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
Status of Claims
Claims 1-15, 17-18, 27, and 34-38 are under consideration in the instant Office Action.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/16/2026 has been entered.
Modified Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-15, 17-18, 27, and 34-38 are rejected under 35 U.S.C. 103 as being unpatentable over Chiu et al. (US 9,695,242 B2, in PTO-892 filed 05/24/2023), in view of Das et al. (US 2011/027,262 A1, in PTO-892 filed 05/24/2023).
Chiu et al. teaches “a pharmaceutical composition of the invention [the bispecific EGFR/c-Met antibody of the invention and a pharmaceutically acceptable carrier] … containing 1 ml sterile buffered water, and about 50 ng to about 30 mg/kg” of the bispecific EGFR/c-Met antibody containing molecules in paragraph 0546. Chiu et al. also teaches that the bispecific EGFR/c-Met antibodies may be administered “to a patient by any suitable route, for example parentally by intravenous (IV) infusion or bolus injection, intramuscularly or subcutaneously or intraperitoneally” and that the dosage is scaled to a therapeutically effective amount, which “may be sometimes 0.1 to 10 mg/kg body weight, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg/kg, but may even higher, for example 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 mg/kg”, see paragraph 0547. This meets the claim limitations of instant claims 1, 7, 15, and 34 wherein a stable aqueous pharmaceutical composition comprises about 44 mg/mL to about 56 mg/mL of the bispecific EGFR/c-Met antibody. It would be routine to optimize the best dosages determined from these ranges for the stable aqueous pharmaceutical composition. The reference teaches the amount as 50 ng to 30 mg/kg, which encompasses 0.5 to 0.7 mg/kg, which is equivalent to 40 mg/ml to 56 mg/mL for an 80 kg patient as claimed in the invention. Chui et al. teaches that “in some embodiments described herein, the bispecific EGFR/c-Met antibody comprises the HC1 and the HC2 of IgG1, IgG2, IgG3 or IgG4 isotype”, see paragraph 0397. This meets the limitations of instant claims 1 and 34 wherein the antibody is of the IgG1 isotype. Chui et al. also teaches some applications of the invention, including “EGFR therapies include both small molecules and anti-EGFR antibodies, approved for treatment of colorectal cancer, pancreatic cancer, head and neck cancer, and non-small cell lung cancer”, see paragraph 0004. This meets the limitations of instant claim 27 wherein the pharmaceutical composition or kit is used in the treatment of cancer and in preparation of a medicine.
Chiu et al. teaches SEQ ID NOs: 210-212 as the HCDRs 1-3, which are 100% identical to instant SEQ ID NOs: 1-3, respectively. SEQ ID NOs: 213-215 are taught as the LCDRs 1-3, which are 100% identical to instant SEQ ID NOs: 4-6, respectively. SEQ ID NOs: 216-218 are taught as the HCDRs 1-3, which are 100% identical to instant SEQ ID NOs: 7-9, respectively. SEQ ID NOs: 219-221 are taught as the LCDRs 1-3, which are 100% identical to instant SEQ ID NOs: 10-12, respectively. This meets the limitations of instant claims 1 and 34 wherein the 12 CDRs of the bispecific EGFR/c-Met antibody are listed. Chiu et al. also teaches SEQ ID NO: 199, which is 100% identical to instant SEQ ID NOs: 13 and 17. Chui et al. teaches SEQ ID NO: 200, which is 100% identical to instant SEQ ID NOs: 14 and 18. Chui et al. teaches SEQ ID NO: 201, which is 100% identical to instant SEQ ID NOs: 15 and 19. Chui et al. teaches SEQ ID NO: 202, which is 100% identical to instant SEQ ID NOs: 16 and 20. This meets the limitations of instant claims 2-6 and new claims 35-38 wherein the sequences for the heavy and light chain regions are recited. As discussed above, Chiu et al. teaches sequences that are 100% matches to the instantly claimed sequences. The instantly claimed sequences belong to the IgG1 isotype and since Chiu is a 100% match, they also belong to the IgG1 isotype and thus meet the limitations of the instant claims.
However, Chiu et al. does not teach a pharmaceutical composition comprising about 8 mM to about 12 mM of histidine and/or pharmaceutically acceptable histidine salt, about 6.8% w/v to about 10/2% w/v of sucrose, about 0.036% w/v to about 0.084% w/v of PS80, about 0.8 mg/mL to about 1.2 mg/mL of methionine, and about 16 microgram/mL to about 24 microgram/mL of EDTA, and a pH from about 5.2 to about 6.2. Das et al. remedies this deficiency.
Das et al. teaches a formulation for an antibody with “the buffer [being] histidine… the histidine can be an enantiomeric (e.g., L- or D-enantiomer) or racemic form of histidine, … , a salt form (e.g., a monohydrochloride, dihydrochloride, hydrobromide, sulfate, or acetate salt) of histidine, a solvated form of histidine, a hydrated form (e.g., monohydrate) of histidine, or an anhydrous form of histidine. In various embodiments, the concentration of the buffer is about 1 mM, about 5 mM, about 10 mM, about 15 mM”, see paragraphs 0184-0185. This meets the limitations of instant claims 1, 8, 9, 15, and 34 wherein the composition contains a histidine buffer that is in the form of a salt, more specifically L-histidine hydrochloride monohydrate. Das et al. also teaches “the tonicity agent is sucrose and is present in the composition at a concentration of about 90 mg/ml”, see paragraph 0193. This meets the limitations of instant claims 1, 10, 15, and 34 as 90 mg/mL is equivalent to the claimed “about 9% w/v”. Das et al. teaches “the composition contains 0.5 mg/mL polysorbate 80”, see paragraph 0199. This meets the limitations of instant claims 1, 11, 15, and 34 as 0.5 mg/mL is equivalent to the claimed “0.036% w/v to about 0.084% w/v”.
Das et al. teaches “suitable antioxidants include, but are not limited to, methionine… for example, the composition may contain methionine in a concentration that ranges from 1 mM to about 100 mM, and in particular, is about 27 mM”, see paragraph 0201. This meets the limitations of instant claims 1, 12, 15, and 34 as the reference teaches the amount from 1 mM to about 100 mM and encompasses the range of 5.4 mM to 8 mM, which is equivalent to 0.8 to 1.2 mg/mL as claimed. Das et al. also teaches “the chelating agent is selected from the group consisting of EDTA… about 0.05 millimolar”, see paragraph 0180. This meets the limitations of instant claims 1, 13, 15, and 34 as 0.05 millimolar is equivalent to about 16 microgram/mL of EDTA. Das et al. teaches “the composition are typically buffered to maintain a pH in the range of … about 5.2 to about 6.3”, see paragraph 0186. This meets the limitations of instant claims 1, 14, and 34 wherein the recited pH is 5.7. Das et al. also teaches “the composition when stored at a temperature from about 2° C. to about 8° C. for … more preferably at least about 24 months”, see paragraph 0308. This meets the limitations of instant claim 16 wherein the composition is stable for at least two years when stored at 2-8 degrees Celsius. Das et al. teaches “the skilled artisan will appreciate that the weight quantities can be proportionally adjusted when different composition volumes are desired”, see paragraph 0376. This meets the limitations of instant claim 18 wherein the desired total volume of the composition ranges from about 5 mL to about 10 mL. Given the specific quantities for the components of the buffer, the skilled artisan is able to adjust quantities to obtain any desired volume.
Instant claims 1, 17, and 34 refer to inherent properties of the claimed formulation. It does not further limit the composition of the formulation and only recites innate characteristics of the claimed formulation. Therefore, one would reasonably expect that the instantly claimed formula would have the same characteristics as the one disclosed in the prior art, considering that the components of the composition are taught. This includes stability of the antibody in formulation when stored at certain temperatures for certain amounts of time.
It would be obvious at the time of the instant invention to use the bispecific antibody taught by Chiu et al., which is used against EGFR and c-Met receptors in the treatment of cancer, with the formulation taught by Das et al. which teaches a formulation that improves the stability of antibodies stored in solution, see paragraph 0084. One would be motivated to combine the references with the expectation that they can be used to “contribute to an improvement in stability of any of the human IgG2 antibodies described herein [see paragraph 0187], the “surfactant” may contribute to an improvement in stability of any of the human IgG2 antibodies described herein… for example, the surfactant may reduce aggregation of the formulated antibody and/or minimize the formation of particulates in the composition and/or reduces adsorption… the surfactant may also improve stability of the antibody during and after a freeze/thaw cycle [see paragraph 0196], and to improve stability at pH ranging from 5.5 and 6.0 [see paragraph 0404]. In summary, Chiu et al. teaches a bispecific anti-EFGR/c-Met antibody used for the treatment of cancer and Das et al. teaches the components of a formulation that is effective in preserving or stabilizing a therapeutic antibody.
Therefore, claims 1-15, 17-18, 27, and 34-38 are rejected as obvious over Chiu et al. and Das et al.
Response to Arguments
Applicant's arguments filed 03/16/2026 have been fully considered but they are not persuasive.
Applicant argues “the combination of Chiu and Das would not have taught or suggested the claimed stable aqueous pharmaceutical antibody composition” was stable at a temperature of about 2 degrees Celsius to about 8 degrees Celsius for at least two years. This is not found persuasive.
As indicated in the rejection above, Chiu and Das teach the limitations regarding the antibody sequences and liquid formulations of the instant invention and thus, are reasonably expected to behave in the same manner as structure confers function. The prior art is not required to recite every possible outcome or characteristics of the antibody being placed in solution; one of ordinary skill in the art would reasonably expect that the same antibody in the same formulation as instantly claimed would result in the same characteristics, such as aggregation or stability until experimentally proven otherwise by Applicant. Applicant points to Table 13 and Table 59 as evidence of protein aggregation and antibody fragmentation that renders the antibody and formulation of the prior art different than the instant invention. However, these examples are not comparable to the instant claims as Tables 13 and 59 report data on storing the antibodies in formulation for 26 weeks at 40 degrees Celsius. The instant claims recite that the formulation remain stable when stored at a range of 2 degrees Celsius to 8 degrees Celsius for at least two years. As such, the antibodies would be expected to behave differently when stored at different temperatures for different lengths of time.
Applicant argues “the Office has failed to establish why one of ordinary skill in the art would have been motivated to use Das' formulations when those formulations caused antibody fragmentation”. This is not found persuasive.
As discussed above, the antibody fragmentation that Applicant is referring to occurs at different temperature and storage lengths than what is instantly claimed. Applicant is encouraged to refer to which formulation of Das resulted in antibody fragmentation and provide data showing how the instant invention does not result in the same characteristics. Additionally, Das teaches ranges for the various components of the formulation that can be routinely adjusted to obtain a desired end goal. As such, Das supplies the necessary teachings to optimize the formulation in order to control the resulting antibody fragmentation. Aggregation data of different antibodies, at different temperatures, and for different lengths do not render the teachings of Das invalid as they are not comparing the same inventions to one another. Applicant is reminded that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005).
Therefore, the rejection is maintained.
Conclusion
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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