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 .
Application Status
This action is written in response to applicant’s correspondence received on 2/29/2024. Claims 16-31 are pending. All pending claims are currently under examination.
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’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), 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 EFS-Web or Patent Center 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 EFS-Web or Patent Center 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 missing or incomplete. See item 1) a) or 1) b) above. In particular, the sequence incorporation statement entitled “Sequence Listing” in the specification refers to the sequence listing file in terms of “kilobytes,” but must refer to the size of the file in terms of “bytes.” See MPEP 2422.03, section I, “ASCII Text File Submitted VIA EFS-Web.”
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 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 16-31 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.
Regarding claim 16, step (c) recites “the first antigen-binding molecule” however, only one antigen-binding molecule (“an antigen-binding molecule) is previously recited in the claim. Thus, recitation of “the first antigen-binding molecule” in step (c) lacks proper antecedent basis as it is unclear if this is in reference to an additional antigen-binding molecule or the molecule recited in step (a) of the claim. Furthermore, step (e) of claim 16 recites “a cell homogenate from the antibody-producing cell culture.” However, multiple cells and antibody producing cells are previously referenced in the claim, and “no antibody-producing cell culture” is previously recited. Claim 16 therefore lacks proper antecedent basis because it is unclear to which cells or antibody-producing cell culture is being referred in step (e) of the claim.
Claims 17-22 depend from claim 16 and do not resolve this issue and are therefore also rejected.
Claim 23 recites in step (e) “a cell homogenate from the antibody-producing cell culture.” However, multiple cells and antibody producing cells are previously referenced in the claim, and no “antibody-producing cell culture” is previously recited. Claim 23 therefore lacks proper antecedent basis because it is unclear to which cells or antibody-producing cell culture is being referred in step (e) of the claim.
Claims 24-31 depend from claim 23 and do not resolve this 112(b) issue. Claims 24-31 are therefore also rejected.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 16-31 are rejected under 35 U.S.C. 103 as being unpatentable over Igawa (US 10,961,530 B2, published 10/20/2016) in view of Towbin (Towbin H et al. J Immunol Methods. 1995 Apr 26;181(2):167-76) in view of
Regarding claim 16, Igawa is a patent which teaches methods of generating antibodies, antigen-binding molecules, and antigen/antigen-binding molecule complexes (Title, Abstract, and throughout). Igawa teaches methods of immunizing non-human mammals to generate cell populations which generate monoclonal antibodies (e.g., column 38, fourth paragraph). Igawa teaches standard methods of generating monoclonal antibodies by immunizing non-human mammals, and screening for cells to identify cells producing monoclonal antibodies (column 38, fourth paragraph). Furthermore, Igawa teaches switch antibodies, which are taught to be antibodies which bind to an antigen/antigen-binding molecule complex with higher affinity than the antigen or antigen-binding molecule alone (e.g., Figure 1, reproduced below):
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As seen in Figure 1, above, the antibody has a higher affinity to the complex of the antigen and antigen-binding molecule compared with each component alone, as shown by the fact that the antibody does not bind the antigen without the antigen-binding molecule. To further support this principle, Igawa also teaches Figure 43, which is reproduced below:
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As shown above in Figure 43, Igawa teaches that the small molecule does not bind with the antigen until it is sandwiched by the antibody. Thus, Igawa teaches antibodies which enhance the binding activity of the antigen-binding molecule to the antigen. Igawa teaches that:
“Such a rationally designed library composed of diverse H chains and L chains having binding activities to adenosine, AMP, ADP, or ATP is thought to be useful as a library containing human antibodies that enable to efficiently obtain AMP/ ADP/ ATP/adenosme switch antibodies against arbitrary antigens, where
adenosine, AMP, ADP, or ATP is sandwiched between the antibody and antigen as shown in FIG. 43,” (column 168, second paragraph).
Thus, Igawa teaches that the generation of such switch antibodies is useful (above).
Igawa teaches methods such as ELISA to determine binding activity (e.g., column 234, fourth paragraph).
Furthermore, Igawa teaches a strong motivation to generate antibodies where the binding of the antibodies to the antigen is regulated by the presence of a small molecule (i.e., increased binding efficiency to the antigen/molecule complex as opposed to the individual parts) because such antibodies would “be very useful because they can act reversibly on lesions such as tumor sites and inflammatory sites, and side-effects can be avoided,” (column 4, final paragraph to column 5, first line). Thus, Igawa teaches a strong motivation to make such antibodies.
Igawa, while teaching antibodies which have higher binding affinity to antigen/antigen-binding molecule complexes when compared with the antigen and/or the antigen-binding molecule alone, and furthermore teaches antibodies which enhance the binding of antigen-binding molecules to antigens and a motivation to make such antibodies, and further teaches general methods of immunizing non-human mammals to recover antibodies, does not teach a specific method of making such antibodies.
Towbin, in the research field of immunoassays based on antibodies against immune complexes, teaches the following pairs of monoclonal antibodies (mAB1 and mAB2) which form a complex with their target antigen, angiotensin II: “all mAb2s stabilized the angiotensin II-mAb1 complex and one mAb2 distinctly improved the specificity of the assay for angiotensin II,” (Towbin, Abstract). Therefore, Towbin has taught that the binding of mAb2 to the angiotensin II-mAB1 complex stabilizes and enhances the binding of mAb1 to its antigen target. In this case, mAb2 is acting as a second antigen-binding molecule, mAB1 is acting as the first antigen-binding molecule, and angiotensin II is acting as the first antigen. Thus, Towbin also teaches antibodies whose affinity for an antigen-binding molecule is enhanced in a complex as compared with each separate component. Furthermore, Towbin teaches “an immunization technique involving tolerization with uncomplexed mAb1 was used to generate mAb2s. None of the mAb2s were able to bind angiotensin II by themselves but all efficiently bound the complex of angiotensin II and mAb1, “(Abstract). Thus, Towbin not only also teaches monoclonal antibodies with higher binding affinities to complexes including an antigen/antigen-binding molecule, but also reduced such an immunization method to practice to generate such antibodies. Furthermore, Towbin teaches that:
“animals were immunized with the complex of A-II and mAb1 their sera indicated that antibodies with the desired specificity for the complex were present,” (page 170, right column, third paragraph). Towbin teaches that: “The hybridoma supernates derived from these animals were screened by ELISA on wells coated with F(ab’), fragments of mAb1 in presence or absence of A-II,” (page 170 final paragraph to top of page 171). Thus, Towbin teaches selecting cell types and their supernatants and also measuring binding activity using ELISA. Towbin teaches that “in the presence of a
limiting amount of mAb1, all mAb2s enhanced the binding of I-A-II in a concentration dependent way,” (page 172, right column, final paragraph). Thus, Towbin teaches the identification/purification from a cell culture a cell which produces a monoclonal antibody that enhances the binding activity of the first antigen-binding molecule to the antigen (page 172, right column, final paragraph).
Additionally, Towbin teaches that:
“Immunizations with immune complexes even seem to be rewarding for larger molecules. Thus, secondary mAbs against human interleukin-beta (MW 17000) have been generated in our laboratory (Towbin, Zingel, Erard, unpublished) that selectively bind the immune complex, but do not recognize the free cytokine,” (page 175, left column, second paragraph).
Thus, Towbin teaches that their method of immunizing a complex to generate antibodies which bind more strongly to the complex than they do alone has been reproduced and therefore predictable (above).
Towbin teaches the collection of supernatants and testing of supernatants using ELISA (page 169, left column, final paragraph).
It would have been obvious to a person of ordinary skill in the art to modify the motivational teachings of Igawa, who teaches the benefits of producing antibodies with higher binding affinities for antigen/antigen-binding molecule complexes when compared to the antigen or binding-molecule alone and also antibodies which increase the binding affinity of a molecule to its antigen with the methodology of Towbin, as such a combination is simply the combination of known prior art elements with predictable results. In the present case, a practitioner would furthermore be motivated to make the antibodies envisioned and taught by Igawa because Igawa teaches that they are very useful for in vivo use. As such, a practitioner would be motivated to use known methods to make such antibodies as those taught by Towbin. Furthermore, the results are predictable because Towbin teaches that the method has been reduced to practice. Furthermore, the method is predictable because Towbin and Igawa are analogous art because they both teach antibody/antigen-binding molecule complex formation where antibodies against the complex have higher binding affinities than they have for each separate molecule.
Regarding claim 17, Figures 1 and 43 of Igawa both show that the antibody does not bind with the antigen or molecule unless they are together. Thus, Igawa teaches that there is no detectable binding of the antibody of (b) could not be detected using an assay such as ELISA.
Regarding claim 18, both Igawa and Towbin teach that the first antigen binding molecule is an antibody (e.g., Igawa Figure 1 and 43, Towbin Abstract).
Regarding claims 19 and 22, Igawa teaches that the antigen can be adenosine (column 8, paragraph 3).
Regarding claim 20, Igawa teaches that the antigen can be on the membrane of a cell (e.g., Figure 1). Igawa teaches that the cell can be a macrophage (column 104, first paragraph).
Regarding claim 21, Igawa teaches that the antigen can be CD3 (column 104, first paragraph).
Regarding claims 22-23, Igawa teaches the method of phage display, where a phage library display method was used to acquire antibodies that bind human IL-6 receptor (hIL-6R) in the presence of small molecules from a human antibody library using a phage display library technique (Example 6). Igawa teaches:
“phages presenting antibodies showing binding activity toward hIL-6R captured onto beads in the presence of small molecules were collected. Phages were collected from the phage elution solution eluted from the beads in the absence of the small molecules. In this acquisition method, biotin-labeled hIL-6R was used as antigen… To efficiently isolate small molecule switch antibodies dependent on small molecules that can play a role as a switch in cancer tissues, panning was carried out, which concentrates antibodies that bind to antigens in the presence of a mixed solution of the following various small molecules (adenosine)… The first panning was carried out to collect phages that can bind in the presence of small molecules, while the second and subsequent pannings were carried out to concentrate phages that can bind to antigens only in the presence of SC [adenosine cocktail]… Three rounds of panning were performed in the presence of SC to obtain antibodies having antigen-binding activity,” (Example 6, column 172 to the top of column 173).
Thus, Igawa teaches a method of selecting antigen-binding molecules using phage display libraries, where antigen-binding molecules are selected which have higher affinities for antigen/antigen-binding complexes compared with the antigen or antigen-binding molecule alone, where furthermore such antigen-binding molecules are selected for to be switch antibodies which Igawa teaches enhance the binding of an antigen-binding molecule to the antigen (e.g., Figure 43).
Furthermore, as discussed above, Towbin teaches methods of collecting supernatants for antibody testing using methods such as ELISA (page 169, left column, final paragraph). While Towbin is directed to mammalian cells, it is understood that known techniques such as collecting supernatants and purifying molecules from supernatants would reasonably apply to a phage display techniques.
Regarding claim 25, , Figures 1 and 43 of Igawa both show that the antibody does not bind with the antigen or molecule unless they are together. Thus, Igawa teaches that there is no detectable binding of the antibody of (b) could not be detected using an assay such as ELISA.
Regarding claims 26-27, Towbin teaches that both antigen-binding molecules can be antibodies (Abstract).
Regarding claims 28 and 31, Igawa teaches that the antigen can be adenosine (column 8, paragraph 3).
Regarding claims 29-30 Igawa teaches that the antigen can be on the membrane of a cell (e.g., Figure 1). Igawa teaches that the cell can be a macrophage (column 104, first paragraph). Igawa teaches that the antigen can be CD3 (column 104, first paragraph).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635