DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
Applicant's response, filed 12 June 2026, has been received and entered. Claims 1, 5 and 8 have been amended and claims 2, 4 and 6 have been canceled. Claims 1, 3, 5, 7-13 are currently pending. Claim 11 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 14 October 2025.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any objection or rejection of record which is not expressly repeated in this action has been overcome by Applicant's response and withdrawn.
Applicant's arguments filed 12 June 2026 have been fully considered but are not found to be persuasive.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12 June 2026 has been considered by the examiner.
Drawings
The drawings were received on 12 June 2026. These drawings are not acceptable.
The drawings remain objected to because they do not comply with 37 CFR 1.84(a)(1) which requires that India ink or its equivalent that secures solid black lines, must be used for drawings as well as 37 CFR 1.84(l) which requires that every line, number, and letter be durable, clean, black and sufficiently dense and dark, and uniformly thick and well-defined. The drawings do not have solid black lines.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Applicant’s substitute specification filed 12 June 2026 has been received and entered.
Applicant’s replacement abstract has been received and entered.
The use of the term Tween®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
See Fig. 6A-6C.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1, 3, 5, 7-10 and 12-13 stand rejected under 35 U.S.C. 103 as being unpatentable over WO 2016044334 A1 (Le et al.) in view of WO 2015/134406 (Gwee) and Wang et al. (Mol. Pharm. 12(12): 4478-4487, 2015) for the reasons of record in the previous Office action, mailed 12 February 2026.
Le et al. teach a pharmaceutical formulation (see [0146]) for monoclonal antibodies with a pH of about 5.5 to about 7.0, antibody concentration of about 25 mg/mL to about 100 mg/ml, trehalose from 45 mM to about 634 mM, buffer from about 35 mM to about 100 mM and also teaches that trehalose may be substituted for a non-trehalose polyol.
Le et al. teach at [0240] that an aqueous formulation is prepared comprising the antibody in a pH-buffered solution with pH range from 5.5 to 6.5. Examples of buffers which control the pH within this range include histidine and “histidine” may refer to any form of histidine known in the art, including without limitation histidine-HCl, histidine acetate, etc. Le et al. teach at [0242] the buffer contains histidine in a concentration of about 40 mM to about 100 mM or about 15-100 mM or about 15, 20, 22, 25, 28, 30 (etc). Le et al. teach at [0245] a polyol other than trehalose may be used instead of trehalose and at [0246] that a surfactant can be added to the antibody formulation and exemplary surfactants include polysorbate 20 or 80 and be present in an amount from about 0.001% to about 0.5%. Bevacizumab is exemplified in [0263] with 20 mM histidine-acetate at pH 5.5 and trehalose 2-8% (wt/v). Le et al. does not teach a pharmaceutical formulation of bevacizumab with a buffer of histidine HCl and sodium acetate and Le et al. does not teach the use of sorbitol.
Gwee teach stable aqueous recombinant protein formulations which comprise an antibody, sodium acetate, arginine hydrochloride,a cryoprotectant and a surfactant (see [004]) and wherein the formulation has a pH of about 5.2 (see [005]). Gwee teach a preferred pH range of about 4.6 to about 5.8 and 5.0 to 5.4 (see [0026]) and suitable surfactants which include polysorbate 20 and polysorbate 80 (see [0027] and [0062]). Gwee teach that the antibody is anti-VEGF and specifically bevacizumab (see [0035]) and that the concentration in the formulation ranges from 10 mg/ml to 200 mg/ml and more preferably 20 mg/ml to 80 mg/ml (see [0057]). Gwee teach that the cryoprotectant is a sugar or sugar alcohol and is sorbitol (see [0061]) and is in the range of 10 mM to 250 mM. Gwee does not teach a pharmaceutical formulation of bevacizumab with a buffer of histidine HCl and sodium acetate.
Wang et al. teach that an antibody composition with a buffer that comprises amino acids and salts has a viscosity lowering effect. Monoclonal antibodies in highly concentrated formulations have high viscosity, high aggregation propensity and low stability due to protein-protein interactions. Wang et al. teach that a combination of HisHCL and NaAc results in lower viscosity of the antibody formulation (see abstract) with no negative effect on aggregation, conformational changes or decreased storage stability. It is well-known in the art that highly viscous pharmaceutical formulations are more painful to administer via injection than less viscous formulations.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to make a pharmaceutical formulation of bevacizumab as taught by Le et al. with a histidine buffer with a concentration of about 10-30 mM, comprising a polyol and polysorbate 20 or 80 with a concentration of about 0.001% to about 0.5%. It would have been obvious to modify the formulation of Le et al. by selecting sorbitol as the polyol because Gwee teaches that sorbitol is a suitable sugar alcohol (polyol) for pharmaceutical formulations of bevacizumab and provides a working range of 10 mM to 250 mM for the formulation and because the simple substitute of one known element for another to obtain predictable results is prima facie obvious. One would have a reasonable expectation of success in making the substitution because the formulations of Le et al. and Gwee are very similar and one would expect that sorbitol would be suitable especially because Le et al. state that a polyol other than trehalose may be used. Furthermore, it would have been obvious to modify the formulation of Le et al. by the addition of sodium acetate to the histidine-HCl buffer because Wang et al. teach that an antibody composition with a buffer that comprises amino acids and salts have the benefit of lowering the viscosity of the composition. Wang et al. teach the specific combination of HisHCl and NaAc and Le et al. already teach that histidine-acetate buffer is acceptable as the buffer system for the antibody formulation, therefore, one would have a reasonable expectation that the addition of NaAc to the histidineHCL buffer would provide the advantage as taught by Wang et al. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
Applicant argues at page 11 of the response that the Examiner has not established a reason for one skilled in the art to combine Le and Gwee, alleging that neither Gwee nor Le provide any motivation to replace the trehalose of Le with sorbitol. Applicant’s argument has been fully considered, but is not found persuasive.
As stated in the rejection, It would have been obvious to modify the formulation of Le et al. by selecting sorbitol as the polyol because Gwee teaches that sorbitol is a suitable sugar alcohol (polyol) for pharmaceutical formulations of bevacizumab and provides a working range of 10 mM to 250 mM for the formulation. The simple substitute of one known element for another to obtain predictable results is an appropriate rationale of obviousness (see MPEP 2141 (III)).
Applicant argues at page 11 of the response that the claimed pharmaceutical formulation is not obvious over the cited references at least because embodiments of the pharmaceutical formulation produced unexpected effects, such as higher stability compared to the Avastin® formulation.
Applicant’s arguments have been fully considered, but are not found persuasive. A showing of unexpected results requires that the claimed subject matter be compared with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). "A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference." In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential).
The Avastin® formulation is a sodium phosphate buffer. The formulation of Le et al. uses a histidine buffer. Because the claims are directed to formulations with a histidine-based buffer, Le is the closest prior art. This is especially true because the alleged superior properties of the formulation rely on the use of a histidine hydrocholoride-sodium acetate buffer.
Applicant concludes that “the stability of bevacizumab in exemplary formulations according to amended claim 1 is superior to that of bevacizumab in the existing formulation (Avastin®, i.e., PB62) and other similar formulations”. Applicant’s argument does not appear to be supported by the evidence of record as comparisons to “other similar formulations” have not been provided and the instant formulation has not been compared to the closest prior art, which is Le et al.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christine J Saoud whose telephone number is (571)272-0891. The examiner can normally be reached M-F, 8am-4pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Z Wu, 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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/Christine J Saoud/Primary Examiner, Art Unit 1645
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