Office Action 5: Non-Final Rejection (2024-08-28)
Rejection types: 103 - Obviousness, 112 - Written Description/Enablement

CLAIMS:
Amendments to the Claims:

This listing of claims will replace all prior versions, and listings, of claims in the application:

Listing of Claims:

Amdt date August 21, 2024 Reply to Office action of February 21, 2024

1 - 22. (canceled)221

23\. (Currently Amended) A preparation method of an antibody-drug conjugate with a structure as shown in formula I:mAb-(L-D)n I wherein,
mAb represents a recombinant anti-CD20 monoclonal antibody, wherein the recombinant anti-CD20 monoclonal antibody is rituximab or a biosimilar thereof;
D represents a small molecule toxin, wherein the small molecule toxin is monomethyl auristatin-E (MMAE);
L is a linker connecting the antibody and the small molecule toxin, wherein the linker is maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl;n is an average number of the small molecule toxins conjugated to the antibody, and n is in a range of 4.2SVG {EMBED HERE} 0.100.080.5; and
"-"is a bond, and
wherein the structure of the antibody-drug conjugate is the following formula:mAb andSVG {EMBED HERE} 1.3836.06

wherein the preparation method comprises the steps of:
(1) performing a reduction reaction between the recombinant anti-CD20 monoclonal antibody and a reducing agent in a PB (phosphate buffer) reaction buffer (pH 7.6) at 25±10C for 90±10 minutes, thereby obtaining a reaction system comprising a reduced recombinant anti-CD20 monoclonal antibody, wherein the reducing agent is tris (2-carboxyethyl) phosphine, and a molar ratio of the recombinant anti-CD20 monoclonal antibody to the reducing agent is 1: 2.9 to 1: 3.1;
(2) adding a solution of maleimidocaproyl-vc-PAB-MMAE in acetonitrile and water dropwise to the reaction system of step (1) and performing a coupling reaction at 4±0.5 0C for 60±10 minutes to obtain a coupling solution, wherein a volume ratio of acetonitrile to water is 1:1, and a molar ratio of the recombinant anti-CD20 monoclonal antibody in step (1) to the small molecule toxin is 1: 7.0 to 1: 8.0;
(3) adding into the reaction system obtained from step (2) a stopping solution of L-cysteine which is prepared by dissolving L-cysteine in a diethylenetriaminepentaacetic acid solution, to terminate the coupling reaction; and
(4) when the coupling reaction in step (3) is terminated, transferring the coupling solution to a tangential flow filtration (TFF) system for buffer replacement, thereby replacing the PB reaction buffer with a HT preparation buffer, and filtering the solution obtained with a 0.22 micrometer Rapid - Flow device to make a residual rate of the PB reaction buffer in a final solution less than 0.25%, wherein the HT preparation buffer contains 3.18 g of L-histidine, 70 g of trehalose dihydrate, and 0.2 mL of Tween 80 per L, with pH adjusted to 6.5 using 0.5 mol/L hydrochloric acid, and then filtered through a 0.22 pm membrane.

24\. (Previously Presented) The preparation method of claim 23, wherein n is in a range of 4.2 ±0.3.

25\. (Previously Presented) The preparation method of claim 23, wherein in step (1), the molar ratio of the recombinant anti-CD20 monoclonal antibody to the reducing agent is about 1:2.95-1:3.05.

26\. (Previously Presented) The preparation method of claim 23, wherein in step (1), the molar ratio of the recombinant anti-CD20 monoclonal antibody to the reducing agent is about 1:2.99-1:3.01.

27\. (Previously Presented) The preparation method of claim 23, wherein in step (1), the molar ratio of the recombinant anti-CD20 monoclonal antibody to the reducing agent is about 1:3.

28\. (Previously Presented) The preparation method of claim 23, wherein in step (2), the molar ratio of the recombinant anti-CD20 monoclonal antibody from step (1) to the small molecule toxin is about 1:7.2-1:7.7.

29\. (Previously Presented) The preparation method of claim 23, wherein in step (2), the molar ratio of the recombinant anti-CD20 monoclonal antibody from step (1) to the small molecule toxin is about 1:7.4-1:7.6.

30\. (Previously Presented) The preparation method of claim 23, wherein in step (2), the molar ratio of the recombinant anti-CD20 monoclonal antibody from step (1) to the small molecule toxin is about 1:7.5.

31\. (Previously Presented) The preparation method of claim 23, wherein n is 4.2, and in step (1), the reduction reaction between the recombinant anti-CD20 monoclonal antibody and the reducing agent is performed in the PB reaction buffer (pH

7.6) at 25 0C for 90 minutes, the molar ratio of the recombinant anti-CD20 monoclonal antibody to the reducing agent is 1:3; andin step (2), the solution of the small molecule toxin in acetonitrile and water is dropwise added to the reaction system of step (1) and the coupling reaction is performed at 4 0C for 60 minutes, and the molar ratio of the recombinant anti-CD20 monoclonal antibody in step (1) to the small molecule toxin is 1: 7.5.

32\. (Previously Presented) An antibody drug conjugate prepared according to the preparation method of claim 23, wherein the average number of the small molecule toxins conjugated to the antibody is 4.2 ± 0.5, and wherein components in the antibody drug conjugate ranked in descending order according to their contents are as follows: a component which has 4 small molecule toxins conjugated to the antibody (D4); a component which has 2 small molecule toxins conjugated to the antibody (D2); a component which has 6 small molecule toxins conjugated to the antibody (D6); a component which has 8 small molecule toxins conjugated to the antibody (D8); a the component which has 0 small molecule toxins conjugated to the antibody (DO).

33\. (Currently Amended) The antibody drug conjugate \[\[of\]\]accordinq to claim 32, wherein the average number of the small molecule toxins conjugated to the antibody is 4.2 ± 0.3, and wherein the components in the antibody drug conjugate ranked in descending order according to their contents are as follows: the component which has 4 small molecule toxins conjugated to the antibody (D4); the component which has 2 small molecule toxins conjugated to the antibody (D2); the component which has 6 small molecule toxins conjugated to the antibody (D6); the component which has 8 small molecule toxins conjugated to the antibody (D8); and the component which has 0 small molecule toxins conjugated to the antibody (DO).

34\. (Currently Amended) An antibody drug conjugate pharmaceutical preparation comprising an antibody drug conjugate prepared according to the preparation method of claim 23, wherein the average number of the small molecule toxins conjugated to the antibody is 4.2 0.5, and wherein components in the antibody drug conjugate pharmaceutical preparation ranked in descending order according to their contents are as follows: a component which has 4 small molecule toxins conjugated to the antibody (D4); a component which has 2 small molecule toxins conjugated to the antibody (D2); a component which has 6 small molecule toxins conjugated to the antibody (D6); a component which has 8 small molecule toxins conjugated to the antibody (D8); and a component which has 0 small molecule toxins conjugated to the antibody (DO).SVG {EMBED HERE} 0.100.08
35\. (Currently Amended) The antibody drug conjugate pharmaceutical preparation according to claim 34, wherein the average number of the small molecule toxins conjugated to the antibody is 4.2 SVG {EMBED HERE} 0.100.080.3, and wherein the components in the antibody drug conjugate pharmaceutical preparation ranked in descending order according to their contents are as follows: the component which has 4 small molecule toxins conjugated to the antibody (D4); the component which has 2 small molecule toxins conjugated to the antibody (D2); the component which has 6 small molecule toxins conjugated to the antibody (D6); the component which has 8 small molecule toxins conjugated to the antibody (D8); and the component which has 0 small molecule toxins conjugated to the antibody (DO).

OFFICE ACTION:
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 8/21/2024 has been entered.
The rejection of claims 23-31 is withdrawn in view of Applicant’s remarks in connection with this ground of rejection.  Namely, the applied references fail to teach or suggest use of the recited reaction buffer system, the ratio of antibody to reducing agent, the ratio of antibody to toxin, the reduction reaction temperature and time, the conjugation reaction temperature and time, and the selected purification system in the preparation process.
The rejection of claims 32-35 is withdrawn in favor of the following new ground of rejection under this section:
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 32-35 are rejected under 35 U.S.C. 103 as being unpatentable over:
Law et al., Clin Cancer Res (2004) 10 (23): 7842–7851 (Law); and
Francisco et al., Blood. 2003 Aug 15;102(4):1458-65 (Francisco).
The applied references all describe preparation of the conjugates
Law:
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Francisco:
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The applied references may not explicitly teach the recite drug to antibody ratio (DAR) component distribution.  However, the recited conjugates were prepared in substantially the same manner as described in the specification.  In this manner, those of ordinary skill would expect that the products of the preparation would have substantially the products, including the recited DAR distribution, see MPEP 2112.01 (“Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).”).
In this regard, the rejected claims are not limited any particular antibody drug conjugate.
Therefore, the recited preparations are prima facie obvious.
The rejection under section 112(b) is withdrawn in favor of the following new ground of rejection under this section:
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 32-35 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA  35 U.S.C. 112, the applicant), regards as the invention.
The criteria of ranking is not clear.  Applicant should amend the claims to clearly recite the intended criteria, e.g., amount or concentration of conjugates with the recited ratios.
Conclusion

APPLICANT REBUTTAL: REMARKS/ARGUMENTS
Claims 23-31 are currently pending in the present application. Claims 1-22 were previously canceled, without prejudice and without disclaimer. Claims 32-35 are canceled herein, without prejudice and without disclaimer. No new matter is added. In view of the amendments and remarks that follow, Applicant respectfully requests a timely issuance of a Notice of Allowance of allowed claims 23-31.
Allowable Sub
j
ect Matter
Applicant wishes to thank the Examiner for indicating that claims 23-31 are allowed.
Rej
ection of Claims Under 35 U.S.C.
§
Claims 32-35 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. In particular, the Office action states that "The criteria of ranking is not clear. Applicant should amend the claims to clearly recite the intended criteria, e.g., amount or concentration of conjugates with the recited ratios.." See OA, page 16.
Without conceding to the propriety of the above definiteness rejection,
in an effort to ex
p
edite allowance
of the present application, Applicant has cancelled claims 32-35, without prejudice and without disclaimer, and thus respectfully submits that the rejection under 35 U.S.C. 112 is now moot and should be withdrawn.
Rej
ection of Claims Under 35 U.S.C.
§
Claims 32-35 were rejected under 35 U.S.C. 103 as allegedly being unpatentable over Law et al., Clin Cancer Res (2004) 10 (23): 7842-7851 (Law); and Francisco et al., Blood. 2003 Aug 15;102(4):1458-65 (Francisco).
In an effort to ex
p
edite allowance
of the present application, and without conceding to this rejection, Applicant has cancelled claims 32-35, without prejudice and without disclaimer, and thus respectfully submits that this rejection under 35 U.S.C. 103 is now moot and should be withdrawn.
For at least the reasons detailed above, it is believed that all rejections are addressed. Thus, Applicant respectfully requests a timely issuance of a Notice of Allowance of allowed claims 23-31.
Concluding Remarks
In view of the foregoing amendments and remarks, Applicant earnestly solicits a timely issuance of a Notice of Allowance. If there are any remaining issues that can be addressed over the telephone, the Examiner is cordially invited to call Applicant's attorney at the number listed below.
Payment of any fee required to enter and process this amendment is provided. The Director is authorized to charge any underpayment of fees or credit any overpayment of fees to Deposit Account No. 03-1728.
Respectfully submitted, LEWIS ROCA ROTHGERBER CHRISTIE LLP

NEXT OFFICE ACTION: 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 .
The following is an examiner’s statement of reasons for allowance:
The rejection under section 103 is moot since the rejected claims have been canceled.
The rejection under section 112(b) is moot since the rejected claims have been canceled.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion