Office Action 2: Final Rejection (2023-02-01)
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: Listinq of Claims:

1\. (Currently Amended) An antibody-drug conjugate pharmaceutical preparation, wherein the preparation comprises:
(a) an antibody-drug conjugates 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 an integer of 4 or a non-integer of 4.2 1; and
"" is a bond; and
(b) a carrier or excipient, wherein the structure of the antibody-drug coniugate is shown as the following formula: SVG {EMBED HERE} 1.3 5.68
and wherein the antibody-drug conjugate is prepared by a preparation method comprises the following steps:
(1) performing a reduction reaction between the recombinant anti-CD20 monoclonal antibody and a reducinq agent, thereby obtaininq a reaction system comprising a reduced recombinant anti-CD20 monoclonal antibody; and a molar ratio of the recombinant anti-CD20 monoclonal antibody to the reducing agent is 1: 2.9 to 1:
3.1; and
(2) performing a coupling reaction between the reaction system of step (1) and a solution of a small molecule toxin in acetonitrile and water to form the antibody-drug coniugate; 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.

2\. (Canceled)

3\. (Canceled)

4\. (Canceled)

5\. (Original) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein the preparation is an injection.

6\. (Original) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein the preparation is a solution or a lyophilized agent.
7\. (Original) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein the carrier or excipient is selected from the group consisting of a pH buffer, an osmotic pressure regulator, a lyophilized powder excipient, a protein protecting agent, a solubilizer, and water for injection.

8\. (Canceled)

9\. (Currently Amended) A method of preparing anti-tumor drugs, the method comprising utilizing the antibody-drug conjugate pharmaceutical preparation according to claim 1 .

10\. (Canceled)

11\. (New) A method for treating or preventing a tumor, comprising administering the antibody-drug conjugate pharmaceutical preparation according to claim 1 to a subject in need thereof.

12\. (New) The method of claim 11, wherein the tumor is lymphoma or leukemia.

13\. (New) The method of claim 11, wherein the tumor is B-cell non-Hodgkin's lymphoma or chronic lymphocytic leukemia.

14\. (New) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein in step (1), the reduction reaction is performed in a PB (phosphate buffer) reaction buffer (pH7.6), and the reduced recombinant anti-CD20 monoclonal antibody is recombinant anti-CD20 monoclonal antibody whose interchain disulfide bond is reduced to sulfhydryl groups.

15\. (New) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein in step (1), the reducing agent is tris (2-carboxyethyl) phosphine, and the molar ratio of the recombinant anti-CD20 monoclonal antibody to the reducing agent is about 1:3.

16\. (New) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein in step (1), the reduction reaction is performed at 25±1 0C for 90±10 minutes.

17\. (New) The antibody-drug conjugate pharmaceutical preparation of claim 1, 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.

18\. (New) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein in step (2), a volume ratio of acetonitrile to water is 1:1.

19\. (New) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein in step (2), the coupling reaction is performed at 4±0.5 0C for 60±10 minutes.

20\. (New) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein step (2) further comprises a mixing step comprising adding a solution of the small molecule toxin in acetonitrile and water dropwise to the reaction system of step (1).

21\. (New) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein the carrier or excipient comprises histidine hydrochloride, trehalose, mannitol, polysorbate 80, and/or water for injection.

22\. (New) The antibody-drug conjugate pharmaceutical preparation of claim 1, wherein the antibody-drug conjugate is prepared by a preparation method comprises the following steps:
(Al) mixing PB (phosphate buffer) reaction buffer (about pH 7.6) and tris (2- carboxyethyl) phosphine (TCEP) to obtain a mixture solution, adding the recombinant anti-CD20 monoclonal antibody into the mixture solution, wherein the molar ratio of the recombinant anti-CD20 monoclonal antibody to TCEP is about 1:3, and stirring the reaction system obtained and performing the reduction reaction between the recombinant anti-CD20 monoclonal antibody and TCEP for 90 min at 25 C;
(A2) adding vcMMAE to 50 % acetonitrile-water to obtain a solution of vcMMAE which is then carefully and gently dropped into the reaction system obtained from step (Al), wherein the molar ratio of the recombinant anti-CD20 monoclonal antibody to vcMMAE is about 1:7.5, and performing a coupling reaction between the reaction system obtained from step (Al) and vcMMAE for 1 h at 4 C;
(A3) adding a solution of L-cysteine in a diethylenetriaminepentaacetic acid (DTPA) solution into the reaction system obtained from step (2) within 10 min to terminate the coupling reaction; and
(A4) transferring the reaction system obtained from step (A3) to a tangential flow filtration (TFF) system, and replacing the PB reaction buffer with a L-histidine/trehalose preparation buffer containing L-histidine, trehalose dihydrate, and Tween 80 (about pH 6.5), and filtering the solution obtained with a 0.22 micrometer Rapid - Flow device, wherein a residual rate of PB reaction buffer in a final solution is less than 0.25%, thereby obtaining the antibody-drug conjugate.
\-2- -3- -4- -5- -6- 119132371.1

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 rejection under section 112(a) is withdrawn in view of Applicant’s Amendments and remarks in connection with this ground of rejection.
The rejections under section 112(b) is maintained, below.  Any new grounds of rejection under this section 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 1, 5-7, 9, 11-22 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 structural criteria of a rituximab “biosimilar” remains undefined.  Applicant argues that the antibody made in the specification (TRS001) is identical to rituximab and that based on this antibody a biosimilar antibody is a monoclonal antibody agent developed utilizing the sequence of rituximab.  However, as Applicant indicated, TRS001 is the same antibody as rituximab.  the specification and claims do not define any other parameters for “biosimilar” other than it is the same antibody as rituximab.  Therefore, it is unclear which antibodies, other than rituximab, Applicant intends to cover by the term “biosimilar”.
Claim 9 still recites a utilizing the instant ADC without any of the required preparation steps for anti-tumor drugs.
The prior art rejection is withdrawn in favor of the following new grounds of rejection under this section, which are necessitated by Applicant’s amendments.
Omission of claim 7 from the previous rejection under this section was an obvious error since the rejection explicitly states that “[t]he recited preparation, such as those suitable for injection are taught, see paragraphs 0242+.” which is covered in claim 7.  The rejection also stated that Wahl also discloses the recited excipients suitable for these ADC.s see paragraphs 247+. Therefore, the rejection of claim 7 is included 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) 1, 5-7, 9, 11-22 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:
PNG
media_image1.png
757
1389
media_image1.png
Greyscale
Jain teaches that these ADC’s with the recited drug-antibody-ratio (DAR) are known:
PNG
media_image2.png
386
677
media_image2.png
Greyscale
The recited preparation, such as those suitable for injection are taught, see paragraphs 0242+.
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:
PNG
media_image3.png
409
446
media_image3.png
Greyscale
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.
Applicant argues that Wahl does not teach or suggest rituximab or a biosimilar thereof conjugating with monomethyl auristatin-E with the average number of the small molecule toxins conjugated to the antibody of 4.2 + 1. Applicant also argues that Wahl provides the drug- antibody ratio of Rituxan-vcMMAE is 7. (See Wahl, table 1).
However, 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:
PNG
media_image4.png
902
955
media_image4.png
Greyscale
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.
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 have been canceled, without prejudice and without disclaimer. Claims 23-35 are newly added. No new matter has been introduced.
In this amendment, Applicant has added various claims and canceled the others to expedite allowance of the application without prejudice or disclaimer. Applicant is not conceding patentability of the subject matter encompassed by the claims prior to this amendment over the art cited by the Examiner. As such, Applicant respectfully reserves the right to pursue these claims in one or more continuing applications, including claims capturing the subject matter encompassed by the claims prior to this amendment and additional claims. With this amendment, Applicant respectfully requests reconsideration and allowance of the pending claims.
Claim Amendments
Without conceding to any issues, in an effort to advance prosecution of the present application, Applicant has canceled Claims 1-22 and added claims 23-35 which are directed to a preparation method to better set forth the subject matter being claimed. Please refer to the new Claim 23, in which the steps and the features claimed are fully supported by paragraphs [0029]-[0043] as well as by Example 2 of the specification as originally filed. Further, new Claims 24-31 are directed to the additional technical features in the process of the preparation method depended from the new Claim 23 and supported by the specification as filed; and additionally, new Claims 32-35 directed to the ADCs and the pharmaceutical preparation obtained by the preparation method according to Claim 23. No new matter has been added.
Rejection of Claims Under 35 U.S.C.
%
Claims 1,5-7, 9, 11 -22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre- AlA), 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.
Without conceding to any issues, in an effort to expedite allowance of the present application and to better set forth the subject matter being claimed, Applicant has canceled Claims 1-22 and added claims 23-35 which are directed to a preparation method. Accordingly, the rejection of the claims should now be moot. Applicant respectfully requests withdrawal of the rejections under 35 U.S.C. @ 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph.
Moreover, Applicant would like to further note that:
For "biosimilar" maintained in Claim 23, according to 42 U S C @ 262, term "biosimilar" or "biosimilarity", in reference to a biological product that is the subject of an application under subsection (k), means:
(A) that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and
(B) there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.
In this case, based on 42 U S C @ 262:
"Rituximab" refers to a monoclonal antibody targeting CD20 developed by Roche, and has brand name "Rituxan". In the present application "Rituximab" is the reference product.
"Rituximab biosimilar" refers to a monoclonal antibody targeting CD20 developed by other companies, which has the same amino acid sequence and similar physicochemical properties, efficacy, pharmacokinetics, and safety to the reference product (Rituximab) developed by Roche.
In the field of biological product, due to different preparation processes, the TRS001 prepared by the Applicant should not be exactly the same as the rituximab prepared by Roche. In the present application, Example 1, the antibody (TRS001) developed by Applicant should be a Rituximab biosimilar.
Rej
ection of Claims Under 35 U.S.C.
§
Claim(s) 1,5-7, 9, 11 -22 are rejected under 35 U.S.C. § 103 as being unpatentable over Jain et al., Pharm Res (2015) 32:3526-3540 (hereinafter "Jain"); in view of U.S. Publication No. 20050180972 based on an application by Wahl et al. (hereinafter "Wahl") and Chen et al., Determination of Drug-to-Antibody Ratio for Antibody-Drug Conjugates Purified from Serum, Agilent Technologies, pp. 1-9, 2016 (hereinafter "Agilent").
Without conceding to any issues, in an effort to expedite allowance of the present application and to better set forth the subject matter being claimed, Applicant has canceled Claims 1-22 and added claims 23-35 which are directed to a preparation method. Applicant respectfully submits that Jain, Wahl, and Agilent, individually or in combination, should not teach, disclose, suggest, or provide for even the insight of the limitations and features recited by claims 23-35. Therefore, the present claims should be allowable over the references of record, and Applicant respectfully requests that the rejection under 35 U.S.C. § 103 be withdrawn.
In addition, Applicant notes Claims 23 - 31 should correspond to the subject matters claimed in CN application No. 201710087313.9 which have been granted as a patent right by the China National Intellectual Property Administration (CNIPA). Please refer to the enclosed Certificate of Invention just issued (Exhibit A), and the granted claims in that issued patent.
It should be noted that, during the examination on CN application No. 201710087313.9 and regarding inventiveness of the claims, U.S. Publication No.
20050180972 was also cited by the Examiner at CNIPA, as the primary or closest prior art. However, the CNIPA Examiner recognized the inventiveness of the claims directed toward the preparation method.
Here, as noted in a related cooperative program between the USPTO and participating foreign patent offices to expedite the allowance of utility patent applications that previously received favorable rulings (i.e., the Patent Prosecution Highway (PPH)), the USPTO notes that:
The Patent Prosecution Highway (PPH) speeds up the examination process for corresponding applications filed in participating intellectual property offices.
Under PPH, participating patent offices have agreed that when an applicant receives a ruling from a first patent office that at least one claim is allowable, the applicant may request fast track examination of corresponding claim(s) in a corresponding patent application that is pending in a second patent office. PPH leverages fast-track examination procedures already in place among participating patent offices to allow applicants to reach final disposition of a patent application more quickly and efficiently than standard examination processing.
As such, Applicant hopes the Examiner here may facilitate the examination of the allowability of the new claims in the USPTO based on at least the information discussed above and/or the work already done by the Examiner at the participating (CNIPA) patent office.
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 6/1/2023 has been entered.
The rejection under section 11(b) is withdrawn in view of Applicant’s amendments.
The rejection under section 103 is moot since the rejected claims have been canceled.  The rejection is newly applied to product-by-process claims 32-35:
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:
PNG
media_image1.png
757
1389
media_image1.png
Greyscale
Jain teaches that these ADC’s with the recited drug-antibody-ratio (DAR) are known:
PNG
media_image2.png
386
677
media_image2.png
Greyscale
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:
PNG
media_image3.png
409
446
media_image3.png
Greyscale
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:
PNG
media_image4.png
902
955
media_image4.png
Greyscale
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)”).
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:
PNG
media_image5.png
737
696
media_image5.png
Greyscale
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:
PNG
media_image6.png
70
1422
media_image6.png
Greyscale
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.
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 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.
Conclusion

CITED REFERENCE SUMMARIES: Ref US20050180972B: [content unavailable]