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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/11/2026 has been entered.
Claims 16 and 17 have been canceled. Claim 1 has been amended. Claims 1, 4-10, 13-15 and 18-25 are pending and under consideration.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-10, 13-16 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Lou et al (‘Bioconjugate Chemistries for ADC Preparation’, World ADC Summit, San Diego, October 2014) in view of Beckley et al (BioConjugate Chemistry, 2013, Vol. 24, pp. 1674-1683).
Lou et al teach the conjugation of IgG1to a non-cleavable maleimide comprising linker-payload, mc-LP (bottom paragraph under “Introduction”), wherein the antibody at 4 degrees in histidine buffer was incubated with 2.2 equivalents of the reducing agent, TCEP to provide a DAR of 4.28 (Table 7) and a lower amount of unconjugated antibody than incubations at 25 or 37 degrees (fourth bullet under Table 7), which meets the limitations of the reaction temperature in claims 1 and 11, the DAR in claim 1, the number of molar equivalents of between 2 and 3 in claim 15, the reducing agent of tris(2-carboxyethyl)phosphine in claim 16, and the histidine buffer in claim 18.
Lou et al do not specifically teach that the reduction is carried out at a temperature between -3 degrees and + 3 degrees, zero degrees to +2 degrees or zero degrees to +1 degree as required in claims 12-14, respectively.
Beckley et al teach that the average drug to antibody ratio, DAR, is controlled largely by the extent to which the bulk antibody interchain disulfide bonds are reduced during the conjugation process (page 1674, bridging sentence between the first and second column).
It would have been prima facie obvious to optimize the temperature at which the reduction was carried out to optimize the reduction of the interchain disulfide bonds and resulting DAR, such as a DAR of 4.0. One of skill in the art would have been motivated to do so by the teachings of Beckley et al on the influence of reduction or interchain disulfide bonds and resulting DAR of the conjugate and the teachings of Lou et al that lower temperature reduced the percentage of unconjugated antibody. Because Lou et al taught 4 degrees, it would be obvious to use 3, 2, 1 or zero degrees.
Section 2144.05 I of the M.P.E.P. states:
… a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.).
It is noted that the specification does not demonstrate any criticality between the reduction carried out at 3 degrees C versus 4 degrees, and in fact the specification teaches carrying out the reduction between -10 to 10+ degrees.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-10, 13-15 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Lou et al (‘Bioconjugate Chemistries for ADC Preparation’, World ADC Summit, San Diego, October 2014) in view of Beckley et al (BioConjugate Chemistry, 2013, Vol. 24, pp. 1674-1683).
Lou et al teach the conjugation of IgG1to a non-cleavable maleimide comprising linker-payload, mc-LP (bottom paragraph under “Introduction”), wherein the antibody at 4 degrees in histidine buffer was incubated with 2.2 equivalents of the reducing agent, TCEP to provide a DAR of 4.28 (Table 7) and a lower amount of unconjugated antibody than incubations at 25 or 37 degrees (fourth bullet under Table 7), which meets the limitations of the reaction temperature in claims 1 and 11, the DAR in claim 1, the number of molar equivalents of between 2 and 3 in claim 15, the reducing agent of tris(2-carboxyethyl)phosphine and the histidine buffer in claim 18. Lou et al teach that higher ion strength gave the better conjugation result (forth point under Table 5).
Lou et al do not specifically teach that the reduction is carried out at a temperature between -3 degrees and + 3 degrees, zero degrees to +2 degrees or zero degrees to +1 degree as required in claims 12-14, respectively.
Lou et al do not specifically teach that the reducing agent is the hydrochloride salt of tris(2-carboxyethyl)phosphine.
Beckley et al teach that the average drug to antibody ratio, DAR, is controlled largely by the extent to which the bulk antibody interchain disulfide bonds are reduced during the conjugation process (page 1674, bridging sentence between the first and second column).
Regarding the temperature limitation of -3 to +3 degrees C, it would have been prima facie obvious to optimize the temperature at which the reduction was carried out to optimize the reduction of the interchain disulfide bonds and resulting DAR, such as a DAR of 4.0. One of skill in the art would have been motivated to do so by the teachings of Beckley et al on the influence of reduction or interchain disulfide bonds and resulting DAR of the conjugate and the teachings of Lou et al that lower temperature reduced the percentage of unconjugated antibody. Because Lou et al taught 4 degrees, it would be obvious to use 3, 2, 1 or zero degrees.
Section 2144.05 I of the M.P.E.P. states:
… a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.).
It is noted that the specification does not demonstrate any criticality between the reduction carried out at 3 degrees C versus 4 degrees, and in fact the specification teaches carrying out the reduction between -10 to 10+ degrees.
Regarding the hydrochloride salt of tris(2-carboxyethyl)phosphine versus the free tris(2-carboxyethyl)phosphine, Lou et al teach that higher ionic strength provide a better conjugation result. Thus, it would have been prima facie obvious at the time of the effective fiilng date to use the hydrochloride salt of tris(2-carboxyethyl)phosphine as the reducing agent versus the tris(2-carboxyethyl)phosphine as the reducing agent. One of skill in the art would have been motivated to do so by the teachings of Lou et al that a higher ionic strength produces a better conjugation result. One of skill in the art would understand that the HCl introduced with the tris(2-carboxyethyl)phosphine would contribute to a higher ionic strength and thus be expected to result in a better conjugation.
Claims 1, 4-10, 13-15, 18, 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Lou et al and Beckley et al as applied to claims 1, 4-10, 13-15 and 18 above, and further in view of Starodub et al (Clinical Cancer Research, Published on-line May 5, 2015, Vol. 21, pp. 3870-3878).
The combined teachings of Lou et al and Beckley et al render obvious teach the limitations of claims 1, 4-10, 13-15 and 18 for the reasons set forth above. Lou et al do not specifically teach that the antibody of the conjugate is an anti- TROP2 antibody as required in claims 21 and 22.
Starodub et al teach the first in human trial of anti-TROP-2 antibody conjugated to SN-38.
It would have been prima facie obvious at the time of the effective filing date to use the method rendered obvious by the combined teachings of Lou et al and Beckley et al for the reduction to free sulfhydryls in the TROP2 antibody using TCEP at lower than 4 degrees, such as 3, 2, 1 or zero degrees followed by conjugation to the linker-SN-38. One of skill in the art would have been motivated to do so to attain a low level of unconjugated antibody remaining in the conjugation mixture when the reduction was carried out at lower temperature. One of skill in the art would be motivated to minimize the amount of unconjugated antibody so that the maximum amount of conjugated drug per dose can be administered to the patient. One of skill in the art would understand that the presence of unconjugated antibody in the composition competes with the conjugated antibody for binding sites in vivo and thus decreases the efficacy of the composition.
Claims 1, 4-10, 13-15, 18, 21 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Lou et al and Beckley et al as applied to claims 1, 4-10, 13-15 and 18 above, and further in view of Peddi and Hurvitz (Therapeutic Advances in Medical Oncology, 2014, Vol. 6, pp. 202-209).
The combined teachings of Lou et al and Beckley et al render obvious teach the limitations of claims1, 4-10, 13-15 and 18 for the reasons set forth above. Lou et al do not specifically teach that the antibody of the conjugate is an anti-Her2 antibody as required in claims 21 and 25.
Peddi and Hurvitz teach the conjugate of Ado-trastuzumab-emtansine for the treatment of Her2 positive metastatic breast cancer (title).
It would have been prima facie obvious at the time of the effective filing date to use the method rendered obvious by the combined teachings of Lou et al and Beckley et al for the reduction to free sulfhydryls in the trastuzumab antibody using TCEP at lower than 4 degrees, such as 3, 2, 1 or zero degrees followed by conjugation to the linker-DM1, emtansine. One of skill in the art would have been motivated to do so to attain a low level of unconjugated antibody remaining in the conjugation mixture when the reduction was carried out at lower temperature. One of skill in the art would be motivated to minimize the amount of unconjugated antibody so that the maximum amount of conjugated drug per dose can be administered to the patient. One of skill in the art would understand that the presence of unconjugated antibody in the composition competes with the conjugated antibody for binding sites in vivo and thus decreases the efficacy of the composition.
Claims 1, 4-10, 13-15, 18, 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Lou et al and Beckley et al as applied to claims 1, 4-10, 13-15 and 18 above, and further in view of Hayes et al (International Journal of Cancer, 2014, Vol. 137, pp. 710-720) and Chari et al (Angew. Chem Int. Ed. 2014, Vol. 53, p. 3796-3827).
The combined teachings of Lou et al and Beckley et al render obvious teach the limitations of claims1, 4-10, 13-15 and 18 for the reasons set forth above. Lou et al do not specifically teach that the antibody of the conjugate is an anti-CD98 antibody as required in claims 21 and 23.
Hayes et al teach an anti-CD98 antibody, IGN523 , which demonstrated robust tumor growth inhibition in leukemic cell line derived xenografts and was as efficacious as standard of care against patient derived non-small cell lung cancer xenografts (abstract). Hayes et al teach that the IGN523 antibody is efficiently internalized and shuttled to the lysosomes (page 718, first column, lines 17-19).
Chari et al teach that in addition to binding at the surface of tumor cells, the ability of the antibody to internalize into the cell to enable intracellular delivery of a linked payload is an important factor (page 3803, lines 15-18 under the heading “The Antibody”). Chari et al additionally teach that while the ADC approach does not require functional activity, , this feature of an antibody can confer additional therapeutic activity (page 3803, lines 15-18 under the heading “The Antibody”).
It would have been prima facie obvious at the time of the effective filing date to make an ADC targeting CD98 and comprising the IGN 523 antibody. One of skill in the art would have been motivated to do so by the teachings of Hayes et al that the IGN523 antibody exhibited anti-tumor efficacy in preclinical models and exhibited internalization and shuttling to the lysosome and because Chari et al teach that internalization to the lysosomes is an important factor for the delivery of an antibody-linked payload It would have been prima facie obvious at the time of the effective filing date to use the method rendered obvious by the combined teachings of Lou et al and Beckley et al for the reduction to free sulfhydryls in the trastuzumab antibody using TCEP at lower than 4 degrees, such as 3, 2, 1 or zero degrees followed by conjugation to the linker-cytotoxic drug. . One of skill in the art would have been motivated to do so to attain a low level of unconjugated antibody remaining in the conjugation mixture when the reduction was carried out at lower temperature. One of skill in the art would be motivated to minimize the amount of unconjugated antibody so that the maximum amount of conjugated drug per dose can be administered to the patient. One of skill in the art would understand that the presence of unconjugated antibody in the composition competes with the conjugated antibody for binding sites in vivo and thus decreases the efficacy of the composition.
Claims 1, 4-10, 13-15, 18, 21 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Lou et al and Beckley et al as applied to claims 1, 4-10, 13-16 and 18 above, and further in view Loo et al (WO2011/109400).
The combined teachings of Lou et al and Beckley et al render obvious teach the limitations of claims 1, 4-10, 13-15 and 18 for the reasons set forth above. Lou et al do not specifically teach that the antibody of the conjugate is an anti-B7-H3 antibody as required in claims 21 and 24.
Loo et al teach antibodies that bind to the extracellular domain of B7-H3, wherein the antibody is internalized up binding to B7-H3 expressed on a cancer cell surface (claim 4). Loo et al teach that the antibodies can be used to make antibody conjugates in which the antibody is linked to a toxic agent and directs that agent to the tumor by specifically binding to the tumor (paragraph [0015]). Loo et al teach that anti-B7-H3 antibodies that binds specifically to B7-H3 on cancer stem cells (paragraph [00171]).
It would have been prima facie obvious at the time of the effective filing date to use the method rendered obvious by the combined teachings of Lou et al and Beckley et al for the reduction to free sulfhydryls in the B7-H3 antibody using TCEP at lower than 4 degrees, such as 3, 2, 1 or zero degrees followed by conjugation to the linker-toxic agent. One of skill in the art would have been motivated to do so to attain a low level of unconjugated antibody remaining in the conjugation mixture when the reduction was carried out at lower temperature. One of skill in the art would be motivated to minimize the amount of unconjugated antibody so that the maximum amount of conjugated drug per dose can administered to the patient. One of skill in the art would understand that the presence of unconjugated antibody in the composition competes with the conjugated antibody for binding sites in vivo and thus decreases the efficacy of the composition.
Applicant argues that the incorporation of tris(2-carboxyethyl)phosphine hydrochloride as a limitation of claim 1 renders moot the instant rejections. This has been considered but not found persuasive for the reasons set forth above.
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, 4-10, 13-15, 18-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11,173,213 is maintained.
The claims of the patent render obvious instant claims 1, 13-15, 18-25. Claim 1 of the patent teaches a method for producing an antibody-drug conjugate comprising a step of reacting an antibody with a reducing agent in a buffer to reduce the number of interchain disulfides, wherein the buffer comprises a chelating agent, wherein after reaction with the drug-linker, the conjugation reaction produces conjugates wherein in 50% or more of the conjugates have four linkers bound to heavy-light interchain thiols. Thus, it would have been obvious to one of skill in the art that the reduction reaction of claim 1(i) of the patent produces a reduced antibody wherein 50% or more of the thiol groups are heavy-light interchain thiols, thus rendering obvious that aspect of instant claim 1. It would be further obvious to use the hydrochloride salt of tris(2-carboxyethyl)phosphine as the reducing as the reducing agent because it is taught by claim 9 of the patent.
It would be further obvious to carry out the reduction of the antibody at -3 to +3 degrees C, 0 to 2+ degrees C or 0 to 1 degree C because these condition are taught in claims 4-6 of the patent, thus rendering obvious the limitation of -3 to 3+ degrees C in instant claim 1 and the reaction temperatures of 0 to 2 degrees, and 0 to 1 degree in instant claims 13 and 14.
Claim 1 of the patent teaches that the reduction is carried out in the presence of a chelating agent, and claim 11 of the patent specifies that the chelating agent is EDTA which renders obvious the same limitations in instant claims 19 and 20.
Instant claims 4-6 are obvious over claim 1 of the patent because the range of 50% to 90%, 50% to 80%, 50% to 70% and 50% to 60% are obvious variants of a range which is over 50%.
Regarding claims 7-10, Section 804II(b) of the M.P.E.P. states:
The specification can be used as a dictionary to learn the meaning of a term in the patent claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999).
In the instant case, the specification defines the resulting conjugate compositions as
wherein the content of antibody-drug conjugates in which four drug linkers are bound to heavy-heavy interchain thiols, in the produced antibody-drug conjugate composition is 5% or less.
which is the limitation of claim 7
wherein the content of antibody-drug conjugates in which four drug linkers are bound to heavy-heavy interchain thiols, in the produced antibody-drug conjugate composition is 1% or less.
which is the limitation of claim 8
wherein the content of antibody-drug conjugates in which two drug linkers are bound to heavy-heavy interchain thiols and two drug linkers are bound to heavy-light interchain thiols, in the produced antibody-drug conjugate composition is 5% or less.
which is the limitation of claim 9
wherein the content of antibody-drug conjugates in which two drug linkers are bound to heavy-heavy interchain thiols and two drug linkers are bound to heavy-light interchain thiols, in the produced antibody-drug conjugate composition is 1% or less.
which is the limitation of claim 10
Thus, the compositions of instant claims 7-10 are obvious variants of claim 1 wherein the produced antibody conjugate in which 50% of the adducts comprise four linkers bound to heavy-light interchain thiols is a result of the reduction of heavy-light chain interchain disulfides to produce a mixture wherein 50% of the reduced thiols are from heavy-light chain disulfides .
Claim 7 of the patent teaches the reducing agent in 2 to 3 molar equivalent which renders obvious instant claim 15.
Claim 10 of the patent teaches that the buffer of claim 1 is a histidine buffer. Thus it would have been prima facie obvious to use the histidine buffer in the method of claim 1, and rendering obvious instant claim 18.
Claim 12 of the patent teaches that the antibody is an anti-TROP2, anti-CD98, anti-B7-H3 and anti-HER2 antibody. Thus, it would be obvious to use those antibodies in instant claim 1, rendering obvious instant claims 21-25.
Applicant argues that the claims of the ‘213 patent do not recite “wherein the reducing agent is tris(2-carboxyethyl)phosphine” but instead recite that the buffer must comprise a chelating agent lending credence to the difference between the instant method and the method of the patent. This has been considered but not found persuasive. With regard to the specific reducing agent, claim 9 of the patent teaches that the reducing agent of claim 1 is tris(2-carboxyethyl)phosphine hydrochloride. With regard to the requirement for a cheating agent in claim 1 of the patent, it is noted that the instant claim 1 does not exclude a chelating agent, and in fact exemplifies the method comprising a chelating agent in instant claims 19 and 20.
Applicant’s arguments are unpersuasive.
All claims are rejected.
All other rejections and/or objections as set forth in the prior Office action are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643