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 .
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 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.
DETAILED ACTION
The amendments filed on 9/26/2025 which claims 62, 70, 73, and 75 were amended is acknowledged.
Claims 62-67 and 69-93 are pending in the instant application.
Priority
This application is a 371 of PCT/EP2019/053178 filed on 2/8/2019.
Claim Interpretation
Applicant has defined “DuoBody-CD3xCD20” as
“an IgG1 bispecific CD3xCD20 antibody wherein the CD3 binding Fab-arm comprise the VH and VL sequences as defined in SEQ ID Nos: 6 and 7, respectively, the constant light chain sequence as defined in SEQ ID NO: 22, and the constant heavy chain sequence as defined in SEQ ID NO: 19 (FEAL) and wherein the CD20 binding Fab-arm comprise the VH and VL sequences of SEQ ID: 13 and 14, respectively, the constant light chain sequence as defined in SEQ ID NO: 23, and the constant heavy chain sequence as defined in SEQ ID NO: 20 (FEAR)”. This bispecific antibody may be prepared as described in WO 2016/110576.".
Information Disclosure Statement
The information disclosure statement (IDS) dated 9/12/2025 complies with the provisions of 27 CFR 1.97, 1.98, and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits.
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.
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.
Claims 62-67, 69-72, and 74-93 are rejected under 35 U.S.C. 103 as being unpatentable over Engelberts et al. (WO2016110576) in view of Williams et al. (US20120301400), Kang et al. (https://www.bioprocessintl.com/formulation/rapid-formulation-development-for-monoclonal-antibodies), Huille et al. (US20150225479), Benedict et al. (US20150209430), Kamerzell et al. (doi: 10.1016/j.addr.2011.07.006) and Sloey et al. (US20100297106). This rejection has been modified solely to address the amendments.
claim 62, 75
Regarding claims 62 and 75, Engelberts teaches a pharmaceutical formulation (pg 82, para 5-9) comprising a bispecific antibody that comprises the CD3-binding (1) VH of instant SEQ ID NO: 6 (SEQ ID NO: 6; pg 8, Table 1):
instant_6 EVKLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYAT 60
Engelberts_6 EVKLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYAT 60
************************************************************
instant_6 YYADSVKDRFTISRDDSKSSLYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTL 120
Engelberts_6 YYADSVKDRFTISRDDSKSSLYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTL 120
************************************************************
instant_6 VTVSS 125
Engelberts_6 VTVSS 125;
*****
(2) the VL of instant SEQ ID NO: 7 (SEQ ID NO: 10):
instant_7 QAVVTQEPSFSVSPGGTVTLTCRSSTGAVTTSNYANWVQQTPGQAFRGLIGGTNKRAPGV 60
Engelberts_10 QAVVTQEPSFSVSPGGTVTLTCRSSTGAVTTSNYANWVQQTPGQAFRGLIGGTNKRAPGV 60
************************************************************
instant_7 PARFSGSLIGDKAALTITGAQADDESIYFCALWYSNLWVFGGGTKLTVL 109
Engelberts_10 PARFSGSLIGDKAALTITGAQADDESIYFCALWYSNLWVFGGGTKLTVL 109
*************************************************
(3) the lambda light chain of instant SEQ ID NO: 22 (SEQ ID NO: 29; pg 10, Table 1):
instant_22 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSK 60
Engelberts_29 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSK 60
************************************************************
instant_22 QSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 106
Engelberts_29 QSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 106;
**********************************************
Engelberts also teaches the bispecific antibody comprises the CD20-binding (1) VH of instant SEQ ID NO: 13 (SEQ ID NO: 27; pg 11, Table 1):
instant_13 EVQLVESGGGLVQPDRSLRLSCAASGFTFHDYAMHWVRQAPGKGLEWVSTISWNSGTIGY 60
Engelberts_27 EVQLVESGGGLVQPDRSLRLSCAASGFTFHDYAMHWVRQAPGKGLEWVSTISWNSGTIGY 60
************************************************************
instant_13 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVTV 120
Engelberts_27 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVTV 120
************************************************************
instant_13 SS 122
Engelberts_27 SS 122;
**
(2) VL of instant SEQ ID NO: 14 (SEQ ID NO: 28; pg 11, Table 1):
instant_14 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
Engelberts_28 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
************************************************************
instant_14 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIK 107
Engelberts_28 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIK 107.
***********************************************
Engelberts teaches the CD3 and CD20 binding moieties comprise two different Fab arms (pg 4, para 3; pg 5, para 1). Engelberts teaches the formulation includes water, a buffer (pg 83, para 2), including ethyl vinyl acetate (pg 83, last para), and sorbitol (pg 83, para 3). Engelberts teaches pharmaceutical compositions comprising the antibody may be prepared that are able to be administered subcutaneously (pg 84, para 4). Engelberts teaches the formulation may be formulated in unit dosage form for ease of administration and dosage uniformity (pg 93, para 5).
Engelberts does not teach a specific concentration of the bispecific antibody, sorbitol, or acetate nor a specific pH range to be used in a pharmaceutical preparation. Engelberts does not teach the kappa light chain of instant SEQ ID NO: 23.
Williams teaches an antibody that binds CD20 (pg 3, para 0024) comprising the kappa light chain of instant SEQ ID NO: 23 (SEQ ID NO: 149) and the LCDRs of instant SEQ ID NO: 11, 12, and the LCDR2 of DAS (underlined below).
instant_23 ------------------------------------------------------------ 0
Williams_149 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
instant_23 -----------------------------------------------RTVAAPSVFIFPP 13
Williams_149 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKRTVAAPSVFIFPP 120
*************
instant_23 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 73
Williams_149 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
************************************************************
instant_23 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 107
Williams_149 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
**********************************
Kang teaches the first step in generating an antibody formulation constitutes finding the ideal pH for a given antibody within the range of 4-8 pH units, wherein the antibody is able to be stable for a week at 50°C (pg 3, para 8-9; pg 4, para 1). Kang teaches that after the ideal pH is found, an appropriate buffer for that pH range is chosen and excipients such as sugars and salts (pg 4, para 2-3). Kang teaches the third step involves screening for the ideal concentrations of buffer and excipients under the desired storage temperature and length of time (pg 4, para 4). Kang teaches the process of identifying the ideal formulation for a given antibody takes about 12 weeks (pg 5, para 1). Kang identifies sorbitol and acetate (NaOAc) as commonly used excipients in pharmaceutical formulations of antibodies (pg 2, Table 1). Thus Kang’s teachings establish that it is routine optimization to alter these result-effective variables, which were known variables used for a predictable purpose.
Huille teaches a pharmaceutical composition containing: 5-200 mg/mL of bispecific antibody (pg 16, paragraph 163), 1-10% wt/v (~55-550 mM) sorbitol as a cryoprotectant 1 (pg 17, paragraph 178/179), 1-50 mM acetate buffer consisting of acetic acid/sodium acetate (pg 18, paragraph 186-188), wherein the pH of the formula ranges from 6.5-7.5 and is adjusted using hydrochloric acid or sodium hydroxide (pg 19, paragraph 193). Huille also teaches an antibody concentration of 50-150 mg (pg 16, para 0163) which lies inside the instantly claimed antibody concentration of 2-150 mg/mL. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Thus is considered obvious. See MPEP § 2144.05(I).
Benedict teaches a pharmaceutical composition comprising 1-150 mg/mL antibody (claim 1). Benedict teaches that the composition includes about 200-300 mM sorbitol (pg 2, para 0029). Benedict teaches the composition includes about 20 mM, about 22.5 mM, about 25 mM, about 30 mM, about 35 mM, or about 40 mM acetate (claim 15; pg 2, para 0023). Benedict teaches the formulation has a pH of 4.0 to 7.5 (claim 1).
Kamerzell teaches sorbitol is added as a protein stabilizer in liquid pharmaceutical formulations (Table 1, reproduced below).
PNG
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165
1142
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Greyscale
Kamerzell teaches “Sugars are frequently used as pharmaceutical excipients to stabilize proteins in both liquid and lyophilized formulations… Sugar alcohols such as sorbitol can stabilize proteins in solution and in the lyophilized state [67,84,85], although sorbitol is destabilizing in the frozen state due to crystallization” (pg 1123, col 1, para 2).
Sloey teaches a pharmaceutical formulation comprising that is stable for at least 6 months at 2-8°C (para 0124). Sloey teaches the formulation can comprise 100 mg/mL of antibody (pg 12, para 103). Sloey teaches the formulation can comprise 10-60 mM buffer, such as acetate buffer (pg 12, para 0126). Sloey teaches the formulation can comprise a polyol, such as sorbitol (pg 12, para 0128), at a concentration of 250 mM (pg 15, para 0153). Sloey teaches the composition can have a pH of about 4.8 to about 5.5 (pg 12, para 0126).
Antibody
Buffer
Sorbitol
pH
Instant claim 62/75
5-150 mg/mL
20-40 mM acetate
145-155 mM
5.0-6.0
Huille
5-200 mg/mL
1-50 mM acetate
55-550 mM
6.5-7.5
Benedict
1-150 mg/mL
20-40 mM acetate
200-300 mM
4.0-7.5
Sloey
100 mg/mL
10-60 mM acetate
250 mM
4.8-5.5
It would have been obvious to combine the teachings of Engelberts, Williams, Kang, Huille, Benedict, Kamerzell, and Sloey arriving at a bispecific antibody targeting CD3 and CD20 and a suitable pharmaceutical composition thereof because (1) Engelberts teaches a bispecific antibody comprising the same CD3 and CD20 binding regions as instantly claimed, and teaches this bispecific antibody is amenable to being formulated with acetate and sorbitol; (2) Williams teaches the same LCDRs as instantly claimed are compatible with the instantly claimed kappa light chain of instant SEQ ID NO: 23 to generate a bispecific antibody targeting CD20; (3) Kang teaches a 3-stage method of developing a stable pharmaceutical formulation of any antibody; (4) Kamerzell teaches sorbitol stabilizes proteins in liquid pharmaceutical formulations; (5) Sloey teaches an exemplary formulation that is known to be stable for 6 months at 2-8°C that comprises similar quantities of antibody, acetate, and sorbitol at a similar pH; and (6) Huille and Benedict supply other antibody formulations comprising acetate and sorbitol at similar pH values which further supply a working range of values for which to implement the optimization step as taught by Kang. One would have had a reasonable expectation of success since Engelberts taught all of the components of the mixture were compatible, and Kang taught a method of finding the optimal quantities of each excipient wherein Huille, Benedict, and Sloey provided working ranges (as shown in the table above) from which one could begin the optimization process of Kang.
claim 63
Regarding claim 63, Benedict teaches a formulation comprising 20-40 mM of acetate encompasses the instantly claimed 30 mM acetate. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Thus is considered obvious. See MPEP § 2144.05(I).
claim 64
Regarding claim 64, Sloey teaches a formulation that comprises 250 mM of sorbitol (pg 15, para 0153) which lies outside of the instantly claimed 150 mM sorbitol. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In the instant case, applicant has not provided any evidence of criticality, thus arriving at an optimal concentration of sorbitol is considered a matter of routine experimentation. See MPEP § 2144.05(II)(A). In the instant case, applicant has not presented any evidence that the 150 mM concentration of sorbitol is critical. Thus one of skill in the art could have arrived at this sorbitol concentration using routine experimentation or the method of Kang described in the rejection of instant claims 62 and 75.
claim 65
Regarding claim 65, Huille teaches a formulation that comprises about 5 mg/mL of a bispecific antibody (pg 16, para 0163), which overlaps with the instantly claimed 5 mg/mL of bispecific antibody. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Thus is considered obvious. See MPEP § 2144.05(I).
claim 66
Regarding claim 66 and 67, Benedict teaches a formulation that comprises 1-150 mg/mL of bispecific antibody (claim 1), which overlaps with the instantly claimed range of 50-120 mg/mL and 60 mg/mL. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Thus is considered obvious. See MPEP § 2144.05(I).
claim 69
Regarding claim 69, Engelberts teaches a bispecific antibody with 100% identity to the HC constant region of instant SEQ ID NOs: 19 (SEQ ID NO: 23), shown below.
instant_19 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
Engelberts_23 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
************************************************************
instant_19 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGG 120
Engelberts_23 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGG 120
************************************************************
instant_19 PSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 180
Engelberts_23 PSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 180
************************************************************
instant_19 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 240
Engelberts_23 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 240
************************************************************
instant_19 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRW 300
Engelberts_23 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRW 300
************************************************************
instant_19 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 330
Engelberts_23 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 330
******************************
Engelberts teaches bispecific antibody with 100% identity to the HC constant region of instant SEQ ID NO: 20 (SEQ ID NO: 24), shown below.
instant_20 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
Engelberts_24 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
************************************************************
instant_20 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGG 120
Engelberts_24 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGG 120
************************************************************
instant_20 PSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 180
Engelberts_24 PSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 180
************************************************************
instant_20 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 240
Engelberts_24 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 240
************************************************************
instant_20 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW 300
Engelberts_24 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW 300
************************************************************
instant_20 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 330
Engelberts_24 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 330
******************************
Engelberts teaches the antibody can be a diabody, thus meeting the limitation of having two HC constant regions (pg 41, para 7), able to be selected from any of the HC constant regions taught by Engelberts. Note, in the absence of evidence for their criticality, the recitation of a particular arrangement of parts is considered obvious. See MPEP § 2144.04 (VI)(C).
claim 70
Regarding claim 70, Benedict teaches a formulation comprising 20-40 mM of acetate (claim 15; pg 2, para 0023), which overlaps with the instantly claimed range of 28-32 mM acetate. Benedict teaches the formulation has a pH of 4.0 to 7.5 (claim 1), which overlaps with the instantly claimed pH of 5.5. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Thus is considered obvious. See MPEP § 2144.05(I). Benedict teaches 200-300 mM of sorbitol (pg 2, para 0029), which lies outside of the instantly claimed range of 148-152 mM. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In the instant case, applicant has not provided any evidence of criticality, thus arriving at an optimal concentration of sorbitol is considered a matter of routine experimentation. See MPEP § 2144.05(II)(A). In the instant case, applicant has not presented any evidence that the 148-152 mM concentration of sorbitol is critical. Thus one of skill in the art could have arrived at this sorbitol concentration using routine experimentation or the method of Kang described in the rejection of instant claims 62 and 75.
claim 71
Regarding claim 71, Huille teaches a pharmaceutical formulation can comprise about 5 mg/mL (pg 16, para 0163) which overlaps with the instantly claimed 5 mg/mL. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Thus is considered obvious. See MPEP § 2144.05(I).
claim 72
Regarding claim 72, Huille teaches a pharmaceutical composition comprising about 50 mg/mL to about 150 mg/mL of bispecific antibody (pg 16, para 0163), which overlaps with the instantly claimed concentration of 60 mg/mL. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Thus is considered obvious. See MPEP § 2144.05(I).
claim 74
Regarding claim 74, Engelberts teaches that the pharmaceutical composition does not contain a surfactant (pg 83, paragraph 2).
claim 76
Regarding claim 76, Benedict teaches a formulation comprising 20-40 mM of acetate (claim 15; pg 2, para 0023), which overlaps with the instantly claimed range of 30 mM acetate. Benedict teaches the formulation has a pH of 4.0 to 7.5 (claim 1), which overlaps with the instantly claimed pH of 5.5. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Thus is considered obvious. See MPEP § 2144.05(I). Benedict teaches 200-300 mM of sorbitol (pg 2, para 0029), which lies outside of the instantly claimed 150 mM sorbitol. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In the instant case, applicant has not provided any evidence of criticality, thus arriving at an optimal concentration of sorbitol is considered a matter of routine experimentation. See MPEP § 2144.05(II)(A). In the instant case, applicant has not presented any evidence that the 150 mM concentration of sorbitol is critical. Thus one of skill in the art could have arrived at this sorbitol concentration using routine experimentation or the method of Kang described in the rejection of instant claims 62 and 75.
claim 77
Regarding claim 77, Engelberts teaches the formulation may be formulated in unit dosage form for ease of administration and dosage uniformity (pg 93, para 5).
Engelberts does not teach the concentrations of ingredients used in the unit dosage form.
Huille teaches a pharmaceutical unit dosage form comprising a total volume of 7-15 mL per vial (pg 22, paragraph 289), which lies outside the instantly claimed total volume of 0.5-2 mL. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In the instant case, applicant has not provided any evidence of criticality, thus arriving at an optimal unit dosage volume is considered a matter of routine experimentation. See MPEP § 2144.05(II)(A). In the instant case, applicant has not presented any evidence that the total volume of the unit dosage is critical. Thus one of skill in the art could have arrived at unit dosage volume using routine experimentation or out of preferred convenience as taught by Engelberts.
It would have been obvious to combine the references for the same rationale provided in the rejection of claims 62 and 75.
claim 78
Regarding claim 78, Engelberts teaches a method of treating cancer comprising administering the bispecific antibody (pg 88, para 7), wherein the antibody can be delivered subcutaneously (pg 94, para 1), and be administered in unit dosage form (pg 93, para 5). It is understood that administering a medicament requires a non-zero value of time, thus Engelberts meets the limitation of injecting the formulation for a time sufficient to treat the cancer.
claim 79
Regarding claim 79, Engelberts teaches a pharmaceutical formulation (pg 82, para 5-9) comprising a bispecific antibody that comprises the CD3-binding VH of instant SEQ ID NO: 6 (SEQ ID NO: 6; pg 8, Table 1):
instant_6 EVKLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYAT 60
Engelberts_6 EVKLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYAT 60
************************************************************
instant_6 YYADSVKDRFTISRDDSKSSLYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTL 120
Engelberts_6 YYADSVKDRFTISRDDSKSSLYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTL 120
************************************************************
instant_6 VTVSS 125
Engelberts_6 VTVSS 125;
*****
Engelberts teaches the VL of instant SEQ ID NO: 7 (SEQ ID NO: 10):
instant_7 QAVVTQEPSFSVSPGGTVTLTCRSSTGAVTTSNYANWVQQTPGQAFRGLIGGTNKRAPGV 60
Engelberts_10 QAVVTQEPSFSVSPGGTVTLTCRSSTGAVTTSNYANWVQQTPGQAFRGLIGGTNKRAPGV 60
************************************************************
instant_7 PARFSGSLIGDKAALTITGAQADDESIYFCALWYSNLWVFGGGTKLTVL 109
Engelberts_10 PARFSGSLIGDKAALTITGAQADDESIYFCALWYSNLWVFGGGTKLTVL 109
*************************************************
Engelberts also teaches the lambda light chain of instant SEQ ID NO: 22 (SEQ ID NO: 29; pg 10, Table 1):
instant_22 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSK 60
Engelberts_29 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSK 60
************************************************************
instant_22 QSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 106
Engelberts_29 QSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 106;
**********************************************
Engelberts also teaches the bispecific antibody comprises the CD20-binding VH of instant SEQ ID NO: 13 (SEQ ID NO: 27; pg 11, Table 1):
instant_13 EVQLVESGGGLVQPDRSLRLSCAASGFTFHDYAMHWVRQAPGKGLEWVSTISWNSGTIGY 60
Engelberts_27 EVQLVESGGGLVQPDRSLRLSCAASGFTFHDYAMHWVRQAPGKGLEWVSTISWNSGTIGY 60
************************************************************
instant_13 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVTV 120
Engelberts_27 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVTV 120
************************************************************
instant_13 SS 122
Engelberts_27 SS 122;
**
Engelberts teaches the VL of instant SEQ ID NO: 14 (SEQ ID NO: 28; pg 11, Table 1):
instant_14 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
Engelberts_28 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
************************************************************
instant_14 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIK 107
Engelberts_28 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIK 107.
***********************************************
Engelberts teaches the formulation includes water, a buffer (pg 83, para 2), including ethyl vinyl acetate (pg 83, last para), and sorbitol (pg 83, para 3). Engelberts teaches pharmaceutical compositions comprising the antibody may be prepared that are able to be administered subcutaneously (pg 84, para 4).
Engelberts does not teach a method of preparing a pharmaceutical composition comprising mixing their bispecific antibody with water in a dosage of 60-120 mg/mL prior to subcutaneous injection. Engelberts does not teach the kappa light chain of instant SEQ ID NO: 23.
Williams an antibody that binds CD20 (pg 3, para 0024) comprising the kappa light chain of instant SEQ ID NO: 23 (SEQ ID NO: 149) and the LCDRs of instant SEQ ID NO: 11, 12, and the LCDR2 of DAS (underlined below).
instant_23 ------------------------------------------------------------ 0
Williams_149 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
instant_23 -----------------------------------------------RTVAAPSVFIFPP 13
Williams_149 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKRTVAAPSVFIFPP 120
*************
instant_23 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 73
Williams_149 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
************************************************************
instant_23 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 107
Williams_149 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
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Kang teaches the first step in generating an antibody formulation constitutes finding the ideal pH for a given antibody within the range of 4-8 pH units, wherein the antibody is able to be stable for a week at 50°C (pg 3, para 8-9; pg 4, para 1). Kang teaches that after the ideal pH is found, an appropriate buffer for that pH range is chosen and excipients such as sugars and salts (pg 4, para 2-3). Kang teaches the third step involves screening for the ideal concentrations of buffer and excipients under the desired storage temperature and length of time (pg 4, para 4). Kang teaches the process of identifying the ideal formulation for a given antibody takes about 12 weeks (pg 5, para 1). Kang identifies sorbitol and acetate (NaOAc) as commonly used excipients in pharmaceutical formulations of antibodies (pg 2, Table 1).
Huille teaches a pharmaceutical composition containing: 5-200 mg/mL of bispecific antibody (pg 16, paragraph 163), 1-10% wt/v (~55-550 mM) sorbitol as a cryoprotectant 1 (pg 17, para 178/179), 1-50 mM acetate buffer consisting of acetic acid/sodium acetate (pg 18, para 186-188), wherein the pH of the formula ranges from 6.5-7.5 and is adjusted using hydrochloric acid or sodium hydroxide (pg 19, paragraph 193). Huille teaches that the pH of the formulation may be adjusted using any means known in the art (pg 19, para 0193), thus meeting the limitation of first generating the formulation, followed by a step of adjusting the pH. Huille teaches the composition can comprise acetic acid as a complement to the sodium acetate buffer (pg 18, para 0186), at a concentration of about 1 to about 50 mM (pg 18, para 0188). Huille teaches a concentration of sodium acetate trihydrate of 1-50 mM (pg 18, para 186-188), which overlaps with the instant concentration of 3.53 mg/mL (~25.9 mM sodium acetate trihydrate). Huille teaches a concentration of acetic acid of 1-50 mM (pg 18, paragraph 186-188) which overlaps with the instantly claimed 0.32 mg/mL (~4.9 mM acetic acid). Huille teaches a concentration of 1-10% wt/v (~55-550 mM) sorbitol as a cryoprotectant 1 (pg 17, para 178/179), which overlaps with the instantly claimed 27.3 mg/mL (~150 mM sorbitol). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Thus is considered obvious. See MPEP § 2144.05(I).
Sloey teaches a pharmaceutical formulation comprising that is stable for at least 6 months at 2-8°C (para 0124). Sloey teaches the formulation can comprise 100 mg/mL of antibody (pg 12, para 103). Sloey teaches the formulation can comprise 10-60 mM buffer, such as acetate buffer (pg 12, para 0126), which overlaps with the instantly claimed 3.53 mg/mL (~25.9 mM sodium acetate trihydrate). Sloey teaches the composition can have a pH of about 4.8 to about 5.5 (pg 12, para 0126), which overlaps with the instantly claim pH of 5.5.
Sloey teaches the formulation can comprise a polyol, such as sorbitol (pg 12, para 0128), at a concentration of 250 mM (pg 15, para 0153), which lies outside of the instantly claimed 27.3 mg/mL (150 mM sorbitol). Sloey teaches the composition can comprise acetic acid at a concentration of 50-200 mM (pg12, para 0127), which lies outside of the instantly claimed 0.32 mg/mL (~25.9 mM sodium acetate trihydrate). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In the instant case, applicant has not provided any evidence of criticality, thus arriving at an optimal concentration of sorbitol or acetic acid is considered a matter of routine experimentation. See MPEP § 2144.05(II)(A). In the instant case, applicant has not presented any evidence that the 150 mM concentration of sorbitol nor the 4.9 mM concentration of acetic acid is critical. Thus one of skill in the art could have arrived at this sorbitol concentration using routine experimentation or the method of Kang.
Antibody
Buffer
Acetic Acid
Sorbitol
pH
Instant claim 79
60-120 mg/mL
3.53 mg/mL sodium acetate x 3H2O
0.32 mg/mL
27.3 mg/mL
5.5
Instant claim 79 (converted)
60-120 mg/mL
25.9 mM NaOAc x 3H2O
4.9 mM
150 mM
5.5
Huille
5-200 mg/mL
1-50 mM acetate
1-50 mM
55-550 mM
6.5-7.5
Sloey
100 mg/mL
10-60 mM acetate
50-200 mM
250 mM
4.8-5.5
It would have been obvious to combine the teachings of Engelberts, Williams, Kang, Huille, and Sloey arriving at a bispecific antibody targeting CD3 and CD20 and a suitable pharmaceutical composition thereof because (1) Engelberts teaches a bispecific antibody comprising the same CD3 and CD20 binding regions as instantly claimed, and teaches this bispecific antibody is amenable to being formulated with acetate and sorbitol; (2) Kang teaches a 3-stage method of developing a stable pharmaceutical formulation of any antibody; (3) Huille teaches the method step of adjusting the pH of the formulation after the excipients are added; (4) Huille and Sloey supply other antibody formulations comprising acetate, acetic acid, and sorbitol at similar pH values which further supply a working range of values for which to implement the optimization step as taught by Kang. One would have had a reasonable expectation of success since Engelberts taught all of the components of the mixture were compatible, and Kang taught a method of finding the optimal quantities of each excipient wherein Huille and Sloey provided working ranges (as shown in the table above) from which one could begin the optimization process of Kang. Furthermore, it is conventional in the art to add all the ingredients of a formulation prior to adjusting the pH, as the addition of excipients after the pH adjusting step, could move the pH away from the desired value, requiring another pH adjusting step to bring the pH back to the desired value. Thus one of skill in the art would have been motivated to save time by doing a single pH adjusting step at the end.
claim 80
Regarding claim 80, Engelberts teaches the antibody is bispecific for CD3 and CD20 (abstract). Thus meeting the limitation of being a CD3xCD20 DuoBody.
Claim 81, 88
Regarding claims 81 and 88, Applicant has defined a DuoBody-CD3xCD20 as referring to the antibodies generated by Engelberts et al. (WO 2016/110576). See the claim interpretation section for further details. Engelberts further teaches the antibodies can comprise L234F+L235E+D265A+F405L (referred to as the FEAL mutation) in the CD3 heavy chain arm to generate antibodies with a non-activating Fc region (pg 72, para 2).
Claim 82, 89
Regarding claim 82 and 89, Applicant has defined a DuoBody-CD3xCD20 as referring to the antibodies generated by Engelberts et al. (WO 2016/110576). See the claim interpretation section for further details. Engelberts further teaches the antibodies can comprise L234F+L235E+D265A+F405R (referred to as the FEAR mutation) in the CD20 heavy chain arm to generate antibodies with a non-activating Fc region (ppg 72, para 2; pg 89, para 11; pg 80, para 3).
Claim 83, 90
Regarding claims 83 and 90, Engelberts teaches a DuoBody-CD3xCD20 comprising both a FEAL mutation in the CD3 heavy chain arm and a FEAR mutation in the CD20 heavy chain arm called “bsIgG1-huCD3-H1L1-FEALxCD20-7D8-FEAR” (pg 80, para 3-4; pg 89; para 11).
Claim 84, 91
Regarding claims 84 and 91, Sloey teaches their pharmaceutical formulations are stable for at least 6 months at 2-8°C (para 0124), which encompasses the instantly claimed storage temperature of 5°C. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Thus is considered obvious. See MPEP § 2144.05(I).
Claim 85, 92
Regarding claims 85 and 92, Sloey teaches their pharmaceutical formulations are stable for at least 9 months at 2-8°C (para 0124).
Claim 85, 93
Regarding claims 85 and 93, Sloey teaches their pharmaceutical formulations are stable for at least 1 year (a.k.a. 12 months) at 2-8°C (para 0124).
Claim 87
Regarding claim 87, Engelberts teaches the antibody is DuoBody-CD3xCD20. See claim interpretation section. Engelberts teaches the formulation may be formulated in unit dosage form for ease of administration and dosage uniformity (pg 93, para 5).
Allowable Subject Matter
Claims 73 is objected to as being dependent upon a rejected base claim, but would be allowable is rewritten in independent form, including all of the limitations of the base claim and any intervening claims.
A subcutaneous antibody formulation comprising 120-150 mg/mL of DuoBody-CD3xCD20 antibody, acetate buffer, and 150 mM sorbitol at pH 5.5 was found allowable over the prior art in view of this formula’s surprisingly low viscosity (instant Fig 2, reproduced below). See Argument VI(2) and “Claim Interpretation” section regarding the definition of DuoBody-CD3xCD20. Applicant is encouraged to include the definition of “DuoBody-CD3xCD20” into the base claim (i.e. include the appropriate SEQ ID NOs).
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Kamerzell teaches “it has been recently shown that sugar molecules can increase the viscosity of monoclonal antibody solutions, presumably due to a preferential hydration mechanism (pg 1123, col 1, para 2).
He (doi: 10.1007/s11095-011-0388-7) teaches
“Monoclonal antibodies are one of the most common classes of biotherapeutic molecules, with more than 150 products on the market and in development (1). To improve patient convenience, there has been a movement towards the use of high concentration protein solutions (i.e. > 100 mg/mL) in prefilled syringes. At these concentrations, many protein solutions become highly viscous, posing considerable challenges for both processing and delivery (2)” (pg 1551, col 2, para 2).
“The viscosity of protein solutions increases nonlinearly as the protein concentration increases … The viscosity increase at lower protein concentrations is minimal, while the slope of viscosity change increases significantly at higher protein concentrations. The addition of sugars increased the solution viscosity at all protein concentrations studied with a greater increase observed as the protein concentration increased… For both mAb molecules, trehalose displayed the highest viscosity, followed by sucrose and sorbitol, while xylose manifested the smallest viscosity increase. The viscosity of sugar-protein solutions are significantly higher than that observed in protein-free solutions at the same sugar concentrations or sugar-free protein solutions.” (pg 1554, col 2, para 2).
“Solution viscosity is also highly dependent upon sugar concentration. Both mAb1 and mAb2 were subjected to viscosity measurements as sugars were titrated into the solution. In general, the increase in viscosity appeared linear over the sugar concentrations examined” (pg 1554, col 2, para 3).
In sum, both Kamerzell and He teach that sorbitol is expected to enhance the viscosity, however, instant Fig 2 shows that when acetate is used as a buffer, one can obtain a surprisingly low-viscosity formulation comprising a high antibody concentration (≥120 mg/mL). Absent the teachings of the instant application, one of skill in the art would have no reasonable expectation of success that the addition of sorbitol would not increase the viscosity of a 120-150 mg/mL concentration DuoBody-CD3xCD20 formulation.
Response to Arguments
Applicant’s arguments filed on 9/26/2025 have been fully considered but they are not persuasive.
103; pg 8, para 2
Applicant argues Engelberts does not teach an acetate buffer, but teaches ethylene vinyl acetate as a biocompatible polymer in the formulation.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore, because the claims do not specify which acetate, Engelberts teaching of the formula comprising ethylene vinyl acetate satisfies the claim limitation of the buffer comprising acetate. Importantly, the claim does not state that the buffer is acetate. Secondly, Kang identifies sorbitol and acetate (NaOAc) as commonly used excipients in pharmaceutical formulations of antibodies (pg 2, Table 1). Thus satisfying the limitation of the buffer being acetate based, e.g. sodium acetate.
103; pg 9, para 2
Applicant argues hindsight reasoning was used to combine the teachings of the references. Applicant argues “there is no reason the skilled artisan would single out these particular secondary references from the plethora of available publications in the antibody formulation art.” Applicant argues the rejection is based on cherry-picking and ignores the teachings of the references as a whole.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Importantly, Applicant is disregarding the reference of Kang which teaches a stepwise method of formulating any antibody. Applicant is ignoring the teachings of Kang as a whole in their argument. Kang teaches the first step in generating an antibody formulation constitutes finding the ideal pH for a given antibody within the range of 4-8 pH units, wherein the antibody is able to be stable for a week at 50°C (pg 3, para 8-9; pg 4, para 1). Kang teaches that after the ideal pH is found, an appropriate buffer for that pH range is chosen and excipients such as sugars and salts (pg 4, para 2-3). Kang teaches the third step involves screening for the ideal concentrations of buffer and excipients under the desired storage temperature and length of time (pg 4, para 4). Kang teaches the process of identifying the ideal formulation for a given antibody takes about 12 weeks (pg 5, para 1).
103; pg 9, para 3
Applicant argues Huille does not teach a single antibody formulation comprising sorbitol and acetate. Applicant argues Huille only teaches these excipients in a laundry list of possible excipients. Applicant admits that Benedict teaches a similar formulation to that instantly claimed, but using a different antibody. Applicant argues Sloey teaches that creatine is superior to sorbitol in preventing aggregation, thus constitutes a teaching away.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Examiner respectfully disagrees. Huille teaches a pharmaceutical composition containing: 5-200 mg/mL of bispecific antibody (pg 16, paragraph 163), 1-10% wt/v (~55-550 mM) sorbitol as a cryoprotectant 1 (pg 17, paragraph 178/179), 1-50 mM acetate buffer consisting of acetic acid/sodium acetate (pg 18, paragraph 186-188), wherein the pH of the formula ranges from 6.5-7.5 and is adjusted using hydrochloric acid or sodium hydroxide (pg 19, paragraph 193). Sloey teaches the formulation can comprise 100 mg/mL of antibody (pg 12, para 103). Sloey teaches the formulation can comprise 10-60 mM buffer, such as acetate buffer (pg 12, para 0126). Sloey teaches the formulation can comprise a polyol, such as sorbitol (pg 12, para 0128), at a concentration of 250 mM (pg 15, para 0153). Furthermore, the reference of Kang identifies sorbitol and acetate (NaOAc) as commonly used excipients in pharmaceutical formulations of antibodies (pg 2, Table 1). Thus one of skill in the art would be very reasonably apprised of this particular combination of additives in an antibody formulation.
103; pg 10, para 2
Applicant argues Kang does not provide enough details for a skilled artisan to practice their method of rapid antibody formulation. Applicant argues the reference of Kang “provides a table of 21 possible excipients but fails to provide any information of how the optimization methods are conducted or how the excipients are selected. Notably, even if only two excipients in the table are selected, there are still over 2 million possible combinations (221) without any reference to their concentrations.” Applicant argues Kang does not teach using sorbitol, thus a skill artisan would be dissuaded from using sorbitol.
Firstly, Kang does teach sorbitol as a common additive (Table 1). Secondly, Applicant did not indicate a specific deficiency in the reference of Kang, specifically, applicant did not point out where the teachings of Kang fail to clarify how to use their method. Kang’s method of routine optimization requires testing several excipients and selecting based on stability of the formula: Kang teaches the first step in generating an antibody formulation constitutes finding the ideal pH for a given antibody within the range of 4-8 pH units, wherein the antibody is able to be stable for a week at 50°C (pg 3, para 8-9; pg 4, para 1). While examiner admits there are many options to try, the process of Kang makes antibody formulation approachable, by dividing it into steps. A person of skill in the art could refer to other successful antibody formulations as a launching point for concentration optimization. Several of these exemplary reference formulations have been cited in the 103 rejection above, such as the formulations of Huille, Benedict, and Sloey.
103; pg 11, para 1
Applicant argues the reference of Kamerzell that teaches that sorbitol may increase the viscosity of a formulation, fails to cure the deficiencies of Kang. Applicant repeats argument about Sloey stating formulations containing creatine are more stable than sorbitol.
The teachings of Kamerzell that sorbitol can modify the viscosity were provided to the Applicant in the Allowable Subject Matter section in order to arrive at the surprisingly low viscosity of the high concentration antibody formulation. However, as discussed in the other arguments herein, that is only applicable to the high concentration formulations, whereas the instant claims are drawn also to low concentration formulations. Importantly, for sorbitol to have a viscosity enhancing effect, it must interact with the antibody, and if there is less antibody, then there are fewer interactions (e.g. hydrogen bonding, dispersion forces, and electrostatic interactions), thus this finding of Kamerzell cannot be used as an example of “teaching away” from using sorbitol in low antibody concentration formulations. The reference of Sloely found that replacing some of the sorbitol of the formulation with creatine, they were able to generate a formula with less aggregation than sorbitol alone. However, the findings of Sloey are consistent with sorbitol having the ability to reduce antibody aggregation over a control that lack sorbitol (Fig 8), thus still providing a motivation to incorporate sorbitol into the formulation.
103; pg 11, para 2
Applicant argues none of the references teach that antibody formulation is “routine” or provide the guidance necessary to perform the optimization. Applicant points to the reference of Wang which indicates that antibodies have different structures and thus need to be formulated on a case-by-case basis. Applicant argues “Applicant respectfully submits that the present rejection is not only based on
impermissible hindsight, but also ignores the complex nature of antibody formulation. Obviousness
cannot be established based on an unsupported allegation that a therapeutic invention is the result of
"routine optimization", given the unpredictable and complex nature of therapeutics.”
While it is appreciated that antibodies must be formulated individually, this optimization process has been detailed by Kang. Kang’s method of routine optimization requires testing several excipients and selecting based on stability of the formula: Kang teaches the first step in generating an antibody formulation constitutes finding the ideal pH for a given antibody within the range of 4-8 pH units, wherein the antibody is able to be stable for a week at 50°C (pg 3, para 8-9; pg 4, para 1). While examiner admits there are many options to try, the process of Kang makes antibody formulation approachable, by dividing it into steps. This process is addressed in more detail in the 103 rejection above, thus negating the assertion that the rejection is based on “an unsupported allegation”.
103; pg 12, para 2
Applicant cites Swiss Phanna International AG v. Biogen IDEC (IPR2016-00915, October 20, 2016; "Swiss Pharma") and Coherus Biosciences Inc., v. Abbvie Biotechnology Ltd. (IPR2016-01018, November 7, 2016; "Coherus").
Applicant cites certain PTAB decisions. Unless these are precedential decisions, routine Board decisions cannot inform future practice because they are specific to the facts in that specific application. Every claim must be considered on its own merits, without reference to the PTAB' s nonprecedential findings on a different rejection.
103; pg 12, para 3
Applicant argues the presently claimed formulation cannot be considered the result of routine optimization. Applicant cites In re Stepan Co., No. 2016-1811 (Fed. Cir. Aug. 25, 2017), to emphasize that person of skill in the art must have a reasonable expectation of success.
Examiner has arrived at this conclusion of non-obviousness as stated in the “Allowable Subject Matter” section. Importantly, this conclusion is limited to high concentration (120-150 mg/mL) antibody formulations. However, the rejection is maintained because the claims encompass low concentration antibody formulations, wherein issues of aggregation and stability are obviated by dilution.
103; pg 13, para 4
Applicant argues that the full breadth of 5-150 mg/mL formulations are non-obvious because the low concentration formulations exhibit “surprisingly stable” formulations. Applicant points to Tables 6-9 as evidence.
In order to arrive at a verdict of “surprising results” Applicant must describe trend and then explain how the instantly claimed invention deviates from that trend. Because there is no control experiment from which to compare, there is no trend from which to deviate from. Table 6 shows a 5 mg/mL over 6 months at 5 C; Table 7 describes a 5 mg/mL over 6 months as 25C; Table 8 shows a 60 mg/mL at 5C; and Table 9 shows 60 mg/mL at 25C. From this data, all that can be concluded is that higher concentration formulas are less stable, and that higher storage temperatures favor faster degradation. These are the expected results, thus are insufficient to overcome the conclusion of obviousness.
103; pg 14, para 2
Applicant argues “Example 3, doses of the CD3xCD20 bispecific antibody in formulations comprising 30 mM acetate, 150 mM sorbitol, pH 5.5 were given to cynomolgus monkeys in concentrations ranging from 0.001 mg/mL to 20 mg/mL at doses ranging from 0.01 mg/kg to 20 mg/kg. Example 3 shows that administration of the formulation resulted in B-cell depletion, with both IV and subcutaneous administration.” Applicant argues that the low concentration formulations is also surprisingly stable.
In order to arrive at a verdict of “surprising results” Applicant must describe trend and then explain how the instantly claimed invention deviates from that trend. Because there is no control experiment from which to compare, there is no trend from which to deviate from. The fact that dilution of the high concentration formula still results in B cell depletion is the expected result. As in the previous argument above, one of skill in the art would have expected the lower concentration formulas to be more stable than their higher concentration counterparts. Thus this argument is insufficient to overcome the conclusion of obviousness.
Conclusion
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675