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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/7/2026 has been entered.
Status of the Claims
2. Claims 1-18 are all the claims filed on 1/26/2023. In the Preliminary Amendment of 2/3/2023, Claims 12-10, 12 and 14-18 are amended, claim 11 is canceled and new claims 19-21 are added. Claims 1-10 and 12-21 are the pending claims. In the Response of 12/1/2025, Claims 1-5, 7, 9-10, 12, 15-16, and 18-21 are amended, Claims 6, 8, 11 and 14 are canceled, and new Claims 22-24 are added. IN the Response After Final Action of 4/14/2026, the claims are not entered. In the Response of 5/7/2026, Claims 1, 10, 21 and 23-24 are amended, claims 3-5, 7, 9, 19-20 and 22 are canceled and new Claims 25 is added.
Claims 1-2, 10 and 12-13, 15-18, 21, and 23-25 are pending.
The Office Action contains new grounds for rejection.
Priority
3. USAN 18/007,012, filed 01/26/2023, and having 1 RCE-type filing therein, is a National Stage entry of PCT/CN2021/ 108455, International Filing Date: 07/26/2021, claims foreign priority to CN 202010733597.6, filed 07/27/2020.
Information Disclosure Statement
4. As of 6/4/2026, a total of six (6) IDS are filed: 4/6/2023; 4/7/2023; 9/24/2024; 2/20/2026; 2/26/2026; and 5/7/2026. The corresponding initialed and dated 1449 form is considered and of record.
Note the references cited in the IDS of 2/20/2026 are duplicated in the IDS of 5/7/2026; and the reference cited in the IDS of 2/26/2026 is duplicated in the IDS of 5/7/2026. The references are redundant but are each considered and of record.
Examiner’s Comments RE: Claim 25 in the Advisory Action
5. Applicants allege the recitation of "citric acid-sodium citrate buffer" in claim 25 is supported by the cancelled portion of claim 23, which was examined in the Office Action dated February 19, 2026. In fact, citric acid-sodium citrate buffer is recited in original claim 2 as filed, which provided "the liquid formulation according to claim 1, wherein the buffer comprises one or more of a histidine-histidine hydrochloride buffer, a succinic acid-sodium succinate buffer and a citric acid-sodium citrate buffer." (US Pub No. 2023/0279138, emphasis added). Original claim 2 was examined in the Office Action of September 17, 2025. Original claim 2 was later amended to specifically recite "the liquid formulation according to claim 1, wherein the buffer comprises a citric acid-sodium citrate buffer." The amended claim 2 was examined in the Office Action of February 19, 2026.
Response to Arguments
Amended claim 1 elements (a)-(d) in the Response of 5/7/2026 is narrower in scope than that previously examined in the record history, and from which claim 2 depends. New claim 25 elements (a)-(d) is narrower in scope than newly amended claim 1 elements (a)-(d). Therefore, the relative scope of the claims as between claims 2 and 25 much less with respect to the species of citric-acid-sodium citrate buffer (i.e., no amount in claim 2 vs an amount (10 mM) in claim 25) is distinct. Accordingly, a determination that new claim 25 raised new grounds for consideration in the Advisory Action of 4/21/2026 is with merit based on the relative change in scope for generic claim 1 vis-à-vis dependent claim 2 and generic claim 1 vis-à-vis dependent claim 25.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
6. The rejection of Claims 5 and 7 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn and moot. Claims 5 and 7 are canceled.
Claim Rejections - 35 USC § 112(b)
7. The rejection of Claims 1-5, 7, 9-10 and 12-13 and 15-23 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot for the canceled claims and withdrawn for the pending claims. Generic claim 1 is amened to delete the phrase comprising the term “about” and claim 4 is canceled.
Claim Rejections - 35 USC § 112(a)
8. The rejection of Claim 21 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement is withdrawn. Claim 21 is amended to clarify and distinguish the patient having the CD20-related cancer from preventing the CD20-related cancer.
Examiner’s Comments RE: Chen Reference
9. It is noted that while Chen shares neither a common assignee nor a common inventor with the instant application, the drawings for Figures 1-12 filed in each application are identical, the figure legends in Chen ([0040-0051]) are identical to the figure legends ([0136-01470]) in the instant specification, and the working examples in Chen (Examples 1-5) are identical to the working examples (Examples 1-5) in the instant application.
Claim Rejections - 35 USC § 103
10. The rejection of Claim(s) 1-2, 10 and 12-13, 15-18, 21, and 23-25 under 35 U.S.C. 103 as being unpatentable over Chen et al (US 17/425,870; US 20220162312; filed at least as of 1/22/2020) is withdrawn.
Chen teaches the bispecific anti-CD3/anti-CD20 polypeptide complex of instant claim 18 having 100% identity to SEQ ID NOS: 41-44 and
where the anti-CD3 HCDR1-3/LCDR1-3 and anti-CD20 HCDR1-3/LCDR1-3 are identical to those recited in instant claims 1, 15 and 24:
SEQ ID NO: 41: Sequence 89, US/17425870
Publication No. US20220162312A1
GENERAL INFORMATION
APPLICANT: WUXI BIOLOGICS (SHANGHAI) CO., LTD.
APPLICANT: WUXI BIOLOGICS IRELAND LIMITED
TITLE OF INVENTION: NOVEL BISPECIFIC CD3/CD20 POLYPEPTIDE COMPLEXES
FILE REFERENCE: IEC186116PCT
CURRENT APPLICATION NUMBER: US/17/425,870
CURRENT FILING DATE: 2021-07-26
PRIOR APPLICATION NUMBER: PCT/CN2019/073418
PRIOR FILING DATE: 2019-01-28
NUMBER OF SEQ ID NOS: 122
SEQ ID NO 89
LENGTH: 700
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: heavy chain 1
SEQ ID NO: 42: Sequence 90, US/17425870
Publication No. US20220162312A1
GENERAL INFORMATION
APPLICANT: WUXI BIOLOGICS (SHANGHAI) CO., LTD.
APPLICANT: WUXI BIOLOGICS IRELAND LIMITED
TITLE OF INVENTION: NOVEL BISPECIFIC CD3/CD20 POLYPEPTIDE COMPLEXES
FILE REFERENCE: IEC186116PCT
CURRENT APPLICATION NUMBER: US/17/425,870
CURRENT FILING DATE: 2021-07-26
PRIOR APPLICATION NUMBER: PCT/CN2019/073418
PRIOR FILING DATE: 2019-01-28
NUMBER OF SEQ ID NOS: 122
SEQ ID NO 90
LENGTH: 447
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: heavy chain 2
SEQ ID NO: 43: Sequence 88, US/17425870
US/17425870
Publication No. US20220162312A1
GENERAL INFORMATION
APPLICANT: WUXI BIOLOGICS (SHANGHAI) CO., LTD.
APPLICANT: WUXI BIOLOGICS IRELAND LIMITED
TITLE OF INVENTION: NOVEL BISPECIFIC CD3/CD20 POLYPEPTIDE COMPLEXES
FILE REFERENCE: IEC186116PCT
CURRENT APPLICATION NUMBER: US/17/425,870
CURRENT FILING DATE: 2021-07-26
PRIOR APPLICATION NUMBER: PCT/CN2019/073418
PRIOR FILING DATE: 2019-01-28
NUMBER OF SEQ ID NOS: 122
SEQ ID NO 88
LENGTH: 213
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: light chain 2
SEQ ID NO: 44: Sequence 87, US/17425870
Publication No. US20220162312A1
GENERAL INFORMATION
APPLICANT: WUXI BIOLOGICS (SHANGHAI) CO., LTD.
APPLICANT: WUXI BIOLOGICS IRELAND LIMITED
TITLE OF INVENTION: NOVEL BISPECIFIC CD3/CD20 POLYPEPTIDE COMPLEXES
FILE REFERENCE: IEC186116PCT
CURRENT APPLICATION NUMBER: US/17/425,870
CURRENT FILING DATE: 2021-07-26
PRIOR APPLICATION NUMBER: PCT/CN2019/073418
PRIOR FILING DATE: 2019-01-28
NUMBER OF SEQ ID NOS: 122
SEQ ID NO 87
LENGTH: 207
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: light chain 1
Chen teaches citrate buffer but does NOT teach any ranges for a liquid formulation comprising the anti-CD3/CD20 polypeptide complex.
Chen does NOT teach or suggest trehalose much less any ranges for a liquid formulation comprising the anti-CD3/CD20 polypeptide complex.
Chen teaches sodium chloride (NaCl) but does NOT teach any ranges for a liquid formulation comprising the anti-CD3/CD20 polypeptide complex.
Chen teaches polysorbate 80 (Tween-80) but does NOT teach any ranges for a liquid formulation comprising the anti-CD3/CD20 polypeptide complex.
Chen does NOT teach or suggest polysorbate 20 (Tween-20) much less any ranges for a liquid formulation comprising the anti-CD3/CD20 polypeptide complex.
Chen teaches liquid formulations encompassing the specific elements of (a)-(b) and (d) and a pH but does not teach the ranges.
Rejections Maintained
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
11. The rejection of Claims 1-2, 10 and 12-13, 15-18, 21, and 23-25 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is moot for the canceled claims and maintained for the pending claims.
Applicants allege the claim chart provided on pp. 10-16 of the Response of 5/7/2026 defines the support for the amended claims.
Response to Arguments
Just as important in identifying literal and/or actual support for a liquid/lyophilized formulation of reagents is for the antibody comprised within the formulation much less being “derived” per se from the anti-CD3 H/LCDR1-3 and anti-CD20 H/LCDR1-3 and linked to a TCR constant region described in generic claims 1, 12-13, 21, and 24.
Claim construction/ interpretation
“derived”/ “derivative”: the specification provides no per se definition for the meaning of what elements of the corresponding CDRs are derived from the recited structure (SEQ ID NO).
The POSA cannot reasonably determine what is encompassed by the derivative of any CDR that is required by structure to possess the function of binding any CD3 protein or any CD20 protein. The generic claims recite only minimal structural features or partial structural features. MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics) or through a sufficient description of a representative number of species. Either is considered sufficient to show the applicant was in possession of the claimed genus.
Regarding structure-function correlation, the specification teaches bispecific CD3/CD20 TCR polypeptide complexes (denoted as “BsAbs”) in Table 2 for HC and LC where the footnote to the table advises “Note: TCR sequences are shown in italic.”
Buffer conditions for the “BsAbs” of the invention
Buffer conditions tested in serum stability assays are for one clone shown in Example 3
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172
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Buffer/ pH conditions are for various assays shown in Tables 9-11 in Example 6 are shown for “the lead Ab”, WBP3278 or W3278-U2T3.F18R-1.uIgG4. No other examples of a BsAbs from Table 2 are analyzed for liquid formulation conditions.
Sugar/Surfactant conditions are for various assays shown in Tables 12-13 in Example 7 are shown for “the lead Ab”, WBP3278 or W3278-U2T3.F18R-1.uIgG4. No other examples of a BsAbs from Table 2 are analyzed for liquid formulation conditions.
Sugar/Surfactant conditions are for various assays shown in Tables 14-17 11 in Example 8.1 are shown for “the lead Ab”, WBP3278 or W3278-U2T3.F18R-1.uIgG4. No other examples of a BsAbs from Table 2 are analyzed for liquid formulation conditions.
Sugar/Surfactant conditions are for an assay shown in Table 18 in Example 8.2 are shown for “the lead Ab”, WBP3278 or W3278-U2T3.F18R-1.uIgG4. No other examples of a BsAbs from Table 2 are analyzed for liquid formulation conditions.
Bioassay with lyophilized buffer conditions are shown in Table 19 of Example 9 for “the lead Ab”, WBP3278 or W3278-U2T3.F18R-1.uIgG4. No other examples of a BsAbs from Table 2 are analyzed for lyophilized formulation conditions.
Buffer conditions for the assay are shown in Table 20 of Example 10 are shown for “the lead Ab”, WBP3278 or W3278-U2T3.F18R-1.uIgG4. No other examples of a BsAbs from Table 2 are analyzed for liquid formulation conditions.
Regarding a reasonable number of species, the specification does not support a reasonable number of species having a structure/function correlation between the claimed buffer conditions and the genus of anti-CD3/anti-CD20 polypeptide complexes. “The lead Ab”, WBP3278 or W3278-U2T3.F18R-1.uIgG4, is the only clone that meets the definition of a “BsAb” that was examined and those data shown in the specification as filed. Insofar as those data shown in Figures 1-12, they correspond to Examples 1-5. Insofar as Examples 6-10, those data correspond to testing buffer conditions for a single inventive clone.
Regarding the state of art for formulations of bispecific polypeptides, formulations are engineered to prevent protein aggregation, mitigate surface absorption, and minimize the oxidation of the polysorbate excipient of the bispecific antibody formulation. Citrate buffer maintains the formulation's required pH of 6.0 to 6.5 and acts as a chelating agent that mitigates the iron-mediated degradation of polysorbate 80. Trehalose stabilizes disaccharides and is a lyoprotectant that protects the antibody's native structure from environmental stress. NaCl (sodium chloride) provides tonicity to the solution to make it isotonic (safe for parenteral administration). Polysorbate 80 (Tween-80) protects the bispecific antibody from interface-induced denaturation, mechanical stress during shipping, and unwanted surface adsorption. (See Strickley et al (PTO 892)). “The lead Ab”, WBP3278 or W3278-U2T3.F18R-1.uIgG4, is the only clone that meets the definition of a “BsAb” that was examined and those data shown in the specification as filed. The specification does not support a reasonable number of species having a structure/function correlation between the claimed buffer conditions and the genus of anti-CD3/anti-CD20 polypeptide complexes in which they are formulated.
The rejection is maintained.
New Grounds for Rejection
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.
12. Claims 1-2, 10 and 12-13, 15-17, 21, and 23-25 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.
Claims 1-2, 10 and 12-13, 15-17, 21, and 23-25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are: the “association” between a first antigen binding portion with a second antigen-binding portion. The bispecific polypeptide complex structure is interpreted as (VH-TCR(C1)-TCR(C2)-VL) or (VL-TCR(C1)-TCR(C2)-VH) and VH-CH-CL-VL. The “association” between the structures is not readily ascertainable. Claims 16-17 do not relate the nature or kind of dimerization domain that serves as the association between (or in addition to) the TCR dimer and the CH-CL dimer. Claims 16-17 do not rectify the deficiencies of the generic claims in defining the anti-CD3/CD20 polypeptide complex.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
13. Claim(s) 1-2, 10 and 12-13, 15-18, 21, and 23-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (US 17/425,870; US 20220162312; filed at least as of 1/22/2020) in view of Zhao et al (WO 2020/258893; filed 2/18/2020) as evidenced by Strickley et al (PTO 892).
The interpretation of the claims in view of Chen is of record.
The claimed formulation is prima facie obvious over Chen in view of Zhao as evidenced by Strickley.
Chen teaches the bispecific anti-CD3/anti-CD20 polypeptide complex of instant claim 18 having 100% identity to SEQ ID NOS: 41-44 and
where the anti-CD3 HCDR1-3/LCDR1-3 and anti-CD20 HCDR1-3/LCDR1-3 are identical to those recited in instant claims 1, 15 and 24:
SEQ ID NO: 41: Sequence 89, US/17425870
Publication No. US20220162312A1
GENERAL INFORMATION
APPLICANT: WUXI BIOLOGICS (SHANGHAI) CO., LTD.
APPLICANT: WUXI BIOLOGICS IRELAND LIMITED
TITLE OF INVENTION: NOVEL BISPECIFIC CD3/CD20 POLYPEPTIDE COMPLEXES
FILE REFERENCE: IEC186116PCT
CURRENT APPLICATION NUMBER: US/17/425,870
CURRENT FILING DATE: 2021-07-26
PRIOR APPLICATION NUMBER: PCT/CN2019/073418
PRIOR FILING DATE: 2019-01-28
NUMBER OF SEQ ID NOS: 122
SEQ ID NO 89
LENGTH: 700
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: heavy chain 1
SEQ ID NO: 42: Sequence 90, US/17425870
Publication No. US20220162312A1
GENERAL INFORMATION
APPLICANT: WUXI BIOLOGICS (SHANGHAI) CO., LTD.
APPLICANT: WUXI BIOLOGICS IRELAND LIMITED
TITLE OF INVENTION: NOVEL BISPECIFIC CD3/CD20 POLYPEPTIDE COMPLEXES
FILE REFERENCE: IEC186116PCT
CURRENT APPLICATION NUMBER: US/17/425,870
CURRENT FILING DATE: 2021-07-26
PRIOR APPLICATION NUMBER: PCT/CN2019/073418
PRIOR FILING DATE: 2019-01-28
NUMBER OF SEQ ID NOS: 122
SEQ ID NO 90
LENGTH: 447
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: heavy chain 2
SEQ ID NO: 43: Sequence 88, US/17425870
US/17425870
Publication No. US20220162312A1
GENERAL INFORMATION
APPLICANT: WUXI BIOLOGICS (SHANGHAI) CO., LTD.
APPLICANT: WUXI BIOLOGICS IRELAND LIMITED
TITLE OF INVENTION: NOVEL BISPECIFIC CD3/CD20 POLYPEPTIDE COMPLEXES
FILE REFERENCE: IEC186116PCT
CURRENT APPLICATION NUMBER: US/17/425,870
CURRENT FILING DATE: 2021-07-26
PRIOR APPLICATION NUMBER: PCT/CN2019/073418
PRIOR FILING DATE: 2019-01-28
NUMBER OF SEQ ID NOS: 122
SEQ ID NO 88
LENGTH: 213
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: light chain 2
SEQ ID NO: 44: Sequence 87, US/17425870
Publication No. US20220162312A1
GENERAL INFORMATION
APPLICANT: WUXI BIOLOGICS (SHANGHAI) CO., LTD.
APPLICANT: WUXI BIOLOGICS IRELAND LIMITED
TITLE OF INVENTION: NOVEL BISPECIFIC CD3/CD20 POLYPEPTIDE COMPLEXES
FILE REFERENCE: IEC186116PCT
CURRENT APPLICATION NUMBER: US/17/425,870
CURRENT FILING DATE: 2021-07-26
PRIOR APPLICATION NUMBER: PCT/CN2019/073418
PRIOR FILING DATE: 2019-01-28
NUMBER OF SEQ ID NOS: 122
SEQ ID NO 87
LENGTH: 207
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: light chain 1
Chen teaches liquid formulations in general at [0301-0302] and specifically at
[0304] To further illustrate, pharmaceutical acceptable carriers may include, for example, aqueous vehicles such as sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, or dextrose and lactated Ringer's injection, nonaqueous vehicles such as fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, or peanut oil, antimicrobial agents at bacteriostatic or fungistatic concentrations, isotonic agents such as sodium chloride or dextrose, buffers such as phosphate or citrate buffers, antioxidants such as sodium bisulfate, local anesthetics such as procaine hydrochloride, suspending and dispersing agents such as sodium carboxymethylcelluose, hydroxypropyl methylcellulose, or polyvinylpyrrolidone, emulsifying agents such as Polysorbate 80 (TWEEN-80), sequestering or chelating agents such as EDTA (ethylenediaminetetraacetic acid) or EGTA (ethylene glycol tetraacetic acid), ethyl alcohol, polyethylene glycol, propylene glycol, sodium hydroxide, hydrochloric acid, citric acid, or lactic acid. Antimicrobial agents utilized as carriers may be added to pharmaceutical compositions in multiple-dose containers that include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Suitable excipients may include, for example, water, saline, dextrose, glycerol, or ethanol. Suitable non-toxic auxiliary substances may include, for example, wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, or agents such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, or cyclodextrin.
Chen teaches lyophilized formulations at [0308].
Chen teaches citrate buffer but does NOT teach any ranges for a liquid formulation comprising the anti-CD3/CD20 polypeptide complex.
Chen does NOT teach or suggest trehalose much less any ranges for a liquid formulation comprising the anti-CD3/CD20 polypeptide complex.
Chen teaches sodium chloride (NaCl) but does NOT teach any ranges for a liquid formulation comprising the anti-CD3/CD20 polypeptide complex.
Chen teaches polysorbate 80 (Tween-80) but does NOT teach any ranges for a liquid formulation comprising the anti-CD3/CD20 polypeptide complex.
Chen does NOT teach or suggest polysorbate 20 (Tween-20) much less any ranges for a liquid formulation comprising the anti-CD3/CD20 polypeptide complex.
Chen teaches liquid formulations encompassing the specific elements of (a)-(b) and (d) and a pH but does not teach the ranges.
Zhao teaches a suitable buffering agent in the formulations including a bispecific BiTE that further includes a tonicity agent such as citrate or sodium chloride, a polyol such as trehalose, a surfactant such as polysorbate 80 or 20 where the formulations of the buffers have a pH of 4.5 to pH 8.5, preferably from about 4.5 to about 6.5, more preferably from about 5.0 to about 6.2.
Zhao teaches a formulation of 0.0% - 10.0% of a polyol selected from sucrose or trehalose; 0.1% -0.25% of surfactants selected from polysorbate 20 or polysorbate 80; 0.0% - 8.0% of one or more amino acids selected from arginine, histidine, ornithine, glycine or alanine, 0.0% -5% of preservative selected from benzyl alcohol, and 1% -10% of buffer salt selected from sodium citrate or citric acid monohydrate for adjusting pH 5.0 - 6.5.
The bispecific protein formulations are engineered to prevent protein aggregation, mitigate surface absorption, and minimize the oxidation of the polysorbate excipient of the bispecific antibody formulation. Citrate buffer maintains the formulation's required pH of 6.0 to 6.5 and acts as a chelating agent that mitigates the iron-mediated degradation of polysorbate 80. Trehalose stabilizes disaccharides and is a lyoprotectant that protects the antibody's native structure from environmental stress. NaCl (sodium chloride) provides tonicity to the solution to make it isotonic (safe for parenteral administration). Polysorbate 80 (Tween-80) protects the bispecific antibody from interface-induced denaturation, mechanical stress during shipping, and unwanted surface adsorption. (See Strickley et al (PTO 892)). Accordingly, the POSA would have been motivated to formulate compositions comprising the elements (a)-(d) based on Chen in view of Zhao as evidenced by Strickley.
The claimed inventions are within the ordinary skill of the art for the formulation for a known active ingredient, namely, WBP3278 or W3278-U2T3.F18R-1.uIgG4, using tonicity agents, a polyol and a surfactant with buffer conditions that are well known in the art in the formulation of immunotherapies comprising bispecific proteins.
Conclusion
14. No claims are allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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