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 504-520 are pending and under examination.
Claim Objections
Claims 512 and 513 are objected to because of the following informalities: Claim 512, which is dependent on claim 504, discloses a second eluate. Similarly, 513 discloses a third eluate. Claim 504 does not provide for a first eluate and thus the use of the terms “second eluate” and “third eluate” of claims 512 and 513 are objected to.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
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.
Claims 504 and 518 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Chang (US2020/0216544A1, published 07/09/2020, effectively filed 08/16/2017).
The disclosure of Chang is directed to multi-specific binding proteins that bind NKG2D, CD16 and the tumor-associated antigen EGFR (see Abstract).
Regarding claim 504, pertaining to a method of purifying a multi-specific protein comprising one or more disclosed purification steps and wherein the multi-specific binding protein comprises a first antigen binding site that binds NKG2D, a second antigen-binding site that binds EGFR, and an antibody Fc domain sufficient to bind CD16, Chang discloses the multi-specific protein of the instant invention (Pg. 38, claim 1) and teaches the multi-specific proteins of the disclosure can be isolated and purified using methods known in the art including mixed-mode chromatography ([0215], Lines 3-9).
Regarding claim 518, wherein: (a) the first antigen-binding site comprises a Fab comprising a VH comprising SEQ ID NOs: 81, 82, and 112, respectively, and a VL comprising SEQ ID NOs: 86, 77, and 87, respectively; and (b) the second antigen-binding site comprises an scFv comprising: a VH comprising SEQ ID NOs: 136, 157, and 138, respectively, and a VL comprising SEQ ID NOs: 140, 141, and 151, respectively, Chang discloses both NKG2D and EGFR binding domains. The alignments are shown below:
Instant NKG2D-binding domain
SEQ ID NO: 81 SYSMN
SEQ ID NO:82 SISSSSSYIYYADSVKG
SEQ ID NO: 112 GAPXGAAAGWFDP
X can be M, L, I, V, Q, or F
SEQ ID NO: 86 RASQGISSWLA
SEQ ID NO: 77 AASSLQS
SEQ ID NO: 87 QQGVSFPRT
Chang, Pg. 24
PNG
media_image1.png
534
559
media_image1.png
Greyscale
PNG
media_image2.png
374
541
media_image2.png
Greyscale
Instant EGFR-binding domain
SEQ ID NO: 136 GGSVSSGDYYWT
SEQ ID NO: 157 HIYYSGNTNYNPXLKS
SEQ ID NO: 138 DRVTGAFDI
X can be R or S
SEQ ID NO: 140 QASQDISNYLN
SEQ ID NO:141 LLIYDASNLET
SEQ ID NO: 151 QHFRHLPLA
Chang, Pg. 17 Table 2
PNG
media_image5.png
288
909
media_image5.png
Greyscale
Claim Rejections - 35 USC § 103
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.
Claims 504-512 and 518 are rejected under 35 U.S.C. 103 as being unpatentable over Chang (US2020/0216544A1) as applied to claims 504 and 518 above, and further in view of Sanaie (US2018/0265543A1, published 09/20/2018).
As disclosed in the 35 U.S.C. 102 rejection above, Chang discloses multi-specific binding proteins that bind NKG2D, CD16 and tumor associated antigen EGFR. Chang teaches the multi-specific proteins of the disclosure can be isolated and purified using methods known in the art including mixed-mode chromatography ([0215], Lines 3-9).
The disclosure of Chang does not teach: (1) the protein A affinity purification step comprising binding the multi-specific binding protein to a protein A resin, eluting at a pH of about 3.7, and the pH of the eluate about 4.3 (claims 505-508), (2) low pH viral inactivation by addition of acetic acid to a pH of about 3.6 and incubation for 30-60 minutes (claims 509-511), or (3) that the mix-mode anion exchange chromatography step comprises flowing the viral inactivation mixture through an anion exchange column (claim 512).
These deficiencies are taught by Sanaie.
The disclosure of Sanaie is directed to methods of producing, processing or purifying antibodies (see Abstract).
Regarding claims 505 and 506, wherein the protein A affinity purification step comprises (a) binding the multi-specific binding protein to a protein A resin; and (b) eluting the bound multi-specific binding protein at a pH of 3.5-3.8, thereby producing a first eluate (claim 505) specifically wherein the protein is eluted at a pH of about 3.7 (claim 506), Sanaie teaches a method for purifying an antibody comprising loading a mixture comprising the antibody onto protein A chromatography and eluting with an elution buffer (Pg. 50, claim 1), wherein the elution buffer is at a pH of 2.5 to 3.5 (Pg. 50, claim 6).
Regarding claims 507 and 508, wherein the pH of the first eluate is 4.0-4.6 (claim 507), specifically the pH of the first eluate is about 4.3 (claim 508), Sanaie teaches the pH of the protein A purified antibody may be adjusted to a pH of about 4.0 to 9.0 ([0092], Lines 1-6).
Regarding claims 509 and 510, wherein the low pH viral inactivation step comprises: (a) addition of an amount of acetic acid to the first eluate sufficient to achieve a pH of 3.5-3.7, thereby producing the viral inactivation reaction mixture; (b) incubation of the viral inactivation reaction mixture for 30-60 minutes (claim 509), specifically wherein the pH of the low viral pH inactivation mixture is about 3.6 (claim 510), Sanaie teaches the method further comprises viral inactivation (Pg. 50, claim 9), wherein the viral inactivation is conducted at a pH below 4.0 for at least 30 minutes (Pg. 50, claim 10).
Regarding claim 511, wherein the method comprises addition of an amount of Tris sufficient to bring the pH of the low pH viral inactivation reaction mixture to a pH of 6.3-6.5 following the incubation, Sanaie teaches adjusting the pH after viral inactivation to a pH of about 5.5 to 6.6 using a Tris base ([0092], Lines 1-8).
Regarding claim 512, wherein the mix-mode anion exchange chromatography step comprises flowing the viral inactivation reaction mixture through an anion exchange column, thereby producing a second eluate, Sanaie teaches the method for purifying further comprises a mixed-mode chromatography (Pg. 50, claim 11) and the mixed-mode chromatography matrix used in the disclosure is, for example, a chromatography matrix consisting of a carrier with a multimodal ligand immobilized thereon, the ligand comprising one or more anion or cation exchange groups ([0095], Lines 1-5).
It would have been obvious to one having ordinary skill in the art to modify the method of Chang using the conventional antibody purification methods of Sanaie resulting in: (1) protein A affinity purification comprising binding the multi-specific binding protein to a protein A resin, eluting at a pH of about 3.7, the pH of the eluate is about 4.3 (claims 505-508), (2) low pH viral inactivation by addition of acetic acid to a pH of about 3.6 and incubation for 30-60 minutes (claims 509-511), and (3) mix-mode anion exchange chromatography step comprising flowing the viral inactivation mixture through an anion exchange column (claim 512). One would have been motivated to do so because Sanaie provides validation of these standard purification methods. There would be an expectation of success in using the methods of Sanaie in the method of Chang because Sanaie teaches purification procedures readily adaptable to Chang’s multi-specific binding molecules.
Claims 504-513 and 518 are rejected under 35 U.S.C. 103 as being unpatentable over Chang (US2020/0216544A1) and Sanaie (US2018/0265543A1) as applied to claims 504-512 and 518 above, and further in view of Chen (J Chromatogr A. 2010 Jan 8;1217(2):216-24).
The combined teachings of Chang and Sanaie teach multi-specific binding proteins that bind NKG2D, CD16 and tumor-associated antigen EGFR and conventional methods of purifying said proteins.
The combined teaches of Chang and Sanaie do not teach wherein the mixed-mode chromatography step comprises flowing the second eluate through a ceramic hydroxyapatite (CHT), type I column.
These deficiencies are taught by Chen.
The disclosure of Chen is directed to the comparison of three mixed-mode resins for antibody purification (see Abstract).
Regarding claim 513, wherein the mixed-mode chromatography step comprises: (a) flowing the second eluate through a ceramic hydroxyapatite (CHT), type I column; and (b) eluting the multi-specific binding protein from the CHT column in a buffer comprising about 200 mM sodium chloride, thereby producing a third eluate (claim 513), Chen teaches use of the mixed-mode resin CHT Type I (Pg. 221, Left column, Paragraph 2 and 3) and elution with a sodium chloride salt gradient. Chen concludes that in the study of ceramic hydroxyapatite, CHT Type I was found to be a powerful tool for impurity removal, including aggregates (Pg. 223, Right column, Lines 2-4).
It would have been obvious to one having ordinary skill in the art to use a CHT Type I resin as taught by Chen in the mixed-mode chromatography method of Chang and Sanaie. One would have been motivated to do so because Chen teaches CHT Type I resin is a powerful tool for purification and removal of aggregates. There would be an expectation of success in using CHT Type I resin in the mixed mode chromatography methods of Chang and Sanaie because Chen provides evidence of successful use of the resin in antibody purification and the methods can be readily applied to purification of the multi-specific protein of Chang.
Claims 504, and 514-518 are rejected under 35 U.S.C. 103 as being unpatentable over Chang (US2020/0216544A1) as applied to claims 504 and 518 above, and further in view of Correia (US2010/0172862A1, published 07/08/2010).
As disclosed in the 35 U.S.C. 102 rejection above, Chang discloses multi-specific binding proteins that bind NKG2D, CD16 and tumor associated antigen EGFR. The disclosure of Chang provides a formulation including the protein of the disclosure with sodium citrate and polysorbate 80 ([0239)].
The disclosure of Chang does not teach a buffer exchange step that provides the specific formulation of claims 514-517, specifically, a final buffer concentration of about 20 mM citrate, about 6% (w/v) mannitol, and about 0.01% (w/v) polysorbate 80, at about pH 6.5 (claims 514 and 515) and concentration of the multi-specific binding protein about 50 mg/mL following the buffer exchange step (claims 516 and 517).
These deficiencies are taught by Correia.
The disclosure of Correia is directed to compositions and methods for inhibiting fractionation of immunoglobulins (see abstract).
Regarding claims 514 to 515, wherein the method of claim 504 further comprises a buffer exchange step of the multi-specific binding protein to achieve a final buffer concentration of 15 mM to 25 mM citrate, 4% to 8% (w/v) mannitol, and 0.005% to 0.05% (w/v) polysorbate 80, at pH 6.2 to 6.8 (claim 514), specifically wherein the method further comprises a buffer exchange step of the multi-specific binding protein to achieve a final buffer concentration of about 20 mM citrate, about 6% (w/v) mannitol, and about 0.01% (w/v) polysorbate 80, at about pH 6.5, Correia claim 52 teaches the excipients of the formulation comprise about 1 to about 30 mM citrate, 1 to 60 mg/ml mannitol (6% w/v), about 0.001% to about 0.5% (w/v) polysorbate 80, claim 67 teaches the pH is 5 to 7 (Pgs. 47-48).
Regarding claims 516 and 517, wherein the concentration of the multi-specific protein of claim 514 is 1 mg/mL to 125 mg/mL following the buffer exchange step (claim 516), specifically wherein the concentration of the multi-specific binding protein is about 50 mg/mL (claim 517), Correia teaches the molecule of the disclosure is an immunoglobulin (Pg. 46, claim 26) and the molecule is present in a concentration range of about 1 mg/ml to about 300 mg/mL (Pg. 46, claim 22).
It would have been obvious to one having ordinary skill in the art to modify the method of Chang by performing a buffer exchange to achieve a final buffer composition as disclosed by Correia. One would have been motivated to do so because Correia provides evidence that a formulation comprising the disclosed excipients provides for long term stability of the protein (see Example 9.12, Pg. 41). There would be an expectation of success in formulating the multi-specific protein of Chang with the formulation of Correia because Correia provides a composition with well-characterized excipients performing their known function within the formulation for the long-term stabilization of proteins.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Application No. 18/003,308
Claims 504-512 and 518-520 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10-12, 17, 24, 30-31, 33, 43, 54, 56-58, 60, 64, 66, 69-72, and 78 of copending Application No. 18/003,308 in view of Sanaie (US2018/0265543A1).
Regarding instant claims 504-512, pertaining to method for purifying the instant disclosed multi-specific protein, ‘308 claim 1 discloses a protein comprising a first antigen-binding site that binds NKG2D; a second antigen-binding site that binds EGFR; and an antibody Fc domain or a portion thereof sufficient to bind CD16. ‘308 claim 78 discloses the protein is a purified protein.
Regarding instant claims 518-520, pertaining to the sequences of the binding domains of the multi-specific protein, ‘308 discloses SEQ ID NOs: 167, 164, and 165, identical to instant SEQ ID NOs: 167, 164, and 165 of instant claim 520. SEQ ID NOs: 167, 164, and 165 comprise all of the instantly claimed CDRs.
‘308 does not teach the specific purification methods disclosed in instant claims 504-512.
These deficiencies are taught by Sanaie as described in the 35 U.S.C. 103 rejection above.
It would have been obvious to one having ordinary skill in the art to modify the method of ‘308 using the conventional antibody purification methods of Sanaie resulting in: (1) protein A affinity purification comprising binding the multi-specific binding protein to a protein A resin, eluting at a pH of about 3.7, the pH of the eluate is about 4.3 (claims 505-508), (2) low pH viral inactivation by addition of acetic acid to a pH of about 3.6 and incubation for 30-60 minutes (claims 509-511), and (3) mix-mode anion exchange chromatography step comprising flowing the viral inactivation mixture through an anion exchange column (claim 512). One would have been motivated to do so because Sanaie provides validation of these standard purification methods. There would be an expectation of success in using the methods of Sanaie with the multi-specific protein of ‘308 because Sanaie teaches purification procedures readily adaptable to the multi-specific binding molecule of ‘308.
This is a provisional nonstatutory double patenting rejection.
Claims 504-513 and 518-520 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10-12, 17, 24, 30-31, 33, 43, 54, 56-58, 60, 64, 66, 69-72, and 78 of copending Application No. 18/003,308 in view of Sanaie (US2018/0265543A1) as applied to claims 504-512 and 518-520 above and further in view of Chen (J Chromatogr A. 2010 Jan 8;1217(2):216-24).
The combined teachings of ‘308 and Sanaie teach methods for purifying a protein comprising a first antigen-binding site that binds NKG2D; a second antigen-binding site that binds EGFR; and an antibody Fc domain or a portion thereof sufficient to bind CD16. ‘308 claim 78 discloses the protein is a purified protein and ‘308 claim 69 teaches a formulation comprising the protein and a pharmaceutically acceptable carrier.
The combined teachings of ‘308 and Sanaie do not teach wherein the mixed-mode chromatography step comprises flowing the second eluate through a ceramic hydroxyapatite (CHT), type I column.
These deficiencies are taught by Chen.
The disclosure of Chen is directed to the comparison of three mixed-mode resins for antibody purification (see Abstract).
Regarding instant claim 513, wherein the mixed-mode chromatography step comprises: (a) flowing the second eluate through a ceramic hydroxyapatite (CHT), type I column; and (b) eluting the multi-specific binding protein from the CHT column in a buffer comprising about 200 mM sodium chloride, thereby producing a third eluate (claim 513), Chen teaches use of the mixed-mode resin CHT Type I (Pg. 221, Left column, Paragraph 2 and 3) and elution with a sodium chloride salt gradient. Chen concludes that in the study of ceramic hydroxyapatite, CHT Type I was found to be a powerful tool for impurity removal, including aggregates (Pg. 223, Right column, Lines 2-4).
It would have been obvious to one having ordinary skill in the art to use a CHT Type I resin as taught by Chen in the mixed-mode chromatography method of ‘308 and Sanaie. One would have been motivated to do so because Chen teaches CHT Type I resin is a powerful tool for purification and removal of aggregates. There would be an expectation of success in using CHT Type I resin in the mixed mode chromatography methods of ‘308 and Sanaie because Chen provides evidence of successful use of the resin in antibody purification and the methods can be readily applied to purification of the multi-specific protein of ‘308.
This is a provisional nonstatutory double patenting rejection.
Claims 504-513 and 518-520 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10-12, 17, 24, 30-31, 33, 43, 54, 56-58, 60, 64, 66, 69-72, and 78 of copending Application No. 18/003,308 in view of Sanaie (US2018/0265543A1) as applied to claims 504-512 and 518-520 above and further in view of Correia (US2010/0172862A1).
The combined teachings of ‘308 and Sanaie teach methods for purifying a protein comprising a first antigen-binding site that binds NKG2D; a second antigen-binding site that binds EGFR; and an antibody Fc domain or a portion thereof sufficient to bind CD16. ‘308 claim 78 discloses the protein is a purified protein.
The combined teachings of ‘308 and Sanaie do not teach a buffer exchange step that provides the specific formulation of claims 514-517, specifically, a final buffer concentration of about 20 mM citrate, about 6% (w/v) mannitol, and about 0.01% (w/v) polysorbate 80, at about pH 6.5 (claims 514 and 515) and concentration of the multi-specific binding protein about 50 mg/mL following the buffer exchange step (claims 516 and 517).
These deficiencies are taught by Correia.
The disclosure of Correia is directed to compositions and methods for inhibiting fractionation of immunoglobulins (see abstract).
Regarding instant claims 514 to 515, wherein the method of claim 504 further comprises a buffer exchange step of the multi-specific binding protein to achieve a final buffer concentration of 15 mM to 25 mM citrate, 4% to 8% (w/v) mannitol, and 0.005% to 0.05% (w/v) polysorbate 80, at pH 6.2 to 6.8 (claim 514), specifically wherein the method further comprises a buffer exchange step of the multi-specific binding protein to achieve a final buffer concentration of about 20 mM citrate, about 6% (w/v) mannitol, and about 0.01% (w/v) polysorbate 80, at about pH 6.5, Correia claim 52 teaches the excipients of the formulation comprise about 1 to about 30 mM citrate, 1 to 60 mg/ml mannitol (6% w/v), about 0.001% to about 0.5% (w/v) polysorbate 80, claim 67 teaches the pH is 5 to 7 (Pgs. 47-48).
Regarding instant claims 516 and 517, wherein the concentration of the multi-specific protein of claim 514 is 1 mg/mL to 125 mg/mL following the buffer exchange step (claim 516), specifically wherein the concentration of the multi-specific binding protein is about 50 mg/mL (claim 517), Correia teaches the molecule of the disclosure is an immunoglobulin (Pg. 46, claim 26) and the molecule is present in a concentration range of about 1 mg/ml to about 300 mg/mL (Pg. 46, claim 22).
It would have been obvious to one having ordinary skill in the art to modify the method of ‘308 and Sanie by performing a buffer exchange to achieve a final buffer composition as disclosed by Correia. One would have been motivated to do so because Correia provides evidence that a formulation comprising the disclosed excipients provides for long term stability of the protein (see Example 9.12, Pg. 41). There would be an expectation of success in formulating the multi-specific protein of ‘308 with the formulation of Correia because Correia provides a composition with well-characterized excipients performing their known function within the formulation for the long-term stabilization of proteins.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671