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 .
Election/Restrictions
Applicant's election with traverse of histidine hydrochloride-sodium acetate buffer and aqueous form in the reply filed on 14 October 2025 is acknowledged. The traversal is on the ground(s) that the office has not shown that the burden imposed on the Office in searching and/or examining aqueous forms for the claimed formulation together with lyophilized forms of the claimed formulation would be serious. This is not found persuasive because the claims were restricted under 371 practice and lack of unity. Search burden is not a consideration with regard to a holding of lack of unity. A formulation which is solid is distinct from a formulation which is aqueous especially in light of the fact that not all aqueous formulations are suitable for lyophilization. Therefore, the different forms lack the same or corresponding technical feature as one is in aqueous form and the other is in solid form.
The requirement is still deemed proper and is therefore made FINAL.
Claim 11 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 14 October 2025.
Response to Amendment
Applicant’s amendment filed 14 October 2025 has been received and entered. Claims 1, 3 and 5 have been amended and claims 2, 4 and 6 have been canceled. Claims 1, 3, 5 and 7-13 are currently pending in the instant application. Claim 11 is withdrawn. Claims 1, 3, 5, 7-10 and 12-13 are under consideration in the instant Office action.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01 September 2022, 06 February 2023, 30 August 2023, 26 December 2023, 24 February 2025 and 23 July 2025 have been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are 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. See screenshot below:
PNG
media_image1.png
215
839
media_image1.png
Greyscale
This screenshot is representative of all of the Figures which have been submitted. Figures 6A-6C have text (numerical values) which are illegible due to the faint shading of the numerals.
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.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is defective. See item 1) a) or 1) b) above.
Applicant attempted to add an incorporation statement in the preliminary amendment filed 01 September 2022. First, the specification cannot be amended in this manner to bring in an incorporation statement – a substitute specification must be filed. Secondly, the statement which was added is not compliant as the file size must be referenced in bytes. Lastly, the file name which is recited in the incorporation statement does not match the file name which was submitted in the instant application.
PNG
media_image2.png
181
961
media_image2.png
Greyscale
PNG
media_image3.png
75
639
media_image3.png
Greyscale
Because this was a 371 filing, an incorporation statement is actually not required. Applicant may file a substitute specification deleting the erroneous incorporation statement OR Applicant may submit a corrected substitute specification as outlined below. The file name and file size in bytes must match what is shown in the screenshot above is the incorporation statement is corrected.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because it makes a comparison with the prior art as well as referring to purported merits. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The use of the term Avastin®, 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.
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 paragraphs [0014], [0016], [0041], [0044], [0060], [0064], and [0069]. See also claims 1 and 8.
Figures 8A-8D refer to Avastin® but do not include the appropriate symbol as required. Correction is required.
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 § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 5, 7-13 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, 5, and 8 contain the trademark/trade name Tween®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the nonionic detergent (surfactant) polysorbate 20 and/or polysorbate 80 and, accordingly, the identification/description is indefinite. The remaining claims are rejected because they depend from rejected claims but do not resolve this ambiguity.
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 is/are 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).
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. One would have a reasonable expectation of success in making the substitution because the formulations of Le et al. and Gwee are vary 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.
Art Made of Record
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Lv et al. A novel histidine-acetate buffer for freeze-dried monoclonal antibody formulations. Eur. J. Pharm. Biopharm. 218: 114940, 2026, pages 1-13.
Strickley et al. A review of formulations of commercially available antibodies. J. Pharm. Sci. 110: 2590-2608, 2021.
Lv et al. Histidine as a versatile excipient in the protein-based biopharmaceutical formulations. Intern. J. Pharm. 662: 1244472, 2024, pages 1-16.
Zbacnik et al. Role of buffers in protein formulations. J. Pharm. Sci. 106: 713-733, 2017.
Karow et al. Buffer capacity of biologics – from buffer salts to buffering by antibodies. Biotechnol. Prog. 29: 480-492, 2013.
Gokarn et al. Self-buffering antibody formulations. J. Pharm. Sci. 97: 3051-3066, 2008.
CN-107537036-A
Conclusion
No claim is allowed.
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.
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, Daniel Kolker, can be reached at 571-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Christine J Saoud/Primary Examiner, Art Unit 1645