Office Action 4: Final Rejection (2024-02-21)
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 December 13, 2023 Reply to Office action of June 13, 2023

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:mAbSVG {EMBED HERE} 1.3275.997SVG {EMBED HERE} 0.1430.347

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 vc-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; and
in 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\. (Currently Amended) 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 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 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).

35\. (Currently Amended) The antibody drug conjugate pharmaceutical preparation prepared according to the preparation method of claim 34, 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 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 .
The rejections under section 103 are maintained, below:
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.
Claim(s) 32-35 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al., Pharm Res (2015) 32:3526–3540 (Jain);
in view of U.S. Publication No. 20050180972 based on an application by Wahl et al. (Wahl) and Chen et al., Determination of Drug-to-Antibody Ratio for Antibody-Drug Conjugates Purified from Serum, Agilent Technologies, pp. 1-9, 2016 (Agilent).
Jain teaches VAL-CIT-MMAE antibody conjugates:
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Jain teaches that these ADC’s with the recited drug-antibody-ratio (DAR) are known:
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Jain may fail to explicitly teach ADC’s with an anti-CD-20 antibody.  However, it is for that proposition that the examiner joins Wahl.  Specifically, Wahl teaches that conjugating mc-vc-PABC-MMAE to anti-CD20 antibodies, like rituximab, was common for cancer therapy:
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Wahl also discloses the recited excipients suitable for these ADC.s see paragraphs 247+.
In this way, those of ordinary skill could have applied anti-CD20 antibodies in the manner required and in a predictable fashion for the purposes of providing the recited ADC’s.  As outlined above, Jain teaches that the recited ADC’s with the recited drug-antibody-ratio (DAR) are common, such as mc-vc-PABC-MMAE.  Wahl is added for the proposition that anti-CD-20 antibodies are applicable to these ADC’s.  Specifically, Wahl teaches that the particular known technique of conjugating anti-CD-20 ADC’s with mc-vc-PABC-MMAE was recognized as part of the ordinary capabilities of one skilled in the art.  In this manner, those of ordinary skill would have recognized that applying the known technique to anti-CD-20 antibodies, like rituximab, would have yielded predictable results.  Accordingly, using anti-CD20 antibodies with mc-vc-PABC-MMAE would have been prima facie obvious.
With regard to the average number of the small molecule toxins conjugated to the antibody of 4.2 + 1, it is understood that the DAR in the table is an average DAR.  Indeed, those of ordinary skill would understand that preparation of the Rituximab vcMMAE in Wahl would produce a number of ADC’s with different DAR’s, including 4.
Nonetheless, there are a limited and finite number of DAR’s for a cysteine-bound antibody-drug conjugate (ADC), around 8. The prior art demonstrates that optimization of the DAR is a critical part of ADC development, since the DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. At the time the invention was made, easy, accurate and reproducible DAR calculation of ADC’s was within the purview of those of ordinary skill, see Agilent:
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In this manner, it would have been obvious to one having ordinary skill in the art at the time of applicant’s invention to have prepared ADC’s within the recited DAR with a reasonable expectation that the resulting ADC would be useful in treating cancer. In this connection, it is well-settled that cysteine-conjugated ADC’s with a DAR from 1-8 are well within the purview of those of ordinary skill (see above); and it would have been obvious to one of ordinary skill in the art at the time the invention was made to have chosen from this finite number of DAR options with a reasonable expectation of success of producing an ADC with a functional DAR.
Specifically, the DAR pf cysteine-bound ADC’s is optimizable.  It is well within the skill of the artisan to try any of the 1-8 DAR targets. As outlined above, a DAR value affects the efficacy of the drug, as low drug loading reduces the potency, while high drug loading can negatively affect pharmacokinetics (PK)1 and toxicity. Here, a skilled chemist at the time would simply make the known ADC’s of the known 8 DAR’s. Indeed, it would have been part and parcel to make the different DAR’s to find one that is pharmaceutically acceptable. See Agilent: (“The DAR is a critical quality attribute of an ADC that is optimized and closely monitored during ADC development, as it can affect efficacy and toxicity.”)  Therefore, the applied references provide ample reason to make the recited ADC’s with a DAR in the recited range.
With regard to any unpredictability associated with the DAR’s, the notion that unpredictability confers patentability in cases of DAR’s of known ADC’s should be disregarded since a rule of law equating unpredictability to patentability, applied in this case, would mean that any new ADC based on a different DAR would be separately patentable, simply because the formation and properties of each ADC must be verified through testing. This cannot be the proper standard since the expectation of success need only be reasonable, not absolute.
Here, the references provide the reasonable expectation of success. Namely, the references demonstrate the reasonable expectation of success since the references sufficiently characterize the instant ADC’s including the required heavy and light chains (i.e., Rituximab), conjugated to MMAE via a val/cit linker (see Jain and Wahl). Again, the expectation of success need only be reasonable, as it is here, and not absolute, (“obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).”).
With regard to any alleged unexpected property possessed by those ADC’s with a DAR within the claimed range, it is error to assume that any superior property is unexpected, especially in the instant case, where the pharmacodynamic and pharmacokinetic properties of different DAR’s are not predictable. In this case, given the range of 8 possible DAR’s, one skilled in the art would expect different DAR’s to provide ADC’s having a range of properties, some of which would be superior, and some of which would be inferior.
Rather, Applicant has conducted a common optimization of the known DAR’s to produce the claimed ADC, which is routine. Specifically, Applicant engaged in routine, verification testing to optimize selection of one of several known and clearly suggested DAR’s to prepare a pharmaceutically-acceptable conjugate. In this regard, creating a “product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient . . . to enhance commercial opportunities . . . is universal—and even common-sensical.” see DyStar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356 at 1368.
Finally, the claims recite product-by-process limitations.  Applicant has not demonstrated how these limitations distinguish the recited ADC, see MPEP 2113 (“[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”).
Therefore, the recited ADC’s with the recited DAR is obvious, within the meaning of section 103.
The rejected claims are product by process claims, the merits of which depend on the product, see MPEP 2113 (““[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”).
Applicant argues that different DAR’s of MMAE-ADC’s were known in the art:
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However, Applicant even demonstrates that optimization of DAR was common, and accepted:
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Therefore, optimization of a known ADC, such as Rituximab vc-MMAE would have been well within the purview of those of ordinary skill, as exemplified by Applicant’s remarks, and as outlined in the rejection above.
Claim(s) 23-31 are rejected under 35 U.S.C. 103 as being unpatentable over Jain et al., Pharm Res (2015) 32:3526–3540 (Jain) in view of (Wahl) and (Agilent); in further view of:
Agarwal et al., Bioconjugate Chem. 2015, 26, 2, 176–192 (Agarwal); and
Sun et al., Bioconjug Chem. 2005; 16: 1282- 1290 (Sun); and
Li Y et al., J Chromatogr A. 2015; 1393: 81- 88 (Li Y); and
Protein Concentration and Diafiltration by Tangential Flow Filtration, Millipore Techinical Brief, 2003, downloaded 7 June 2023 from http://wolfson.huji.ac.il/purification/PDF/dialysis/MILLIPORE_TFF.pdf (Millipore);
Teeters et al., Biotechnology and Bioengineering, Vol. 108, No. 6, June, 2011 (Teeters); and
U.S. Publication No. 20160045615 based on an application by Li et al. (Li); and
U.S. Publication No. 20170326251 based on an application by Evan et al. (Evans); and
Package Insert Herceptin (Trastuzumab) Genetech, Inc., 2000, downloaded 7 June 2023 from https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/trasgen020900lb.htm (Herceptin).
The recited ADC is prima facie obvious, see section 103 rejection above citing Jain in view of Wahl and Agilent, which is incorporated herein by reference.  These references may fail to teach the required preparation steps.  However, it is for that proposition that the examiner joins the following references.
See Agarwal, teaching that the reduction steps were known:
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TCEP = tris(carboxyethyl)phosphine.
Once the conjugation is complete, cysteines, or N-acetyl-l-cysteine (NAC) can be used to quench any excess amount of thiol-reactive drug-linkers, often maleimide-containing drug-linkers, see for example, ADC preparation from Kozak.
For ADCs using reduced interchain cysteines for conjugation, the chemical steps include reduction of interchain disulfide bonds, conjugation, and quench of thiol-reactive drug-linkers before the final ultrafiltration and diafiltration (UF/DF) operation, see Sun and Li Y.
The TFF unit operation is a mainstay in concentration of proteins and buffer exchanges and has shown to be effective at removing solutes when the molar masses of the solutes are significantly lower than the protein.  Ultrafiltration (UF) is one of the most widely used forms of TFF and is used to separate proteins from buffer components for buffer exchange, desalting, or concentration, see Millipore.
For drug substance manufacturing, ultrafiltration/diafiltration (UF/DF) is typically the final process step performed to concentrate and exchange the purified drug substance to achieve the protein concentration, pH, and excipient concentrations necessary for product formulation, see Teeters.
See also, Li teaching ADC purification with TFF.
The prior art also provides sufficient reasons to exchange with the recited buffer in order to formulae the ADC, see paragraph 0386 of Evans.
See also Herceptin:
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The claims also cover relative amounts of reagents/reactants and solvents that may not be explicitly taught by the references.  However, these are results-effective parameters since they affect the efficiency of the process.  In this manner, their optimization by those of ordinary skill in the art is well within the ordinary skill of the purview of those of ordinary skill, and therefore, prima facie obvious.
Applicant has not distinguished the residual rate of PB from that of the references.
Moreover, the references demonstrate that vc-MMAE have known to have a DAR of 4, see Jain:
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The references demonstrate that optimization of DAR was known, and routine.
Applicant submits references that show the recited DAR was common:
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Applicant has not shown why those of ordinary skill would not have reason to optimize DAR’ of the instant ADC’s.  In this regard, Applicant has not shown why those of ordinary skill would not expect a reasonable expectation of therapeutic success of the instant ADC’s with a DAR of 4.
Therefore, the rejection is maintained.
The rejection under section 112(b) is withdrawn in favor of the following new grounds of rejection, which are necessitated by Applicant’s amendments.
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 23-35 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 claims have been amended to recite that vc-MMAE is used as a conjugation reagent.  However, the formula in claim 23 also contains a maleimidocaproyl component not structurally-accounted for by vc-MMAE.
Claims 32-35 recite components of the instant ADC’s.  Some of the components are outside the recited DAR, e.g., 2, 6, 8, 0.    It is unclear how these components relate to the recited ADC’s. Moreover, if these are “components” of the instant ADC’s, it is unclear if Applicant is claiming an ADC or a composition of different ADC’s, some of which are outside the recited DAR.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action.  Accordingly, THIS ACTION IS MADE FINAL.  See MPEP § 706.07(a).  Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action.  In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action.  In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Conclusion

APPLICANT REBUTTAL: REMARKS/ARGUMENTS
Claims 23-35 are currently pending in the present application. Claims 1-22 were previously canceled, without prejudice and without disclaimer. Claims 23 and 32-35 are amended herein, without prejudice and without disclaimer. No new matter is added. In view of the amendments and remarks that follow, Applicant respectfully requests reconsideration and allowance of claims 23-35.
Rej
ection of Claims Under 35 U.S.C.
§
Claims 23-35 are rejected under 35 U.S.C. 112(b) as allegedly 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 instant conjugation step recites adding a solution of the small molecule toxin to the system. However, in order to prepare the ADC of the formula in claim 23, conjugation is required between the linker/small molecule toxin. The definition of the small molecule toxin in the specification does not include the linker portion. Therefore, it is unclear how conjugation between the small molecule toxin and the reduced antibody can prepare the conjugate of claim 23, if the linker is not present.
Without conceding to the propriety of the above definiteness rejection,
in an effort to ex
p
edite allowance
of the present application and to better set forth the subject matter being claimed, Applicant has amended Claim 23 to recite, in the relevant part and among other things, "(2) adding a solution of
vc-MMAE
in acetonitrile and water dropwise to the reaction system of step (1) and performing a coupling reaction at 4±0.5 °C for 60±10 minutes to obtain a coupling solution." The support can be, e.g., found in Example 2 section of the instant application as filed. No new matter is added. According to the structure of the antibody drug conjugate described in Claim 23 and the description of the
application, it should at least now be undoubtedly determined that the reduced rituximab or a biosimilar thereof obtained in step (1) of the preparation method is to be reacted with vc-MMAE, thereby forming an antibody drug conjugate.
In view of the above, Applicant respectfully submits that the amendment should now render the rejection under 35 U.S.C. §112(b) moot and respectfully requests withdrawal of the rejections under 35 U.S.C. § 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph.
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 Jain et al., Pharm Res (2015) 32:3526-3540 (Jain); in view of U.S. Publication No. 2005/0180972 (Wahl) and Chen et al., "Determination of Drug-to-Antibody Ratio for Antibody-Drug Conjugates Purified from Serum," Agilent Technologies, pp. 1-9, 2016 (Aglient).
Claims 23-31 are rejected under 35 U.S.C. 103 as allegedly being unpatentable over Jain in view of Wahl and Agilent; in further view of Agarwal et al., Bioconjugate Chem. 2015, 26, 2, 176-192 (Agarwal); and Sun et al., Bioconjug Chem. 2005; 16: 1282- 1290 (Sun); and Li Yet al., J Chromatogr A. 2015; 1393: 81-88 (Li Y); and Protein Concentration and Diafiltration by Tangential Flow Filtration, Millipore Technical Brief (Millipore), Teeters et al., Biotechnology and Bioengineering, Vol. 108, No. 6, June, 2011 (Teeters); and U.S. Publication No. 2016/0045615 (Li); and U.S. Publication No. 2017/0326251(Evans); and Package Insert Herceptin (Trastuzumab) Genetech, Inc., 2000 (Herceptin).
In order to establish a prima facie case of obviousness under 35 U.S.C. § 103, however, the Office Action must provide a clear articulated reasoning with some rational underpinning to support the legal conclusion of obviousness, demonstrating why a person
having ordinary skill in the art at the time the invention was made would have combined the disclosures of the cited references to arrive at each of the claimed features of a rejected claim. MPEP 2143.03 entitled "All Claim Limitations must be Considered" states: "all words in a claim must be considered in judging the patentability of that claim against the prior art." In re Wilson, 424 F.2d 1382, 1385, 165 USPQ 494, 496 (CCPA 1970)." Furthermore, there should be some explanation why any differences between the prior art and the claimed inventions would have been obvious to a person having ordinary skill in the art. See MPEP § 2141. Lastly, the mere fact that certain teachings in cited references can be combined or that modifications of the prior art were within the ability of one of ordinary skill the art, does not render a claimed invention obvious. MPEP 2143.01, III and IV; see also KSR, supra at 1740-1741. A fact finder should be aware, of course, of the distortions caused by hindsight bias and must be cautious of arguments reliant upon ex post reasoning. One cannot use hindsight reconstruction to pick and choose among isolated disclosures of elements in the prior art to obviate the claimed invention. In re Fine, 837 F.2d 1071, 1075 (Fed. Cir. 1988).
In view of the above legal principles and tenets to the present case, Applicant respectfully traverses as follow.
Regarding to Claims 32-35, which claim an antibody drug conjugate or an antibody drug conjugate pharmaceutical preparation prepared according to the preparation method of claim 23, the Office action concedes that "Jain may fail to explicitly teach ADC's with an anti-CD20 antibody", for example, rituximab (that is to say, Jain does not disclose rituximab or a biosimilar thereof can be made into an ADC with a DAR of 4 ). To remedy the deficiencies of Jain, the Office joins Wahl. However, Wahl should not teach or even suggest rituximab or a biosimilar thereof conjugating with vc-MMAE with a DAR of 4.2
+
1. Indeed, when study this reference in its entirety (e.g., as whole), Wahl should only provide the drug antibody ratio of Rituxan vcMMAE is 7. (See Wahl ,table 1)
Applicant further notes that the ADCs in Table I of Jain are all from Seattle Genetics' technology platform, so the ADCs developed by the same company on the same technology platform should not be used as evidence of widely representative. On the contrary, substantially number of institutions or researchers have taught to develop ADCs with lower DAR than 4, for example, Reference 1 (Dennler et al.) teaches MMAE- ADC with DAR 2 (see abstract), Reference 2(Cui et al.) teaches MMAE-ADC with DAR 2.5 (see abstract), Reference 3 (CN103145847B ) teaches the MMAE-ADC with DAR 1- 2 (see claim 1).
On an opposite side, some other institutions or researchers have taught to develop ADCs with higher DAR than 4, such as Reference 4 (Law et al.) teaches MMAE-ADC with DAR 7-7.5 (see Materials and Methods), Reference 5 (Francisco et al.) teaches a DAR 8 cAC10-vcMMAE (see Materials and Methods), Reference 6 (CN103254317B) teaches MMAE-ADC with DAR 8 (see abstract and claim 3), and
Wah
l
teaches MMAE-
ADC
with DAR 7.
In summary, it should be seen that the DARs of different MMAE-ADCs generally are selected from 1-8, and different institutions and researchers have different choices for the DAR, and in addition to a DAR of 4, prior arts also teach that the DAR can be less than 4 or greater than 4, that is,
DAR 4 is neither the unified understandin
g
of those skilled in the art, nor the preferred choice of those skilled in the art.
So that Rituxan-vcMMAE ADC with a DAR of 4 should not be obvious, and those skilled in the art based on the teachings of Jain and Wahl should not readily and obviously obtain a technical solution of the present application.
Applicant would like to further point out that Claims 32-35 include product-by- process limitations,1 and the process limitations play an important role on the ADC obtained and enable the ADC obtained substantially distinguished from those known.
It is known that an antibody-drug conjugate is indeed a mixture of different products obtained from a coupling reaction between the reduced antibody and a small molecule compound via a linker, and a particular DAR value is an average number of the small
1 The MPEP states that the "structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product." MPEP § 2113. In Exparte Inoue, the application at issue included a claim directed, in part, to a non-heat treated and hot forged steel product "improved by hot coining or hot sizing." Appeal 2009-1248, page 3 (BPAI, April 29, 2009). The BPAI considered the claim including hot coining and hot sizing to be a product-by-process claim. The Examiner apparently did not address the process limitations recited by the claim, and thus did not address the resulting structural changes implied by the process limitations. The BPAI held that the process steps of hot coining and hot sizing recited in the claim "impart a structural change in the steel product ... as disclosed in the Specification." Id. at 12. As the Examiner did not "provide any articulated reasoning with rationale underpinning" to support the rejection and failed to address the structural limitations implied by the recited process steps, the Examiner's rejection was reversed. Id.; see also Ex parte Lach, Appeal 2009-003510, page 5 (BPAI, June 25, 2009) (where the BPAI held that the Examiner failed to provide evidence or reasoning indicating that the cited reference would produce substantially the same product as would be obtained by the claimed product-by-process of appealed claim 1, as the Examiner did not explain why the cited reference would produce the same product despite differences between the process of the cited reference and the process of the product-by-process claims, but rather, merely alleged that the cited reference taught a final product that was substantially the same as the claimed product despite differences in the processes) and Ex parte Nishitani, Appeal 2008-4625, pages 3-4 (BPAl, Dec. 18, 2008) (where the BPAI found that the specification explained the structural differences between a final product made by a method of the cited reference and a final product made by the claimed process steps in the product-by-process claim and held that the "Examiner's refusal to give effect to the structure imparted to the claimed golf clubs by the product-by-process limitations [was] improper.").
molecule compounds conjugated to the antibody. Coupling products with a high proportion of component with a target DAR (in this case, the target DAR is 4, and the ADC obtained finally have an average in a range of 4.2 ± 0.5) in general have a drug stability and efficacy, so improving the proportion of the target the ADC obtained from the coupling reaction is the goal that researchers and technicians in this field hope to achieve.
The preparation method of the ADC is defined in Claim 23. The buffer system, reducing agent, reaction solvent, reaction temperature and time, and the like in the preparation method as a whole constitute a complete coupling reaction system, and have a significant impact in improving the proportion of the coupling product with a DAR of 4(D4). As shown in Fig. 1 of this application (see below), it should be clearly determined that in the instant application, the target component of DAR4(D4) in the ADC prepared is relatively high, and reaches the expected goal of drug development.
In this regard, Reference 7 (Mang et al.) is submitted as an illustrative counter example. Reference 7 discloses ADC with a DAR of 3.97; however, as shown in Figure 3 in Reference 7, the component with target DAR of 4 accounts for a low proportion, and components with a DAR of 0 and a DAR of 6 are the main components.
A
B
C
structure
SEC-HPLC
HIC-HPLC
M290-MC-vc-PAB-MMAE
Purity=99.0%  Average DAR=3.97
Figure 3 (a part) of Reference 7
It should be clearly seen that even if the average value of DAR is close, different preparation processes have an important impact on the proportions of the components with different DAR values, thus bringing essential differences to the structure and properties of the final product. The ADC obtained using the preparation method defined in Claim 23 is not just simply a reaction product between the reduced rituximab or a biosimilar thereof and vc- MMAE, while the preparation method defined in Claim 23 directly determines the composition and properties of the final product.
In addition, the HT preparation buffer used in step (4) recited in claim 23 is defined to contain 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(see paragraph [0105-0106] which described Buffer C, and Buffer C is just the HT preparation buffer).Such a buffer may maintain the high stability of the preparation and extend the shelf-life of the product. The cited references of record should not provide and disclose the formulation of the present application, and the formulation of the preparation is the determined formulation established by the insights of the inventors through the insight of screening experiments, which should not be obvious to those skilled in the art.
Moreover, Applicant would like to point out that although TFF unit operation is a related art buffer replacement technology, the inventors of this application specifically select TFF unit operation according to TFF buffer replacement after the coupling reaction (step 3) according to the characteristics of the reaction system in this application, and finally make the residual rate of reaction buffer less than 0.25% (see Example 2 section
of the specification of this application).The TFF unit operation has a direct effect on the properties of the ADC finally obtained.
Lastly, without to the propriety of the above definiteness rejection,
in an effort to
exp
edite allowance
of the present application and to better set forth the subject matter being claimed, Applicant has further amended claim 23 to recite, in the relevant part and among things,
(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."
Support can be found, as discussed above, e.g., in Example 2 section of the specification of this application. No new matter is added.
To further
ex
p
edite allowance and
distinguish the present invention from the references of record, claims 32-35 have been amended to each recite, in the relevant part and among other things,
"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
small molecule toxins conjugated to the antibody (DO)"
or the
similar. Support can be found, e.g., in FIG. 1 of the instant application as filed. No new matter is added.
In view of at least the above, Applicant respectfully submits claims 32-35 should be patentably distinguishable from the references of record.
Regarding Claims 23-31, since the ADC claimed in Claims 32-35 should not be obvious to those skilled in the art, the preparation method for the ADC should not be obvious either.
In addition to the discussion above, Applicant further noted differences between the cited references and the instant claimed invention.
First, although Sun disclosed that the preparation process of ADC includes the reduction of interchain disulfide bond, coupling reaction and termination reaction, and then UF/DF filtration, it can be seen from the comparison of three different methods (DNTB, TCTP, and DTT) that the ADC prepared by DTNB method has the highest DAR 4 enrichment percentage of 42%; DTNB method is followed by TCEP which provides a DAR 4 enrichment percentage of only 36%; and then TCEP method is followed by DTT, providing a DAR 4 enrichment percentage of only 32% (see Fig. 2 and the last paragraph of page 1285). It can be seen that the DTNB method provides the highest DAR 4 enrichment percentage and the best homogeneity of the product. In addition, the MTD of the E4 ADC prepared by DTNB method is 120 mg/kg, while the MTD of the E4 ADC prepared by DTT method is 100 mg/kg (see the last two lines of the right column on page 1287 to lines 1-5 of the left column on page 1288). Therefore, the ADC prepared by DTNB has the best safety and has higher potential for druggability. In summary, it can be seen that compared with TECP and DTT, DTNB has better physicochemical properties (especially with respect to DAR value distribution), better safety and higher potential as a medicine. Therefore, based on the instruction given by Sun, those skilled in the art should
believe the preferred method for the preparation of ADC should be the DTNB method because that method could bring the best effect to ADC, and those skilled in the art will not think of using the TCEP method which has the relatively worse effect.
In addition, the TCEP method does not disclose/provide the ratio of antibody to vcMMAE (in addition, the buffer, pH, time and temperature of the reduction reaction are different from those of the present application, see preparation method B on page 1283). According to the distribution of ADC DARs obtained, DAR 4 accounts for more than 45% in the present application, while DAR 4 only accounts for 36% in the references. In addition, DAR 2 accounts for the second place in the present application, higher than DAR 6, while the Sun is just the opposite. Therefore, Sun should not teach how to determine the appropriate ratio of antibody to vcMMAE and other important parameters (such as buffer, pH, time, and temperature, etc.) in the case of TCEP as a reducing agent (see preparation method B on page 1283) to obtain an ADC with higher DAR 4 enrichment and better drug potential.
Second, although Agarwal teaches that TCEP can be used for the reduction reaction, but conditions and the ratio of antibodies to reducing agents for the reduction reaction have not been disclosed in Agarwal. Based on Agarwal's teachings, those skilled in the art should not obtain an ADC preparation method which can provide suitable DAR and excellent DAR distribution, as the present application does.
Third, Kozak only teaches that excessive N-acetyl cysteine can be used to terminate the coupling reaction, but should not disclose specific reaction conditions, the ratio of antibodies to reducing agents, the ratio of antibodies to vcMMAE, and other parameters. Moreover, the average DAR of ADC prepared by Kozak is approximately 3.5. Based on above, those skilled in the art should not obtain the ADC preparation method which can provide ADC product with suitable DAR and excellent DAR distribution prepared based on Kozak's teachings.
More importantly, see Reference 8, Kozak used his preparation method to prepare six ADCs (anti-B,-C,-F,-M,-N, and -S) for different targets. According to the data recorded in its "SUPPORTING INFORMATION Table S1 (see below). Percent of DAR species
present in each ADC", although the average DAR values of the six ADCs are similar (3.6- 3.9), the distribution of DAR of different ADCs is very different, especially the proportion of the main component DAR 4 ranges from 36.4%-49.9% (the difference is greater than 13%). The most significant ones are anti-B and anti-N, whose DAR2(%) is basically equivalent to DAR4(%), which further indicates that antibodies target to different targets. Due to the unique physical and chemical properties of the antibody itself, the preparation method of its ADC is not universal, and in order to prepare the ADC with the expected DAR distribution, it is necessary to adjust the preparation process of the coupling reaction according to the physical and chemical properties of the antibody itself. So those skilled in the art should not obtain any technical insights from the provided references to adjust the coupling process parameters.
SUPPORTING TABLES
Table S1. Percent of DAR species present in each ADC.
Fourth, although Evans teaches that TFF can be used for buffer exchanging, but the method still requires cleaning of the reduced trastuzumab after the reduction reaction (see paragraph 0384), which followed by coupling reaction. It means more steps and reduced yield. In addition, the preparation buffer of Evans is not the same as that of the present application. The preparation buffer of the present application contains mannitol (see
paragraph [0117]of the present application), meanwhile the pH and content ratio of each component are also different, resulting in significant differences in the stability of the preparation. Those skilled in the art should not obtain the ADC formulation in this application based on Evans's teachings.
Finally, the Office cites a substantial number of references, which itself may proves the preparation method claimed cannot readily determined according to any prior art without impermissible hindsight and undue experimentation. In other words, such a preparation method for providing an antibody-drug conjugate of rituximab or a biosimilar thereof and vc-MMAE does not appear to be provided in any of the cited references and should not be easily or obviously obtained. Applicant respectfully requests that the ADC preparation method of this application shall be considered as a whole by the Office, rather than breaking it down into individual technical features, which would result in weak combination of insights. The citation is improper and highly suggestive of impermissible hindsight in the Office's analysis on the non-obviousness.
In Interconnect Planning Corp. v. Feil, 774 F.2d 1132, 1138 (Fed. Cir. 1985), the Federal Circuit noted that "[t]he invention must be viewed not with the blueprint drawn by the inventor, but in the state of the art that existed at the time." Likewise, in In re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992), the Federal Circuit admonished against hindsight reconstruction of an invention in the manner reflected by the present rejections. According to the Federal Circuit:
[lI]t is impermissible to use the claimed invention as an instruction manual or 'template' to piece together the teachings of the prior art so that the claimed invention is rendered obvious. ... This court has previously stated that '[o]ne cannot use hindsight reconstruction to pick and choose among
isolated disclosures in the prior art to deprecate the claimed invention.'
See also In re Gorman, 933 F.2d 982, 987 (Fed. Cir. 1991) ("As in all determinations under 35 U.S.C. § 103, the decision maker must bring judgment to bear. It is impermissible, however, simply to engage in a hindsight reconstruction of the claimed
invention, using the applicant's structure as a template and selecting elements from references to fill the gaps.").
Indeed, the recited biological drug is very complex, especially ADC products. Due to the large molecular weight and complex spatial structure of biomolecules, a change in any parameter may result in high uncertainty and unpredictability, as compared to chemical drugs or conventional mechanical structures. So, Applicant respectfully requests the inventiveness of this application based on the understanding that biopharmaceutical development is very complex and high uncertainty.
For at least the reasons detailed above, claims 23-35, as a whole, should at least now be patentably distinguishable over the references of record. Thus, Applicant respectfully requests the Office that the rejection under 35 U.S.C. § 103 be withdrawn, and that claims 23-35 be allowed.
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 .
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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695
493
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252
553
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156
482
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Francisco:
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247
497
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596
440
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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

CITED REFERENCE SUMMARIES: Ref CN103145847B: Claims:
anti-CD20 antibodies-aplysiatoxin conjugate, it is characterized in that, formed by connecting arm coupling anti-CD20 antibodies by aplysiatoxin, the light-chain amino acid sequence of described anti-CD20 antibodies is as shown in SEQ ID No.1, heavy chain amino acid sequence is as shown in SEQ ID No.2, described connecting arm is the amine-modified α-amino-isovaleric acid-citrulline dipeptides of maleimide, 1～2 aplysiatoxin molecule of each anti-CD20 antibodies molecule coupling.
a preparation method for anti-CD20 antibodies-aplysiatoxin conjugate, comprising:
(1) anti-CD20 antibodies is mixed with the aplysiatoxin with connecting arm, carry out linked reaction;
(2), after having reacted, separation and purification obtains described anti-CD20 antibodies-aplysiatoxin conjugate;
The light-chain amino acid sequence of described anti-CD20 antibodies is as shown in SEQ ID No.1, and heavy chain amino acid sequence is as shown in SEQ ID No.2;
Described connecting arm is the amine-modified Î±-amino-isovaleric acid-citrulline dipeptides of maleimide;
Before aplysiatoxin coupling, need make the cysteine sulfydryl of anti-CD20 antibodies in unbound state, concrete grammar comprises:
(a) anti-CD20 antibodies going out from host cell expression is dissolved in the PBS damping fluid of pH7.4, adds trichloroethyl phosphate, 30～40 ℃ of water-bath 1～3h;
(b) ultrafiltration remove in reaction solution molecular weight lower than the material of 10kDa with PBS washing;
(c) add L-dehydroascorbic acid, 30～40 ℃ of water-bath 1～3h;
(d) ultrafiltration remove molecular weight in reaction solution with PBS washing and, lower than the material of 10kDa, obtain the anti-CD20 antibodies with free cysteine sulfydryl.
preparation method as claimed in claim 2, is characterized in that, the temperature of described linked reaction is below 4 ℃, and the time is 60～120min.
preparation method as claimed in claim 2, it is characterized in that, described separation purification method is: utilize ultrafiltration to remove in reaction solution molecular weight lower than the material of 10kDa, then through the centrifugal precipitation of going, by the filtration sterilization of gained supernatant, be described anti-CD20 antibodies-aplysiatoxin conjugate.
Ref CN103254317B: Claims:
a preparation method for anti-CD-20 monoclonal antibody-aplysiatoxin conjugate, comprising:
(1) in the PBS damping fluid that contains 10mg/mL Ofatumumab monoclonal antibody, add tricresyl phosphate (β-chloroethyl) ester of 5.5-10 times of molar weight, 37 ℃ of water-bath 2h, are placed on ice;
The pH value of described PBS damping fluid is 7.4;
(2) add while stirring 10 times of excessive aplysiatoxins with connecting arm that dissolve by 30% acetonitrile/water, 4 ℃ of reaction 60min, add excessive halfcystine termination reaction;
(3) cross HiPrepTM26/10desalting post, use PBS wash-out, remove small molecules, obtain described anti-CD-20 monoclonal antibody-aplysiatoxin conjugate.
preparation method as claimed in claim 1, is characterized in that, described connecting arm is the amine-modified Î±-amino-isovaleric acid-citrulline dipeptides of maleimide.
anti-CD-20 monoclonal antibody-aplysiatoxin conjugate that the preparation method as described in as arbitrary in claim 1～2 obtains, is characterized in that 8 aplysiatoxin molecules of each anti-CD-20 monoclonal antibody molecule coupling.
the application of anti-CD-20 monoclonal antibody-aplysiatoxin conjugate as claimed in claim 3 in preparing antitumor drug; It is characterized in that, described antitumor drug is anti-B lymphoid tumor medicament.
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