , CDRH2: that is a CDRH2 in SEQ ID NO: 173 , and CDRH3: that is a CDRH3 in SEQ ID NO: 174, and the anti-VEGF-A antibody light chain comprises CDRL1: that is a CDRL1 in SEQ ID NO: 199 , CDRL2: that is a CDRL2 in SEQ ID NO: 200, and CDRL3: that is a CDRL3 in SEQ ID NO: 201 .
However, Kodiak 2019 teaches wherein the anti-VEGF-A (the antibody is IL-6 Ab VEGF Trap fusion protein, VEGF trap component binds tightly to VEGF-A (see paragraph 0334-0339, and 0576) light chain and an anti-VEGF-a heavy chain, an isolated antagonist IL-6 antibody comprising: a heavy chain variable region (VH) comprising 3 complementarity determining regions: VH (CDRl ), VH CDR2, and VH CDR3 having an ammino acid sequence from the CDRs listed in SEQ ID NO: 256; and a light chain variable region (VL) comprising a VL CDRl, VL CDR2, and VL CDR3 having an amino acid sequence selected from the group of CDRs listed in SEQ ID NO: 91-93.
The full sequence of SEQ ID NO. 256 is listed in Table 1A of Kodiak 2019:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSPFAMHWVRQAPGKGLEWVAKISPGGSWTYYSDTVTDRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCARQAWGYYALDIWGQGTLVTVSS
Kodiak 2019 teaches that the CDRs are underlined in the Anti-IL-6 heavy chain variable region sequence shown above. (see Table 1A, pg. 19).
Alignment with SEQ ID NO. 256 of Table 1A (Kodiak 2019) and SEQ ID NO. 172 of instant application. CDRH1
Query Match 100.0%; Score 30; DB 1; Length 119;
Best Local Similarity 100.0%;
Matches 5; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 PFAMH 5
|||||
Db 31 PFAMH 35
Alignment with SEQ ID 256 of Table 1A (Kodiak 2019) and SEQ ID NO. 172 of instant application. CDRH2
Alignment with SEQ ID 256 and SEQ ID NO. 172
Query Match 100.0%; Score 96; DB 1; Length 119;
Best Local Similarity 100.0%;
Matches 17; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 KISPGGSWTYYSDTVTD 17
|||||||||||||||||
Db 50 KISPGGSWTYYSDTVTD 66
Alignment with SEQ ID 256 of Table 1A (Kodiak 2019) and SEQ ID NO. 172 of instant application. CDRH3
Query Match 100.0%; Score 96; DB 1; Length 119;
Best Local Similarity 100.0%;
Matches 17; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 KISPGGSWTYYSDTVTD 17
|||||||||||||||||
Db 50 KISPGGSWTYYSDTVTD 66
The full sequence of SEQ ID NO. 91 is listed in Table 1B of Kodiak 2019:
DIQLTQSPSSLSASVGDRVTITCSASISVSYLYWYQQKPGKAPKLLIYDDSSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWSGYPYTFGQGTKVEIK
Kodiak 2019 teaches that the CDRs are underlined in the Anti-IL-6 light chain variable region sequences (see Table 1B, pg. 19).
Alignment of SEQ ID NO. 91 of the Anti-IL-6 heavy chain (Table 1B) with SEQ ID NO. 199 of instant application. CDLR1
Query Match 100.0%; Score 46; DB 1; Length 106;
Best Local Similarity 100.0%;
Matches 10; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SASISVSYLY 10
||||||||||
Db 24 SASISVSYLY 33
Alignment of SEQ ID NO. 91 of the Anti-IL-6 heavy chain (Table 1B) with SEQ ID NO. 200 of instant application. CDLR2
Query Match 100.0%; Score 32; DB 1; Length 106;
Best Local Similarity 100.0%;
Matches 7; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DDSSLAS 7
|||||||
Db 49 DDSSLAS 55
Alignment of SEQ ID NO. 91 of the Anti-IL-6 heavy chain (Table 1B) with SEQ ID NO: 201 of instant application. CDLR3
Query Match 100.0%; Score 57; DB 1; Length 106;
Best Local Similarity 100.0%;
Matches 9; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QQWSGYPYT 9
|||||||||
Db 88 QQWSGYPYT 96
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application to have modified the teachings of Wyeth/Kodiak by substituting an antibody that is further conjugated to a polymer to form an antibody conjugate having the structure of Formula I and comprising a heavy chain variable region comprising 3 complementary determining regions: VH CDR1, VH CDR2, and VH CDR3 haivng an amino acid sequence from the CDRs listed in SEQ ID NO: 256 and a light chain variable region comprising a VL CDR1, VLCD2, and VL CDR3 having an amino acid sequence selected from the group of CDRs listed in SEQ ID NO: 91-93, as taught by Kodiak 2019, as the protein of interest to be purified by Protein A affinity chromatography. One of ordinary skill in the art would be motivated to do so since because both Wyeth/Kodiak and Kodiak 2019 teach methods of purifying antibodies by affinity chromatography. The modification of Wyeth/Kodiak’s teachings by substituting the antibody conjugated to a polymer taught by Kodiak 2019 would simply be a substitution of the protein of interest as Wyeth teaches that Protein A affinity chromatography can be used to purify antibodies by binding to an Fc portion of an IgG antibody, rather than the general properties of the molecule (see paragraph 0047, pg. 11). One of ordinary skill in the art of protein purification would have high expectation of success as both Wyeth/Kodiak and Kodiak 2019 teach all the necessary methods and protocols needed to perform the purification.
Therefore, claims 68-69 are rejected under 35 U.S.C. 103 as being unpatentable over Wyeth (WIPO International Publication Number WO 2010/147686 A2; published December 23, 2010), hereinafter referred to as Wyeth, as applied to claims 17-24 above, and further in view of Wyeth and Kodiak Sciences (WIPO International Publication Number WO 2017/117464A1, hereinafter referred to as (Wyeth/Kodiak) as applied to claim 25 above and further in view of Kodiak (US Patent Application Publication No: US 2019/0270806 A1; published Sep. 5, 2019), hereinafter referred to as Kodiak 2019.
Claims 87-88 are rejected under 35 U.S.C. 103 as being unpatentable over Blake et al., (US Patent Application Publication US 2006/0216789 A1; published September 28, 2006), hereinafter referred to as Blake et al., as applied to claim 85 above, and further in view of Holstein et al. (BioProcess International, Vendor Voice, published February 2015), hereinafter referred to as Holstein et al..
The teachings of Blake et al. as applied to claim 85 are taught above.
With respect to claim 87-88, Blake et al. do not teach that the chaotropic salt is guanidinium.
However, Holstein et al. teach Protein A affinity chromatography wash strategies where the concentration of guanidine Hcl is increased from 0M-6M. Guanidinium ion is the free ion of guanidinium HCl. Guanidinium is the free ion of guanidinium hydrochloride as evidenced by BenchChem Technical Report (published 2025, listed in Form 892).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application, to substitute the chaotropic salt, guanidium, for MgCl2 in the method of Blake et al. since Holstein et al. teach its use in Protein A affinity chromatography One of ordinary skill in the art would be motivated to do so, as Holstein demonstrates is efficacy as a component in Protein A affinity chromatography washes. One of ordinary skill in the art of protein purification would have expectation of high success in doing so as Blake et al. and Holstein et al. teach all the necessary methods and protocols.
Therefore, claims 87-88 are rejected under 35 U.S.C. 103 as being unpatentable over Blake et al., (US Patent Application Publication US 2006/0216789 A1; published September 28, 2006), hereinafter referred to as Blake et al., as applied to claim 85 above, and further in view of Holstein et al. (BioProcess International, Vendor Voice, published February 2015), hereinafter referred to as Holstein et al..
Conclusion
No claims are allowed.
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/GEORGE THEMISTOCLIS LOUNTOS/ Examiner, Art Unit 1652
/RICHARD G HUTSON/ Primary Examiner, Art Unit 1652
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