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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The application claims benefit to U.S. Provisional Application 62/783,565, filed December 21, 2018.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 9, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Claim Status
Claims 1-28 are under consideration in this office action.
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (pg 24, 27, and 32). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 1 and 7 are objected to because they use acronyms without first defining what they represent (TCEP, PBS, HPLC). While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 16 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 16 contains the trademark/trade name Sephadex. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a desalting column, and, accordingly, the identification/description is indefinite.
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 1, 22-25, and 27-28 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 20160130358, published May 12, 2016 (“Bhakta”; instant PTO-892).
The claims are drawn to a method of producing a re-oxidized antibody and a method for producing an antibody drug conjugate.
Bhakta teaches a method for generating cysteine engineered antibodies having free cysteines in the heavy or light chain [0008]. Cysteine adducts are reductively cleaved with a reducing agent, such as DTT or TCEP, to give a reduced form of the antibody [0570], and the interchain disulfide bonds between paired cysteine residues are reformed under partial oxidation conditions [0569]-[0570], which reads on the method of claim 1 and the adduct comprising a cysteine of claim 22.
Bhakta teaches that excess of drug-linker intermediate is combined with the re-oxidized antibody to effect conjugation and form the antibody-drug conjugate, which reads on the method of instant claim 27 comprising contacting the re-oxidized antibody with a linker-drug moiety to produce an antibody drug conjugate. Bhakta teaches an antibody drug conjugate with a DAR of 2 [0637], which reads on the DAR of instant claim 28.
Bhakta teaches exemplary light chain cysteine mutations, according to EU numbering, including amino acid 174 of a heavy chain constant region and amino acid 108 of light chain constant region [0012]-[0013], which reads on instant claims 23-25.
Bhakta anticipates claims 1, 22-25, and 27-28.
Claims 1-2, 14-18, and 22-28 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 20160067351, published March 10, 2016 (“Geierstanger”; IDS from 10/9/2024).
The claims are drawn to a method of producing a re-oxidized antibody and a method for producing an antibody drug conjugate.
Geierstanger teaches a method of modifying antibodies for the preparation of antibody-drug conjugates (ADCs) [0001], the method comprising contacting an antibody containing engineered cysteines with the reducing agent DTT and then incubating the reduced antibody under oxidation conditions ([0006], [0012], [0469]-[0470]), which reads on instant claim 1. In the method of Geierstanger, all native disulfide bonds and the disulfide bonds between the cysteine adducts of the engineered cysteine residues of the antibody are reduced [0469], which reads on the adduct comprising cysteine of 22. The reducing agent of the mixture is removed by dialyzing at 4 °C against PBS for three days with daily buffer exchange to remove DTT [0469], which reads on claims 2 and 14. In another embodiment taught by Geierstanger, the reducing reagents may be removed through a desalting column, Sephadex G-25 [0469], which reads on instant claims 2 and 15-16. Once the protein is fully reduced, 1 mM oxidized ascorbate (dehydro-ascorbic acid) is added to the desalted samples and the re-oxidation incubations are carried out for 20 hours [0469], which reads on claims 17-18.
Geierstanger teaches exemplary light chain cysteine mutations according to EU numbering, including amino acid 174 of a heavy chain constant region and amino acid 108 of light chain constant region (Tables 1 and 2), which reads on instant claims 23-25. Geierstanger also teaches cysteine amino acid substitution at positions 152 and 375 (Table 1), which reads on instant claim 26.
Geierstanger also teaches a method for producing an antibody drug conjugate, the method comprising contacting re-oxidized antibodies with maleimide-MMAF in PBS from 1 to 24 hours [0470], which reads on instant claim 27. The drug to antibody ratio of the antibody drug conjugate of Geierstanger is about 6 or 8 ([0063], [0067]), which reads on instant claim 28.
Geierstanger anticipates claims 1-2, 14-18, and 22-28.
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.
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.
Claims 1-2, 14-19, and 22-28 are rejected under 35 U.S.C. 103 as being unpatentable over US 20160067351, published March 10, 2016 (“Geierstanger”).
Claim 19 is drawn to a method of producing a re-oxidized antibody further comprising monitoring re-oxidation of the antibody using HPLC reverse phase chromatography. Although Geierstanger does not explicitly teach this monitoring step, Geierstanger teaches a method comprising HPLC reverse phase analysis to monitor the antibody conjugation process [0470]. During the re-oxidation process, the engineered cysteine residue may interfere with reforming of the proper native disulfide bonds through a process of disulfide shuffling either between the engineered cysteine and a native cysteine residue or between incorrectly matched native disulfide bonds; such mismatched disulfide bonds may affect the retention of the antibody on the reverse-phase HPLC column [0470].
Because Geierstanger was aware that such cysteine mismatch was a potential problem in a method of producing re-oxidized antibodies and teaches HPLC reverse chromatography as a known technique for monitoring antibody drug conjugate configuration, it would have been obvious to one of ordinary skill in the art to monitor the re-oxidation of the reduced antibody using this process. Such would amount to the application of a known technique (i.e. HPLC reverse phrase chromatography) to improve a process ready for improvements to yield predictable results (i.e. the detection of re-oxidized antibody structures), see MPEP 4143.
.
Claims 1-3 and 6-28 are rejected under 35 U.S.C. 103 as being unpatentable over US 20160067351, published March 10, 2016 (“Geierstanger”) in view of WO 2018116178, published June 28, 2018 (“Wen”; instant PTO-892).
As discussed above, Geierstanger teaches a method of producing a re-oxidized antibody.
This reference does not teach the limitation of 10 mM DTT, as required by claims 13 and 21, the limitation wherein the reducing agent comprises reduced cysteines, as required by claim 20, the limitation of claim 6 wherein the reducing agent is contacted for 30-60 min at room temperature, the limitation wherein the antibody is bound to a resin, as required by claim 3, 7-8, and 20, and the limitation drawn to an accelerant of claims 9-12.
Wen teaches methods for making antibody drug conjugates, wherein the antibody is linked to a drug moiety [0006]. Antibodies with engineered cysteines were reduced and re-oxidized using an on-resin method, wherein the resin is Protein A [00362], as in claims 3, 7-8 and 20. Protein A Sepharose beads were mixed with the antibody, and 20 mM cysteine was added to the mixture at room temperature for 30-60 min [00362], as in instant claims 6. The beads were washed with PBS for 30 min [00362], as in claim 20. Optionally, copper chloride at 50 nM to 1 mM was added to modulate the rate of re-oxidation [00362], as in the accelerant of claims 9-11. Since the addition of copper chloride is optional, Wen also teaches the limitation of claim 12 wherein step (c) does not comprise copper chloride.
Wen teaches a method of reducing disulfide bonds of antibodies by adding DTT at a final concentration of 10 mM [00361], as in instant claims 13 and 21.
Given that Geierstanger teaches a method for producing re-oxidized antibodies and further given that Wen teaches a method for making antibody drug conjugate using a resin, it would have been obvious to one of ordinary skill in the art to apply the additional steps of binding the antibody to a resin and using reduced cysteine as the reducing agent, because these steps were known in the antibody drug conjugate art at the time the application was filed. One would use the method of Wen and have a reasonable expectation of successfully making a re-oxidized antibody. Such amounts to application of a known technique (i.e. the method of Wen) to a known method ready for improvement (i.e. the method of Geierstanger) to yield predictable results, see MPEP 2143.
Claims 1-28 are rejected under 35 U.S.C. 103 as being unpatentable over US 20160067351 (“Geierstanger”) in view of WO 2018116178 (“Wen”), as applied to claims 1-3 and 6-28 above, and further in view of US 20170369567, published December 28, 2017 (“Heitzmann”; instant PTO-892).
As discussed above, Geierstanger in view Wen teach a method of producing a re-oxidized antibody. These references do not teach the limitation wherein the reducing agent is cysteine-HCl, as required by claims 4-5.
Heitzmann teaches methods for selectively reducing specific cysteine residues in an antibody (abstract). In the method of Heitzmann, the reducing agent for reducing cysteine residues in antibodies is “cysteine”, which includes cysteine and cysteine-HCl [0073], as in instant claims 4. The concentration of cysteine is 1.0-20 mM [0081], as in instant claims 5.
As Geierstanger in view of Wen teach the method of producing a re-oxidized antibody and Heitzmann teaches a similar method using cysteine-HCl as the reducing agent, it would have been obvious to one of ordinary skill in the art to substitute the reducing agent of Geierstanger with the reducing agent and have a reasonable expectation of success. Such would amount to the simple substitution of one known element for another (i.e. cysteine-HCl of Heitzmann for the DTT of Geierstanger and Wen) to obtain predictable results, see MPEP 2143.
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.
Claims 1-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 40-73 of copending Application No. 18/454,457 in view of US 20160067351, published March 10, 2016 (“Geierstanger”). Although the claims at issue are not identical, they are not patentably distinct from each other because they are both drawn to the same method of producing a re-oxidized antibody, comprising the steps of providing an antibody, contacting the antibody with a reducing agent, and incubating the reduced antibody under oxidation conditions, and method for producing an antibody drug conjugate.
Claims 40-50 and 53-62 of ‘457 teach a method of producing a re-oxidized antibody, including limitations wherein the reducing agent is DTT, reduced cysteine, or cysteine HCl, and the antibody is bound to a resin; the method comprises steps for dialyzing the reduced antibody, subjecting the reduced antibody to a desalting column, and contacting the reduced antibody with reduced ascorbate, which reads on instant claims 1-22. Claim 52 of ‘457 teaches a method of producing an antibody drug conjugate, which reads on the method of instant claim 27 and the ratio of claim 28.
‘457 claims do not teach the amino acid substitutions of instant claims 23-26.
Geierstanger teaches a method of producing a re-oxidized antibody and teaches exemplary light chain cysteine mutations according to EU numbering, including amino acid 174 of a heavy chain constant region and amino acid 108 of light chain constant region (Tables 1 and 2), as in instant claims 23-25. Geierstanger teaches cysteine amino acid substitutions at positions 152 and 375 (Table 1), as in instant claim 26. Because Geierstanger teaches a method of producing a re-oxidized antibody and a method of producing an antibody drug conjugate as well as preferred amino acid substitutions to cysteine for the re-oxidized antibody, it would have been obvious to one of ordinary skill in the art to apply the substitutions of Geierstanger in the method of ‘457 claims and have a reasonable expectation of success. Such would amount to the combination of prior art elements according to known methods and use of a known technique to improve similar product in the same way to yield predictable results.
Conclusion
No claim is allowed.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
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