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/Restriction
The response filed on 05/11/26 to the restriction requirement of 03/23/26 has been received. With traverse, Applicant has elected the species of VL: SEQ ID NO: 32 and VH: SEQ ID NO: 21. The traversal is based on amended claim 1 which recites that the VH sequence is restricted to select from SEQ ID NOs: 21, 22, 23, 24, 25; and the VL sequence is restricted to SEQ ID NO: 32. Furthermore, claims 3-4 have been canceled and as such, the amended claims define the VH and VL sequences corresponding to the VH and VL sequences of #219 antibodies disclosed in the specification (Table 3: antibodies 219-Hu1, 219-Hu2, 219-Hu3, 219-Hu4 and 219-Hu5). Even further, Applicant noted that all VL sequences of the five antibodies are the same (SEQ ID NO: 32) and the five VH sequences comprise the same CDRs and the five VH sequences share a sequence identity as high as 97% (alignment in the Response indicated color blocks showing the positions with amino acid variants). In addition, 219-Hul, 219-Hu2, 219-Hu3, 219-Hu4 and 219-Hu5 show very close Kd (Table 5), indicating that they share similar properties such that Applicant submits that the unity requirement for the enumerated antibodies has been met.
For the purpose of compact prosecution, the Examiner has rejoined all species in claim 1 to include examination of VH sequence of SEQ ID NOs: 21, 22, 23, 24 and 25; and VL sequence of SEQ ID NO: 32.
Status of Claims
Claims 1, 5-18, 20, 21 and 23 are pending.
Claims 1 has been amended.
Claims 1, 5-18, 20, 21 and 23 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The U.S. effective filing date of all claims under examination is set at 01/29/2021 and 08/31/2021 based on the CN202110140980.5 application (filed on 01/29/2021) and the CN202111016307.7 application (filed on 08/31/2021) respectively.
Information Disclosure Statement
The information disclosure statements (IDS) submitted are being considered by the examiner.
Drawings
The drawings are objected to because:
Figure 5A: The x-axis label of the graphs of antibodies tested at both concentrations of 0.2 µg/ml and 2 µg/ml are illegible;
Figures 6A-C: The size of the wordings in the legend for all graphs seems a little small and are difficult to read and/or decipher. It is suggested that graphs A, B and C are separately presented on different pages rather than being on one single page;
Figures 8A and B: In Figure 8A, the size of the wordings for y-axis and x-axis of the three horizontal set of graph, as well as the all the wordings in the right most three vertical graphs seem a little small and are difficult to read and/or decipher. The same issue is seen for the x-axis labels in Figure 8B left graph. It is suggested that graphs A and B are separately presented on different pages rather than being on one single page;
Figure 9A: the size of the wordings for both the y-axis and x-axis seems a little small and are difficult to read and/or decipher. In addition, it is difficult to differentiate between the dotted line and solid line in all the four graphs of Figure 9A;
Figure 10A and B: In Figure 10A, the size of the wordings for both the y-axis and x-axis seems a little small and are difficult to read and/or decipher. In addition, it is difficult to differentiate between the dotted line and solid line in all the four graphs of Figure 10A. In Figure 10B, the x-axis labels are somewhat illegible;
Figure 12A: the size of the wordings in all graphs of this figure seems a little small and are nearly illegible. It is suggested that Figure 12A be presented on at least a single page or on separate pages if needed so that wordings can be legible;
Figures 13A-C: the size of the wordings in all graphs of this figure seems a little small and are nearly illegible in most of the graphs; and
Figure 17A: the size most of the wordings (y-axis labels, x-axis labels, words appearing within the square of each separate graph) seems a little small and are nearly illegible in most.
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 deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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.
Claim Objections
Claims 6, 10 and 16 are objected to because of the following informalities:
Claim 6 recites the phrase “the heavy chain constant region and/or the light chain constant region are/is a human heavy chain constant region and/or a human light chain constant region”. It is suggested that the phrase be amended to recite “the heavy chain constant region is a human heavy chain constant region and/or the light chain constant region is a human light chain constant region”.
Claim 10 seems to have a typographical error. The word “TIGHT” for “the other antigens” should be “TIGIT”. Also, the words “HAS” and “P1GF” for “the other antigens” seem to be typographical errors.
Claim 16 seems to have a typographical error. There is an unnecessary hyphen “-“ in the phrase “the method comprises culturing-a host cell” in lines 2-3 between “culturing” and “a”. It is suggested that the hyphen be deleted.
Claim Rejections - 35 USC § 112(b)
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 6-10, 12, 15, 18, 20, 21 and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), 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-AlA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 6, 7, 8, 10, 12, 15, 18, 20 and 21 are rejected because the claims recite the word “preferably” and claim 15 further recites the phrase “more preferably”. In addition, claim 7 and claim 20 recite the phrase “e.g.”; and claim 15, claim 20, and claim 21 recite the phrase “such as”. Further, the following claims recite phrases in parenthesis: claim 7, “a multispecific antibody (e.g., a bispecific antibody)”; and claim 15, “a bacterial (Escherichia coli) cell”, “a fungal (yeast cell”, and “a mammalian cell (a CHO cell line or a 293T cell line)”. These are all exemplary terms which render the claims indefinite because it is unclear how, or if, the limitations following the exemplary terms of “preferably”, “more preferably’, “e.g.”, “such as” and phrases in parenthesis, limit the claims or are part of the claimed invention. See MPEP § 2173.05(d). Description of preferences should be properly set forth in the specification rather than the claims. If stated in the claims, preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made. It is suggested that Applicant revises the claims to remove the terms “preferably”, “more preferably”, “e.g.”, the phrase “such as” and the limitations following them, as well as remove any phrases in parenthesis.
Claim 9 recites the following limitations of:
“(3)….the binding of TNFα to a TNFR2 protein”;
“(4)….the binding of TNFα to a TNFR2 expressed on the cell surface”;
“(5)….the Treg proliferation and/or Treg function mediated by TNFα”;
“(6)….the degradation of IКBα mediated by TNFα”;
“(7)….the inhibition of Tcon cell proliferation by Treg”;
“(8)….the ADCC function”;
“(9)….the ratio of CD8+ T/Treg cells in tumour infiltrating lymphocytes (TILs)”; and
“(10)….the tumor growth”.
There is insufficient antecedent basis for “the binding of TNFα to a TNFR2 protein”, “the binding of TNFα to a TNFR2 expressed on the cell surface”, “the Treg proliferation and/or Treg function mediated by TNFα”, “the degradation of IКBα mediated by TNFα”, “the inhibition of Tcon cell proliferation by Treg”, “the ADCC function”, “the ratio of CD8+ T/Treg cells in tumour infiltrating lymphocytes (TILs)”, and “the tumor growth” in the claim. This rejection can be obviated if the claim were amended to remove the words “the” in each of these phrases.
Claim 23 recites the limitation "… the step of contacting a sample….” There is insufficient antecedent basis for “the step of contacting a sample” in the claim. This rejection can be obviated if the claim were amended to remove the phrase “the step of”.
Claim Rejections 35 U.S.C.112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 20 and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a disease related to immune abnormalities comprising administering an antibody or antigen-binding fragment of claim 1, does not reasonably provide enablement for a method of “preventing” a disease related to immune abnormalities comprising administering an antibody or antigen-binding fragment of claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claims 20 and 21, as written, include methods of preventing a disease related to immune abnormalities in an individual predisposed to a disease related to immune abnormalities. The specification lacks guidance and or objective evidence with regards to vaccination of a population of subjects predisposed to a disease related to immune abnormalities. It is well known in the art that the prevention of a disease, in general, is highly unpredictable and Applicant has not demonstrated, with any predictability, that the claimed humanized antibody that specifically binds to TNFR2, or an antigen-binding fragment thereof, would predictably prevent the occurrence of a disease related to immune abnormalities. Reasonable guidance with respect to preventing any disease relies on quantitative analysis from defined populations. In terms of a disease that is cancer, it is currently well established that some populations have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, family histories, or randomized controlled trials.
For example, Byers (CA Cancer Journal for Clinicians, Vol. 49, No. 6, Nov/Dec. 1999) teaches that randomized controlled trials are commonly regarded as the definitive study for proving causality (1st col., p.358), and that in controlled trials the random assignment of subjects to the intervention eliminates the problems of dietary recalls and controls the effects of both known and unknown confounding factors. Further, Byers suggests that chemo-preventative trials be designed “long-term” such that testing occurs over many years (2nd col., p. 359). Even further, the essential element towards the validation of any preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer. This would require monitoring a large population with the claimed agents and linking such results with subsequent histological confirmation of the presence or absence of disease. Thus, while the specification is enabling for treating a disease related to immune abnormalities in a patient who has been diagnosed with the disease related to immune abnormalities comprising administering an antibody or antigen-binding fragment of claim 1, the specification lacks reasonable guidance, predictability, and objective evidence that enables the “prevention” of a disease related to immune abnormalities comprising administering an antibody or antigen-binding fragment of claim 1.
Allowable Subject Matter
Claims 1, 5, 11, 13, 14, and 17 are allowed.
The VH sequences of SEQ ID NOs: 21, 22, 23, 24 and 25, and the VL sequence of SEQ ID NO: 32 are free of prior art.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yie-Chia Lee (Tonya) whose telephone number is (571)272-0123. The examiner can normally be reached Monday - Friday 7.30a - 3.30p Eastern Time Zone.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached on 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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